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IE45922B1 - Improved morphine/apomorphine rearrangement process - Google Patents

Improved morphine/apomorphine rearrangement process

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Publication number
IE45922B1
IE45922B1 IE237377A IE237377A IE45922B1 IE 45922 B1 IE45922 B1 IE 45922B1 IE 237377 A IE237377 A IE 237377A IE 237377 A IE237377 A IE 237377A IE 45922 B1 IE45922 B1 IE 45922B1
Authority
IE
Ireland
Prior art keywords
apomorphine
yield
process according
reaction
morphine
Prior art date
Application number
IE237377A
Other versions
IE45922L (en
Original Assignee
Sterling Drug Inc
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 Sterling Drug Inc filed Critical Sterling Drug Inc
Publication of IE45922L publication Critical patent/IE45922L/en
Publication of IE45922B1 publication Critical patent/IE45922B1/en

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D221/00Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04Ortho- or peri-condensed ring systems
    • C07D221/18Ring systems of four or more rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)

Abstract

Apomorphine derivatives are prepared with an improved yield by transposition of the corresponding morphine derivative in the presence of anhydrous phosphoric acid under a partial vacuum, generally between 9 and 20 mm of mercury and at a temperature between 125 DEG C and 140 DEG C.

Description

This invention relates to an improved process . certain thereof for preparing apomorphine and /. derivative /by rearrangement of the corresponding morphine derivative.
Apomorphines are very valuable compounds for use 5 in medicine as emetics, hypotensive agents and CNS stimulants (Archer, U.S. Patent 3,717,643^ or in the treatment of Parkinsonism (German Application 2,154,162) While apomorphines have been successfully synthesized in the laboratory [see for example Fpath and Hromatka, Ber. 62, 325 (1929); Avenarius and Pschorr, Ber. 62, 321 (1929), whose claim to a total synthesis has however been challenged by Gulland, Chem. and Ind. 16, 774 (1938); Neumeyer et al., J. Med. Chem. 16, 1223 (1973) and Neumayer et al., J, Med. Chem. 16, 1228 (1973)], none of the methods so far devised are commercially feasible, since they all involve multiple synthetic steps and furthermore require resolution of optical isomers at some stage in the synthesis. The classical morphine/apomorphine rearrangement thus remains the most practical source of apomorphines, since derivatives of naturally occurring morphine or its relatives (e.g. heroin or codeine) are readily available, can be conveniently derivatized by simple chemical transformations either prior ur subsequent to 'rearrangement, and during rearrangement maintain the natural steric configuration of the only original -2f i .11. 43322 asymmetric center which is not destroyed by the rearrangement. The use of a variety of acids to effect the morphine/apomorphine type rearrangement by heating the corresponding morphine derivative with the acid is known, including concentrated agueous zinc chloride solutions [Mayer, Ber. £, 121-128 (1871) - apomorphine (no yield given); Matthieseen et al., Ann, 15JB, 131-135 (1871) - apocodeine (no yield given); German Patent 489,185, Frdl. 16 (II), 2485-2486 (1927-1929) - apocodeine (25% yield) and apomorphine ethyl ether (2% yield)], concentrated hydrochloric acid [Matthiessen et al., Proc. Boy. Soc. (London) B17, 455-462 (1869) - apomorphine (no yield given], anhydrous oxalic acid [Knorr et al., Ber. 40, 3355-3358 (1907) - apocodeine (no yield given); Folkers, J. Am. Chem, Soc. 58, 1814-1815 (1936) 15 apocodeine (12,8% yield); Corrodi et al., Helv. Chim. Acta. 38, 2038-2043 (1955) - norapocodeine (13% yield)], 85% or 90% phosphoric acid with current of anhydrous hydrogen chloride passed through mixture [Oparina, Khim. Farm. Prom. 15, 18-19 (1934); U.S.S.R. Patent 40,981 (January 31, 1935); C.A, 30, 7285 (1936) - apomorphine (40-42%); Hensiak, J.
Med. Chem. 8, 557-559 (1965) - N-allylnorapomorphine (46% yield)], 85% phosphoric acid with current of nitrogen passed through mixture [Koch ef al., J. Med. Chem. 11, 977981 (1968) - apocodeine (20% yield), norapomorphine (13% yield), N-ethylnorapomorphine (36% yield), N-propylnorapomorphine (37% yield), N-propargylnorapomorphine (20% yield), N-cyclopropylmethylnorapomorphine (33% yield), N-benzylnorapomorphine (37% yield), N-phenethylnorapomorphine (16% yield)], aqueous glacial phosphoric acid [(HPO3)n -See Merck Index-Eighth Edition, page 824] [Wright, J. Chem. -3ί Soc. 25, 652-657 (1872) - apomorphine (0.6% yield)] and glacial phosphoric acid [Small et al., J. Org. Chem. 5, 334-349 (1940) - apocodeine (30% yield)].
The present invention provides a process for 5 preparing apomorphine, an ether derivative thereof or an N-substituted-norapomorphine derivative which comprises heating a corresponding morphine, ether derivative thereof or N-substituted-normorphine derivative in the presence of an acid, the reaction being carried out with anhydrous orthophosphoric acid under a partial vacuum.
This process can be used to prepare, inter alia, apomorphine itself, apocodeine and N-substituted norapomorphine derivatives in vastly improved yield over what was previously available using prior art processes.
A preferred group of apomorphines and Rj-norapomorphines prepared by the present prooess are those having where R^ is hydrogen or lower-alkyl; and R2 is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, phenyl-loweralkyl or cycloalkyl-lower-alkyl which are prepared by rearrangement of morphine derivatives of the Formula II: where R. and R_ have the meanings given above. A 1 2 -4-particu2arly preferred group of apomorphines and R^-norapomerphines prepared by the present process are those of Formula I, where R^ is hydrogen or lower-alkyl; and R2 is lower-alkyl or phenyl-lower-alkyl. preferably The process of the invention is/carried out by heating the compounds of Formula II, in anhydrous orthophosphoric acid (H3PO4) at a temperature in the rance from 125 to 140°Ct under a partial vacuum. While the practical lower limit to the operable pressure that can be used cannot be precisely defined, the pressure and temperature obviously should be such that the phosphoric acid is not evaporated off during the course of the reaction. In practice it has been found that a vacuum obtained from a water aspirator vacuum pump (i.e, 9 to 20 mm Kg) is entirely suitable, In some instances, the reaction mixture tends to froth in the early minutes of the reaction, and such frothing is best controlled by increasing the pressure slightly until the frothing subsides. Thus it may be necessary to use pressures up to 50 or 60 mm Hg in the early minutes of the reaction. The rearrangement is usually completed in 12-25 minutes, and it is advantaceous to terminate the reaction and work up the product as soon as the rearrangement is complete. The course of the reaction is readily followed by thin layer chromatography, and since the products of the reaction are all known, they can be .identified, for example, by comparison of their melting points with the known melting point values for the caxoiiids or by mixed melting point determinations.
As used herein the term lower-alkyl means a 43332 saturated hydrocarbon group, which may be straight or branched, containing.from one to five carbon atoms. The term thus includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl and amyl.
The term lower-alkenyl means an unsaturated radical having one double bond, which may be straight or branched, and containing from three to five carbon atoms.
The term thus includes, but is not limited to, 12-propenyl , 2-methy1-2-propenyl , 3-methyl-2-butenyl or 2butenyl . < λ The term lower-alkynyl means an unsaturated .. radical having one triple bond, which may be straight or branched, and containing from three to five carbon atoms.
The term thus includes, but is not limited to, 2-propynyl , 2-methyl-2-propynyi ,. 3-methyl-2-butynyl . or 2butynyl , _____--------The term cycloalkyl means a saturated carbocyclic group containing from three to six ring carbon atoms as illustrated, for example, by cyclopropyl, cyclobutyl, cyclopentyl, cyelohexyl, 2-methylcyclobutyl or 4-ethylcyclohexyl.
The process of the present invention is illustrated by the following description, EXAMPLE A series of morphine/apomorphine rearrangements was carried out under five sets of process conditions designed to compare the yields obtained under the conditions of the present invention (Condition D) either as compared with conditions used in the prior art (Condition A - Koch et al.) or under conditions designed to determine the effect of other single reaction parameters such as the -630 nature of the acid used (Condition B) or combinations of reaction parameters such as the use of nitrogen, a vacuum or anhydrous vs. 85% phosphoric acid (Conditions C and E). These reaction conditions are as follows: Condition A- The starting material was heated with 85% orthophosphoric acid while passing a stream of nitrogen through the mixture.
Condition B- The starting material was heated with 85% orthophosphoric aoid under water aspirator vacuum.
Condition C- The 85% orthophosphoric acid was flushed with nitrogen while heating, and rearrangement was then carried out with heating under application of a water aspirator vacuum.
Condition D- The starting material was heated with anhydrous orthophosphoric acid under a water aspirator vacuum = Condition E- The starting material was heated with anhydrous orthophosphoric acid while passing a stream of nitrogen through the mixture. in each case the starting material was added to the phosphoric acid after the latter had been heated to 70’C. When reaction was complete in each case, as indicated by thin layer chromatography analysis, each reaction mixture was worked up according to a standard procedure which is described as follows: The reaction mixture was poured into 600 ml. of ice water and allowed to stand overnight, The working up includes hydrolysis of the phosphate ester formed (by reaction with phosphoric acid) by reaction of said ester with water, which hydrolysis is substantially the same as that carried out -745822 on the corresponding phosphate ester formed by the reaction With 85% or 90% phosphoric acid as taught in Hensiak and Koch et. al., acknowledged above. The mixture was then heated to boiling for fifteen minutes to ensure complete hydrolysis of the phosphate esters, then cooled and poured slowly into 650 ml. of saturated brine. The aqueous layer was decanted from the gum which formed, and the gum was dis-845922 solved in 400 ml- of water and made basic by the addition of sodium sulfite, The mixture was then extracted with isopropyl acetate, the organic solution filtered, dried over anhydrous calcium sulfate and then acidified with ethereal hydrogen chloride. The hydrochloride salt which thus formed was collected, recrystallized from an appropriate solvent, identified by its melting point and weighed. The results obtained, expressed in terms of percent yield, are given in the following tables where the reaction condition used, i,e. Conditions A,B,C,D/ or E, and the maximum temperature and the total time of heating are given.
Results obtained in a series of runs for the rearrangement of N-propylnormorphine to N-propylnorapomorphine are given in the following table. The product in each case was recrystallized from n-butanol. % Yield Run Cond. Max. T (°C,) /Time (min, 1 1 A 142/41 49-0 2 A 142/38 50,8 3 A 145/75 39,2 4 A 142/44 21.7 5 A 142/45 33.0 6 - A 143/55 30.1 7 A 148/50 33.9 8 A 145/50 13,2 9 A 145/4Q. 33.9 10-1 A 146/43?. , 145/40/31 10-2 A 9c 4 11 A N,A,lb) 15.4 12 A 145/20 24,1 13 A 145/25 16.3 14 A 140/18 AVERAGE YIELD 23,6 2871 1 B 140/25 32,1 2 B 130/13 AVERAGE YIELD 28.3 "5K2" 1 C 130/10 41,6 2 C 130/13 AVERAGE YIELD 42.5 1 D 130/15 53.5 Run Cond. MaxT( °C,j/Time(min.) % Yield 2 D 128/13 40.6 3 D 132/13 46.8 4 D 132/17 43.6 5 D 134/15 50.1 6 D 130/15 39.3 7 D 130/15 48.6 8 D 128/16 49.1 9 D 130/13 58.6 10 D 130/15 51.1 AVERAGE YIELD(c) 40. Ϊ ' 1 ε 150/25 22.6 2 E 150/25 21.8 AVERAGE YIELD Ύ2.2 (a) Two runs. Yield based on combined products (b) Not available- (c) Does not include two runs in which products were worked up in a totally different manner than the standard procedure and atypical yields, 30.2% and 23.6% respectively, obtained.
Results obtained for the rearrangement of codeine to apocodeine are given in the following table. The product in each case was recrystallized from water.
Run Cond. Max,T(°C,)/Time(min.) % Yield 1 A 145/45 19.7 2 A 145/45 17.2 3 A 140/40 18.3 AVERAGE YIELD 1 D 140/20 59.2 2 D 140/25 70.5 AVERAGE YIELD ' ·6Ϊ.5γ ' Results obtained in the rearrangement of morphine to apomorphine are given in the following table. The products in each case were recrystallized from isopropyl acetate/diethyl ether.
Run Cond.. Max, T (° C,) /Time (min, ) % Yield 1 A 140/45 10.0 2 A 140/45 AVERAGE YIELD 14.0 ~ΊΊΓΠΓ~ 1 D 130/14 58.4 2 D 130/15 AVERAGE YIELD 54.6 "KT5'~ - 10 P 4022 Results obtaired for the rearrangement of K-pher.ethyl normorphine to N-phenethylnorapomorphine are given in the following table. The products m each case were recrystal lized from isoprovl ai □etate/diethyl ether. 5 Run Cond. Max-T(°C.)/Time(min .) % Yield 1 A 138/45 25,4 2 A l-j/45 22.9 AVERAGE YIELD 1 D 130/15 s 64.0 10 2 D 130/15 68.0 AVERAGE YIELD Γβ.Ο 1 E 150/40 53.0 2 3-1 E E (a) N,A. 150/25 / 61.0 15 3-2 E 150/25_> 35,6 AVERAGE YIELD "42Ϊ9~· These results show that, under the conditions of the present process, i,e. reaction Condition D, the yield obtained in the morphine/apomorphine rearrangement for a variety of morphine derivatives is in the range from 48-66%, In contrast the conditions used in the prior art (i.e, Condition A - Koch et al.) afford yields in the range from 12-28%. an ether derivative thereof

Claims (11)

1. A process for preparing an 'apomorphine/or sn N-substituted-norapomorphine derivative which comprises ether derivative thereof heating a corresponding morphine/or H'-substxiuted-'norjnorphine derivative in the presence of an acid, the reaction, being carried out with anhydrous orthophosphoric acid under a partial vacuum¢. A process according tc claim 1, wherein the reaction is carried out at a temperature from 125°Cto 140°C.
2. 3. A process according to claim 1 or 2, wherein the reaction is carried out at a pressure of 9 to 20 mm Hg.
3. 4. A process according to any one of the preceding claims, which comprises preparing a compound having the Formula I (herein) from a compound of Formula II (herein) wherein 'Rl is hydrogen or lower-alkyl; and Rj is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl, phenyl-loweralkyl or cycloalkyl-lower-alkyl.
4. 5. A process according to claim 4, which comprises preparing N- propylnorapomorphine from N-propylnormorphine.
5. 6. A process according to claim 4, which comprises preparing apocodeine from codeine.
6. 7. A process according-to claim 4, which comprises preparing apomorphine from morphine.
7. 8. A process according to claim 4, which comprises preparing N-phenethylnorapomorphine from N-phenethylnor-12I i... morphine. A prooess according to any one of the preceding claims, in which the process is carried out at a pressure in the range of
8.
9.to 60 mm. Hg.
10. A process for preparing an apomorphine or an N-substituted-norapomorphine derivative substantially as herein described with reference to the Examples.
11. An apomorphine or an N-substituted-norapomorphine derivative when prepared by the process according to any one of the preceding claims.
IE237377A 1977-01-10 1977-11-23 Improved morphine/apomorphine rearrangement process IE45922B1 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US75788877A 1977-01-10 1977-01-10

Publications (2)

Publication Number Publication Date
IE45922L IE45922L (en) 1978-07-10
IE45922B1 true IE45922B1 (en) 1982-12-29

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JP (1) JPS5387359A (en)
AU (1) AU510976B2 (en)
BE (1) BE862389A (en)
CA (1) CA1092122A (en)
CH (1) CH624674A5 (en)
DE (1) DE2758954A1 (en)
DK (1) DK584077A (en)
FR (1) FR2376847A1 (en)
GB (1) GB1566049A (en)
IE (1) IE45922B1 (en)
LU (1) LU78790A1 (en)
NL (1) NL7714227A (en)
NZ (1) NZ185799A (en)
SE (1) SE7713456L (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0040074B1 (en) * 1980-05-08 1985-07-31 Northeastern University N-substituted aporphines, a method of inducing emesis and a method of controlling psychosis utilising the same
WO1990012574A1 (en) * 1989-04-25 1990-11-01 Northeastern University Dopamine agonist compounds
GB201915911D0 (en) * 2019-11-01 2019-12-18 Johnson Matthey Plc Process

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DK584077A (en) 1978-07-11
AU510976B2 (en) 1980-07-24
NZ185799A (en) 1979-12-11
SE7713456L (en) 1978-07-11
FR2376847B1 (en) 1980-08-22
FR2376847A1 (en) 1978-08-04
BE862389A (en) 1978-06-28
CH624674A5 (en) 1981-08-14
CA1092122A (en) 1980-12-23
DE2758954A1 (en) 1978-07-13
IE45922L (en) 1978-07-10
LU78790A1 (en) 1978-07-11
AU3101377A (en) 1979-06-07
GB1566049A (en) 1980-04-30
JPS5387359A (en) 1978-08-01
NL7714227A (en) 1978-07-12

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