CN107501243A - A kind of synthetic method of his Wei of Dacca - Google Patents
A kind of synthetic method of his Wei of Dacca Download PDFInfo
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- CN107501243A CN107501243A CN201710804326.3A CN201710804326A CN107501243A CN 107501243 A CN107501243 A CN 107501243A CN 201710804326 A CN201710804326 A CN 201710804326A CN 107501243 A CN107501243 A CN 107501243A
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- wei
- dacca
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The invention discloses a kind of synthetic method of his Wei of Dacca, it is with two（2 acetyl bromides）Biphenyl, tertbutyloxycarbonyl L proline are initiation material, and intermediate N 4, N 3, N 2, N 1 are respectively synthesized through four steps, and his Wei of product Dacca is finally made.Synthetic method of the present invention, production technology is short, product yield is high, cost is low, raw materials used easily acquisition, is suitable for industrialization large-scale production.
Description
Technical field
The present invention relates to a kind of synthetic method of efficiently his Wei of hepatitis C virus inhibitor Dacca, belong to field of medicine and chemical technology.
Background technology
His Wei of Dacca, English name daclatasir, also known as N, N'- [[1,1'- biphenyl] -4,4'- diyls it is double [1H- imidazoles -
5,2- diyls-(2S) -2,1- pyrrolidines diyl [(1S) -1- (1- Methylethyls) -2- oxo -2,1- ethane diyl]]] double ammonia
Base formic acid C, C'- dimethyl ester, molecular formula is C40H50N8O6, molecular weight 738.875, CAS registration numbers are 1009119-64-5,
Faint yellow solid.
Daclatavir is the research and development of Bristol-Myers Squibb companies, and is obtained in August in 2014 in Europe within 22nd
Approval.On July 24th, 2015, the approval that his Wei of Dacca obtains food and drug administration are used for the type of hepatitis C genotype 3
The treatment of infection.
His Wei of Dacca is first medicine of display security and the HCV infection of curative treatment genotype 3, without common
Give interferon [interferon] or Ribavirin [ribavirin].It is chronic suitable for being used in conjunction with treating with Suo Feibuwei
The type HCV infection of gene 3.
Daclatavir is most important inventory in basic health department in world's essential drugs inventory.The medicine is
Hepatitis C virus NS 5 A highly efficient depressor, but because its is expensive, many patients do not afford to do high expense.Therefore develop
New synthetic route, it is particularly important to reduce its cost.
The content of the invention
It is an object of the invention to provide a kind of suitable industrialized production, and cost is relatively low, the conjunction of his Wei of the Dacca of high income
Into method.
The present invention is achieved through the following technical solutions, a kind of preparation method of his Wei of Dacca, course of reaction such as formula I,
Specifically comprise the following steps：
Formula I；
（1）The synthesis of intermediate N 4：1000ml there-necked flask adds a certain amount of acetonitrile, two（2- acetyl bromides）Biphenyl, tertiary fourth
Oxygen carbonyl-L-PROLINE, triethylamine, stirring reaction 5h ~ 8h under normal temperature, filter and are evaporated after 65 DEG C, obtain intermediate N 4；
（2）The synthesis of intermediate N 3：（1）It is middle to add a certain amount of toluene and ammonium acetate, 55 DEG C of stirring reaction 18h are warming up to,
There is solid precipitation.Filtering, solid is dried to moisture content under the conditions of 70 DEG C is less than 1.0%, obtains intermediate N 3；
（3）The synthesis of intermediate N 2：Dried intermediate N 3 is taken, toluene, methanol and 31% hydrochloric acid is added, is warming up to 50
Reaction 10h DEG C is hydrolyzed, is cooled to 20 DEG C of crystallization 3h, is filtrated to get solid, being dried under vacuum to moisture at 55 DEG C is less than
1.0%, obtain intermediate N 2；
（4）The synthesis of intermediate N 1：Intermediate N 2 is taken, adds acetonitrile and MOC-L- valines, is cooled to 0 DEG C, three second are added dropwise
Amine, 20 DEG C after completion of the reaction, and 2h is stirred at 55 DEG C, filters and is concentrated under reduced pressure after 55 DEG C, obtains intermediate N 1；
（5）The synthesis of his Wei of Dacca：（4）Middle addition methanol and 31% hydrochloric acid, being warming up to 55 DEG C makes its dissolved clarification, is cooled to 20
DEG C crystallization 3h, obtains crude product, adds methanol and activated carbon is warming up to 55 DEG C and refiltered, filtrate is concentrated into original one after filtering
Half, 20 DEG C are cooled to, crystallizes 4h, the solid after filtering is dried under vacuum to moisture content less than 1.0% at 55 DEG C, obtains final products
His Wei of Dacca.
Described two（2- acetyl bromides）The mol ratio of biphenyl and tertbutyloxycarbonyl-L-PROLINE is 1:1.5~1:2.0.
Described two（2- acetyl bromides）Mass ratio with acetonitrile is 1:8.0~1:9.0.
Described two（2- acetyl bromides）Mol ratio with triethylamine is 1:1.0~1:1.3.
Described hydrolysising reacting temperature is 50 DEG C.
Described intermediate moisture content, which all needs to dry to less than 1.0% side, can carry out the next step.
Described crystallization process needs gradient cooling, prevents from analysing cruelly, and rearing crystal time at least needs 3h.
Described reaction dissolvent is recyclable to be applied mechanically again.
Described crystallization temperature is not higher than 20 DEG C.
Embodiment
In order that those skilled in the art more fully understands technical scheme, it is non-that some are disclosed further below
Limiting embodiment, the present invention is described in further detail.
Embodiment 1.
A kind of preparation method of his Wei of Dacca.Comprise the following steps：
The synthesis of 1-1 intermediate Ns 4：1000ml there-necked flask adds 600g acetonitriles, 70g bis-（2- acetyl bromides）Biphenyl,
23.5g tertbutyloxycarbonyls-L-PROLINE, 15.8g triethylamines, stirring reaction 5h under normal temperature, 65 DEG C are evaporated filtrate after filtering, obtain
Intermediate N 4.
The synthesis of 1-2 intermediate Ns 3：600g toluene and 32g ammonium acetates are added to 1-1, is warming up to 55 DEG C of stirring reactions
18h, there is solid precipitation.It is filtrated to get solid and is dried at 70 DEG C to moisture content and be less than 1.0%, obtains intermediate N 3.
The synthesis of 1-3 intermediate Ns 2：Solid N-3 after drying is taken, adds 200g toluene, 400g methanol and 75g 31%
Hydrochloric acid, it is warming up to 50 DEG C and reaction 10h is hydrolyzed, is cooled to 20 DEG C of crystallization 3h, is dried in vacuo at 55 DEG C of the solid being filtrated to get
It is less than 1.0% to moisture.Obtain intermediate N 2.
The synthesis of 1-4 intermediate Ns 1：The intermediate N 2 in 1-3 is taken, adds 400 g acetonitriles and 35g MOC-L- figured silk fabrics ammonia
Acid, 0 DEG C is cooled to, 20.5 g triethylamines are added dropwise, 20 DEG C after completion of the reaction, and 2h is stirred at 55 DEG C, filters after 55 DEG C of concentration filters
Liquid, obtain intermediate N 1.
The synthesis of his Wei of 1-5 Daccas：400g methanol and 20g 31% hydrochloric acid are added in 1-4, be warming up to 55 DEG C make its dissolved clarification,
20 DEG C of crystallization 3h are cooled to, crude product is obtained after filtering, 400g methanol is added and 5g activated carbons is warming up to 55 DEG C and refiltered, filtrate is dense
Reduced concentration is reduced to original half, is cooled to 20 DEG C, crystallizes 4h, solid is dried under vacuum to moisture content at 55 DEG C and is less than after filtering
1.0%, obtain his Wei 111.9g of final products Dacca, purity 99.2%, yield 85.7%.
Embodiment 2.
Repeat embodiment 1, distinguish in 1-1 add tertbutyloxycarbonyl-L-PROLINE be 20g, finally give Dacca he
Wei 102.3g, yield 78.3%.
Embodiment 3.
Embodiment 1 is repeated, it is 30g to distinguish adding MOC-L- valines in 1-4, finally gives his Wei of Dacca
100.7g yield 77.2%.
Embodiment 4.
Embodiment 1 is repeated, it is 40g to distinguish adding MOC-L- valines in 1-4, finally gives his Wei of Dacca
110.7g yield 84.8%.
Embodiment 5.
Embodiment 1 is repeated, distinguishes and 800g acetonitriles is being added in 1-1,8h reacted, and finally gives his Wei of Dacca
108.9g yield 83.4%.
Embodiment 6.
Embodiment 1 is repeated, difference is that all crystallization temperatures are 30 DEG C, finally gives his Wei 70.3g of Dacca, yield
53.9%。
Claims (9)
1. a kind of synthetic method of his Wei of Dacca, course of reaction such as formula I, specifically comprise the following steps：
Formula I；
（1）The synthesis of intermediate N 4：1000ml there-necked flask adds a certain amount of acetonitrile, two（2- acetyl bromides）Biphenyl, tertiary fourth
Oxygen carbonyl-L-PROLINE, triethylamine, stirring reaction 5h ~ 8h under normal temperature, filter and are evaporated after 65 DEG C, obtain intermediate N 4；
（2）The synthesis of intermediate N 3：（1）It is middle to add a certain amount of toluene and ammonium acetate, 55 DEG C of stirring reaction 18h are warming up to,
There is solid precipitation, filter, solid is dried to moisture content under the conditions of 70 DEG C is less than 1.0%, obtains intermediate N 3；
（3）The synthesis of intermediate N 2：Dried intermediate N 3 is taken, toluene, methanol and 31% hydrochloric acid is added, is warming up to 50
Reaction 10h DEG C is hydrolyzed, is cooled to 20 DEG C of crystallization 3h, is filtrated to get solid, being dried under vacuum to moisture at 55 DEG C is less than
1.0%, obtain intermediate N 2；
（4）The synthesis of intermediate N 1：Intermediate N 2 is taken, adds acetonitrile and MOC-L- valines, is cooled to 0 DEG C, three second are added dropwise
Amine, 20 DEG C after completion of the reaction, and 2h is stirred at 55 DEG C, filters and is concentrated under reduced pressure after 55 DEG C, obtains intermediate N 1；
（5）The synthesis of his Wei of Dacca：（4）Middle addition methanol and 31% hydrochloric acid, being warming up to 55 DEG C makes its dissolved clarification, is cooled to 20
DEG C crystallization 3h, obtains crude product, adds methanol and activated carbon is warming up to 55 DEG C and refiltered, filtrate is concentrated into original one after filtering
Half, 20 DEG C are cooled to, crystallizes 4h, the solid after filtering is dried under vacuum to moisture content less than 1.0% at 55 DEG C, obtains final products
His Wei of Dacca.
2. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described two（2- acetyl bromides）Connection
The mol ratio of benzene and tertbutyloxycarbonyl-L-PROLINE is 1:1.5~1:2.0.
3. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described two（2- acetyl bromides）With
The mass ratio of acetonitrile is 1:8.0~1:9.0.
4. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described two（2- acetyl bromides）With
The mol ratio of triethylamine is 1:1.0~1:1.3.
5. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described hydrolysising reacting temperature is 50
℃。
6. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described intermediate moisture content all needs to do
It is dry to carry out the next step to less than 1.0% side.
7. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described crystallization process needs gradient to drop
Temperature, prevent from analysing cruelly, and rearing crystal time at least needs 3h.
8. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described reaction dissolvent is recyclable
Apply mechanically again.
9. the synthetic method of his Wei of Dacca according to claim 1, it is characterised in that described crystallization temperature is not higher than
20℃。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105753844A (en) * | 2016-02-16 | 2016-07-13 | 江苏苏利精细化工股份有限公司 | Novel method for synthesizing dimethyl dicarbamate dihydrochloride compound |
-
2017
- 2017-09-08 CN CN201710804326.3A patent/CN107501243A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105753844A (en) * | 2016-02-16 | 2016-07-13 | 江苏苏利精细化工股份有限公司 | Novel method for synthesizing dimethyl dicarbamate dihydrochloride compound |
Non-Patent Citations (1)
| Title |
|---|
| XI ZONG, ET AL: "Design and synthesis of imidazole N–H substituted amide prodrugs as inhibitors of hepatitis C virus replication", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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Application publication date: 20171222 |