Method for co-producing valproamide and sodium valproate

Abstract

Provided is a method for preparing valproamide represented by chemical structural formula I and sodium valproate represented by formula II. The method is characterized in that cyanoacetate and 1-chlor

Description

A method for co-producing valproamide and sodium valproate Technical Field

[0001] The present invention relates to a phase transfer composite catalytic preparation method of 2-cyano-2-valproic acid ester and application of the method in the co-production of valproic acid (sodium) and valproamide. Background Art

[0002] Sodium valproate and valproamide are both antiepileptic drugs, but their therapeutic ranges differ. Sodium valproate is the drug of choice for primary grand mal seizures and petit mal absence seizures, but is less effective for partial seizures (simple partial, complex partial, and partial seizures followed by grand mal seizures). Sodium valproate has some efficacy for benign myoclonic epilepsy of infancy and infantile spasms, but myoclonic absence seizures require the addition of ethosuximide or other antiepileptic drugs. Valproamide is a new antiepileptic drug, and pharmacological experiments have shown that its antiepileptic effect is twice that of sodium valproate.

[0003] Zhou Qiqun et al. [Improvement of the synthesis process of sodium valproate. Chinese Journal of Pharmaceutical Industry. 1993, 24(8): 347-348] selected methyl acetoacetate to undergo alkylation, deacylation, hydrolysis and salt formation by quaternary ammonium salt solid-liquid phase transfer catalysis to prepare sodium valproate:

[0004] Wang Xueqin et al. [New process for the synthesis of sodium valproate. Chinese Journal of Pharmaceutical Industry, 1999, 30(9):389-390] selected methyl acetoacetate and potassium carbonate and condensed them with 1-bromopropane under TBAB catalysis to obtain dipropyl acetoacetate with a yield of 63.1%. In 2019, Lin Fanyou [A synthesis process for sodium valproate, CN110563572A, 2019-12-13] also used TBAB phase transfer catalysis to prepare sodium valproate.

[0005] Li Xinyuan et al. [Synthesis of valproic acid-based antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Pharmaceutical Industry, 1984, 5: 4-6] and U.S. Patent No. 4127604 used methyl cyanoacetate, 1-bromopropane, and solid potassium carbonate for dipropyl alkylation in the presence of a quaternary ammonium salt. Valproamide was then hydrolyzed, decarboxylated, and hydrolyzed again to produce valproic acid. The latter reacted with nitrous acid to produce valproic acid, which was then salted to sodium valproate. Nitric oxide and nitrogen dioxide produced by the decomposition of nitrous acid are environmentally polluting and corrosive to equipment.

[0006] Valproic acid is prepared by decarboxylation and hydrolysis of 2-cyano-2-propylpentanoic acid to produce valproamide, which is used to prepare valproic acid as follows:

[0007] Shanghai Qingping Pharmaceutical Co., Ltd. [A new method for preparing valproic acid, CN 2021103366414, 2021.8.3; A method for preparing sodium valproate, CN2021103339474, 2021.8.3; A method for preparing valproic acid, CN2021103366274, 2021.7.27] discloses a method for preparing valproic acid and sodium valproate: valproic acid is prepared by a one-pot process using valproonitrile or 2-cyano-2-propylpentanoic acid as the starting material. Using valproonitrile or 2-cyano-2-propylpentanoic acid as the raw material and aqueous sulfuric acid as the catalyst, the reaction is carried out at 120-160°C for 20h-40h to obtain valproic acid with a yield of 70%-80%; the hydrolysis temperature of this method is high and the reaction time is long. The synthetic route is as follows:

[0008] This process uses high-temperature decarboxylation and hydrolysis with sulfuric acid, which may cause side reactions and has a high risk factor.

[0009] Liu Weiguo [A method for preparing sodium valproate, CN201811564128.5, 2020-06-3] selected ethyl valerate as a raw material to prepare sodium valproate, and the process route is as follows:

[0010] The process for preparing valproic acid of the invention requires a very strong base, lithium pyrrole salt, and low temperature.

[0011] Summary of the Invention

[0012] The present invention aims, on the one hand, to provide a method for the co-production of valproamide represented by chemical formula I and sodium valproate represented by formula II, characterized in that cyanoacetate and 1-chloropropane are subjected to a complex catalytic dipropylation reaction under the action of a base to produce 2-cyano-2-valproate represented by formula III; 2-cyano-2-valproate is hydrolyzed and deacidified to produce valproonitrile represented by formula V; valproonitrile is alcoholyzed under acid catalysis to produce valproamide represented by formula I and valproate represented by formula VI; and valproate is hydrolyzed in a sodium hydroxide solution to produce sodium valproate represented by formula II. The preparation reaction is as follows:

[0013] The method for preparing 2-cyano-2-valerate ester represented by formula III is characterized in that cyanoacetate and 1-chloropropane are subjected to a complex catalytic dipropylation reaction under the action of a base to obtain 2-cyano-2-valerate ester represented by formula III; the preparation reaction is as follows:

[0014] R = methyl or ethyl;

[0015] The catalyst consists of catalyst A and catalyst B;

[0016] Catalyst A selection: R3N, PhNR2, R4NX or R3R 1 NX; wherein R=C1~C4 linear alkyl, C5~C8 linear alkyl; R 1 =PhCH2, C1-C5 straight-chain alkyl, C6-C18 straight-chain alkyl; wherein X=F, Cl, Br, I or HSO4;

[0017] Catalyst B is selected from MX, wherein M=Na, Li, Cs, K, and X=F, Cl, Br or I.

[0018] R4NX is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetraethylammonium hydrogen sulfate, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, or tetrapropylammonium bromide.

[0019] R3R 1 NX is selected from the group consisting of hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, triethylbenzylammonium chloride, trimethylbenzylammonium chloride, triethylbenzylammonium bromide, hexadecyltriethylammonium bromide, dodecyltriethylammonium bromide, octyltriethylammonium bromide, hexyltriethylammonium bromide, and trioctylmethylammonium chloride.

[0020] R3N is selected from: trimethylamine, triethylamine, tripropylamine, tributylamine; PhNR2 is selected from: N,N-dimethylaniline, N,N-diethylaniline, N,N-dipropylaniline or N,N-dibutylaniline.

[0021] MX is selected from: NaBr, KBr, NaI or KI.

[0022] Solvent selection: one or two of THF, 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 or butyl acetate.

[0023] The base is selected from: solid MOH or solid M2CO3, wherein M=Na, Li, Cs or K; solid MOH is selected from granular or powdered MOH; solid M2CO3 is selected from granular M2CO3 or powdered M2CO3; wherein M=Na, Li, Cs or K.

[0024] Powdered M2CO3 options: 100 mesh M2CO3, 150 mesh M2CO3, 200 mesh M2CO3, 250 mesh M2CO3, 300 mesh M2CO3 or 350 mesh M2CO3, where M = Na, Li, Cs or K.

[0025] Reaction temperature selection: 60℃~120℃; reaction time selection: 1.0h~12h;

[0026] The catalytic dosage is selected as follows: cyanoacetate: catalyst A: catalyst B = 1: 0.01-0.10: 0.005-0.05 molar ratio; the cyanoacetate is selected from: methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate, tert-butyl cyanoacetate or benzyl cyanoacetate.

[0027] The alcoholysis method of valproonitrile represented by formula V is characterized in that valproonitrile reacts with alcohol under acid catalysis to produce valproamide (solid) and valproate (liquid) represented by formula VI; the preparation reaction is as follows:

[0028] Wherein, R=methyl or ethyl; in the alcoholysis reaction, the acid (acidic substance) is selected from: HCl (g), AlCl3, sulfuric acid, dichlorothionyl, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trimethylsilyl trifluoromethanesulfonate.

[0029] In the alcoholysis reaction, the molar amount of the acid is selected from: valproic acid: acid = 1: 1.2 to 4;

[0030] In the alcoholysis reaction, the mass concentration of the acid is selected from: 30% to 70%;

[0031] The molar amount of alcohol ROH is selected from: propionitrile: ROH = 1: 3 to 8;

[0032] In the alcoholysis reaction, the alcoholysis temperature is selected from: 25℃~100℃

[0033] In the alcoholysis reaction, the alcoholysis time is selected from: 4h to 24h;

[0034] The second aspect of the present invention is to provide a method for co-producing valproamide represented by Formula I and sodium valproate represented by Formula II, characterized in that valproonitrile represented by Formula V is subjected to alcoholysis and hydrolysis to produce valproamide and sodium valproate; the preparation reaction is as follows:

[0035] Wherein, R = methyl or ethyl.

[0036] The acid is selected from: HCl (g), AlCl3, sulfuric acid, thionyl chloride, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trimethylsilyl trifluoromethanesulfonate; the molar ratio of the product: n 丙戊酰胺 ∶n 丙戊酸钠 =1:1.5~8.0.

[0037] The third aspect of the present invention is to provide a method for co-producing valproamide represented by formula I and valproic acid represented by formula VII, characterized in that valproonitrile represented by formula V is subjected to alcoholysis and hydrolysis to produce valproamide and valproic acid; the preparation reaction is as follows:

[0038] Wherein, R = methyl or ethyl.

[0039] The acid is selected from: HCl (g), AlCl3, sulfuric acid, thionyl chloride, trifluoromethanesulfonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trimethylsilyl trifluoromethanesulfonate; the molar ratio of the product: n 丙戊酰胺 ∶n 丙戊酸 =1:1.5~8.0.

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] 1. This invention utilizes a combined catalytic dipropylation method using cyanoacetate and 1-chloropropane. 1-chloropropane is in plentiful, abundant, and inexpensive supply. This critical dipropylation reaction is complete, ensuring high-quality final products. This single production route can co-produce two high-quality antiepileptic drugs—sodium valproate and valproamide.

[0042] 2. The production process of the present invention does not use strong bases such as sodium methoxide, sodium ethoxide, or tert-butyl potassium, nor does it use expensive 1-bromopropane; it creatively avoids the production of the following by-products:

[0043] 3. The intermediates and products in the production process of the present invention are of high purity and simple to separate. The production ratio of the co-produced raw materials valproic acid (sodium) and valproamide can be adjusted according to market demand by controlling the reaction conditions of the alcoholysis. The production equipment investment is small, the equipment utilization rate is high, the production cost is low, and the quality is good. It has excellent social and economic benefits. DETAILED DESCRIPTION

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

[0045] Example 1

[0046] Preparation of methyl 2-cyano-2-propionate

[0047] 29.73g (0.30mol) of methyl cyanoacetate, 12.0mmol of tetrabutylammonium bromide, 3.0mmol of KI, 91.21g (0.66mol) of K2CO3, 120ml of DMF and 58.91g (0.75mol) of 1-chloropropane were stirred at 85°C for 3.0h (the reaction was monitored for completion by TLC). After the reaction was completed, the inorganic salts were filtered out after cooling slightly; 110ml of DMF was recovered under reduced pressure; the inorganic salts were washed with petroleum ether; the organic phase was washed with water until the aqueous phase was colorless, and the organic phase was dried over anhydrous sodium sulfate, filtered to recover sodium sulfate, and the organic phase was rotary evaporated and dried to obtain 53.06g of methyl 2-cyano-2-propanoate, with a yield of 96.50% (based on methyl cyanoacetate); 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).

[0048] Example 2

[0049] Preparation of 2-cyano-2-propanoic acid

[0050] 29.73g (0.30mol) of methyl cyanoacetate, 12.0mmol of tetrabutylammonium chloride, 3.0mmol of KI, 91.21g (0.66mol) of K2CO3, 120ml of ethylene glycol dimethyl ether and 58.91g (0.75mol) of 1-chloropropane were stirred at 85°C for 2.5h (TLC monitoring of the reaction completion). After the reaction was completed, the inorganic salts were filtered after cooling slightly; 110ml of ethylene glycol dimethyl ether was recovered under reduced pressure; the inorganic salts were washed with ethyl acetate; the inorganic salts were KCl and KHCO3, which were recovered; the organic phase was washed with water until the aqueous phase was colorless, and ethyl acetate was recovered by distillation. 150ml of 15% KOH was added to the residual light yellow transparent liquid (methyl 2-cyano-2-propionate), and the temperature was raised for hydrolysis for 3h. Concentrated hydrochloric acid was added to neutralize the solution, and a solid was precipitated and dried to obtain 48.69g of a white solid. 2-Cyano-2-propanoic acid, yield 95.90% (calculated as methyl cyanoacetate), melting point 49-50°C. 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).

[0051] Example 3

[0052] Preparation of 2-cyano-2-propanoic acid

[0053] 29.73g (0.30mol) of methyl cyanoacetate, 3.33g (9.0mmol) of TBAB, 3.0mmol of KI, 91.21g (0.66mol) of K2CO3, 120ml of DMF and 58.91g (0.75mol) of 1-chloropropane were stirred at 85°C for 3.3h (the reaction was monitored to be complete by TLC). After the reaction was completed, the mixture was cooled and the inorganic salts were filtered out; 110ml of DMF was recovered under reduced pressure; the inorganic salts were washed with petroleum ether (100ml×3), which were KCl and KHCO3; the organic phase was washed with water (50ml×3), and the petroleum ether was recovered by distillation to obtain a light yellow transparent liquid (2-cyano-2-propionvalerate). To the pale yellow transparent liquid of 2-cyano-2-propionvalerate, add 150 ml of 15% KOH and hydrolyze at 65°C for 3 h. Neutralize with concentrated hydrochloric acid under ice bath to precipitate a white precipitate. Filter and dry to obtain 49.10 g of 2-cyano-2-propionvalerate as a white solid with a yield of 96.72% (based on methyl cyanoacetate) and a melting point of 49-50°C. 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 4

[0055] Preparation of ethyl 2-cyano-2-valproate

[0056] 22.6 g (0.20 mol) of ethyl cyanoacetate, 10 mmol TBAC, 5 mmol KI, 60.8 g (0.44 mol) of K2CO3 (200 mesh), 80 ml of DMF and 39.3 g (50 mmol) of 1-chloropropane were stirred at 80°C for 6 h, and the inorganic salts were recovered by filtration; 72 ml of DMF was recovered under reduced pressure, 100 ml of petroleum ether was added, and the organic phase was washed with water until the aqueous phase was colorless, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation to obtain 37.4 g of ethyl 2-cyano-2-propanoate, with a yield of 94.9% (based on ethyl cyanoacetate). 1 HNMR (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).

[0057] Example 5

[0058] Preparation of 2-cyano-2-propanoic acid

[0059] 22.6g (0.20mol) of ethyl cyanoacetate, 1mmol of TBAC, 60.8g (0.44mmol) of K2CO3 (100 mesh), 20ml of DMF, 60ml of butyl acetate and 5mmol of potassium bromide, 39.3g (0.5mmol) of 1-chloropropane were stirred at 80°C for 6h, and the inorganic salts were recovered by filtration; 52ml of butyl acetate and 17ml of DMF were recovered under reduced pressure, and 100ml of petroleum ether was added. The organic phase was washed with water until the aqueous phase was colorless, and the petroleum ether was recovered by rotary evaporation. 15ml of 15% KOH was added to the residual light yellow transparent liquid (ethyl 2-cyano-2-propionic acid ester), and the mixture was hydrolyzed at elevated temperature for 3h. The mixture was neutralized with concentrated hydrochloric acid to precipitate a solid, which was dried to give 3.13g of 2-cyano-2-propionic acid as a white solid with a yield of 92.60% (based on ethyl cyanoacetate) and a melting point of 49-50°C. 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).

[0060] Example 6

[0061] Preparation of methyl 2-cyano-2-propionate

[0062] 29.73 g (0.30 mol) of methyl cyanoacetate, 15.0 mmol of tributylamine, 91.21 g (0.66 mol) of K2CO3 (300 mesh), 120 ml of recovered DMF, 5.0 mmol of potassium iodide, and 58.91 g (0.75 mol) of 1-chloropropane were stirred at 85°C for 4.0 h (completion of the reaction was monitored by TLC). After the reaction, the inorganic salts were recovered by filtration; the mixture was washed with petroleum ether, and the organic phase was washed with water until the aqueous phase was colorless, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 53.46 g of methyl 2-cyano-2-propanoate in a yield of 94.36%. 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).

[0063] Example 7

[0064] Preparation of methyl 2-cyano-2-propionate

[0065] 29.73 g (0.30 mol) of methyl cyanoacetate, 9.0 mmol of recovered tetrabutylammonium bromide, 91.21 g (0.66 mol) of K2CO3 (300 mesh), 120 ml of recovered DMF, 2.0 mmol of potassium iodide and 58.91 g (0.75 mol) of 1-chloropropane were stirred at 85°C for 3.0 h (completion of the reaction was monitored by TLC), and the inorganic salts were recovered by filtration; the mixture was washed with petroleum ether, and the organic phase was washed with water until the aqueous phase was colorless, dried over anhydrous sodium sulfate, filtered, and dried by rotary evaporation to obtain 53.46 g of methyl 2-cyano-2-propanoate in a yield of 94.36%. 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).

[0066] Example 8

[0067] Preparation of 2-cyano-2-propionylvalerate

[0068] According to the method of Example 1, n-propyl cyanoacetate was selected to prepare n-propyl 2-cyano-2-propionvalerate.

[0069] Example 9

[0070] Preparation of 2-cyano-2-propanoic acid

[0071] According to the method of Example 2, n-propyl cyanoacetate was selected to prepare 2-cyano-2-propanoic acid.

[0072] Example 10

[0073] Preparation of Isopropyl 2-Cyano-2-Propanvalerate

[0074] According to the method of Example 1, isopropyl cyanoacetate was selected to prepare isopropyl 2-cyano-2-propionate.

[0075] Example 11

[0076] Preparation of 2-cyano-2-propanoic acid

[0077] According to the method of Example 2, isopropyl cyanoacetate was selected to prepare 2-cyano-2-propanoic acid.

[0078] Example 12

[0079] Preparation of propvaleronitrile

[0080] 84.6 g of 2-cyano-2-valproic acid was added to a 250 ml round-bottom flask, and the temperature was raised to 150-155 ° C. Deacidification was performed for 4.0 h, and fractionation was performed. The fraction at 165-175 ° C was collected to obtain 55.7 g of colorless oily valproic acid, with a yield of 89%.

[0081] Example 13

[0082] Preparation of valproamide and sodium valproate

[0083] (1) Preparation of valproamide

[0084] 25.04 g of valproate nitrile and 25.63 g of methanol were placed in an ice bath, and 39.23 g of concentrated sulfuric acid was added dropwise with stirring. The mixture was stirred at 85°C for 5 h, and 100 ml of water was added and stirred. The pH was adjusted to 8 with sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, rotary evaporated, and dried to obtain a solid-liquid mixture. 150 ml of petroleum ether was added and stirred for 0.5 h. The mixture was allowed to stand overnight, filtered, washed with petroleum ether, and the filtrate was treated according to step (2). The white solid was dried to obtain 7.04 g of valproate amide, with a yield of 24.6% (based on valproate nitrile); the melting point was 125.5-126°C. 1 HNMR (400MHz, DMSO-d6) δ: 7.26 (s, 1H, CONH2), 6.71 (s, 1H, CONH2), 2.18–2.10 (m, 1H, CH ), 1.47–1.36 (m, 2H, CH2), 1.28–1.17 (m, 6H, CH2+CH2×2), 0.85 (t, J=5.8Hz, 6H, CH3×2).

[0085] (2) Preparation of sodium valproate

[0086] The filtrate in step (1) was subjected to rotary evaporation to recover petroleum ether, and 26g sodium hydroxide, 20ml water and 20ml methanol were added to the residual liquid, and the mixture was heated under reflux for 5h; cooled, the filtrate was extracted with 50ml ethyl acetate (2×25ml), the organic phase was separated, and ethyl acetate was recovered by rotary evaporation. A small amount of residue was valproate nitrile, which was recovered; the aqueous phase was concentrated by rotary evaporation, cooled to room temperature, and a white solid was precipitated. The solid was filtered and dried under vacuum at 50°C to obtain sodium valproate. The solid was dissolved by heating with ethyl acetate, and the filtrate was slowly cooled to room temperature to precipitate a large amount of white solid. The solid was filtered and dried under vacuum at 50°C to obtain 17.57g sodium valproate, with a yield of 52.9% (based on valproate nitrile).

[0087] Example 14

[0088] Preparation of valproamide and sodium valproate

[0089] 25.04g of valproic acid and 25.63g of methanol were placed in an ice bath and 39.23g of concentrated sulfuric acid was added dropwise with stirring; the reaction solution was stirred at 75℃ for 10h, the reaction solution was cooled to room temperature, 100ml of water was added to the reaction solution with stirring, and the mixture was stirred; sodium hydroxide solution was added dropwise and the mixture was neutralized with stirring to pH~8, and 150ml of ethyl acetate (3×50ml) was used for extraction. The ethyl acetate was recovered by rotary evaporation to obtain a solid-liquid mixture, 150ml of petroleum ether was added, the solid was precipitated, and the mixture was filtered with suction. The filtrate was treated according to step (2); the white solid was dried to obtain 5.4g of valproic acid amide, with a yield of 18.9% (based on valproic acid nitrile) and a melting point of 125.5~126℃. 1 HNMR(400MHz, DMSO-d6)δ:7.26(s, 1H, CONH2), 6.71 (s, 1H, CONH2), 2.18–2.10 (m, 1H, CH), 1.47–1.36 (m, 2H, CH2), 1.28–1.17 (m, 6H, CH2+CH2×2), 0.85 (t, J=5.8Hz, 6H, CH3×2).

[0090] The filtrate in step (1) was subjected to rotary evaporation to recover petroleum ether, and 26g sodium hydroxide, 20ml water and 20ml methanol were added to the residual liquid, and the mixture was heated under reflux for 5h; cooled, the filtrate was extracted with 50ml ethyl acetate (2×25ml), the organic phase was separated, and ethyl acetate was recovered by rotary evaporation. A small amount of residue was valproate nitrile, which was recovered; the aqueous phase was concentrated by rotary evaporation, cooled to room temperature, and a white solid was precipitated. The solid was filtered and dried under vacuum at 50°C to obtain sodium valproate. The solid was dissolved by heating with ethyl acetate, and the filtrate was slowly cooled to room temperature to precipitate a large amount of white solid. The solid was filtered and dried under vacuum at 50°C to obtain 17.96g sodium valproate, with a yield of 54.1% (based on valproate nitrile).

[0091] Example 15

[0092] Preparation of valproamide and sodium valproate

[0093] (1) Preparation of valproamide

[0094] 25.04 g of valproate nitrile and 25.63 g of methanol were placed in an ice bath, and 39.23 g of concentrated sulfuric acid was added dropwise with stirring. The mixture was stirred at 85°C for 6 h, and 100 ml of water was added and stirred. The pH was adjusted to 8 with sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, rotary evaporated, and dried to obtain a solid-liquid mixture. 150 ml of petroleum ether was added and stirred for 0.5 h. The mixture was allowed to stand overnight, filtered, washed with petroleum ether, and the filtrate was treated according to step (2). The white solid was dried to obtain 6.95 g of valproate amide, with a yield of 24.3% (based on valproate nitrile); the melting point was 125.5-126°C. 1HNMR (400MHz, DMSO-d6) δ: 7.26 (s, 1H, CONH2), 6.71 (s, 1H, CONH2), 2.18–2.10 (m, 1H, CH ), 1.47–1.36 (m, 2H, CH2), 1.28–1.17 (m, 6H, CH2+CH2×2), 0.85 (t, J=5.8Hz, 6H, CH3×2).

[0095] (2) Preparation of sodium valproate

[0096] The filtrate in step (1) was subjected to rotary evaporation to recover petroleum ether, and 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 under reflux for 5 h; the mixture was cooled, and the aqueous phase was concentrated by rotary evaporation, cooled to room temperature, and a white solid was precipitated. The solid was filtered and dried under vacuum at 50° C. to obtain sodium valproate. The solid was dissolved by heating with ethyl acetate, and the filtrate was slowly cooled to room temperature to precipitate a large amount of white solid. The solid was filtered and dried under vacuum at 50° C. to obtain 18.6 g of sodium valproate, with a yield of 56.2% (calculated as valproonitrile).

[0097] Example 16

[0098] Preparation of valproamide and sodium valproate

[0099] CH3OH-HCl (g) was used instead of methanol and sulfuric acid, and the feed ratio and reaction conditions were followed according to Example 15, and the same post-treatment method was used to obtain valproamide and sodium valproate, respectively.

[0100] Example 17

[0101] Preparation of valproamide and sodium valproate

[0102] Benzenesulfonic acid or p-toluenesulfonic acid was used instead of sulfuric acid, and the feed ratio and reaction conditions were followed according to Example 15, and the same post-treatment method was used to obtain valproamide and sodium valproate, respectively.

[0103] Example 18

[0104] Preparation of valproamide and sodium valproate

[0105] Trifluoromethanesulfonic acid or methanesulfonic acid was used instead of sulfuric acid, and the feed ratio and reaction conditions were followed as in Example 15, and the same post-treatment method was used to obtain valproamide and sodium valproate, respectively.

[0106] Example 19

[0107] Preparation of valproamide and sodium valproate

[0108] Ethanol was selected to replace methanol, and valproamide and sodium valproate were obtained respectively by the same post-treatment method according to the feed ratio and reaction conditions of Example 15.

[0109] Example 20

[0110] Preparation of valproamide and methyl valproate

[0111] (1) Preparation of valproamide

[0112] 125 g of valproate nitrile and 128 g of methanol were added dropwise with stirring in an ice bath. The mixture was stirred at 85°C for 5.5 h. 500 ml of water was added and stirred. The pH was adjusted to 8 with sodium hydroxide solution. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The mixture was filtered and rotary evaporated to obtain a solid-liquid mixture. 700 ml of petroleum ether was added and stirred for 0.5 h. The mixture was allowed to stand overnight. The mixture was filtered and washed with petroleum ether. The filtrate was treated according to step (2). The white solid was dried to obtain 35 g of valproate amide. The yield was 24.5% (based on valproate nitrile). The melting point was 125.5-126°C. 1 HNMR (400MHz, DMSO-d6) δ: 7.26 (s, 1H, CONH2), 6.71 (s, 1H, CONH2), 2.18–2.10 (m, 1H, CH ), 1.47–1.36 (m, 2H, CH2), 1.28–1.17 (m, 6H, CH2+CH2×2), 0.85 (t, J=5.8Hz, 6H, CH3×2).

[0113] (2) Preparation of methyl valproate

[0114] The filtrate in step (1) was subjected to rotary evaporation to recover petroleum ether, and the product was purified under reduced pressure to obtain 95 g of methyl valproate, with a yield of 60.1% (calculated as valproonitrile); 1 HNMR (400MHz, CDCl3) δ: 3.67 (s, 3H, OCH3), 2.43–2.32 (m, 1H, CH), 1.65–1.53 (m, 2H, C H2), 1.47–1.36 (m, 2H, CH2), 1.33–1.23 (m, 4H, CH2×2), 0.89 (t, J=7.2Hz, 6H, CH3×2).

[0115] Example 21

[0116] Preparation of valproamide and valproic acid

[0117] (1) Preparation of valproamide

[0118] 125 g of propionitrile and 128 g of methanol were added dropwise with 196 g of concentrated sulfuric acid under stirring in an ice bath. The mixture was stirred at 80°C for 8 h. 500 ml of water was added and stirred. The pH was adjusted to 8 with sodium hydroxide solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, rotary evaporated, and dried to obtain a solid-liquid mixture. 700 ml of petroleum ether was added and stirred for 0.5 h. The mixture was allowed to stand overnight. The mixture was filtered, washed with petroleum ether, and the filtrate was treated according to step (2). The white solid was dried to obtain 34 g of valproamide with a yield of 23.7% (based on propionitrile); the melting point was 125.5-126°C. 1 HNMR (400MHz, DMSO-d6) δ: 7.26 (s, 1H, CONH2), 6.71 (s, 1H, CONH2), 2.18–2.10 (m, 1H, CH ), 1.47–1.36 (m, 2H, CH2), 1.28–1.17 (m, 6H, CH2+CH2×2), 0.85 (t, J=5.8Hz, 6H, CH3×2).

[0119] (2) Preparation of valproic acid

[0120] The filtrate in step (1) was subjected to rotary evaporation to recover petroleum ether, and potassium hydroxide aqueous solution (KOH: 120 g, H2O: 200 g) was added dropwise to the light yellow liquid, and the mixture was heated to 85°C and stirred for hydrolysis for 5 h; cooled, and the aqueous layer was separated; 350 ml of water was added to the organic phase, and the mixture was allowed to stand for stratification, and the oil phase was separated and valproate was recovered. Hydrochloric acid was added to the aqueous phase to adjust the pH to 1, and the mixture was allowed to stand for stratification. The oil phase was dried and subjected to vacuum distillation to collect 84 g of valproate acid in the 85-90°C / 0.4 kPa fraction, with a yield of 58.3% (calculated as valproate); 1 HNMR (400MHz, DMSO-d6) δ: 11.99 (s, 1H, COOH), 2.24–2.18 (m, 1H, CH), 1.53–1.44 (m, 2H , CH2), 1.39–1.34 (m, 2H, CH2), 1.32–1.22 (m, 4H, CH2×2), 0.86 (t, J=7.2Hz, 6H, CH3×2).

[0121] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations may be made without departing from the spirit and scope of the present invention. Therefore, the description is to be regarded as illustrative rather than restrictive.

Claims

1. A method for preparing valproamide represented by chemical formula I and sodium valproate represented by formula II, characterized in that Cyanoacetate and 1-chloropropane are subjected to a combined catalytic dipropylation reaction under the action of a base to produce 2-cyano-2-valproic acid ester represented by formula III; 2-cyano-2-valproic acid ester is hydrolyzed and deacidified to produce valproonitrile represented by formula V; valproonitrile is alcoholyzed under acid catalysis to produce valproamide represented by formula I and valproic acid ester represented by formula VI; valproic acid ester is hydrolyzed in a sodium hydroxide solution to produce sodium valproate represented by formula II. The preparation reaction is as follows: Among them, R 2 = methyl, ethyl, C3-C5 straight-chain alkyl or C3-C5 branched-chain alkyl; R 3 = methyl or ethyl; The catalyst for the preparation reaction of 2-cyano-2-valerate represented by formula III is composed of catalyst A and catalyst B; Catalyst A is selected from R3N, PhNR2, R4NX or R3R 1 NX; wherein R=C1~C4 linear alkyl, C5~C8 linear alkyl; R 1 =PhCH2, C1-C5 linear alkyl, C6-C18 linear alkyl; wherein X = Cl, Br or I; catalyst B is selected from NaBr, KBr, NaI or KI; The solvent for the preparation reaction of 2-cyano-2-propionate represented by formula III is selected from one or two of THF, 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 or butyl acetate; The base for the preparation reaction of 2-cyano-2-propionate represented by formula III is selected from granular M2CO3 or powdered M2CO3; wherein M = Na or K; The acid used in the alcoholysis reaction of the valproonitrile represented by formula V is selected from hydrogen chloride gas, aluminum chloride, thionyl chloride, trifluoromethanesulfonic acid, trimethylsilyl trifluoromethanesulfonate, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or sulfuric acid.

2. The preparation method according to claim 1, wherein wherein R4NX is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide or tetrapropylammonium bromide; R3R 1 NX is selected from hexadecyltrimethylammonium bromide, octadecyltrimethylammonium bromide, triethylbenzylammonium chloride, trimethylbenzylammonium chloride, triethylbenzylammonium bromide, hexadecyltriethylammonium bromide, dodecyltriethylammonium bromide, octyltriethylammonium bromide, hexyltriethylammonium bromide or trioctylmethylammonium chloride; R3N is selected from trimethylamine, triethylamine, tripropylamine, and tributylamine; PhNR2 is selected from N,N-dimethylaniline, N,N-diethylaniline, N,N-dipropylaniline, or N,N-dibutylaniline.

3. The preparation method according to claim 1, wherein Among them powder M2CO3 is selected from 100 mesh M2CO3, 150 mesh M2CO3, 200 mesh M2CO3, 250 mesh M2CO3, 300 mesh M2CO3 or 350 mesh M2CO3, wherein M=Na or K.

4. The preparation method according to claim 1, wherein the preparation method of 2-cyano-2-valerate ester represented by formula III is characterized in that The reaction temperature is selected from 60° C. to 120° C.; the reaction time is selected from 1.0 h to 12 h.

5. The preparation method according to claim 1, wherein the preparation method of 2-cyano-2-valerate of formula III is characterized in that The molar ratio of cyanoacetate: catalyst A: catalyst B is 1: 0.01-0.10: 0.005-0.05; the cyanoacetate is selected from methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate or tert-butyl cyanoacetate.

6. The preparation method according to claim 1, wherein the alcoholysis reaction of valproic acid nitrile represented by formula V is characterized in that Valproate nitrile: acid = 1: 1.2 to 4 molar ratio; the mass concentration of the acid is selected from 30% to 70%; Valproate nitrile: R 3 OH=1:3~8 molar ratio.

7. The preparation method according to claim 1, wherein the alcoholysis reaction of valproic acid nitrile represented by formula V is characterized in that The reaction temperature is selected from 25° C. to 100° C.; and the alcoholysis reaction time is selected from 4 h to 24 h.

8. The preparation method according to claim 1, wherein the alcoholysis reaction of valproonitrile represented by formula V produces valproamide represented by formula I and valproate represented by formula VI; and valproate represented by formula VI is hydrolyzed in a sodium hydroxide solution to produce sodium valproate represented by formula II; The molar ratio of Ⅰ and Ⅱ is selected from n 丙戊酰胺 ∶n 丙戊酸钠 =1:1.5~8.

0.

9. A method for co-producing valproamide represented by formula I and valproic acid represented by formula VII, characterized in that: The valproonitrile of formula V is prepared by the method according to any one of claims 1 to 5; the valproonitrile is subjected to alcoholysis and hydrolysis to obtain valproamide of formula I and valproic acid of formula VII; the preparation reaction is as follows: Among them, R 3 and acid as defined in claim 1; the molar ratio of Ⅰ and Ⅶ is selected from n 丙戊酰胺 ∶n 丙戊酸 =1:1.5~8.0.