CN107814789B - Method for synthesizing daclatasvir starting material - Google Patents
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- CN107814789B CN107814789B CN201711207599.6A CN201711207599A CN107814789B CN 107814789 B CN107814789 B CN 107814789B CN 201711207599 A CN201711207599 A CN 201711207599A CN 107814789 B CN107814789 B CN 107814789B
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- 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
- C07D403/02—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 two hetero rings
- C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a method for synthesizing daclatasvir starting material, which comprises the steps of reacting 2, 4' -dibromoacetophenone shown in a formula I, L-BOC-proline shown in a formula II, potassium carbonate and toluene to generate an intermediate product shown in a formula III, and reacting the intermediate product shown in the formula III with ammonium acetate to generate a compound shown in a formula IV. The synthesis method of the daclatasvir starting material has the advantages of simple reaction route and low cost of raw materials, and is suitable for industrial production.
Description
Technical Field
The invention relates to an industrial synthesis method of an intermediate raw material for preparing daclatasvir, belonging to the technical field of chemical synthesis.
Background
Hepatitis C is the abbreviation of viral hepatitis C, is an infectious disease of liver inflammation necrosis caused by Hepatitis C Virus (HCV), and has great harm to human health and life. Daclatasvir (Daclatasvir) is a Hepatitis C Virus (HCV) NS5A inhibitor developed by behcet mascibo, and is suitable for the treatment of chronic HCV genotype 3 infection, and is used in combination with other drugs for the treatment of adult human infected patients with 1, 2, 3, 4 genotype chronic Hepatitis C (HCV). The cure rate is over 95 percent. The structural formula of daclatasvir is as follows:
at present, the existing process methods for synthesizing daclatasvir are multiple, and international patents WO2009020825, WO2012048421, Chinese patents CN106256825A and CN106496199A all disclose corresponding technical schemes. Most of the process methods have the defects of complex process route, complex operation, harsh reaction conditions, higher raw material cost and the like, and are not beneficial to industrialization.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for synthesizing a daclatasvir starting material, which has a simple reaction route and low raw material cost and is suitable for industrial production.
The invention provides a technical scheme for solving the technical problems, which comprises the following steps: a method for synthesizing daclatasvir starting material comprises the following steps of reacting 2, 4' -dibromoacetophenone shown in a formula I, L-BOC-proline shown in a formula II, potassium carbonate and toluene to generate an intermediate product shown in a formula III, wherein the reaction formula is as follows:
the intermediate product shown in the formula III reacts with ammonium acetate to generate a compound shown in the formula IV, and the reaction formula is as follows
And (3) heating in a water bath, stirring, controlling the reaction temperature to be 25-30 ℃, and controlling the reaction time to be 6-10 hours when the intermediate product shown as the formula III is generated.
After the intermediate product shown as the formula III is generated, adding water for quenching, stirring for 15 to 20 minutes, standing for layering, collecting an upper toluene layer, adding pure water into the toluene layer, stirring for 15 to 20 minutes, standing for layering, collecting the upper toluene layer, heating the toluene layer to reflux, keeping reflux for water diversion for 30 to 60 minutes, stopping reflux, and keeping the liquid for later use.
And (3) carrying out the reaction of the compound shown as the formula IV under the protection of nitrogen, heating, refluxing and stirring overnight, and controlling the reaction temperature to be 65-110 ℃.
And (3) after the compound shown as the formula IV is completely reacted, cooling to room temperature, washing with saturated saline solution, drying a toluene phase with anhydrous sodium sulfate, and crystallizing to obtain a light white solid after concentration.
The molar ratio of the 2, 4' -dibromoacetophenone to the L-BOC-proline is 1: 1-1.2; the molar ratio of the 2, 4' -dibromoacetophenone to the potassium carbonate is 1: 2-2.2; the molar ratio of the 2, 4' -dibromoacetophenone to the ammonium acetate is 1: 1-1.2; the mass of the toluene is 10 times to 15 times of that of the 2, 4' -dibromoacetophenone.
The invention provides a technical scheme for solving the technical problems, which comprises the following steps: a compound shown in a formula IV, which is prepared by adopting the synthesis method of the daclatasvir starting material.
The invention provides a technical scheme for solving the technical problems, which comprises the following steps: a method for preparing daclatasvir by adopting a compound shown as a formula IV prepared by the synthesis method of the daclatasvir starting material.
The invention provides a technical scheme for solving the technical problems, which comprises the following steps: daclatasvir prepared by adopting the compound shown as the formula IV and prepared by the synthesis method of the Daclatasvir starting material.
The invention has the positive effects that: the method adopts 2, 4' -dibromoacetophenone, L-BOC-proline, potassium carbonate and ammonium acetate as main raw materials, can be directly purchased in the market, is low in price, can be directly used for reaction, has a simple reaction route, low requirements on reaction conditions, is easy to control, has few byproducts and high yield, and is suitable for industrial production. The toluene is used as the organic solvent for reaction and the organic solvent for recrystallization, so that a new crystallization solvent is not used, the process is simple, the operation and the recovery are convenient, and the cost is low.
Detailed Description
The present invention is described in detail below by way of examples, it should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and those skilled in the art can make some insubstantial modifications and adaptations of the present invention based on the above-described disclosure. 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.
Example 1
The method for synthesizing the daclatasvir starting material comprises the following steps:
27.8g of 2, 4' -dibromoacetophenone, 21.6g of L-BOC-proline, 27.6g of potassium carbonate and 300g of toluene are added into a 500mL reaction bottle, mechanical stirring and water bath heating are carried out, the temperature is controlled at 28 ℃, the reaction is carried out for 8 hours, sampling detection is carried out, water is added for quenching after the reaction is finished, stirring is carried out for 20 minutes, standing and layering are carried out, an upper toluene layer is collected, a lower water phase is discarded, 1L of pure water is added into the toluene layer again, stirring is carried out for 20 minutes, standing and layering are carried out, the upper toluene layer is collected, the toluene layer is heated to reflux, the reflux is kept for water diversion for 60 minutes, the reflux is stopped, and the reaction liquid is collected for later use in the next reaction.
Adding ammonium acetate into the reaction solution, heating, refluxing and stirring overnight under the protection of nitrogen, and controlling the reaction temperature to be 85 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with saturated brine and dried over anhydrous sodium sulfate. And (3) crystallizing after concentrating to obtain a light white solid, namely the daclatasvir starting material, wherein the HPLC content is more than 95%, and the yield is 87%.
The reaction formula is as follows:
example 2
The method for synthesizing the daclatasvir starting material comprises the following steps:
27.8g of 2, 4' -dibromoacetophenone, 22g of L-BOC-proline, 28g of potassium carbonate and 280g of toluene are added into a 500mL reaction bottle, mechanical stirring is carried out, the temperature is raised in a water bath, the temperature is controlled at 30 ℃, the reaction is carried out for 7 hours, sampling detection is carried out, water is added for quenching after the reaction is finished, the mixture is stirred for 18 minutes, standing and layering are carried out, an upper toluene layer is collected, a lower water phase is discarded, 1L of pure water is added into the toluene layer again, the mixture is stirred for 18 minutes, standing and layering are carried out, the upper toluene layer is collected, the temperature of the toluene layer is raised to reflux, the reflux is stopped after the reflux and the reaction liquid is collected for next reaction.
Adding ammonium acetate into the reaction solution, heating, refluxing and stirring overnight under the protection of nitrogen, and controlling the reaction temperature to be 95 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with saturated brine and dried over anhydrous sodium sulfate. And (3) crystallizing after concentrating to obtain a light white solid, namely the daclatasvir starting material, wherein the HPLC content is more than 95%, and the yield is 86%.
Example 3
The method for synthesizing the daclatasvir starting material comprises the following steps:
27.8g of 2, 4' -dibromoacetophenone, 21.6g of L-BOC-proline, 27.6g of potassium carbonate and 350g of toluene are added into a 500mL reaction bottle, mechanical stirring and water bath heating are carried out, the temperature is controlled at 25 ℃, the reaction is carried out for 9 hours, sampling detection is carried out, after the reaction is finished, water is added for quenching, stirring is carried out for 15 minutes, standing and layering are carried out, an upper toluene layer is collected, a lower water phase is discarded, 1L of pure water is added into the toluene layer again, stirring is carried out for 15 minutes, standing and layering are carried out, an upper toluene layer is collected, the toluene layer is heated to reflux, reflux is kept for 30 minutes, and then the reflux is stopped, and reaction liquid is collected for later use in the next reaction.
Adding ammonium acetate into the reaction solution, heating, refluxing and stirring overnight under the protection of nitrogen, and controlling the reaction temperature to be 80 ℃. After completion of the reaction, the reaction mixture was cooled to room temperature, washed with saturated brine and dried over anhydrous sodium sulfate. And (3) crystallizing after concentrating to obtain a light white solid, namely the daclatasvir starting material, wherein the HPLC content is more than 95%, and the yield is 85%.
The reagents used in the present invention are chemically pure at concentrations not otherwise specified.
It should be understood that the above examples are only for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And such obvious variations or modifications which fall within the spirit of the invention are intended to be covered by the scope of the present invention.
Claims (4)
1. A method for synthesizing a daclatasvir starting material is characterized by comprising the following steps: 2, 4' -dibromoacetophenone shown in a formula I, L-BOC-proline shown in a formula II, potassium carbonate and toluene react to generate an intermediate product shown in a formula III, wherein the reaction formula is as follows:
reacting the intermediate product shown in the formula III with ammonium acetate to generate a compound shown in the formula IV, wherein the reaction formula is as follows:
after the intermediate product shown as the formula III is generated, adding water for quenching, stirring for 15 to 20 minutes, standing for layering, collecting an upper toluene layer, adding pure water into the toluene layer, stirring for 15 to 20 minutes, standing for layering, collecting the upper toluene layer, heating the toluene layer to reflux, keeping reflux for water diversion for 30 to 60 minutes, stopping reflux, and keeping liquid for later use;
adding ammonium acetate into the reaction solution, heating, refluxing and stirring overnight under the protection of nitrogen;
and (3) carrying out the reaction under the protection of nitrogen when the compound shown as the formula IV is generated, heating, refluxing and stirring overnight, and controlling the reaction temperature to be 65-110 ℃.
2. The method for synthesizing the daclatasvir starting material as claimed in claim 1, wherein: when the intermediate product shown as the formula III is generated, the temperature is raised in a water bath, stirring is carried out, the reaction temperature is controlled to be 25-30 ℃, and the reaction time is 6-10 hours.
3. The method for synthesizing the daclatasvir starting material as claimed in claim 1, wherein:
and after the compound shown as the formula IV is completely reacted, cooling to room temperature, washing with saturated saline solution, drying a toluene phase with anhydrous sodium sulfate, and crystallizing to obtain a light white solid after concentration.
4. The method for synthesizing daclatasvir starting material as claimed in any one of claims 1 to 3, wherein: the molar ratio of the 2, 4' -dibromoacetophenone to the L-BOC-proline is 1: 1-1.2; the molar ratio of the 2, 4' -dibromoacetophenone to the potassium carbonate is 1: 2-2.2; the molar ratio of the 2, 4' -dibromoacetophenone to the ammonium acetate is 1: 1-1.2; the mass of the toluene is 10 times to 15 times of that of the 2, 4' -dibromoacetophenone.
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| CN201711207599.6A CN107814789B8 (en) | 2017-11-27 | 2017-11-27 | Method for synthesizing daclatasvir starting material |
| CN202011464085.0A CN112409336B (en) | 2017-11-27 | 2017-11-27 | Synthetic method of daclatasvir starting material suitable for industrial production |
| CN202011462952.7A CN112480084B (en) | 2017-11-27 | 2017-11-27 | Synthetic method of daclatasvir starting material with simple reaction route |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010094977A1 (en) * | 2009-02-23 | 2010-08-26 | Arrow Therapeutics Limited | Novel biphenyl compounds useful for the treatment of hepatitis c |
| CN103189371A (en) * | 2010-11-04 | 2013-07-03 | 施万制药 | Novel inhibitors of hepatitis C virus |
| WO2015017382A1 (en) * | 2013-07-29 | 2015-02-05 | Enanta Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
| WO2015124063A1 (en) * | 2014-02-21 | 2015-08-27 | 常州寅盛药业有限公司 | Hepatitis c virus inhibitors and uses thereof in preparation of drugs |
| CN106256825A (en) * | 2016-07-04 | 2016-12-28 | 四川同晟生物医药有限公司 | The synthetic method of his Wei of Dacca |
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|---|---|---|---|---|
| US8221737B2 (en) * | 2009-06-16 | 2012-07-17 | Enanta Pharmaceuticals, Inc. | Hepatitis C virus inhibitors |
| CN104530079B (en) * | 2009-12-18 | 2017-10-20 | 北京凯因科技股份有限公司 | The new inhibitor that hepatitis C virus is replicated |
| WO2012048421A1 (en) * | 2010-10-14 | 2012-04-19 | Boehringer Ingelheim International Gmbh | Hepatitis c inhibitor compounds |
| US9206159B2 (en) * | 2012-04-25 | 2015-12-08 | Theravance Biopharma R&D Ip, Llc | Piperazine-piperidine compounds as hepatitis C virus inhibitors |
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- 2017-11-27 CN CN202011462952.7A patent/CN112480084B/en active Active
- 2017-11-27 CN CN201711207599.6A patent/CN107814789B8/en active Active
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010094977A1 (en) * | 2009-02-23 | 2010-08-26 | Arrow Therapeutics Limited | Novel biphenyl compounds useful for the treatment of hepatitis c |
| CN103189371A (en) * | 2010-11-04 | 2013-07-03 | 施万制药 | Novel inhibitors of hepatitis C virus |
| WO2015017382A1 (en) * | 2013-07-29 | 2015-02-05 | Enanta Pharmaceuticals, Inc. | Hepatitis c virus inhibitors |
| WO2015124063A1 (en) * | 2014-02-21 | 2015-08-27 | 常州寅盛药业有限公司 | Hepatitis c virus inhibitors and uses thereof in preparation of drugs |
| CN106256825A (en) * | 2016-07-04 | 2016-12-28 | 四川同晟生物医药有限公司 | The synthetic method of his Wei of Dacca |
Non-Patent Citations (1)
| Title |
|---|
| Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect;Min Gao等;《Nature》;20100506;第465卷;第96-100页 * |
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| CN107814789B8 (en) | 2021-01-01 |
| CN112409336A (en) | 2021-02-26 |
| CN112409336B (en) | 2021-09-14 |
| CN112480084A (en) | 2021-03-12 |
| CN112480084B (en) | 2021-09-21 |
| CN107814789A (en) | 2018-03-20 |
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Inventor after: You Xinyu Inventor after: Tao Xin Inventor after: Han Jiaqi Inventor after: Shi Hefeng Inventor after: Ji Xiang Inventor after: Luo Anmao Inventor before: Tao Xin Inventor before: Han Jiaqi Inventor before: Shi Hefeng Inventor before: Ji Xiang Inventor before: Luo Anmao |
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Correction item: Inventor Correct: You Xinyu|Tao Xin|Han Jiaqi|Shi Hefeng|Ji Xiang|Luo Anmao False: Tao Xin|Han Jiaqi|Shi Hefeng|Ji Xiang|Luo Anmao Number: 51-01 Page: The title page Volume: 36 Correction item: Inventor False: Tao Xin|Han Jiaqi|Shi Hefeng|Ji Xiang|Luo Anmao Number: 51-01 Volume: 36 |
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