CN107445964A - A kind of synthetic method of Vardenafil hydrochloric acid impurity - Google Patents
A kind of synthetic method of Vardenafil hydrochloric acid impurity Download PDFInfo
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Abstract
The invention discloses a kind of synthetic method of Vardenafil hydrochloric acid impurity, it is related to pharmaceutical chemistry technical field, comprises the following steps：With alanine (A) for raw material and acetic anhydride, 2 acetylamino propionic acid (B) are generated, then reacted with ethyl oxalyl chloride, reaction of formation product (C)；By 2 ethoxybenzene carbonamidine hydrochlorides (D) and hydration hydrazine reaction, reaction of formation product (E), then reacted with reaction product (C), generation impurity intermediate I (F)；By impurity intermediate I (F) under POCl3 effect, impurity intermediate II (G) is generated；Impurity intermediate II (G) is subjected to sulfonating reaction, reaction of formation product (H)；N ethyl piperazidines are added dropwise into reaction product (H), obtain target product (I) 4 ethyoxyl 3 (3,4 dihydro, 5 methyl, 4 oxo 7 propyl imidazole [5,1 f] [1,2,4] triazinone) benzene sulfonic acid.This method production cost is low, and reaction condition is less demanding, is advantageous to industrialized production, and the purity of target product is higher.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, more particularly to a kind of synthetic method of Vardenafil hydrochloric acid impurity.
Background technology
Vardenafil hydrochloric acid (Vardenafil hydrochloride), chemical name：2- [2- ethyoxyls -5- (4- ethyls -
Piperazine -1- sulfophenyls)-phenyl] three nitrogen -4- ketone mono-hydrochloric salts of -5- methyl -7- propyl group -3H- imidazoles [5,1-f] [1,2,4],
Trade name Ai Lida, succeeded in developing by Bayer A.G, part of in August, 2003 obtains U.S. FDA approval listing, for treating
Male erectile dysfunction (ED), its chemical structural formula are as follows：
The key of Vardenafil hydrochloric acid synthesis is the control of its impurity, therefore the impurity study on the synthesis of Vardenafil has
Significance.2- [2- ethyoxyls -5- (4- ethyl-piperazin -1- sulfonyls) phenyl] -5- methyl -7- methyl -3H- imidazoles [5,1-
F]-[1,2,4] three nitrogen -4- ketone is caused a kind of impurity in Vardenafil hydrochloric acid production preparation process, its structural formula is as follows：
At present, it is less that report is synthesized to it both at home and abroad.A kind of therefore it provides conjunction of the Vardenafil impurity of simple and effective
Into method, Research Significance is great, the impurity quantification that can be used in the production of Vardenafil impurity and quantitative analysis, so as to
The quality standard of Vardenafil is improved, important directive significance is provided for people's masses'safety medication.
The content of the invention
Based on technical problem existing for background technology, the present invention proposes a kind of synthesis side of Vardenafil hydrochloric acid impurity
Method, production cost is low, high income.
A kind of synthetic method of Vardenafil hydrochloric acid impurity proposed by the present invention, synthetic route are as follows：
Comprise the following steps：
S1, with alanine (A) for raw material and acetic anhydride, generate 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B) and ethyl oxalyl chloride reacted, reaction of formation product (C)；
S3, by 2- ethoxybenzene carbonamidine hydrochlorides (D) with hydration hydrazine reaction, reaction of formation product (E), to reaction product
(E) reaction product (C), generation impurity intermediate I (F) are added in；
S4, by impurity intermediate I (F) POCl3 effect under, generate impurity intermediate II (G)；
S5, by impurity intermediate II (G) carry out sulfonating reaction, reaction of formation product (H)；
S6, NEP is added dropwise into reaction product (H), obtains target product (I) 4- ethyoxyls -3- (3,4- dihydro -5-
Methyl -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulfonic acid.
Further, in step S1, alanine (A) is dissolved in glacial acetic acid, acetyl acid anhydride is added dropwise, is warming up to backflow 1-
3h, cooling are quenched, and are spin-dried for solvent, add ethyl acetate stirring and crystallizing, obtain 2- acetylaminos propionic acid (B)；
Preferably, in step S2,2- acetylaminos propionic acid (B), pyridine, DMAP, tetrahydrofuran are added in reactor,
45-55 DEG C is warming up to, is incubated 20-40min, is cooled to 0 DEG C, ethyl oxalyl chloride is added dropwise, is added dropwise, is warming up to backflow, TLC
Plate tracking reaction process, reaction finish, and cooling filtering, filtrate is spin-dried for, and obtains reaction product (C), add ethanol dissolving, standby；
Preferably, in step S3,2- ethoxybenzene carbonamidine hydrochlorides (D) are dissolved in ethanol, are cooled to 0 DEG C, water is added dropwise
Hydrazine is closed, 20-40min is incubated, reacts at room temperature, TLC plate tracking reaction process, reaction of formation product (E), to reaction product (E)
The middle reaction product (C) added in step S2, is warming up to 35-45 DEG C, insulation reaction, TLC plate tracking reaction process, cooled
Filter, filtrate are spin-dried for, add water washing, be extracted twice using dichloromethane, are merged organic layer, are added saturated common salt water washing, anhydrous sulphur
Sour sodium is dried, and filtering, filtrate is spin-dried for, and obtains impurity intermediate I (F)；
Preferably, in step S4, impurity intermediate I (F) is dissolved in glacial acetic acid, POCl3 is added dropwise, is added dropwise, is heated up
To back flow reaction, TLC plate tracking reaction process, cooling, add and be quenched into water, rotation removes glacial acetic acid, regulation pH to neutrality, uses
Dichloromethane is extracted twice, and merges organic layer, is spin-dried for, is obtained with saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate
Impurity intermediate II (G)；
Preferably, in step S5, chlorosulfonic acid is added into reactor, is cooled to 0 DEG C, impurity intermediate II is added portionwise
(G), reaction temperature is 0-5 DEG C, insulation reaction, TLC plate tracking reaction process, and reaction finishes, reaction solution is poured into ice and is quenched,
It is extracted twice using dichloromethane, merges organic layer, with saturated common salt water washing, anhydrous sodium sulfate drying, filtering, production must be reacted
The dichloromethane solution of thing (H)；
Preferably, in step S6, the dichloromethane solution of reaction product (H) is cooled to 0 DEG C, N- ethyls are added dropwise thereto
Piperazine, it is added dropwise, insulation reaction, TLC plate tracking reaction process, reaction finishes, and adds water washing, then washed with saturated ammonium chloride
To wash, saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate is spin-dried for, and adds alcohol reflux to dissolve, and adds activated carbon decolorizing,
Filtering, filtrate cooling crystallization, obtains target product (I) 4- ethyoxyls -3- (3,4- dihydro -5- methyl -4- oxo -7- propyl imidazoles
[5,1-f] [1,2,4]-three nitrogen -one) benzene sulfonic acid.
Specifically, the mass ratio of alanine and acetic anhydride is 10 in the step S1：20-30, preferably 10：23；It is preferred that
Ground, the mass volume ratio (g/mL) of the alanine and glacial acetic acid is 1：7-15, preferably 1：10.
Specifically, 2- acetylaminos propionic acid, pyridine, DMAP mass ratio are 10 in the step S2：15-24：0.1-
0.5, preferably 10：18：0.3；The mass volume ratio (g/mL) of the 2- acetylaminos propionic acid and tetrahydrofuran is 10：80-
130, preferably 10：100.
Specifically, the mass ratio of 2- acetylaminos propionic acid and ethyl oxalyl chloride is 10 in the step S2：20-27, it is excellent
Elect 10 as：23.
Specifically, the mass volume ratio (g/mL) of 2- ethoxybenzene carbonamidine hydrochlorides and ethanol is 1 in the step S3：
10-16, preferably 1：13；Preferably, the mass ratio 1.7-2.5 of 2- ethoxybenzenes carbonamidine hydrochloride and hydrazine hydrate：1, be preferably
2：1.
Specifically, the mass ratio 1-1.5 of 2- acetylaminos propionic acid and 2- ethoxybenzene carbonamidine hydrochlorides in the step S3：
1, preferably 1.3：1.
Specifically, the mass volume ratio (g/mL) of impurity intermediate I (F) and glacial acetic acid is 1 in the step S4：7-12,
Preferably 1：9.
Specifically, chlorosulfonic acid and the mass volume ratio of impurity intermediate II are 1-1.5 in the step S5：1, be preferably
1.1：1.
Specifically, the mass ratio of impurity intermediate II and NEP is 5-6 in the step S6：1, preferably 5.4：
1。
Using technical scheme, it has the advantages that：The present invention is using alanine as raw material, through acid anhydrides acyl
Change, ethyl oxalyl chloride reaction decarboxylation, then with raw material 2- ethoxybenzene carbonamidine hydrochlorides by cyclic condensation twice, then it is sulfonated
React to obtain target product Vardenafil hydrochloric acid impurity 4- ethyoxyls -3- (3,4- dihydro -5- methyl -4- oxos -7- third with piperazine
The nitrogen -one of base imidazoles [5,1-f] [1,2,4]-three) benzene sulfonic acid, production cost is low, and reaction condition is less demanding, is advantageous to industrialize
Production, the purity of target product is higher, the impurity quantification that can be used in Vardenafil production and quantitative analysis, so as to carry
The quality standard of high Vardenafil.
Embodiment
Embodiment
A kind of synthetic method of Vardenafil hydrochloric acid impurity, synthetic route are as follows：
Comprise the following steps：
S1, with alanine (A) for raw material and acetic anhydride, generate 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B) and ethyl oxalyl chloride reacted, reaction of formation product (C)；
S3, by 2- ethoxybenzene carbonamidine hydrochlorides (D) with hydration hydrazine reaction, reaction of formation product (E), to reaction product
(E) reaction product (C), generation impurity intermediate I (F) are added in；
S4, by impurity intermediate I (F) POCl3 effect under, generate impurity intermediate II (G)；
S5, by impurity intermediate II (G) carry out sulfonating reaction, reaction of formation product (H)；
S6, NEP is added dropwise into reaction product (H), obtains target product (I) 4- ethyoxyls -3- (3,4- dihydro -5-
Methyl -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulfonic acid.
It should be noted that it can be added simultaneously in above-mentioned steps S1, S2, S3, S4, S5, S6 other for collecting production
Thing, the additional step for improving yield, improving product purity, going the removal of impurity etc., such as filtering, the multiple concentration of filtrate, washing, extraction
The common supplementary means such as take, dry.
Below, technical scheme is described in detail by specific embodiment.
Embodiment 1
A kind of synthetic method of Vardenafil hydrochloric acid impurity proposed by the present invention, step are as follows：
S1, alanine (A) is dissolved in glacial acetic acid, the mass volume ratio (g/mL) of alanine and glacial acetic acid is 1：7, drop
Add acetyl acid anhydride, the mass ratio of alanine and acetic anhydride is 10：20, backflow 1h is warming up to, cooling is quenched, and is spin-dried for solvent, adds second
Acetoacetic ester stirring and crystallizing, obtain 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B), pyridine, DMAP, tetrahydrofuran be added in reactor, 2- acetylaminos third
Acid, pyridine, DMAP mass ratio are 10：15：The mass volume ratio (g/mL) of 0.1,2- acetylamino propionic acid and tetrahydrofuran is
10：80,45 DEG C are warming up to, is incubated 20min, is cooled to 0 DEG C, ethyl oxalyl chloride, 2- acetylaminos propionic acid and oxalyl chloride is added dropwise
The mass ratio of mono ethyl ester is 10：20, it is added dropwise, is warming up to backflow, TLC plate tracking reaction process, reaction is finished, cooled
Filter, filtrate are spin-dried for, and obtain reaction product (C), add ethanol dissolving, standby；
S3,2- ethoxybenzene carbonamidine hydrochlorides (D) are dissolved in ethanol, the matter of 2- ethoxybenzene carbonamidine hydrochlorides and ethanol
It is 1 to measure volume ratio (g/mL)：10,0 DEG C is cooled to, the quality of hydrazine hydrate, 2- ethoxybenzene carbonamidine hydrochlorides and hydrazine hydrate is added dropwise
Than 1.7：1,20min is incubated, is reacted at room temperature, TLC plate tracking reaction process, reaction of formation product (E), to reaction product (E)
The middle reaction product (C) added in step S2, the preparing raw material 2- acetylaminos propionic acid and 2- ethoxy benzonitriles of reaction product (C)
The mass ratio 1.5 of amidine hydrochloride：1,35 DEG C are warming up to, insulation reaction, TLC plate tracking reaction process, cool filtering, filtrate rotation
It is dry, add water washing, be extracted twice using dichloromethane, merge organic layer, add saturated common salt water washing, anhydrous sodium sulfate drying,
Filtering, filtrate are spin-dried for, and obtain impurity intermediate I (F)；
S4, impurity intermediate I (F) is dissolved in glacial acetic acid, impurity intermediate I (F) and the mass volume ratio (g/ of glacial acetic acid
ML it is) 1：7, POCl3 is added dropwise, is added dropwise, is warming up to back flow reaction, TLC plate tracking reaction process, cooling, adds to water
In be quenched, rotation remove glacial acetic acid, regulation pH to neutrality, is extracted twice using dichloromethane, merging organic layer, is washed with saturated common salt
Wash, anhydrous sodium sulfate drying, filter, filtrate is spin-dried for, and obtains impurity intermediate II (G)；
S5, chlorosulfonic acid is added into reactor, be cooled to 0 DEG C, be added portionwise impurity intermediate II (G), chlorosulfonic acid and miscellaneous
The mass volume ratio of matter intermediate II (G) is 1：1, reaction temperature is 0-5 DEG C, insulation reaction, TLC plate tracking reaction process, instead
It should finish, reaction solution is poured into ice and is quenched, be extracted twice using dichloromethane, merge organic layer, with saturated common salt water washing,
Anhydrous sodium sulfate drying, filter, obtain reaction product (H) dichloromethane solution；
S6, the dichloromethane solution of reaction product (H) is cooled to 0 DEG C, NEP, reaction product are added dropwise thereto
(H) preparing raw material impurity intermediate II (G) and the mass ratio of NEP is 5：1, it is added dropwise, insulation reaction, TLC plates
Tracking reaction process, reaction are finished, and add water washing, then are washed with saturated ammonium chloride, saturated common salt water washing, and anhydrous sodium sulfate is done
Dry, filtering, filtrate is spin-dried for, and adds alcohol reflux to dissolve, and adds activated carbon decolorizing, filtering, filtrate cooling crystallization, obtains target product
(I) 4- ethyoxyls -3- (3,4- dihydros -5- methyl -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulphur
Acid.
Embodiment 2
A kind of synthetic method of Vardenafil hydrochloric acid impurity proposed by the present invention, step are as follows：
S1, alanine (A) is dissolved in glacial acetic acid, the mass volume ratio (g/mL) of alanine and glacial acetic acid is 1：9, drop
Add acetyl acid anhydride, the mass ratio of alanine and acetic anhydride is 10：25, backflow 2h is warming up to, cooling is quenched, and is spin-dried for solvent, adds second
Acetoacetic ester stirring and crystallizing, obtain 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B), pyridine, DMAP, tetrahydrofuran be added in reactor, 2- acetylaminos third
Acid, pyridine, DMAP mass ratio are 10：18：The mass volume ratio (g/mL) of 0.5,2- acetylamino propionic acid and tetrahydrofuran is
10：90,50 DEG C are warming up to, is incubated 30min, is cooled to 0 DEG C, ethyl oxalyl chloride, 2- acetylaminos propionic acid and oxalyl chloride is added dropwise
The mass ratio of mono ethyl ester is 10：22, it is added dropwise, is warming up to backflow, TLC plate tracking reaction process, reaction is finished, cooled
Filter, filtrate are spin-dried for, and obtain reaction product (C), add ethanol dissolving, standby；
S3,2- ethoxybenzene carbonamidine hydrochlorides (D) are dissolved in ethanol, the matter of 2- ethoxybenzene carbonamidine hydrochlorides and ethanol
It is 1 to measure volume ratio (g/mL)：12,0 DEG C is cooled to, the quality of hydrazine hydrate, 2- ethoxybenzene carbonamidine hydrochlorides and hydrazine hydrate is added dropwise
Than 1.9：1,30min is incubated, is reacted at room temperature, TLC plate tracking reaction process, reaction of formation product (E), to reaction product (E)
The middle reaction product (C) added in step S2, the preparing raw material 2- acetylaminos propionic acid and 2- ethoxy benzonitriles of reaction product (C)
The mass ratio 1.4 of amidine hydrochloride：1,45 DEG C are warming up to, insulation reaction, TLC plate tracking reaction process, cool filtering, filtrate rotation
It is dry, add water washing, be extracted twice using dichloromethane, merge organic layer, add saturated common salt water washing, anhydrous sodium sulfate drying,
Filtering, filtrate are spin-dried for, and obtain impurity intermediate I (F)；
S4, impurity intermediate I (F) is dissolved in glacial acetic acid, impurity intermediate I (F) and the mass volume ratio (g/ of glacial acetic acid
ML it is) 1：10, POCl3 is added dropwise, is added dropwise, is warming up to back flow reaction, TLC plate tracking reaction process, cooling, adds extremely
It is quenched in water, rotation removes glacial acetic acid, regulation pH to neutrality, is extracted twice using dichloromethane, merges organic layer, uses saturated aqueous common salt
Washing, anhydrous sodium sulfate drying, filtering, filtrate are spin-dried for, and obtain impurity intermediate II (G)；
S5, chlorosulfonic acid is added into reactor, be cooled to 0 DEG C, be added portionwise impurity intermediate II (G), chlorosulfonic acid and miscellaneous
The mass volume ratio of matter intermediate II (G) is 1.2：1, reaction temperature is 0-5 DEG C, insulation reaction, TLC plate tracking reaction process,
Reaction is finished, and reaction solution is poured into ice and is quenched, and is extracted twice using dichloromethane, is merged organic layer, is washed with saturated common salt
Wash, anhydrous sodium sulfate drying, filter, obtain reaction product (H) dichloromethane solution；
S6, the dichloromethane solution of reaction product (H) is cooled to 0 DEG C, NEP, reaction product are added dropwise thereto
(H) preparing raw material impurity intermediate II (G) and the mass ratio of NEP is 5.2：1, it is added dropwise, insulation reaction, TLC
Plate tracking reaction process, reaction finish, and add water washing, then are washed with saturated ammonium chloride, saturated common salt water washing, anhydrous sodium sulfate
Dry, filtering, filtrate is spin-dried for, and adds alcohol reflux to dissolve, and adds activated carbon decolorizing, filtering, filtrate cooling crystallization, obtains target product
(I) 4- ethyoxyls -3- (3,4- dihydros -5- methyl -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulphur
Acid.
Embodiment 3
A kind of synthetic method of Vardenafil hydrochloric acid impurity proposed by the present invention, step are as follows：
S1, alanine (A) is dissolved in glacial acetic acid, the mass volume ratio (g/mL) of alanine and glacial acetic acid is 1：13,
The mass ratio of dropwise addition acetyl acid anhydride, alanine and acetic anhydride is 10：27, backflow 2.5h is warming up to, cooling is quenched, is spin-dried for solvent, adds
Enter ethyl acetate stirring and crystallizing, obtain 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B), pyridine, DMAP, tetrahydrofuran be added in reactor, 2- acetylaminos third
Acid, pyridine, DMAP mass ratio are 10：20：The mass volume ratio (g/mL) of 0.3,2- acetylamino propionic acid and tetrahydrofuran is
10：120,50 DEG C are warming up to, is incubated 35min, is cooled to 0 DEG C, ethyl oxalyl chloride, 2- acetylaminos propionic acid and oxalyl chloride is added dropwise
The mass ratio of mono ethyl ester is 10：25, it is added dropwise, is warming up to backflow, TLC plate tracking reaction process, reaction is finished, cooled
Filter, filtrate are spin-dried for, and obtain reaction product (C), add ethanol dissolving, standby；
S3,2- ethoxybenzene carbonamidine hydrochlorides (D) are dissolved in ethanol, the matter of 2- ethoxybenzene carbonamidine hydrochlorides and ethanol
It is 1 to measure volume ratio (g/mL)：14,0 DEG C is cooled to, the quality of hydrazine hydrate, 2- ethoxybenzene carbonamidine hydrochlorides and hydrazine hydrate is added dropwise
Than 2.3：1,40min is incubated, is reacted at room temperature, TLC plate tracking reaction process, reaction of formation product (E), to reaction product (E)
The middle reaction product (C) added in step S2, the preparing raw material 2- acetylaminos propionic acid and 2- ethoxy benzonitriles of reaction product (C)
The mass ratio 1.2 of amidine hydrochloride：1,40 DEG C are warming up to, insulation reaction, TLC plate tracking reaction process, cool filtering, filtrate rotation
It is dry, add water washing, be extracted twice using dichloromethane, merge organic layer, add saturated common salt water washing, anhydrous sodium sulfate drying,
Filtering, filtrate are spin-dried for, and obtain impurity intermediate I (F)；
S4, impurity intermediate I (F) is dissolved in glacial acetic acid, impurity intermediate I (F) and the mass volume ratio (g/ of glacial acetic acid
ML it is) 1：11, POCl3 is added dropwise, is added dropwise, is warming up to back flow reaction, TLC plate tracking reaction process, cooling, adds extremely
It is quenched in water, rotation removes glacial acetic acid, regulation pH to neutrality, is extracted twice using dichloromethane, merges organic layer, uses saturated aqueous common salt
Washing, anhydrous sodium sulfate drying, filtering, filtrate are spin-dried for, and obtain impurity intermediate II (G)；
S5, chlorosulfonic acid is added into reactor, be cooled to 0 DEG C, be added portionwise impurity intermediate II (G), chlorosulfonic acid and miscellaneous
The mass volume ratio of matter intermediate II (G) is 1.3：1, reaction temperature is 0-5 DEG C, insulation reaction, TLC plate tracking reaction process,
Reaction is finished, and reaction solution is poured into ice and is quenched, and is extracted twice using dichloromethane, is merged organic layer, is washed with saturated common salt
Wash, anhydrous sodium sulfate drying, filter, obtain reaction product (H) dichloromethane solution；
S6, the dichloromethane solution of reaction product (H) is cooled to 0 DEG C, NEP, reaction product are added dropwise thereto
(H) preparing raw material impurity intermediate II (G) and the mass ratio of NEP is 5.7：1, it is added dropwise, insulation reaction, TLC
Plate tracking reaction process, reaction finish, and add water washing, then are washed with saturated ammonium chloride, saturated common salt water washing, anhydrous sodium sulfate
Dry, filtering, filtrate is spin-dried for, and adds alcohol reflux to dissolve, and adds activated carbon decolorizing, filtering, filtrate cooling crystallization, obtains target product
(I) 4- ethyoxyls -3- (3,4- dihydros -5- methyl -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulphur
Acid.
Embodiment 4
A kind of synthetic method of Vardenafil hydrochloric acid impurity proposed by the present invention, step are as follows：
S1, alanine (A) is dissolved in glacial acetic acid, the mass volume ratio (g/mL) of alanine and glacial acetic acid is 1：15,
The mass ratio of dropwise addition acetyl acid anhydride, alanine and acetic anhydride is 10：30, backflow 3h is warming up to, cooling is quenched, and is spin-dried for solvent, adds
Ethyl acetate stirring and crystallizing, obtain 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B), pyridine, DMAP, tetrahydrofuran be added in reactor, 2- acetylaminos third
Acid, pyridine, DMAP mass ratio are 10：24：The mass volume ratio (g/mL) of 0.4,2- acetylamino propionic acid and tetrahydrofuran is
10：130,55 DEG C are warming up to, is incubated 40min, is cooled to 0 DEG C, ethyl oxalyl chloride, 2- acetylaminos propionic acid and oxalyl chloride is added dropwise
The mass ratio of mono ethyl ester is 10：27, it is added dropwise, is warming up to backflow, TLC plate tracking reaction process, reaction is finished, cooled
Filter, filtrate are spin-dried for, and obtain reaction product (C), add ethanol dissolving, standby；
S3,2- ethoxybenzene carbonamidine hydrochlorides (D) are dissolved in ethanol, the matter of 2- ethoxybenzene carbonamidine hydrochlorides and ethanol
It is 1 to measure volume ratio (g/mL)：16,0 DEG C is cooled to, the quality of hydrazine hydrate, 2- ethoxybenzene carbonamidine hydrochlorides and hydrazine hydrate is added dropwise
Than 2.5：1,40min is incubated, is reacted at room temperature, TLC plate tracking reaction process, reaction of formation product (E)；To reaction product (E)
The middle reaction product (C) added in step S2, the preparing raw material 2- acetylaminos propionic acid and 2- ethoxy benzonitriles of reaction product (C)
The mass ratio 1 of amidine hydrochloride：1,35 DEG C are warming up to, insulation reaction, TLC plate tracking reaction process, cool filtering, and filtrate is spin-dried for,
Add water washing, be extracted twice using dichloromethane, merge organic layer, add saturated common salt water washing, anhydrous sodium sulfate drying, mistake
Filter, filtrate are spin-dried for, and obtain impurity intermediate I (F)；
S4, impurity intermediate I (F) is dissolved in glacial acetic acid, impurity intermediate I (F) and the mass volume ratio (g/ of glacial acetic acid
ML it is) 1：12, POCl3 is added dropwise, is added dropwise, is warming up to back flow reaction, TLC plate tracking reaction process, cooling, adds extremely
It is quenched in water, rotation removes glacial acetic acid, regulation pH to neutrality, is extracted twice using dichloromethane, merges organic layer, uses saturated aqueous common salt
Washing, anhydrous sodium sulfate drying, filtering, filtrate are spin-dried for, and obtain impurity intermediate II (G)；
S5, chlorosulfonic acid is added into reactor, be cooled to 0 DEG C, be added portionwise impurity intermediate II (G), chlorosulfonic acid and miscellaneous
The mass volume ratio of matter intermediate II (G) is 1.5：1, reaction temperature is 0-5 DEG C, insulation reaction, TLC plate tracking reaction process,
Reaction is finished, and reaction solution is poured into ice and is quenched, and is extracted twice using dichloromethane, is merged organic layer, is washed with saturated common salt
Wash, anhydrous sodium sulfate drying, filter, obtain reaction product (H) dichloromethane solution；
S6, the dichloromethane solution of reaction product (H) is cooled to 0 DEG C, NEP, reaction product are added dropwise thereto
(H) preparing raw material impurity intermediate II (G) and the mass ratio of NEP is 6：1, it is added dropwise, insulation reaction, TLC plates
Tracking reaction process, reaction are finished, and add water washing, then are washed with saturated ammonium chloride, saturated common salt water washing, and anhydrous sodium sulfate is done
Dry, filtering, filtrate is spin-dried for, and adds alcohol reflux to dissolve, and adds activated carbon decolorizing, filtering, filtrate cooling crystallization, obtains target product
(I) 4- ethyoxyls -3- (3,4- dihydros -5- methyl -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulphur
Acid.
Embodiment 5
A kind of synthetic method of Vardenafil hydrochloric acid impurity proposed by the present invention, step are as follows：
S1, alanine (A) 10g, glacial acetic acid 100ml are added into 250ml there-necked flasks, stirring and dissolving, acetic anhydride is added dropwise
23.1g, it is added dropwise, flows back 2 hours, cooling is quenched, and is spin-dried for solvent, adds ethyl acetate 30ml stirring and crystallizings, obtains 10.5g whites
Solid 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B) 10g, pyridine 18.1g, DMAP0.3g, tetrahydrochysene furan are added into 250ml there-necked flasks
Mutter 100ml, is warming up to 50 DEG C, is incubated 30min, is cooled to 0 DEG C, and ethyl oxalyl chloride 22.9g is added dropwise, is added dropwise, is warming up to
Backflow.4h is maintained the reflux for, TLC plates track to reaction and finished, and cooling filtering, filtrate is spin-dried for, obtains reaction product (C), add 100ml second
Alcohol dissolving is standby.
S3,2- ethoxybenzene carbonamidine hydrochloride (D) 7.68g, ethanol 100ml are added into 250ml there-necked flasks, stirred to complete
It is molten, 0 DEG C is cooled to, hydrazine hydrate 3.82g is added dropwise, drips off insulation 30min, is placed in room temperature reaction 2h, TLC plates, which track to, to have reacted
Finish, reaction of formation product (E), reaction product (C) is walked in dropwise addition, drop, which finishes, is warming up to 40 DEG C, and insulation reaction 1h, TLC plate tracks to
Reaction finishes, and cooling filtering, filtrate is spin-dried for, adds water washing, add methylene chloride and be extracted twice, and merges organic layer, adds saturated common salt
Water washing, anhydrous sodium sulfate drying, filtering are spin-dried for, and add 20ml ethyl acetate stirring and crystallizings, are obtained among 6.6g white solid impurity
Body I (F).
S4, impurity intermediate I (F) 16.6g, glacial acetic acid 60ml are added into 100ml there-necked flasks, stirred to complete molten, dropwise addition
POCl3, drop, which finishes, is warming up to backflow, and maintains the reflux for 1 hour, and TLC plates track to reaction and finished, and cooling, add and are quenched into water
Go out, rotation removes glacial acetic acid, and hydrogenation potassium oxide solution adjusts pH value to add methylene chloride extraction to neutrality three times, merge organic layer, add saturation
Brine It, anhydrous sodium sulfate drying, filtering are spin-dried for obtaining 6.4g impurity intermediate II (G).
S5, chlorosulfonic acid 29.5g is added into 100ml there-necked flasks, be cooled to 0 DEG C, impurity intermediate II (G) is added portionwise
26g, 0~5 DEG C of temperature is controlled, is finished, insulation reaction 30min, TLC plate tracks to reaction and finished.Reaction solution is poured into ice
It is quenched, adds methylene chloride and be extracted twice, add saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate is cooled to 0 DEG C, drop
Add NEP 4.8g, be added dropwise, insulation reaction 30min, TLC plate tracks to reaction and finished, and adds water washing once, adds full
Washed twice with ammonium chloride, add saturated common salt water washing, anhydrous sodium sulfate drying, filtering is spin-dried for, and adds ethanol 35ml, is flowed back molten
Solution, adds activated carbon decolorizing, filters, and filtrate cooling crystallization, obtains 4.1g target products (I) 4- ethyoxyls -3- (3,4- dihydro -5- first
Base -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulfonic acid.
The foregoing is only a preferred embodiment of the present invention, but protection scope of the present invention be not limited thereto,
Any one skilled in the art the invention discloses technical scope in, technique according to the invention scheme and its
Inventive concept is subject to equivalent substitution or change, should all be included within the scope of the present invention.
Claims (10)
1. a kind of synthetic method of Vardenafil hydrochloric acid impurity, it is characterised in that synthetic route is as follows：
Comprise the following steps：
S1, with alanine (A) for raw material and acetic anhydride, generate 2- acetylaminos propionic acid (B)；
S2,2- acetylaminos propionic acid (B) and ethyl oxalyl chloride reacted, reaction of formation product (C)；
S3, by 2- ethoxybenzene carbonamidine hydrochlorides (D) with hydration hydrazine reaction, reaction of formation product (E), into reaction product (E)
Add reaction product (C), generation impurity intermediate I (F)；
S4, by impurity intermediate I (F) POCl3 effect under, generate impurity intermediate II (G)；
S5, by impurity intermediate II (G) carry out sulfonating reaction, reaction of formation product (H)；
S6, NEP is added dropwise into reaction product (H), obtains target product (I) 4- ethyoxyls -3- (3,4- dihydro -5- first
Base -4- oxo -7- propyl imidazoles [5,1-f] [1,2,4]-three nitrogen -one) benzene sulfonic acid.
2. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 1, it is characterised in that, will in step S1
Alanine (A) is dissolved in glacial acetic acid, and acetyl acid anhydride is added dropwise, and is warming up to backflow 1-3h, and cooling is quenched, and is spin-dried for solvent, adds acetic acid
Ethyl ester stirring and crystallizing, obtain 2- acetylaminos propionic acid (B)；
Preferably, in step S2,2- acetylaminos propionic acid (B), pyridine, DMAP, tetrahydrofuran are added in reactor, heated up
To 45-55 DEG C, be incubated 20-40min, be cooled to 0 DEG C, ethyl oxalyl chloride is added dropwise, is added dropwise, be warming up to backflow, TLC plates with
Track course of reaction, reaction finish, and cooling filtering, filtrate is spin-dried for, and obtains reaction product (C), add ethanol dissolving, standby；
Preferably, in step S3,2- ethoxybenzene carbonamidine hydrochlorides (D) are dissolved in ethanol, are cooled to 0 DEG C, hydrazine hydrate is added dropwise,
20-40min is incubated, is reacted at room temperature, TLC plate tracking reaction process, reaction of formation product (E), is added into reaction product (E)
Reaction product (C) in step S2,35-45 DEG C is warming up to, insulation reaction, TLC plate tracking reaction process, cool filtering, filtrate
It is spin-dried for, adds water washing, be extracted twice using dichloromethane, merges organic layer, add saturated common salt water washing, anhydrous sodium sulfate is done
Dry, filtering, filtrate is spin-dried for, and obtains impurity intermediate I (F)；
Preferably, in step S4, impurity intermediate I (F) is dissolved in glacial acetic acid, POCl3 is added dropwise, is added dropwise, is warming up to back
Stream reaction, TLC plate tracking reaction process, cooling, adds and is quenched into water, and rotation removes glacial acetic acid, and pH is to neutrality for regulation, using dichloro
Methane is extracted twice, and merges organic layer, is spin-dried for saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate, is obtained impurity
Intermediate II (G)；
Preferably, in step S5, chlorosulfonic acid is added into reactor, is cooled to 0 DEG C, impurity intermediate II is added portionwise, is reacted
Temperature is 0-5 DEG C, and insulation reaction, TLC plate tracking reaction process, reaction finishes, reaction solution is poured into ice and is quenched, using dichloro
Methane is extracted twice, and merges organic layer, with saturated common salt water washing, anhydrous sodium sulfate drying, filtering, obtains reaction product (H)
Dichloromethane solution；
Preferably, in step S6, the dichloromethane solution of reaction product (H) is cooled to 0 DEG C, N- ethyl piperazines are added dropwise thereto
Piperazine, it is added dropwise, insulation reaction, TLC plate tracking reaction process, reaction finishes, and adds water washing, then washed with saturated ammonium chloride,
Saturated common salt water washing, anhydrous sodium sulfate drying, filtering, filtrate are spin-dried for, and add alcohol reflux to dissolve, and add activated carbon decolorizing, mistake
Filter, filtrate cooling crystallization, obtains target product.
3. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S1
The mass ratio of alanine and acetic anhydride is 10：20-30, preferably 10：23；Preferably, the quality of the alanine and glacial acetic acid
Volume ratio (g/mL) is 1：7-15, preferably 1：10.
4. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S2
2- acetylaminos propionic acid, pyridine, DMAP mass ratio are 10：15-24：0.1-0.5, preferably 10：18：0.3；The 2- acetyl
The mass volume ratio of alanine and tetrahydrofuran (g/mL) is 10：80-130, preferably 10：100.
5. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S2
The mass ratio of 2- acetylaminos propionic acid and ethyl oxalyl chloride is 10：20-27, preferably 10：23.
6. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S3
The mass volume ratio (g/mL) of 2- ethoxybenzene carbonamidine hydrochlorides and ethanol is 1：10-16, preferably 1：13；Preferably, 2- second
The mass ratio 1.7-2.5 of epoxide Amidinobenzene hydrochloride and hydrazine hydrate：1, preferably 2：1.
7. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S3
The mass ratio 1-1.5 of 2- acetylaminos propionic acid and 2- ethoxybenzene carbonamidine hydrochlorides：1, preferably 1.3：1.
8. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S4
The mass volume ratio (g/mL) of impurity intermediate I (F) and glacial acetic acid is 1：7-12, preferably 1：9.
9. a kind of synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that in the step S5
Chlorosulfonic acid and the mass ratio of impurity intermediate II are 1-1.5：1, preferably 1.1：1.
A kind of 10. synthetic method of Vardenafil hydrochloric acid impurity as claimed in claim 2, it is characterised in that the step S6
The mass ratio of middle impurity intermediate II and NEP is 5-6：1, preferably 5.4：1.
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| CN113583003A (en) * | 2021-08-05 | 2021-11-02 | 广东西捷药业有限公司 | Vardenafil analogue and synthetic method and application thereof |
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