CN103073424A - Green preparation method for intermediate of valproic acid derivatives - Google Patents

Abstract

利用二丙基丙二酸二乙酯生产过程中回收的溴化钠作为原料，经下述循环过程制备二丙基丙二酸二乙酯：。The present invention relates to the green preparation method of dipropyl malonate shown in chemical structural formula I:

Utilize the sodium bromide that reclaims in the production process of dipropyl malonate as raw material, prepare diethyl dipropyl malonate through following circulation process: .

Description

A kind of green preparation method of the intermediate of valproic acid derivative

technical field

The invention relates to a green preparation method of dipropyldipropylmalonate, a key intermediate of valproic acid derivatives.

Background technique

Diethyl dipropylmalonate is the key intermediate for preparing sodium valproate, magnesium valproate and valproamide, and the preparation reaction is as follows:

Sodium valproate is a widely used antiepileptic drug. Its preparation method is to use diethyl malonate or ethyl cyanoacetate as raw material, through alkylation, hydrolysis, decarboxylation, and salt formation to obtain the finished product. Concrete method and synthetic route are as follows:

Diethyl malonate and 1-bromopropane were used as raw materials to prepare sodium valproate through four steps of alkylation, hydrolysis, decarboxylation and salt formation [Hunan Institute of Pharmaceutical Industry, Antiepileptic Drug Antiepileptic Synthetic method. Chinese Journal of Pharmaceutical Industry, 1978, 1:34-35; Qu Di. Exploration of conditions for laboratory synthesis of sodium valproate. Shandong Chemical Industry, 2012, 41 (3): 30-31, 35].

Methyl cyanoacetate is used as raw material, 1-bromopropane is used as alkylating agent, solid potassium carbonate is used as base to carry out dipropane alkylation under the catalysis of quaternary ammonium salt, and then four-step reaction of hydrolysis, decarboxylation and salt formation Sodium/magnesium valproate or valproamide can be obtained in the preparation [Li Xinyuan et al. Synthesis of valproic acid antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Chinese Journal of Pharmaceutical Industry, 1984, 5: 4-6].

Sodium valproate was prepared from methyl acetoacetate by solid-liquid phase transfer catalytic alkylation, deacylation, hydrolysis, and salt formation [Zhou Qiqun et al. Improvement of the synthesis process of sodium valproate. Chinese Journal of Pharmaceutical Industry. 1993, 24 (8): 347-348; Wang Xueqin, Tian Yongguang. New process for the synthesis of sodium valproate. Chinese Journal of Pharmaceutical Industry. 1999, 30(9): 389-390]:

1-Bromopropane generally adopts the synthesis process of reacting n-propanol with hydrobromic acid or sodium (potassium) bromide under the catalysis of concentrated sulfuric acid, and the preparation method is as follows.

The reaction of n-propanol and hydrobromic acid under the catalysis of concentrated sulfuric acid to prepare 1-bromopropane ); 538-540, 546; Longfa. Improvement of Bromide-n-Propane Synthesis Process Operation. Hunan Chemical Industry. 1998, 28 (2): 34-35]:

Bromine reacts with sulfur to generate sulfur bromide, and in the presence of water, hydrolysis occurs to generate hydrogen bromide and sulfuric acid. Hydrogen bromide is used as the reaction raw material, and sulfuric acid is used as the catalytic dehydrating agent to prepare 1-bromopropane; the overall reaction is as follows [Liu Yaoyuan, Shen Shitang, Zhou Fuqiang et al. Synthesis of 1-bromopropane by sulfur bromine method. Sea Lake Salt and Chemical Industry, 1998, 27(2): 12-13]:

The preparation method using propylene method: under the action of peroxide, hydrogen bromide and propylene gas undergo reverse Markov addition to produce 1-bromopropane [Tang Changsheng, research on the production of 1-bromopropane by addition method. Haihu salt and Chemical Industry, 2004, 33 (5): 17-18; Liang Li. "One-step" synthesis of 1-bromopropane from propylene. Guangdong University of Technology, 2004]:

In the existing technical method for preparing 1-bromopropane, when concentrated sulfuric acid is used as a catalyst, a large amount of concentrated sulfuric acid is required, and the yield of 1-bromopropane is only 80-90%. The sulfuric acid waste liquid obtained by the reaction has environmental pollution and waste of resources, etc. problem, making the economic benefit and social benefit of the method lower; the raw materials required by the sulfur bromine method are serious to environmental pollution; Security Question.

Existing production method of 1-bromopropane: use concentrated sulfuric acid in recovered sulfuric acid waste liquid to prepare 70% sulfuric acid as catalyst. Due to the sulfuric acid waste liquid, residual hydrobromic acid and concentrated sulfuric acid can undergo redox reactions:

The bromine and sulfur dioxide produced in the reaction are poisonous, seriously affecting the health of operators and causing serious environmental pollution. Residual impurities such as 2-bromopropane in the waste liquid seriously affect the quality of preparing 1-bromopropane.

Contents of the invention

The present invention provides a green preparation method of dipropyl malonate shown in chemical structural formula I:

It is characterized in that the sodium bromide recovered in the production process of dipropyl malonate is used as raw material to prepare diethyl dipropyl malonate through the following circulation process:

The invention provides the method that by-product sodium bisulfate can be decomposed to obtain sodium sulfate and sulfuric acid:

The invention provides a treatment and recycling method for sulfuric acid waste liquid: add an organic solvent and an oxidant to the sulfuric acid waste liquid, dissolve the 2-bromopropane remaining in the reaction waste liquid in the organic solvent, and oxidize the residual hydrobromic acid into bromine, bromine Soluble in organic solvents, organic solvents containing bromine are distilled to recover bromine and organic solvents, and organic solvents are recycled; oxidants are selected from: hydrogen peroxide, manganese dioxide, tert-butyl peroxide, perbenzoic acid or peracetic acid; organic The solvent is selected from: chloroform, carbon tetrachloride, dichloroethane, trichloroethane, tetrachloroethane or benzene.

The invention provides the production of 1-bromopropane by means of distillation while reacting. The preparation reaction of 1-bromopropane is a reversible reaction, and the 1-bromopropane generated by the reaction is distilled out of the system in time, which is beneficial to the preparation reaction.

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

1. In the present invention, make full use of the by-product sodium bromide that reclaims in the dipropyl malonate production process as raw material, produce 1-bromopropane with sulfuric acid and propanol, reduce the pollution of by-product to environment, Reduced production costs.

2. Sodium sulfate and sulfuric acid can be obtained by decomposing the by-product sodium bisulfate; the sulfuric acid obtained by decomposition can be used to prepare 1-bromopropane; reduce the amount of concentrated sulfuric acid in the preparation of 1-bromopropane; the consumed sulfuric acid is converted into sodium sulfate.

3. Using the distillation method while reacting, the reaction yield is increased to 95~97%.

4. Fully and effectively utilize the waste acid produced in the production of 1-bromopropane; the waste acid is recycled after treatment; the waste acid is zero discharged during the reaction process, which solves the problem of waste acid environmental pollution and has good social and economic benefits.

Detailed ways

The present invention will be further described in detail below in conjunction with the examples.

Example 1

Preparation of 1-bromopropane

1.0~1.2 mol of recovered sodium bromide (derived from Example 8), 1.0 mol of n-propanol, stirred evenly at 56°C, added dropwise 1.89 mol of 70% sulfuric acid, after dropping, heated up to 66°C, and kept the temperature for 1.0 h. Raise the temperature to 76°C, react for 1.0~1.5 h, then raise the temperature to 86°C, distill 1-bromopropane while reacting, the total reaction time is 4.0~4.5 h. The collected crude 1-bromopropane was washed with water, washed with sodium carbonate solution to pH 6~7, and dried with calcium chloride to obtain 116 g~119 g of clear and transparent colorless liquid 1-bromopropane, with a yield of 95~97% and a content of ≥97 %.

Example 2

Recovery of sodium bisulfate

1-Bromopropane was collected by distillation in Example 1, and the residual reaction solution in the reactor was left standstill to separate out sodium bisulfate solid, and suction filtered to obtain 135 ~ 136g of sodium bisulfate monohydrate, and the filtrate was recovered to obtain 165 ~ 167 g of spent acid.

Example 3

Sodium bisulfate decomposition to produce sodium sulfate

In Example 2, 136 g of sodium bisulfate monohydrate and 1.0 mol of propanol were recovered, stirred at 48-50 °C for 1.0 h, filtered to recover sodium sulfate, and dried to obtain 70 g of sodium sulfate. 108 g of sulfuric acid-containing filtrate (~0.5 mol sulfuric acid+~1.0 mol propanol) were recovered for the preparation of 1-bromopropane (see Example 4).

Example 4

Preparation of 1-bromopropane

Add 1.0~1.2 mol of recovered sodium bromide to the 108 g of filtrate obtained in Example 3, stir evenly at 56°C, add 1.39 mol of new 70% sulfuric acid, drop the temperature to 66°C, keep the temperature for 1.0 h, and heat up to 76°C, 1-bromopropane was collected by distillation while reacting, and the reaction time was 3.5 h. The crude 1-bromopropane collected by distillation was post-treated to obtain 119 g of a clear, transparent, colorless liquid with a content ≥ 97% and a yield of 96.7%.

Example 5

Recycling of Waste Sulfuric Acid

In the 166 g waste acid that reclaims in embodiment 2, add 4～6 mL 30% H ₂ O ₂ and 80～120mL carbon tetrachloride, stir, leave standstill separatory, reclaim the solution containing sulfuric acid that obtains (～159 g , ~0.86mol) was used as a catalyst, and a new 1 mol of sulfuric acid (100 g, 98%) was added to configure 70% sulfuric acid for use in the preparation of 1-bromopropane in Example 6. Organic solvents are collected and recycled by distillation.

Example 6

Preparation of 1-bromopropane

1.0~1.2 mol recovered sodium bromide and 1.0 mol n-propanol, at 56°C, stir evenly, add dropwise the 70% sulfuric acid prepared in Example 5, after dropping, heat up to 66°C, keep the temperature for 1.0 h, and heat up to 76°C ℃, distilling 1-bromopropane while reacting. After steaming, the reaction raffinate was allowed to stand, and sodium bisulfate crystals were separated out, and 135 to 136 g of sodium bisulfate monohydrate were obtained by suction filtration, and 165 to 167 g of spent acid (recycled and reused, see Example 5) was obtained by suction filtration. 1-bromopropane was post-treated to obtain 116 g~119 g of 1-bromopropane, the yield was 95~97%, and the content was ≥97%.

Example 7

Preparation of diethyl dipropylmalonate

Prepared according to the operation method of the literature [Hunan Institute of Pharmaceutical Industry. Synthesis method of antiepileptic drug antiepileptic. Chinese Journal of Pharmaceutical Industry, 1978, (1): 34-35]. Its operation process is as follows:

In a 3-liter three-necked flask equipped with a sealed stirrer, a constant pressure dropping funnel, and a reflux condenser, put sodium ethoxide solution into it, under stirring, heat the external bath to about 80°C, and start adding diethyl malonate dropwise. After the addition was completed, after stirring and reacting for 10 minutes, 1-bromopropane was added dropwise, and the addition was completed in about 30 minutes, and then stirred and refluxed for 2 hours. Stand at room temperature for 2 hours, filter to recover sodium bromide, wash the filter cake with a small amount of absolute ethanol, combine the filtrate and lotion, and recover the ethanol by atmospheric distillation to obtain 274 grams of oily dipropyldiethylmalonate crude product. After drying with anhydrous sodium sulfate, carry out vacuum distillation, collect the fraction at 110~124℃/7~8mmHg, the product is 263g of colorless oily liquid, the yield is 90%.

Example 8

Recovery of sodium bromide

Sodium bromide was recovered according to the literature [Shi Qizeng. Research on the recycling of bromine in the production of norfloxacin. Environmental Science and Technology, 2006, 29 (8): 23-24]. Example 7 Sodium bromide was recovered by filtration to obtain sodium bromide solid, which was purified to obtain 95% sodium bromide, which was used as a raw material for the synthesis of 1-bromopropane (see Example 9).

Example 9

Preparation of 1-bromopropane

Add the sodium bromide that 1.0～1.2 mol reclaims in the about 108 g sulfuric acid-containing filtrate of embodiment 3 gained and the about 159 g sulfuric acid solution that embodiment 5 reclaims, stir evenly under 56 ℃, make up drop 0.5 mol new 75% Sulfuric acid, after dripping, raised the temperature to 66°C, kept the temperature for 1.0 h, raised the temperature to 76°C, and distilled and collected 1-bromopropane while reacting, the reaction time was 3.5 h. The crude 1-bromopropane collected by distillation was post-treated to obtain 120 g of a clear, transparent, colorless liquid with a content ≥ 97% and a yield of 97%.

Claims (6)

1. The green preparation method of dipropyl diethyl malonate shown in chemical structural formula I:

It is characterized in that the sodium bromide recovered in the production process of dipropyl malonate is used as raw material to prepare diethyl dipropyl malonate through the following circulation process:

. 2. the described preparation method of claim 1 is characterized in that by product sodium bisulfate or sodium bisulfate monohydrate decomposes and can obtain sodium sulfate and sulfuric acid, and decomposition reaction is as follows:

The sulfuric acid obtained by decomposition can be recycled as a catalyst. 3. the described preparation method of claim 1 is characterized in that sulfuric acid waste liquid is recyclable after treatment: in sulfuric acid waste liquid, add organic solvent and oxidizing agent, the 2-bromopropane remaining in reaction waste liquid is dissolved in organic solvent, The residual hydrobromic acid is oxidized to bromine, and the bromine is dissolved in the organic solvent, and the organic solvent containing bromine is distilled to recover the bromine and the organic solvent, and the organic solvent is recycled. 4. the described preparation method of claim 1, it is characterized in that utilizing the side reaction distillation method to produce 1-bromopropane; The preparation reaction of 1-bromopropane is a reversible reaction; The 1-bromopropane generated by the reaction steams out from the system in time , which facilitates the preparation reaction:

. 5. The oxidant according to claim 3 is selected from the group consisting of hydrogen peroxide, manganese dioxide, tert-butyl peroxide, perbenzoic acid or peracetic acid. 6. The organic solvent according to claim 3 is selected from the group consisting of chloroform, carbon tetrachloride, ethylene dichloride, trichloroethane, tetrachloroethane or benzene.