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Preparation method of (2S)-indoline-2-methanoic acid

A technology of indoline and formic acid, applied in the direction of organic chemistry, etc., to achieve the effect of less environmental pollution, low equipment requirements and safe operation

Active Publication Date: 2011-08-03
安徽美诺华药物化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The method fully recycles the mother liquor after splitting, and the yield is improved, but an autoclave is required

Method used

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  • Preparation method of (2S)-indoline-2-methanoic acid
  • Preparation method of (2S)-indoline-2-methanoic acid
  • Preparation method of (2S)-indoline-2-methanoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] A1, preparation (2S)-indoline-2-carboxylic acid

[0038] Add 7.5Kg of (R)-α-methylbenzylamine and 10Kg of racemic indoline-2-carboxylic acid into 92 liters of ethanol, heat to completely dissolve, stir at 25°C for 4 hours, and filter to obtain a filter cake (2S)- Indoline-2-carboxylic acid ① (3.54Kg), the chemical purity is 98%, the optical purity ee value is 99.8%, and the yield is 35.4%.

[0039]B1, the filtrate A1 obtained in step A1 is concentrated to dryness, and the evaporated product is a mixture (10Kg) of (2S) isomer and (2R) isomer in which the absolute amount of (2R) isomer is dominant, and 80 liters of water is added, Use concentrated hydrochloric acid to adjust the pH value to 3.5, stir for 2 hours, filter, take the filter cake and wash it with water, and dry it under normal pressure to obtain the recovered product (2R)-indoline-2-carboxylic acid (2S)- Indoline-2-carboxylic acid and (2R)-indoline-2-carboxylic acid mixture (5.5 Kg).

[0040] C1, get the (2...

Embodiment 2

[0042] Embodiment 2: (recovery operation 1 time)

[0043] A2. Add 3.43Kg of (R)-α-methylbenzylamine and 4.58Kg of racemic indoline-2-carboxylic acid prepared in step C1 to 42 liters of ethanol, heat to dissolve and stir at 25°C for 4 Filter after 1 hour to obtain filter cake A2 (2.1Kg) and filtrate A2, add 16 liters of water in filter cake A2, adjust the pH value to 3.5 with concentrated hydrochloric acid, stir for 2 hours and filter, get filter cake and wash with water, obtain after normal pressure drying (2S)-indoline-2-formic acid 2. (1.6Kg) in crystal form, chemical purity is 98%, optical purity ee value is 99.5%, and (2S)-indoline obtained in Example 1 - 2-formic acid ① combined, the calculated yield was 51.4%.

[0044] B2, the filtrate A2 obtained in step A2 is concentrated to dryness, and the evaporated product is a mixture (5.0Kg) of (2S) isomer and (2R) isomer in which the absolute amount of (2R) isomer is dominant, and 40 liters of water is added , adjust the pH va...

Embodiment 3

[0046] Embodiment 3: (recovery operation twice)

[0047] A3. Add 1.5Kg of (R)-α-methylbenzylamine and 2.0Kg of racemic indoline-2-carboxylic acid prepared in step C2 to 19 liters of ethanol, heat to dissolve and stir at 25°C for 4 Filter after 1 hour to obtain filter cake A3 (1.5Kg) and filtrate A3, add 12 liters of water in filter cake A3, adjust the pH value to 3.5 with concentrated hydrochloric acid, stir for 2 hours and filter, get filter cake and wash with water, obtain after normal pressure drying (2S)-indoline-2-carboxylic acid ③ (0.65Kg) in crystal form, chemical purity is 98%, optical purity ee value is 99.6%, and (2S)-indoline-2-carboxylic acid ① and (2S)-indoline-2-carboxylic acid ② combined, the calculated yield was 57.9%.

[0048] B3. The filtrate A3 obtained in step A3 of Example 3 was concentrated to dryness, and the evaporated product was a mixture (2.1Kg) of (2S) isomer and (2R) isomer in which the absolute amount of (2R) isomer was dominant, Add 18 liters o...

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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 [0001] The invention relates to a preparation method of (2S)-indoline-2-carboxylic acid. (2) Background technology [0002] Controlling hypertension and protecting vascular endothelial function are important goals of secondary prevention of coronary heart disease, and angiotensin-converting enzyme inhibitors (ACEI) are the core drugs to achieve this goal. The main property of perindopril and its pharmaceutically acceptable salts is to inhibit angiotensin I converting enzyme (or kininase II). Moreover, in clinical practice, the benefits of perindopril in controlling blood pressure and preventing events in the chain of cardiovascular events have also been confirmed. [0003] Racemic indoline-2-formic acid obtains (2S) indoline-2-formic acid shown in formula (I) by resolution, and (2S) indoline-2-formic acid can be used for Synthesis of pharmaceutically acceptable salts of perindopril of formula (V) having pharmacological value. [0004] [0005] The u...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/42
Inventor 沈正清杨吉
Owner 安徽美诺华药物化学有限公司