METHOD FOR CO-PRODUCING VALPROAMIDE AND SODIUM VALPROATE

Abstract

A process for preparing valpromide of formula I and sodium valproate of formula II which comprises: cyanoacetate and 1-chloropropane are subjected to composite catalytic dipropylation in the presence of alkali to obtain 2-cyano-2-valproate of formula III; 2-cyano-2-valproate is hydrolyzed and deacidified to give propylvaleronitrile of formula V; propylvaleronitrile is alcoholized in the presence of acid to give valpromide of formula I and valproate ester of formula VI; and valproate ester is hydrolyzed in a sodium hydroxide solution to afford sodium valproate of formula II.

Claims

1. A process for the preparation of valpromide of formula I and sodium valproate of formula II which comprises: performing composite catalytic dipropylation on cyanoacetate and 1-chloropropane in the presence of alkali to obtain 2-cyano-2-valproate of formula III; hydrolyzing and deacidifying 2-cyano-2-valproate to give propylvaleronitrile of formula V; alcoholizing propylvaleronitrile in the presence of acid to give valpromide of formula I and valproate ester of formula VI; and hydrolyzing valproate ester in a sodium hydroxide solution to afford sodium valproate of formula II, wherein the process thereof is as follows: ##STR00031## wherein R.sup.2 is methyl, ethyl, C3-C5 linear alkyl, or C3-C5 branched alkyl; and R.sup.3 is methyl or ethyl; the catalyst for the preparation of 2-cyano-2-valproate of formula III consists of catalyst A and catalyst B; the catalyst A is R.sub.3N, PhNR.sub.2, R.sub.4NX, or R.sub.3R.sup.1NX, wherein R is C1-C4 linear alkyl or C5-C8 linear alkyl; R.sup.1 is PhCH.sub.2, C1-C5 linear alkyl, or C6-C18 linear alkyl; and X is Cl, Br, or I; and the catalyst B is NaBr, KBr, NaI, or KI; the solvent for the preparation of 2-cyano-2-valproate of formula III is one or two selected from the group consisting of THE, DMF, DMC, DMSO, acetonitrile, propionitrile, butyronitrile, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, ethyl acetate and butyl acetate; the alkali for the preparation of 2-cyano-2-valproate of formula III is granular M.sub.2CO.sub.3 or powdery M.sub.2CO.sub.3, wherein M is Na or K; the acid for an alcoholysis reaction of propylvaleronitrile of formula V is hydrogen chloride gas, aluminum trichloride, thionyl chloride, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or sulfuric acid.

2. The process according to claim 1, wherein R.sub.4NX is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, or tetrapropylammonium bromide; and R.sub.3R.sup.1NX is hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, benzyltriethylammonium chloride, b benzyltrimethylammonium chloride, benzyltriethyl-ammonium bromide, hexadecyltriethylammonium bromide, dodecyltriethylammonium bromide, decyltriethylammonium bromide, octyltriethylammonium bromide, hexyltriethylammonium bromide, or trioctylmethylammonium chloride; and R.sub.3N is trimethylamine, triethylamine, tripropylamine and tributylamine; and PhNR.sub.2 is selected from the group consisting of N,N-dimethylaniline, N,N-diethylaniline, N,N-dipropyl-aniline, or N,N-dibutylaniline.

3. The process according to claim 1, wherein the powdery M.sub.2CO.sub.3 is 100-mesh M.sub.2CO.sub.3, 150-mesh M.sub.2CO.sub.3, 200-mesh M.sub.2CO.sub.3, 250-mesh M.sub.2CO.sub.3, 300-mesh M.sub.2CO.sub.3, or 350-mesh M.sub.2CO.sub.3, wherein M is Na or K.

4. The process according to claim 1, wherein the reaction to form the 2-cyano-2-valproate of formula III is conducted in a temperature of 60-120 C.; and the reaction time is in the range of 1.0-12 h.

5. The process according to claim 1, wherein the reaction to form the 2-cyano-2-valproate of formula III is carried out at a molar ratio of cyanoacetate, the catalyst A, and the catalyst B in the range of 1:0.01-0.10:0.005-0.05; and cyanoacetate is methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, or t-butyl cyanoacetate.

6. The process according to claim 1, wherein the alcoholysis reaction of propylvaleronitrile of formula V is carried out at a molar ratio of propylvaleronitrile to acid in the range of 1:1.2-4; the mass concentration of the acid is in the range of 30-70%; and the molar ratio of propylvaleronitrile to R.sup.3OH is in the range of 1:3-8.

7. The process according to claim 1, wherein the alcoholysis reaction of propylvaleronitrile of formula V is conducted in a temperature of 25-100 C.; and the alcoholysis reaction time is in the range of 4-24 h.

8. The process according to claim 1, wherein propylvaleronitrile of formula V is alcoholized to prepare valpromide of formula I and valproate ester of formula VI; and the valproate ester is hydrolyzed in the sodium hydroxide solution to give sodium valproate of formula II, wherein the molar ratio of I to II is in the range of 1:1.5-8.0.

9. A process for co-producing valpromide of formula I and valproic acid of formula VII, comprising preparing propylvaleronitrile of formula V according to claim 1; and performing alcoholysis and hydrolysis on propylvaleronitrile to prepare valpromide of formula I and valproic acid of formula VII, wherein the process thereof is as follows: ##STR00032## wherein R.sup.3 and acid are defined as those in claim 1; and a molar ratio of I to VII is in the range of 1:1.5-8.0.

10. The process according to claim 9, wherein R.sub.4NX is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, or tetrapropylammonium bromide; and R.sub.3R.sub.1NX is hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, benzyltriethyl-ammonium bromide, hexadecyltriethylammonium bromide, dodecyltriethylammonium bromide, decyltriethylammonium bromide, octyltriethylammonium bromide, hexyltriethylammonium bromide, or trioctylmethylammonium chloride; and R.sub.3N is trimethylamine, triethylamine, tripropylamine and tributylamine; and PhNR.sub.2 is selected from the group consisting of N,N-dimethylaniline, N,N-diethylaniline, N,N-dipropyl-aniline, or N,N-dibutylaniline.

11. The process according to claim 9, wherein the powdery M.sub.2CO.sub.3 is 100-mesh M.sub.2CO.sub.3, 150-mesh M.sub.2CO.sub.3, 200-mesh M.sub.2CO.sub.3, 250-mesh M.sub.2CO.sub.3, 300-mesh M.sub.2CO.sub.3, or 350-mesh M.sub.2CO.sub.3, wherein M is Na or K.

12. The process according to claim 9, wherein the reaction to form the 2-cyano-2-valproate of formula III is conducted in a temperature of 60-120 C.; and the reaction time is in the range of 1.0-12 h.

13. The process according to claim 9, wherein the reaction to form the 2-cyano-2-valproate of formula III is carried out at a molar ratio of cyanoacetate, the catalyst A, and the catalyst B in the range of 1:0.01-0.10:0.005-0.05; and cyanoacetate is methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, or t-butyl cyanoacetate.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0042] The present disclosure will be further described in detail below in conjunction with examples.

Example 1

Preparation of 2-cyano-2-valproic methyl ester

##STR00013##

[0043] 29.73 g (0.30 mol) Of methyl cyanoacetate, 12.0 mmol tetrabutylammonium bromide, 3.0 mmol KI, 91.21 g (0.66 mol) of K.sub.2CO.sub.3, 120 ml of DMF and 58.91 g (0.75 mol) of 1-chloropropane were stirred and reacted at 85 C. for 3.0 h (completion of reaction was monitored by TLC). After reaction was completed, the resultant was slightly cooled and then an inorganic salt was filtered out, and 110 ml of DMF was recovered under a reduced pressure. The inorganic salt was washed with petroleum ether, and the organic phase was washed with water until the aqueous phase become colorless. Then the organic phase was dried over anhydrous sodium sulfate, the sodium sulfate was recovered by suction filtration, and the organic phase was distilled under reduced pressure and dried to give 53.06 g of 2-cyano-2-valproic methyl ester, with a yield of 96.50% (based on methyl cyanoacetate). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 3.76 (s, 3H, OCH.sub.3), 1.85-1.75 (m, 4H, CH.sub.22), 1.52-1.38 (m, 2H, CH.sub.2), 1.30-1.17 (m, 2H, CH.sub.2), 0.91 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 2

Preparation of 2-cyano-2-valproic acid

##STR00014##

[0044] 29.73 g (0.30 mol) Of methyl cyanoacetate, 12.0 mmol tetrabutylammonium chloride, 3.0 mmol KI, 91.21 g (0.66 mol) of K.sub.2CO.sub.3, 120 ml of ethylene glycol dimethyl ether and 58.91 g (0.75 mol) of 1-chloropropane were stirred and reacted at 85 C. for 2.5 h (completion of reaction was monitored by TLC). After reaction was completed, the resultant was slightly cooled and then an inorganic salt was filtered out, and 110 ml of ethylene glycol dimethyl ether was recovered under a reduced pressure. The inorganic salt was washed with ethyl acetate, wherein the recovered inorganic salt was KCl and KHCO.sub.3. The organic phase was washed with water until the aqueous phase became colorless. Ethyl acetate was recovered by distillation. Thereafter, 150 ml of 15% KOH was added to the residual yellowish transparent liquid (2-cyano-2-valproic methyl ester), and the mixture was heated and hydrolyzed for 3 h, neutralized by adding concentrated hydrochloric acid to precipitate a solid, which was dried to give 48.69 g of 2-cyano-2-valproic acid as a white solid, with a yield of 95.90% (based on methyl cyanoacetate), and a melting point of 49-50 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 13.76 (s, 1H, CO.sub.2H), 1.84-1.67 (m, 4H, CH.sub.22), 1.54-1.41 (m, 2H, CH.sub.2), 1.36-1.21 (m, 2H, CH.sub.2), 0.92 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 3

Preparation of 2-cyano-2-valproic acid

##STR00015##

[0045] 29.73 g (0.30 mol) Of methyl cyanoacetate, 3.33 g (9.0 mmol) of TBAB, 3.0 mmol KI, 91.21 g (0.66 mol) of K.sub.2CO.sub.3, 120 ml of DMF and 58.91 g (0.75 mol) of 1-chloropropane were stirred and reacted at 85 C. for 3.3 h (completion of reaction was monitored by TLC). After the reaction was completed, the resultant was cooled, and an inorganic salt was filtered out, and 110 ml of DMF was recovered under a reduced pressure. The inorganic salt was washed with petroleum ether (100 ml3), wherein the recovered inorganic salt was KCl and KHCO.sub.3. The organic phase was washed with water (50 ml3), and the petroleum ether was recovered by distillation to give a yellowish transparent liquid (2-cyano-2-valproate). Into the yellowish transparent liquid 2-cyano-2-valproate, 150 ml of 15% KOH was added. The mixture was hydrolyzed at 65 C. for 3 h, and neutralized in an ice bath by adding concentrated hydrochloric acid to precipitate a white precipitate, which was filtered and dried to give 49.10 g of 2-cyano-2-valproic acid as a white solid, with a yield of 96.72% (based on methyl cyanoacetate) and a melting point of 49-50 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 13.76 (s, 1H, CO.sub.2H), 1.84-1.67 (m, 4H, CH.sub.22), 1.54-1.41 (m, 2H, CH.sub.2), 1.36-1.21 (m, 2H, CH.sub.2), 0.92 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 4

Preparation of 2-cyano-2-valproic ethyl ester

##STR00016##

[0046] 22.6 g (0.20 mol) of ethyl cyanoacetate, 10 mmol TBAC, 5 mmol KI, 60.8 g (0.44 mol) of K.sub.2CO.sub.3 (200 meshes), 80 ml of DMF and 39.3 g (0.50 mol) of 1-chloropropane were stirred and reacted at 80 C. for 6 h. After the reaction was completed, an inorganic salt was filtered out and recovered, and 72 ml of DMF was recovered under a reduced pressure. Thereafter, 100 ml of petroleum ether was added, the organic phase was washed with water until the aqueous phase became colorless, and the organic phase was dried over anhydrous sodium sulfate, followed by suction filtration, rotary evaporation, and drying to give 37.4 g of 2-cyano-2-valproic ethyl ester, with a yield of 94.9% (based on ethyl cyanoacetate). .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 4.22 (q, J=7.2 Hz, 2H, OCH.sub.2), 1.84-1.75 (m, 4H, CH.sub.22), 1.52-1.39 (m, 2H, CH.sub.2), 1.31-1.18 (m, 5H, CH.sub.2+CH.sub.3), 0.91 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 5

Preparation of 2-cyano-2-valproic acid

[0047] 22.6 g (0.20 mol) Of ethyl cyanoacetate, 1 mmol TBAC, 60.8 g (0.44 mol) of K.sub.2CO.sub.3 (100 meshes), 20 ml of DMF, 60 ml of butyl acetate, 5 mmol of potassium bromide, and 39.3 g (0.5 mol) of 1-chloropropane were stirred and reacted at 80 C. for 6 h. The resultant was filtered to recover an inorganic salt, and 52 ml of butyl acetate and 17 ml of DMF were recovered under a reduced pressure. Thereafter, 100 ml of petroleum ether was added, and the organic phase was washed with water until the aqueous phase became colorless. The petroleum ether was recovered by rotary evaporation, and 15 ml of 15% KOH was added to the residual yellowish transparent liquid (2-cyano-2-valproic ethyl ester). The mixture was heated and hydrolyzed for 3 h, and neutralized by adding concentrated hydrochloric acid to precipitate a solid, which was dried to give 3.13 g of 2-cyano-2-valproic acid as a white solid, with a yield of 92.60% (based on ethyl cyanoacetate), and a melting point of 49-50 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 13.76 (s, 1H, CO.sub.2H), 1.84-1.67 (m, 4H, CH.sub.22), 1.54-1.41 (m, 2H, CH.sub.2), 1.36-1.21 (m, 2H, CH.sub.2), 0.92 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 6

Preparation of 2-cyano-2-valproic methyl ester

[0048] 29.73 g (0.30 mol) Of methyl cyanoacetate, 15.0 mmol of tributylamine, 91.21 g (0.66 mol) of K.sub.2CO.sub.3 (300 meshes), 120 ml of recovered DMF, 5.0 mmol potassium iodide and 58.91 g (0.75 mol) of 1-chloropropane were stirred and reacted at 85 C. for 4.0 h (completion of reaction was monitored by TLC). After reaction was completed, the resultant was filtered to recover an inorganic salt, which was washed with petroleum ether. Thereafter, the organic phase was washed with water until the aqueous phase became colorless. Then the organic phase was dried over anhydrous sodium sulfate, followed by suction filtration, rotary evaporation, and drying to give 53.46 g of 2-cyano-2-valproic methyl ester, with a yield of 94.36%. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 3.76 (s, 3H, OCH.sub.3), 1.85-1.75 (m, 4H, CH.sub.22), 1.52-1.38 (m, 2H, CH.sub.2), 1.30-1.17 (m, 2H, CH.sub.2), 0.91 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 7

Preparation of 2-cyano-2-valproic methyl ester

[0049] 29.73 g (0.30 mol) Of methyl cyanoacetate, 9.0 mmol of recovered tetrabutylammonium bromide, 91.21 g (0.66 mol) of K.sub.2CO.sub.3 (300 meshes), 120 ml of recovered DMF, 2.0 mmol potassium iodide and 58.91 g (0.75 mol) of 1-chloropropane were stirred and reacted at 85 C. for 3.0 h (completion of reaction was monitored by TLC). After reaction was completed, the resultant was filtered to recover an inorganic salt, which was washed with petroleum ether. Thereafter, the organic phase was washed with water until the aqueous phase became colorless. Then the organic phase was dried over anhydrous sodium sulfate, followed by suction filtration, rotary evaporation, and drying to give 53.46 g of 2-cyano-2-valproic methyl ester, with a yield of 94.36%. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 3.76 (s, 3H, OCH.sub.3), 1.85-1.75 (m, 4H, CH.sub.22), 1.52-1.38 (m, 2H, CH.sub.2), 1.30-1.17 (m, 2H, CH.sub.2), 0.91 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 8

Preparation of 2-cyano-2-valproic n-propyl ester

##STR00017##

[0050] 2-Cyano-2-valproic n-propyl ester was prepared from n-propyl cyanoacetate by the method of Example 1.

Example 9

Preparation of 2-cyano-2-valproic acid

##STR00018##

[0051] 2-Cyano-2-valproic acid was prepared from n-propyl cyanoacetate by the method of Example 2.

Example 10

Preparation of 2-cyano-2-valproic isopropyl ester

##STR00019##

[0052] 2-Cyano-2-valproic isopropyl ester was prepared from isopropyl cyanoacetate by the method of Example 1.

Example 11

Preparation of 2-cyano-2-valproic acid

##STR00020##

[0053] 2-Cyano-2-valproic acid was prepared from isopropyl cyanoacetate by the method of Example 2.

Example 12

Preparation of Propylvaleronitrile

##STR00021##

[0054] 84.6 g of 2-Cyano-2-valproic acid was added into a 250 mL round-bottom flask, heated to 150-155 C., deacidified for 4.0 h, and then subjected to fractional distillation. 165-175 C. fraction was collected to give 55.7 g of propylvaleronitrile as a colorless oil-like substance, with a yield of 89%.

Example 13

Preparation of Valpromide and Sodium Valproate

##STR00022##

(1) Preparation of Valpromide

[0055] 25.04 g of Propylvaleronitrile and 25.63 g of methanol, in an ice bath, were dropwise added with 39.23 g of concentrated sulfuric acid under stirring. The mixture was stirred and reacted at 85 C. for 5 h. Thereafter, 100 ml of water was added, and the mixture was stirred, adjusted to pH 8 with a sodium hydroxide solution. Then the solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and was subjected to suction filtration, rotary evaporation, and drying to give a solid-liquid mixture. Then 150 ml of petroleum ether was added and stirred for 0.5 h. The solution was left to stand overnight, followed by suction filtration, and washing with petroleum ether. The filtrate was treated according to step (2). The residue was dried to give 7.04 g of valpromide as a white solid, with a yield of 24.6% (based on propylvaleronitrile), and a melting point of 125.5-126 C. .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 7.26 (s, 1H, CONH.sub.2), 6.71 (s, 1H, CONH.sub.2), 2.18-2.10 (m, 1H, CH), 1.47-1.36 (m, 2H, CH.sub.2), 1.28-1.17 (m, 6H, CH.sub.2+CH.sub.22), 0.85 (t, J=5.8 Hz, 6H, CH.sub.32).

(2) Preparation of Sodium Valproate

[0056] The filtrate in (1) was subjected to rotary evaporation to recover petroleum ether. 26 g Of sodium hydroxide, 20 ml of water and 20 ml of methanol were added to the residual liquid, and the mixture was heated and refluxed for 5 h. The resultant was cooled, the filtrate was extracted with 50 ml of ethyl acetate (225 ml). The organic phase was separated and subjected to rotary evaporation to recover ethyl acetate, and a small amount of residues were propylvaleronitrile, which was recovered. The aqueous phase was concentrated by rotary evaporation and cooled to a room temperature to precipitate a white solid, which was filtered and dried at 50 C. in vacuum to give sodium valproate. Sodium valproate was heated to dissolve with ethyl acetate, and the filtrate was slowly cooled to a room temperature, to precipitate a large amount of white solids, which were filtered and dried at 50 C. in vacuum to give 17.57 g of sodium valproate, with a yield of 52.9% (based on propylvaleronitrile).

Example 14

Preparation of Valpromide and Sodium Valproate

##STR00023##

[0057] 25.04 g Of propylvaleronitrile and 25.63 g of methanol, in an ice bath, were dropwise added with 39.23 g of concentrated sulfuric acid under stirring. The reaction solution was stirred at 75 C. for 10 h, and cooled to a room temperature. Then 100 ml of water was added into the reaction solution with stirring. The mixture was neutralized to pH8 with sodium hydroxide solution, and extracted with 150 ml of ethyl acetate (350 ml). Then ethyl acetate was recovered by rotary evaporation to give a solid-liquid mixture. 150 ml of petroleum ether was added to precipitate a solid, which was subjected to suction filtration. The filtrate was treated according to step (2). The residue was dried to give 5.4 g of valpromide as a white solid, with a yield of 18.9% (based on propylvaleronitrile), and a melting point of 125.5-126 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 7.26 (s, 1H, CONH.sub.2), 6.71 (s, 1H, CONH.sub.2), 2.18-2.10 (m, 1H, CH), 1.47-1.36 (m, 2H, CH.sub.2), 1.28-1.17 (m, 6H, CH.sub.2+CH.sub.22), 0.85 (t, J=5.8 Hz, 6H, CH.sub.32).

[0058] The filtrate in (1) was subjected to rotary evaporation to recover petroleum ether. Into the residual liquid, 26 g of sodium hydroxide, 20 ml of water and 20 ml of methanol were added. The mixture was heated and refluxed for 5 h, then the resultant was cooled, and filtrate was extracted with 50 ml of ethyl acetate (225 ml). The organic phase was separated, and subjected to rotary evaporation to recover ethyl acetate, and a small amount of residues were propylvaleronitrile, which was recovered. The aqueous phase was concentrated by rotary evaporation and cooled to a room temperature to precipitate a white solid, which was filtered, and dried at 50 C. in vacuum to give sodium valproate. Sodium valproate was heated to dissolve with ethyl acetate, and the filtrate was slowly cooled to a room temperature to precipitate a large amount of white solids, which were filtered and dried at 50 C. in vacuum to give 17.97 g of sodium valproate, with a yield of 54.1% (based on propylvaleronitrile).

Example 15

Preparation of Valpromide and Sodium Valproate

##STR00024##

(1) Preparation of Valpromide

[0059] 25.04 g Of propylvaleronitrile and 25.63 g of methanol, in an ice bath, were dropwise added with 39.23 g of concentrated sulfuric acid under stirring. The mixture was stirred and reacted at 85 C. for 6 h, then 100 ml of water was added with stirring. The solution was adjusted to pH 8 with a sodium hydroxide solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, subjected to suction filtration, rotary evaporation, and drying to give a solid-liquid mixture. Thereafter, 150 ml of petroleum ether was added, and mixture was stirred for 0.5 h, left to stand overnight, followed by suction filtration, and washing with petroleum ether. The filtrate was treated according to step (2). The residue was dried to give 6.95 g of valpromide as a white solid, with a yield of 24.3% (based on propylvaleronitrile), and a melting point of 125.5-126 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 7.26 (s, 1H, CONH.sub.2), 6.71 (s, 1H, CONH.sub.2), 2.18-2.10 (m, 1H, CH), 1.47-1.36 (m, 2H, CH.sub.2), 1.28-1.17 (m, 6H, CH.sub.2+CH.sub.22), 0.85 (t, J=5.8 Hz, 6H, CH.sub.32)

(2) Preparation of Sodium Valproate

[0060] The filtrate in (1) was subjected to rotary evaporation to recover petroleum ether. Into a residual liquid, 26 g of sodium hydroxide, 20 ml of water and 20 ml of methanol were added. The mixture was heated and refluxed for 5 h. The resultant was cooled, and the aqueous phase was concentrated by rotary evaporation and cooled to room temperature to precipitate a white solid, which was filtered and dried at 50 C. in vacuum to give sodium valproate. Sodium valproate was heated to dissolve with ethyl acetate, the filtrate was slowly cooled to room temperature to precipitate a large amount of white solids, which were filtered and dried at 50 C. in vacuum to give 18.6 g of sodium valproate, with a yield of 56.2% (based on propylvaleronitrile).

Example 16

Preparation of Valpromide and Sodium Valproate

##STR00025##

[0061] CH.sub.3OHHCl (g) substituted methanol and sulfuric acid, and according to feed ratios and reaction conditions in Example 15, valpromide and sodium valproate were respectively obtained by the same post-treatment method.

Example 17

Preparation of Valpromide and Sodium Valproate

##STR00026##

[0062] Benzenesulfonic acid or p-toluenesulfonic acid substituted sulfuric acid, and according to feed ratios and reaction conditions in Example 15, valpromide and sodium valproate were respectively obtained by the same post-treatment method.

Example 18

Preparation of Valpromide and Sodium Valproate

##STR00027##

[0063] Trifluoromethanesulfonic acid or methanesulfonic acid substituted sulfuric acid, and according to feed ratios and reaction conditions in Example 15, valpromide and sodium valproate were respectively obtained by the same post-treatment method.

Example 19

Preparation of Valpromide and Sodium Valproate

##STR00028##

[0064] Ethanol was selected to substitute methanol, and according to feed ratios and reaction conditions in Example 15, valpromide and sodium valproate were respectively obtained by the same post-treatment method.

Example 20

Preparation of Valpromide and Valproic Acid Methyl Ester

##STR00029##

(1) Preparation of Valpromide

[0065] 125 g Of propylvaleronitrile and 128 g of methanol, in an ice bath, were dropwise added with 196 g of concentrated sulfuric acid under stirring. The mixture was stirred and reacted at 85 C. for 5.5 h, 500 ml of water was added, and the mixture was stirred, adjusted to pH 8 with a sodium hydroxide solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, subjected to suction filtration, rotary evaporation, and drying to give a solid-liquid mixture. Thereafter, 700 ml of petroleum ether was added, the mixture was stirred for 0.5 h, left to stand overnight, followed by suction filtration, and washing with petroleum ether. The filtrate was treated according to step (2). The residue was dried to give 35 g of valpromide as a white solid, with a yield of 24.5% (based on propylvaleronitrile), and a melting point of 125.5-126 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 7.26 (s, 1H, CONH.sub.2), 6.71 (s, 1H, CONH.sub.2), 2.18-2.10 (m, 1H, CH), 1.47-1.36 (m, 2H, CH.sub.2), 1.28-1.17 (m, 6H, CH.sub.2+CH.sub.22), 0.85 (t, J=5.8 Hz, 6H, CH.sub.32).

(2) Preparation of Valproic Acid Methyl Ester

[0066] Filtrate in (1) was subjected to rotary evaporation to recover petroleum ether, followed by reduced-pressure rectification to give 95 g of valproic acid methyl ester, with a yield of 60.1% (based on propylvaleronitrile). .sup.1H NMR (400 MHZ, CDCl.sub.3) : 3.67 (s, 3H, OCH.sub.3), 2.43-2.32 (m, 1H, CH), 1.65-1.53 (m, 2H, CH.sub.2), 1.47-1.36 (m, 2H, CH.sub.2), 1.33-1.23 (m, 4H, CH.sub.22), 0.89 (t, J=7.2 Hz, 6H, CH.sub.32).

Example 21

Preparation of Valpromide and Valproic Acid

##STR00030##

(1) Preparation of Valpromide

[0067] 125 g Of propylvaleronitrile and 128 g of methanol, in an ice bath, were dropwise added with 196 g of concentrated sulfuric acid under stirring. The mixture was stirred and reacted at 80 C. for 8 h, then 500 ml of water was added, and the mixture was stirred, adjusted to pH 8 with a sodium hydroxide solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, subjected to suction filtration, rotary evaporation, and drying to give a solid-liquid mixture. Thereafter, 700 ml of petroleum ether was added, and the mixture was stirred for 0.5 h, left to stand overnight, followed by suction filtration, and washing with petroleum ether. The filtrate was treated according to step (2). The residue was dried to give 34 g of valpromide as a white solid, with a yield of 23.7% (based on propylvaleronitrile), and a melting point of 125.5-126 C. .sup.1H NMR (400 MHZ, DMSO-d.sub.6) : 7.26 (s, 1H, CONH.sub.2), 6.71 (s, 1H, CONH.sub.2), 2.18-2.10 (m, 1H, CH), 1.47-1.36 (m, 2H, CH.sub.2), 1.28-1.17 (m, 6H, CH.sub.2+CH.sub.22), 0.85 (t, J=5.8 Hz, 6H, CH.sub.32).

(2) Preparation of Valproic Acid

[0068] The filtrate in (1) was subjected to rotary evaporation to recover petroleum ether. Into yellowish liquid, a potassium hydroxide aqueous solution (KOH: 120 g, H.sub.2O: 200 g) was added dropwise, and the mixture was heated to 85 C. and hydrolyzed for 5 h by stirring. The resultant was cooled, and a water layer was separated. The organic phase was added with 350 ml of water, and left to stand for layering to separate an oil phase, and recover propylvaleronitrile. The aqueous phase was adjusted to pH 1 by adding hydrochloric acid and left to stand for layering. The oil phase was dried and rectificated under a reduced pressure to collect 84 g of 85-90 C./0.4 kPa fraction valproic acid, with a yield of 58.3% (based on propylvaleronitrile). .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 11.99 (s, 1H, COOH), 2.24-2.18 (m, 1H, CH), 1.53-1.44 (m, 2H, CH.sub.2), 1.39-1.34 (m, 2H, CH.sub.2), 1.32-1.22 (m, 4H, CH.sub.22), 0.86 (t, J=7.2 Hz, 6H, CH.sub.32).

[0069] In the present description, the present disclosure has been described with reference to specific examples thereof. However, various modifications and changes evidently can be made without departing from the spirit and scope of the present disclosure. Therefore, the description should be regarded as illustrative rather than restrictive.