CN118108656A - Chemical synthesis method of gabapentin Ding Zazhi D - Google Patents
Chemical synthesis method of gabapentin Ding Zazhi D Download PDFInfo
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- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 title claims abstract description 210
- 229960002870 gabapentin Drugs 0.000 title claims abstract description 104
- 238000000034 method Methods 0.000 title claims abstract description 51
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 14
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 12
- 238000006281 Stork reaction Methods 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 11
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 56
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 230000002829 reductive effect Effects 0.000 claims description 30
- 239000007810 chemical reaction solvent Substances 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000002994 raw material Substances 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 230000008569 process Effects 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 13
- 238000004440 column chromatography Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 abstract description 15
- 229940079593 drug Drugs 0.000 abstract description 13
- 238000002360 preparation method Methods 0.000 abstract description 8
- 239000012535 impurity Substances 0.000 abstract description 6
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- 239000000047 product Substances 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000010992 reflux Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- 150000002081 enamines Chemical class 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000001276 controlling effect Effects 0.000 description 6
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 6
- 230000006837 decompression Effects 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
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- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of preparation of medicine impurities, and discloses a chemical synthesis method of gabapentin Ding Zazhi D, which comprises the following steps: (A) Carrying out condensation reaction on the compound of the formula I and diisobutylamine to obtain a compound of the formula II; (B) Performing Stork reaction and hydrolysis reaction on the compound of the formula II and ethyl bromoacetate to obtain a compound of the formula III; (C) And (3) carrying out reductive amination reaction on the compound shown in the formula III, the gabapentin and the reducing agent to obtain the gabapentin Ding Zazhi D. The chemical synthesis method can realize the mass preparation of the gabapentin Ding Zazhi D, and the prepared product can be used as a reference substance for quality control of the gabapentin bulk drug.
Description
Technical Field
The invention relates to the technical field of preparation of medicine impurities, in particular to a chemical synthesis method of gabapentin Ding Zazhi D.
Background
Gabapentin (Gabapentin) is a neuromodulation agent, which is mainly used as an antiepileptic agent, and is also useful for the treatment of neuropathic pain, and has the chemical name 1- (aminomethyl) cyclohexylacetic acid, the molecular formula C 9H17NO2, and the structural formula:
Gabapentin Ding Zazhi D is an impurity occurring during the production of gabapentin, and has the molecular formula of C 18H29NO2, and the structural formula is as follows:
The amount of gabapentin Ding Zazhi D content is related to the quality of the finished gabapentin product. The gabapentin powder injection adopts gabapentin Ding Zazhi D as a reference substance, can carry out qualitative and quantitative analysis on the impurities in the gabapentin bulk drug, helps control the impurity content in the production process, and further improves the quality of the gabapentin finished product.
In the prior art, the gabapentin Ding Zazhi D is prepared by separating the gabapentin crude drug from the gabapentin crude drug, for example, in patent CN112679412a, by separating trace impurity D in the gabapentin crude drug by adopting a countercurrent chromatography method. Since the content of impurity D in the gabapentin bulk drug is extremely low and is usually below 0.5%, the gabapentin Ding Zazhi D is difficult to obtain in a large scale by the separation preparation method, and the commercial gabapentin Ding Zazhi D has high price. The chemical synthesis of gabapentin Ding Zazhi D has not been reported.
Disclosure of Invention
The invention provides a chemical synthesis method of gabapentin Ding Zazhi D in order to solve the technical problem that the existing preparation method of gabapentin Ding Zazhi D is difficult to realize mass production. By adopting the chemical synthesis method, the mass preparation of the gabapentin Ding Zazhi D can be realized, and the prepared product can be used as a reference substance for quality control of the gabapentin bulk drug.
The specific technical scheme of the invention is as follows:
A chemical synthesis method of gabapentin Ding Zazhi D, comprising the steps of:
(A) Carrying out condensation reaction on the compound of the formula I and diisobutylamine to obtain a compound of the formula II; the reaction process is as follows:
(B) Performing Stork reaction and hydrolysis reaction on the compound of the formula II and ethyl bromoacetate to obtain a compound of the formula III; the reaction process is as follows:
(C) Carrying out reductive amination reaction on a compound of the formula III, gabapentin and a reducing agent to obtain gabapentin Ding Zazhi D; the reaction process is as follows:
By adopting the method, the method for separating the gabapentin crude drug from the gabapentin crude drug is avoided, the synthetic route is short, the sources of raw materials and auxiliary materials are convenient, the post-treatment is simple, the reaction yield and the purity of the product are high, and the synthesized gabapentin Ding Zazhi D can be used as a reference substance for qualitative and quantitative analysis of the impurity in the gabapentin crude drug, so that the quality of the gabapentin crude drug is improved.
Preferably, the specific process of step (a) comprises the following steps: the compound of the formula I, diisobutylamine and the reaction solvent a are mixed, and after condensation reaction, the product is separated, and the compound of the formula II is obtained.
Preferably, in the step (A), the temperature of the condensation reaction is 110-115 ℃ and the time is 20-24h.
Preferably, in the step (A), the mass ratio of the compound of the formula I to the diisobutylamine is 1:1-2.
Preferably, in the step (A), the product is isolated by concentrating under reduced pressure to remove the reaction solvent a.
Preferably, the specific process of step (B) comprises the following steps: mixing the compound of the formula II, ethyl bromoacetate and a reaction solvent b, performing Stork reaction, adding acetic acid, acetate and water, performing hydrolysis reaction, and separating a product to obtain the compound of the formula III.
Preferably, in the step (B), the temperature of the Stork reaction is 80-85 ℃ and the time is 20-24h.
Preferably, in the step (B), the temperature of the hydrolysis reaction is 80-85 ℃ and the time is 3-4h.
Preferably, in the step (B), the mass ratio of the compound of the formula II to ethyl bromoacetate is 1:0.7-0.9.
Preferably, in the step (B), the ratio of the compound of the formula II to the acetic acid to the acetate is 1g:0.33-0.45mL:0.15-0.30g.
Preferably, in step (B), after the hydrolysis reaction, the product is isolated to obtain a compound of formula III; the process for separating the product comprises the following steps: after the reaction solvent was removed by concentration under reduced pressure, extraction was performed with ethyl acetate, the obtained organic phase was washed with hydrochloric acid, the solvent was removed by concentration under reduced pressure, and the obtained oily substance was subjected to column chromatography.
By adopting the method to separate and purify the product of the step (B), the residual cyclohexane formaldehyde and diisobutylamine in the reaction system can be removed, the competition reaction during the subsequent reductive amination reaction of the step (C) is avoided, and the selectivity of the reductive amination reaction is improved.
Further, in the step (B), in the process of column chromatography separation, the eluent adopts a mixed solution of petroleum ether and ethyl acetate with the volume ratio of 35-45:1.
Preferably, the specific process of step (C) comprises the following steps: and mixing the compound shown in the formula III, gabapentin, a reaction solvent c and a reducing agent, carrying out a reduction reaction, then carrying out a ring closure reaction, and separating out a product to obtain the gabapentin Ding Zazhi D.
Preferably, in step (C), the reducing agent is sodium cyanoborohydride.
Preferably, in the step (C), the temperature of the reduction reaction is 20-30 ℃ and the reaction is carried out until the raw materials disappear; the temperature of the ring closing reaction is 60-70 ℃ and the time is 3-4h.
Preferably, in the step (C), the mass ratio of the compound of the formula III, the gabapentin and the reducing agent is 1:1.0-1.5:0.6-0.8.
Preferably, in step (C), the process of separating the product comprises the steps of: concentrating under reduced pressure, adding water, adjusting pH to 1.0-2.0, extracting with dichloromethane, drying the obtained organic phase with anhydrous sodium sulfate, concentrating under reduced pressure to remove solvent, and separating by column chromatography.
Compared with the prior art, the invention has the following advantages:
(1) The invention realizes the chemical synthesis of the gabapentin Ding Zazhi D, is beneficial to the amplified preparation, can realize the mass preparation of the gabapentin Ding Zazhi D, and has obvious advantages compared with the scheme of separating from the gabapentin bulk drug.
(2) The chemical synthesis method of the gabapentin Ding Zazhi D can realize higher yield and product purity, and the obtained gabapentin Ding Zazhi D can be used as a reference substance for quality control of gabapentin bulk drug, and has the advantages of shorter synthesis route, convenient sources of raw and auxiliary materials and simple post-treatment.
(3) In the process of synthesizing the gabapentin Ding Zazhi D, the method carries out specific separation and purification operation on the III compound, and can improve the selectivity of the subsequent reductive amination reaction.
Drawings
FIG. 1 is an HPLC chart of gabapentin Ding Zazhi D;
FIG. 2 is an HPLC chart of gabapentin Ding Yangpin;
fig. 3 is an HPLC profile of a mixed sample of gabapentin and gabapentin Ding Zazhi D.
Detailed Description
The invention is further described below with reference to examples.
General examples
Chemical synthesis method of gabapentin Ding Zazhi D:
A chemical synthesis method of gabapentin Ding Zazhi D, comprising the steps of:
(A) Carrying out condensation reaction on the compound of the formula I and diisobutylamine to obtain a compound of the formula II; the reaction process is as follows:
(B) Performing Stork reaction and hydrolysis reaction on the compound of the formula II and ethyl bromoacetate to obtain a compound of the formula III; the reaction process is as follows:
(C) Carrying out reductive amination reaction on a compound of the formula III, gabapentin and a reducing agent to obtain gabapentin Ding Zazhi D; the reaction process is as follows:
The "compounds of formula I", "compounds of formula II", "compounds of formula III" described in steps (a) - (C) correspond to the compounds labeled "I", "II", "III", respectively, during the reaction, and are all herein and throughout this patent.
The condensation reaction of the method step (A):
As a specific embodiment, the specific process of step (a) includes the steps of: the compound of the formula I, diisobutylamine and the reaction solvent a are mixed, and after condensation reaction, the product is separated, and the compound of the formula II is obtained.
As a specific embodiment, in the step (A), the temperature of the condensation reaction is 110-115 ℃ and the time is 20-24h.
In a specific embodiment, in step (a), the mass ratio between the compound of formula I and diisobutylamine is 1:1-2.
In a specific embodiment, in the step (a), the product is isolated by concentrating under reduced pressure to remove the reaction solvent a.
In the step (A), the amount of the reaction solvent a is not strictly limited, and can be adjusted by conventional means depending on the amount of the reaction raw materials: the amount of the reaction solvent a is increased when the amount of the reaction raw materials is large, and the amount of the reaction solvent a is reduced when the amount of the reaction raw materials is small; the reaction solvent a may be selected according to common knowledge of those skilled in the art, such as alcohols, ketones, ethers, etc.
Method step (B) Stork reaction and hydrolysis reaction:
As a specific embodiment, the specific process of step (B) includes the steps of: mixing the compound of the formula II, ethyl bromoacetate and a reaction solvent b, performing Stork reaction, adding acetic acid, acetate and water, performing hydrolysis reaction, and separating a product to obtain the compound of the formula III.
In a specific embodiment, in the step (B), the temperature of the Stork reaction is 80-85 ℃ and the time is 20-24 hours; the temperature of the hydrolysis reaction is 80-85 ℃ and the time is 3-4h.
As a specific embodiment, in step (B), the mass ratio between the compound of formula II and ethyl bromoacetate is 1:0.7-0.9.
As a specific embodiment, in the step (B), the ratio of the compound of the formula II to the acetic acid to the acetate is 1g:0.33-0.45mL:0.15-0.30g.
In a specific embodiment, in step (B), after the hydrolysis reaction, the product is isolated to obtain a compound of formula III; the process for separating the product comprises the following steps: after the reaction solvent was removed by concentration under reduced pressure, extraction was performed with ethyl acetate, the obtained organic phase was washed with hydrochloric acid, the solvent was removed by concentration under reduced pressure, and the obtained oily substance was subjected to column chromatography. In the column chromatography separation process, the eluent can be a mixed solution of Petroleum Ether (PE) and Ethyl Acetate (EA) with the volume ratio of 35-45:1.
In the step (B), the amounts of the reaction solvent B and water are not strictly limited, and may be adjusted by conventional means depending on the amounts of the reaction raw materials: the use amount of the reaction solvent b and water is increased when the reaction raw materials are more, and the use amount of the reaction solvent b and water is reduced when the reaction raw materials are less; the reaction solvent b may be selected according to common knowledge of those skilled in the art, such as alcohols, ketones, ethers, etc.
Method step (C) reductive amination:
as a specific embodiment, the specific process of step (C) includes the following steps: and mixing the compound shown in the formula III, gabapentin, a reaction solvent c and a reducing agent, carrying out a reduction reaction, then carrying out a ring closure reaction, and separating out a product to obtain the gabapentin Ding Zazhi D.
In one embodiment, in step (C), the reducing agent is sodium cyanoborohydride.
In step (C), the temperature of the reduction reaction is 20-30 ℃ and the reaction is carried out until the raw materials disappear; the temperature of the ring closing reaction is 75-80 ℃ and the time is 3-4h.
As a specific embodiment, in the step (C), the mass ratio of the compound of formula III, gabapentin and the reducing agent is 1:1.0-1.5:0.6-0.8.
As a specific embodiment, in step (C), the process of separating the product comprises the steps of: after concentrating under reduced pressure, water was added and the pH was adjusted to 1.0-2.0, extraction was performed with Dichloromethane (DCM), and the resulting organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent therefrom, and then subjected to column chromatography.
In the step (C), the amount of the reaction solvent C is not strictly limited, and may be adjusted by conventional means depending on the amount of the reaction raw materials: the consumption of the reaction solvent c is increased by more reaction raw materials, and the consumption of the reaction solvent c is reduced by less reaction raw materials; the reaction solvent c may be selected according to common knowledge of those skilled in the art, such as alcohols, ketones, ethers, etc.
The invention is illustrated by the following specific examples. It is to be understood that these embodiments are merely for illustrating the present invention and are not to be construed as limiting the scope of the present invention, and that variations and advantages which can be conceived by those skilled in the art are included therein without departing from the spirit and scope of the inventive concept, and the appended claims and any equivalents thereof are intended to be protected by the present invention.
Example 1: synthesis of gabapentin Ding Zazhi D
Gabapentin Ding Zazhi D was synthesized by the following steps:
(A) Synthesis of compounds of formula II:
The reaction process is as follows:
The method comprises the following specific steps:
In 500mL single port bottle, adding cyclohexane formaldehyde 22.4g, diisobutylamine 28g, toluene 200mL, controlling the temperature at 112.5+ -2.5deg.C for reflux water separation for 20h (about 4.5 mL), cooling, vacuum concentrating to remove toluene, obtaining enamine intermediate (i.e. compound of formula II) 55.0g, yield 100%.
(B) Synthesis of compounds of formula III:
The reaction process is as follows:
The method comprises the following specific steps:
All enamine intermediates obtained in the step (A) are added into a 500mL three-necked flask, 200mL of acetonitrile and 40g of ethyl bromoacetate are added, reflux reaction is carried out for 20h at the temperature of 82.5+/-2.5 ℃, 20mL of acetic acid, 10.0g of sodium acetate and 100mL of water are added, reflux reaction is carried out for 3h at the temperature of 82.5+/-2.5 ℃ continuously, after acetonitrile is removed by decompression concentration, 200mL of ethyl acetate is added, extraction and delamination are carried out, the obtained organic phase is washed (50 mL multiplied by 2 times) by using 2mol/L hydrochloric acid, and the solvent is removed by decompression concentration, thus obtaining 45.8g of oily matter. The resulting oil was column chromatographed using PE: ea=40: 1 (v: v) as eluent, 18.0g of the compound of formula III are obtained in a yield of 45.5%.
(C) Synthesis of gabapentin Ding Zazhi D:
The reaction process is as follows:
The method comprises the following specific steps:
In a 100mL single port bottle, 8.0g of the compound of formula III obtained in the step (B), 8.2g of gabapentin, 50mL of methanol, 5.0g of sodium cyanoborohydride are added in batches under ice water bath, the temperature is raised to room temperature (23 ℃) after the addition is finished, after the reaction is carried out for 3 hours, the point plate is monitored to monitor the reaction, the raw materials disappear, the reflux reaction is carried out for 3 hours at 65+/-5 ℃, the temperature is reduced, 30mL of water is added after the concentration under reduced pressure, the pH is regulated to 1 by 2mol/L of HCl (the release of gas is carried out in a fume hood), the water phase is extracted by DCM (150 mL multiplied by 3), the organic phases are combined, anhydrous sodium sulfate is dried, and the crude product of 12.0g is obtained after the concentration under reduced pressure. The crude product obtained is subjected to silica gel column chromatography to obtain 6.0g of crude gabapentin Ding Zazhi D product with a yield of 48.8%. 3.0g of crude gabapentin Ding Zazhi D is taken for continuous column chromatography purification, and 2.6g of refined gabapentin Ding Zazhi D product with the purity of 96.3 percent is obtained.
Example 2: synthesis of gabapentin Ding Zazhi D
Gabapentin Ding Zazhi D was synthesized by the following steps:
(A) Synthesis of compounds of formula II:
The reaction process is as follows:
The method comprises the following specific steps:
23.5g of cyclohexane formaldehyde, 47g of diisobutylamine and 200mL of toluene are added into a 500mL single-port bottle, reflux water separation is carried out for 24h (about 4.5 mL) at the temperature of 112.5+/-2.5 ℃ and then the temperature is reduced, the toluene is removed by vacuum concentration, and 60g of enamine intermediate (namely the compound of the formula II) is obtained, and the yield is 100%.
(B) Synthesis of compounds of formula III:
The reaction process is as follows:
The method comprises the following specific steps:
Adding all enamine intermediates obtained in the step (A) into a 500mL three-necked flask, adding 200mL of acetonitrile and 40g of ethyl bromoacetate, controlling the temperature to 82.5+/-2.5 ℃ for reflux reaction for 24 hours, adding 20mL of acetic acid, 18.0g of sodium acetate and 100mL of water, continuously controlling the temperature to 82.5+/-2.5 ℃ for reflux reaction for 3 hours, concentrating under reduced pressure to remove acetonitrile, adding 200mL of ethyl acetate, extracting and layering, washing the obtained organic phase with 2mol/L hydrochloric acid (50 mL multiplied by 2 times), concentrating under reduced pressure to remove solvent, and obtaining 61g of oily matter. The resulting oil was column chromatographed using PE: ea=35: 1 (v: v) as eluent, 20.5g of the compound of formula III was obtained in a yield of 51.8%.
(C) Synthesis of gabapentin Ding Zazhi D:
The reaction process is as follows:
The method comprises the following specific steps:
To a 100mL single-port flask, 8.0g of the compound of formula III obtained in step (B), 8.0g of gabapentin, 50mL of methanol, 6.4g of sodium cyanoborohydride were added in portions under an ice-water bath, the reaction was allowed to proceed to room temperature (23 ℃ C.) after completion of the addition, the reaction was monitored by a spot plate, the starting material disappeared, the reflux reaction was performed at 65.+ -. 5 ℃ for 4 hours, the temperature was lowered, concentrated under reduced pressure, 30mL of water was added, the pH was adjusted to 1 with 2mol/L HCl (with gas evolution in a fume hood), the aqueous phase was extracted with DCM (150 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 12.5g of crude product. The crude product obtained is subjected to silica gel column chromatography to obtain 5.8g of crude gabapentin Ding Zazhi D product with a yield of 47.1%. 3.0g of crude gabapentin Ding Zazhi D is taken for continuous column chromatography purification, and 2.5g of refined gabapentin Ding Zazhi D product with the purity of 96.5 percent is obtained.
Example 3: synthesis of gabapentin Ding Zazhi D
Gabapentin Ding Zazhi D was synthesized by the following steps:
(A) Synthesis of compounds of formula II:
The reaction process is as follows:
The method comprises the following specific steps:
in a 500mL single-port bottle, 22.5g of cyclohexane formaldehyde, 22.5g of diisobutylamine and 200mL of toluene are added, reflux water separation is carried out at a temperature of 112.5+/-2.5 ℃ for 22h (about 4.5 mL), the temperature is reduced, the toluene is removed by vacuum concentration, and 40.0g of enamine intermediate (namely a compound of formula II) is obtained, and the yield is 95.2%.
(B) Synthesis of compounds of formula III:
The reaction process is as follows:
The method comprises the following specific steps:
All enamine intermediates obtained in the step (A) are added into a 500mL three-necked flask, 200mL of acetonitrile and 36g of ethyl bromoacetate are added, reflux reaction is carried out for 20h at the temperature of 82.5+/-2.5 ℃, 18mL of acetic acid, 6.0g of sodium acetate and 100mL of water are added, reflux reaction is carried out for 4h at the temperature of 82.5+/-2.5 ℃ continuously, after acetonitrile is removed by decompression concentration, 200mL of ethyl acetate is added, extraction and delamination are carried out, the obtained organic phase is washed (50 mL multiplied by 2 times) by using 2mol/L hydrochloric acid, and the solvent is removed by decompression concentration, thus obtaining 42.0g of oily substance. The resulting oil was column chromatographed using PE: ea=45: 1 (v: v) as eluent, 15.0g of the compound of formula III are obtained in a yield of 37.7%.
(C) Synthesis of gabapentin Ding Zazhi D:
The reaction process is as follows:
The method comprises the following specific steps:
In a 100mL single port bottle, 8.0g of the compound of formula III obtained in the step (B), 12g of gabapentin and 50mL of methanol are added in batches under ice water bath, 4.8g of sodium cyanoborohydride is added, the temperature is raised to room temperature (23 ℃) after the addition is finished, after the reaction is carried out for 3 hours, the point plate is monitored to monitor the disappearance of raw materials, the reflux reaction is carried out for 3 hours at 65+/-5 ℃, the temperature is reduced, after the decompression concentration, 30mL of water is added, the pH is regulated to 1 by 2mol/L HCl (the release of gas is carried out in a fume hood), the water phase is extracted by DCM (150 mL multiplied by 3), the organic phases are combined, and after the anhydrous sodium sulfate is dried, the decompression concentration is carried out, 19.0g of crude products are obtained. The crude product obtained is subjected to silica gel column chromatography to obtain 9.0g of crude gabapentin Ding Zazhi D product with a yield of 72.5%. 3.0g of crude gabapentin Ding Zazhi D is taken for continuous column chromatography purification, and 2.8g of refined gabapentin Ding Zazhi D product with the purity of 97.0 percent is obtained.
Comparative example 1: synthesis of gabapentin Ding Zazhi D
Gabapentin Ding Zazhi D was synthesized by the following steps:
(A) Synthesis of compounds of formula II:
The reaction process is as follows:
The method comprises the following specific steps:
In 500mL single port bottle, adding cyclohexane formaldehyde 22.4g, diisobutylamine 28g, toluene 200mL, controlling the temperature at 112.5+ -2.5deg.C for reflux water separation for 20h (about 4.5 mL), cooling, vacuum concentrating to remove toluene, obtaining enamine intermediate (i.e. compound of formula II) 50.0g, yield 100%.
(B) Synthesis of compounds of formula III:
The reaction process is as follows:
The method comprises the following specific steps:
Adding the enamine intermediate obtained in the step (A) into a 500mL three-necked flask, adding 200mL of acetonitrile, 40g of ethyl bromoacetate, controlling the temperature to 82.5+/-2.5 ℃ for reflux reaction for 20h, adding 20mL of acetic acid, 10.0g of sodium acetate and 100mL of water, continuously controlling the temperature to 82.5+/-2.5 ℃ for reflux reaction for 3h, concentrating under reduced pressure to remove acetonitrile, adding 200mL of ethyl acetate, extracting and layering, washing the obtained organic phase with 2mol/L hydrochloric acid (50 mL multiplied by 2 times), concentrating under reduced pressure to remove solvent, and obtaining 44.8g of oily matter.
(C) Synthesis of gabapentin Ding Zazhi D:
The reaction process is as follows:
The method comprises the following specific steps:
19.9g of the oily substance obtained in the step (B), 8.2g of gabapentin and 50mL of methanol are added into a 100mL single-port bottle, 5.0g of sodium cyanoborohydride is added in batches under ice water bath, the temperature is raised to room temperature (23 ℃) after the addition is finished, the reaction is monitored by a dot plate, the raw material disappears, the reflux reaction is carried out for 3 hours at 65+/-5 ℃, the temperature is reduced, 30mL of water is added after the concentration under reduced pressure, the pH is regulated to 1 by 2mol/LHCl (the extraction is carried out in a fume hood with gas evolution), the water phase is extracted by DCM (150 mL multiplied by 3 times), the organic phases are combined, and the crude product is obtained after the drying by anhydrous sodium sulfate, and the concentration under reduced pressure. The crude product obtained is subjected to silica gel column chromatography to obtain 1.0g of crude product of gabapentin Ding Zazhi D with the yield of 8.1%. And (3) taking 1.0g of crude gabapentin Ding Zazhi D, and carrying out column chromatography purification to obtain 0.5g of refined gabapentin Ding Zazhi D with the purity of 93.5%.
Analysis and conclusion of experimental results: the results of the experiments in comparative example 1 and comparative example 1 show that the yield and purity of the product in step (C) in comparative example 1 are significantly lower than in example 1, compared to example 1. This is because, in comparative example 1, it is difficult to remove the residual cyclohexane formaldehyde and diisobutylamine more thoroughly during the separation and purification of the product of step (B), which may undergo a competition reaction during the subsequent reductive amination of step (C), resulting in poor selectivity of the reductive amination reaction and thus lower product yield and purity.
Application example: qualitative analysis of gabapentin sample for gabapentin Ding Zazhi D
The refined gabapentin Ding Zazhi D product obtained in example 1 was subjected to detection analysis by High Performance Liquid Chromatography (HPLC), and the obtained spectrum is shown in fig. 1.
The gabapentin Ding Yangpin was prepared according to the method in WO201390357 and the sample was subjected to detection analysis by HPLC and the obtained profile is shown in figure 2.
The refined gabapentin Ding Zazhi D (5% of the added amount) obtained in example 1 was added to gabapentin Ding Yangpin, and after mixing, the obtained mixed sample was subjected to detection analysis by HPLC, and the obtained spectrum was shown in fig. 3.
As can be seen from fig. 1-3: in the HPLC profile (fig. 1 and 3) of gabapentin Ding Zazhi D concentrate and the mixed sample (gabapentin Ding Yangpin with gabapentin Ding Zazhi D concentrate added), a higher chromatographic peak appeared at the 14.03min position; in the HPLC profile of gabapentin Ding Yangpin (FIG. 2), no chromatographic peak was observed at the position of 14.03 min. The above results indicate that the peak position of gabapentin Ding Zazhi D is 14.03min, and the gabapentin sample prepared and detected in this application example does not contain the impurity D.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The raw materials and equipment used in the invention are common raw materials and equipment in the field unless specified otherwise; the methods used in the present invention are conventional in the art unless otherwise specified.
The foregoing description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and any simple modification, variation and equivalent transformation of the above embodiment according to the technical substance of the present invention still fall within the scope of the technical solution of the present invention.
Claims (10)
1. A chemical synthesis method of gabapentin Ding Zazhi D, which is characterized by comprising the following steps:
(A) Carrying out condensation reaction on the compound of the formula I and diisobutylamine to obtain a compound of the formula II; the reaction process is as follows:
(B) Performing Stork reaction and hydrolysis reaction on the compound of the formula II and ethyl bromoacetate to obtain a compound of the formula III; the reaction process is as follows:
(C) Carrying out reductive amination reaction on a compound of the formula III, gabapentin and a reducing agent to obtain gabapentin Ding Zazhi D; the reaction process is as follows:
2. the chemical synthesis process according to claim 1, wherein the specific process of step (a) comprises the steps of: the compound of the formula I, diisobutylamine and the reaction solvent a are mixed, and after condensation reaction, the product is separated, and the compound of the formula II is obtained.
3. The chemical synthesis according to claim 1 or2, wherein in step (a), the condensation reaction is carried out at a temperature of 110-115 ℃ for a time of 20-24 hours.
4. The chemical synthesis process according to claim 1, wherein the specific process of step (B) comprises the steps of: mixing the compound of the formula II, ethyl bromoacetate and a reaction solvent b, performing Stork reaction, adding acetic acid, acetate and water, performing hydrolysis reaction, and separating a product to obtain the compound of the formula III.
5. The chemical synthesis process according to claim 1 or 4, wherein in step (B), after the hydrolysis reaction, the product is isolated to obtain the compound of formula III; the process for separating the product comprises the following steps: after the reaction solvent was removed by concentration under reduced pressure, extraction was performed with ethyl acetate, the obtained organic phase was washed with hydrochloric acid, the solvent was removed by concentration under reduced pressure, and the obtained oily substance was subjected to column chromatography.
6. The chemical synthesis process according to claim 1 or 4, wherein in step (B), the temperature of the Stork reaction is 80-85 ℃ for 20-24 hours; the temperature of the hydrolysis reaction is 80-85 ℃ and the time is 3-4h.
7. The chemical synthesis process according to claim 4, wherein in step (B), the ratio among the compound of formula II, acetic acid and acetate is 1g:0.33-0.45ml:0.15-0.30g.
8. The chemical synthesis process according to claim 1, wherein the specific process of step (C) comprises the steps of: and mixing the compound shown in the formula III, gabapentin, a reaction solvent c and a reducing agent, carrying out a reduction reaction, then carrying out a ring closure reaction, and separating out a product to obtain the gabapentin Ding Zazhi D.
9. The chemical synthesis according to claim 1 or 8, wherein in step (C), the reducing agent is sodium cyanoborohydride.
10. The chemical synthesis method according to claim 1, wherein in the step (C), the temperature of the reduction reaction is 20 to 30 ℃, and the reaction is carried out until the raw materials disappear; the temperature of the ring closing reaction is 60-70 ℃ and the time is 3-4h.
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