CN112375028A - Method for synthesizing (2S) -indoline-formic acid - Google Patents

Method for synthesizing (2S) -indoline-formic acid Download PDF

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CN112375028A
CN112375028A CN202011464840.5A CN202011464840A CN112375028A CN 112375028 A CN112375028 A CN 112375028A CN 202011464840 A CN202011464840 A CN 202011464840A CN 112375028 A CN112375028 A CN 112375028A
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indoline
carboxylic acid
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per
formic acid
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熊世武
潘启娇
张飞
张华�
刘文金
孙海涛
宁方青
刘刚
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Anhui Menovo Pharmaceuticals Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04Indoles; Hydrogenated indoles
    • C07D209/30Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07Optical isomers

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Abstract

The invention relates to a method for synthesizing (2S) -indoline-formic acid, belonging to the technical field of chiral isomer resolution. The method sequentially comprises the following steps: reacting racemic indole-2-carboxylic acid with acetic anhydride, hydrogenating, reacting with hydrochloric acid, and reacting with chiral amine; after the reaction is finished, on one hand, separating out the (2S) isomer, and treating the isomer with hydrochloric acid to obtain (2S) indoline-2-formic acid; on the other hand, the mixture is separated, treated with hydrochloric acid and then racemized by reaction with a base to give racemic indoline-2-carboxylic acid after separation; the above procedure was repeated and then all the components of indoline-2-carboxylic acid were combined. The invention takes indole-2-formic acid as raw material to replace indoline-2-formic acid in the prior art; compared with indoline-2-formic acid, the indole-2-formic acid has the advantage of low price, and can obviously reduce the production cost.

Description

Method for synthesizing (2S) -indoline-formic acid
Technical Field
The invention relates to a preparation method of perindopril intermediate, in particular to a method for synthesizing (2S) -indoline-formic acid, belonging to the technical field of chiral isomer resolution.
Background
Perindopril (Perindopril, with the trade name of Yaschada) is an angiotensin converting enzyme inhibitor without sulfhydryl developed by Shivica corporation in the eighties of the last century, is a chiral medicine with good clinical curative effect, high safety and small side effect in the current angiotensin converting enzyme inhibitor antihypertensive medicines internationally, and has good market prospect.
The perindopril intermediate (S) -indoline-2-formic acid (III) is a synthetic route for preparing (S) -indoline-2-formic acid (III) by taking indole-2-formic acid (I) aS a raw material in a plurality of routes for synthesizing perindopril main ring (2S,3a S,7aS) -octahydroindole-2-formic acid (IV), and is an industrial research hotspot because the synthetic route meets the advantages of easy operability, environmental friendliness and the like.
Figure 835949DEST_PATH_IMAGE002
The invention patent publication No. CN1768019A reports that racemic indoline-2-formic acid reacts with chiral amine under the condition of taking alcohol as solvent, the obtained crystal is filtered, and then (S) -indoline-2-formic acid (III) is obtained by dissociation. However, the (S) -indoline-2-carboxylic acid (III) obtained in practice often needs to be refined again to obtain the product (III) having high optical purity.
The process for synthesizing the optically active (S) -indoline-2-carboxylic acid (III) further comprises: the hydrolysis of optically active indole-formates using biocatalysts (see Takashi Sugai, et al, Bull. chem. Jpn., 77, 1021. sup. 1025 (2004)) is carried out in water, and therefore the reaction rate is slow and the yield is low.
Disclosure of Invention
In order to overcome the defects of the method and meet the requirement of industrial production, the method adopts a mixture (1: 0.1-5.0) of ketones and water which are soluble in water as a resolution solvent to successfully obtain a perindopril intermediate (S) -indoline-2-formic acid (III) with high optical purity, and the total yield can reach 81%.
The technical scheme for solving the problems is as follows:
a method of synthesizing (2S) -indoline-carboxylic acid comprising the steps of:
s1: reacting racemic indole-2-carboxylic acid of formula (I) with acetic anhydride to give N-acetylindole-2-carboxylic acid of formula (PER-1);
s2: placing N-acetylindole-2-formic acid of formula (PER-1), a solvent and a hydrogenation reaction catalyst into an autoclave, heating to 60-120 ℃, introducing hydrogen, and reacting for 3-10 hours under the pressure of 0.3-1.0 MPa to obtain N-acetylindoline-2-formic acid of formula (PER-2);
s3: adding N-acetyl indoline-2-formic acid of the formula (PER-2) into hydrochloric acid, and carrying out reflux reaction for 30-60 min to obtain racemic indoline-2-formic acid of the formula (PER-3);
s4: reacting racemic indoline-2-carboxylic acid of formula (PER-3) with chiral amine, after the reaction is finished, on one hand, separating (2S) isomer of formula (PER-4 a) in crystal form, and then treating (2S) isomer of formula (PER-4 a) with hydrochloric acid to obtain (2S) indoline-2-carboxylic acid of formula (PER-5); on the other hand, a mixture comprising the (2S) isomer of the formula (PER-4 a) and the (2R) isomer of the formula (PER-4 b) in which the (2R) isomer is dominant is separated by evaporating the filtrate, and the mixture is treated with hydrochloric acid to give a mixture of (2R) -indoline-2-carboxylic acid and (2S) -indoline-2-carboxylic acid, wherein (2R) -indoline-2-carboxylic acid is predominant, followed by racemization by reaction with a base at a temperature of 140 to 200 ℃ and a pressure of 5 to 15bar, after separation, racemic indoline-2-formic acid of formula (PER-3) is obtained, repeating the above steps, and then combining all the components of (2S) indoline-2-carboxylic acid of formula (PER-5) after 2-6 cycles have been performed.
Figure DEST_PATH_IMAGE003
Preferably, in the step S4, when reacting racemic indoline-2-carboxylic acid of formula (PER-3) with a chiral amine, (R) - α -methylbenzylamine is added to a solution of a mixed solvent of racemic indoline-2-carboxylic acid of formula (PER-3) and stirred; the mixed solvent is a mixture of acetone and water.
Preferably, the solvent in step S2 is ethanol, and the hydrogenation catalyst is PdCl2/C。
Preferably, step S1 is specifically: dissolving indole-2-formic acid, 4-methylamino pyridine, triethylamine and acetone in 40-45%oC, stirring for 15-45 min, and cooling to 15-25oC, adding acetic anhydride, stirring for 30-60 min, dripping the obtained mixture into hydrochloric acid, and controlling the temperature to be not more than 15 DEGoAnd C, stirring for 45-80 min, filtering the obtained solid, washing a filter cake, and drying to obtain the N-acetylindole-2-formic acid.
Preferably, step S2 is specifically: mixing N-acetyl indole-2-formic acid, ethanol and PdCl2Placing the/C into a high-pressure kettle, replacing gas in the kettle with nitrogen, and heating to 70-80 DEGoAnd C, introducing hydrogen until no hydrogen is absorbed, slowly heating to 95-105 ℃, reacting for 1-5 h under the pressure of 0.3-0.6 Mpa, cooling to 10-25 ℃, replacing gas in the kettle with nitrogen, filtering the catalyst, distilling the solvent under reduced pressure, adding isopropyl acetate, refluxing for 0.5-2 h, cooling to 10-25 ℃, filtering, washing a filter cake with isopropyl acetate, and drying to obtain the N-acetylindoline-2-formic acid.
Preferably, step S3 is specifically: adding N-acetylindoline-2-formic acid into hydrochloric acid in batches, slowly heating to an internal temperature of 100-105 ℃, performing reflux reaction for 30-60 min, cooling to 65-75 ℃, adding activated carbon for decolorization, filtering, cooling filtrate to 10-25 ℃, adjusting the pH value to 2.0-5.0 by using NaOH, stirring for 15-45 min, filtering, washing filter cakes by using purified water, and drying to obtain the racemized indoline-2-formic acid.
Preferably, in step S4, the racemization is specifically performed by mixing a mixture of (2R) -indoline-2-carboxylic acid and (2S) -indoline-2-carboxylic acid in which (2R) -indoline-2-carboxylic acid predominates, acetic anhydride, and acetic acid, slowly heating to 90 to 120 ℃, stirring for 2 to 5 hours, cooling, then dropwise adding water and hydrochloric acid, continuing heating to 90 to 120 ℃, stirring for 3 to 6 hours, concentrating the obtained solution under vacuum, diluting with water, cooling to 0 to 5 ℃, then dropwise adding sodium hydroxide solution to adjust the pH value to 2.0 to 4.0, stirring for 30 to 60 minutes, filtering, washing the filter cake with water, and drying the solid under vacuum to obtain the racemic indoline-2-carboxylic acid.
The invention has the following beneficial effects:
1. the invention takes indole-2-formic acid as raw material to replace indoline-2-formic acid in the prior art; compared with indoline-2-formic acid, the indole-2-formic acid has the advantage of low price, and can obviously reduce the production cost;
2. according to the invention, indole-2-formic acid is taken as a raw material, when indoline-2-formic acid is prepared, firstly a target group is protected through acylation, then catalytic hydrogenation is carried out, and then hydrochloric acid is added for reaction to carry out deprotection, so that indoline-2-formic acid is obtained; in the process, acetic anhydride is used for processing, PER-1 (amide structure) is generated through reaction, the power supply property of the power supply group of the amido can be reduced, the subsequent reduction reaction is convenient, and harsh conditions (otherwise, higher reaction pressure is needed) are not needed; on the other hand, if the scheme is not adopted and the hydrogenation is directly catalyzed, the existence of the imino group can reduce the catalytic activity of palladium/carbon and increase the cost;
3. the invention adopts a mixed solvent method, and has the advantage of good effect compared with the resolution of a single solvent method; because the effect of separating the indoline-2-formic acid with the S configuration by the mixed solvent method is better.
Detailed Description
The following examples are intended to illustrate the invention but are not to be construed as limiting it.
Figure DEST_PATH_IMAGE005
Example 1
Preparation of N-acetylindole-2-carboxylic acid (PER-1)
32.2g (0.2mol) of indole-2-carboxylic acid (I), 0.24g of 4-methylaminopyridine, 35ml of triethylamine and 45ml of acetone are added into 40-45oC stirring for 0.5 hour, cooling to 20oC, adding 21ml of acetic anhydride, stirring for 45 minutes, dropping the obtained mixture into a mixture containing 26ml of 33% hydrochloric acid, 50g of ice cubes and 80ml of water, and controlling the temperature not to exceed 15 DEGoC, stirring for 1 hour, filtering the obtained solid, washing a filter cake by using ice water, and drying to obtain 37.4g N-acetylindole-2-formic acid with the yield of 92.7%.
Example 2
Preparation of N-acetylindoline-2-carboxylic acid (PER-2)
40.6g (0.2mol) of N-acetylindole-2-carboxylic acid, 150ml of 90% ethanol, 5% PdCl2Placing C3 g into an autoclave, replacing with nitrogen at 0.1Mpa for three times, and heating to 75oC, introducing hydrogen until no hydrogen is absorbed, taking about 5 hours, and slowly heating to 100 DEG CoCReacting under 0.5Mpa for 2 hr, cooling to 20 oCReplacing with nitrogen for three times, filtering catalyst, distilling solvent under reduced pressure, adding isopropyl acetate 150ml, refluxing for 1 hr, cooling to 10 deg.C oCFiltering, washing the filter cake with cold isopropyl acetate, drying to obtain 36.1g N-acetyl indoline-2-formic acid with 88% yield.
EXAMPLE 3 preparation of indoline-2-carboxylic acid (PER-3)
41.1 g (0.2mol) of N-acetylindoline-2-carboxylic acid are added in portions to 100ml of 5N hydrochloric acid and the slurry is slowly warmed up to an internal temperature of 102 oCReflux reaction for 45min, cooling to 70% oCAdding 1.5g of active carbon for decolorization, filtering, and cooling the filtrate to 20oCThe pH =4 was adjusted with 50% NaOH, and the mixture was stirred for 0.5 hour, filtered, and the filter cake was washed with purified water and dried to obtain 28.4g of indoline-2-carboxylic acid with a yield of 87%.
Content (HPLC) 99.6% (area normalization method)
Example 4 preparation of (2S) -indoline-2-carboxylic acid (PER-5)
(A) And a step of splitting
37 g of (R) - α -methylbenzylamine was added to 50g of indoline-2-carboxylic acid in 150ml of an acetone-water (1:1) mixed solvent, and the mixture was stirred for 2 hours and then filtered to obtain (R) - α -methylbenzylamine salt of (2S) -indoline-2-carboxylic acid.
The white precipitate collected in the above resolution step was recrystallized from acetone-water (1:1), then dissolved in 130ml of water and 120ml of lN hydrochloric acid solution was added. After stirring for 2 hours, the precipitate is filtered off, washed and dried, giving 18g of crystalline (2S) -indoline-2-carboxylic acid having a chemical purity of 98% and an enantiomeric purity of more than 99.5%.
The filtrate collected in step a was evaporated and the resulting residue was dissolved in 130ml of water, followed by addition of 120ml of lN hydrochloric acid solution. After stirring for 2 hours, the precipitate was filtered off, washed and dried to give indoline-2-carboxylic acid (26 g) as a mixture of the (2R) and (2S) enantiomers in which the (2R) enantiomer predominates.
(B) Racemization step
The mixture of (R) and (S) -indole-2-carboxylic acid (16.4 g), acetic anhydride (26.0 g) and acetic acid (33 ml) was mixed, slowly heated to 100 ℃ and stirred for 3 hours. The temperature is reduced to 85 ℃, a mixed solution of 80ml of water and 17.1g of 32% hydrochloric acid is added dropwise, the mixture is stirred for 5 hours at 100 ℃, and then the obtained solution is concentrated to 30ml under vacuum, diluted by 50ml of water and cooled to 0 ℃. The pH was adjusted to 2.0 by dropwise addition of 25% sodium hydroxide solution. After stirring for 1h at 0-5 ℃, the resulting suspension was filtered and the filter cake was washed with water. The solid was dried under vacuum to give 14.9g of (RS) -indole-2-carboxylic acid, [ alpha ]]D 20=0 (c =1, lN HCl). Can be directly used in step (A)
By resolution, and by-product racemization reuse, the total resolution yield is 81%.
Example 5 preparation of (2S) -indoline-2-carboxylic acid (PER-5) (different acetone-water ratios)
(A) The resolution step (acetone: water = 1:0.5 v/v)
37 g of (R) - α -methylbenzylamine was added to 50g of indoline-2-carboxylic acid in 150ml of an acetone-water (1:0.5) mixed solvent, and the mixture was stirred for 2 hours and then filtered to obtain (R) - α -methylbenzylamine salt of (2S) -indoline-2-carboxylic acid. 18.2g of crystalline (2S) -indoline-2-carboxylic acid having a chemical purity of 98% and an enantiomeric purity of more than 99.5% are obtained.
The filtrate collected in step a was evaporated and the resulting residue was dissolved in 130ml of water, followed by addition of 120ml of lN hydrochloric acid solution. After stirring for 2 hours, the precipitate was filtered off, washed and dried to give indoline-2-carboxylic acid (26.1 g) as a mixture of the (2R) and (2S) enantiomers in which the (2R) enantiomer predominates.
(B) Racemization step
The mixture of (R) and (S) -indole-2-carboxylic acid (16.4 g), acetic anhydride (26.0 g) and acetic acid (33 ml) was mixed, slowly heated to 100 ℃ and stirred for 3 hours. The temperature is reduced to 85 ℃, a mixed solution of 80ml of water and 17.1g of 32% hydrochloric acid is added dropwise, the mixture is stirred for 5 hours at 100 ℃, and then the obtained solution is concentrated to 30ml under vacuum, diluted by 50ml of water and cooled to 0 ℃. The pH was adjusted to 2.5 by dropwise addition of 25% sodium hydroxide solution. After stirring for 1h at 0-5 ℃, the resulting suspension was filtered and the filter cake was washed with water. The solid was dried under vacuum to give 14.7g of (RS) -indole-2-carboxylic acid, [ alpha ]]D 20=0 (c =1, lN HCl). Can be directly used in step (A)
Through resolution and racemization and reutilization of byproducts, the total resolution yield is 80.6 percent.

Claims (4)

1. A method of synthesizing (2S) -indoline-carboxylic acid comprising the steps of:
s1: reacting racemic indole-2-carboxylic acid of formula (I) with acetic anhydride to give N-acetylindole-2-carboxylic acid of formula (PER-1);
s2: placing N-acetylindole-2-formic acid of formula (PER-1), a solvent and a hydrogenation reaction catalyst into an autoclave, heating to 60-120 ℃, introducing hydrogen, and reacting for 3-10 hours under the pressure of 0.3-1.0 MPa to obtain N-acetylindoline-2-formic acid of formula (PER-2);
s3: adding N-acetyl indoline-2-formic acid of the formula (PER-2) into hydrochloric acid, and carrying out reflux reaction for 30-60 min to obtain racemic indoline-2-formic acid of the formula (PER-3);
s4: reacting racemic indoline-2-carboxylic acid of formula (PER-3) with chiral amine, after the reaction is finished, on one hand, separating (2S) isomer of formula (PER-4 a) in crystal form, and then treating (2S) isomer of formula (PER-4 a) with hydrochloric acid to obtain (2S) indoline-2-carboxylic acid of formula (PER-5); on the other hand, a mixture comprising the (2S) isomer of the formula (PER-4 a) and the (2R) isomer of the formula (PER-4 b) in which the (2R) isomer is dominant is separated by evaporating the filtrate, and the mixture is treated with hydrochloric acid to give a mixture of (2R) -indoline-2-carboxylic acid and (2S) -indoline-2-carboxylic acid, wherein (2R) -indoline-2-carboxylic acid is predominant, followed by racemization by reaction with a base at a temperature of 140 to 200 ℃ and a pressure of 5 to 15bar, after separation, racemic indoline-2-formic acid of formula (PER-3) is obtained, repeating the above steps, and then combining all the components of (2S) indoline-2-carboxylic acid of formula (PER-5) after 2-6 cycles have been performed.
Figure DEST_PATH_IMAGE001
2. A process for the synthesis of (2S) -indoline-carboxylic acid according to claim 1, characterised in that: in step S4, when reacting racemic indoline-2-carboxylic acid of formula (PER-3) with chiral amine, (R) - α -methylbenzylamine is added to a solution of a mixed solvent of racemic indoline-2-carboxylic acid of formula (PER-3), followed by stirring; the mixed solvent is a mixture of acetone and water.
3. A method for synthesizing (2S) -indoline-carboxylic acid, characterized by: the solvent in the step S2 is ethanol, and the hydrogenation catalyst is PdCl2/C。
4. A method for synthesizing (2S) -indoline-carboxylic acid, characterized by: in the step S4, the racemization process comprises the steps of mixing a mixture of (2R) -indoline-2-formic acid and (2S) -indoline-2-formic acid with (2R) -indoline-2-formic acid dominating (2R) -indoline-2-formic acid, acetic anhydride and acetic acid, slowly heating to 90-120 ℃, stirring for 2-5 h, cooling, dropwise adding water and hydrochloric acid, continuously heating to 90-120 ℃, stirring for 3-6 h, concentrating the obtained solution under vacuum, diluting with water, cooling to 0-5 ℃, dropwise adding sodium hydroxide solution to adjust the pH value to 2.0-4.0, stirring for 30-60 min, filtering, washing a filter cake with water, and drying the solid under vacuum to obtain the racemic indoline-2-formic acid.
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6183159A (en) * 1984-09-28 1986-04-26 Toray Ind Inc Racemization of n-acetylindoline-2-carboxylic acid
US4935525A (en) * 1987-09-17 1990-06-19 Adir Et Cie Process for the industrial synthesis of (2S, 3aS, 7aS) 2-carboxy perhydroindole, application to the industrial synthesis of carboxyalkyl dipeptides
CN1228423A (en) * 1998-02-13 1999-09-15 Dsm有限公司 Process for preparation of optically active indoline-2-carboxylic acid or derivative thereof
CN1768019A (en) * 2003-04-09 2006-05-03 瑟维尔实验室 method for synthesis of (2s)-indoline-2-carboxylic acid and use in the synthesis of perindopril
WO2006053440A1 (en) * 2004-11-22 2006-05-26 Apotex Pharmachem Inc. New processes for the preparation of optically pure indoline-2-carboxylic acid and n-acetyl-indoline-2-carboxylic acid
CN101774960A (en) * 2009-12-31 2010-07-14 安徽美诺华药物化学有限公司 Preparation method of (2S)-indoline-2-methanoic acid
CN101823993A (en) * 2010-03-31 2010-09-08 安徽世华化工有限公司 Preparation method of L-octohydroindoline-2-formic acid
CN102060745A (en) * 2010-11-23 2011-05-18 安徽世华化工有限公司 Preparation method of (S)-indoline-2-carboxylic acid

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6183159A (en) * 1984-09-28 1986-04-26 Toray Ind Inc Racemization of n-acetylindoline-2-carboxylic acid
US4935525A (en) * 1987-09-17 1990-06-19 Adir Et Cie Process for the industrial synthesis of (2S, 3aS, 7aS) 2-carboxy perhydroindole, application to the industrial synthesis of carboxyalkyl dipeptides
CN1228423A (en) * 1998-02-13 1999-09-15 Dsm有限公司 Process for preparation of optically active indoline-2-carboxylic acid or derivative thereof
CN1768019A (en) * 2003-04-09 2006-05-03 瑟维尔实验室 method for synthesis of (2s)-indoline-2-carboxylic acid and use in the synthesis of perindopril
WO2006053440A1 (en) * 2004-11-22 2006-05-26 Apotex Pharmachem Inc. New processes for the preparation of optically pure indoline-2-carboxylic acid and n-acetyl-indoline-2-carboxylic acid
CN101774960A (en) * 2009-12-31 2010-07-14 安徽美诺华药物化学有限公司 Preparation method of (2S)-indoline-2-methanoic acid
CN101823993A (en) * 2010-03-31 2010-09-08 安徽世华化工有限公司 Preparation method of L-octohydroindoline-2-formic acid
CN102060745A (en) * 2010-11-23 2011-05-18 安徽世华化工有限公司 Preparation method of (S)-indoline-2-carboxylic acid

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