CN101774960B - Preparation method of (2S)-indoline-2-methanoic acid - Google Patents
Preparation method of (2S)-indoline-2-methanoic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of (2S)-indoline-2-methanoic acid. The method is as follows: the mixture of (2S)-indoline-2-methanoic acid and (2R)-indoline-2-methanoic acid with the absolute quantity of (2S)-indoline-2-methanoic acid being dominant flows back at normal pressure in n-butyl alcohol solution of NaOH for racemization reaction, racemized indoline-2-methanoic acid obtained by separation of reaction liquid after the reaction is complete is tracked and detected; racemized indoline-2-methanoic acid reacts with (R)-alpha-methylbenzylamine in ethanol by adequately stirring, after reaction is ended, the reaction liquid is filtered to obtain filter cake A and filtrate A, and the filter cake A is acidized by hydrochloric acid to obtain (2S)-indoline-2-methanoic acid. The invention has the beneficial effects that reaction can be carried out just by flowing back at normal pressure in the method, autoclave is unnecessary, requirement on equipment is low, operation is safe, the method is suitable for industrialized production, the solvent n-butyl alcohol can be recycled, and pollution to the environment is small.
Description
(1) technical field
The present invention relates to the preparation method of a kind of (2S)-indoline-2-formic acid.
(2) background technology
Control hypertension, protection function of vascular endothelium are the important goals of coronary heart disease secondary prevention, and angiotensin converting enzyme inhibitor (ACEI) is the core drug of realizing this goal.And the main character of perindopril and pharmacologically acceptable salt thereof suppresses angiotonin I saccharase (or kininase II) exactly.And in clinical practice, perindopril benefit in controlling blood pressure, the prevention incident in the cardiovascular event chain has also obtained confirmation.
Racemic indoline-2-formic acid is by splitting (2S) indoline-2-formic acid shown in the acquisition formula (I), and (2S) indoline-2-formic acid can be used for synthetic pharmacologically acceptable salt with perindopril of the formula V that pharmacology is worth.
Perindopril acting in therapeutics has in the U.S. Pat 4508729 describes.
In view of the pharmacy value of this compound, it is very important finding the preparation method of (2S) indoline-2-formic acid shown in the ground acquisition formula (I) that a kind of yield is good and the purity selectivity is high.
U.S. Pat 4508729 and European patent EP 0308339 disclose the method for preparation formula (I) compound, this method mainly is by the indoline-2-formic acid with (R)-Alpha-Methyl benzylamine resolution of racemic, obtains (2S)-indoline-2-formic acid by fractional crystallization and acidifying then.
China Patent No. CN100337996C discloses the preparation of racemic indoline-2-formic acid, its method is by the NaOH aqueous solution, under 140 ℃-200 ℃ temperature, the pressure of in 5 to 15 crust is down with (2S)-indoline-2-formic acid of (2R) sour dominant formula (I) and (2R)-indoline-2-formic acid mixtures of formula (III), react and with its racemization, split the compound that obtains formula (I) by Chiral Amine then.
This method has fully been recycled the mother liquor after splitting, and yield has improved, but needs to use autoclave.
(3) summary of the invention
The objective of the invention is to reduce equipment requirements simultaneously for the yield that improves (2S)-indoline-2-formic acid, invented the novel method of synthetic (2S)-indoline-2-formic acid, this processing unit requires low, operational safety, is suitable for suitability for industrialized production.
For reaching goal of the invention the technical solution used in the present invention be:
A kind of preparation method suc as formula (2S) shown in (I)-indoline-2-formic acid, described method may further comprise the steps:
(1) (2R)-indoline-2-formic acid mixtures shown in (2S) shown in the formula (I)-indoline-2-formic acid and the formula (III), in the butanol solution of NaOH, atmospheric pressure reflux is carried out racemization reaction, and liquid chromatography is followed the tracks of the complete afterreaction liquid of detection reaction separating treatment and obtained the racemic indoline-2-formic acid shown in the formula (II); The absolute magnitude of (2R) shown in the described mixture Chinese style (III)-indoline-2-formic acid is preponderated; The consumption of described NaOH is 0.2～1 times for (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures quality;
(2) the racemic indoline-2-formic acid shown in the formula (II) that obtains of step (1) with (R)-the Alpha-Methyl benzylamine is in ethanol, stir fully reaction, reaction finishes afterreaction liquid and filters, obtain filter cake A and filtrate A, filter cake A is (2S) isomer shown in the formula (IVa), handles obtaining (2S) shown in the formula (I)-indoline-2-formic acid with hcl acidifying.
Comparatively preferred, the filtrate A that described step (2) obtains operates according to following steps (3)～(4):
(3) the filtrate A evaporate to dryness that obtains of step (2) obtains (2S) isomer shown in the dominant formula of absolute magnitude (IVa) of (2R) isomer shown in the formula (IVb) and (2R) mixture of isomers shown in the formula (IVb), handles obtaining reclaiming absolute magnitude dominant (2S)-indoline-2-formic acid of product (2R)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures with hcl acidifying;
(4) get absolute magnitude dominant (2S)-indoline-2-formic acid of recovery product (2R)-indoline-2-formic acid that step (3) obtains and (2R)-indoline-2-formic acid mixtures according to step (1), (2),
(3) repetitive operation is 2～6 times, and (2S)-indoline-2-formic acid that at every turn obtains is merged, and obtains (2S)-indoline-2-formic acid product;
In the step of the present invention (1), the consumption of described propyl carbinol is counted 8.2～11.4L/kg with the quality of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures.
In the described step (1), the reaction times is 2～16 hours.
In the step of the present invention (1), the step of reaction solution separating treatment is: after reaction finishes, the reaction solution evaporate to dryness removes and desolvates, recyclable propyl carbinol, adding the hydrochloric acid adjust pH is 3.0～5.0, stirs fully reaction, filters, filter cake washing, drying obtain the racemic indoline-2-formic acid shown in the formula (II).
The mass ratio of racemic indoline-2-formic acid and (R) in the step of the present invention (2)-Alpha-Methyl benzylamine is 1: 0.6～0.9.
The step that the hcl acidifying of filter cake A is handled in the step of the present invention (2) is: filter cake A is dissolved in water, and adding the hydrochloric acid adjust pH is 3.0～4.0, stirs fully reaction, filters, and obtains after filter cake washing, the drying (2S)-indoline-2-formic acid.The consumption of described water is 6～8 times of quality of filter cake A.
Consumption of ethanol is counted 6.4～9.6L/kg with the quality of racemic indoline-2-formic acid in the described step (2).
In the step of the present invention (3), the step of the hcl acidifying of (2R) mixture of isomers shown in (2S) isomer shown in the dominant formula of (2R) isomer absolute magnitude (IVa) shown in the formula (IVb) and the formula (IVb) is: (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers be dissolved in water, with the hydrochloric acid adjust pH is 3.0～4.0, stir fully reaction, filter, filter cake washing, drying obtains reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures.The consumption of described water is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) 8～10 times of L/kg of the quality of mixture of isomers.
The present invention is used for the common use concentrated hydrochloric acid of hydrochloric acid of adjust pH.
Comparatively concrete, recommend the described method of method of the present invention to carry out according to following steps:
(1) (2R)-indoline-2-formic acid mixtures shown in (2S) shown in the formula (I)-indoline-2-formic acid and the formula (III), in the butanol solution of NaOH, atmospheric pressure reflux is carried out racemization reaction, after the tracking detection reaction is complete, the reaction solution evaporate to dryness, adding the hydrochloric acid adjust pH is 3.0～5.0, stir fully reaction, filter, filter cake washing, drying obtain the racemic indoline-2-formic acid shown in the formula (II); The absolute magnitude of (2R) shown in the described mixture Chinese style (III)-indoline-2-formic acid is preponderated; The consumption of described NaOH is 0.2～1 times of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures quality; The consumption of described propyl carbinol is counted 8.2～11.4L/kg with the quality of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures;
(2) the racemic indoline-2-formic acid shown in the formula (II) that obtains of step (1) with (R)-the Alpha-Methyl benzylamine is in ethanol, stir fully reaction, reaction finishes afterreaction liquid and filters, obtain filter cake A and filtrate A, filter cake A is (2S) isomer shown in the formula (IVa), and filter cake A adds in the entry, adding the hydrochloric acid adjust pH is 3.0～4.0, stir fully reaction, filter, obtain after filter cake washing, the drying (2S)-indoline-2-formic acid; The mass ratio of described racemic indoline-2-formic acid and (R)-Alpha-Methyl benzylamine is 1: 0.6～0.9; Described consumption of ethanol is counted 6.4～9.6L/kg with the quality of racemic indoline-2-formic acid;
(3) the filtrate A evaporate to dryness that obtains of step (2) obtains (2S) isomer shown in the dominant formula of absolute magnitude (IVa) of (2R) isomer shown in the formula (IVb) and (2R) mixture of isomers shown in the formula (IVb) adds in the entry, with the hydrochloric acid adjust pH is 3.0～4.0, stir fully reaction, filter, filter cake washing, drying obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures;
(4) get absolute magnitude dominant (2S)-indoline-2-formic acid of recovery product (2R)-indoline-2-formic acid that step (3) obtains and (2R)-indoline-2-formic acid mixtures according to step (1), (2), (3) repetitive operation 2～6 times, (2S)-indoline-2-formic acid that at every turn obtains is merged, obtain (2S)-indoline-2-formic acid product.
Beneficial effect of the present invention is embodied in: this method atmospheric pressure reflux can be reacted, and does not need to use autoclave, and, operational safety low for equipment requirements are suitable for suitability for industrialized production, the recyclable utilization of solvent for use propyl carbinol, and environmental pollution is little.
(4) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited thereto.
Embodiment 1:
A1, preparation (2S)-indoline-2-formic acid
(R)-Alpha-Methyl benzylamine and the racemic indoline of the 10Kg-2-formic acid of 7.5Kg are joined in 92 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A1 (6.3Kg) and filtrate A1, add 42 premium on currency among the filter cake A1, with the concentrated hydrochloric acid adjust pH is 3.5, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (3.54Kg) 1., chemical purity is 98%, optical purity ee value is 99.8%, yield 35.4%.
B1, the filtrate A1 that obtains in the steps A 1 is concentrated dried, the evaporate to dryness thing is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers (10Kg), add 80 liters in water, transferring pH value with concentrated hydrochloric acid is 3.5, stir after 2 hours, filter, get filter cake and wash with water, obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (5.5Kg) behind the constant pressure and dry.
C1, fetch and receive product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (5.5Kg), be dissolved in 55 liters of propyl carbinols, add NaOH2.75Kg, temperature rising reflux reaction 3h concentrates reaction solution then and does, and the evaporate to dryness thing adds concentrated hydrochloric acid adjust pH to 3.5, then this mixture was stirred 1 hour, filter, get filter cake, obtain racemic indoline-2-formic acid (4.58Kg) with propyl carbinol washing, constant pressure and dry.
([α] D
20=0 ° of C=1, the hydrochloric acid of 1mol/L)
Embodiment 2:(reclaimer operation 1 time)
A2, (the R)-Alpha-Methyl benzylamine of 3.43Kg and the racemic indoline-2-formic acid of 4.58Kg step C1 preparation are joined in 42 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A2 (2.1Kg) and filtrate A2, add 16 premium on currency among the filter cake A2, with the concentrated hydrochloric acid adjust pH is 3.5, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (1.6Kg) 2., chemical purity is 98%, optical purity ee value is 99.5%, and 1. (2S)-indoline-2-formic acid that makes with embodiment 1 merge, and calculating its yield is 51.4%.
B2, the filtrate A2 that obtains in the steps A 2 is concentrated dried, the evaporate to dryness thing is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers (5.0Kg), add 40 liters in water, transferring pH value with concentrated hydrochloric acid is 3.5, stir after 2 hours, filter, get filter cake and wash with water, obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (2.47Kg) behind the constant pressure and dry.
C2, fetch and receive product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (2.47Kg), be dissolved in 24.7 liters of propyl carbinols, add NaOH 1.19Kg, temperature rising reflux reaction 5h, then reaction solution is concentrated and do, the evaporate to dryness thing adds concentrated hydrochloric acid adjust pH to 3.5, then this mixture was stirred 1 hour, filter, get filter cake with propyl carbinol washing, constant pressure and dry, obtain racemic indoline-2-formic acid (2.0Kg).
Twice of embodiment 3:(reclaimer operation)
A3, (the R)-Alpha-Methyl benzylamine of 1.5Kg and the racemic indoline-2-formic acid of 2.0Kg step C2 preparation are joined in 19 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A3 (1.5Kg) and filtrate A3, add 12 premium on currency among the filter cake A3, with the concentrated hydrochloric acid adjust pH is 3.5, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (0.65Kg) 3., chemical purity is 98%, optical purity ee value is 99.6%, with (2S)-indoline-2-formic acid 1. and (2S)-2. indoline-2-formic acid merge, calculating its yield is 57.9%.
B3, get the filtrate A3 that obtains in embodiment 3 steps A 3 and concentrate and do, the evaporate to dryness thing is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers (2.1Kg), add 18 liters in water, transferring pH value with concentrated hydrochloric acid is 3.5, stir after 2 hours, filter, get filter cake and wash with water, obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (1.2Kg) behind the constant pressure and dry.
C3, fetch and receive product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (1.2Kg), be dissolved in 12 liters of propyl carbinols, add NaOH0.6Kg, temperature rising reflux reaction 5h concentrates reaction solution then and does, and the evaporate to dryness thing adds concentrated hydrochloric acid adjust pH to 3.5, then this mixture was stirred 1 hour, filter, get filter cake, obtain racemic indoline-2-formic acid (1.05Kg) with propyl carbinol washing, constant pressure and dry.
Embodiment 4:(reclaimer operation 3 times)
A4, (the R)-Alpha-Methyl benzylamine of 0.78Kg and the racemic indoline-2-formic acid of 1.05Kg step C3 preparation are joined in 9.5 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A4 (0.6Kg) and filtrate A4, add 4.8 premium on currency among the filter cake A4, with the concentrated hydrochloric acid adjust pH is 4.0, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (0.33Kg) 4., chemical purity is 98%, optical purity ee value is 99.4%, 1.～3. merges with (2S)-indoline-2-formic acid, and calculating its yield is 61.2%.
Embodiment 5:
A5, preparation (2S)-indoline-2-formic acid
(R)-Alpha-Methyl benzylamine and the racemic indoline of the 12Kg-2-formic acid of 7.2Kg are joined in 115 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A5 (8.0Kg) and filtrate A5, add 48 premium on currency among the filter cake A5, with the concentrated hydrochloric acid adjust pH is 3.5, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (4.08Kg) 1., chemical purity is 98%, optical purity ee value is 99.8%, yield 34%.
B5, the filtrate A5 that obtains in the steps A 5 is concentrated dried, the evaporate to dryness thing is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers (12Kg), add 96 liters in water, transferring pH value with concentrated hydrochloric acid is 3.5, stir after 2 hours, filter, get filter cake and wash with water, obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (6.84Kg) behind the constant pressure and dry.
C5, fetch and receive product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (6.84Kg), be dissolved in 56 liters of propyl carbinols, add NaOH1.37Kg, temperature rising reflux reaction 3h concentrates reaction solution then and does, and the evaporate to dryness thing adds concentrated hydrochloric acid adjust pH to 3.5, then this mixture was stirred 1 hour, filter, get filter cake, obtain racemic indoline-2-formic acid (6.08Kg) with propyl carbinol washing, constant pressure and dry.
([α] D
20=0 ° of C=1, the hydrochloric acid of 1mol/L)
Embodiment 6:(reclaimer operation 1 time)
A6, (the R)-Alpha-Methyl benzylamine of 5.47Kg and the racemic indoline-2-formic acid of 6.08Kg step C5 preparation are joined in 48.64 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A6 (3.6Kg) and filtrate A6, add 22 premium on currency among the filter cake A6, with the concentrated hydrochloric acid adjust pH is 3.5, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (2.08Kg) 2., chemical purity is 98%, optical purity ee value is 99.5%, and 1. (2S)-indoline-2-formic acid that makes with embodiment 1 merge, and calculating its yield is 51.3%.
B6, the filtrate A6 that obtains in the steps A 6 is concentrated dried, the evaporate to dryness thing is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers (7.2Kg), add 72 liters in water, transferring pH value with concentrated hydrochloric acid is 3.5, stir after 2 hours, filter, get filter cake and wash with water, obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (3.33Kg) behind the constant pressure and dry.
C6, fetch and receive product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (3.33Kg), be dissolved in 37.96 liters of propyl carbinols, add NaOH 3.33Kg, temperature rising reflux reaction 5h, then reaction solution is concentrated and do, the evaporate to dryness thing adds concentrated hydrochloric acid adjust pH to 3.5, then this mixture was stirred 1 hour, filter, get filter cake with propyl carbinol washing, constant pressure and dry, obtain racemic indoline-2-formic acid (2.96Kg).
Twice of embodiment 7:(reclaimer operation)
A7, (the R)-Alpha-Methyl benzylamine of 2.66Kg and the racemic indoline-2-formic acid of 2.96Kg step C6 preparation are joined in 28.4 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A7 (1.8Kg) and filtrate A7, add 14.4 premium on currency among the filter cake A7, with the concentrated hydrochloric acid adjust pH is 3.0, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (0.98Kg) 3., chemical purity is 98%, optical purity ee value is 99.6%, with (2S)-indoline-2-formic acid 1. and (2S)-2. indoline-2-formic acid merge, calculating its yield is 59.5%.
B7, get the filtrate A7 that obtains in embodiment 7 steps A 7 and concentrate and do, the evaporate to dryness thing is (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers (2.8Kg), add 28 liters in water, transferring pH value with concentrated hydrochloric acid is 4.0, stir after 2 hours, filter, get filter cake and wash with water, obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (1.6Kg) behind the constant pressure and dry.
C7, fetch and receive product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures (1.6Kg), be dissolved in 16 liters of propyl carbinols, add NaOH0.8Kg, temperature rising reflux reaction 5h concentrates reaction solution then and does, and the evaporate to dryness thing adds concentrated hydrochloric acid adjust pH to 3.5, then this mixture was stirred 1 hour, filter, get filter cake, obtain racemic indoline-2-formic acid (1.4Kg) with propyl carbinol washing, constant pressure and dry.
Embodiment 8:(reclaimer operation 3 times)
A8, (the R)-Alpha-Methyl benzylamine of 1.26Kg and the racemic indoline-2-formic acid of 1.4Kg step C7 preparation are joined in 13.44 liters of ethanol, heating is stirred 4 hours after-filtration for complete molten back 25 ℃, obtain filter cake A8 (0.8Kg) and filtrate A8, add 4.8 premium on currency among the filter cake A8, with the hydrochloric acid adjust pH is 4.0, restir filtered in 2 hours, getting filter cake washes with water, (2S)-indoline-2-formic acid that obtains crystalline form behind the constant pressure and dry is (0.46Kg) 4., chemical purity is 98%, optical purity ee value is 99.4%, 1.～3. merges with (2S)-indoline-2-formic acid, and calculating its yield is 63.3%.
Claims (10)
1. preparation method suc as formula (2S) shown in (I)-indoline-2-formic acid is characterized in that described method may further comprise the steps:
(1) (2R)-indoline-2-formic acid mixtures shown in (2S) shown in the formula (I)-indoline-2-formic acid and the formula (III), in the butanol solution of NaOH, atmospheric pressure reflux is carried out racemization reaction, follows the tracks of the complete afterreaction liquid of detection reaction separating treatment and obtains the racemic indoline-2-formic acid shown in the formula (II); The absolute magnitude of (2R) shown in the described mixture Chinese style (III)-indoline-2-formic acid is preponderated; The consumption of described NaOH is 0.2～1 times of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures quality;
(2) the racemic indoline-2-formic acid shown in the formula (II) that obtains of step (1) with (R)-the Alpha-Methyl benzylamine is in ethanol, stir fully reaction, reaction finishes afterreaction liquid and filters, obtain filter cake A and filtrate A, filter cake A is (2S) isomer shown in the formula (IVa), handles obtaining (2S) shown in the formula (I)-indoline-2-formic acid with hcl acidifying;
2. the method for claim 1 is characterized in that the filtrate A that described step (2) obtains operates according to following steps (3)～(4):
(3) the filtrate A evaporate to dryness that obtains of step (2) obtains (2S) isomer shown in the dominant formula of absolute magnitude (IVa) of (2R) isomer shown in the formula (IVb) and (2R) mixture of isomers shown in the formula (IVb), handles obtaining reclaiming absolute magnitude dominant (2S)-indoline-2-formic acid of product (2R)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures with hcl acidifying;
(4) get absolute magnitude dominant (2S)-indoline-2-formic acid of recovery product (2R)-indoline-2-formic acid that step (3) obtains and (2R)-indoline-2-formic acid mixtures according to step (1), (2), (3) repetitive operation 2～6 times, (2S)-indoline-2-formic acid that at every turn obtains is merged, obtain (2S)-indoline-2-formic acid product;
3. the method for claim 1 is characterized in that in the described step (1), and the consumption of described propyl carbinol is counted 8.2～11.4L/kg with the quality of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures.
4. the method for claim 1 is characterized in that in the described step (1), the reaction times is 2～16 hours.
5. the method for claim 1, it is characterized in that in the described step (1), the step of reaction solution separating treatment is: after reaction finishes, the reaction solution evaporate to dryness, adding the hydrochloric acid adjust pH is 3.0～5.0, stirs fully reaction, filters, filter cake washing, drying obtain the racemic indoline-2-formic acid shown in the formula (II).
6. the method for claim 1 is characterized in that the mass ratio of racemic indoline-2-formic acid in the described step (2) and (R)-Alpha-Methyl benzylamine is 1: 0.6～0.9.
7. the method for claim 1, the step that it is characterized in that the hcl acidifying processing of filter cake A in the described step (2) is: filter cake A adds in the entry, and adding the hydrochloric acid adjust pH is 3.0～4.0, stirs fully reaction, filter, obtain after filter cake washing, the drying (2S)-indoline-2-formic acid.
8. the method for claim 1 is characterized in that consumption of ethanol is counted 6.4～9.6L/kg with the quality of racemic indoline-2-formic acid in the described step (2).
9. method as claimed in claim 2, it is characterized in that in the described step (3), the step of the hcl acidifying of (2R) mixture of isomers shown in (2S) isomer shown in the dominant formula of (2R) isomer absolute magnitude (IVa) shown in the formula (IVb) and the formula (IVb) is: (2R) isomer absolute magnitude dominant (2S) isomer and (2R) mixture of isomers add in the entry, with the hydrochloric acid adjust pH is 3.0～4.0, stir fully reaction, filter, filter cake washing, drying obtains reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures.
10. as the described method of one of claim 1～9, it is characterized in that said method comprising the steps of:
1. (2R)-indoline-2-formic acid mixtures shown in (2S) shown in the formula (I)-indoline-2-formic acid and the formula (III), in the butanol solution of NaOH, atmospheric pressure reflux is carried out racemization reaction, after the tracking detection reaction is complete, the reaction solution evaporate to dryness, adding the hydrochloric acid adjust pH is 3.0～5.0, stir fully reaction, filter, filter cake washing, drying obtain the racemic indoline-2-formic acid shown in the formula (II); The absolute magnitude of (2R) shown in the described mixture Chinese style (III)-indoline-2-formic acid is preponderated; The consumption of described NaOH is 0.2～1 times of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures quality; The consumption of described propyl carbinol is counted 8.2～11.4L/kg with the quality of (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures;
2. the racemic indoline-2-formic acid shown in the formula (II) that 1. obtains of step with (R)-the Alpha-Methyl benzylamine is in ethanol, stir fully reaction, reaction finishes afterreaction liquid and filters, obtain filter cake A and filtrate A, filter cake A is (2S) isomer shown in the formula (IVa), and filter cake A adds in the entry, adding the hydrochloric acid adjust pH is 3.0～4.0, stir fully reaction, filter, obtain after filter cake washing, the drying (2S)-indoline-2-formic acid; The mass ratio of described racemic indoline-2-formic acid and (R)-Alpha-Methyl benzylamine is 1: 0.6～0.9; Described consumption of ethanol is counted 6.4～9.6L/kg with the quality of racemic indoline-2-formic acid;
3. the filtrate A evaporate to dryness that 2. obtains of step obtains (2S) isomer shown in the dominant formula of absolute magnitude (IVa) of (2R) isomer shown in the formula (IVb) and (2R) mixture of isomers shown in the formula (IVb) adds in the entry, with the hydrochloric acid adjust pH is 3.0～4.0, stir fully reaction, filter, filter cake washing, drying obtain reclaiming product (2R)-indoline-2-formic acid absolute magnitude dominant (2S)-indoline-2-formic acid and (2R)-indoline-2-formic acid mixtures;
4. get absolute magnitude dominant (2S)-indoline-2-formic acid of recovery product (2R)-indoline-2-formic acid that 3. step obtain and (2R)-indoline-2-formic acid mixtures according to step 1., 2., 3. repetitive operation 2～6 times, (2S)-indoline-2-formic acid that at every turn obtains is merged, obtain (2S)-indoline-2-formic acid product.
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| CA2488324A1 (en) * | 2004-11-22 | 2006-05-22 | Apotex Pharmachem Inc. | Optical resolution of n-acetyl-indoline-2-carboxylic acid with phenylglycinol |
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| CA2488324A1 (en) * | 2004-11-22 | 2006-05-22 | Apotex Pharmachem Inc. | Optical resolution of n-acetyl-indoline-2-carboxylic acid with phenylglycinol |
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