Nothing Special   »   [go: up one dir, main page]

MXPA06011281A - METHODS FOR THE PREPARATION OF (3R,3aS,6aR) HEXAHYDRO-FURO[2,3-b]FURAN-3-OL - Google Patents

METHODS FOR THE PREPARATION OF (3R,3aS,6aR) HEXAHYDRO-FURO[2,3-b]FURAN-3-OL

Info

Publication number
MXPA06011281A
MXPA06011281A MXPA/A/2006/011281A MXPA06011281A MXPA06011281A MX PA06011281 A MXPA06011281 A MX PA06011281A MX PA06011281 A MXPA06011281 A MX PA06011281A MX PA06011281 A MXPA06011281 A MX PA06011281A
Authority
MX
Mexico
Prior art keywords
formula
compound
compounds
acid
further characterized
Prior art date
Application number
MXPA/A/2006/011281A
Other languages
Spanish (es)
Inventor
Bart Rudolf Romanie Kesteleyn
Peter Jan Leonard Mario Quaedflieg
Robert Jan Vijn
Constantinus Simon Maria Liebregts
Jacob Hermanus Matheus Hero Kooistra
Franciscus Alphons Marie Lommen
Original Assignee
Bart Rudolf Romanie Kesteleyn
Jacob Hermanus Matheus Hero Kooistra
Constantinus Simon Maria Liebregts
Franciscus Alphons Marie Lommen
Peter Jan Leonard Mario Quaedflieg
Tibotec Pharmaceuticals Ltd
Robert Jan Vijn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bart Rudolf Romanie Kesteleyn, Jacob Hermanus Matheus Hero Kooistra, Constantinus Simon Maria Liebregts, Franciscus Alphons Marie Lommen, Peter Jan Leonard Mario Quaedflieg, Tibotec Pharmaceuticals Ltd, Robert Jan Vijn filed Critical Bart Rudolf Romanie Kesteleyn
Publication of MXPA06011281A publication Critical patent/MXPA06011281A/en

Links

Abstract

The present invention relates to methods for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol (6) as well as a novel intermediate, (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one (4) for use in said methods. More in particular the invention relates to a stereoselective method for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol, as well as methods for the crystallization of (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan- 2-one and for the epimerization of (3aR,4R,6aS) 4-methoxy-tetrahydro-furo[3,4-b]-furan-2-one to (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one.

Description

METHODS FOR THE PREPARATION OF (3R, 3a, 6aR) HEXAHIDRO-FUR? R2,3-b1FURAN-3-OL TECHNICAL FIELD The present invention relates to methods for the preparation of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol as well as new intermediates, (3aR, 4S, 6aS) 4-methoxy -tetrahydro-furo [3,4-b] furan-2-one for use in the methods. More particularly, the invention relates to a stereoselective method for the preparation of (3R, 3AS, 6aR) hexahydro-furo [2,3-b] furan-3-ol, and to a method treatable to increase on an industrial scale.
BACKGROUND OF THE INVENTION Hexahydro-furo [2,3-b] furan-3-ol is an important pharmacological moiety present in the structure of retroviral protease inhibitors such as those described by Ghosh et al. in J. Med. Chem. 1996, 39 (17), 3278-3290, EP 0 715 618, WO 99/67417, and WO 99/65870. The publications are hereby incorporated by reference. Various methods are known for the preparation of hexahydro-furo [2,3-b] furan-3-ol.
Ghosh et al. in J. Med. Chem. 1996, 39 (17), 3278-3290, describes an enantioselective synthesis to obtain both (3R, 3as, 6aR) and (3S, 3AR, 6aS) hexahydro-furo [2,3-b] furan-3-ol in optically pure form starting from 3 (R) -diethyl malate and 3 (S) -diethyl malate, respectively. Ghosh et al. also describes the synthesis of a racemic mixture of the enantiomers (3R, 3aS, 6aR) and (3S, 3aR, 6aS) of hexahydro-furo [2,3-] furan-3-ol, starting from 2,3-dihydrofuran, followed by enzymatic resolution of the final product. Pezeck et al. in Tetrahedron Lett. 1986, 27, 3715-3718, also describes a route for the synthesis of hexahydro-furo [2,3-b] -furan-3-ol using ozonolysis. Hexahydro-furo [2,3-b] furan-3-ol is also described as an intermediate in the synthesis of optically active perhydrofuro [2,3-b] furan derivatives in the Uchiyama et al. Publication, in Tetrahedron Lett. 2001, 42, 4653-4656. WO 03/022853 refers to an alternative method which involves the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol, the method part of a 2,3-dihydroxy 2,3-deprotected propionaldehyde, which is transformed into a derivative comprising a nitromethyl and one or two carboxylate moieties. The derivative is subsequently transformed by a Nef reaction into a tetrahydrofuran compound, which is reduced and subjected to an intramolecular cyclization reaction to obtain the (3R, 3aS, 6aR) hexahydro-furo [2,3-bjfuran-3-ol. To transform the starting material, ie 2,3-dihydroxy-propionaldehyde 2,3-deprotected, into a derivative comprising one or two carboxylate moieties, WO03 / 022853 describes different routes, which include a Wittig reaction using iluros phosphorus; a Horner-Emmons reaction using phosphonates in the presence of a base; Knoevenagel type condensation reaction using malonate derivatives; or alternatively applying Reformatsky reagents, ie precursors of portions C (= 0) -0- such as cyanide. In particular, the examples described herein focus on two routes; the routes of Knoevenagel and Wittig. The Knoevenagel route as illustrated in WO03 / 022853, consists of the addition of dimethyl malonate to a dry solution of the 2,3-O-isopropylidene-glyceraldehyde starting material to produce the 2- (2,2-dimethyl ester. -dimethyl- [1, 3] d -oxolan-4-ylmethylene) -malonic with 2 incorporated carboxylates. Since the starting material is produced in aqueous solution, a laborious isolation procedure comprising an extraction with tetrahydrofuran and water removal needs to be applied. This extraction and removal of water requires large amounts of tetrahydrofuran and production time. In addition, the yield of the Knoevenagel reaction of 2,3-O-isopropylidene-glyceraldehyde to 2- (2,2-dimethyl- [1, 3] dioxolan-4-ylmethylene) -malonic acid dimethyl ester exhibits a maximum value of approximately 77% since intrinsically unavoidable lateral reactions occur, even after the optimization of conditions. Due to the fact that the di-carboxylated intermediate obtained is a viscous oil, ie 2- (2,2-dimethyl- [1, 3] -dioxolan-4-ylmethylene) -malonic acid dimethyl ester, needs to be introduced in the subsequent Michael addition as a solution in methanol. The distillation of methanol after cooling in aqueous NaHC03 solution, after the cyclization and Nef acid reactions, but before extraction with an organic solvent such as ethyl acetate has disadvantages. Since the intermediate resulting from the reactions of cyclization and acid Nef, ie 4-methoxy-2-oxo-hexahydro-furo [3,4-b] furan-3-carboxylic acid methyl ester, is a water-labile compound , and the distillation of methanol requires relatively high temperatures (up to 30 ° C to 40 ° C), the decomposition of the intermediate occurs to polar compounds. These polar compounds remain in the aqueous phase and are further lost because they are not extracted into the organic phase. Since methanol can not be removed prior to extractions, a considerable volume is required in the preparation of 4-methoxy-2-oxo-hexahydro-furo [3,4-b] furan-3-carboxylic acid methyl ester . During the decarboxylation of 4-methoxy-2-oxo-hexahydro-furo [3,4-b] furan-3-carboxylic acid methyl ester there is significant by-product formation, ie (4-hydroxy-2-methoxy) tetrahydro-furan-3-yl) -acetic). In addition, the crystallization of 4-methoxy-tetrahydro-furo [3,4-b] -furan-2-one results in a brown solid due to the concomitant polymerizations. In addition, for the purification of 4-methoxy-tetrahydro-furo [3,4-b] furan-2-one, at least two acid-base extraction cascades are needed to remove the acid for cyclization, resulting in a yield total of 4-methoxy-tetrahydro-furo [3,4-bjfuran-2-one 52% based on 4-methoxy-2-oxo-hexahydro-furo [3,4-b] furan-3 methyl ester -carboxylic, which is considered sub-optimal. All the factors mentioned above discourage the use of the Knoevenagel route. In effect, the decarboxylation step in this route presents an intrinsic disadvantage when compared to the Wittig route because such a decarboxylation step is not required with the latter. WO03 / 022853 in Example I provides a Wittig route which uses triethyl phosphono acetate (TEPA) to obtain 3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) ethyl ester) -acrylic. Subsequent addition of Michael to 3- (2,2-dimethyl [1,3] dioxolan-4-yl) -acrylic acid ethyl ester has limitations because it produces an adduct of nitromethane, ie ethyl 3- ( 2,2-dimethyl- [1,3] dioxolan-4-yl) -4-nitro-butyric, with a syn: anti ratio of about 8: 2. The subsequent reduction followed by Nef / cyclization reactions produces (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol seriously contaminated with its exo-diastereoisomer, ie (3R, 3aR, 6aS ) hexahydro-furo [2,3-b] furan-3-ol, with an endo: exo ratio of about 8: 2. Although this method does not have several disadvantages attached to the Knoevenagel process, it does not produce pure endo-diastereomer since there is no purification step available, such as crystallization, to remove the unwanted exo-diastereomers that have formed during the Michael addition. the anti configuration.
In the alternative Wittig route as described in Example II of WO03 / 022853, the Michael addition product exhibits the same disadvantageous anti: (8: 2) ratio as in Example 1. The ethoxy intermediates (3aR, 4S , 6aS) 4-ethoxy-tetrahydro-furo [3,4-b] -furan-2-one and (3aR, 4R, 6aS) 4-ethoxy-tetrahydro-furo [3,4-b] furan-2-one obtained from the Nef / cyclization reaction were present in a relationship (3aR, 4S, 6aS) / (3aR, 4R, 6aS) of about 2.5 / 1, together with a significant amount of anti-isomers, i.e. with the no: ant ratio of about 8: 2. The purification of the intermediates (3aR, 4S, 6aS) 4-ethoxy-tetrahydro-furo [3,4-b] furan-2-one and (3aR, 4R, 6aS) 4-ethoxy-tetrahydro-furo [3,4 -b] furan-2-one by removal of undesired anti-diastereoisomers by crystallization seems to be impossible to date. The reduction of the mixture and cyclization produces (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol, severely contaminated with its exo-diastereoisomer, i.e. (3R, 3aR, 6aS) hexahydro- furo [2,3-b] -furan-3-ol, with an endo: exo ratio of approximately 8: 2. Like the Wittig procedure of Example I above, this method does not have several disadvantages attached to the Knoevenagel process, but in its present form does not yet provide (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan- 3-ol pure with high industrial performances. Furthermore, the reactor volumes used for the processes of the known art are large and the number of operations too high, the factors work to the detriment of a cost-efficient process, and thus produce non-optimal procedures for industrial scale. Accordingly, there is a need for optimized procedures for the industrial preparation of diastereomerically pure (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol.
It has surprisingly been found that when a route of Wittig is employed and the isomers of the intermediate of formula (4) and (4 ') of WO03 / 022853 are produced in the methyl acetal form (ie, R '"is methyl, and R" is hydrogen), the yield of the crude intermediate of the formula (4) based on the intermediate of the formula (2) is much greater when compare for example with the ethoxy- or isopropoxy-acetals (where R "'is ethyl or isopropyl, respectively and R" is hydrogen). (4) (4 ') Furthermore, it has surprisingly been found that this form of methyl acetal of the intermediate of the formula (4) in the form isomer (3aR, 4S, 6aS), it can be crystallized from the mixture of the isomers (3aR, 4S, 6aS) and (3aR, 4R, 6aS) of the compound of the formula (4) and the relatively large amount of isomers (4 '). The increased yield and the possibility of crystallization of the isomeric form (3aR, 4S, 6aS) allows the production of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol in diastereomerically pure form and improved performance. The compound of the formula (4), (3aR, 4S, 6aS) 4-methoxy-tetrahydro-furo [3,4-b] furan-2-one, will be referred to below as the compound of the formula a- (4) or an alpha epimer or a-isomer. Likewise, (3aR, 4R, 6aS) 4-methoxy-tetrahydro-furo [3,4-b] furan-2-one will be referred to below as composed of the formula ß- (4), or beta epimer or ß-isomer. (3áR, 4S, 6aS) (3áR, 4R, 6aS) a- (4) ß- (4) compounds of the formula (4) Not only is it surprising that the methoxy acetal of the formula a- (4) can be crystallized, but even more surprising that this crystallization is successful despite the low alpha / beta ratio of less than 4/1 of the crude intermediates of the formula (4) that go into crystallization. It should be understood that in the Knoevenagel procedure a relationship alpha / beta of at least 6: 1 is required to have a crystallizable intermediate of the formula a- (4).
Accordingly, the present invention provides an improved Wittig method and the use of the 4-alpha isomer of 4-methoxy-tetrahydro-furop [3,4-b] furan-2-one, in particular (3aR, 4S, 6aS ), which significantly contributes to a treatable industrial preparation of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol in diastereomerically pure form. Furthermore, it has surprisingly been found that a mixture in any ratio of the alpha and beta epimers of the formula (4) can be transformed into a mixture of predominantly the alpha epimer, which can subsequently be isolated in pure form by crystallization. As such, the present invention provides a novel alkoxy acetal epimerization of the compound of the formula (4) which significantly contributes in a cost effective procedure for the preparation of (3R, 3aS, 6aR) hexahydro-furo [2,3 -b] furan-3-ol. Furthermore, it has also surprisingly been found that a mixture in almost any ratio of the alpha and beta epimers of the formula (4) can be transformed into a single step in the crystalline alpha epimer by simultaneous crystallization and epimerization, also known as induced asymmetric transformation by crystallization. As such, the present invention further provides simultaneous epimerization and crystallization for the isolation of pure (3aR, 4S, 6aS) 4-methoxy-tetrahydro-furo [3,4-b] furan-2-one.
BRIEF DESCRIPTION OF THE INVENTION The present invention provides an improved Wittig method and the use of (3aR, 4S, 6aS) 4-methoxy-tetrahydro-furo [3,4-b] furan-2-one as an intermediate, more in particular in crystalline form, in the preparation of diastereomerically pure (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol, which is suitable for industrial scale increase. The present invention provides a novel epimerization of alkoxy acetal of the compound of the formula β- (4) to the compound of the formula a- (4) which significantly contributes in a cost effective procedure for the preparation of (3R, 3aS, 6aR) diastereomerically pure hexahydro-furo [2,3-b] furan-3-ol. The present invention further provides a simultaneous crystallization and epimerization for the isolation of diastereomerically pure (3aR, 4S, 6aS) 4-methoxy-tetrahydro-furo [3,4-b] furan-2-one. Another embodiment of the invention is provided with a method that allows the production of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol with a higher yield than for the methods described in the state of The technique. Another object of the present invention is to provide highly pure, crystallizable intermediate compounds, which are useful in the synthesis of diastereomerically pure (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) the method comprises the use of intermediates of the formula (4). (4) The present invention also relates to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) the method comprises the use of the intermediate of the formula a- (4). a- (4) The present invention additionally refers to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol that has the structure of formula (6), (6) the method comprises the steps of: a) treating the compound of the formula (3) with a base and subsequently with an acid in the presence of methanol, OP, (3) wherein P1 and P2 are each independently a hydrogen, a hydroxy protecting group or together can form a vicinal-diol protecting group, R1 is alkyl, aryl or aralkyl; resulting in intermediaries of the formula (4); Y (4) b) reduce the intermediates of formula (4) with a reducing agent and apply an intramolecular cyclization reaction to obtain the compound of the formula (6). In one embodiment, the present invention relates to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) which comprises the steps of: a) treating the compound of the formula (3) with a base and subsequently with a acid in the presence of methanol, (3) where P1 and P2 are as defined above, R1 is as defined above; resulting in intermediaries of the formula (4); (4) b) crystallize with a solvent the intermediate of the formula a- (4); and a- (4) c) reducing the intermediate of the formula a- (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain the compound of the formula (6). In another embodiment, the present invention relates to the acid epimerization of the compound of the formula β- (4) in the compound of the formula a- (4). ß- (4) a- (4) In another embodiment, the present invention relates to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) which comprises the steps of: a) treating the compound of the formula (3) with a base and subsequently with an acid in the presence of methanol, (3) where P1 and P2 are as defined above, R1 is as defined above; resulting in intermediaries of the formula (4); (4) b) epimerize with acid the intermediate of the formula β- (4) in the intermediate of the formula a- (4); ß- (4) a- (4) c) crystallize with a solvent the intermediate of the formula a- (4); and * < «C) reducing the intermediate of the formula a- (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain the compound of the formula (6). In another embodiment, the present invention relates to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) which comprises the steps of: a) treating the compound of the formula (3) with a base and subsequently with an acid in the presence of methanol, (3) where P1 and P2 are as defined above, R1 is as defined above; resulting in intermediaries of the formula (4); (4) b) crystallize with a solvent the intermediate of the formula a- (4); a- (4) b) epimerizing with acid the intermediate of the formula β- (4) in the mother liquor of the crystallization mentioned above in the intermediate of the formula a- (4); ß- (4) a- (4) d) crystallize the intermediary of the formula a- (4) with a solvent, producing a second intermediate crop of formula a- (4); and (4) e) reducing the intermediate of the formula a- (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain the compound of the formula (6). In yet another embodiment, the present invention relates to to a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol of the formula (6), as described in the above methods wherein the epimerization and crystallization of the compound of the formula a- (4) occurs simultaneously The present invention additionally provides a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol of the formula (6) ), as described in the above methods wherein the compound of the formula (3) is obtained by reacting the compound of the formula (2) with nitromethane and a base.
QP, "COOR1 (2) And still in another embodiment, the present invention provides a method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol of the formula (6) ), as described in the above methods wherein the compound of the formula (2) is obtained by condensing an intermediate of the formula (1), or its hydrate, hemihydrate or a mixture thereof, with phosphonates of the formula (R60) ) 2P (= 0) -CH2-C (= 0) OR1, wherein P1 and P2 are as defined above, R1 is as defined above, R6 is alkyl, aryl or aralkyl, OP2 O (1) The term "hydroxy protecting group" as used herein refers to a substituent which protects the hydroxyl groups from undesirable reactions during synthetic procedures such as those O protecting groups described in Greene and Muts, "Protective Groups In. Organic Synthesis ", (John Wiley &Sons, New York, 3rd edition, 1999). The hydroxy protecting groups comprise substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; ethers of substituted ethyl, for example, 2,2,2-trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyl-dimethylsilyl and t-butyldiphenylsilyl; and esters, for example, acetate, propionate, benzoate and the like. The term "vicinal-diol protecting group" as used herein refers to protecting groups in the acetal or ketal form and in the orthoester form .. Specific examples of the protecting group in the acetal or ketal radical form include methylene, diphenylmethane, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, isopropylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4 - dimethoxybenzylidene, 2-nitrobenzylidene, etc. and specific examples of the protective group in the orthoester form include methoxymethylene, ethoxymethylene, 1-methoxyethylidene, 1-ethoxyethylidene, 1,1-dimethoxy-ethylidene, alpha-methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene, alpha- (N, N-dimethylamino) benzylidene, 2-oxacyclopentylidene, etc. . In a preferred embodiment, the vicinal-diol protecting group is isopropylidene. The term "alkyl", as used herein alone or as part of a group, refers to saturated monovalent hydrocarbon radicals having straight or branched hydrocarbon chains or, in the case where at least 3 carbon atoms are present, hydrocarbons cyclic or combinations thereof and contains 1 to 20 carbon atoms (C? -2 alquiloo alkyl), suitably 1 to 10 carbon atoms (C ^--alkyl), preferably 1 to 8 carbon atoms (C alquilo-alkyl) ? -8), more preferably 1 to 6 carbon atoms (C 1-6 alkyl), and still more preferably 1 to 4 carbon atoms (C- alkyl). Examples of alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "alkenyl" as used herein alone or as part of a group refers to monovalent hydrocarbon radicals having straight or branched hydrocarbon chains having one or more double bonds and containing from 2 to about 18 carbon atoms. carbon, preferably from 2 to about 8 carbon atoms, more preferably from 2 to about 5 carbon atoms. Examples of suitable alkenyl radicals include ethenyl, propenyl, alkyl, 1,4-butadienyl and the like. The term "alkynyl" as used herein alone or as part of a group refers to monovalent hydrocarbon radicals having straight or branched hydrocarbon chains having one or more triple bonds and containing from 2 to about 10 carbon atoms. carbon, more preferably from 2 to about 5 carbon atoms. Examples of alkynyl radicals include ethynyl, propynyl, (propargyl), butynyl, and the like. The term "aryl" as used herein, alone or as part of a group, includes an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, and includes monocyclic and polycyclic radicals, such as phenyl, biphenyl, naphthyl. The term "alkoxy" as used herein, alone or as part of a group, refers to an alkyl ether radical wherein the term "alkyl" is as defined above. Examples of alkyl ether radical include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. The terms "aralkyl" and "aralkoxy" as used herein, alone or in combination, mean an alkyl or alkoxy radical as defined above in which at least one hydrogen atom is replaced by an aryl radical as defined above , such as benzyl, benzyloxy, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, and the like. The term "aralkoxycarbonyl" as used herein, alone or in combination, means a radical of the formula aralkyl-C- (O) - wherein the term "aralkyl" has the meaning given above. Examples of an aralkoxycarbonyl radical are benzyloxycarbonyl and 4-methoxy-phenylmethoxycarbonyl. The term "cycloalkyl" as used herein, alone or in combination, means a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic portion contains from about 3 to about 8 carbon atoms, more preferably about 3 to about 6 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The term "cycloalkylalkyl" as used herein, alone or in combination, means an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above.
Examples of such cycloalkylalkyl radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl, and the like. The term "heterocycloalkyl" as used herein, alone or in combination, refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle preferably having 3 to 12 members in the ring, more preferably 5 to 10 members in the ring. ring and most preferably 5 to 6 atoms in the ring, which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur, and which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl and the like, and / or at a secondary nitrogen atom (i.e., -NH-) by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl and / or at a tertiary nitrogen atom (is say, = N-) by oxide. Heterocycloalkyl also includes benzylated monocyclic cycloalkyl groups having at least one heteroatom. The heterocycloalkyl in addition to sulfur and nitrogen also includes sulfoxides and N-oxides of heterocycloalkyl groups containing tertiary nitrogen. The term "heteroaryl" as used herein, alone or in combination, refers to an aromatic monocyclic, bicyclic or tricyclic heterocycloalkyl radical as defined above and is optionally substituted as defined above with respect to the definitions of aryl and heterocycloalkyl . Examples of such heterocycloalkyl and heteroaryl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazol-4-yl, 1-benzyloxycarbonylimidazol-4-yl, pyrazolyl, pyridyl, 2- (1-piperidinyl) pyridyl. , 2- (4-benzyl-piperazin-1-yl-1-pyridinyl), pyrazinyl, pyrimidinyl, furyl, tetrahydrofuryl, thienyl, triazolyl, oxazolyl, thiazolyl, 2-indolyl, 2-quinolinyl, 3-quinolinyl, 1-oxide -2-quinolinyl, isoquinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, tetrahydroquinolinyl, 1, 2,3,4-tetrahydro-2-quinolyl, 1, 2,3,4-tetrahydroisoquinolinyl, 1, 2,3,4-tetrahydro -1-oxo-isoquinolinyl, quinoxalinyl, 2-benzofurancarbonyl, 1-, 2-, 4- or 5-benzimidazolyl, and the like. The term "silyl" as used herein refers to a silicon atom optionally substituted by one or more alkyl, aryl and aralkyl groups. The terms "isomer", "isomeric form", "stereochemically isomeric forms" or "stereoisomeric forms", as used herein, define all possible isomeric as well as conformational forms, made from the same atoms joined by the same sequence of links but that have different structures of three dimensions which are not interchangeable, which the compounds or intermediaries obtained during the procedure may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound includes the mixture of all possible stereochemically isomeric forms which the compound may possess. The mixture may contain all diastereoisomers, epimers, enantiomers and / or conformants of the basic molecular structure of the compound. More particularly, stereogenic centers may have the R or S configuration, the diastereomers may have a syn or anti configuration, the substituents on saturated divalent cyclic radicals may have either the cis or trans configuration and the alkenyl radicals may have the E or Z configuration. All stereochemically isomeric forms of the composed both in pure form as well as in mixture among themselves are proposed to be included within the scope of this present invention. The term "diastereomer" or "diastereomeric form" is applied to molecules with identical chemical constitution and which contain a stereocenter, which differ in configuration in one or more of these stereocenters. The term "epimer" in the present invention refers to molecules with identical chemical constitution and containing more than one stereocenter, but which differ in configuration in only one of these stereocenters. In particular, the term "epimer" is intended to include compounds of the formula (4) which differ in the orientation of the bond between carbon 4 (C-4), and the methoxy substituent, ie compounds of the formula a- (4) and ß- (4), respectively, where, the C-4 is 4S and 4R, respectively. (4) The stereoisomeric forms of the intermediate of the formula (1), (4), (6) and the starting material as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same molecular structure basic of the compounds or starting material. Suitably, the term "stereoisomerically pure" starting material or compounds refers to starting materials or compounds having a stereoisomeric excess of at least 50% (ie, at least 75% of an isomer and maximum 25% of the other possible isomers). ) to a stereoisomeric excess of 100% (ie, 100% of one isomer and none of the other), preferably, compounds or starting material having a stereoisomeric excess of 75% to 100%, more preferably, compounds, starting material or reagents having a stereoisomeric excess of 90% up to 100%, even more preferred compounds or intermediates having a stereoisomeric excess of 94% up to 100% and very preferred, having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but then have in respect to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question. As such, a preferred embodiment employs S-2,3-0-isopropylidene-glyceraldehyde as the starting material in an enantiomeric excess of more than 95%, more preferably in an enantiomeric excess of more than 97%, even more preferably in an excess Enantiomeric of more than 99%.
Compounds of the formula (1) (i) The compounds of the formula (1) can be obtained from commercially available sources. The synthesis of compounds of the formula (1) either in enantiomerically pure form or in racemic form has been described in the literature. For example, the preparation of 2,3-O-isopropylidene-S-glyceraldehyde is described in C. Hubschwerlen, Synthesis 1986, 962; the preparation of 2,3-O-isopropylidene-R-glyceraldehyde is described in C. R. Schmid et al., J. Org. Chem. 1991, 56, 4056-4058; and the preparation of 2,3-0-isopropylidene- (R, S) -glyceraldehyde is described in A. Krief et al., Tetrahedron Lett. 1998, 39, 1437-1440. Accordingly, the intermediate of formula (1) can be purchased, prepared prior to the reaction or formed in situ. In a preferred embodiment, the compound is formed in situ by, for example, oxidation in aqueous or partially aqueous solution. In the case that the compound is in aqueous or partially aqueous solution it is usually partially present in the hydrate or hemihydrate forms thereof.
Suitably, the invention relates to a method wherein P1 and P2 together form a vicinal-diol protecting group, and particularly, which is an acid labile protecting group that remains unaffected during the base treatment step of the subsequent Nef reaction. Preferably, the vicinal diol protecting group is selected from the group consisting of methylene, diphenylmethylene, ethylidene, 1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, isopropylidene, cyclopentylidene , cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene and 2-nitrobenzylidene. In a more preferred embodiment, P1 and P2 together form a dialkyl methylene such as an isopropylidene or a 3-pentylidene radical. In the most preferred embodiment P1 and P2 together form an isopropylidene radical. A specific advantage of the use of isopropylidene compared to other protecting groups is that the reagents required for the diol protection, ie, dimethoxypropane, 2-methoxypropene or acetone, are commercially available and cheap. Interesting vicinal-diol protecting groups are those protecting groups that do not originate one or more additional stereogenic centers in the intermediates of formula (1), (2), and (3). The aforementioned hydroxy protecting group and vicinal diol protecting groups can be easily cleaved by methods known in the art such as hydrolysis, reduction, etc., which are appropriately selected depending on the protecting group used. According to a more preferred embodiment, the vicinal-diol protecting group is an acid labile protecting group, wherein the term "acid labile" as used herein refers to vicinal diol protecting groups which are readily cleaved using acidic conditions .
Compounds of the formula (2) (2) The compounds of the formula (1) or their hydrate, hemihydrate or mixtures thereof are subsequently transformed to compounds of the formula (2) by means of phosphonates in the presence of a base. The reaction employs phosphonates of the formula (R60) 2P (= 0) -CH2-C (= 0) OR1, wherein R1 is alkyl, aryl or aralkyl; • R6 is alkyl, aryl or aralkyl. Suitably, R1 is C6-6 alkyl, aryl or arylalkyl of C6-6, in particular, C1-6alkyl, more in particular, R1 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec -butyl, tert-butyl and pentyl, preferably, R1 is methyl, ethyl or tere-butyl, and most preferably R1 is ethyl. Examples of phosphonates include ethyl 2- (diethylphosphono) propionate, ethyl 2- (dimethylphosphono) propionate, triethyl phosphonoacetate (TEPA), among others. Preferably, the compound of the formula (1) and the phosphonate are present in the reaction mixture in a molar ratio range of about 0.9: 1.1 to about 1.1: 0.9, more preferably in a molar ratio of about 1: 1. When the compound of formula (1) is prepared in situ, its contents in the reaction mixture should be determined and based on about 1 equivalent of phosphonate being added. Suitable temperatures for the condensation reaction range from about -5 ° C to about 50 ° C, preferably from about -2 ° C to about 35 ° C, more preferably from about 0 ° to about 25 ° C. Examples of suitable bases that can be employed for the conversion of the compound of the formula (1) to the compounds of the formula (2) include, but are not limited to, alkylamines, sodium, potassium, lithium or cesium or hydroxide carbonates or alkoxides of sodium, potassium, lithium or cesium, and mixtures thereof. Preferably, the base is potassium carbonate, even more preferably, the base is added as a solid and not as a solution in water. Also more preferably, the amount of potassium carbonate as a solid is at least about 2.5 equivalents based on the compound of formula (1). Preferably, the pH of the reaction mixture is maintained within a range of about 7 to about 13, more preferably within a range of about 8 to about 12, even more preferably the pH is maintained between about 9 and about 11. The Suitable solvents for this reaction are water, any hydrocarbon, ether, halogenated hydrocarbon, or aromatic solvents known in the art for condensation reactions. These could include, but are not limited to, pentane, hexane, heptane, toluene, xylenes, benzene, mesitylenes, t-butylmethyl ether, dialkyl ethers (ethyl butyl), diphenyl ether, chlorobenzene, methylene chloride, chloroform. , carbon tetrachloride, acetonitrile, dichlorobenzene, dichloroethane, trichloroethane, cyclohexane, ethyl acetate, isopropyl acetate, tetrahydrofuran, dioxane, methanol, ethanol, and isopropanol. Preferably water is used as the solvent, either as the single solvent or as a mixture with another solvent, for example with tetrahydrofuran. In one embodiment, a work-up procedure can be applied in the reaction mixture containing compounds of the formula (2) by separating the organic and aqueous phases and subsequently extracting from the aqueous phase an additional portion of the compounds of the formula (2) with an organic solvent, different from the organic phase. As such, the tetrahydrofuran phase can be separated from the aqueous phase and the latter can be extracted with, for example, two portions of toluene. The preferred solvents for the extraction are ethyl acetate, toluene, tetrahydrofuran. The most preferred solvent is toluene. The compounds of the formula (2) are preferably not purified on silica gel. Although this produces fewer pure compounds of the formula (2) than the purified product on silica gel, the quality is sufficient to produce the compound of the formula (4) with satisfactory quality and yield. The non-purification over time aids in the simplification of the industrial process of the present invention. The compounds of the formula (2) can be obtained in two isomeric forms, the E and Z isomers with E being the preferred isomer.
Compounds of the formula (3) (3) The compounds of the formula (2) can be subsequently subjected to a Michael addition, in which nitromethane is added as a precursor formyl group to α, β-unsaturated ester intermediates of the formula (2), together with one base. Nitromethane is commercially available as a solution in methanol, and is preferred in such a composition. Examples of bases that are suitable for catalyzing Michael's additions are sodium, potassium, lithium, cesium, TBAF (tetra-n-butylammonium fluoride), DBU (1,8-diazabicyclo [5.4.0] undec) hydroxide or alkoxides. -7-ene), TMG (1,1,3,3-tetramethylguanidine), preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, lithium methoxide, TBAF, DBU, TMG and mixtures of them, more preferably DBU and TMG and most preferably DBU. When DBU is used as the base in the conversion of the compounds of the formula (2) to compounds of the formula (3), suitably the amount of base added is greater than about 0.5 equivalents based on the compounds of the formula (2) , more preferably greater than about 0.8 equivalents, still more preferably between about 0.8 and about 1.2 equivalents, most preferably between about 0.9 and about 1.1 equivalents. In a preferred embodiment, DBU is present in approximately 1 equivalent. Any suitable solvent for performing a Michael addition can be employed. Examples of suitable solvents are methanol, ethanol and acetonitrile. Preferably, the solvent is methanol, which allows the operation of a process in a vessel with the subsequent transformations of the compounds obtained from the formula (3) in the compounds of the formula (4). The addition form without the compound of the formula (3) is predominantly present. The sin / anti ratio is approximately 8/2. (3) without (4) anti Compounds of the formula (4) (4) The compounds of the formula (4), i.e. a- (4) and ß- (4), are obtained by a number of transformations starting from the compounds of the formula (3) and consisting of a Nef reaction in the corresponding formyl derivative, simultaneous acid catalyzed deprotection of the diol and two cyclization reactions. These transformations are made by treating the intermediaries of the formula (3) with a base and subsequently treating the reaction mixture with an acid in the presence of methanol, preferably by adding or pouring the reaction mixture to an acid in the presence of methanol, resulting in the intermediates of the formula (4). The reactions mentioned above also produce compounds of the formula (4 '). (4 ') In the Nef reaction, a primary or secondary nitroalkane is converts to the corresponding carbonyl compound (N. Kornblum Organic reactions 1962, 12, 101 and H. W. Pinnick Organic Reactions 1990, 38, 655). In the classical procedure, the nitroalkane is deprotonated with a base in the a-position to the nitro function, followed by acid-catalyzed hydrolysis of the intermediate 'nitronate salt' via addition to a strong acid present in excess, to produce the carbonyl derivative. Suitable bases can be selected by one skilled in the art of organic synthesis. Suitable bases include, but are not limited to, inorganic bases such as alkali metal, alkaline earth metal, and ammonium hydroxide and alkoxides. Examples of suitable bases are lithium diisopropylamide, sodium methoxide, potassium methoxide, lithium methoxide, potassium t-butoxide, calcium dihydroxide, barium dihydroxide, and quaternary alkylammonium hydroxides, DBN (1,3-diazabicyclo [ 3.4.0] non-5-ene), DBu, DABCO (1,4-diazabicyclo [2.2.2] octane), TBAF, TMG, potassium carbonate and sodium carbonate or mixtures thereof. The preferred bases are sodium methoxide, potassium methoxide, lithium methoxide, TBAF, DBU, TMG, or mixtures thereof, the most preferred bases are sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof, and sodium methoxide is more preferred. As an acid, any acid may be employed, preferably a strong acid, more preferably a mineral acid such as concentrated sulfuric acid, concentrated hydrochloric acid, and most preferably concentrated sulfuric acid. Using anhydrous conditions or near anhydrous conditions and methanol as the solvent in the Nef reaction, the cyclic methyl acetal of the formyl group is obtained. The methyl substituents in the intermediates of the formula (4) and (4 ') originate from the methanol solvent.
Alternatively, if the Nef reaction and prior Michael addition are performed in a non-methanolic solvent, for example acetonitrile, different acids of the compounds of the formula (4) and (4 ') will be obtained instead, usually a mixture of the semiacetals and the alkyl acetals corresponding to the substituent R1 in the compounds of the formula (3). The semiacetal and acetal congeners can be converted into the desired methyl acetals of the formula (4) and (4 ') by reacting again those with methanol under acidic conditions. Alternatively, when the previous Michael addition is made with DBU or TMG and the compounds of the formula (3) are not isolated and the subsequent Nef reaction is carried out with a strong base, in particular with sodium methoxide or lithium methoxide, surprisingly a significant increase in the yield of the compounds of the formula (4) is obtained. As such, the presence of DBU or TMG during the Nef reaction with a strong base is a preferred embodiment of this invention. For example, when the addition of Michael with nitromethane is performed in methanol with hydroxides, alkoxides or TBAF in various amounts, the yield of the compounds of the formula (3) based on the compounds of the formula (2) is about 80%. When the subsequent cyclization and reaction Nef are performed with non-isolated compounds of the formula (3) using sodium methoxide as the additional base and sulfuric acid in methanol as the acid solution, 43% of the compound of the formula (4) can be obtained based on the compounds of the formula (2) with a relation to (4) / β (4) of at least about 3/1. When the Michael addition is performed with about 1 equivalent of DBU or TMG based on the compounds of the formula (2), the yield of the compounds of the formula (3) based on the compounds of the formula (2) is also about 80% However, when the Nef reactions and cyclization are subsequently carried out with non-isolated compounds of the formula (3), combined with 1.0 equivalent of sodium or lithium methoxide based on the compounds of the formula (2), the compound of the formula ( 4) can be obtained with 53-58% yield based on the compounds of the formula (2) with a relation to (4) / β (4) of at least about 3/1. The bicyclic intermediates of the formula (4) are the expected cyclization products originated from the intermediates of the formula (3) in an unsupported configuration. The intermediates of the formula (4 ') are the expected reaction products originated from the intermediate of the formula (3) in the anti-configuration, which are not cyclized, and also the expected reaction products originated from the intermediary of the formula (3) ) in a configuration without, since the cyclization of the isomers without usually is not completely complete. The trans configuration of the substituents on the carbon atom number 3 (C-3) and carbon atom number 4 (C-4) in the tetrahydrofuran ring of the intermediate of the formula (4 ') prevents the formation of lactone ring as seen in the intermediaries of formula (4).
Preferably, the acid cooling of the Nef reactions and cyclization is carried out with an excess of concentrated sulfuric acid, preferably with 2 to 10 equivalents based on the compounds of the formula (2), more preferably with 2.5 to 5 equivalents, even more preferably with 3 to 4 equivalents and most preferably to about 3.5 equivalents, such as 20% by weight to 80% by weight of solution in methanol, preferably as 40% by weight to 60% by weight of solution in methanol. A large excess of sulfuric acid results in a higher alpha / beta ratio for compounds of the formula (4) but also requires more base for the subsequent neutralization in the alkaline cooling. For example, when 3.5 equivalents of sulfuric acid based on the compounds of the formula (2) are used in the acid cooling as 50% by weight of methanol solution, a relation to (4) / ß (4) of up to 4/1 can be achieved. The acid cooling of the Nef reactions and cyclization can be carried out at temperatures ranging from about -40 ° C to about 70 ° C, preferably at temperatures between about -25 ° C and about 15 ° C, most preferably at temperatures between about - 15 ° C and approximately 0 ° C. The reaction times may vary up to about 24 hours, suitably in a range between about 15 minutes and about 12 hours, even more suitably in a range between about 20 minutes and about 6 hours.
For the isolation of the compounds of the formula (4), an aqueous preparation may be required to remove the salts and part of the intermediates of the formula (4 '). A base will neutralize the previously employed acid, since acidic aqueous conditions could cause hydrolysis of the methyl acetal of the compound of the formula (4) to the semiacetal congener, thus resulting in product loss. As such, the isolation of the compound of the formula (4) is optimally carried out by an alkaline cooling reaction, preferably by an aqueous alkaline cooling reaction, followed by extraction of the compound of the formula (4) with an organic solvent immiscible in water. . Preferably, the acid mixture resulting from the Nef reactions and cyclization is added to the aqueous alkaline solution. Since during the alkaline aqueous cooling reaction, a large reactor volume is needed, it is preferable to minimize the volume as much as possible. This can be done in different ways, for example using highly soluble bases, or using bases in the form of slurry. As such, suitable bases for the preparation of the compound of formula (4) are a bicarbonate or carbonate, preferably sodium, potassium, lithium or cesium bicarbonate, preferably sodium, potassium, lithium or cesium bicarbonate, even more preferably sodium bicarbonate. sodium or potassium, most preferably potassium bicarbonate, either completely in solution or as a watery paste. As such, the use of saturated potassium carbonate acid solution for alkaline cooling in place of saturated sodium acid carbonate solution has, because of its higher solubility, the advantage that the volume of the aqueous phase can be further reduced and the Potassium sulfate formed surprisingly has a much better filterability than sodium sulfate. Advantageously, during alkaline cooling the pH is maintained between about 2 and about 9, preferably between about 3 and about 8, more preferably between about 3.5 and about 7.5. Also advantageously, at the end of the alkaline cooling the pH is adjusted between about 3.5 and about 6, preferably between about 3.5 and about 5, most preferably between about 3.8 and about 4.5. These required pH ranges can be realized by the use of carbonate and bicarbonates as indicated above. Optionally, the base or additional acid can be used to adjust the pH to a certain value at the end of the cooling reaction. Within the preferred pH range, the methanol can be evaporated from the reaction mixture after alkaline cooling and before extractions with organic solvent at temperatures between about 0o and about 65o, preferably between about 20o and about 45o C. Under these conditions the compounds of the formula (4) do not degrade, even when residence times are applied on a large scale. The removal of methanol by evaporation before extractions with organic solvent has the advantage that the extraction efficiency significantly increases, so that less organic solvent is consumed and the productivity additionally increases. Suitable organic water immiscible solvents are any ester, hydrocarbon, ether, halogenated hydrocarbon, or aromatic solvent. These could include, but are not limited to, pentane, hexane, heptane, toluene, xylenes, benzene, mesitylenes, t-butylmethyl ether, dialkyl ethers (ethyl, butyl), diphenyl ether, chlorobenzene, dichloromethane, chloroform, tetrachloride. carbon, acetonitrile, dichlorobenzene, 1,2-dichloroethane, 1,1-trichloroethane, ethyl acetate, isopropyl acetate, preferably ethyl acetate. To improve the extraction yield of the compounds of the formula (4), soluble salts in water they can be added to the mixture prior to extraction. A preferable salt includes NaCl. An advantage of the method described in the present invention when compared to the Knoevenagel route of the prior art is that during the alkaline aqueous cooling it is not necessary to simultaneously extract the compounds of the formula (4) with an organic solvent. The absence of the organic solvent during the alkaline cooling additionally aids in the decrease of the reactor volume and the filtration of the inorganic salts formed is much easier. On the route of Knoevenagel, the presence of organic solvent during alkaline cooling is required if the loss of product will be avoided. To further isolate the compound of the formula a-) 4) in pure form, the crystallization of the compound can be applied.
Crystallization The compound of the formula a- (4) can be crystallized from a solvent, such as organic, inorganic solvents or water, and mixtures thereof. Suitable solvents for crystallization include isopropanol, t-amyl alcohol, t-butanol, ethyl acetate, ethanol and methyl isobutyl ketone. Especially isopropanol, t-amyl alcohol, and t-butanol are preferred when they produce a high crystallization yield and product with high purity. More preferably isopropanol or t-amyl alcohol are used, most preferably isopropyl alcohol. If the isopropyl alcohol is the solvent used in the crystallization, the preferred concentration prior to crystallization of the compound of the formula a- (4) is between about 5 to about 30% by weight, more preferably between about 10 and about 25% by weight. weight, even more preferably between about 15 and about 20% by weight. Crystallization produces compounds of the formula a- (4) with high purity although small amounts of the compound of the formula β- (4) may be present, ie less than about 5%, in particular in amounts less than about 3%.
Epimerization The compound of the formula (4) in its beta isomeric form can be epimerized in the compound of the formula a- (4) with an acid, for example with organic or inorganic acids, preferably in the absence of water and in the presence of methanol. The epimerization is preferably carried out with MeS03H in methanol, or any comparable acid with a similar acid concentration since this prevents the formation of side products. Preferably, the amount of MeS03h in methanol employed ranges from about 0.05 to about 1.5 equivalents, based on the compounds of the formula (4), more preferably between about 0.1 and about 0.3 equivalents. The temperature for carrying out the epimerization is between about 0 ° C and about the reflux temperature, preferably between about 20 ° C and about the reflux temperature, more preferably between about 40 ° C and about the reflux temperature, still more preferably at around the reflux temperature. Various alternatives may exist for some of the procedures described above. For example, in one embodiment, after obtaining a mixture of the compound of the formula a- (4) and a compound of the formula β- (4), the compound of the formula a- (4) is crystallized and the synthetic process continue to produce the compound of the formula (6). In another embodiment, the artisan can choose to crystallize the compound of the formula a- (4), proceed with an epimerization of the remaining mother liquor, which contains a relatively large amount of the undesired β- (4) epimer, to obtain a mixture with a relatively large amount of the epimer a- (4), and apply a second crystallization of the epimer a- (4). For example, when the crude mixture of the compound of the formula (4) having an a- (4) / β- (4) ratio ranging from about 3.5 / 1 to about 4/1, a first crop of a- (4) is isolated and the remaining mother liquor has an a- (4) / β- (4) ratio ranging from about 0.3 / 1 to about 1.5 / 1. After the epimerization of the β- (4) epimer, the ratio a- (4) / β- (4) in the mother liquor is approximately 3/1 and a second crop of a- (4) is obtained by crystallization which has at least one purity comparable with the first harvest of a- (4). Alternatively, one can proceed by performing a simultaneous crystallization of the α- (4) epimer and epimerization reaction of the β- (4) epimer to a- (4). In another embodiment, one can start by epimerizing the β- (4) epimer to a- (4), and then crystallizing the epimer a- (4). In still another embodiment, one can start by epimerizing the β- (4) epimer to a- (4), subsequently crystallizing the epimer a- (4), applying a second epimerization of the remaining mother liquor and an additional crystallization producing a second crop of the epimer a- (4). As such, in one embodiment, the mother liquor of a pre-crystallization of the compound of the formula a- (4) from isopropanol can be epimerized by evaporation of the isopropanol, taking the residue in methanol and refluxing for about 30 minutes to about 4 hours. hours with MeS03H, preferably with about 0.1 to about 0.3 equivalents. If the reaction mixture is subsequently poured into aqueous NaHC03, extracted with EtOAc and the organic phase is changed with solvent to isopropanol, a second portion of the pure compound of the formula a- (4) can be obtained by crystallization. In a preferred embodiment, a mixture of the α- (4) and β- (4) epimers can be transformed in one stage into 100% or almost 100% alpha isomer with 100% or almost 100% yield, without sub formation. -product, via a direct crystallization of the epimer a- (4) and simultaneous epimerization of the ß- (4) epimer to a- (4), also known as asymmetric transformation induced by crystallization. An asymmetric transformation induced by crystallization can be carried out by dissolving the mixture of the epimers a- (4) and β- (4) in methanol in the presence of about 0.10 equivalents of MeS03H based on the sum of both epimers, and evaporating the methanol in Vacuum from about 30 ° C to about 40 ° C. This embodiment is particularly preferable since the mixture of the epimers a- (4) and β- (4) can be transformed to only the epimer a- (4) in a step which has lower production costs and a batch of - (4) with homogeneous quality is obtained. In a preferred embodiment, the neutralization of the acid, such as MeSOaH, is performed prior to the change of methanol solvent to the crystallization solvent such as isopropanol. The neutralization can be carried out by adding a slight molar excess of a base, based on the epimerization acid used. As a base, any base can be used as long as the salt of the base with the epimerization acid does not contaminate the crystals of the epimer a- (4). For example, in the case that MeS03H is used as the epimerization acid, a tertiary amine may be used, preferably triethylamine, producing the triethylammonium methanesulfonate salt, which does not contaminate the epimer crystals a- (4) during crystallization. from isopropanol. The addition of a slight excess of NEt3 on MeS03H for neutralization prevents the formation of isopropyl acetals as byproducts which could be formed under acidic conditions during the subsequent solvent change from methanol to isopropanol. The subsequent solvent exchange of methanol to isopropanol and crystallization affords the compound of the formula a- (4) in high purity without some or minimal contamination with triethylammonium methanesulfonate salt.
Compound of the formula (6) The compound of the formula (6) is obtained by reduction of the compound of the formula a- (4) followed by a cyclization reaction. The intermediate resulting from the reduction of the compound of the formula a- (4) is the compound of the formula (5). (5) The compound of the formula (5) is preferably not isolated but directly cyclized to the compound of the formula (6).
The reduction step can be conveniently carried out by treating the intermediate of the formula a- (4) with metal hydrides such such as lithium borohydride, sodium borohydride, sodium borohydride-lithium chloride in suitable anhydrous solvents.
Examples of suitable anhydrous solvents include but are not limited to dichloromethane, toluene, xylene, benzene, pentane, hexane, heptane, petroleum ether, 1,4-thioxane, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and in general any anhydrous solvent capable of being used in a chemical reduction process using the reduction agents mentioned above. A solvent preferred is tetrahydrofuran. According to a preferred embodiment, the Reduction stage is carried out using lithium borohydride or borohydride sodium in tetrahydrofuran. In the case that lithium borohydride is used as the reducing agent, the amount of reducing agent varies between about 1 and about 1.5 equivalents based on the amount of the compound of the formula or (4), preferably between about 1.1 and about 1.3 equivalents. The reduction step can be carried out at temperatures ranging from about -78 ° C to about 55 ° C, preferably between about -15 ° C and about 45 ° C, and most preferably between about 0 ° C and about 40 ° C. The reaction time may vary up to about 24 hours, and suitably ranges from about 2 to about 24 hours. The compound of the formula (5) can be converted to the desired compound of the formula (6) by a cyclization reaction. The cyclization reaction occurs via an intramolecular transacetylation and can be carried out in any organic solvent compatible with acid or a combination of a solvent miscible in water and water and in the presence of a strong inorganic or organic acid. The reaction is suitably carried out by treatment of the compound of the formula (5) with a catalytic amount of a strong acid. In a preferred embodiment, the strong acid is selected from a group consisting of hydrochloric acid and sulfuric acid in tetrahydrofuran. The cyclization step is preferably carried out at temperatures below about 5 ° C, more preferably below about -5 ° C. (6) In a particularly preferred embodiment the compound of the formula (5), which in the reduction with lithium or sodium borohydride in tetrahydrofuran is obtained as a boron complex, is treated with a concentrated mineral acid and the decomplexation of the compound of the formula (5) and the cyclization of the compound of the formula (5) to the compound of the formula (6) are carried out simultaneously. Preferably a strong mineral acid is used, more preferably concentrated sulfuric acid or concentrated hydrochloric acid, most preferably concentrated hydrochloric acid. The amount of hydrochloric acid can vary between 1.0 and 1.4 equivalents based on the applied amount of lithium or sodium borohydride, but preferably is between 1.1 and 1.3 equivalents. With respect to the isolation of the compound of the formula (6) in pure form, it is desirable to remove the inorganic salts resulting from the reagents used in the stages of reduction, decomplexation and cyclization. This can be done by an aqueous organic solvent extraction process, but preferably this is done by adding a small excess of a base on the acid applied for the decomplexation of the compound of the formula (5) and cyclization reaction thereof to the compound of the formula (6). Later, a change of solvent to a more polar solvent is made resulting in the precipitation of the salts resulting from the reduction and decomplexation. As a base used in the preparation of the compound of the formula (6) any base can be used as long as the solubility of its salt with the mineral acid used for the decomplexation reaction and cyclization of the compound of the formula (5) is low. compound of the formula (6) in the final solvent after the change of solvent. For example, if lithium borohydride in tetrahydrofuran is used in the reduction, concentrated aqueous HCl is used in the decomplexation / cyclization and ethyl acetate is the final solvent, then the tertiary amines are suitable bases for the neutralization of the acid, particularly triethylamine. In this case, the boron and triethylamine hydrochloride salts are almost completely precipitated and the compound of the formula (6) completely remains in solution. After filtration of the solids a solution of the compound of the formula (6) with high purity remains which can be processed to any desired form. It is observed that the other enantiomer of the compound of the formula (6), mainly the compound of the formula (6d), (3S, 3aR, 6aS) hexahydro-furo [2,3-b] furan-3-ol, is also an active portion for inhibitors of HIV protease. (6d) As such, the identical methods, procedures, reagents and conditions described in the present invention, including the corresponding crystallization and epimerization, can be applied in the preparation of the compound of the formula (6d), using compounds of the formula (1d), precursors thereof, and other intermediates in the preparation of the compound of the formula (6d), such as the compounds of the following formula (4d).
(Id) (4d) The compounds of the formula (6) and (6d) find their particular use in the preparation of a medicament. According to a preferred embodiment, the present compounds of the formula (6) and (6d) are used as precursors in the preparation of anti-viral drugs, in particular anti-HIV drugs, more in particular HIV protease inhibitors. The compound of the formula (6) and all the intermediates which lead to the formation of the stereoisomerically pure compound are of particular interest in the preparation of HIV protease inhibitors as described in WO 95/24385, WO 99/65870, WO 00 / 47551, WO 00/76961 and US 6,127,372, WO 01/25240, EP 0 715 618 and WO 99/67417 all incorporated herein by reference, and in particular, the following HIV protease inhibitors. Ester (3R, 3aS, 6aR) - [(1S, 2R) -2-hydroxy-3 - [[(4-methoxyphenyl) sulfonyl] (2-methyl) -hexahydrofuro [2,3-b] furan-3-yl Lpropyl) amino] -1- (phenylmethyl) propyl] -carbamic (HIV 1 protease inhibitor); Ester (3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl acid [(1S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenyl-methyl) propyl] -carbamic acid (HIV 2 protease inhibitor); Ester (3R, 3aS, 6aR) - [(1 S, 2R) -3 - [(1,3-benzodioxol-5-ylsulfonyl) (2-methylpropyl) -hexahydrofuro [2,3-b] furan-3-yl acid amino] -2-hydroxy-1- (phenylmethyl) propyl] -carbamic acid (HIV 3 protease inhibitor), or any pharmaceutically acceptable addition salt thereof. Accordingly, the present invention also relates to inhibitors of HIV protease 1, 2, 3 or any pharmaceutically acceptable salt or prodrug thereof, obtained by using a compound of formula (6) prepared according to the present invention in the chemical synthesis of HIV protease inhibitors. Such chemical synthesis is described in the literature, for example in WO 01/25240, EP 0 715 618 and WO 99/67417. As such, the protease inhibitors referred to above can be prepared using the following general procedure. An N-protected amino epoxide of the formula wherein P is an amino protecting group, and R2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, the radicals are optionally substituted with a selected group of alkyl and halogen radicals, nitro, cyano, trifluoromethyl, -OR9 and -SR9, wherein R9 represents hydrogen, alkyl, and halogen radicals; it is prepared from the corresponding chloroketone in the presence of a base and a solvent system. Suitable solvent systems for preparing the amino epoxide include ethanol, methanol, sodium propane, tetrahydrofuran, dioxane, and the like including mixtures thereof. Suitable bases for producing the epoxide from reduced chloroketone include potassium hydroxide, sodium hydroxide, potadium t-butoxide, DBU and the like. Alternatively, a protected amino epoxide can be prepared by starting with an L-amino acid which is reacted with a suitable amino protecting group in a suitable solvent to produce a protected amino acid L-amino acid ester of the formula: wherein P "'represents a carboxyl protecting group, eg, methyl, ethyl, benzyl, tertiary butyl and the like, R2 is as defined above, and F and P" independently are selected from amine protecting groups, including but not limited to, arylalkyl, substituted arylalkyl, cycloalkenylalkyl and substituted cycloalkenylalkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl. Additionally, the P 'and / or P "protecting groups can form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups In addition, the heterocyclic groups can be mono-, di- or tri-substituted, for example, nitroftalimidil.The protected amino-L amino acid ester is then reduced to the corresponding alcohol. , the protected amino acid L-amino acid ester can be reduced with diisobutylaluminum hydride at -78 ° C in a suitable solvent such as toluene.
They include lithium aluminum hydride, lithium borohydride, sodium borohydride, borane, lithium hydride and tri-terbutoxyaluminium, borane / THF complex. The resulting alcohol is then converted, for example, via an oxidation of Swern, to the corresponding aldehyde of the formula: where P ', P "and R2 are as defined above, Therefore, the dichloromethane solution of the alcohol is added to a cold solution (-75 ° C to -68 ° C) of oxalyl chloride in dichloromethane and DMSO in dichloromethane and stirred for 35 minutes Acceptable oxidation reagents include, for example, sulfur trioxide-pyridine complex and DMSO, oxalyl chloride and DMSO, acetyl chloride or anhydride and DMSO, trifluoroacetyl anhydride or chloride and DMSO, methanesulfonyl chloride and DMSO or thiaphene S-oxide tetrahydro, toluene sulfonyl bromide and DMSO, trifluoromethanesulfonyl anhydride (triflic anhydride) and DMSO, phosphorus pentachloride and DMSO, dimethylphosphoryl chloride and DMSO and isobutyl chloroformate and DMSO. aldehydes of this process can also be prepared by methods for reducing the protected phenylalanine and phenylalanine analogs or their ester or amide derivatives by, for example, sodium amalgam with HCl in ethane l or lithium or sodium or potassium or calcium in ammonia. The reaction temperature can be from about -20 ° C to about 45 ° C, and preferably from about 5 ° C to about 25 ° C. Two additional methods of obtaining nitrogen-protected aldehyde include the oxidation of the corresponding alcohol with bleach in the presence of a catalytic amount of free radical 2,2,6,6-tetramethyl-1-pyridyloxy. In a second method, the oxidation of the alcohol to the aldehyde is carried out by a catalytic amount of tetrapropylammonium perruthenate in the presence of N-methylmorpholine-N-oxide. Alternatively, an acid chloride derivative of a protected phenylalanine or phenylalanine derivative as described above can be reduced with hydrogen and a catalyst such as Pd over barium carbonate or barium sulfate, with or without an additional catalyst moderating agent such as sulfur or a thiol (Reduction of Rosenmund). The aldehyde resulting from the Swem oxidation is then reacted with a halomethyl lithium reagent, the reagent is generated in situ by reacting an alkyl lithium or aryl lithium compound with a dihalomethane represented by the formula X 1 CH 2 X 2 wherein X 1 and X 2 independently represent iodine, bromine or chlorine. For example, a solution of the aldehyde and chloroiodomethane in THF is cooled to -78 ° C and a solution of n-butyl lithium in hexane is added. The resulting product is a mixture of diastereomers of the corresponding amino-protected epoxides of the formulas: The diastereomers can be separated for example, by chromatography, or alternatively, once they react in subsequent stages the diastereomeric products can be separated. For compounds that have the stereochemistry (S), a D-amino acid can be used in place of the L-amino acid. The addition of chloromethyl lithium or bromomethyl lithium to a chiral amino aldehyde is highly diastereoselective. Preferably, chloromethyl lithium or bromomethyl lithium is generated in situ from the reaction of dihalomethane and n-butyl lithium. Acceptable methylene halometanes include chloroiodomethane, bromine, chloromethane, dibromomethane, diiodomethane, bromofluoromethane and the like. The sulfonate ester of the addition product of, for example, hydrogen bromide to formaldehyde is also a methyleneizing agent. Tetrahydrofuran is the preferred solvent, however alternative solvents such as toluene, dimethoxyethane, ethylene dichloride, methylene chloride can be used as pure solvents or as a mixture. Dipolar aprotic solvents such as acetonitrile, DMF, N-methylpyrrolidone are useful as solvents or as part of a solvent mixture. The reaction can be carried out under an inert atmosphere such as nitrogen or argon. For n-butyl lithium other organometallic reagents such as methyl lithium can be substituted, tert-butyl lithium, sec-butyl lithium, phenyl-lyo, phenyl-sodium and the like. The reaction can be carried out at temperatures between about -80 ° C to 0 ° C but preferably between about -80 ° C to -20 ° C. The conversion of the aldehydes to their epoxide derivative can also be carried out in multiple stages. For example, the addition of the thioanisole anion prepared from, for example, a butyl or aryl lithium reagent, to the protected aminoaldehyde, the oxidation of the resulting protected aminosulfide alcohol with well-known oxidizing agents such as hydrogen peroxide, tertiary hypochlorite, Butyl, bleach or sodium periodate to produce a sulfoxide. The alkylation of the sulfoxide with, for example, methyl bromide or iodide, methyl tosylate, methyl mesylate, methyl triflate, ethyl bromide, isopropyl bromide, benzyl chloride or the like, in the presence of an organic base or inorganic Alternatively, the protected aminosulfide alcohol can be alkylated with, for example, the above alkylating agents, to provide sulfonium salts which are subsequently converted to the epoxides bound with tertamine or mineral bases. The desired epoxides formed, using the most preferred conditions, diastereoselectively in ratio amounts of at least about an 85:15 ratio (S: R). The product can be purified by chromatography to produce the diastereomerically or enantiomerically pure product but is more conveniently used directly without purification to prepare retroviral protease inhibitors. The above procedure is applicable to mixtures of optical isomers as well as redissolved compounds. If a particular optical isomer is desired, it may be selected by the choice of the starting material, for example, L-phenylalanine, D-phenylalanine, L-phenylalaninol, D-phenylalaninol, D-hexahydrophenylalaninol and the like, or the resolution may occur in intermediate or final stages. Chiral auxiliaries such as one or two equivalents of camphor sulphonic acid, camphoric acid, 2-methoxy-phenyl acetic acid and the like can be used to form salts, esters or amides of the compounds of this invention. These compounds or derivatives can be crystallized or separated chromatographically using either a chiral or achiral column as is well known to those skilled in the art. The amino epoxide is then reacted, in a suitable solvent system, with an equal amount, or preferably an excess of, a desired amine of the formula R 3 NH 2, wherein R 3 is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl radicals , alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl and mono- and di-substituted aminoalkyl, wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl radicals , heterocycloalkyl, and heterocycloalkylalkyl, or in the case of a disubstituted aminoalkyl radical, the substituents together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl radical. The reaction can be conducted over a wide range of temperatures, for example, from about 10 ° C to about 100 ° C, but is preferably, but not necessarily, conducted at a temperature at which the solvent begins to reflux. Suitable solvent systems include protic, non-protic and polar aprotic organic solvents such as, for example, those in which the solvent is an alcohol, such as methanol, ethanol, sodium propane, and the like, ethers such as tetrahydrofuran, dioxane, and the like. , and toluene, N, N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. A preferred solvent is sodium propane. Exemplary amines corresponding to the formula R3NH2 include benzylamine, isobutylamine, n-butylamine, isopentylamine, isoamylamine, cyclohexanomethylamine, naphthylene methylamine and the like. The resulting product is a 3- (N-protected-amino) -3- (R2) -1- (NHR3) -propan-2-ol derivative, later referred to as an amino alcohol, and represented by the formulas: wherein P, P ', P ", R2 and R3 are as described above Alternatively, a haloalcohol can be used in place of the amino epoxide The amino alcohol defined above is then reacted in a suitable solvent with a sulfonyl chloride (R S02CI) or sulfonyl anhydride in the presence of an acid scavenger Suitable solvents in which the reaction can be conducted include methylene chloride, tetrahydrofuran Suitable acid scavengers include triethylamine, pyridine The preferred sulfonyl chlorides are methanesulfonyl chloride and benzenesulfonyl chloride The resulting sulfonamide derivative can be represented, depending on the epoxide used, by the formulas wherein P, P ', P ", R2, R3 and R4 are as defined above These intermediates are useful for the preparation of protease inhibitor compounds and are also active retroviral protease inhibitors.Sulfonyl halides of the formula R4S02X they can be prepared by the reaction of a suitable alkyl lithium or Grignard reagent with sulfonyl chloride, or sulfur dioxide followed by oxidation with a halogen, preferably chlorine, Also, thiols can be oxidized to sulfonyl chlorides using chlorine in the presence of In addition, sulfonic acids can be converted to sulfonyl halides using reagents such as PCI5, and also to anhydrides using suitable dehydration reagents.Sulfonic acids can in turn be prepared using procedures well known in the art. Such sulfonic acids are also commercially available, instead of sulfonyl halides or, sulfinyl halides (R4SOX) or sulfenyl halides (R4SX) can be used to prepare compounds wherein the -S02- portion is replaced by an -SO- or -S- portion respectively. After the preparation of the sulfonamide derivative, the amino protecting group P or amino protecting groups P 'and P "are removed under conditions which will not affect the remaining portion of the molecule.These methods are well known in the art and include hydrolysis of acid, hydrogenolysis and the like A preferred method involves the removal of the protecting group, for example, removal of a carbobenzoxy group, by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures of Where the protecting group is a t-butoxycarbonyl group, it can be removed using an inorganic or organic acid, for example, HCl or trifluoroacetic acid, in a suitable solvent system, for example, dioxane or methylene chloride. resulting is the amine salt derivative of the formula: This amine can be coupled to a carboxylate represented by the formula wherein R is the group (3R, 3aS, 6aR) hexahydrofuro [2,3-b] furan-3-oxy and L is an appropriate leaving group such as a halide. A solution of the free amine (or amine acetate salt) and about 1.0 equivalents of the carboxylate is mixed in an appropriate solvent system and optionally treated with up to five equivalents of a base such as, for example, N-methylmorpholine, a approximately room temperature. Suitable solvent systems include tetrahydrofuran, methylene chloride or N, N-dimethyl formamide, and the like, including mixtures thereof. Alternatively, the amine can be coupled to a carbonate of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol succinimidyl. The activation of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol can be carried out, for example, by reaction with disuccinimidyl carbonate and triethylamine.
EXAMPLES The following examples are proposed to be illustrative of the present invention. These examples are represented to exemplify the invention and will not be construed as limiting the scope of the invention. All reactions are carried out under a nitrogen atmosphere. The solvents and reagents were used as supplied without further purification. The 1 H NMR spectra were recorded at 200 MHz in CDCl 3 or DMSO-d 6 on a Bruker AC-200 NMR spectrometer. The 1H quantitative NMR was performed with chlorobenzene as the internal standard. All the reported yields have been corrected for the impurity of the product. The gas chromatography (GC) assay and determination e.e. from S-2, 3-0-isopropylidene-glyceraldehyde in reaction mixtures is performed with an Agilent 6890 GC (EPC) and a Betadex column (part number 24305, Supelco or equivalent) of 60 m and with a film thickness of 0.25 μm using a pressure of column head of 26.4 kPa, a column flow of 1.4 ml / min, a division flow of 37.5 ml / min and an injection temperature of 150 ° C. The ramp used was: initial temperature 60 ° C (3 min), speed 5 ° C / min. intermediate temperature 130 ° C (1 min), speed 25 ° C / min, final temperature 230 ° C (8 min). The detection is carried out with an FID detector at a temperature of 250 ° C. The reaction times were as follows: chlorobenzene (internal standard) 13.9 min, S-2,3-0-isopropylidene-glyceraldehyde 15.9 min, R-2,3-0-isopropylidene-glyceraldehyde 16.2 min. The CG test and determination e.e. of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethyl ester is carried out with equipment described above but using an injection temperature of 250 ° C. The ramp used was: initial temperature 80 ° C (1 min), speed 5 ° C / min, final temperature 255 ° C (10 min). The detection is carried out with an FID detector at a temperature of 250 ° C. The retention times were as follows: toluene 7.3 min, chlorobenzene (internal standard) 9.4 min, S-2,3-0-isopropylidene-glyceraldehyde 10.7 min, R-2,3-0-isopropylidene-glyceraldehyde 10.9 min, ethyl ester of the acid Z-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic 20.4 min, ethyl ester of the acid ER-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic 22.6 min, ES-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethyl ester 22.9 min, triethyl phosphonoacetate (TEPA) 25.5 min . The CG test for the compounds a- (4) and ß- (4) is carried out with an Agilent 6890 GC (EPC) and a CP-Sil 5 CB column (part number CP7680 (Varian) or equivalent) of 25 m with a film thickness of 5 μm using a column head pressure of 5.1 kPa, a division flux of 40 ml / min and an injection temperature of 250 ° C. The ramp used was: initial temperature 50 ° C (5 min), speed 10 ° C / min, final temperature 250 ° C (15 min). The detection is carried out with an FID detector at a temperature of 250 ° C. The retention times were as follows: chlorobenzene (internal standard) 17.0 min, a- (4) 24.9 min, ß- (4) 25.5 min.
EXAMPLE 1 Preparation of S-2,3-O-isopropylidene-glyceraldehyde and conversion to R-3- (2,2-dimethyl-ri, 31-dioxolan-4-yl) -acrylic acid ethyl ester To a well stirred aqueous paste of KI04 (530 g, 2.3 mol, 2.3 eq.), KHC03 (230 g, 2.3 mol, 2.3 eq.) In water (1200 g) is added dropwise a solution of L-5,6 -0-isopropylidene-gulono-1,4-lactone (218.5 g, 1 mol) in water (135 g) and tetrahydrofuran (1145 g) for 3 h at 32-34 ° C. The reaction mixture is stirred for 4.5 h at 32 ° C. According to the GC the oxidation is complete since the content of S-2,3-0-isopropylidene-glyceraldehyde was 4.38% by weight and does not increase further. The reaction mixture is cooled to 5 ° C and maintained at this temperature for 14 h. The solids (mainly consisting of KI03) are removed by filtration and the cake is washed with tetrahydrofuran (115 ml) and with another portion of tetrahydrofuran (215 ml) by reformation of slurry. A sample is taken from the filtrate (2975 g) and analyzed by quantitative 1 H NMR (DMSO-d 6) showing that the content of S-2,3-0-isopropylidene-glyceraldehyde in the filtrate is 3.69% by weight corresponding to 109.6 g (0.843 mol) and a yield of 84% based on L-5,6-0-isopropylidene-gulono-1,4-lactone. To 2953 g of the obtained filtrate (containing 108.8 g = 0.837 mol of S-2,3-0-isopropylidene-glyceraldehyde) at 13 ° C is added dropwise with stirring with triethyl phosphonoacetate (TEPA, 194.7 g, 97% pure , 0.843 mol, 1.01 eq.) For 25 min at 13-17 °. Subsequently, K2C03 (838 g, 6.07 mol, 7.26 eq.) Is added dropwise during 30 min at 17-25 ° C. The final pH of the reaction mixture was 11.6. The reaction mixture is stirred for a further 17 h at 20 ° C. The aqueous phases and tetrahydrofuran are separated and the aqueous phase is extracted twice with 660 ml of toluene. The combined tetrahydrofuran and toluene phases are concentrated in vacuo (260-25 mbar, temperature 28-56 ° C) for 8 h producing 175.5 g of a light yellow liquid. The quantitative 1 H NMR indicates the presence of 78% by weight of ethyl ester of ER-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid, 2.5% by weight of ethyl ester of the Z-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid, 4.4% by weight of TEPA (4.1% mole of the initial amount) and 6.8% by weight of toluene. This corresponds to a yield of ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid total of 141.2 g (0.706 mol) which is 71% yield based in L-5,6-0-isopropylidene-gulono-1,4-lactone and 84% yield based on S-2,3-0-isopropylidene glyceraldehyde. The CG indicates that the e.e. of ethyl ester of the acid E-R-3- (2,2-dimethyl- [1,3-dioxolan-4-yl) -acrylic was > 99% EXAMPLE 2 Preparation of a mixture of compounds a- (4) and β- (4) from ethyl ester of the acid R-3- (2,2-dithmethoxy, 3-dioxolan-4-yl) -acr? co using various types and amounts of bases without isolation of the nitro addition compound EXAMPLE 2A Use of DBU in the addition of Michael and NaOMe as additional base in the Nef reaction To the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (21.2 g of oil, 94.5% by pure weight, 0.1 mol) is added nitromethane (13.0 g) of a solution of 51.7% by weight in methanol, 0.11 mol, 1.1 eq.) and the solution is cooled to 0 ° C. Subsequently, DBU (15.2 g, 0.1 mol, 1 eq.) Is added dropwise during 25 min and the funnel is rinsed with methanol (1 g). The reaction mixture is heated to 20 ° C and stirred at this temperature for 17 h. The resulting solution (50 g) is divided into 2 equal parts; the other part of 25 g is further processed as described in example 2B. A portion of 25 g is cooled to 0 ° C and NaOMe (10.0 g of a solution of 29.6% by weight in methane, 0.055 mol, 1.1 eq.) Is added dropwise for 10 min at 0 ° C and the funnel is rinsed with methanol (1.6 g). The reaction mixture is stirred for 50 min at 0 ° C and then quenched in a solution of H2SO4 (17.9 g, 96% by weight, 0.175 mol, 3.5 eq.) In methanol (30.4 g) at 0-5 ° C. by drip addition for 60 min under vigorous stirring. The funnel is rinsed with methanol (2 x 4 g). The resulting reaction mixture is stirred for 2 h at 0 ° C and then quenched in a stirred mixture of saturated aqueous NaHCO 3 (300 ml) and ethyl acetate (100 ml) at 0-5 ° C by dropwise addition for 15 min. . The final pH was 6.9. Another portion of ethyl acetate (50 ml) is added and the pH is adjusted to 4.2 with H2SO4 (96% by weight). After phase separation the aqueous phase is extracted with ethyl acetate (1 x 150 ml3 x 100 ml). The combined organic phases are concentrated in vacuo at 40-50 ° C yielding 8.1 g of an orange solid. According to the quantitative 1 H NMR analysis this solid contains 4.2 g (0.026 mol) of the compounds a- (4) and ß- (4), corresponding to a total yield of 53% based on the ethyl ester of R-acid 3- (2,2-dimethy1- [1,3] dioxolan-4-yl) -acrylic acid. The relation a- (4): ß- (4) was 3.1: 1.
EXAMPLE 2B Use of DBU in the addition of Michael and no additional base in the Nef reaction The other 25 g of solution as obtained after the addition of Michael in example 2A are cooled to 0 ° C and quenched in a solution of H2SO (7.8 g, 96% by weight, 0.076 mol, 1.5 eq.) In methanol (13.2 g) at 0 ° C by dropwise addition over 40 min under vigorous stirring. The funnel is rinsed with methanol (7.7 g). The resulting reaction mixture is stirred for 4 h at 0 ° C and then worked up according to the procedure of Example 2A yielding a solid which, according to the quantitative 1 H NMR analysis, contains 2.8 g (0.0175 mol) of compound a- (4) and ß- (4), corresponding to a yield of 35% based on the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid .
EXAMPLE 2C Use of TMG in the addition of Michael and NaOMe as additional base in the Nef reaction To the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (47.5 g of oil, 84.2% by pure weight, 0.2 mol) is added nitromethane (26.0 g) of a solution of 51.7% by weight in methanol, 0.22 mol, 1.1 eq.) and the solution is cooled to 0 ° C. Subsequently, TMG (23 g, 0.2 mol, 1 eq.) Is added dropwise during 20 min and the funnel is rinsed with methanol (2 g). The reaction mixture is heated to 20 ° C and stirred at this temperature for 22 h. The solution is cooled to 0 ° C and NaOMe (40.2 g of a 29.6% by weight solution in methanol, 0.22 mol, 1.1 eq.) Is added dropwise for 15 min at 0 ° C and the funnel is rinsed with methanol (6.4 g). After stirring for a further 70 min at 0 ° C the mixture is quenched in a solution of H2SO4 (71.6 g, 96 wt.%, 0.7 mol, 3.5 eq.) In methanol (121.6 g) at 0-5 ° C. trickling for 70 min under vigorous stirring. The funnel is rinsed with methanol (2 x 15 g). The resulting reaction mixture is stirred for 145 min at 0 ° C and then quenched in a stirred mixture of saturated aqueous NaHCO 3 (1200 ml) and ethyl acetate (400 ml) at 0 ° C by dropwise addition over 30 min. The final pH was 7.4. After the addition of an additional portion (200 ml) of ethyl acetate the pH is adjusted to 4.2 with H2SO4 (96% by weight). After phase separation the aqueous phase is extracted with ethyl acetate (4 x 400 ml). The combined organic phases are concentrated in vacuo at 40-50 ° C yielding 38.5 g of a yellow-orange solid which, according to the quantitative 1 H NMR analysis, contains a- (4) (12.2 g, 0.077 mol) and ß- (4) (4.6 g, 0.029 mol) corresponding to a total yield of 53% based on the ethyl ester of R-3- (2,2-dimethyl-1- [1,3] dioxolan-4-il) ) -acrylic and a relation a- (4): ß- (4) of 2.7: 1.
EXAMPLE 2D Use of NaOMe only in the addition of Michael and in the Nef reaction To the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (47.5 g, 84.2% pure weight, 0.2 mol) in methanol (200 g) is added nitromethane (26.0 g of a 51.7% by weight solution in methanol, 0.22 mol, 1.1 eq.) and the solution is cooled to 0 ° C. NaOMe (40 g of a solution of 30% by weight in methanol, 0.22 mol, 1.1 eq.) Is added and the reaction mixture is stirred for 18 h at 0 ° C and then quenched in a solution of H2SO4 (58 g, 96% by weight, 0.57 mo, 2.9 eq.) In methanol (140 g) at -3-0 ° C by dropwise addition over 75 min under vigorous stirring. The reaction mixture is stirred for 4 h at 0 ° C and subsequently maintained for 16 h at -30 ° C. According to the quantitative 1 H NMR analysis the total yield (in the reaction mixture) of a- (4) and β- (4) based on the ethyl ester of the acid R-3- (2,2-dimethyl- [ 1, 3] dioxolan-4-yl) -acrylic is 45% and the ratio a- (4): ß- (4) 2.5: 1. The reaction mixture is subsequently quenched in a stirred solution of NaHCO 3 (80 g) in water (1 L) at 0-5 ° C by dropwise addition over 90 min. At the end of cooling a solution of NaHCO3 (4 g) in water (50 ml) is added to adjust the pH to 5-5.5. After phase separation, the aqueous solution is extracted with ethyl acetate (4 x 500 ml) and the combined organic phases are concentrated in vacuo at 30-40 ° C yielding 32 g of a red oil. According to the quantitative 1 H NMR analysis, this oil contains 13.2 g (0.084 mol) of a- (4) and ß- (4) corresponding to a total yield of 42% based on the ethyl ester of R-3 acid (2,2-dimethyl [1,3] dioxolan-4-yl) -acrylic with the relation a- (4): β- (4) being 3: 1.
EXAMPLE 3 Preparation of a- (4) from R-3- (2,2-dimethyl-1,3-dioxolan-4-yl) -acrylic acid ethyl ester using DBU in the addition of Michael, NaOMe as additional base in the reaction Nef and crystallization of a- (4) isopropanol EXAMPLE 3A Use of an unimproved processing procedure for a- (4) and ß- (4) To the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (42.3 g, 94.5% pure weight, 0.2 mol) is added nitromethane (26.0 g of a solution of 51.7% by weight in methanol, 0.22 mol, 1.1 eq.) and the solution is cooled to 0 ° C. Subsequently, DBU (30.4 g, 0.2 mo, 1 eq.) Is added dropwise during 20 min and the funnel is rinsed with methanol (4 g). The reaction mixture is heated to 20 ° C, stirred for another 16.5 h at this temperature and then cooled to 0 ° C. Then, NaOMe (40.4 g of a solution of 29.6% by weight in methanol, 0.22 mol, 1.1 eq.) Is added dropwise during 20 min at 0 ° C and the funnel is rinsed with methanol (6.4 g). The resulting solution is stirred for 50 min at 0 ° C and then quenched in a solution of H2SO4 (71.6 g, 96 wt.%, 0.7 mol, 3.5 eq.) In methanol (121.6 g) at 0-5 ° C. trickling for 70 min under vigorous stirring. The funnel is rinsed with methanol (2 x 16 g) and the reaction mixture is stirred for 2 h at 0-2 ° C and then quenched in a stirred mixture of saturated aqueous NaHC03 solution (1.2 L) and ethyl acetate ( 400 ml) at 0-9 ° C by dropwise addition for 17 min. The final pH was 7.2. The funnel is rinsed with methanol (40 ml) and the pH is adjusted to 4.0 with H2SO4 (96% by weight) at 9 ° C. After the addition of ethyl acetate (200 ml) and phase separation, the aqueous solution is extracted with ethyl acetate (600 ml, 3 x 400 ml). The combined organic phases are concentrated in vacuo at 40-50 ° C yielding 35.9 g of a yellow-orange semi-solid which, according to the quantitative 1 H NMR analysis, contains 16.5 g (0.104 mol) of a- ( 4) and ß- (4) corresponding to a total yield of 52% based on the ethyl ester of R-3- (2,2-dimethyl [1, 3] dioxolan-4-yl) -acrylic acid. The relation a- (4): ß- (4) was 3.0: 1. The crude semi-solid product is dissolved in isopropanol (69.5 g) at 80 ° C. The resulting solution is cooled to 60 ° C, further seeded and cooled to 0 ° C for 2 h which results in crystallization of a- (4). The solids are isolated by filtration, washed with isopropanol (30 ml, 20 ° C) and dried in the air to produce 12.0 g of whitish crystalline product which, according to quantitative 1 H NMR, consists of 9.8 g of a- ( 4) (31% yield based on the ethyl ester of R-3- (2,2-dimethyl- [1,3-dioxolan-4-yl) -acrylic acid) and 0.38 g of β- (4) (1.2% of yield based on the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid). This corresponds to a crystallization efficiency of 60% (output of a- (4) / [input of a- (4) + ß- (4)]) and a relation a- (4): ß- (4) of 26: 1.
EXAMPLE 3B Use of an improved processing procedure for a- (4) and ß- (4) To the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (47.5 g, 84.2% pure weight, 0.2 mol) is added nitromethane (26.0 g of a solution of 51.7% by weight in methanol, 0.22 mol, 1.1 eq.) and the solution is cooled to 0 ° C. DBU (30.4 g, 0.2 mol, 1 eq.) Is added dropwise for 30 min at 0-20 ° C and the funnel is rinsed with methanol (4 g). The reaction mixture is heated to 20 ° C, stirred for another 18 h at this temperature and then cooled to below 0 ° C. Subsequently, NaOMe (40 g of a solution of 29.6% by weight in methanol, 0.22 mol, 1.1 eq.) Is added dropwise during 20 min at 0 ° C and the resulting solution is stirred for 1 h at 0 ° C. The mixture is then quenched in a solution of H2SO4 (72 g, 96% by weight, 0.7 mol, 3.5 eq.) In methanol (72 g) at 0-5 cC by dropwise addition over 3 h under vigorous stirring. The reaction mixture is stirred for another 2 h at 0-5 ° C and then quenched in a stirred slurry of KHC03 (99 g) in water (200 ml) at 0-5 ° C by dropwise addition over 1 h. The final pH was 4.1. After heating to 20 ° C, the salts are removed by filtration and washed with ethyl acetate (500 ml). The aqueous mother liquor from the filtration (454 g) is concentrated in vacuo at 35 ° C to remove the methanol to a final weight of 272 g and extracted with ethyl acetate (6 x 150 ml.; first portions with the washing liquor of the salt filtration, then with fresh). The combined organic phases are concentrated in vacuo at 40-50 ° C yielding 40.4 g of a solid which, according to GC, confers 14.5 g of a- (4) and 3.4 g of β- (4) corresponding to a yield total of 57% based on the ethyl ester of R-3- (2,2-dimethyl [1, 3] dioxolan-4-yl) -acrylic acid and an a- (4): ß- (4) ratio of 4.3 :1. The crude solid product is dissolved in ethyl acetate (300 ml) and the solution is washed with a mixture of saturated aqueous NaCl solution (25 ml) and water (10 ml). The organic layer which, according to GC, contains 14.1 g of a- (4) and 3.4 g of β- (4), is concentrated in vacuo to 42.4 g of a cloudy solid. To 38 g of this crude product isopropanol (62 g) is added and the solid is dissolved by heating to 60 ° C. The resulting solution is cooled to 50 ° C, sowed, and further cooled to 0 ° C for 2 h which results in crystallization of a- (4). The solids are isolated by filtration, washed with isopropanol (2 x 20 ml, 0 ° C) and dried in the air yielding 12.9 g of whitish crystalline product which, according to GC, contains 12.2 g of a- (4). ). This corresponds to a yield of 39% based on the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid and a crystallization yield of 78% (exit from - (4) / [entry of a- (4) + ß- (4)]). The ß- (4) can not be detected.
EXAMPLE 4 Preparation of pure a- (4) from R-3- (2,2-dimethyl-1 [1,3] dioxolan-4-yl) -acrylic acid ethyl ester by crystallization from α- (4) , epimerization of ß- (4) and second crystallization of a- (4) To the ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (42.3 g, 94.6% pure weight, 0.2 mol) is added nitromethane (26.0 g of a solution of 51.7% by weight in methanol, 0.22 mol, 1.1 eq.) and the solution is cooled to 0 ° C. Subsequently, DBU (30.4 g, 0.2 mol, 1 eq.) Is added dropwise for 30 min at 0-20 ° C and the reaction mixture is warmed to 20 ° C and stirred for another 18 h at this temperature. The resulting reaction mixture is cooled to 0 ° C and NaOMe (40.4 g of a solution of 29.6% by weight in methanol, 0.22 mol, 1.1 eq.) Is added dropwise at 0 ° C. The resulting solution is stirred for 1 h at 0 ° C and quenched in a solution of H2SO4 (72 g, 96% by weight, 0.7 mol, 3.5 eq.) In methanol (72 g) at 0-5 ° C by addition by drip for 1 1/2 h under vigorous stirring. The reaction mixture is stirred for 2 h at 0-5 ° C and then quenched in a stirred slurry of NaHCO 3 (100 g), water (400 ml) and ethyl acetate (300 ml) at 0-5 ° C by addition by drip for 1 h. NaHCO3 (40 g) is added dropwise to maintain the pH above 3.5. The salts are removed by filtration at 0-5 ° C and washed with ethyl acetate (300 ml). After phase separation the aqueous phase is extracted with ethyl acetate (300 ml of wash liquor, 3 x 150 ml). The combined organic phases are concentrated in vacuo, ethyl acetate (200 ml) is added and the mixture is concentrated in vacuo once more yielding 33.2 g of a semi-solid which, according to the quantitative 1 H NMR analysis, contains 13.5 g. of a- (4) and 4.0 g of ß- (4) corresponding to a total yield based on the ethyl ester of R-3- (2,2-dimethyl [1, 3] dioxolan-4-yl) -acrylic acid of 53% and a relation a- (4): ß- (4) of 3.5: 1. The crude product is dissolved in isopropanol (70 g) at 60 ° C. The resulting solution is cooled to 50 ° C, further seeded and cooled to 0 ° C resulting in crystallization of a- (4) which is isolated by filtration, washed with cold isopropanol (0 ° C) (2 x 15 ml ) and dries in the air. This produces 12.3 g of a- (4) which according to the 1 H NMR quantitafive analysis is 97.1% by pure weight and does not contain β- (4). This corresponds to a yield (first crop) of 38% based on the ethyl ester of R-3- (2,2-dimethyl- [1,3] dioxolan-4-yl) -acrylic acid) and a crystallization yield of 68% (output from a- (4) / [input from a- (4) + ß- (4)]). The combined mother liquors and wash liquors of the first crystallization (108 g, containing 4.0 g of β- (4) and 1.2 g of a- (4)) are concentrated in vacuo to 17.9 g of a liquid. Subsequently, methanol (9.05 g) and MeSOsH (0.91 g, 0.29 eq.) Are added and the mixture is heated to reflux. After 2 h of reflux, the epimerization reaction is complete (ratio a- (4): ß- (4) > 3). After cooling to 20 ° C, triethyl amine (0.96 g, 1 eq. Based on MeSO3H) is added and the mixture is concentrated in vacuo to 18.7 g of a viscous residue. The residue is redissolved in isopropanol (13.9 g) at 50 ° C.
After cooling to 45 ° C the mixture is seeded and cooled to below 0 ° C resulting in crystallization of a- (4) which is isolated by filtration, washed with cold isopropanol (0 ° C) (2 x 6 ml ) and dries in the air. This produces 2.24 g of a- (4) which, according to the quantitative 1 H NMR analysis, is 95.3% by pure weight and does not contain β- (4). This corresponds to a yield (second crop) of 6% based on the ethyl ester of R-3- (2,2-dimethyl [1, 3] dioxolan-4-yl acid and a crystallization yield of 43% (exit from a- (4) / [entry of a- (4) + ß- (4)] after the epimerization.) Therefore, the yield of a- (4) total (harvest 1 and 2) based on the ethyl ester of R-3- (2,2-dimethyI- [1, 3] dioxolan-4-yl) -acrylic acid is 44%.
EXAMPLE 5 Crystallization of a- (4) starting from crude mixtures of a- (4) and β- (4) of different solvents of isopropanol EXAMPLE 5A From tert-butanol A mixture cmda (6.5 g) of a- (4) and ß- (4) as obtained in example 2A (containing 3.37 g of a- (4) + ß- (4) in a ratio of 3.1: 1 ) is dissolved in tert-butanol (16 g) at 72 ° C. Cooling to 55 ° C, seeding and further cooling to 25 ° C results in the crystallization of a- (4) which is isolated by filtration, washed with isopropanol (5 ml, 20 ° C) and dried in vacuo.
This produces a- (4) (1.85 g) which, according to the quantitative 1 H NMR analysis, consists of 82.9% by pure weight of a- (4) corresponding to a crystallization yield of 46% [(output from a- (4) + ß- (4)] / [entry of a- (4) + ß- (4)]) with a relation a- (4): ß- (4) of 30: 1.
EXAMPLE 5B From tere-amyl alcohol A crude mixture (7.25 g) of a- (4) and ß- (4) (containing 3.44 g of a- (4) + ß- (4) in a ratio of 2.9: 1) is dissolved in tererate alcohol. amyl (15, .7 g) at 70 ° C. Cooling to 60 ° C, seeding and further cooling to 40 ° C results in crystallization. After sowing once more at 40 ° C the solution is further cooled and the crystallization of a- (4) starts at 27 ° C. The mixture is further cooled to below 2 ° C and the crystals of a- (4) are isolated by filtration, washed with tere-amyl alcohol (7.5 ml, 20 ° C) and dried in vacuo. This produces 2.35 g of a whitish product which, according to the quantitative 1 H NMR analysis, consists of 1.91 g of a- (4) and 0.11 g of ß- (4) corresponding to a crystallization yield of 59% [ (output of a- (4) + ß- (4)] / [entry of a- (4) + ß- (4)]) ratio of 18: 1.
EXAMPLE 6 Crystallization of pure a- (4) from a mixture of α- (4) and β- (4) with simultaneous epimerization of β- (4) A solution of a- (4) light coffee (5.0 g, 96.6% pure weight, 30.6 mmol, which does not contain ß- (4)) and MeS03H (0.3 g, 0.1 eq) in methanol (200 ml) is stirred at 20 ° C for 92 h resulting in epimerization at a ratio a- (4): ß- (4) of 3.6: 1. The reaction mixture is subsequently concentrated in vacuo (20 mbar, 45 ° C) to yield 5.2 g of a sticky solid. This is recovered in methanol (50 ml) and concentrated once more in vacuo (20 mbar, 50 ° C) to yield 5.1 g of a dry light brown solid which, according to the quantitative 1 H NMR analysis, contains - (4) with 90% by weight purity (4.6 g, 29 mmol). No ß- (4) is detected. Therefore, almost all (96%) of the initial (4) has been recovered.
EXAMPLE 7 Preparation of pure a- (4) from freshly prepared S-2,3-O-isopropylidene-glyceraldehyde using an improved process and crystallization of α- (4), epimerization of β- (4) and a second crystallization from a- (4) To 175 g of ER-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid ethyl ester as prepared in Example 1 (78% by pure weight, 136.5 g, 0.68 mol) is added nitromethane (88.6 g of a solution of 51.7% by weight in methanol, 0.75 mol, 1.1 eq.) and the solution is cooled to 0 ° C. Subsequently, DBU (103.4 g, 0.68 mol, 1 eq.) Is added dropwise during 35 min at 10-21 ° C and the funnel is rinsed with methanol (7 g). After stirring for 18 h at 20 ° C the resulting dark red solution is cooled to 0 ° C and NaOMe (134.6 g of a 30% by weight solution in methanol, 0.748 mol, 1.1 eq.) Is added dropwise over the course of the reaction. min at 0 ° C and the funnel is rinsed with methanol (10 g). After stirring for 30 min at 0 ° C, the reaction mixture is quenched in a solution of H2SO4 (243 g, 96% by weight, 2.38 mol, 3.5 eq.) In methanol (243 g) at 0-5 ° C. add by dripping for 3 h under vigorous stirring and the funnel is rinsed with methanol (2 x 15 g). After stirring for 2 h at 0-2 ° C the reaction mixture is quenched in a stirred slurry of KHCO3 (353 g) in water (680 ml) at 0-6 ° C by dropwise addition over 1 h. The pH was 7 at the end of cooling and is adjusted to 4.1 with H2SO4 (96% by weight) at 0 ° C. After heating to 20 ° C the salts are removed by filtration and washed with ethyl acetate (3 x 375 ml). The wash liquor is used later in the extractions. The mother liquor of filtration (1380 g), according to CG, contains 3.08% by weight of a- (4) and 0.82% by weight of ß- (4) (corresponding to a total yield of 50% based on the ethyl ester of ER-3- acid (2). , 2-dimethyl [1, 3] dioxolan-4-yl) -acrylic and an a- (4): ß- (4) ratio of 3.75: 1) is concentrated in vacuo to remove the methanol. To the resulting residue (760 g) water (80 g) is added and the pH is adjusted to 4.1 with H2SO4 (96% by weight). The resulting aqueous solution is extracted with ethyl acetate (700 ml, 4 x 500 ml). The combined organic phases are concentrated in vacuo at 35-40 ° C to 181 g of a residue. The volatiles are coevaporated 3x with iopropanol (2 x 140 g and 90 g) yielding a residue (146 g) consisting of a crude mixture of a- (4) and ß- (4). The crude mixture (146 g) is dissolved in isopropanol (202 g) at 70 ° C. The insoluble material is removed by filtration and washed with isopropanol (5 ml); the weight after drying is 0.33 g. The filtrate (346 g) is cooled to 50 ° C resulting in spontaneous crystallization of a- (4). The slurry is then cooled to 1 ° C for 4 h and the crystals are isolated by filtration, washed with sodium propane (2 x 100 ml, 0 ° C) and dried in vacuo for 17 h at 35 ° C to provide a crystalline product. discolored (44.2 g). According to quantitative CG it consists of 89.0% by weight a- (4) and 1.0% by weight ß- (4) which corresponds to a total yield of 37% based on ethyl ester of ER-3- acid (2,2- dimethyl- [1, 3] dioxolan-4-yl) -acrylic and an a- (4): ß- (4) ratio of 89: 1. The mother liquor and the washing liquors of the first crystallization of a- (4) (totally 374 g) are concentrated in vacuo to 90.8 g, methanol (1.20 ml) is added and the resulting mixture is concentrated to 83 g. Methanol (120 ml) is added once and the mixture is concentrated to 83 g. To the residue is added methanol (45 g) and MeS03H (2.66 g, 0.0277 mol, 0.2 eq. Based on a- (4) + ß- (4) total present in the mother liquor and washing liquors) and the solution is maintained at reflux. After 1 h at reflux (60-65 ° C) the GC indicates that the epimerization is complete (the ratio a- (4): ß- (4) is 3.1: 1) and the solution is cooled to 33 ° C, neutralize with triethyl amine (2.94 g, 1.05 eq based on MeS03H) and concentrate in vacuo. To the resulting residue isopropanol (120 ml) is added and the mixture is concentrated in vacuo to yield 88 g of a residue. The residue is dissolved in isopropanol (37 g) at 47 ° C. The resulting solution is cooled below 2 ° C for 2.5 h; the crystallization starts spontaneously at 30 ° C. The crystalline product is isolated by filtration, washed with isopropanol (3 x 20 ml, 0 ° C) and dried in vacuo (17 h at 35 ° C) to yield 10.1 g of a white crystalline product which according to CG consists of of 96.4% by weight a- (4) and 0.065% by weight ß- (4), corresponding to a total yield based on ethyl ester of ER-3- (2,2-dimethyl- [1, 3] dioxolan- 4-il) -acrylic of 9% and a ratio of a- (4): ß- (4) of > 1000: 1 Accordingly, the total yield of the first and second culture of ethyl ester of a- (4) acid based on E-R-3- (2,2-dimethyl- [1,3-dioxolan-4-yl) -acrylic is 46%.
EXAMPLE 8 Preparation of pure (3R, 3aS, 6aR) hexahydro-furo-r2,3-b1furan-3-ol of intermediate a- (4) The procedure described in WO03 / 022853, Example IV, last stage.
EXAMPLE 9 Preparation of pure a- (4) of ethyl ester of R-3- (2,2-dimethyl- [1,31-dioxolan-4-yl.] Acrylic acid by direct crystallization of a- (4) of a mixture crude of ß- (4) and a- (4) and simultaneous epimerization of ß- (4) to a- (4) To ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid (399.5 g, 75.1% by pure weight, 1.5 mol) is added nitromethane (915.0 g of a solution in methanol at 11% by weight, 1.65 mol, 1.1 eq.) and the solution is cooled to 0 ° C. Subsequently, DBU (233.3 g, 1.5 mol, 1 eq.) Is added dropwise during 50 min. at 0-5 ° C and the reaction mixture is maintained at 20 ° C and stirred for another 16 h at this temperature. The resulting reaction mixture is cooled to 0 ° C and NaOMe (594.0 g of a 15% by weight solution in methanol, 1.65 mol, 1.1 eq.) Is added dropwise over 50 min. at 0 ° C. The resulting solution is stirred for 1 h at 0 ° C and quenched in a solution of H2SO4 (368 g, 96% by weight, 3.6 mol, 2.4 eq.) In methanol (370 g) at 0-5 ° C by addition by Drip for 3 h under vigorous shaking. The reaction mixture is stirred for 2 h at 0-5 ° C and then quenched in a stirred slurry of KHC03 (457.6 g), in water (870 ml) at 0-5 ° C by dropwise addition over 1 h. KHCO3 is added in portions to keep the pH above 3.5. The formed salts are removed by filtration at 0-5 ° C and washed with methanol (530 ml). After concentration in vacuo of the combined filtrate and washing to approximately 1000 ml the aqueous phase is extracted with toluene (2 x 2100 ml, 3 x 1050 ml). The combined organic phases are concentrated in vacuo, providing 202.9 g of a semi-solid. Subsequently, methanol (42.6 g) and MeS03H (6.06 g, 0.04 eq.) Are added and the mixture is heated to 50 ° C. After 2 h of stirring at this temperature the mixture is cooled to 20 ° C and the stirring is continued for an additional 12 h. After cooling to -5 ° C, triethylamine (6.60 g, 1.1 eq. Based on MeS03H) is added and the mixture is stirred for another 2 h. The a- (4) crystalline which is isolated by filtration, washed with cold isopropanol (-5 ° C) (3 x 70 ml) and dried in air. This produces 120.0 g of a- (4) which, according to the quantitative CG analysis, is 99.0% by pure weight and contains 0.09% area of ß- (4). This corresponds to a yield of 51% based on ethyl ester of R-3- (2,2-dimethyl- [1, 3] dioxolan-4-yl) -acrylic acid.

Claims (27)

  1. NOVELTY OF THE INVENTION CLAIMS 1. - A method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) the method comprises the use of intermediates of the formula (4). (4) 2.- A method for the synthesis of (3R, 3aS, 6aR) hexahydro-furo [2,3-b] furan-3-ol having the structure of the formula (6), (6) the method comprises the use of the intermediate of the formula a- (4). a- (4) 3. - The method according to claim 1, further characterized in that the method comprises the steps of: a) treating the compound of the formula (3) with a base and subsequently with an acid in the presence of methanol; (3) where; P1 and P2 are each independently a hydrogen, a hydroxy protecting group or together can form a vicinal-diol protecting group; R1 is alkyl, aryl or aralkyl; resulting in intermediaries of the formula (4); Y (4) b) reducing the intermediates of the formula (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain the compound of the formula (6). (6) 4. The method according to any of claims 1 to 3, further characterized in that the method further comprises crystallizing the intermediate of the formula a- (4) with a solvent prior to the reduction thereof. 5. The method according to any of claims 1 to 4, further characterized in that the method further comprises a) the acid epimerization of the intermediate of the formula ß- (4) in the intermediate of the formula a- (4); Y β- (4) a- (4) b) the crystallization of the intermediates of the formula a- (4) with a solvent prior to the reduction thereof. 6. The method according to claim 4, further characterized in that the method additionally comprises after crystallizing the intermediate of the formula a- (4), a) the epimerization with acid of the intermediate of the formula β- (4) in the mother liquor of the crystallization in the intermediate of the formula a- (4); Y ß- (4) a- (4) b) the crystallization of the intermediate of the formula a- (4) with a solvent prior to the reduction thereof. 7. - The method according to any of claims 5 to 6, further characterized in that the epimerization of the compound of the formula β- (4) to the compound of the formula a- (4) and the crystallization of the compound of the formula a- ( 4) occur simultaneously. 8. The method according to claim 7, further characterized by the simultaneous epimerization of the compound of the formula β- (4) to the compound of the formula a- (4) and the crystallization of the compound of the formula a- (4) ) are carried out in methanol in the presence of an acid by evaporation or partial evaporation of methanol. 9. The method according to claim 1, further characterized in that the method comprises the steps of: a) treating the compound of the formula (3) with a base and then with an acid in the presence of a non-methanolic solvent; and subsequently reacting it with methanol under acidic conditions; (3) wherein P1 and P2 are each independently a hydrogen, a hydroxy protecting group or together can form a vicinal-diol protecting group; R1 is alkyl, aryl or aralkyl; resulting in intermediaries of the formula (4); and (4) b) reducing the intermediate of formula (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain the compound of the formula (6). (6) 10. - The method according to any of claims 3 and 9, further characterized in that the compounds of the formula (3) are obtained by reacting the compounds of the formula (2) with nitromethane and a base. 11. - The method according to claim 10, further characterized in that the compounds of the formula (2) are obtained by condensing an intermediate of the formula (I) or its hydrate, hemihydrate or a mixing thereof with phosphonates of the formula (R60) 2P (= 0) -CH2-C (= 0) OR1; wherein P1 and P2 are as defined in claim 2; R1 is as defined in claim 2; R6 is alkyl, aryl or aralkyl, (i) 12.- The method of compliance with any of the claims 3, 9, 10, and 11, further characterized in that P1 and P2 together form a dialkyl methylene radical. 13. - The method according to claim 10, further characterized because the base used for the conversion of the compounds of the formula (2) in compounds of the formula (3) is DBU or TMG or derivatives thereof. 14. The method according to claim 11, further characterized in that the phosphonate of the formula (R60) 2P (= 0) -CH2-C (= 0) OR1 is triethyl phosphonoacetate (TEPA). 15.- The method of compliance with any of the claims 3 and 9, further characterized in that the conversion of the compounds of the formula (3) to compounds of the formula (4) is carried out with a base selected from the group of sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof. 16. The method according to any of claims 10 and 13, further characterized in that the conversion of the compounds of the formula (2) in compounds of the formula (4) is carried out using DBU or TMG as the base in the conversion of compounds of the formula (2) to compounds of the formula (3), the compounds of the formula (3) and sodium or lithium method is used as additional base in the conversion of compounds of the formula (3) to compounds of the formula (4). 17. The method according to any of claims 3, 9, 15 and 16, further characterized in that the acid used in the conversion of the compounds of the formula (3) into compounds of the formula (4) is concentrated sulfuric acid in an amount of 2.5 to 5 equivalents based on the compound of the formula (2) as a methanol solution of 20 to 80% by weight. 18. The method according to any of claims 4 to 8, further characterized in that the crystallization of the compound of the formula a- (4) is carried out in an alcohol. 19. The method according to claim 8, further characterized in that the alcohol is isopropanol, t-amyl alcohol or t-butanol. 20. A method for the conversion of a compound of the formula β- (4) into the compound of the formula a- (4), characterized in that it comprises an epimerization with acid β- (4) a- (4) 21. The method according to any of claims 5 to 8 and 20, further characterized in that the epimerization of the compound of the formula β- (4) in the compound of the formula a - (4) is carried out with 0.05 to 1.5 equivalents of MeS03H in methanol. 22. - The method of compliance with any of the claims 5 to 8 and 20 to 21, further characterized in that the epimerization is carried out at a temperature between 40 ° C and reflux temperature. 23. An intermediary that has the formula a- (4). 24.- An intermediary that has the formula ß- (4). 25. - An intermediate with formula a- (4) that is in crystalline form. 26. - An intermediary having the formula (5) OH HO ^ O OMe (5) 27. Use of the compound of the formula (6) obtained by the methods according to any one of claims 1 to 18 in the preparation of (3R, 3aS, 6aR) -hexahydrofuro-2,3-b] furan-3-yl acid ester [(1S, 2R) -3 - [[(4-aminophenyl) sulfonyl] (2-methylpropyl) amino] -2-hydroxy-1- (phenylmethyl) propyl] -carbamic (6)
MXPA/A/2006/011281A 2004-03-31 2006-09-29 METHODS FOR THE PREPARATION OF (3R,3aS,6aR) HEXAHYDRO-FURO[2,3-b]FURAN-3-OL MXPA06011281A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP04101336.8 2004-03-31

Publications (1)

Publication Number Publication Date
MXPA06011281A true MXPA06011281A (en) 2007-04-20

Family

ID=

Similar Documents

Publication Publication Date Title
NO338175B1 (en) Process for Preparation of (3R, 3aS, 6aR) -hexahydro-furo [2,3-b] furan-3-ol
EP2200992B1 (en) Intermediates and methods for the synthesis of halichondrin b analogs
KR100894673B1 (en) Method for the preparation of hexahydro-furo[2,3-B]furan-2-ol
RU2464266C2 (en) METHODS OF PRODUCING HEXAHYDROFURO[2, 3-b] FURAN-3-OL
WO2009030733A1 (en) Method for the synthesis of 4-alkoxy-, 4-hydroxy- and 4-aryloxy-substituted tetrahydro-furo[3,4-b]furan-2(3h)-one compounds
MXPA06011281A (en) METHODS FOR THE PREPARATION OF (3R,3aS,6aR) HEXAHYDRO-FURO[2,3-b]FURAN-3-OL
DK2643326T3 (en) A process for the preparation of (3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-ol