GB1579464A

GB1579464A - Processes for the preparation of lactonediol derivatives

Info

Publication number: GB1579464A
Application number: GB2232577A
Authority: GB
Original assignee: Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
Current assignee: Chinoin Private Co Ltd
Priority date: 1977-05-26
Filing date: 1977-05-26
Publication date: 1980-11-19
Also published as: SE431750B; SE7706083L; JPS545965A; CA1131238A

Description

(54) PROCESSES FOR THE PREPARATION OF LACTONE DIOL DERIVATIVES (71) We, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT., a body corporate organised under the laws of Hungary of 1-5 To-utca, Budapest IV., Hungary, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: The present invention relates to processes for the preparation of certain racemic and optically active lactone diol derivatives.

There are a number of known methods for the total synthesis of various prostaglandin analogues. Of the known synthetic methods, that elaborated by E.J. Corey et al. is of particular interest since it solves inter alia certain stereochemical problems [J. Amer. Chem.

Soc., 91, 5675 [1969], ibid: 92, 397 [1970], ibid: 93, 1490 [1961]]. This method is also of importance with regard to industrial production. The product of the Corey syntheses is PGF2a, which can be easily converted into other pharmaceutically important natural prostaglandins, for example, PGE1, PGE2, PGE1a, and PGE,ss. The key intermediate of the synthesis is the "Corey aldehyde" of formula I as hereinafter depicted (wherein R1 represents a phenyl-benzoyl orp-phenylphenylcarbamoyl group) in which the four asymmetric carbon atoms have the same absolute and relative configurations as those of PGF2c, and which contain both free and masked carbonyl functions serving for the preparation of the sidechains during the reaction, and thep-phenylbenzoyl orp-phenylphenylcarbamoyl hydroxylprotecting groups, which control the stereoselective reduction of the C1s-keto group. J.

Amer. Chem. Soc. 94, 8616 [1972]]. According to the synthesis, the "Corey aldehyde" and the other acyloxy lactone aldehydes of formula I

are prepared by oxidising acyloxy-lactones of formula II as hereinafter defined wherein R represents an acyl group. The preparation of the compounds of formula II in this way, however, is extremely complicated, owing to the large number of reaction steps, and to the fact that the reagents are expensive and difficult to obtain.

Other known synthetic methods for the preparation of the compounds of formula I and II and of compounds having similar fields of application fail to overcome similar difficulties (See for example J. Amer. Soc., 95, 6853 [19731, J.C.S. Perkin I. 2796 [1973]).

The present invention is based on the discovery that the compounds of formula II may be prepared by selective acylation of the racemic or optically active lactone diol of formula III |(-)-III or ( +)-III]. Moreover the lactone diol of formula III is a convenient starting material, since it is readily available, especially when prepared according to the cheap four-step synthesis disclosed in Hungarian Patent No. 173,711 using cyclopentadiene as starting substance.

According to the present invention there is provided a process for the preparation of a compound of the formula:

[wherein R' represents a group selected from:- R3- CH2 - CR4- OR5, - Si R6R7R8, R9CO - or R1-NH-CO (in which R, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group or R3 and R5 together represent an alkylene chain and R4 represents a hydrogen atom or an alkyl group; R6, R7 and R8, which may be the same or different, each represents an alkyl group; R represents an alkyl, aryl substituted aryl or aralkyl group; and R'O represents an alkyl, aryl or substituted aryl group)] in racemic or optically active form. which process comprises protecting the primary hydroxy group of a racemic or optically active compound of the formula:

by reaction of the said compound of formula III with a compound of the formula:

(wherein R3, R4, R5, R6, R7, R8, R9 and Rl are as herein defined, X1 represents a chlorine, bromine or iodine atom, x2 represents a chlorine, bromine or iodine atom or a dialkylamino group, X3 represents a chlorine or iodine atom and R l l represents a benzyl or trichloroethyl group) to form a compound of the formula:

[wherein R2, represents the group: R3 - CH2 -CR-OR5, - SiR6R7R8, R9 - CO -, R10-NH-CO-, benzyl, benzyloxycarbonyl or triethoxycarbonyl (in which R3, R4, R5, R6, R7, R8, R9 and Rl are as herein defined)], reacting the said compound of formula V with a compound of formula VII, VIII, IX or X (as herein defined) to form a compound of the formula:

(wherein R' represents a R9-CO- or R"'-NH-CO- group when R represents a R3-CH2 CR4-oR5 or -SiR6R7R8 group or R represents a R3-CH2-CR -OR or -SiR6R7R8 group when R2 represents a R9-CO-group or R' represents a R9-CO-, R3-CH2-CR4-OR5 or -SiR6R7R8 group when R2 represents a benzyl benzyloxycarbonyl or trichloroethoxy- carbonyl group, R3, R4, R5, R6. R7, R8, R9 and R 0being as herein defined) and deprotecting the protected primary hydroxy group of the said compound of formula XVI to form a racemic or optically active compound of formula II as herein defined.

Thus in one embodiment of the present invention there is provided a process for the preparation of compounds of formula II wherein Rl represents a R9-CO- or R'QNH-CO- group (in which R9 an R10 are as hereinbefore defined), wherein a racemic or optically active comnound of formula III

is reacted with a compound of formula VII

(wherein R3, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group or R3 and R5 together represent an alkylene chain and R4 represents a hydrogen atom or an alkyl group) or with a compound of the formula:

(wherein R6, R7, R8 and X2 are as hereinbefore defined) to form a compound of formula V as hereinbefore defined) in which R2 represents a R3-CH2-CR4-oR5 or -SiR6R7R8 group, R3, R4, R5, R6, R7 and R8 being as hereinbefore defined) which compound of formula V is reacted with a compound of the formula:

(wherein R9 and X3 are as hereinbefore defined) or with a compound of the formula: R'O-N=C=O X (wherein R "' is as hereinbefore defined) to form a compound of formula XIV as defined in claim 1 (wherein R' represents a R9-CO- or R'O-NH-CO-group and R2 represents a CH2-CR4-oR5 or -SiR R7R8 group in which R6, R7, RS, R9 and Rt are as hereinbefore defined the protected primary hydroxy group of which compond of formula XIV is deprotected by acid hydrolysis to form a racemic or optically active compound of formula II (wherein R' represents a R9-CO- or R"'-NH-CO-group as herein defined).

A compound of formula IX is preferably used in which R9 represents ap-phenylphenyl, phenyl or methyl group. Where a compound of formula X is used R "' preferably represents a p-phenylphenyl or phenyl group.

The deprotection is preferably effected in the presence of acetic acid at a temperature not exceeding 50 C.

In a further embodiment of the present invention there is provided a process for the preparation of compounds of formula II wherein R' represents a R3-CH2-CH4-oR5 or -SiR6R7R8 group (in which R3. R4 RS, R6, R7 and R8 are as hereinbefore defined) wherein a racemic or optically active compound of formula III as hereinbefore defined is reacted with a compound of formula IX as hereinbefore defined to form a compound of formula V as herebefore defined (in which R7 represents the group R9-CO- wherein R9 is as hereinbefore defined) which compound of formula V is reacted with a compound of formula VII as hereinbefore defined or with a compound of formula VIII as hereinbefore defined to form a compound of formula XIV as hereinbefore defined (wherein R' represents a R3-CH2-(hR4 ORf or -SiR6R7R8 group and R2 represents a R9-CO- group in which R3, R4. R5, R6, R7, R8 and R9 are as hereinbefore defined) and the protected primary hydroxy group of the said compound of formula XIV is deprotected by alkaline solvolysis to form a racemic or optically active compound of formula II (where;. R represents a R3-CH2-CR4-oR5 or -SiR6R7R group as hereinbefore defined).

In this further embodiment of the present invention a compound of formula IX is preferably used in which R9 represents an alkyl or aryl group e.g. a phenyl or methyl group. Where a compound of formula VII is used it is preferable to use a compound i) in which R3 represents a hydrogen atom or an alkyl group and R4 and R5 each represents an alkyl group; or a hydrogen atom and R5 represents an ethyl group.

The dcprotection of the protected primary hydroxy group is advantageously effected by solvolysis in the presence of an alkanol with l to 6 carbon atoms and a base e.g. potassium carbonate.

In a still further embodiment of the present invention there is a process for the preparation of compounds of formula II wherein R' represents a R9-CO-, R3-CH2-CR4-oR5 or -SiRR'R' group (in which R3. R4, R5. R6, R7 R8 and R9 are as hereinbefore defined) wherein a compound of formula III as hereinbefore defined is reacted with a compound of formula Xl or XII as hereinbefore defined to form a compound of formula V as hereinbefore defined (in which R2 represents a benzyl. benzyloxycarbonyl or trichloroethoxycarbonyl group) which compound of formula V is reacted with a compound of formula VII, VIII or IX as hereinbefore defined to form a compound of formula XIV as hereinbefore defined (in which R' represents a R9-CO-, R3-CH2-CR4-oR5 or -SiR6R7R8 group and R2 represents a beuzyl, benzyloxycarbonyl or trichloroethoxycarbonyl group; R3, R4, R5, R6, R7, Rs and R9 being as hereinbefore defined), the protected primary hydroxy group of which compound of formula XIV is deprotected by catalytic hydrogenation or with nascent hydrogen to form a racemic or opticallya ctive compound of formula formula II wherein R1 represents a R9-CO-, R3-CH2-CR -OR3 or -SiR6R7R8, group as hereinbefore defined.

In this still further embodiment a compound of formula XII is preferably used in which X' represents a chlorine atom. Where a compound of formula IX is used R9 preferably represents a phenylphenyl or phenyl group. Where a compound of formula VII is used it is preferably dihydropyran. Where a compound of formula VIII is used R6, R7 and R8, which may be the same or different preferably each represent an alkyl group with 1 to 6 carbon atoms.

The deprotection step in this still further embodiment is preferably effected by the use of nascent hydrogen, produced by the reaction of zinc with an acid, in the presence of a palladium catalyst under a pressure of about 3 atmospheres guage.

Among the intermediates prepared in the process according to the present invention 3,3xx ,4,5,6,6a - hexahydro-2-oxo- 4p- trityloxymethyl-5lx- hydroxy-2H- cyclopenta [b] furan are novel compounds.

Certain compounds of formula II, for example, the compound in which R l is acetyl, can be prepared by partial deacetylation of the lactone diol diacetate of formula IV

wherein R' and R2 each represent an acetyl group. This method, however, cannot be extended to the preparation of compounds of formula II in general, since the acyl-migration taking place during the reaction has unfavourable consequences. It has been found that the primary hydroxyl of the racemic or optically active lactone diol of formula III can be subjected to a selective blocking reaction using various suitable reagents, and then the compound of formula V, initially obtained, in which R2 is a blocking group, can be protected on its free hydroxyl by any kind of acyl, for example a p-phenylbenzoyl, p-phenylphenylcarbamoyl or hydrocarbyl, for example tetrahydropyranyl, group. Finally the blocking group of the primary hydroxyl is removed without attacking the ether or ester bond on the secondary hydroxyl.

A method for the selective treatment of the primary and secondary hydroxyl group of the compound of formula III is already a known method [J. Amer. Chem. Soc. 93,1491/1971].

A foot-note indicates, without any experimental details, the following procedure: The primary hydroxyl of the lactone diol of formula (-)-III is subjected to a selective trichloroacetylating reaction, the secondary hydroxyl of the hydroxy-lactone trichloroacetate of formula V obtained, wherein R2 is trichloroacetyl, is subsequently protected by a tetrahydropyranyl group, and the compound of formula IV obtained, (in which Rl is tetrahydropyranyl and R2 is trichloroacetyl) is subjected to a saponification reaction. Thus tetrahydropyranyloxy-lactone- alcohol is obtained of formula II, in which R' represents a tetrahydropyranyl group.

The selective blocking of the primary hydroxyl in the lactone diol is an important reaction step in our synthesis. Blocking can be achieved by various reactions, for example by acylation, alkylation or silylation. The regioselectivity of the above reactions, however, is a function of the acylating, alkylating and silylating agents applied and of the reaction conditions. Generally the reaction also results in the production of secondary mono-acyl, mono-alkyl or mono-silyl side-products. which may, however, be separated from the corresponding primary main-product by column chromatography. The acylating reaction carried out by trichloroacetyl chloride however did not prove to be regioselective, the desired primary monoacyl product was, however, easy to isolate by column chromatography in all of the abovementioned cases.

Results obtained when etherifying the compound of the structural formula III were very similar. Thus, for example reacting the above compound with 1 mole equivalent of benzyl.

chloride resulted in the production of a mono-primary benzyl ether of formula V (wherein R2 is benzyl) as a main product, together with a mono-secondary-benzyl ether of formula II (wherein Rl represents benzyl) and a small amount of the dibenzyl ether of formula IV, wherein R' and R2 each represent benzyl.

The case is similar when silylating the compound of formula III with 1 mole equivalent of trimethyl chloride silane in the presence of a base. Neither at 0 C nor at room temperature could we achieve a 100% selectivity in a pyridine- dichloromethane solvent mixture and at 30-40% completion of the reaction both mono-silyl ethers and the di-silyl ether were detected.

We have surprisingly found that with certain reagents under certain reaction conditions near 100% regioselectivity can be achieved for the blocking reaction of the primaryhydroxyl group of the compound of formula III. Thus, for example, silylating the racemic or optically active compound of formula III with 1.0 to 1.1 mole equivalents of trimethylsilyldiethylamine [Acta Chem. Aca. Sci. Hung., 58, 189 [1968]lin acetonitrile at OOC, the reaction proceeds smoothly in some minutes, resulting in the production of a mono-primarysilyl ether of formula V (in which R2 represents a trimethyl-silyl group), together with traces of the secondary silyl ether, which can be detected only chromatographically.

It should be noted that using 2 to 2.5 equivalents of the above reagent the di-silyl ether can also be produced in 30 to 45 minutes.

Among the alkylating agents triphenyl-methyl chloride was found to be capable of producing a similar regioselective reaction. When carrying out the tritylating reaction in pyridine, at room temperature, the crystalline mono-primarytrityl ether of the structural formula V, in which R2 is trityl, is obtained practically quantitatively.

The free secondary hydroxyl of the compounds of formula V can be subjected to acylation or alkylation. The compounds of formula V preferably used in prostaglandin synthesis can be acylated in a manner knownperse usingp-phenylbenzoyl chloride orp-phenylisocyanate as acylting agent, but also the tetrahydropyranyl ether of these compounds can also be prepared employing 3,4-2H-dihydropyran. Thus products of the structural formula IV are obtained, in which R' and R2 represent different acyl. alkyl or silyl groups.

In the last step of our synthesis the primary hydroxyl is deblocked by methods known per se. Care must be taken, however, that the reagents applied should not attack on the ester or other bond on the secondary hydroxyl. Tri-methylsilyl and trityl are easily removable by hydrolysis effected under mild acid conditions. with heating. This last reation step also can be carried out simultaneously with the separation step following the acylation of the secondary hydroxyl.

Should the primary hydroxyl be blocked by acyl, for example acetyl or benzoyl, it is advisable to protect the secondary hydroxyl by a protecting group resistant to mild alkaline hydrolysis. thus for example by an ether type group. preferably by tetrahydropyranyl. When proceeding according to this method. the compounds of the structural formula IV, wherein R' is hydrocarbon. for example tetrahyropyranyl or benzyl and R2 represents acyl, are treated with sodium alcoholate in an alcoholic medium. and thus compounds of the structural formula II are prepared.

The following Examples l-5 illustrate the process of the present invention.

Example 1 (-)-3,3ap,4,5,6,6np- Hexahydro-4 - llydroxymethyl-Scx- tetrahydropyranyloxy- 2H- cyc lopetitano [b]filran-2-one 354 mg (2 mmoles) of laevorotato -y lactone diol of formula III are dissolved in a mixture of 2 ml of dry pyridine and 10 ml of dil;i!:,romethane, the mixture is ice-cooled to OOC and a solution of 295 g (2.1 mmoles) of benzoyl chloride in 5 ml of dichloromethane is added gradually. The course of the reaction is followed by t.l.c. After two hours the following spots are to be observed: spots corresponding to a small amount of the starting material, and to traces of the secondary monobenzoate (Rf = 0.34. ethyl acetate), respectively, but the main spot is to be found at Rf = 0.60 (ethyl acetate). which corrcsponds to the primary monobenzoate. The reaction mixture is diluted with 30 ml of dichloromethane and is poured into 30 ml of 7% aqueous sulfuric acid solution with ice-cooling. washed with 10 ml of 2.5% aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is then evaporated whereupon 550 mg of a colourless oil is obtained. which is chromatographed on 60 g of silica gel and eluted in 2:1 to 1:1 benzene-ethyl acetate solvent mixture, using the gradient eluting technique. Evaporating the fractions containing the main product 399 mg (72%of the (-)-3ap.4.5.66a- hexahydro-4p- benzoyloxymethyl-5a- hydroxy-2H- cyclopeptano [b] furan-2-one are obtained which proved to be uniform according to the t.l.c. measurements.

[a] 23 = -22 (c = 1.37. ethyl acetate) IR: 3400.3010.2920. 1770.1710.1600.1590. 1450,1265,1200,1165. 1110,1065,1030, 710 cm~'.

230 mg (0.83 mmoles) of the laevorotatory lactone diol primary monobenzoate of formula V, (in which R2 is benzoyl) thus obtained are dissolved in 5 ml of dry benzene, 0.5 ml (5.5 mmoles) of 3,4-2H- dihydropyran and 1 drop of phosphorous oxychloride are added.

According to t.l.c. measurements the reaction is completed in one hours. Thereafter four drops of triethylamine and 5 ml of pentane are added and after 1 to 2 hours the resulting downy precipitate is filtered off. Upon removing the solvent on a rotary evaporator in vacua 300 mg (100 HO) of the 4p-benzoyloxymethyl- Sa-tetrahydropyranyloxy compound is obtained as a colourless oil having the following physical characteristics: Rf = 0.33 (on a GF254 "Kieselgel nach Stahl" plate, with benzene-ethyl acetate 3:1). ~~ IR: 3010,2910,2850, 1770,1710,1600,1260, 1160,1110,1070,1030, '.

300 mg (0.83 mmoles) of laevorotatory lactone diol derivative of the structural formula IV (in which R' represents tetrahydropyranyl and R2 represents benzoyl) thus obtained are dissolved in 5 ml of dry methanol and 2 ml of 0.5 M methanolic solution of sodium methoxide are added.

According to the t.l.c. measurement the debenzoylating reaction is completed in 50 minutes. 1 ml of 1 M methanolic solution of acetic acid is then added the the solvent is removed on a rotary evaporator, in vacuo. The residue is dissolved in 15 ml. of ethyl acetate and the solution is subsequently washed with 3 ml of 5 So sodium carbonate solution, 2-fold 3 ml of water and 3 ml of brine, dried over sodium sulfate and evaporated. 201 mg (96 No) of the title (-) lactone diol secunder tetrahydropyranyl ether are obtained. Physical properties: [am23 = -30.70 il0 (c = 0.94, methanol).

IR (max.): 3420, 2910, 1850, 1760, 1345, 1165, 1120, 1110, 1070, 1030, 1010 cam~' Rf = 0.20 (ethyl acetate) 0.43 (6:1 ethyl acetate - methanol) on a GR254 "Kieselgel nach Stahl" plate.

Example 2 (-)-3,3a p-4, 5,6 6a p-hexahydro-4 P- hydroxymethyl- 5 a-benzoyloxy- 2H-cyclopentano [b] furan-2-one 172 mg (1 mmoles) of laevorotatory lactone diol of the structural formula III are dissolved in 5 ml of acetonitrile and 1.1 ml of a 1 M solution of trimethyl silyl-diethylamine in acetonitrile are added dropwise, at room temperature, with stirring over a period of 1 to 2 minutes. According to t.l.c. measurement benzene-ethyl acetate 1:1) the reaction is completed in 10 minutes. The main spot is found at Rf = 0.36. but another spot at Rf = 0.69 shows that traces of bis-silyl ether are also present. The solvent and the diethylamine formed are removed on a rotary evaporator, under a pressure of 12 to 15 torr, and at a temperature not exceeding 30"C. The residue is 257 mg of a yellowish oil which is then dissolved in 5 ml of dichloromethane and the solution is added to a mixture of 1 ml of dry pyridine and 162 mg (1.15 mmoles) of benzoyl chloride at OOC over a period of 5 to 6 minutes. After two hours of stirring the reaction mixture is poured into 10 ml of a 40% aqueous acetic acid solution, the container is washed out with 2 to 3 ml of dichloromethane, which is added to the reaction mixture, and then the mixture is allowed to stir for 30 to 35 minutes or shaken in a separating funnel very intensively. The phases are separated, the aqueous phase is extracted with four 10 ml portions of dichloromethane and the combined organic extracts are washed to neutral in small portions, with a 5% solution of sodium carbonate, and then dried over magnesium sulfate. Upon removing the solvent 240 mg of the title compound remain in the form of a colourless oil, which can be turned into crystalline form by stirring with a glass rod. After recrystallization from a mixture of ethyl acetate and hexane 210 mg (76 ito) of lactone diol secondary mono-benzoate are obtained, melting at 117 to 1180C.

[a]23 = -79.3" (c = 1.23, chloroform) IR (max): 3450,2920,1770,1710,1600* 1600,1580,1540,1270. 1200,1165,1110,1090, 1070, 1030,710 cm-'.

Example 3 (-)-3,3ap,4,5,6,6ap- hexahydro-4p- hydroxymethyl- 5 a- (p-phenyl-benzoyloxy)- 2H cyclopentano [b] furan-2-one The procedure set forth in the Example 2 is followed until the addition of the acylating agent. At this stage a solution of 249 mg (1.15 mmoles) ofp-phenylbenzoyl chloride (instead of benzoyl chloride) in 2 ml of pyridine is added dropwise to the solution of the mono primary-silyl ether in dichloromethane, at room temperature, 5 to 6 minutes. The mixture is stirred for two hours and the course of the reaction is controlled by t.l.c. The reaction mixture is then poured into 10 ml of a 40% aqueous solution of acetic acid, the container is washed with 2 to 3 ml of dichloromethane, which are then added to the reaction mixture. The mixture is vigorously stirred for 30-35 minutes, or is shaken in a separating funnel. After separating the phases the combined organic extracts are washed to neutral with 5% aqueous sodium carbonate solution. and are dried over magnesium sulfate. After removing the solvent 360 mg of a colourless oil are obtained, which are then recrystallized from the mixture of dichloromethane and hexane. giving 301 mg (85%) of the title compound. The physical characteristics of the title compound are: [a]95 = -88.7 (c = 1.0, chloroform).

NMR (CDCL3): 7.0 to 8.0 (m, 7H, aromatic protons), 6.2 (m, 2H, aromatic protons), 4.85 (m, 1H, -CH-O-), 4,5 (t, 1H, -CH-O), 1.85 to 2.7 (m, 9H).

Example 4 (-) -3,3a p, 4,5,6, 6a p-h exahydro- 4p- hydroxymethyl- 5 a- (p-phenyl- phenylcarbamoyloxy) -2H- cyclopentano [b] firnn-2-one The procedure set forth in Example 2 is followed for the preparation of the mono primary silyl ether. The oil obtained is then taken up in 10 ml of dry tetrahydrofuran and 223.2 g (1.2 mmoles) ofp -phenylphenyl-isocyanate and 121 mg of triethylamine are subsequently added.

The reaction mixture is then stirred at room temperature for 5 hours, controlling the course of the reaction by t.l.c. measurement. The reaction mixture obtained is poured into 10 ml of 40% aqueous acetic acid solution, the container is washed out with 2 to 3 ml of dichloromethane, and the washings added to the reaction mixture and stirred vigorously for 30 to 35 minutes. The phases are separated, the aqueous layer is extracted with four 10 ml portions of dichloromethane and the combined organic extracts are washed to neutral with 5% aqueous sodium carbonate solution, in small portions. The residue is dried over magnesium sulfate, the solvent is removed, 350 mg of a colourless oil are obtained. Recrystallization from the mixture of dichloromethane and hexane yields 295 mg of the title compounds.

Rf = 0.35 (ethyl acetate - hexane, on a GF254 "Kieselgel nach Stahl" plate).

Example 5 (-)-3,3a p, 4,5,6, 6a p-h exahydrn- 4 p-hydrnxymethyl-5 a - (p-phenyl-benzoyloxy) - 2Hcyclopentano [b] furan-2-one 303 mg (1.76 mmoles) of laevorotatory lactone 25 diol of formula III are dissolved in 2 ml of dry pyridine and 502 mg (1.8 mmoles) of trityl chloride are added in one portion. The resulting orange solution is stirred for 20 to 40 hours, and 30 ml of 1 N ice-cooled hydrochloric acid and 20 ml of ethyl acetate are subsequently added. The organic layer is separated.

washed with 5 ml of 5 % sodium bicarbonate solution and 5 ml of brine and dried over sodium sulfate. The solvent is distilled off in vacuo on a rotary eva and the reaction is followed by t.l.c. The main spot is to be observed at Rf = 0.46 (GF254 "Kieselgel nach Stahl" plate, ethyl acetate) which corresponds to the main product of primary benzyl ether. The solvent is then evaporated, the residue taken up in ethyl acetate, subsequently washed with water and brine, dried over magnesium sulfate and chromatographed on a chromatographic column made of 60 g of silica gel. The elution is carried out with a 2:1 to 1:1 mixture of benzene and ethyl acetate using the conventional gradient eluting technique. The fractions containing the main product are pooled and evaporated to give the title compound in form of a pale-yellow oil.

IR: 3400 (-OH), 1760 (-CO-lactone), 1080 (-CO-), 700, 740 (-CH-) Cm-l.

Example C (-)-3,3a p, 4, 5, 6, 6a p- hexahydro-4 p- trimethylsilyloxymethyl- 5 a-hydroxy-2H- cyclopentano [b] furan-2-one 167 mg (0.97 mmoles) of the laevorotatory compound of formula III are dissolved in 5 ml of acetonitrile at room temperature, and 1 ml of a 1 M solution of trimethyl-silyldiethylamine in acetonitrile are added with stirring. After a reaction period of 20 minutes the solvent is evaporated. 250 mg of a pale-yellow oil are obtained. Recrystallization from 1 ml of ether with addition of 3 to 5 ml of hexane yields 193 mg (81.5SO) of the title compound.

Melting point: 48.5 to 49.5 C [a]D5 = -26.9 (c = 0.9, acetonitrile) Rf = 0.70 (ethyl acetate, 0.36 (benzene - ethyl acetate 1:1).

It should be noted that the product may also be recrystallized from a mixture of benzene and hexane.

WHAT WE CLAIM IS: 1. A process for the preparation of a compound of the formula:

[wherein R represents a group selected from: R3-CH2-CR4-OR5, -SiR6R 'R8, R9CO- or R 10-NH-CO-, (in which R3, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group or R3 and R5 together represent an alkylene chain and R4 represents a hydrogen atom or an alkyl group which and R8, which may be the same or different. each represents an alkyl group; R9 represents an alkyl, aryl, substituted aryl or aralkyl group; and R "' represents an alkyl, aryl or substituted aryl group)] in racemic or optically active form, which process comprises protect ing the primary hydroxy group of a racemic or optically active compound of the formula:

by reaction of the said compound of formula III with a compound of the formula

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **.

and the reaction is followed by t.l.c. The main spot is to be observed at Rf = 0.46 (GF254 "Kieselgel nach Stahl" plate, ethyl acetate) which corresponds to the main product of primary benzyl ether. The solvent is then evaporated, the residue taken up in ethyl acetate, subsequently washed with water and brine, dried over magnesium sulfate and chromatographed on a chromatographic column made of 60 g of silica gel. The elution is carried out with a 2:1 to 1:1 mixture of benzene and ethyl acetate using the conventional gradient eluting technique. The fractions containing the main product are pooled and evaporated to give the title compound in form of a pale-yellow oil.

IR: 3400 (-OH), 1760 (-CO-lactone), 1080 (-CO-), 700, 740 (-CH-) Cm-l.

Example C (-)-3,3a p, 4, 5, 6, 6a p- hexahydro-4 p- trimethylsilyloxymethyl- 5 a-hydroxy-2H- cyclopentano [b] furan-2-one

167 mg (0.97 mmoles) of the laevorotatory compound of formula III are dissolved in 5 ml of acetonitrile at room temperature, and 1 ml of a 1 M solution of trimethyl-silyldiethylamine in acetonitrile are added with stirring. After a reaction period of 20 minutes the solvent is evaporated. 250 mg of a pale-yellow oil are obtained. Recrystallization from 1 ml of ether with addition of 3 to 5 ml of hexane yields 193 mg (81.5SO) of the title compound.

Melting point: 48.5 to 49.5 C [a]D5 = -26.9 (c = 0.9, acetonitrile) Rf = 0.70 (ethyl acetate, 0.36 (benzene - ethyl acetate 1:1).

It should be noted that the product may also be recrystallized from a mixture of benzene and hexane.

WHAT WE CLAIM IS: 1. A process for the preparation of a compound of the formula:

[wherein R represents a group selected from: R3-CH2-CR4-OR5, -SiR6R 'R8, R9CO- or R 10-NH-CO-, (in which R3, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group or R3 and R5 together represent an alkylene chain and R4 represents a hydrogen atom or an alkyl group which and R8, which may be the same or different. each represents an alkyl group; R9 represents an alkyl, aryl, substituted aryl or aralkyl group; and R "' represents an alkyl, aryl or substituted aryl group)] in racemic or optically active form, which process comprises protect ing the primary hydroxy group of a racemic or optically active compound of the formula:

by reaction of the said compound of formula III with a compound of the formula

(wherein R3, R4, R5, R6, R7, R8, R9 and R'are as herein defined, X represents a chlorine, bromine or iodine atom, X represents a chlorine. bromine or iodine atom or a dialkylamino group, X3 represents a chlorine or iodine atom and R represents a benzyl or trichloroethyl group) to form a compound of the formula:

[wherein RZ represents the group: R -CH2-CR4-OR5, -SiR6R R8,R9-CO-, R10-NH-CO, benzyl, benzyloxycarbonyl or triethoxycarbonyl (in which R3, R4, R5, R6, R7, R8, R9 and R' are as herein defined)] reacting the said compound of formula V with a compound of formula VII, VIII, IX and X (as herein defined) to form compound of the formula:

(wherein R represents a R9-CO- or R"'-NH-CO- group when R2 represents a R3-CH2 CR4-OR5 or -SiR6R7R8 group or R' represents a R3-CH2-CR4-OR5 or -SiR6R7R8 group when R2 represents a R -CO- group or R' represents a R9-CO-, R3-CH2-CR4-OR5 or -SiR6R7R8group when R2 represents a beozyl, benzyloxycarbonyl or trichlorethoxycarbonyl group, R3. R4, R5, R6 R7, R8, R9 and R"' being as herein defined) and deprotecting the protected primary hydroxyl group of the said compound of formula XVI to form a racemic or optionally active compound of formula II as herein defined.
2. A process as claimed in claim 1 for the preparation of compounds of formula II wherein R represents a R9-CO- or R ',-NH-CO- group (in which R9 and R "' are as defined in claim 1) wherein a racemic or optica!'v active compound of formula III

is reacted with a compound of formula VII

(wherein R3, R4 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group R3 and R4 together represent an alkylene chain and R4 represents a hydrogen atom or an alkyl group) or with a compound of the formula:

(wherein R6, R', R8 and X2 are as defined in claim 1) to form a compound of formula V as defined in claim 1 (in which R2 represents R3-CH2-CR4-OR5 or -SiR6R7R8 group, R3, R4, R5, R6, R7andR8being as defined in claim 1) which compound of formula V is reacted with a compound of the formula:

(wherein R9 and X3 are as defined in claim 1) or with a compound of the formula: R'O-N =C-O X (wherein R lo is as defined in claim 1) to form a compound of formula XIV as defined in claim 1 (wherein Rl rePresents a R9-CO- or R"'-NH-CO- group and R2 represents a R3-CH2~ CR4-oR5 or -SiR6R7R8 group in which R3, R4, R5, R6, R', R8. R9 and R10 are as defined in claim 1) the protected primary hydroxy group of which compound of formula XIV is deprotected by acid hydrolysis to form a racemic or optically active compound of formula II (wherein Rl represents a R9-CO- or R"'-NH-CO group as herein defined).
3. A process as claimed in claim 2 wherein a compound of formula IX is used in which R9 represents a p-phenylphenyl, phenyl or methyl group.
4. A process as claimed in claim 2 wherein a compound of formula X is used in which R'O represents ap-phenylphenyl or phenyl group.
5. A process as claimed in any one of claims 2 to 4 wherein the deprotection is effected in the presence of acetic acid at a temperature not exceeding 50"C.
6. A process as claimed in claim 1 for the preparation of compounds of formula II wherein R1 represents a R3-CH2-CR4-OR5 or -SiR6R 'R8 group (in which R3, R4, R5, R6, R7 and R8 are as defined in claim 1) wherein a racemic or opticaly active compound of formula III (as defined in claim 1) is reacted with a compound of formula IX (as defined in claim 1) to form a compound of formula V as defined in claim 1 (in which R2 represents the group R9-CO- wherein R9 is as defined in claim 1) which compound of formula V is reacted with a compound of formula VII as defined in claim 1 or with a compound of formula VIII as defined in claim 1 to form a compound of formula XIV as defined in claim 1 (wherein R represents a R3-CH2-CR4-oR5 or -SiR6R7R8 group and R2 represents a R9-CO- group in which R3, R4, R5. R6, R7, R8 or R9 are as defined in claim 1) and the protected primary hydroxy group of the said compound of formula XIV is deprotected by alkaline solvolysis to form a racemic or optically active compound of formula II (wherein Rl represents a CH2-CR4-OR5 or -SiR6R7R8 group as herein defined).
7. A process as claimed in claim 6 wherein a compound of formula IX is used in which R9 represents an alkyl or aryl group.
8. A process as claimed in claim 7 wherein a compound of formula IX is used in which R9 represents a phenyl or methyl group.
9. A process as claimed in any one of claims 6 to 8 wherein a compound of formula VII is used in which R3 represents a hydrogen atom or an alkyl group and R4 and R5 each represent an alkyl group.
10. A process as claimed in any one of claims 6 to 8 wherein a compound of formula VII is used in which a) R 3 represents a hydrogen atom and R4 and R5 each represent a methyl group or b) R3 and R4 each represent a hydrogen atom and R5 represents an ethyl group.
11. A process as claimed in any one of claims 6 to 10 wherein the deprotection of the protected primary hydroxy group is effected by solvolysis in the presence of an alkanol with 1 to 6 carbon atoms and a base.
12. A process as claimed in claim 11 wherein the base is potassium carbonate.
13. A process as claimed in claim 1 fqr the preparation of compounds of formula II wherein R represents a R9-CO-, R3-CH2-CR4-oR5 or -SiR6R7R8 group (in which R3, R4, R5, R6, R 7, R8 and R9 are as defined in claim 1) wherein a compound of formula III as defined in claim 1 is reacted with a compound of formula XI or XII as defined in claim 1 to form a compound of formula V as defined in claim 1 (in which R2 represents a benzyl, benzyloxycarbonyl or trichloroethoxycarbonyl group) which compound of formula V is reacted with a compound of formula VII, VIII, or IX as defined in claim 1 to form a compound of formula XIV as defined in claim 1 (in which R l represents a R9-CO-, R3-CH2-tR4-OR5 or -SiR6R 7R8 group and R2 represents a benzyl, benzyloxycarbonyl or trichloroethoxycarbonyl group; R3, R4, R5, R6, R7, RS and R9 being defined in claim 1), the protected primary hydroxy group of which compound of formula XIV is deprotected by catalytic hydrogenation or with nascent hydrogen to form a racemic or optically active compound of formula II wherein R l represents a R9-CO-, R3-CH2-CR4-oR5 or -SiR6R7R8 group as defined in claim 1.
14. A process as claimed in claim 13 wherein a compound of formula XII is used in which Xl represents a chlorine atom.
15. A process as claimed in claim 13 or claim 14 wherein a compound of formula IX is used in which R9 represents a phenylphenyl or phenyl group.
16. A process as claimed in claim 13 or claim 14 wherein dihydropyran is used as the compound of formula VIII.
17. A process as claimed in claim 13 or claim 14 wherein a compound of formula VIII is used in which R6, R7 and R8, which may be the same or different, each represent an alkyl group with 1 to 6 carbon atoms.
18. A process as claimed in any one of claims 13 to 17 wherein the deprotection is effected by the use of nascent hydrogen, produced by the reaction of zinc with an acid, in the presence of a palladium catalyst under a pressure of about 3 atmospheres guage.
19. A process as claimed in claim 1 substantially as herein described.
20. A process for the preparation of formula II as defined in claim 1 substantially as herein described in Examples 1-5.
21. Compounds of formula II as defined in claim 1 when prepared by a process as claimed in any one of the preceding claims.