CN102690207B - Gabapentin synthesizing method - Google Patents
Gabapentin synthesizing method Download PDFInfo
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- CN102690207B CN102690207B CN201210175237.4A CN201210175237A CN102690207B CN 102690207 B CN102690207 B CN 102690207B CN 201210175237 A CN201210175237 A CN 201210175237A CN 102690207 B CN102690207 B CN 102690207B
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Abstract
The invention belongs to the technical field of anti-epileptic synthetic medicaments, particularly discloses a gabapentin synthesizing method. The gabapentin synthesizing method. includes steps: (1) obtaining 1,1-cyclohexanediacetic acid monohydrazide (B) by acylation reaction between hydrazine hydrate and 1,1-cyclohexane diacetic anhydride (A) which serves as a raw material; (2) obtaining azide compound (C) by reaction between 1,1-cyclohexanediacetic acid monohydrazide (B) and sodium nitrite by the aid of acid; and (3) heating the azide compound (C) in a solvent, and directly obtaining the object gabapentin. By the aid of the gabapentin synthesizing method, gabapentin with high purity can be directly obtained without utilization of virulent sodium azide as an azide reagent or an intermediate process of gabapentin hydrochloride, so that the gabapentin synthesizing method is simple in technique process, high in production yield and easy to realize industrialized production.
Description
Technical field
The present invention relates to antiepileptic chemicals synthesis technical field, be specifically related to a kind of synthetic method of gabapentin.
Background technology
Gabapentin is the antiepileptic drug that first U.S. Warner-Lanbert company develops, and in 1993, goes on the market first in Britain.Gabapentin is a kind of antiepileptic drug of novelty, and it is the derivative of γ-aminobutyric acid (GABA), and its pharmacological action is different from existing antiepileptic drug, and research recently shows that the effect of gabapentin produces by changing GABA metabolism.It is good that it has tolerance, the advantage that side effect is slight.
Traditional technology is in the market first to prepare key intermediate Gabapentin hydrochloride mostly, take Gabapentin hydrochloride as raw material again, Gabapentin hydrochloride is dissolved with alcoholic solvent, add the inorganic salts neutralizations such as saleratus, stir, reflux, crystallisation by cooling obtains gabapentin crude product; It is refining that gabapentin crude product adds absolute alcohol kind solvent, then with a small amount of anhydrous alcohols or ketone washing, obtain gabapentin.Traditional technology has operational path length, complex operation, use diversification of feedstock, cost is high and be not easy to the shortcomings such as suitability for industrialized production.The present invention does not need the intermediate process through Gabapentin hydrochloride, do not need to use hypertoxic sodiumazide as azide reagent, can directly obtain highly purified gabapentin, the production cycle is shortened greatly, save cost, solved the shortcoming that traditional technology is not easy to suitability for industrialized production.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of synthetic method of gabapentin.
Technical conceive of the present invention is as follows: with 1,1-cyclohexanediacetic acid acid anhydride (A), for raw material and hydrazine hydrate carry out acylation reaction, obtain 1,1-cyclohexanediacetic acid list hydrazides (B); 1,1-cyclohexanediacetic acid list hydrazides (B) reacts under sour effect with Sodium Nitrite and obtains 1,1-cyclohexanediacetic acid list acylazide (C); 1,1-cyclohexanediacetic acid list acylazide (C) heats and directly obtains target product gabapentin (D) in solvent.
Chemical principle is as follows:
In order to realize object of the present invention, the present invention has taked following technical measures:
A synthetic method for gabapentin, its step is as follows:
(1) with 1,1-cyclohexanediacetic acid acid anhydride (A), be, that the acylation reaction that raw material and hydrazine hydrate carry out 2-24 hour at-10 ℃-100 ℃ in solvent orange 2 A obtains 1,1-cyclohexanediacetic acid list hydrazides (B);
Raw material 1, the mol ratio of 1-cyclohexanediacetic acid acid anhydride (A) and hydrazine hydrate is 1:1-1:10;
Described solvent orange 2 A is the arbitrary proportion mixture of a kind of or 2-7 kind in methylene dichloride, ethylene dichloride, chloroform, acetone, acetonitrile, toluene, dimethylbenzene;
Described raw material 1,1-cyclohexanediacetic acid acid anhydride (A) is 1:2-1:20 with the mass ratio of solvent orange 2 A;
(2), in solvent B, 1,1-cyclohexanediacetic acid list hydrazides (B) reacts and within 2-24 hour, obtains 1,1-cyclohexanediacetic acid list acylazide (C) with Sodium Nitrite under sour effect, temperature of reaction is :-10 ℃-60 ℃;
Wherein, reactant 1, the mol ratio of 1-cyclohexanediacetic acid list hydrazides (B) and Sodium Nitrite is 1:1.05-1:2.0;
Described acid is the arbitrary proportion mixture of a kind of or 2-6 kind in hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichoroacetic acid(TCA), trifluoroacetic acid;
The mol ratio of acid used and Sodium Nitrite is: 1.1:1-5.0:1;
Described solvent B is the arbitrary proportion mixture of a kind of or 2-9 kind in methylene dichloride, ethylene dichloride, chloroform, acetone, acetonitrile, toluene, dimethylbenzene, ethyl acetate, butylacetate;
Reactant 1,1-cyclohexanediacetic acid list hydrazides (B) is 1:2-1:20 with the mass ratio of solvent B;
(3), 1,1-cyclohexanediacetic acid list acylazide (C) reacts and within 1-24 hour, directly obtains target product gabapentin (D) in solvent C at 40 ℃-150 ℃.
Described solvent C is the arbitrary proportion mixture of a kind of or 2-13 kind in methylene dichloride, ethylene dichloride, chloroform, acetone, acetonitrile, toluene, dimethylbenzene, ethyl acetate, butylacetate, sherwood oil, dimethyl formamide (DMF), methyl-sulphoxide (DMSO), N,N-dimethylacetamide (DMAC);
Wherein, reactant 1,1-cyclohexanediacetic acid list acylazide (C) is 1:2-1:20 with the mass ratio of solvent C.
Compared with prior art, the present invention has the following advantages and effect:
Technological design is reasonable, easy and simple to handle, with short production cycle, facility investment is few, and cost is low, be easy to suitability for industrialized production, good product quality, production process safety and environmental protection.
Embodiment
Applicant is described in detail method of the present invention in connection with specific embodiment below, so that those skilled in the art has further and understands the present invention, but following examples are interpreted as limiting the scope of the invention never in any form.
Embodiment 1:
A synthetic method for gabapentin, its step is as follows:
(1) in reactor, add 1 mole of (182.2g) 1,1-cyclohexanediacetic acid acid anhydride (A), drop into again 1822g methylene chloride, be stirred to dissolve, add until completely dissolved 2 moles of (143g) hydrazine hydrates (70%), stir and temperature is controlled to 20 ℃, carry out acylation reaction, isothermal reaction 15 hours, has crystallization, suction filtration obtains 205.5g1,1-cyclohexanediacetic acid list hydrazides (B) wet product;
(2) by 205.5g 1,1-cyclohexanediacetic acid list hydrazides wet product (B) is dissolved in 1928g methylene dichloride, add again 1.3 moles of Sodium Nitrites, add 2.7 moles of vitriol oils (98%), stir 30 ℃ of temperature controls, react 6 hours, suction filtration obtains 198.6g1,1-cyclohexanediacetic acid list acylazide (C) wet product;
(3) by 198.6g 1,1-cyclohexanediacetic acid list acylazide (C) wet product is dissolved in 993g solvent acetone, be heated to 55 ℃, react 8 hours, be cooled to 10 ℃ of following crystallizations, suction filtration, ice Virahol drip washing for filter cake is dried gained solid 3 hours at 80 ℃, obtains 125g target product gabapentin (D), the content that records gabapentin is 99.7%, fusing point 160-164 ℃.
Embodiment 2:
A synthetic method for gabapentin, its step is as follows:
(1) in reactor, add 1 mole of (182.2g) 1,1-cyclohexanediacetic acid acid anhydride (A), then drop into 1000g solvent acetone, be stirred to dissolve, add until completely dissolved 5 moles of (357.5g) hydrazine hydrates (70%), stir and temperature is controlled to 55 ℃, carrying out acylation reaction, isothermal reaction 4 hours, be cooled to room temperature, crystallization 20 minutes, suction filtration obtains 195.5g 1,1-cyclohexanediacetic acid list hydrazides (B) wet product;
(2) by 195.5g 1,1-cyclohexanediacetic acid list hydrazides (B) wet product is dissolved in 977.5g chloroform, add again 1.38 moles of Sodium Nitrites, add 6.9 mole hydrochlorides (36%), stir 10 ℃ of temperature controls, react 10 hours, suction filtration obtains 180.5g1,1-cyclohexanediacetic acid list acylazide (C) wet product;
(3) by 180.5g1,1-cyclohexanediacetic acid list acylazide (C) wet product is dissolved in 541.5g solvent acetonitrile, be heated to 80 ℃, react 2 hours, be cooled to 10 ℃ of following crystallizations, suction filtration, ice methyl alcohol drip washing for filter cake is dried gained solid 3 hours at 80 ℃, obtains 135.7g target product gabapentin (D), the content that records gabapentin is 99.3%, fusing point 160-164 ℃.
Embodiment 3:
A synthetic method for gabapentin, its step is as follows:
(1) in reaction flask, add 1 mole of (182.2g) 1,1-cyclohexanediacetic acid acid anhydride (A), then drop into 3644g solvent xylene, be stirred to dissolve, add until completely dissolved 8 moles of (572.1g) hydrazine hydrates (70%), stir and temperature is controlled to 100 ℃, carrying out acylation reaction, isothermal reaction 10 hours, be cooled to room temperature, crystallization 30 minutes, suction filtration obtains 208.6g1,1-cyclohexanediacetic acid list hydrazides (B) wet product;
(2) by 208.6g1,1-cyclohexanediacetic acid list hydrazides (B) wet product is dissolved in 3129g toluene, add again 1.96 moles of Sodium Nitrites, add total amount and be acetic acid and the trichoroacetic acid(TCA) mixture (wherein acetic acid and trichoroacetic acid(TCA) mol ratio are 1:1) of 5.88 moles, stir 60 ℃ of temperature controls, react 20 hours, cooling rear suction filtration obtains 190.5g1,1-cyclohexanediacetic acid list acylazide (C) wet product;
(3) by 190.5g1,1-cyclohexanediacetic acid list acylazide (C) wet product is dissolved in the mixture (toluene and DMF mass ratio are 5:1) of 1905g solvent toluene and DMF, be heated to 110 ℃, react 5 hours, be cooled to 10 ℃ of following crystallizations, suction filtration, ice methyl alcohol drip washing for filter cake is dried gained solid 3 hours at 80 ℃, obtains 142.8g target product gabapentin (D), the content that records gabapentin is 99.5%, fusing point 160-164 ℃.
Embodiment 4:
A synthetic method for gabapentin, its step is as follows:
(1) in reaction flask, add 1 mole of (182.2g) 1,1-cyclohexanediacetic acid acid anhydride (A), drop into again 2733g methylene dichloride and ethylene dichloride mixture (methylene dichloride and ethylene dichloride mass ratio are 1:1), be stirred to dissolve, add until completely dissolved 10 moles of (715.15g) hydrazine hydrates (70%), stir and temperature is controlled to 40 ℃, carry out acylation reaction, isothermal reaction 7 hours, be cooled to room temperature, crystallization 30 minutes, suction filtration obtains 200g1,1-cyclohexanediacetic acid list hydrazides (B) wet product;
(2) by 200g1,1-cyclohexanediacetic acid list hydrazides (B) wet product is dissolved in 2000g ethylene dichloride, then adds 1.04 moles of Sodium Nitrites, add 4.16 mole of acetic acid, stir 60 ℃ of temperature controls, react 10 hours, cooling rear suction filtration obtains 188g1,1-cyclohexanediacetic acid list acylazide (C) wet product;
(3) by 188g1,1-cyclohexanediacetic acid list acylazide (C) wet product is dissolved in 2256gDMF, be heated to 150 ℃, react 3 hours, be cooled to 10 ℃ of following crystallizations, suction filtration, ice methyl alcohol drip washing for filter cake is dried gained solid 3 hours at 80 ℃, obtains 108g target product gabapentin (D), the content that records gabapentin is 99.1%, fusing point 160-164 ℃.
Claims (1)
1. a synthetic method for gabapentin, its step is as follows:
(1) in reactor, add 1 mole 1,1-cyclohexanediacetic acid acid anhydride, drop into again 1822g methylene chloride, be stirred to dissolve, add until completely dissolved 2 mole of 70% hydrazine hydrate, stir and temperature is controlled to 20 ℃, carry out acylation reaction, isothermal reaction 15 hours, has crystallization, suction filtration obtains 205.5g 1,1-cyclohexanediacetic acid list hydrazides wet product;
(2), by 205.5g 1,1-cyclohexanediacetic acid list hydrazides wet product is dissolved in 1928g methylene dichloride, then adds 1.3 moles of Sodium Nitrites, add 2.7 mole of 98% vitriol oil, stir 30 ℃ of temperature controls, react 6 hours, suction filtration obtains 198.6g 1,1-cyclohexanediacetic acid list acylazide wet product;
(3), by 198.6g 1,1-cyclohexanediacetic acid list acylazide wet product is dissolved in 993g solvent acetone, is heated to 55 ℃, react 8 hours, be cooled to 10 ℃ of following crystallizations, suction filtration, ice Virahol drip washing for filter cake is dried gained solid 3 hours at 80 ℃, obtains 125g gabapentin.
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| CN104151180A (en) * | 2014-08-28 | 2014-11-19 | 太仓运通生物化工有限公司 | Preparation method of gabapentin hydrochloride |
| CN110583654A (en) * | 2019-09-18 | 2019-12-20 | 北京农学院 | Plant source nematicide |
| CN112592289B (en) * | 2020-12-15 | 2022-09-20 | 内蒙古永太化学有限公司 | Preparation method of gabapentin intermediate |
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| CN1727329A (en) * | 2004-07-28 | 2006-02-01 | 长春吉大天元化学技术股份有限公司 | New method for synthesizing Gabapentin hydrochloride |
| CN100361964C (en) * | 2005-06-13 | 2008-01-16 | 江苏恩华药业股份有限公司 | Gabapentin hydrochloride and its intermediate preparation method |
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| ITMI20072262A1 (en) * | 2007-12-03 | 2009-06-04 | Dipharma Francis Srl | PROCEDURE FOR THE PREPARATION OF ACID (S) (+) - 3- (AMINOMETHYL) -5-METHYLESANOIC |
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