CN1293039C - Preparation of [(S)-(-)-alpha-methylamino phenylketone]2.(2R,3R)-tartaric acid derivative - Google Patents

Abstract

The present invention discloses a preparation method for [(S)-(-)-alpha-methylamino phenylketone]2. (2R, 3R)-tartaric acid derivatives, which comprises: (+/-)-alpha-methylamino propiophenone, (R)-(+)-alpha-methylamino propiophenone, or (R)-(+)-alpha-methylamino propiophenone containing partial (S)-(-)-alpha-methylamino propiophenone and (2R, 3R)-tartarate derivatives react in solvent to form salt, and a target product is collected from a reaction product with a conventional method. The present invention can obtain the target product by only controlling the proportion and the total amount of mixed solvent. The target product with high split optical yield and optical purity can be directly used for synthesizing (1R, 2S)-(-)-ephedrine. The present invention also discloses a directly heating method for racemizing the (R)-(-)-alpha-methylamino propiophenone with no need of additional acid or alkali.

Description

Preparation method of [(S)-(-)-α-methylaminopropiophenone]2·(2R, 3R)-tartaric acid derivative

technical field

The present invention relates to an intermediate for the preparation of (1R, 2S)-(-)-ephedrine: [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R, 3R)-tartaric acid derivative method of preparation.

Background technique

(S)-(-)-α-methylaminopropiophenone or (S)-(-)-α-methylaminopropiophenone salt is an important pharmaceutical intermediate, which can be used to prepare (1R, 2S)- (-)-Ephedrine.

[(S)-(-)-α-Methylamino Propiophenone] ₂ ·(2R,3R)-Tartaric acid derivatives are generally prepared by splitting the compound (±)-α-Methylamino Propiophenone.

Chinese patent CN1298867A takes (1R, 3S)-(+)-camphoric acid as a resolving agent, and equimolar (±)-alpha-methylaminopropiophenone and (1R, 3S)-(+)-camphoric acid are placed In ethanol, heat to dissolve, cool and crystallize, and separate (R)-(+)-α-methylaminopropiophenone (1R, 3S)-(+)-camphoric acid; The required (S)-(-)-α-methylaminopropiophenone (1R, 3S)-(+)-camphoric acid needs to undergo heating and cooling processes, and the preparation process is relatively complicated.

Chinese patents CN1267664A and CN1265391A use (1R)-(-)-camphorsulfonic acid as a resolving agent, (±)-α-methylaminopropiophenone and (1R)-(-)-camphorsulfonic acid are placed in water, Heating to dissolve, cooling and crystallization to obtain (S)-(-)-α-methylaminopropiophenone (1R)-(-)-camphorsulfonic acid.

However, the salt formed by α-methylaminopropiophenone and organic acid is more sensitive to temperature, and under the condition of heating (>50° C.), side reactions are prone to occur, which reduces the resolution optical yield.

U.S. Patent No. 2802865 dissolves the salt formed by (±)-α-methylaminopropiophenone and (1S)-(+)-camphorsulfonic acid or (2R, 3R)-(-)-dibenzoyl tartaric acid at room temperature In a single solvent: alcohol, and then cooled to 0-5 ° C, crystals will be precipitated, but the optical purity is not high, usually need to crystallize several times. Since the solubility of the salt is less sensitive to temperature, the resolution is not efficient and the operation is complicated.

Takamatsu (H.Takamatsu, J.Pharm.Soc.Japan, 76,1219 (1956)) discloses (2R, 3R)-(-)-dibenzoyl tartaric acid as a resolving agent, (±)-α -Methylaminopropiophenone and (2R, 3R)-(-)-dibenzoyltartaric acid were dissolved in ethyl acetate, placed, crystals were precipitated, and then recrystallized with absolute ethanol, Takamatsu claimed to have achieved asymmetric transformation . However, [(±)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(-)-dibenzoyl tartaric acid is insoluble in ethyl acetate, and the target product can be obtained after recrystallization from absolute ethanol , the experimental results are difficult to reproduce.

For resolving the mother liquor, CN1267664A, CN1265391A and CN1298867A all add a certain amount of alkali to the resolving mother liquor, and heat to make α-methylaminopropiophenone racemize. Because α-methylaminopropiophenone is unstable, after heating for 15-31h, a side reaction occurs, and the recovery rate of α-methylaminopropiophenone is low.

Contents of the invention

The technical problem to be solved in the present invention is to disclose the preparation method of [(S)-(-)-α-methylaminopropiophenone] ₂ (2R, 3R)-tartaric acid derivatives to overcome the above-mentioned defects in the prior art .

Method of the present invention comprises the steps:

Methylaminopropiophenone and (2R, 3R)-tartaric acid derivatives are reacted to form a salt in a salt-forming solvent, and then [(S)-(-)-α-methylaminopropiophenone] ₂ · (2R, 3R)-tartaric acid derivatives are precipitated, and [(S)-(-)-α-methylaminopropiophenone] ₂ (2R, 3R)- The tartaric acid derivative was preferentially precipitated, while the other diastereoisomer was present in the mother liquor due to its greater solubility. Then adopt conventional methods to collect [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R, 3R)-tartaric acid derivatives from the reaction product;

Said methylaminopropiophenone includes: (±)-α-methylaminopropiophenone, (R)-(+)-α-methylaminopropiophenone or inclusion part (S)-(-)-α- (R)-(+)-α-methylaminopropiophenone of methylaminopropiophenone;

Reaction temperature is 0～40 ℃, and the reaction time is 2～48 hours; The structural general formula of said methylaminopropiophenone is:

Said (2R, 3R)-tartaric acid derivatives include: (2R, 3R)-(-)-di-p-toluyl tartaric acid, (2R, 3R)-(-)-di-p-toluyl tartaric acid Tartaric acid monohydrate, (2R,3R)-(-)-di-m-toluoyl tartaric acid, (2R,3R)-(-)-di-m-toluoyl tartaric acid monohydrate, (2R,3R )-(-)-di-o-tolyl tartaric acid, (2R,3R)-(-)-di-o-tolyl tartaric acid monohydrate, (2R,3R)-(-)-benzoyl tartaric acid Acyl tartaric acid, (2R,3R)-(-)-dibenzoyl tartaric acid monohydrate, (2R,3R)-(-)-diacetyl tartaric acid, (2R,3R)-(-)-diacetyl tartaric acid Tartaric acid monohydrate.

The salt-forming solvent mentioned is selected from one or a mixture of alcohols or aqueous alcohols, esters or ethers;

The mixed solvent mentioned is selected from one of a mixture of alcohol and ester, a mixture of alcohol and ester containing water, a mixture of alcohol and ether or a mixture of alcohol and ether containing water.

Wherein: said alcohol is C1-C5 alcohol, namely C1-C5OH, and ester is an ester composed of C ₁ -C ₅ acid and C ₁ -C ₅ alcohol, namely C ₁ -C ₄ COOC ₁ -C ₅ , the ether is an ether composed of C ₁ -C ₅ alcohol and C ₁ -C ₅ alcohol (that is, C ₁ -C ₅ OC ₁ -C ₅ ), tetrahydrofuran or dioxane;

When the mixture of ester or ether and alcohol or water-containing alcohol is used as solvent, its volume ratio is:

Ester or ether: alcohol or water-containing alcohol = 0.5-8.0: 1.0;

The volume of mixed solvent and the weight ratio of (±)-α-methylamino Propiophenone are:

1.0-25.0ml/1.0g;

Its general reaction formula is as follows:

Wherein R is: p-toluyl, o-toluyl, m-toluyl, benzoyl or acetyl; x is 0 or 1.

Further, since there is still a certain amount of (R)-(+)-α-methylaminopropiophenone in the resolution mother liquor, it is necessary to racemize the α-methylaminopropiophenone of this configuration and apply it to the next batch of resolution point.

The racemization method of (R)-(+)-alpha-methylaminopropiophenone of the present invention comprises the steps:

Heat the separation mother liquor at about 40-90°C for 0.5-4 hours, add hydrochloric acid, sulfuric acid or phosphoric acid until the pH of the system is about 1-3, stir, separate the organic layer for recovery of the resolving agent, add alkali to the water layer Metal or alkaline earth metal hydroxide to a pH value of 10-14, extract the racemized α-methylaminopropiophenone with an organic solvent, and apply it to the next batch of resolution.

The present invention salts with 2 moles of (±)-alpha-methylaminopropiophenone and 1 mole of resolving agent, if with chiral camphoric acid or camphorsulfonic acid as resolving agent, then 1 mole of resolving agent can only be with 1 Mole (±)-alpha-methylaminopropiophenone is salified, so the utilization rate of the resolving agent of the present invention is higher.

Research finds: splitting result has nothing to do with feeding mode, detailed situation can refer to each embodiment.

The present invention does not require heating to dissolve the solids generated during the salt-forming process, and cools the heated solution to re-precipitate the solids, that is, there is no need to change the temperature of the system. At the set temperature, the present invention only needs to continue after feeding. After stirring for a period of time or standing for a period of time after stirring, [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-tartaric acid derivative can be obtained after filtration.

Another feature of the present invention is: the resolution optical yield exceeds the theoretical amount, which can reach 158.7%; the diastereomer purity (%de) is measured as 97.2% by capillary electrophoresis, and the optical purity is relatively high without further refining , indicating that part of the asymmetric transformation was realized during the splitting process. This is because [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R, 3R)-tartaric acid derivatives with low solubility broke the balance in the system after being precipitated in the solvent, and another (R)-(+)-α-methylaminopropiophenone in the two diastereomers undergoes asymmetric transformation under the resolution conditions to generate [(S)-(-)-α-methylaminopropiophenone Propiophenone] ₂ ·(2R,3R)-tartaric acid derivatives, the resolution optical yield exceeds the theoretical amount, reaching 158.7%.

Since asymmetric transformation can be achieved during the resolution process, (R)-(+)-α-methylaminopropiophenone or (R) After -(+)-α-methylaminopropiophenone and (2R,3R)-tartaric acid derivatives are salted in a solvent, [(S)-(-)-α-methylamine should be formed under appropriate conditions Propiophenone] ₂ · (2R, 3R) - tartaric acid derivatives, the solubility of the salt is small, can be precipitated from the reaction solution, the present invention is called asymmetric conversion method. In the present invention, (R)-(+)-α-methylaminopropiophenone or the (R)-(+)-α-methylaminopropiophenone containing part (S)-(-)-α-methylaminopropiophenone Propiophenone and (2R, 3R)-tartaric acid derivatives form a salt in a solvent, and the [(S)-(-)-α-methylamine generated due to the asymmetric transformation occurs by controlling the ratio and the total amount of the mixed solvent [(R)-(+)-α-methylaminopropiophenone] ₂ ·(2R,3R)-tartaric acid derivatives are selectively precipitated, and some unconverted [(R)-(+)-α-methylaminopropiophenone] ₂ ·(2R,3R)-tartaric acid Derivatives have high solubility and can be dissolved in mother liquor. In the present invention, there is no need to change the temperature of the system during the conversion process, and it only needs to continue stirring for a period of time or leave it for a period of time after stirring. After filtration, [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-tartaric acid derivative can be obtained, from which (S)-(-)-α- Methylaminopropiophenone.

The invention can realize the racemization of α-methylaminopropiophenone by heating and splitting the mother liquor in a short time, and the destruction of α-methylaminopropiophenone is reduced due to the short heating time. In addition, because α-methylaminopropiophenone still exists in the form of salt, it is more stable than the form of free base, and the recovery rate of α-methylaminopropiophenone is improved; in addition, because no need to add acid or alkali, reduce Material consumption; at the same time, under this condition, the hydrolysis of the resolving agent is very slow and the loss is small.

Detailed ways

Example 1

Resolution method of (±)-α-methylaminopropiophenone 1

Dissolve 24.2g (±)-α-methylaminopropiophenone in 80ml methanol, slowly add dropwise a mixed solution consisting of 27.2g (2R, 3R)-(-)-dibenzoyltartaric acid and 80ml methanol, while stirring, After the dropwise addition, 400ml of ethyl acetate was slowly added and left for 16h, a large amount of solids were precipitated. Filter, wash with a little 2:5 mixed solvent of methanol and ethyl acetate, and dry to obtain 40.3g [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-( -)-dibenzoyl tartrate, mp 140-142°C, [α] _D -102.0° (c=1.0, CH ₃ OH), resolution optical yield 158.7%.

The salt was placed in an aqueous solution of sodium carbonate, the temperature was controlled below 5°C, and extracted with dichloromethane. Distill out dichloromethane to obtain (S)-(-)-α-methylaminopropiophenone.

Example 2

Resolution method of (±)-α-methylaminopropiophenone 2

Dissolve 24.2g (±)-α-methylaminopropiophenone in 400ml ethyl acetate, slowly add dropwise under stirring solution, a large amount of solids precipitated during the dropping process, and the solution was placed for 16 hours after the dropping. Filter, wash with a little 2:5 mixed solvent of methanol and ethyl acetate, and dry to obtain 37.0g [(S)-(-)-α-methylaminopropiophenone] ₂ (2R, 3R)-(-) -Dibenzoyl tartrate, mp 140-142°C, [α] _D -102° (c=1.0, CH ₃ OH). Resolution optical yield 145.9%.

The salt was placed in an aqueous solution of sodium carbonate, the temperature was controlled below 5°C, and extracted with dichloromethane. Distill out dichloromethane to obtain (S)-(-)-α-methylaminopropiophenone.

Example 3

Resolution method of (±)-α-methylaminopropiophenone 3

Dissolve 27.2g (2R, 3R)-(-)-dibenzoyl tartaric acid in 400ml ethyl acetate, slowly add dropwise under stirring solution, a large amount of solids precipitated during the dropwise addition, and continued to stir for 16 hours after the dropwise addition. Filter, wash with a little 2:5 mixed solvent of methanol and ethyl acetate, and dry to obtain 38.1g [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(- )-dibenzoyl tartrate, mp 140-142°C, [α] _D -102° (c=1.0, CH ₃ OH), resolution optical yield 150.2%.

The salt was placed in an aqueous solution of sodium carbonate, the temperature was controlled below 5°C, and extracted with dichloromethane. Distill out dichloromethane to obtain (S)-(-)-α-methylaminopropiophenone.

Example 4

Preparation of (S)-(-)-α-methylaminopropiophenone from (R)-(+)-α-methylaminopropiophenone

Dissolve 2.4g (R)-(+)-α-methylaminopropiophenone in 8ml of methanol, and slowly add dropwise under stirring For the solution composed of ethyl ester, a large amount of solids will be precipitated during the dropwise addition, and the solution should be left for 24 hours after the dropwise addition. Filter, wash with a little 2:5 mixed solvent of methanol and ethyl acetate, and dry to obtain 2.6g [(S)-(-)-α-methylaminopropiophenone] ₂ (2R, 3R)-(- )-dibenzoyl tartrate, mp 140-141°C, [α] _D -102° (c=1.0, CH ₃ OH), yield 51.6%.

Example 5

Racemization of (R)-(+)-α-methylaminopropiophenone

Heat the resolution mother liquor in Example 1 at about 50°C for about 1 hour, add 4N hydrochloric acid until the pH of the system is about 1, stir, and separate the organic layer for recovery of the resolution agent. Add 30% NaOH aqueous solution to the aqueous layer until the pH value is about 14, extract the racemic α-methylaminopropiophenone with ethyl acetate, and use it for the next batch of resolution.

Example 6-13

Using the same method as in Example 1, 24.2g (0.148mol) (±)-α-methylaminopropiophenone was dissolved in 80ml of methanol, and slowly added dropwise with 0.074mol of (2R, 3R)-(- )-di-p-toluyl tartaric acid (Example 6), (2R, 3R)-(-)-di-p-toluyl tartaric acid monohydrate (Example 7), (2R, 3R)-( -)-Di-m-toluoyl tartaric acid (Example 8), (2R, 3R)-(-)-Di-m-toluoyl tartaric acid monohydrate (Example 9), (2R, 3R)- (-)-Di-o-tolyl tartaric acid (Example 10), (2R, 3R)-(-)-Di-o-toluyl tartaric acid monohydrate (Example 11), (2R, 3R) -(-)-Diacetyl tartaric acid (Example 12), (2R, 3R)-(-)-Diacetyl tartaric acid monohydrate (Example 13) and 80ml methanol mixed solution, dropwise slowly add 400ml The ethyl acetate was left for 16h, and a large amount of solid was precipitated. Filter, wash with a little 2:5 mixed solvent of methanol and ethyl acetate, and dry to obtain [(S)-(-)-α-methylaminopropiophenone] ₂ ·(2R,3R)-(-) - Tartaric acid derivative salts, the results are as follows:

Split optical yield %

Example 6 150.7%

Example 7 148.5%

Example 8 149.6%

Example 9 145.3%

Example 10 151.2%

Example 11 148.3%

Example 12 142.9%

Example 13 140.1%

Claims (5)

1.[(S)-(-)-α-methylamino Propiophenone] ₂(2R 3R)-preparation method of tartaric acid derivatives, is characterized in that comprising the steps: with the methylamino Propiophenone with (2R 3R)-tartaric acid derivatives reacts salify in becoming salt solvent, makes in mixed solvent [(S)-(-)-α-methylamino Propiophenone] then ₂(2R 3R)-tartaric acid derivatives separates out, adopts conventional method to collect [(S)-(-)-α-methylamino Propiophenone] then ₂(2R, 3R)-tartaric acid derivatives;

Said methylamino Propiophenone comprise (±)-α-methylamino Propiophenone, (R)-(+)-α-methylamino Propiophenone or be mingled with the part (S)-(-)-α-methylamino Propiophenone (R)-(+)-α-methylamino Propiophenone in a kind of;

The one-tenth salt solvent of being addressed is selected from a kind of or its mixture in alcohol or aqueous alcohol, ester or the ether;

The mixed solvent of being addressed is selected from alcohol and the mixture of mixture, aqueous alcohol and the ester of ester, pure and the mixture of ether or the mixture of aqueous alcohol and ether; When the mixture that adopts ester or ether and alcohol or aqueous alcohol was solvent, its volume ratio was: ester or ether: pure or aqueous alcohol=0.5-8.0: 1.0;

Wherein: said alcohol is C _1-5OH; Said ester is C _1-4COOC _1-5Said ether is C _1-5OC _1-5, a kind of in tetrahydrofuran (THF) or the dioxane;

The ratio of the volume of mixed solvent and methylamino Propiophenone weight is:

1.0-25.0ml/1.0g。

2. method according to claim 1 is characterized in that: temperature of reaction is 0～40 ℃, and the reaction times is 2～48 hours.

3. method according to claim 1; it is characterized in that: said (2R; 3R)-tartaric acid derivatives comprises (2R; 3R)-(-)-two pair methyl benzoyl tartrate; (2R; 3R)-(-)-two pair methyl benzoyl tartrate monohydrate; (2R; 3R)-(-)-two a methyl benzoyl tartrate; (2R; 3R)-(-)-two a methyl benzoyl tartrate monohydrate; (2R; 3R)-(-)-two o-methyl-benzene formyl radical tartrate; (2R; 3R)-(-)-two o-methyl-benzene formyl radical tartrate monohydrate; (2R; 3R)-(-)-dibenzoyl tartaric acid; (2R; 3R)-(-)-the dibenzoyl tartaric acid monohydrate; (2R; 3R)-(-)-diacetyl tartrate; (2R, 3R)-(-)-diacetyl tartrate monohydrate.

4. according to each described method of claim 1～3, it is characterized in that, also comprise the steps: the fractionation mother liquor is heated 0.5～4h about 40～90 ℃, adding hydrochloric acid, sulfuric acid or phosphoric acid to the pH value of system is about 1～3, stir, tell organic layer for reclaiming resolving agent usefulness, add the oxyhydroxide of basic metal or alkaline-earth metal in the water layer to pH value 10～14, with the α-methylamino Propiophenone of organic solvent extraction racemization.

5. method according to claim 4 is characterized in that: the α of racemization-methylamino Propiophenone cover is used for the fractionation of next batch.