A kind of 2-cyano-2-valproic acid ester and its preparation method and application

Abstract

The invention relates to a preparation method of 2-cyano-2-valproate shown in a chemical structural formula I. Specifically, cyanoacetate and 1-chloropropane are subjected to composite catalytic dipropylation under the action of a base to prepare 2-cyano-2-valproate. The preparation reaction is as follows: #imgabs0#R=benzyl, C1-C5 straight-chain alkyl or C3-C5 branched-chain alkyl; the solvent is selected from one or two of THF, DMF, DMC, DMSO, ethyl / propyl / butyronitrile, 1,4-dioxane, ethylene glycol dimethyl / ethyl ether, diethylene glycol dimethyl / ethyl ether, and ethyl / butyl acetate; the base is selected from powdered M2CO3; wherein M=Na, Li, Cs or K; the catalyst is composed of a catalyst A and a catalyst B; the catalyst A is selected from R3N, PhNR2, R4NX, R3R 1 One or two of NX, wherein R = C1-C5 straight chain alkyl, R 1 =PhCH2, C 16 Straight chain alkyl or C 18 Straight chain alkyl, X = F, Cl, Br, I or HSO4; catalyst B is selected from MX, wherein M = Na, Li, Cs, K, X = F, Cl, Br or I. Use of 2-cyano-2-valproic acid ester (I) in the preparation of valproic acid, sodium valproate, magnesium valproate and valproamide.

Description

Technical Field

[0001] The invention relates to a phase transfer composite catalytic preparation method of 2-cyano-2-valproate and application of the method in the preparation of valproic acid, sodium valproate, magnesium valproate and valproamide. Background Art

[0002] Hunan Institute of Pharmaceutical Industry et al. [Synthesis of the anti-epileptic drug Kangdianling. Chinese Journal of Pharmaceutical Industry, 1978, 1: 34-35; Qu Di. Shandong Chemical Industry, 2012, 41(3): 30-31, 35] selected diethyl malonate and 1-bromopropane to prepare sodium valproate through a four-step reaction of alkylation, hydrolysis, decarboxylation and salt formation.

[0003]

[0004] In 2016, Zong Zhihui et al. [Improved Synthesis Process of Sodium Valproate. Journal of Changchun Normal University, 2016, 08:64-67] optimized the preparation process of sodium valproate using diethyl malonate and 1-bromopropane as raw materials; and explored ethyl acetate and acetone as recrystallization solvents, with recrystallization yields of sodium valproate reaching 96% and 90%, respectively.

[0005]

[0006] In 2016, Zhang Jing [Synthesis process of sodium valproate, CN105622390A.2016-06-01] invented a preparation process of sodium valproate using diethyl malonate and 1-bromopropane as raw materials:

[0007]

[0008] In 2012, Fu Jingguang [Improvement of the Synthesis Process of Sodium Valproate. Shandong Chemical Industry, 2012, 41(10):3-4] selected dimethyl malonate, reacted it with 1-bromopropane under the catalysis of PEG-400 and the action of sodium methoxide, then hydrolyzed it with sodium hydroxide, heated for decarboxylation, and finally salified to obtain sodium valproate.

[0009]

[0010] Zhou Qiqun et al. [Improved synthesis process of sodium valproate. Chinese Journal of Pharmaceutical Industry. 1993, 24(8): 347-348; Wang Xueqin, Tian Yongguang. New synthesis process of sodium valproate. Chinese Journal of Pharmaceutical Industry. 1999, 30(9): 389-390] selected methyl acetoacetate to be alkylated, deacylated, hydrolyzed and salified by TEBA solid-liquid phase transfer catalysis to obtain sodium valproate:

[0011]

[0012] In 1999, 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 of sodium valproate, CN110563572A, 2019-12-13] also used TBAB phase transfer catalysis to prepare a sodium valproate.

[0013]

[0014] In 1984, Li Xinyuan et al. [Synthesis of valproic acid antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Pharmaceutical Industry, 1984, 5: 4-6] selected methyl cyanoacetate, 1-bromopropane and solid potassium carbonate, dipropane alkylated under the catalysis of quaternary ammonium salt, and then prepared sodium / magnesium valproate or valproamide through hydrolysis, decarboxylation and salt formation.

[0015]

[0016] In 2011, Tao Jing et al. [A method for preparing dipropylmalonate. Chinese invention patent. CN103183612A, 2013-07-03; A method for preparing 2-propylvaleric acid, CN103183599B, ​​2015-04-01] selected a method for preparing valproic acid using malonate and 1-chloropropane as raw materials, wherein the crude product yield of the dipropylation reaction was 70.5%.

[0017]

[0018] In 2018, Li 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:

[0019] Summary of the invention

[0020] The present invention aims to provide a method for preparing 2-cyano-2-valproic acid ester shown in chemical formula I, characterized in that cyanoacetic acid ester and 1-chloropropane are subjected to complex catalytic dipropylation under the action of a base to obtain the compound shown in I; the preparation reaction is as follows:

[0021]

[0022] R = benzyl, C1-C5 straight chain alkyl or C3-C5 branched chain alkyl;

[0023] The catalyst consists of catalyst A and catalyst B;

[0024] Catalyst A options: R3N, PhNR2, R4NX, R3R 1 One or both of NX or MX; wherein R=C1~C5 linear alkyl; R 1 =PhCH2, C16 straight chain alkyl or C18 straight chain alkyl; wherein X = F, Cl, Br, I or HSO4;

[0025] Catalyst B is selected from MX; wherein M=Na, Li, Cs, K, and X=F, Cl, Br or I.

[0026] R4NX is selected from: TBAF, TBAC, TBAB, TBAI, TEAF, TEAC, TEAB, TEAI, TMAF, TMAC, TMAB, TMAI, TEAHSO4, TMAHSO4 or TBAHSO4; TBAF, TBAC, TBAB, TBAI or TBAHSO4 are tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide or tetrabutylammonium hydrogen sulfate, respectively; TEAF, TEAC, TEAB, TEAI or TEAHSO4 are tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide or tetraethylammonium hydrogen sulfate, respectively; TMAF, TMAC, TMAB, TMAI or TMAHSO4 are tetramethylammonium fluoride, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide or tetramethylammonium hydrogen sulfate, respectively.

[0027] R3R 1 NX is selected from: 1631, 1831, TEBA or TMBA; 1631 is hexadecyltrimethylammonium bromide; 1831 is octadecyltrimethylammonium bromide; TEBA is triethylbenzylammonium chloride; TMBA is trimethylbenzylammonium chloride.

[0028] 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.

[0029] MX is selected from: NaBr, KBr, NaI or KI.

[0030] 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.

[0031] The base is selected from: powdered M2CO3; wherein M = Na, Li, Cs or K.

[0032] 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.

[0033] Reaction temperature selection: 60℃~120℃; reaction time selection: 1.0h~12h;

[0034] 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.

[0035] The second object of the present invention is to provide the use of 2-cyano-2-valproic acid ester shown in formula Ⅰ in the preparation of valproic acid amide. The 2-cyano-2-valproic acid ester shown in formula Ⅰ is subjected to three-step reaction to prepare valproic acid amide. The preparation reaction is as follows:

[0036]

[0037] R = benzyl, C1-C5 straight chain alkyl or C3-C5 branched chain alkyl; the base is selected from: MOH, wherein M = Na, Li, Cs or K; the acid is selected from: hydrochloric acid or sulfuric acid.

[0038] The third aspect of the present invention is to provide the use of 2-cyano-2-valproic acid ester shown in formula I in the preparation of valproic acid, characterized in that 2-cyano-2-valproic acid ester shown in formula I is selected to prepare valproic acid through three-step reaction, and the preparation reaction is as follows:

[0039]

[0040] R = benzyl, C1-C5 straight chain alkyl or C3-C5 branched chain alkyl; the base is selected from: MOH, wherein M = Na, Li, Cs or K; the acid is selected from: HCl, AlCl3 or sulfuric acid.

[0041] The fourth aspect of the present invention is to provide the use of 2-cyano-2-valproate ester shown in formula I in the preparation of sodium valproate, characterized in that 2-cyano-2-valproate ester shown in formula I is selected to prepare sodium valproate through a four-step reaction, and the preparation reaction is as follows:

[0042]

[0043] R = benzyl, C1-C5 straight chain alkyl or C3-C5 branched chain alkyl; the base is selected from: MOH, wherein M = Na, Li, Cs or K; the acid is selected from: HCl, AlCl3 or sulfuric acid.

[0044] The fifth aspect of the present invention is to provide the use of 2-cyano-2-valproate ester shown in formula I in the preparation of magnesium valproate, characterized in that 2-cyano-2-valproate ester shown in formula I is selected to prepare magnesium valproate by four-step reaction, and the preparation reaction is as follows:

[0045]

[0046] R = benzyl, C1-C5 straight chain alkyl or C3-C5 branched chain alkyl; the base is selected from: MOH, wherein M = Na, Li, Cs or K; the acid is selected from: HCl, AlCl3 or sulfuric acid.

[0047] Compared with the prior art, the present invention has the following advantages:

[0048] 1. In the present invention, a composite catalytic dipropylation method using cyanoacetate and 1-chloropropane is used: 1-chloropropane is in sufficient supply, rich in sources, and cheap; the key dipropylation reaction is complete, which provides a guarantee for the high quality of the final product! Four valproic acids and their derivatives - valproic acid, sodium valproate, magnesium valproate and valproamide share this key reaction; one production route can produce four high-quality valproic acids and their derivatives:

[0049]

[0050] 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 generation of the following by-products:

[0051]

[0052] 3. The intermediates and products in the process are of high purity and simple to separate; the production cost of raw materials is low and the quality is good. It has good social and economic benefits. DETAILED DESCRIPTION

[0053] The present invention is further described in detail below in conjunction with the embodiments.

[0054] Example 1

[0055] Preparation of methyl 2-cyano-2-valeroponic acid ester

[0056]

[0057] 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 (TLC monitored the reaction completion). After the reaction was completed, the inorganic salt was filtered after cooling slightly; the inorganic salt was washed with petroleum ether; the organic phase was washed with water until the aqueous phase was colorless, the organic phase was dried over anhydrous sodium sulfate, the sodium sulfate was recovered by suction filtration, the organic phase was rotary evaporated, and dried to obtain 53.06g of methyl 2-cyano-2-valeric acid, 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).

[0058] Example 2

[0059] Preparation of 2-cyano-2-valeric acid

[0060]

[0061] 29.73g (0.30mol) methyl cyanoacetate, 12.0mmol tetrabutylammonium chloride, 3.0mmol KI, 91.21g (0.66mol) K2CO3, 120ml ethylene glycol dimethyl ether and 58.91g (0.75mol) 1-chloropropane were stirred at 85°C for 2.5h (TLC monitoring showed that the reaction was complete). After the reaction was completed, the inorganic salts were filtered after cooling slightly; 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 the ethyl acetate was recovered by distillation. 150ml 15% KOH was added to the residual light yellow transparent liquid (methyl 2-cyano-2-valproate), and the temperature was raised for hydrolysis for 3h. Concentrated hydrochloric acid was added for neutralization, and a solid was precipitated. The solid was dried to obtain 48.69g of a white solid. 2-Cyano-2-propanoic acid, yield 95.90% (based on 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).

[0062] Example 3

[0063] Preparation of 2-cyano-2-valeric acid

[0064]

[0065] 29.73g (0.30mol) methyl cyanoacetate, 3.33g (9.0mmol) TBAB, 3.0mmol KI, 91.21g (0.66mol) K2CO3, 120ml DMF and 58.91g (0.75mol) 1-chloropropane were stirred at 85°C for 3.3h (the reaction was monitored by TLC to be complete). After the reaction was completed, the mixture was cooled and the inorganic salt was filtered; the inorganic salt was washed with petroleum ether (100ml×3), and the inorganic salt was 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-propanoic acid valerate). Add 150 ml of 15% KOH to the light yellow transparent liquid of 2-cyano-2-valerioic acid ester, hydrolyze at 65°C for 3 h, add concentrated hydrochloric acid in an ice bath to neutralize, precipitate a white precipitate, filter and dry to obtain 49.10 g of 2-cyano-2-valerioic acid 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).

[0066] Example 4

[0067] Preparation of ethyl 2-cyano-2-valproate

[0068]

[0069] 2.26g (20mmol) ethyl cyanoacetate, 1mmol TBAC, 0.5mmol KI, 6.08g (44mmol) K2CO3 (200 mesh), 8ml DMF and 3.93g (50mmol) 1-chloropropane were stirred at 80°C for 6h, and the inorganic salt was 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, rotary evaporated, and dried to obtain 3.74g ethyl 2-cyano-2-valproate, with a yield of 94.9% (based on ethyl cyanoacetate). 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).

[0070] Example 5

[0071] Preparation of 2-cyano-2-valeric acid

[0072]

[0073] 2.26g (20mmol) ethyl cyanoacetate, 1mmol TBAC, 6.08g (44mmol) K2CO3 (100 mesh), 2ml DMF, 6ml butyl acetate and 0.5mmol potassium bromide, 3.93g (50mmol) 1-chloropropane, stir and react at 80℃ for 6h, filter and recover inorganic salts; wash with petroleum ether, wash the organic phase with water until the water phase is colorless, and recover petroleum ether by rotary evaporation. Add 15ml 15% KOH to the residual light yellow transparent liquid (ethyl 2-cyano-2-valeric acid ester), heat and hydrolyze for 3h, add concentrated hydrochloric acid to neutralize, precipitate solid, and dry to obtain 3.13g 2-cyano-2-valeric acid as a white solid, with a yield of 92.60% (based on ethyl cyanoacetate), and a melting point of 49-50℃. 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).

[0074] Example 6

[0075] Preparation of methyl 2-cyano-2-valeroponic acid ester

[0076] 29.73g (0.30mol) of methyl cyanoacetate, 15.0mmol of tributylamine, 91.21g (0.66mol) of K2CO3 (300 mesh), 120ml of recovered DMF, 5.0mmol of potassium iodide and 58.91g (0.75mol) of 1-chloropropane were stirred at 85°C for 4.0h (the reaction was completed after monitoring by TLC). After the reaction, the inorganic salt was 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, rotary evaporated, and dried to obtain 53.46g of methyl 2-cyano-2-valproate, with 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).

[0077] Example 7

[0078] Preparation of methyl 2-cyano-2-valeroponic acid ester

[0079] 29.73g (0.30mol) of methyl cyanoacetate, 9.0mmol of recovered tetrabutylammonium bromide, 91.21g (0.66mol) of K2CO3 (300 mesh), 120ml of recovered DMF, 2.0mmol of potassium iodide and 58.91g (0.75mol) of 1-chloropropane were stirred at 85°C for 3.0h (the reaction was completed as monitored by TLC), and the inorganic salt was 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, rotary evaporated, and dried to obtain 53.46g of methyl 2-cyano-2-valproate, with 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).

[0080] Example 8

[0081] Preparation of 2-cyano-2-valeric acid n-propyl ester

[0082]

[0083] According to the method of Example 1, n-propyl cyanoacetate was selected to prepare n-propyl 2-cyano-2-propanoate.

[0084] Example 9

[0085] Preparation of 2-cyano-2-valeric acid

[0086]

[0087] According to the method of Example 2, n-propyl cyanoacetate was selected to prepare 2-cyano-2-propanoic acid.

[0088] Example 10

[0089] Preparation of Isopropyl 2-Cyano-2-Provalerate

[0090]

[0091] According to the method of Example 1, isopropyl cyanoacetate was selected to prepare isopropyl 2-cyano-2-propanoate.

[0092] Embodiment 11

[0093] Preparation of 2-cyano-2-valeric acid

[0094]

[0095] According to the method of Example 2, isopropyl cyanoacetate was selected to prepare 2-cyano-2-valeric acid.

[0096] Example 12

[0097] Preparation of tert-butyl 2-cyano-2-valerioate

[0098]

[0099] According to the method of Example 1, tert-butyl cyanoacetate was selected to prepare tert-butyl 2-cyano-2-valproate.

[0100] Embodiment 13

[0101] Preparation of 2-cyano-2-valeric acid

[0102]

[0103] According to the method of Example 2, tert-butyl cyanoacetate was selected to prepare 2-cyano-2-valeric acid.

[0104] Embodiment 14

[0105] Preparation of valproic acid

[0106]

[0107] 29.73g (0.30mol) methyl cyanoacetate, 12.0mmol tetrabutylammonium bromide, 3.0mmol KI, 91.21g (0.66mol) K2CO3 (300 mesh), 80ml butyl acetate, 40ml DMF and 58.91g (0.75mol) 1-chloropropane were stirred at 85°C for 4.0h (the reaction was completed after TLC monitoring). After the reaction was completed, the inorganic salt was filtered after cooling slightly; the inorganic salt was washed with petroleum ether; the organic phase was washed with water until the aqueous phase was colorless, and the petroleum ether was recovered by rotary evaporation. Methanol was added to the residual liquid (methyl 2-cyano-2-propanoate), and HCl was passed through. After the ventilation was completed, the reaction was stirred. After the reaction was completed, potassium hydroxide aqueous solution (KOH: 150g, H2O: 200g) was added dropwise at 65°C to the reaction solution, and refluxed at 85°C for 3h to obtain a solid. 250 mL of water was added to dissolve the solid, and the insoluble matter was removed by filtration. The pH of the filtrate was adjusted to 1-1.5 with concentrated hydrochloric acid. Solid precipitated and was filtered and dried to obtain 49.10 g of 2,2-dipropylmalonic acid.

[0108] According to the method in Example 1 of the patent [A method for preparing 2-propyl valeric acid, CN103183599B, ​​2015-04-01]: 31g of 2,2-dipropylmalonic acid was added to a 200mL round-bottomed bottle, replaced with nitrogen three times, and placed in a pre-stabilized 170°C oil bath for reaction. CO2 was released during the reaction, and the reaction was complete in 3h. The temperature was lowered to obtain 23g of valeric acid. HPLC results showed that the purity was 99.84%. 1 H NMR (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).

[0109] Embodiment 15

[0110] Preparation of valproic acid

[0111]

[0112] 22.6g (200mmol) ethyl cyanoacetate, 10mmol TBAC, 60.8g (44mmol) K2CO3 (100 mesh), 80ml DMF and 5.0mmol potassium iodide and 39.3g (50mmol) 1-chloropropane, stir at 80℃ for 6h, filter and recover inorganic salts; wash with petroleum ether, wash the organic phase with water until the water phase is colorless, and recover petroleum ether by rotary evaporation. Add ethanol to the remaining light yellow transparent liquid (ethyl 2-cyano-2-valproate), pass HCl, and stir to react after the ventilation is completed. After the reaction is completed, add potassium hydroxide aqueous solution (KOH: 150g, H2O: 200g) dropwise at 65℃, heat to 85℃ and reflux vigorously for 3h, and desolventize to obtain solid. Add water to dissolve the solid, add concentrated hydrochloric acid dropwise to adjust the pH to 1-1.5, and solid precipitates. Filter and obtain 32.4g of light yellow solid-2,2-dipropylmalonic acid.

[0113] According to the method in Example 1 of the patent [A method for preparing 2-propyl valeric acid, CN103183599B, ​​2015-04-01]: 31g of 2,2-dipropylmalonic acid was added to a 200mL round-bottomed bottle, replaced with nitrogen three times, and placed in a pre-stabilized 170°C oil bath for reaction. CO2 was released during the reaction, and the reaction was complete in 3h. The temperature was lowered to obtain 23g of valeric acid. HPLC results showed that the purity was 99.84%. 1H NMR (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).

[0114] Example 16

[0115] Preparation of Sodium Valproate

[0116]

[0117] Prepared according to the method in the literature [Li Xinyuan et al. Synthesis of valproic acid antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Pharmaceutical Industry, 1984, 5: 4-6]: 43g of valproic acid (prepared by the method of Example 10 or 11), 12g of sodium hydroxide and 86g of water were dissolved and adjusted to pH 8-9, 0.4g of activated carbon was added for decolorization, filtered, and the filtrate was concentrated to dryness to obtain 49g of sodium 2-valproate, with a yield of 98% (calculated as valproic acid).

[0118] Embodiment 17

[0119] Preparation of magnesium valproate

[0120]

[0121] Preparation according to the method in the literature [Li Xinyuan et al. Synthesis of valproic acid antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Pharmaceutical Industry, 1984, 5: 4-6]: Add 500 ml of water and 5 g of magnesium oxide to a reaction kettle, heat to 40°C with stirring, slowly add 25 g of valproic acid (prepared by the method of Example 10 or 11), heat to 70°C, and react for 1 hour. After the reaction, add 0.5 g of activated carbon for decolorization, filter by pressure, concentrate the filtrate, and dry to obtain 26 g of 2-valproic acid magnesium, with a yield of 96%.

[0122] Embodiment 18

[0123] Preparation of valproamide

[0124]

[0125] Prepared according to the method of the literature [Li Xinyuan. Synthesis of a new anti-epileptic drug - valeramide, Pharmaceutical Industry, 1981, (11): 1-2]:

[0126] (1) Preparation of 2-propylvaleronitrile

[0127] 83 g of 2-cyano-2-propanoic acid (prepared by the method of Example 2 or 7) was added to a 250 ml round-bottom flask, heated to 145-150° C., refluxed for 3 h, and fractionated. The fraction at 165-175° C. was collected to obtain a colorless oily substance, 2-propylvaleronitrile, with a pure yield of 70%.

[0128] (2) Preparation of valproamide

[0129] In a 500ml three-necked round-bottom flask, add 62g of 2-propylvaleronitrile, add 145g of 80% sulfuric acid while stirring, react at 80-82℃ for 3h, cool the reaction solution to room temperature, pour into 640ml of ice water, stir well, and let stand at 1℃ for 1h. Filter out the crude valproamide, wash with 10% sodium carbonate solution until neutral, and dry to obtain 65g of valproamide.

[0130] (3) Refining

[0131] 65g crude valproamide and 97ml ethanol were heated to 70℃ to dissolve, 0.1g activated carbon was added for decolorization, and the filtrate was poured into 900ml distilled water, stirred evenly, and placed at 1℃ for 2h. White needle-shaped crystals of valproamide were filtered out, and 53.5g valproamide was obtained after drying. 1.3g valproamide can also be obtained from the mother liquor, a total of 54.8g valproamide, and the total yield is 57.2%. The melting point of valproamide is 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).

[0132] Embodiment 19

[0133] Preparation of valproic acid

[0134]

[0135] According to the method of Example 14 or Example 15, n-propyl cyanoacetate was selected to prepare n-propyl 2-cyano-2-propanoate. Propanol was added to the residual light yellow transparent liquid (n-propyl 2-cyano-2-propanoate), HCl was passed, and the aeration was completed. The reaction was stirred. After the reaction was completed, potassium hydroxide aqueous solution was added dropwise at 65°C, the temperature was raised to 85°C, and the reaction was vigorously refluxed for 3 hours to obtain a solid. Water was added to dissolve the solid, and concentrated hydrochloric acid was added dropwise to adjust the pH to 1-1.5. Solid precipitated and 2,2-dipropylmalonic acid was obtained by suction filtration.

[0136] According to the method in Example 1 of the patent [A method for preparing 2-propyl valeric acid, CN103183599B, ​​2015-04-01]: 31g of 2,2-dipropylmalonic acid was added to a 200mL round-bottomed bottle, replaced with nitrogen three times, and placed in a pre-stabilized 170°C oil bath for reaction. CO2 was released during the reaction, and the reaction was complete in 3h. The temperature was lowered to obtain 23g of valproic acid. HPLC results showed that the purity was 99.84%. 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).

[0137] 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. The preparation method of 2-cyano-2-valproic acid ester represented by chemical structural formula I is characterized in that The compound shown in formula I is prepared by the complex catalytic dipropylation of cyanoacetate and 1-chloropropane in the presence of a base. The preparation reaction is as follows: R = n-propyl, isopropyl, n-butyl or tert-butyl; the catalyst is composed of catalyst A and catalyst B; catalyst A is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide or tributylamine; catalyst B is selected from potassium bromide or potassium iodide; The solvent is selected from: DMF, DMC, diethylene glycol dimethyl ether or ethylene glycol diethyl ether; the base is selected from powdered K2CO3.

2. The method for preparing 2-cyano-2-valproate according to claim 1, characterized in that Powdered K2CO3 options: 100 mesh K2CO3, 150 mesh K2CO3, 200 mesh K2CO3, 250 mesh K2CO3, 300 mesh K2CO3 or 350 mesh K2CO3.

3. The method for preparing 2-cyano-2-valproate as claimed in claim 1, characterized in that Reaction temperature selection: 60℃~120℃; reaction time selection: 1.0h~12h.

4. The method for preparing 2-cyano-2-valproate according to claim 1, characterized in that The catalytic dosage is selected as follows: cyanoacetate: catalyst A: catalyst B = 1: 0.01-0.10: 0.005-0.05 molar ratio, wherein the cyanoacetate is selected from n-propyl cyanoacetate, isopropyl cyanoacetate, n-butyl cyanoacetate or tert-butyl cyanoacetate.

5. A method for preparing valproamide, characterized in that 2-cyano-2-valproic acid ester (I) is prepared by the method according to any one of claims 1 to 4, and 2-cyano-2-valproic acid ester is reacted in three steps to obtain valproamide, and the preparation reaction is as follows: Wherein, R, catalyst, base and solvent are defined as in claim 1; R is defined as in claim 1; the base is selected from KOH or NaOH; the acid is selected from hydrochloric acid or sulfuric acid.

6. A method for preparing valproic acid, characterized in that 2-Cyano-2-valproic acid ester (I) is prepared by the method according to any one of claims 1 to 4. 2-Cyano-2-valproic acid ester is subjected to three-step reaction to obtain valproic acid. The preparation reaction is as follows: Wherein, R, catalyst, base and solvent are defined as in claim 1; R is defined as in claim 1; the base is selected from KOH or NaOH; the acid is selected from HCl, AlCl3 or sulfuric acid.

7. A method for preparing sodium valproate, characterized in that 2-cyano-2-valproate (I) is prepared by the method according to any one of claims 1 to 4, and 2-cyano-2-valproate is reacted in four steps to obtain sodium valproate, and the preparation reaction is as follows: Wherein, R, catalyst, base and solvent are defined as in claim 1; R is defined as in claim 1; the base is selected from KOH or NaOH; the acid is selected from HCl, AlCl3 or sulfuric acid.

8. A method for preparing magnesium valproate, characterized in that 2-cyano-2-valproate (I) is prepared by the method according to any one of claims 1 to 4, and 2-cyano-2-valproate is subjected to four-step reaction to obtain magnesium valproate, and the preparation reaction is as follows: Wherein, R, catalyst, base and solvent are defined as in claim 1; R is defined as in claim 1; the base is selected from KOH or NaOH; the acid is selected from HCl, AlCl3 or sulfuric acid.

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