CN106188015B - A method of preparing his Wei of Dacca - Google Patents
A method of preparing his Wei of Dacca Download PDFInfo
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- CN106188015B CN106188015B CN201510226141.XA CN201510226141A CN106188015B CN 106188015 B CN106188015 B CN 106188015B CN 201510226141 A CN201510226141 A CN 201510226141A CN 106188015 B CN106188015 B CN 106188015B
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Abstract
The present invention provides a kind of method for preparing his Wei of Dacca, the method uses N- (methoxycarbonyl group)-Valine and 5,5 '-(4,4 '-biphenyl diyls) bis- (2- ((2S) -2- pyrrolidinyl) -1 hydrogen-imidazoles) four hydrochlorides are as reaction mass, in the case where activator 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride and alkaline reagent participate in, using 2- oxime ethyl cyanoacetate as catalysts, carried out in alcohols solvent.His method of Wei of preparation Dacca provided by the invention is easy to operate, relatively cheap, Environmental Safety, and the rate of recovery is high, is suitable for industrialized production.
Description
Technical field
The present invention relates to field of medicine and chemical technology, and in particular, to a kind of synthetic method for preparing his Wei of Dacca.
Background technique
His Wei of Dacca, entitled ((1S) -1- (((2S) -2- (5- (4 '-(2- ((2S) -1- ((2S) -2- ((the methoxy carbonyls of chemistry
Base) amino) -3- methylbutyryl) -2- pyrrolidinyl) -1H- imidazoles -5- base) -4- xenyl) -1H- imidazoles -2- base) -1- pyrrole
Cough up alkyl) carbonyl) -2- methyl-propyl) methyl carbamate, structure is as follows:
He has disclosed Wei in CN 101558059A for Dacca, belongs to a kind of NS5A inhibitor, is mainly used for treatment third
Type virus infection.
A kind of method for preparing his Wei compound of Dacca is disclosed in prior art CN 101558059A, this method passes through
100mL acetonitrile (ACN), 13.69g are sequentially added in 1 liter of jacketed flask equipped with nitrogen pipeline and overhead stirrer
(89.4mmol, 2.5 moles of times of equivalents) hydroxy benzotriazole hydrate (HOBt), 15.07g (86mmol, 2.4 moles of times of equivalents)
N- (methoxycarbonyl group)-Valine (compound 1), 16.46g (85.9mmol, 2.4 moles of times of equivalents) 1- (3- dimethylamino third
Base) -3- ethyl-carbodiimide hydrochloride (EDC) and other 100mL acetonitrile (ACN).Acquired solution is small in 20 DEG C of stirrings 1
When, bis- (2- ((2S) -2- pyrroles of 5,5 '-(4,4 '-biphenyl diyls) of 20.4g (35.8mmol, 1 mole of times of equivalent) purifying are added
Alkyl) -1 hydrogen-imidazoles) four hydrochlorides (compound 2).The slurry is cooled to about 0 DEG C, 18.47g is added in 30 minutes
(142.9mmol, 4 moles of times of equivalents) diisopropylethylamine (DIPEA), while keeping temperature lower than 10 DEG C.It, will in 3 hours
The solution is slowly heated to 15 DEG C and is kept for 12 hours at 15 DEG C.Then it is reached by subsequent processings such as extraction, filterings
Catarrh Wei compound.Reaction equation is as follows:
Acetonitrile is in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use (English name International
Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use, abbreviation ICH) in classification belong to two class solvents, it is remaining in bulk pharmaceutical chemicals
Guidance standard is 410ppm, belongs to the organic solvent being more toxic.
And the method that his Wei of Dacca is synthesized in CN 101558059A uses acetonitrile as reaction dissolvent, acetonitrile toxicity is big
And it cannot recycle, therefore environment can be caused seriously to pollute, while serious threat is constituted to producers' health of human body.
Summary of the invention
In order to overcome the above problem present in the method for current preparation his Wei of Dacca, a kind of more low toxic and environment-friendly is developed
Industrial process be necessary.
The present inventor is by long-term endeavour, and by many experiments, discovery is used as reactant using compound 1 and compound 2
Material, using ECA as catalysts, is reacted in the case where activator and alkaline reagent are participated in less toxic alcohols solvent, can be effective
His Wei compound of ground preparation high-purity Dacca.
Method Environmental Safety of the present invention, product recoveries are high, the rate of recovery up to 95% or more, be very suitable to Dacca he
The industrialized production of Wei.
Summary of the invention
The present invention provide one kind using compound 1 and compound 2 as reaction mass, using alcohols solvent as reaction solution,
The method for carrying out preparation his Wei compound of Dacca.
Term definition
" compound 1 " refers to N- (methoxycarbonyl group)-Valine in this specification.
" compound 2 " refers to bis- (2- ((2S) -2- pyrrolidinyl) -1 hydrogen-of 5,5 '-(4,4 '-biphenyl diyls) in this specification
Imidazoles) four hydrochlorides.
" DIPEA " refers to diisopropylethylamine in this specification.
" EDC " refers to 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride in this specification.
" ECA " refers to 2- oxime ethyl cyanoacetate in this specification.
" ACN " refers to acetonitrile in this specification.
" HOBt " refers to hydroxybenzotriazole in this specification.
Detailed description of the invention
The method of preparation his Wei compound of Dacca provided by the invention, the method is using compound 1 and compound 2 as instead
Material is answered,
In the presence of activator and alkaline reagent, using ECA as catalysts, carry out synthesizing in alcohols solvent anti-
It answers.
In some embodiments, the alcohols solvent can be methanol, ethyl alcohol, isopropanol, propyl alcohol, butanol, isobutanol
Or ethanol-water mixture.
In further embodiments, the activator can be EDC.
In further embodiments, the alkaline reagent can be DIPEA, triethylamine, N-methylmorpholine, hydroxide
Sodium, potassium carbonate, sodium carbonate or potassium hydroxide.
In some embodiments, alcohols solvent is added into reaction vessel first, then controls reaction dissolvent temperature -10
DEG C~35 DEG C, compound 1, compound 2, ECA, activator and alkaline reagent is added；Material controls reaction system temperature after adding
Degree is 15 DEG C~45 DEG C, reacts 1h~10h.After completion of the reaction, reaction solution is added into water, stir, filtering, obtain Dacca he
Wei.
In some embodiments, alcohols solvent and alkaline reagent are added first into reaction vessel, then control reaction is molten
Compound 1, compound 2, ECA and activator is added at -10 DEG C~35 DEG C in agent temperature；Reaction system temperature control after material adds
15 DEG C~45 DEG C, react 1h~10h.After completion of the reaction, reaction solution is added into water, stirs, and filtering obtains his Wei of Dacca.
In some embodiments, a certain amount of compound 2 is put into, so that concentration of the compound 2 in alcohols solvent is about 0.2
~0.35g/ml (is equivalent to 1.0 moles of times of equivalents).
In some embodiments, 1 inventory of compound is equivalent to 1.0~3.5 moles of times of equivalents of compound 2；Some
It is 2.1~2.5 moles of times of equivalents in embodiment.
In some embodiments, ECA inventory is equivalent to 0.1~1.0 mole of times of equivalent of compound 2；In some implementations
It is 0.1~0.4 mole of times of equivalent in example.
In some embodiments, activator inventory is equivalent to 1.0~3.5 moles of times of equivalents of compound 2；In some realities
Applying in example is 2.1~2.5 moles of times of equivalents.
In some embodiments, alkaline reagent inventory is equivalent to 3.0~6.0 moles of times of equivalents of compound 2；Some
It is 4.0~4.5 moles of times of equivalents in embodiment.
In some embodiments, after completion of the reaction, reaction solution instills in water, wherein every 2 inventory of 1g compound needs 5mL
~50mL water；Then it stirs at 5 DEG C~40 DEG C of temperature control, filters again, obtain his Wei of Dacca.
In some embodiments, after completion of the reaction, reaction solution instills in water, wherein every 2 inventory of 1g compound needs
15mL~25mL water；Then it stirs at 10 DEG C~30 DEG C of temperature control, filters again, obtain his Wei of Dacca.
In some embodiments, alcohols solvent and alkaline reagent are added first into reaction flask, then controls reaction dissolvent
Compound 1, compound 2, ECA and EDC is added at 10 DEG C~20 DEG C in temperature；15 DEG C~35 DEG C of temperature control reactions after material adds
2h~4h.After completion of the reaction, reaction solution is added dropwise in water, wherein every 2 inventory of 1g compound needs 15mL~25mL water；Then
Stir 1h~2h at 10 DEG C~30 DEG C of temperature control again, filtering obtains his Wei of Dacca；The alcohols solvent is methanol, ethyl alcohol or isopropyl
Alcohol；The alkaline reagent is DIPEA, triethylamine or N-methylmorpholine.
Specific embodiment
In order to make those skilled in the art more fully understand technical solution of the present invention, disclose further below some non-
Limiting embodiment, the present invention is described in further detail.
Reagent used in the present invention is available on the market or can described method system through the invention
It is standby and obtain.
Embodiment 1
Addition 450mL ethyl alcohol and DIPEA (142.8g, 1.105mol) into reaction flask at room temperature, 10 DEG C~20 DEG C of temperature control
Compound 2 (150.0g, 0.263mol), compound 1 (106.0g, 0.605mol), ECA (15.0g, 0.106mol), EDC is added
(116.0g, 0.605mol).35 DEG C of reaction 2h~4h of temperature control after material adds have been reacted with thin-layered chromatography detection raw material
Entirely, reaction solution is added dropwise in 2250mL water, is added dropwise after 10 DEG C~30 DEG C stirring 1h of rear temperature control and is filtered to obtain his Wei of Dacca, drying
After obtain 212.6g, yield 99.5%.
Embodiment 2
15ml methanol and DIPEA (4.76g, 0.037mol) is added into reaction flask at room temperature, 10 DEG C~20 DEG C of temperature control add
Enter compound 2 (5.0g, 0.009mol), compound 1 (3.53g, 0.020mol), ECA (0.5g, 0.004mol) and EDC
(3.87g, 0.020mol).35 DEG C of reaction 2h~4h of temperature control after material adds detect raw material fully reacting with thin-layered chromatography,
Reaction solution is added dropwise in 75mL water, is added dropwise after 10 DEG C~30 DEG C stirring 1h of rear temperature control and is filtered to obtain his Wei of Dacca, after drying
To 6.4g, yield 99%.
Embodiment 3
Addition 70mL isopropanol and N-methylmorpholine (14.2g, 0.140mol) into reaction flask at room temperature, 10 DEG C of temperature control~
20 DEG C of addition compounds 2 (20.0g, 0.035mol), compound 1 (13.5g, 0.077mol), ECA (1.0g, 0.007mol),
EDC (14.8g, 0.077mol).35 DEG C of reaction 2h~4h of temperature control after material adds have been reacted with thin-layered chromatography detection raw material
Entirely, reaction solution is added dropwise in 350mL water, is added dropwise after 10 DEG C~30 DEG C stirring 1h of rear temperature control and is filtered to obtain his Wei of Dacca, drying
After obtain 25.6g, yield 99.0%.
Embodiment 4
30mL methanol and N-methylmorpholine (7.6g, 0.075mol), temperature control 10 DEG C~20 is added into reaction flask at room temperature
DEG C be added compound 2 (10.0g, 0.018mol), compound 1 (6.5g, 0.037mol), ECA (0.75g, 0.005mol), EDC
(7.4g, 0.039mol).35 DEG C of reaction 2h~4h of temperature control after material adds detect raw material fully reacting with thin-layered chromatography,
Reaction solution is added dropwise in 180mL water, is added dropwise after 10 DEG C~30 DEG C stirring 1h of rear temperature control and is filtered to obtain his Wei of Dacca, after drying
To 12.33g, yield 95.5%.
Embodiment 5
75mL ethyl alcohol and triethylamine (12.0g, 0.119mol) is added into reaction flask at room temperature, 10 DEG C~20 DEG C of temperature control add
Enter compound 2 (15.0g, 0.026mol), compound 1 (11.5g, 0.066mol), ECA (1.5g, 0.011mol), EDC
(12.6g, 0.066mol).35 DEG C of reaction 2h~4h of temperature control after material adds detect raw material fully reacting with thin-layered chromatography,
Reaction solution is added dropwise in 370mL water, is added dropwise after 10 DEG C~30 DEG C stirring 1h of rear temperature control and is filtered to obtain his Wei of Dacca, after drying
To 19.1g, yield 98.5%.
Embodiment 6
100mL isopropanol and triethylamine (18.6g, 0.184mol), temperature control 10 DEG C~20 is added into reaction flask at room temperature
DEG C be added compound 2 (25.0g, 0.044mol), compound 1 (17.7g, 0.101mol), ECA (1.3g, 0.009mol), EDC
(21.0g, 0.110mol).35 DEG C of reaction 2h~4h of temperature control after material adds detect raw material fully reacting with thin-layered chromatography,
Reaction solution is added dropwise in 500mL water, is added dropwise after 10 DEG C~30 DEG C stirring 1h of rear temperature control and is filtered to obtain his Wei of Dacca, after drying
To 32.1g, yield 99.2%.
To sum up described in embodiment,
The method of preparation his Wei of Dacca provided according to the present invention, is starting material with compound 1 and compound 2, ECA is
Catalyst, EDC are activator, and DIPEA, triethylamine or N-methylmorpholine are as basic solvent, while with methanol, ethyl alcohol or isopropyl
Alcohol is as reaction solution, and the yield of his Wei of reaction product Dacca can achieve 95% or more, while easy to operate, Environmental Safety.
Method of the invention is described by preferred embodiment, related personnel obviously can the content of present invention,
To method described herein and application is modified or appropriate changes and combinations in spirit and scope, carry out the implementation and application present invention
Technology.Those skilled in the art can use for reference present disclosure, be suitably modified realization of process parameters.In particular, it should be pointed out that institute
There are similar replacement and change apparent to those skilled in the art, they are considered as being included in the present invention
It is interior.
Claims (13)
1. a kind of method for preparing his Wei of Dacca, the method is using compound 1 and compound 2 as reaction mass, wherein chemical combination
Object 1 and 2 structural formula of compound are as follows:
In the presence of activator and alkaline reagent, using 2- oxime ethyl cyanoacetate as catalysts, in alcohols solvent into
Row reaction；Wherein, the activator is 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride, the alkalinity examination
Agent is diisopropylethylamine, triethylamine or N-methylmorpholine.
2. according to the method described in claim 1, wherein the alcohols solvent be methanol, ethyl alcohol, isopropanol, propyl alcohol, butanol,
Isobutanol or ethanol-water mixture.
3. then controlling reaction dissolvent temperature according to the method described in claim 1, alcohols solvent is added into reaction flask first
Compound 1, compound 2,2- oxime ethyl cyanoacetate, activator and alkaline reagent are added at -10 DEG C~35 DEG C；Material adds complete
Afterwards, 15 DEG C~45 DEG C reaction 1h~10h of reaction system temperature control；After completion of the reaction, reaction solution is added stirs into water, and filtering obtains
His Wei of Dacca.
4. then being controlled according to the method described in claim 1, alcohols solvent and alkaline reagent are added first into reaction vessel
Reaction dissolvent temperature is in -10 DEG C~35 DEG C addition compounds 1, compound 2,2- oxime ethyl cyanoacetate and activator；Material adds
15 DEG C~45 DEG C reaction 1h~10h of reaction system temperature control after finishing；After completion of the reaction, reaction solution is added dropwise in water and stirs, and filtering obtains
His Wei of Dacca.
5. the method according to claim 3 or 4 puts into a certain amount of compound 2, so that compound 2 is in alcohols solvent
Concentration is about 0.2g/ml~0.35g/ml.
6. the method according to claim 3 or 4,1 inventory of compound be equivalent to compound 2 1.0~3.5 moles are worked as again
Amount or 2.1~2.5 moles of times of equivalents.
7. the method according to claim 3 or 4,2- oxime ethyl cyanoacetate inventory is equivalent to the 0.1~1.0 of compound 2
Mole times equivalent or 0.1~0.4 mole of times of equivalent.
8. the method according to claim 3 or 4, activator inventory be equivalent to compound 2 1.0~3.5 moles are worked as again
Amount or 2.1~2.5 moles of times of equivalents.
9. the method according to claim 3 or 4, alkaline reagent inventory is equivalent to 3.0~6.0 moles times of compound 2
Equivalent or 4.0~4.5 moles of times of equivalents.
10. then being controlled according to the method described in claim 1, alcohols solvent and alkaline reagent are added first into reaction flask
Compound 1, compound 2,2- oxime ethyl cyanoacetate and 1- (3- dimethylamino third is added in reaction dissolvent temperature at 10 DEG C~20 DEG C
Base) -3- ethyl-carbodiimide hydrochloride；15 DEG C~35 DEG C reaction 2h~4h of temperature control after material adds；After completion of the reaction, instead
Drop is answered to be added to the water, wherein every 2 inventory of 1g compound needs 15mL~25mL water；Then under the conditions of 10 DEG C~30 DEG C of temperature control
Stirring, filtering obtain his Wei of Dacca.
11. according to the method described in claim 10, wherein the alcohols solvent is methanol, ethyl alcohol or isopropanol.
12. according to the method described in claim 10, wherein, 1h~2h is stirred at 10 DEG C~30 DEG C of temperature control.
13. the alkaline reagent is diisopropyl according to the method described in claim 10, wherein the alcohols solvent is ethyl alcohol
Ethamine；After completion of the reaction, reaction solution is added dropwise in water, wherein every 2 inventory of 1g compound needs 15mL~25mL water, is then controlled
1h~2h is stirred under the conditions of 10 DEG C~30 DEG C of temperature.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
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| US8329159B2 (en) * | 2006-08-11 | 2012-12-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2012048421A1 (en) * | 2010-10-14 | 2012-04-19 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101778841A (en) * | 2007-08-08 | 2010-07-14 | 百时美施贵宝公司 | Be used for the synthetic method that is used for the treatment of the compound of hepatitis C |
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