IE910854A1 - Process for preparing (-)-[methyl¹(2r,3s)-2,3-epoxy-3-(4-methoxyphenyl) propionate] or its¹enatiomer - Google Patents
Process for preparing (-)-[methyl¹(2r,3s)-2,3-epoxy-3-(4-methoxyphenyl) propionate] or its¹enatiomerInfo
- Publication number
- IE910854A1 IE910854A1 IE085491A IE85491A IE910854A1 IE 910854 A1 IE910854 A1 IE 910854A1 IE 085491 A IE085491 A IE 085491A IE 85491 A IE85491 A IE 85491A IE 910854 A1 IE910854 A1 IE 910854A1
- Authority
- IE
- Ireland
- Prior art keywords
- propionate
- methyl
- epoxy
- methoxyphenyl
- enantiomer
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
- C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epoxy Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Process for the preparation of methyl (-)-(2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate, characterised in that a solution of a mixture of enantiomers of trans methyl (+/-)-2,3-epoxy-3-(4-methoxyphenyl)propionate, rich in laevorotatory enantiomer, is prepared first of all and then a crystal seed of laevorotatory enantiomer is then added to the solution, which is allowed to crystallise, and the crystals formed are isolated.
Description
PROCESS FOR PREPARING (-)-ΓMETHYL (2R.3S)-2.3-EPOXY3-(4-METHOXYPHENYL)PROPIONATE1 OR ITS ENANTIOMER The present invention relates to a process for the preparation of (-)-[methyl (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl) propionate] or its enantiomer by preferential crystallisation.
The compound (-)-[methyl (2R,3S)-2,3-epoxy-3-(4methoxyphenyl)propionate] is an important intermediate in the preparation of compounds such as (+)-(2S,3S)3-acetyloxy-2,3-dihydro-5-(2-dimethylaminoethyl)2-(4-methoxyphenyl)-1,5-5H-benzothiazepin-4-one, or diltiazem (INN), and its derivatives.
Much effort has recently been made to obtain (-)-[methyl (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)propionate], by resolution via a diastereoisomer (Patent Applications JP-13,776/1985, JP-145,174/1986 and EP-0,342,903) or by enzymatic hydrolysis of the undesired enantiomer (Patent Application EP-0,343,714).
These known processes are tedious and/or give poor yields, making the desired product expensive.
In contrast, the process according to the invention 20 permits resolution of the racemate without recourse to the methods mentioned above and avoids their drawbacks.
It is known that racemic compounds can exist in two crystalline forms, of which one is a homogeneous, true racemic mixture, the enantiomers of which cannot be separated, and the other is referred to as a conglomerate. Known racemic compounds which exist in the form of a conglomerate, that is to say in the form of a mixture of mechanically separable enantiomers, are very limited in number (see Enantiomers, Racemates and Resolutions, by J. Jacques, A. Collet and S. H. Wilen, published by John Wiley & Sons, 1981).
We have discovered that trans-(+)-[methyl 2,310 epoxy-3-(4-methoxyphenyl)propionate] can exist in the form of a conglomerate under certain conditions.
According to the invention there is provided a process for the preparation of an enantiomer of trans-(+)[methyl 2,3-epoxy-3-(4-methoxyphenyl)propionate], which comprises preparing a solution of a mixture of enantiomers of trans-(+)-[methyl 2,3-epoxy-3-(4methoxyphenyl)propionate] enriched in the desired enantiomer, adding a crystalline seed of the desired enantiomer to the solution, allowing crystallisation to take place and isolating the crystals formed.
The process of the invention can be carried out by mixing a saturated solution of trans-(+)-[methyl 2,3-epoxy3-(4-methoxyphenyl)propionate] with a saturated solution of the desired enantiomer, and collecting larger quantities of the desired enantiomer by crystallisation. The saturated solution may be prepared, for example, at the refluxing temperature of the chosen solvent.
This corresponds to a partial or total resolution of the racemic compound from a system in which the compound exists as a conglomerate. trans-(+)-[Methyl 2,3-epoxy3-(4-methoxyphenyl)propionate] may be prepared, for example, from p-anisaldehyde and methyl chloroacetate by a Darzens reaction, as described in Chem. Pharm. Bull., 21. (12), 2786-2789 (1973), and (-)-[methyl (2R,3S)-2,3-epoxy10 3-(4-methoxyphenyl)propionate] may be prepared from the racemate, for example as described in Patent Application JP-13,776/1985 or in Patent Applications EP-0,342,903 and EP-0,343,714, already cited above.
The starting solution may be obtained, for example, from trans-(+)-[methyl 2,3-epoxy3-(4-methoxyphenyl)propionate] and (-)-[methyl (2R,3S)- or (+)-[methyl (2S,3R)-2,3-epoxy-3-(4-methoxyphenyl) propionate]. These esters are dissolved in a suitable organic solvent such as diethyl ether, diisopropyl ether, t-butyl methyl ether, toluene, xylene, chlorobenzene, methanol, 2-propanol, ethyl acetate, and the like. The preferred solvent is t-butyl methyl ether.
The quantity of optically pure ester to be used is up to 5 parts by weight per part of racemic ester, and the concentration of the mixture of esters in the solvent is preferably between 2 and 50%.
The dissolution is performed under heat, for example at the refluxing temperature of the solvent, and when it is complete, a crystal of optically pure ester is added to the solution while the latter is still hot or has returned to room temperature, and the mixture is allowed to cool, where appropriate by placing it in a refrigerated chamber.
Preferential crystallisation of the desired enantiomer takes place, hence it is in excess relative to the quantity employed at the start, and it is isolated in a known manner, for example by filtration.
The (-)-[methyl (2R,3S)- or (+)-[methyl (2S,3R)-2,3-epoxy-3-(4-methoxyphenyl)propionate] thereby obtained is practically pure. If so desired, it may be further purified by recrystallisation in a known manner.
The examples which follow illustrate in detail embodiments of the process of the invention.
Example 1 Laevorotatory enantiomer g of racemic trans-(+)-[methyl 2,3-epoxy3-(4-methoxyphenyl)propionate] and 2 g of (-)-[methyl (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl) propionate] were dissolved in 100 ml of t-butyl methyl ether heated to reflux, while stirring. Stirring was stopped, a crystal of (-)-[methyl (2R,3S)-2,3-epoxy3-(4-methoxyphenyl)propionate] was added to the hot solution and the mixture was allowed to return to room temperature and then placed at 5‘C for 12 hours. The crystals formed were filtered off and dried. 2.92 g of (-)[methyl (2R,3S)-2,3-epoxy-3-(4-methoxyphenyl)-propionate] were thereby obtained.
Melting point: 85’C.
Purity *: ee > 95% (HPLC, Daicel® OD chiral column). [a] = -199’ (c = 1; MeOH).
D [S] - [R] * (ee = _ x 100%, [S] and [R] being the [S] + [R] concentrations of the two enantiomers) Example 2 Laevorotatory enantiomer. 1.5 g of racemic trans-(+)-[methyl 2,3-epoxy-3-(4methoxyphenyl)propionate] and 2 g of (-)-[methyl (2R,3S)2,3-epoxy-3-(4-methoxyphenyl)propionate] were dissolved in ml of t-butyl methyl ether heated to reflux, without stirring. A crystal of (-)-[methyl (2R,3S)-2,3-epoxy-3-(4methoxyphenyl)propionate] was added at 50*C to the solution obtained. The mixture was kept at room temperature for 1 h 15 min and then placed at 5*C for 5 h.
The crystals formed were filtered off and dried, and 2.23 g of (-)-[methyl (2R,3S)-2,3-epoxy3-(4-methoxyphenyl)propionate] were isolated.
Purity: ee > 98%.
Example 3 Laevorotatory enantiomer. 1.5 g of racemic trans-(+)-[methyl 2,3-epoxy-3-(4methoxyphenyl)propionate] and 3 g of (-)-[methyl (2R,3S)5 2,3-epoxy-3-(4-methoxyphenyl)-propionate] were dissolved in ml of t-butyl methyl ether heated to reflux.
A crystal of (-)-[methyl (2R,3S)-2,3-epoxy-3-(4methoxyphenyl)propionate] was added at 22’C to the solution obtained. The mixture was kept at room temperature for 30 min and then placed at 5’C for 2 h 30 min.
The crystals formed were filtered off and dried, and 3.22 g of (-)-[methyl (2R,3S)-2,3-epoxy3-(4-methoxyphenyl)propionate] were isolated.
Example 4 Dextrorotatory enantiomer.
A crystal of (+)-[methyl (2S,3R)-2,3-epoxy-3-(4methoxyphenyl)propionate] was added at 22’C to a solution composed of 1.1 g of racemic trans-(+)-[methyl 2,3-epoxy-3(4-methoxyphenyl)propionate] and 0.18 g of (+)-[methyl (2S,3R)-2,3-epoxy-3-(4—methoxyphenyl)-propionate] in 5 ml of t-butyl methyl ether.
The mixture was left at room temperature for 30 min, the crystals formed were then filtered off and dried and 0.3 g of compound was obtained.
Purity: ee = 84%.
The compound was recrystallised in 1 ml of t-butyl 854 - 7 methyl ether heated to reflux, and 0.25 g of (+)-[methyl (2S,3R)-2,3-epoxy-3-(4-methoxyphenyl)-propionate] was finally isolated.
Melting point: 85 - 87°C 5 Purity: ee = 99%. [a] = + 198*C (C = 1.15; MeOH).
Claims (6)
1. A process for the preparation of an enantiomer of trans-(+)-[methyl
2. ,3-epoxy-3-(4-methoxyphenyl)propionate], which comprises preparing a solution of a 5 mixture of enantiomers of trans-(+)-[methyl 2,3-epoxy-3-(4methoxyphenyl)propionate], enriched in the desired enantiomer, adding a crystalline seed of the desired enantiomer to the solution, allowing crystallisation to take place and isolating the crystals formed. 10 2. A process according to Claim 1, wherein the mixture of enantiomers is enriched in the laevorotatory enantiomer and crystals of (-)-[methyl (2R,3S)-2,3-epoxy-3(4-methoxyphenyl)propionate] are isolated.
3. A process according to Claim 2, wherein the 15 starting solution is prepared from trans-(+)-[methyl 2,3epoxy-3-(4-methoxyphenyl)-propionate] and (-)-[methyl (2R,3 S)-2,3-epoxy-3-(4-methoxyphenyl)-propionate].
4. A process according to Claim 2 or 3, wherein up to 5 parts by weight of laevorotatory enantiomer are 20 used per part of the racemate.
5. A process according to any one of the preceding claims, wherein t-butyl methyl ether is used as a solvent.
6. A process for the preparation of an enantiomer 25 of trans-(+)-[methyl 2,3-epoxy-3-(4methoxyphenyl)propionate] substantially as hereinbefore described in any one of Examples 1 to 4.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9003310A FR2659657B1 (en) | 1990-03-15 | 1990-03-15 | PROCESS FOR THE PREPARATION OF (-) (2R, 3S) -2,3-EPOXY-3- (4-METHOXYPHENYL) METHYL PROPIONATE. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE910854A1 true IE910854A1 (en) | 1991-09-25 |
Family
ID=9394762
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE085491A IE910854A1 (en) | 1990-03-15 | 1991-03-14 | Process for preparing (-)-[methyl¹(2r,3s)-2,3-epoxy-3-(4-methoxyphenyl) propionate] or its¹enatiomer |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0453330B2 (en) |
| JP (1) | JP2854155B2 (en) |
| KR (1) | KR910016671A (en) |
| AT (1) | ATE85316T1 (en) |
| CS (1) | CS67191A2 (en) |
| DE (1) | DE69100026D1 (en) |
| FI (1) | FI911264A (en) |
| FR (1) | FR2659657B1 (en) |
| HU (1) | HU206696B (en) |
| IE (1) | IE910854A1 (en) |
| IL (1) | IL97529A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL123352A0 (en) | 1997-02-27 | 1998-09-24 | Tanabe Seiyaku Co | Process for preparing an optically active trans-3-substituted glycidic acid ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4885375A (en) * | 1988-05-18 | 1989-12-05 | Marion Laboratories, Inc. | Resolution of 3-(4-methoxyphenyl)glycidic acid with in situ conversion to alkyl esters |
-
1990
- 1990-03-15 FR FR9003310A patent/FR2659657B1/en not_active Expired - Fee Related
-
1991
- 1991-03-04 DE DE9191400586T patent/DE69100026D1/en not_active Expired - Lifetime
- 1991-03-04 EP EP91400586A patent/EP0453330B2/en not_active Expired - Lifetime
- 1991-03-04 AT AT91400586T patent/ATE85316T1/en not_active IP Right Cessation
- 1991-03-12 IL IL9752991A patent/IL97529A/en not_active IP Right Cessation
- 1991-03-13 HU HU91826A patent/HU206696B/en not_active IP Right Cessation
- 1991-03-13 KR KR1019910003984A patent/KR910016671A/en not_active Application Discontinuation
- 1991-03-14 CS CS91671A patent/CS67191A2/en unknown
- 1991-03-14 FI FI911264A patent/FI911264A/en not_active Application Discontinuation
- 1991-03-14 JP JP3074710A patent/JP2854155B2/en not_active Expired - Fee Related
- 1991-03-14 IE IE085491A patent/IE910854A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2659657A1 (en) | 1991-09-20 |
| EP0453330B2 (en) | 1997-12-03 |
| IL97529A0 (en) | 1992-06-21 |
| CS67191A2 (en) | 1991-11-12 |
| KR910016671A (en) | 1991-11-05 |
| EP0453330A1 (en) | 1991-10-23 |
| HU910826D0 (en) | 1991-09-30 |
| DE69100026D1 (en) | 1993-03-18 |
| HUT56838A (en) | 1991-10-28 |
| FR2659657B1 (en) | 1994-09-23 |
| JPH04217969A (en) | 1992-08-07 |
| ATE85316T1 (en) | 1993-02-15 |
| HU206696B (en) | 1992-12-28 |
| IL97529A (en) | 1995-12-31 |
| FI911264A0 (en) | 1991-03-14 |
| EP0453330B1 (en) | 1993-02-03 |
| JP2854155B2 (en) | 1999-02-03 |
| FI911264A (en) | 1991-09-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |