Recovery method of 2-cyano-2-valproic acid

Abstract

The invention relates to a recovery method of 2-cyano-2-valproic acid as shown in a chemical structural formula I. The recovery method is characterized in that 2-cyano-2-valproic acid as shown in a formula II is prepared by catalytic dipropylation of cyanoacetate and 1-chloropropane under the action of K2CO3: # imgabs0 # R is selected from methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl or amyl; pTC is selected from quaternary ammonium salts; in a process for preparing 2-cyano-2-valproate as shown in a formula II, 2-cyano-2-potassium valproate K remaining in inorganic salt is dissolved in water and acidified into 2-cyano-2-valproic acid as shown in a formula I; and extracting with an organic solvent, and distilling to obtain the 2-cyano-2-valproic acid. # imgabs1 #

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical industry, in particular to a method for recovering 2-cyano-2-valproic acid in a 2-cyano-2-valproic acid ester preparation process and an application thereof in preparing valproic acid or valproamide by a cyanoacetate method. Background Art

[0002] Peng Xiangyun and Xu Chengzhi [Study on solid-liquid phase alkylation reaction I. Alkylation reaction of diethyl malonate and ethyl cyanoacetate using potassium carbonate as base. Acta Chimica Sinica, 1983, 41(6):514-518.] Ethyl cyanoacetate was reacted with 1-bromopropane for 7 hours to obtain ethyl 2-cyanovalerate with a yield of 54.2% and ethyl 2-cyano-2-valeric acid with a yield of 10.2%.

[0003]

[0004] Indian patent [IN486MU2014A, 2015-09-25] selects ethyl cyanoacetate and 1-bromopropane to undergo dipropylation under the action of sodium propoxide to prepare ethyl 2-cyano-2-valeroponic acid, and the latter is catalytically hydrolyzed to obtain 2-cyano-2-valeroponic acid with a yield of 90% to 94%; 2-cyano-2-valeroponic acid is catalytically hydrolyzed with sulfuric acid to prepare valeroponic acid with a yield of 85% to 90%; the preparation reaction is as follows:

[0005]

[0006] British patent [GB2068962A, 1981-08-19] describes the preparation of valproic acid by hydrolysis of valproonitrile catalyzed by sulfuric acid; the preparation reaction is as follows:

[0007]

[0008] Shanghai Qingping Pharmaceutical Co., Ltd. [A new method for preparing valproic acid, CN 2021103366414, published on August 3, 2021; A method for preparing sodium valproate, CN2021103339474, published on August 3, 2021; A method for preparing valproic acid, CN 2021103366274, published on July 27, 2021] describes a method for preparing valproic acid and sodium valproate: using valproonitrile or 2-cyano-2-valproic acid as a raw material, sulfuric acid as a catalyst, reacting at 120-160°C for 20h-40h to obtain valproic acid with a yield of 70%-80%; its synthetic route is as follows:

[0009]

[0010] Hunan Xiangzhong Pharmaceutical Co., Ltd. and Hunan University [A composite catalytic preparation method of 2-cyano-2-valproic acid methyl ester, ZL2022101320660, authorized on 2023.03.31; A preparation method and application of 2-cyano-2-valproic acid, ZL2022101320389, authorized on 2023.03.17; A 2-cyano-2-valproic acid ester and its preparation method and application, CN2022101320374, published on 2023.08.22; A cyanoacetate method for preparing valproic acid, CN118373735A, published on 2024.07.23] selected the cyanoacetate method to prepare valproic acid.

[0011]

[0012] R is selected from: methyl or ethyl;

[0013] In the process of preparing the intermediate 2-cyano-2-valproate, potassium 2-cyano-2-valproate (K) may remain in the inorganic salt solid obtained by filtration:

[0014] Summary of the invention

[0015] The present invention provides a method for recovering 2-cyano-2-valeric acid shown in formula I, wherein cyanoacetate and 1-chloropropane are selected, and catalytic dipropylation is performed under the action of K2CO3 to obtain 2-cyano-2-valeric acid ester shown in formula II:

[0016]

[0017] R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl.

[0018] The dipropylated PTC is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide or benzyltrimethylammonium iodide.

[0019] The 2-cyano-2-valproic acid ester is selected from methyl 2-cyano-2-valproate, ethyl 2-cyano-2-valproate, propyl 2-cyano-2-valproate or butyl 2-cyano-2-valproate.

[0020] In the process for preparing 2-cyano-2-valproic acid ester shown in formula II, potassium 2-cyano-2-valproic acid (K) remains in the inorganic salt solid obtained by filtration; the potassium 2-cyano-2-valproic acid K remaining in the inorganic salt is dissolved in water and acidified to obtain 2-cyano-2-valproic acid shown in formula I; 2-cyano-2-valproic acid (I) is obtained by extraction with an organic solvent and distillation, and I is decarboxylated to obtain valproonitrile:

[0021]

[0022] In the recovery method of 2-cyano-2-valproic acid, hydrochloric acid is used for acidification, and the acidification pH value is controlled at 1.0 to 5.5.

[0023] The organic solvent is selected from ethyl acetate, methyl acetate, dichloromethane, chloroform, n-hexane, cyclohexane, methyl tert-butyl ether or petroleum ether.

[0024] Valproic acid is prepared by hydrolysis catalyzed by sulfuric acid as described in British Patent [GB2068962A, 1981-08-19].

[0025] The present invention also provides a method for recovering 2-cyano-2-valeric acid shown in formula I, wherein methyl cyanoacetate and 1-chloropropane are selected, and catalyzed by dipropylation under the action of K2CO3 to obtain methyl 2-cyano-2-valeric acid shown in formula IIa:

[0026]

[0027] The dipropylated PTC is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide or benzyltrimethylammonium iodide.

[0028] In the process for preparing methyl 2-cyano-2-valproate shown in formula IIa, potassium 2-cyano-2-valproate (K) remains in the inorganic salt solid obtained by filtration; the potassium 2-cyano-2-valproate K remaining in the inorganic salt is dissolved in water and acidified to obtain 2-cyano-2-valproate acid shown in formula I; 2-cyano-2-valproate (I) is extracted with an organic solvent and distilled to obtain 2-cyano-2-valproate, and I is decarboxylated to obtain valproonitrile:

[0029]

[0030] In the recovery method of 2-cyano-2-valproic acid, hydrochloric acid is used for acidification, and the pH value of acidification is controlled at 1.0-5.5.

[0031] The organic solvent is selected from ethyl acetate, methyl acetate, dichloromethane, chloroform, n-hexane, cyclohexane, methyl tert-butyl ether or petroleum ether.

[0032] The present invention also provides a method for recovering 2-cyano-2-valeric acid shown in formula I, wherein ethyl cyanoacetate and 1-chloropropane are selected, and catalyzed by dipropylation under the action of K2CO3 to obtain ethyl 2-cyano-2-valeric acid ester shown in formula IIb:

[0033]

[0034] The dipropylated PTC is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide or benzyltrimethylammonium iodide.

[0035] In the process for preparing ethyl 2-cyano-2-valproate shown in formula IIb, potassium 2-cyano-2-valproate (K) remains in the inorganic salt solid obtained by filtration; the potassium 2-cyano-2-valproate K remaining in the inorganic salt is dissolved in water and acidified to obtain 2-cyano-2-valproate acid shown in formula I; 2-cyano-2-valproate (I) is extracted with an organic solvent and distilled to obtain 2-cyano-2-valproate, and I is decarboxylated to obtain valproonitrile:

[0036]

[0037] In the recovery method of 2-cyano-2-valproic acid, hydrochloric acid is used for acidification, and the pH value of acidification is controlled at 1.0-5.5.

[0038] The organic solvent is selected from ethyl acetate, methyl acetate, dichloromethane, chloroform, n-hexane, cyclohexane, methyl tert-butyl ether or petroleum ether.

[0039] Compared with the prior art, the present invention has the following advantages:

[0040] (1) The present invention is the first to recover 2-cyano-2-valerioic acid represented by formula I from the inorganic salt solid obtained by post-treatment filtration and separation in the process of preparing 2-cyano-2-valerioic acid ester.

[0041]

[0042] (2) Decarboxylation of 2-cyano-2-valproic acid produces valproonitrile; the latter is hydrolyzed with sulfuric acid to produce valproamide or valproic acid.

[0043] (3) By recovering and utilizing 2-cyano-2-valproic acid, the total yield of valproic acid or valproamide can be increased, the production cost of valproic acid or valproamide can be reduced, and environmental pressure can also be reduced. DETAILED DESCRIPTION

[0044] The present invention is further described in detail below in conjunction with the embodiments.

[0045] Example 1

[0046] Preparation of 2-cyano-2-valerioic acid methyl ester (Ⅱa)

[0047]

[0048] 99.1g (1.0mol) methyl cyanoacetate, 0.02mol tetrabutylammonium bromide, 1.18g potassium bromide, 263.2g (1.9mol) K2CO3 (300 mesh), 400ml (377.6g) DMF, 180g (2.29mol) 1-chloropropane. After the addition, set the oil bath temperature to 75℃ for 2h under stirring, the reaction liquid gradually darkens in color, and then stir at 95℃ (oil bath) for 3h; after the reaction, cool to below 45℃, filter inorganic salts, wash the filter cake until white, and drain. The filtrate is vacuum distilled to recover until there is basically no distillation, cool to below 30℃, add 300mL petroleum ether, wash the organic phase with 10% NaOH, then wash with water, recover petroleum ether by atmospheric distillation, and vacuum distill to obtain 187.4g 2-cyano-2-valeric acid methyl ester (Ⅱa) as a colorless transparent liquid with a yield of 95.0%. 2-Cyano-2-valerioic acid methyl ester (Ⅱa): 1 H NMR (400MHz, DMSO-d6) δ: 3.76 (s, 3H, OCH3), 1.85-1.75 (m, 4H, CH2×2), 1.52-1.38 (m, 2H, CH2), 1.30-1.17 (m, 2H, CH2), 0.91 (t, J=7.2Hz, 6H, CH3×2).

[0049] Example 2

[0050] Recovery of 2-cyano-2-valeric acid (Ⅰ)

[0051]

[0052] Water was added to dissolve the inorganic salt obtained in Example 1, hydrochloric acid was added to acidify to pH 1.5, petroleum ether or cyclohexane was selected for extraction, petroleum ether or cyclohexane was recovered by distillation, and 3.4 g of 2-cyano-2-valeric acid (I) was obtained by cooling.

[0053] 2-Cyano-2-propanoic acid (Ⅰ): 1 HNMR (400MHz, DMSO-d6) δ: 13.76 (s, 1H, CO2H), 1.84-1.67 (m, 4H, CH2×2), 1.54-1.41 (m, 2H, CH2), 1.36-1.21 (m, 2H, CH2), 0.92 (t, J=7.2Hz, 6H, CH3×2).

[0054] Example 3

[0055] Preparation of ethyl 2-cyano-2-valeroponic acid ester (Ⅱb)

[0056]

[0057] 113.1g (1.0mol) ethyl cyanoacetate, 0.02mol tetraethylammonium bromide, 1.18g potassium bromide, 207g (1.5mol) K2CO3 (300 mesh), 283g DMF, 172.7g (2.2mol) 1-chloropropane. After the addition, stir and react at 85℃ (oil bath) for 2h, then heat to 100℃ (oil bath) and stir and react for 3h (LC monitors the reaction end point). After the reaction, cool to below 45℃, filter inorganic salts, wash the filter cake with recovered DMF until white, and drain. The filtrate is vacuum distilled and recovered until there is basically no distillation, cool to below 30℃, add petroleum ether, wash the organic phase with 10% NaOH, then wash with water, recover petroleum ether by atmospheric distillation, and vacuum distill to obtain 191.1g 2-cyano-2-valeric acid ethyl ester (Ⅱb) as a colorless transparent liquid with a yield of 96.9%.

[0058] 2-Cyano-2-valeric acid ethyl ester (Ⅱb): 1 H NMR (400MHz, DMSO-d6) δ: 4.22 (q, J=7.2Hz, 2H, OCH2), 1.84-1.75 (m, 4H, CH2×2), 1 .52-1.39 (m, 2H, CH2), 1.31-1.18 (m, 5H, CH2+CH3), 0.91 (t, J=7.2Hz, 6H, CH3×2).

[0059] Example 4

[0060] Recovery of 2-cyano-2-valeric acid (Ⅰ)

[0061]

[0062] Water was added to dissolve the inorganic salt obtained in Example 3, hydrochloric acid was added to acidify to pH 1.5, petroleum ether or ethyl acetate was selected for extraction, petroleum ether or ethyl acetate was recovered by distillation, and 2.5 g of 2-cyano-2-valeric acid (I) was obtained by cooling.

[0063] 2-Cyano-2-propanoic acid (Ⅰ): 1 HNMR (400MHz, DMSO-d6) δ: 13.76 (s, 1H, CO2H), 1.84-1.67 (m, 4H, CH2×2), 1.54-1.41 (m, 2H, CH2), 1.36-1.21 (m, 2H, CH2), 0.92 (t, J=7.2Hz, 6H, CH3×2).

[0064] Example 5

[0065] Preparation of Propylvaleronitrile

[0066]

[0067] Propyl valeronitrile was prepared according to the method [A composite catalytic preparation method for methyl 2-cyano-2-valeronitrile, ZL2022101320660, authorized on March 31, 2023; A preparation method and application of 2-cyano-2-valeronitrile, ZL2022101320389, authorized on March 17, 2023]: 2-cyano-2-valeronitrile was added to a decarboxylation distillation flask, the oil bath temperature was adjusted to 140°C, water was evaporated, the internal temperature was raised to 130-160°C for decarboxylation, and the reaction was kept warm for 3 hours; after decarboxylation, low boiling points were collected to an internal temperature of 180°C, and normal boiling points were collected instead. Normal boiling points were collected under normal pressure to an internal temperature of 210°C. When there was no distillate, vacuum distillation was performed to collect the mixture until the internal temperature was 210°C to obtain colorless transparent liquid propyl valeronitrile.

[0068] Example 6

[0069] Preparation of 2-cyano-2-valeric acid n-propyl ester (Ⅱc)

[0070]

[0071] According to the method of Example 1, n-propyl cyanoacetate was selected to prepare n-propyl 2-cyano-2-propanoate (IIc).

[0072] 2-Cyano-2-propylpentanoate (Ⅱc), 1H NMR (400MHz, CDCl3) δ: 4.16 (t, J=6.6Hz, 2H, OCH2), 1.93-1.84 (m, 2H, CH2), 1.81-1.68 ( m, 4H, CH2×2), 1.66-1.54 (m, 2H, CH2), 1.40-1.29 (m, 2H, CH2), 1.02-0.93 (m, 9H, CH3×3).

[0073] Example 7

[0074] Recovery of 2-cyano-2-valeric acid (Ⅰ)

[0075]

[0076] Water was added to dissolve the inorganic salt obtained in Example 6, concentrated hydrochloric acid was added to acidify to pH 2.0, petroleum ether or ethyl acetate was selected for extraction, petroleum ether or ethyl acetate was recovered by distillation, and 2-cyano-2-valeric acid (I) was obtained by cooling.

[0077] Example 8

[0078] Preparation of valproic acid

[0079] Valproic acid is prepared by hydrolysis catalyzed by sulfuric acid as described in British Patent [GB2068962A, 1981-08-19].

[0080] Example 9

[0081] Preparation of valproic acid

[0082] 2-Cyano-2-valproic acid is prepared by sulfuric acid-catalyzed hydrolysis according to Indian patent [IN486MU2014A, 2015-09-25].

[0083] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it is apparent that various modifications and variations may be made without departing from the spirit and scope of the present invention. Therefore, the description should be regarded as illustrative rather than restrictive.

Claims

1. A method for recovering 2-cyano-2-valproic acid represented by chemical formula I, Features Cyanoacetate and 1-chloropropane, in K 2 CO 3 Under the action of , 2-cyano-2-propanoic acid ester shown in formula II is prepared by catalytic dipropylation: R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl; dipropylated PTC is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetradecyltrimethylammonium chloride, tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium iodide, hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium bromide or benzyltrimethylammonium iodide; In the process for preparing 2-cyano-2-valproic acid ester shown in formula II, potassium 2-cyano-2-valproic acid K remains in the inorganic salt solid obtained by filtration; the potassium 2-cyano-2-valproic acid K remaining in the inorganic salt is dissolved in water and acidified to obtain 2-cyano-2-valproic acid shown in formula I; 2-cyano-2-valproic acid is extracted with an organic solvent and distilled to obtain 2-cyano-2-valproic acid:

2. The method for recovering 2-cyano-2-valproic acid as claimed in claim 1, wherein hydrochloric acid is used for acidification and the acidification pH value is controlled at 1.0 to 5.

5.

3. The recovery method of 2-cyano-2-valproic acid as claimed in claim 1, wherein hydrochloric acid is used for acidification, and the acidification pH value is controlled at 1.5 to 4.

5.

4. The method for recovering 2-cyano-2-valproic acid as claimed in claim 1, wherein hydrochloric acid is used for acidification, and the acidification pH value is controlled at 1.5 to 3.

5.

5. The method for recovering 2-cyano-2-valproic acid as claimed in claim 1, Features The organic solvent is selected from ethyl acetate, methyl acetate, dichloromethane, chloroform, n-hexane, cyclohexane, methyl tert-butyl ether or petroleum ether.

6. The method for recovering 2-cyano-2-valeric acid as claimed in claim 1, Features The organic solvent is selected from ethyl acetate, methyl acetate, n-hexane, cyclohexane or petroleum ether.

7. The method for recovering 2-cyano-2-valeric acid as claimed in claim 1, Features The organic solvent is selected from ethyl acetate, methyl acetate, n-hexane or cyclohexane.

8. The method for recovering 2-cyano-2-valproic acid as claimed in claim 1, wherein the 2-cyano-2-valproic acid ester shown in Formula II is selected from methyl 2-cyano-2-valproate, ethyl 2-cyano-2-valproate, propyl 2-cyano-2-valproate or butyl 2-cyano-2-valproate.

9. The method for recovering 2-cyano-2-valproic acid as claimed in claim 1, wherein the 2-cyano-2-valproic acid ester shown in formula II is selected from methyl 2-cyano-2-valproate, ethyl 2-cyano-2-valproate or propyl 2-cyano-2-valproate.

10. The method for recovering 2-cyano-2-valproic acid according to claim 1, wherein the 2-cyano-2-valproic acid ester represented by formula II is selected from methyl 2-cyano-2-valproate or ethyl 2-cyano-2-valproate.

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