CN111039951A - Preparation method of darunavir - Google Patents
Preparation method of darunavir Download PDFInfo
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- CN111039951A CN111039951A CN201911295964.2A CN201911295964A CN111039951A CN 111039951 A CN111039951 A CN 111039951A CN 201911295964 A CN201911295964 A CN 201911295964A CN 111039951 A CN111039951 A CN 111039951A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 52
- 229960005107 darunavir Drugs 0.000 title claims abstract description 50
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 title claims abstract description 50
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000000843 powder Substances 0.000 claims abstract description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 15
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 125000003118 aryl group Chemical group 0.000 claims abstract description 15
- 229910017052 cobalt Inorganic materials 0.000 claims abstract description 15
- 239000010941 cobalt Substances 0.000 claims abstract description 15
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims abstract description 15
- JDBBTVFYDZWUFI-UHFFFAOYSA-K iron(3+) trinitrite Chemical compound [Fe+3].[O-]N=O.[O-]N=O.[O-]N=O JDBBTVFYDZWUFI-UHFFFAOYSA-K 0.000 claims abstract description 15
- 229910052751 metal Inorganic materials 0.000 claims abstract description 15
- 239000002184 metal Substances 0.000 claims abstract description 15
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 15
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 15
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 15
- 239000011701 zinc Substances 0.000 claims abstract description 15
- -1 hydroxyl compound Chemical class 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 9
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims description 41
- 239000012046 mixed solvent Substances 0.000 claims description 36
- 238000010438 heat treatment Methods 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 26
- 238000001035 drying Methods 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 238000007873 sieving Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 8
- 239000012535 impurity Substances 0.000 claims description 7
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 239000011787 zinc oxide Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 6
- 230000000694 effects Effects 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 229940122440 HIV protease inhibitor Drugs 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000798 anti-retroviral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004970 cd4 cell Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- BUJQWGJSJATKQK-UHFFFAOYSA-N octyl 3-hydroxy-2-[[4-oxo-4-(4-sulfamoylanilino)butanoyl]amino]-3-phenylpropanoate Chemical compound C=1C=CC=CC=1C(O)C(C(=O)OCCCCCCCC)NC(=O)CCC(=O)NC1=CC=C(S(N)(=O)=O)C=C1 BUJQWGJSJATKQK-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Catalysts (AREA)
Abstract
The invention relates to the technical field of medicine preparation and application, and discloses a preparation method of darunavir, which comprises the following steps: 1) 2), 3), 4), 5), 6). The preparation method of the darunavir comprises the steps of selecting N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent weight of methyl hamine, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal alkali, hydroxyl compound, aluminum oxide, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution, and preparing the darunavir according to the steps 1) to 4) to obtain fine powder.
Description
Technical Field
The invention relates to the technical field of medicine preparation and application, in particular to a preparation method of darunavir.
Background
Darunavir is a chemical substance with the chemical formula of C27H37N3O7S, is a non-peptide HIV protease inhibitor, acts by blocking the formation process of releasing new or mature virus particles from the surface of infected host cells and inhibiting the protease of the virus, and when the darunavir is used for a long time, can generally reduce HIV viral vectors in blood, increase the count of CD4 cells, reduce the chance of infecting AIDS, improve the quality of life and prolong life, and is suitable for adults infected with AIDS virus but who have no curative effect when taking the existing antiretroviral drugs.
The application of darunavir is common at present, the preparation process of the medicament is also disclosed and is fully applied, but the preparation efficiency of the preparation method of darunavir is lower at present, so that the preparation cost is higher, and meanwhile, the preparation process of darunavir has higher requirements on the preparation environment, so that the price of prepared darunavir is higher, and further the popularization of darunavir is more troublesome, and therefore, the preparation method of darunavir is provided to solve the problems.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a preparation method of darunavir, which has the advantages of simple preparation, low cost and the like, and solves the problems of high price and difficult popularization of darunavir due to low preparation efficiency and high requirement on preparation environment in the preparation process of darunavir.
(II) technical scheme
In order to realize the purposes of simple preparation and low cost, the invention provides the following technical scheme: a preparation method of darunavir comprises the following raw materials: N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hydrogen carbonate, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal base, hydroxyl compound, alumina, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution.
A preparation method of darunavir comprises the following steps:
1) taking out N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hydrogen carbonate, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal alkali, hydroxyl compound, alumina, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution for later use, wherein the storage temperature is indoor temperature, and the interval is 20-25 ℃;
2) placing the ferric nitrite solution, the tetrahydrofuran solvent and the ethanol solution prepared in the step 1) into a reaction container, stirring, wherein the stirring rotation speed is 200-350 rpm, the stirring duration is 10-15 min, obtaining a mixed solvent A after stirring, and placing the mixed solvent A for later use;
3) taking out the mixed solvent A prepared in the step 2), placing the mixed solvent A into a reaction container, pouring N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalents of methyl hamine, cobalt, ferrous oxide, zinc, metal alkali, aluminum oxide, silicon dioxide and butyl lithium into the mixed solvent A, stirring, wherein the stirring rotation speed is 150-200 rpm, the stirring duration is 20-23 min, heating is carried out after stirring, the heating temperature is 40-45 ℃, the heating duration is 2-4 h, and obtaining a mixed solvent B after heating;
4) taking out the mixed solvent B prepared in the step 3), placing the mixed solvent B into a reaction container, taking out the halogenated aromatic ring, triethylamine and the hydroxyl compound, pouring the mixture into the mixed solvent B, stirring, wherein the stirring rotation speed is 150-200 rpm, the stirring duration is 20-23 min, heating is carried out after the stirring is finished, the heating temperature is 40-45 ℃, and the heating duration is 1-2 h, so as to obtain a mixed solvent C;
5) taking out the mixed solvent C prepared in the step 4), placing the mixed solvent C in a drying device for heating and drying, wherein the drying temperature of the drying device is 400 ℃, the duration of the drying treatment is 5 hours, obtaining a powder mixture A with the shape of mixed granular powder after the drying is finished, and placing the powder mixture A for later use;
6) sieving the powder mixture A prepared in the step 5) through a filtering device to remove impurities with larger particle sizes in the powder mixture A, wherein the filtering process lasts for three times, and obtaining a powder mixture B with a fine powder shape after filtering is finished, wherein the powder mixture B is the required darunavir.
Preferably, the content of each of the following raw materials in the step 1) is: the content of N-dibenzyl-L-phenylalanine methyl ester is 15-30 parts, the content of 1.2 equivalent weight of methyl hamine is 10-15 parts, the content of halogenated aromatic ring is 30-50 parts, the content of triethylamine is 10-20 parts, the content of cobalt is 18-25 parts, the content of ferrous oxide is 12-18 parts, the content of zinc oxide is 12-15 parts, the content of zinc is 15-18 parts, the content of ferric nitrite solution is 100-120 parts, the content of metal alkali is 25-28 parts, the content of hydroxyl compound is 60-70 parts, the content of aluminum oxide is 50-70 parts, the content of silicon dioxide is 5-10 parts, the content of butyl lithium is 90-100 parts, the content of tetrahydrofuran solvent is 80-100 parts, and the content of ethanol solution is 90-100 parts.
Preferably, the reaction vessels in step 2), step 3) and step 4) are all cylindrical vessels, and the vessels are equipped with a stirring structure and a heating structure.
Preferably, the filtering screen for sieving the powder mixture B in the step 6) is 1200 meshes, and the preservation temperature of the darunavir in the step 6) is 20 ℃ to 25 ℃.
(III) advantageous effects
Compared with the prior art, the invention provides a preparation method of darunavir, which has the following beneficial effects:
1. the preparation method of the darunavir comprises the steps of selecting N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hamine, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal alkali, hydroxyl compounds, aluminum oxide, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution, and preparing the darunavir according to the steps 1) to 4) to obtain fine powder.
2. According to the preparation method of darunavir, the filtering screen used for sieving the powder mixture B in the step 6) is used for high-precision sieving with 1200 meshes, so that impurities can be fully filtered, the preservation temperature of darunavir prepared in the step 6) can be normal temperature of 20-25 ℃, the situations that the preparation quality is poor and the medicine is difficult to preserve due to excessive impurities in the preparation process of darunavir can be effectively avoided, the reaction containers used in the steps 2), 3) and 4) are cylindrical containers provided with stirring structures and heating structures, the convenience of the preparation method for darunavir can be effectively enhanced, and the problems that the darunavir is high in price and difficult to popularize due to low preparation efficiency and high requirements on the preparation environment in the preparation process of darunavir are effectively solved.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of darunavir comprises the following raw materials: N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hydrogen carbonate, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal base, hydroxyl compound, alumina, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution.
A preparation method of darunavir comprises the following steps:
1) taking out N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hydrogen carbonate, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal alkali, hydroxyl compound, alumina, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution for later use, wherein the storage temperature is indoor temperature, the interval is 20-25 ℃, and the contents of the following raw materials in the step 1) are respectively: the content of N-dibenzyl-L-phenylalanine methyl ester is 15-30 parts, the content of 1.2 equivalent weight of methyl hamine is 10-15 parts, the content of halogenated aromatic ring is 30-50 parts, the content of triethylamine is 10-20 parts, the content of cobalt is 18-25 parts, the content of ferrous oxide is 12-18 parts, the content of zinc oxide is 12-15 parts, the content of zinc is 15-18 parts, the content of ferric nitrite solution is 100-120 parts, the content of metal alkali is 25-28 parts, the content of hydroxyl compound is 60-70 parts, the content of aluminum oxide is 50-70 parts, the content of silicon dioxide is 5-10 parts, the content of butyl lithium is 90-100 parts, the content of tetrahydrofuran solvent is 80-100 parts, and the content of ethanol solution is 90-100 parts;
2) placing the ferric nitrite solution, the tetrahydrofuran solvent and the ethanol solution prepared in the step 1) into a reaction container, stirring, wherein the stirring rotation speed is 200-350 rpm, the stirring duration is 10-15 min, obtaining a mixed solvent A after stirring, and placing the mixed solvent A for later use;
3) taking out the mixed solvent A prepared in the step 2), placing the mixed solvent A into a reaction container, pouring N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalents of methyl hamine, cobalt, ferrous oxide, zinc, metal alkali, aluminum oxide, silicon dioxide and butyl lithium into the mixed solvent A, stirring, wherein the stirring rotation speed is 150-200 rpm, the stirring duration is 20-23 min, heating is carried out after stirring, the heating temperature is 40-45 ℃, the heating duration is 2-4 h, and obtaining a mixed solvent B after heating;
4) taking out the mixed solvent B prepared in the step 3), placing the mixed solvent B into a reaction vessel, taking out the halogenated aromatic ring, triethylamine and a hydroxyl compound, pouring the mixture into the mixed solvent B, stirring, wherein the stirring rotation speed is 150-200 rpm, the stirring duration is 20-23 min, heating is carried out after the stirring is finished, the heating temperature is 40-45 ℃, the heating duration is 1-2 h, and then obtaining a mixed solvent C, wherein the reaction vessels in the step 2), the step 3) and the step 4) are cylindrical vessels which are provided with a stirring structure and a heating structure;
5) taking out the mixed solvent C prepared in the step 4), placing the mixed solvent C in a drying device for heating and drying, wherein the drying temperature of the drying device is 400 ℃, the duration of the drying treatment is 5 hours, obtaining a powder mixture A with the shape of mixed granular powder after the drying is finished, and placing the powder mixture A for later use;
6) sieving the powder mixture A prepared in the step 5) through a filtering device to remove impurities with larger particle sizes in the powder mixture A, wherein the filtering process lasts for three times, and obtaining a powder mixture B with a fine powder shape after filtering, wherein the powder mixture B is the required darunavir, a filtering screen for sieving the powder mixture B in the step 6) is 1200 meshes, and the preservation temperature of the darunavir in the step 6) is 20-25 ℃.
The invention has the beneficial effects that: the preparation method of the darunavir comprises the steps of selecting N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hamine, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal alkali, hydroxyl compound, aluminum oxide, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution, and preparing according to the steps 1) to 4) to obtain the darunavir in fine powder form, wherein the whole process of the preparation method is very simple and efficient, the effect of simple preparation is achieved, devices used for preparing the darunavir by using the preparation method are a reaction container, a drying device and a filter layer device, and the preparation process is carried out at normal temperature, so that the preparation method has low requirement on preparation environment and is convenient to popularize and use, and the preparation method of the darunavir, the filtering screen for sieving the powder mixture B in the step 6) is used for high-precision sieving of 1200 meshes, so that impurities can be fully filtered, the preservation temperature of the prepared darunavir in the step 6) is 20-25 ℃, the conditions that the preparation quality is poor and the medicine is difficult to preserve due to excessive impurities in the preparation of the darunavir can be effectively avoided, the reaction container used in the steps 2), 3) and 4) is a cylindrical container provided with a stirring structure and a heating structure, the convenience of the preparation method for the darunavir can be effectively enhanced, and the problems that the darunavir is high in price and difficult to popularize due to low preparation efficiency and high requirements on the preparation environment in the preparation process of the darunavir can be effectively solved.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. The preparation method of darunavir is characterized by comprising the following raw materials: N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hydrogen carbonate, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal base, hydroxyl compound, alumina, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution.
2. A preparation method of darunavir is characterized by comprising the following steps:
1) taking out N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalent of methyl hydrogen carbonate, halogenated aromatic rings, triethylamine, cobalt, ferrous oxide, zinc, ferric nitrite solution, metal alkali, hydroxyl compound, alumina, silicon dioxide, butyl lithium, tetrahydrofuran solvent and ethanol solution for later use, wherein the storage temperature is indoor temperature, and the interval is 20-25 ℃;
2) placing the ferric nitrite solution, the tetrahydrofuran solvent and the ethanol solution prepared in the step 1) into a reaction container, stirring, wherein the stirring rotation speed is 200-350 rpm, the stirring duration is 10-15 min, obtaining a mixed solvent A after stirring, and placing the mixed solvent A for later use;
3) taking out the mixed solvent A prepared in the step 2), placing the mixed solvent A into a reaction container, pouring N-dibenzyl-L-phenylalanine methyl ester, 1.2 equivalents of methyl hamine, cobalt, ferrous oxide, zinc, metal alkali, aluminum oxide, silicon dioxide and butyl lithium into the mixed solvent A, stirring, wherein the stirring rotation speed is 150-200 rpm, the stirring duration is 20-23 min, heating is carried out after stirring, the heating temperature is 40-45 ℃, the heating duration is 2-4 h, and obtaining a mixed solvent B after heating;
4) taking out the mixed solvent B prepared in the step 3), placing the mixed solvent B into a reaction container, taking out the halogenated aromatic ring, triethylamine and the hydroxyl compound, pouring the mixture into the mixed solvent B, stirring, wherein the stirring rotation speed is 150-200 rpm, the stirring duration is 20-23 min, heating is carried out after the stirring is finished, the heating temperature is 40-45 ℃, and the heating duration is 1-2 h, so as to obtain a mixed solvent C;
5) taking out the mixed solvent C prepared in the step 4), placing the mixed solvent C in a drying device for heating and drying, wherein the drying temperature of the drying device is 400 ℃, the duration of the drying treatment is 5 hours, obtaining a powder mixture A with the shape of mixed granular powder after the drying is finished, and placing the powder mixture A for later use;
6) sieving the powder mixture A prepared in the step 5) through a filtering device to remove impurities with larger particle sizes in the powder mixture A, wherein the filtering process lasts for three times, and obtaining a powder mixture B with a fine powder shape after filtering is finished, wherein the powder mixture B is the required darunavir.
3. The process for the preparation of darunavir according to claim 2, characterized by comprising: the content of each raw material in the step 1) is as follows: the content of N-dibenzyl-L-phenylalanine methyl ester is 15-30 parts, the content of 1.2 equivalent weight of methyl hamine is 10-15 parts, the content of halogenated aromatic ring is 30-50 parts, the content of triethylamine is 10-20 parts, the content of cobalt is 18-25 parts, the content of ferrous oxide is 12-18 parts, the content of zinc oxide is 12-15 parts, the content of zinc is 15-18 parts, the content of ferric nitrite solution is 100-120 parts, the content of metal alkali is 25-28 parts, the content of hydroxyl compound is 60-70 parts, the content of aluminum oxide is 50-70 parts, the content of silicon dioxide is 5-10 parts, the content of butyl lithium is 90-100 parts, the content of tetrahydrofuran solvent is 80-100 parts, and the content of ethanol solution is 90-100 parts.
4. The process for the preparation of darunavir according to claim 2, characterized by comprising: the reaction vessels in the step 2), the step 3) and the step 4) are all cylindrical vessels, and the vessels are provided with a stirring structure and a heating structure.
5. The process for the preparation of darunavir according to claim 2, characterized by comprising: the filtering screen for sieving the powder mixture B in the step 6) is 1200 meshes, and the preservation temperature of the darunavir in the step 6) is 20-25 ℃.
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| CN201911295964.2A CN111039951A (en) | 2019-12-16 | 2019-12-16 | Preparation method of darunavir |
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| CN201911295964.2A CN111039951A (en) | 2019-12-16 | 2019-12-16 | Preparation method of darunavir |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120251826A1 (en) * | 2009-09-17 | 2012-10-04 | Siva Rama Prasad Vellanki | Process for the preparation of darunavir |
| CN108822123A (en) * | 2018-09-06 | 2018-11-16 | 南通雅本化学有限公司 | A kind of preparation method of darunavir |
| CN110698492A (en) * | 2019-09-05 | 2020-01-17 | 雅本化学股份有限公司 | Preparation method of darunavir |
-
2019
- 2019-12-16 CN CN201911295964.2A patent/CN111039951A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120251826A1 (en) * | 2009-09-17 | 2012-10-04 | Siva Rama Prasad Vellanki | Process for the preparation of darunavir |
| CN108822123A (en) * | 2018-09-06 | 2018-11-16 | 南通雅本化学有限公司 | A kind of preparation method of darunavir |
| CN110698492A (en) * | 2019-09-05 | 2020-01-17 | 雅本化学股份有限公司 | Preparation method of darunavir |
Non-Patent Citations (2)
| Title |
|---|
| 刘鸿 等: "达芦那韦合成路线图解", 《中国药物化学杂志》, vol. 23, no. 1, pages 72 - 74 * |
| 庞永毅 等: "HIV蛋白酶抑制剂Darunavir的合成研究进展", 《山东化工》, vol. 46, no. 9, pages 38 - 43 * |
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Application publication date: 20200421 |