CN110698492A - Preparation method of darunavir - Google Patents
Preparation method of darunavir Download PDFInfo
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- CN110698492A CN110698492A CN201910839142.XA CN201910839142A CN110698492A CN 110698492 A CN110698492 A CN 110698492A CN 201910839142 A CN201910839142 A CN 201910839142A CN 110698492 A CN110698492 A CN 110698492A
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- 229960005107 darunavir Drugs 0.000 title claims abstract description 37
- 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 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 48
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 32
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims abstract description 28
- 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 22
- 229910052751 metal Inorganic materials 0.000 claims abstract description 20
- 239000002184 metal Substances 0.000 claims abstract description 20
- 229910017052 cobalt Inorganic materials 0.000 claims abstract description 16
- 239000010941 cobalt Substances 0.000 claims abstract description 16
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 16
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 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
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 239000012716 precipitator Substances 0.000 claims abstract description 14
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 14
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 14
- 239000011787 zinc oxide Substances 0.000 claims abstract description 14
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims abstract description 11
- -1 p-acetamidobenzoyl sulfonyl chloride Chemical compound 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 46
- 239000011259 mixed solution Substances 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 239000011159 matrix material Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 18
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KRKXGCJUNKZXOY-UHFFFAOYSA-N 4-acetamidobenzoyl chloride Chemical compound CC(=O)NC1=CC=C(C(Cl)=O)C=C1 KRKXGCJUNKZXOY-UHFFFAOYSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- VPBPOXIFRZBJEU-UHFFFAOYSA-L iron(2+);dinitrite Chemical compound [Fe+2].[O-]N=O.[O-]N=O VPBPOXIFRZBJEU-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 10
- 235000017550 sodium carbonate Nutrition 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000007603 infrared drying Methods 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000005859 coupling reaction Methods 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 5
- 239000011736 potassium bicarbonate Substances 0.000 claims description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical compound COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 abstract 1
- 238000001816 cooling Methods 0.000 description 7
- 230000008901 benefit Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 230000009286 beneficial effect Effects 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
- 241000700605 Viruses Species 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
- 230000000694 effects Effects 0.000 description 1
- 239000004030 hiv protease inhibitor Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000003612 virological effect Effects 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention relates to the technical field of medicines and discloses a preparation method of darunavir, which comprises the following steps of taking 20-30 parts of cobalt, 10-20 parts of triethylamine, 10-20 parts of ferrous oxide, 10-20 parts of zinc oxide, 3-5 parts of 1.2 equivalent weight of methyl hamine, 20-30 parts of zinc, 50-80 parts of ferric nitrite solution, 30-40 parts of metal alkali, 40-50 parts of aluminum oxide, 10-20 parts of silicon dioxide, 3-5 parts of p-acetamidobenzene sulfonyl chloride, 3-5 parts of precipitator, 50-80 parts of ethanol solution and 20-30 parts of nickel for later use. The preparation method of darunavir comprises the steps of taking 20-30 parts of cobalt, 10-20 parts of triethylamine, 10-20 parts of ferrous oxide, 10-20 parts of zinc oxide, 3-5 parts of 1.2 equivalent weight of methyl hamine, 10-20 parts of silicon dioxide, 3-5 parts of p-acetamidobenzoyl sulfonyl chloride, 3-5 parts of a precipitator, 50-80 parts of an ethanol solution and 20-30 parts of nickel for later use.
Description
Technical Field
The invention relates to the technical field of medicine production, in particular to a preparation method of darunavir.
Background
Darunavir is a non-peptide HIV protease inhibitor, which acts by inhibiting viral protease by blocking the formation process of releasing new and mature virus particles from the surface of infected host cells, and when the darunavir is used for a long time, it can generally reduce HIV viral vectors in blood, increase the count of CD4 cells, reduce the chance of AIDS infection, improve quality of life, and prolong life, and is suitable for adults infected with AIDS virus but who have no therapeutic effect when taking the existing antiretroviral drugs.
The preparation line of darunavir is disclosed for a long time, but in the disclosed line method, the preparation efficiency of darunavir is low, the preparation cost is high, and the requirement on the preparation environment is high, so that the finally prepared darunavir is high in price, patients cannot bear the high price, and the popularization of darunavir is hindered, thereby providing the preparation method of darunavir.
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 low preparation cost and the like, and solves the problems that the preparation line of darunavir is disclosed, but in the disclosed line method, the preparation efficiency of darunavir is low, the preparation cost is high, the requirement on the preparation environment is high, the finally prepared darunavir is high in price, and patients cannot bear the high price.
(II) technical scheme
In order to realize the aim of low preparation cost, the invention provides the following technical scheme: a preparation method of darunavir comprises the following steps:
1) taking 20-30 parts of cobalt, 10-20 parts of triethylamine, 10-20 parts of ferrous oxide, 10-20 parts of zinc oxide, 3-5 parts of 1.2 equivalent weight of methyl hamine, 20-30 parts of zinc, 50-80 parts of ferric nitrite solution, 30-40 parts of metal alkali, 40-50 parts of alumina, 10-20 parts of silicon dioxide, 3-5 parts of p-acetamidobenzoyl chloride, 3-5 parts of precipitator, 50-80 parts of ethanol solution and 20-30 parts of nickel for later use;
2) placing 50-80 parts of an iron nitrite solution in a reaction container, adding 20-30 parts of nickel, 20-30 parts of cobalt and 20-30 parts of zinc into 50-80 parts of the iron nitrite solution, adjusting the reaction temperature to be fifty ℃, stirring for 1-2 hours by using stirring equipment, and setting the stirring frequency to be one hundred twenty revolutions per minute to prepare a mixed solution 1;
3) adding 40-50 parts of aluminum oxide and 10-20 parts of silicon dioxide into the mixed solution 1 prepared in the step 2, uniformly mixing, adding 3-5 parts of precipitator, adding 10-20 parts of ferrous oxide and 10-20 parts of zinc oxide after precipitation is generated, keeping the reaction temperature at thirty ℃, and standing for 3-5 hours to obtain a mixed solution 2;
4) putting the mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 12 hours at 450 ℃ for 3 hours in a hydrogen state, and finally heating the mixed solution to 600 ℃ to obtain a matrix 1;
5) 10-20 parts of triethylamine, 3-5 parts of 1.2 equivalent weight of methyl hydrogen carbonate, 30-40 parts of metal alkali and 3-5 parts of p-acetamido-benzoyl-sulfonyl chloride are placed in a container, stirred uniformly and heated to 200 ℃, cooled to 50 ℃, added with 50-80 parts of ethanol solution, heated to 100 ℃ in a sealed environment, stopped heating after reacting for 3 hours, and cooled to room temperature to obtain a substrate 2;
6) and (3) uniformly mixing the matrix 1 prepared in the step (4) and the matrix 2 prepared in the step (2), adding a catalyst, performing coupling reaction for 0.5 hour, stopping the reaction, and filtering large-particle impurities to obtain fine powder, namely the required darunavir.
Preferably, the purity of the ferric nitrite in 50-80 parts of the ferric nitrite solution is ninety-eight percent, and the purity of the ethanol in 50-80 parts of the ethanol solution is ninety-five percent.
Preferably, the metal base is one or a mixture of two of lithium hydroxide, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
(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 darunavir comprises the steps of taking 20-30 parts of cobalt, 10-20 parts of triethylamine, 10-20 parts of ferrous oxide, 10-20 parts of zinc oxide, 3-5 parts of 1.2 equivalent weight of methyl hamine, 20-30 parts of zinc, 50-80 parts of ferric nitrite solution, 30-40 parts of metal alkali, 40-50 parts of aluminum oxide, 10-20 parts of silicon dioxide, 3-5 parts of p-acetamidobenzoyl chloride, 3-5 parts of precipitator, 50-80 parts of ethanol solution and 20-30 parts of nickel for later use, taking 50-80 parts of ferric nitrite solution, placing 20-30 parts of nickel, 20-30 parts of cobalt and 20-30 parts of zinc into 50-80 parts of ferric nitrite solution, adjusting the reaction temperature to fifty ℃ and stirring for 1-2 hours by using a stirring device, the stirring frequency is set to be one hundred twenty revolutions per minute, the mixed solution 1 is prepared, the price of the reaction materials used in the method is low, the requirement on the reaction environment is low, correspondingly, the preparation cost of the darunavir is greatly reduced, the darunavir can be used by patients, and the darunavir can really benefit the patients.
2. The preparation method of darunavir comprises the steps of putting a mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 3 hours at 450 ℃ in a hydrogen state after drying for 12 hours, heating the dried mixed solution to 600 ℃ to obtain a matrix 1, placing 10-20 parts of triethylamine, 3-5 parts of 1.2 equivalent of methyl hamine, 30-40 parts of metal alkali and 3-5 parts of p-acetamidobenzoyl chloride in a container, heating the mixture to 200 ℃ after stirring uniformly, adding 50-80 parts of ethanol solution after cooling to 50 ℃, heating the mixture to 100 ℃ in a sealed environment, stopping heating after reacting for 3 hours, cooling to room temperature to obtain a matrix 2, mixing the matrix 1 prepared in the step 4 and the matrix 2 prepared in the step 2 uniformly, adding a catalyst, stopping the reaction after coupling reaction for 0.5 hour, the method has the advantages of industrial production means and steps which are mature in embodying, extremely low requirement on equipment, greatly reduced threshold for entrance of preparation and convenient popularization.
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.
The first embodiment is as follows: a preparation method of darunavir comprises the following steps:
1) taking 20 parts of cobalt, 10 parts of triethylamine, 10 parts of ferrous oxide, 10 parts of zinc oxide, 3 parts of 1.2 equivalent weight of methyl hamine hydride, 20 parts of zinc, 50 parts of ferric nitrite solution, 30 parts of metal alkali, 40 parts of aluminum oxide, 10 parts of silicon dioxide, 3 parts of p-acetamidobenzoyl chloride, 3 parts of precipitator, 50 parts of ethanol solution and 20 parts of nickel for later use;
2) placing 50 parts of an iron nitrite solution in a reaction container, adding 20 parts of nickel, 20 parts of cobalt and 20 parts of zinc into the iron nitrite solution 50, adjusting the reaction temperature to be fifty ℃, stirring for 1-2 hours by using stirring equipment, and setting the stirring frequency to be one hundred twenty revolutions per minute to prepare a mixed solution 1;
3) adding 40 parts of aluminum oxide and 10 parts of silicon dioxide into the mixed solution 1 prepared in the step 2, uniformly mixing, adding 3 parts of precipitator, adding 10 parts of ferrous oxide and 10 parts of zinc oxide after precipitation is generated, keeping the reaction temperature at thirty ℃, and standing for 3 hours to obtain a mixed solution 2;
4) putting the mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 12 hours at 450 ℃ for 3 hours in a hydrogen state, and finally heating the mixed solution to 600 ℃ to obtain a matrix 1;
5) 10 parts of triethylamine, 3 parts of 1.2 equivalent weight of methyl bihydrogen, 30 parts of metal alkali and 3 parts of p-acetamidobenzoyl chloride are placed in a container, the mixture is heated to 200 ℃ after being uniformly stirred, 50 parts of ethanol solution is added after the mixture is cooled to 50 ℃, the mixture is heated to 100 ℃ in a sealed environment, the heating is stopped after the reaction is carried out for 3 hours, and the substrate 2 is obtained after the mixture is cooled to room temperature;
6) and (3) uniformly mixing the matrix 1 prepared in the step (4) and the matrix 2 prepared in the step (2), adding a catalyst, performing coupling reaction for 0.5 hour, stopping the reaction, and filtering large-particle impurities to obtain fine powder, namely the required darunavir.
The purity of ferric nitrite in 50 parts of ferric nitrite solution was ninety-eight percent, and the purity of ethanol in 50 parts of ethanol solution was ninety-five percent.
The metal base is one or two of lithium hydroxide, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
And 4, putting the mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 3 hours at the high temperature of 450 ℃ in a hydrogen state after the drying time is 12 hours, and finally heating the mixed solution to 600 ℃ to obtain a matrix 1, wherein the drying temperature is eighty ℃ and the oxidation of the material at the high temperature is avoided.
Example two: a preparation method of darunavir comprises the following steps:
1) taking 25 parts of cobalt, 15 parts of triethylamine, 15 parts of ferrous oxide, 15 parts of zinc oxide, 4 parts of 1.2 equivalent weight of methyl hamine, 25 parts of zinc, 65 parts of ferric nitrite solution, 35 parts of metal alkali, 45 parts of aluminum oxide, 15 parts of silicon dioxide, 4 parts of p-acetamidobenzoyl chloride, 4 parts of precipitator, 65 parts of ethanol solution and 25 parts of nickel for later use;
2) putting 65 parts of an iron nitrite solution into a reaction container, putting 25 parts of nickel, 25 parts of cobalt and 25 parts of zinc into the iron nitrite solution 65, adjusting the reaction temperature to be fifty ℃, stirring for 1-2 hours by using stirring equipment, and setting the stirring frequency to be one hundred twenty revolutions per minute to prepare a mixed solution 1;
3) adding 45 parts of aluminum oxide and 15 parts of silicon dioxide into the mixed solution 1 prepared in the step 2, uniformly mixing, adding 4 parts of precipitator, adding 15 parts of ferrous oxide and 15 parts of zinc oxide after precipitation is generated, keeping the reaction temperature at thirty ℃, and standing for 4 hours to obtain a mixed solution 2;
4) putting the mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 12 hours at 450 ℃ for 3 hours in a hydrogen state, and finally heating the mixed solution to 600 ℃ to obtain a matrix 1;
5) placing 15 parts of triethylamine, 4 parts of 1.2 equivalent weight of methyl bihydrogen, 35 parts of metal alkali and 4 parts of p-acetamidobenzoyl chloride in a container, uniformly stirring, heating to 200 ℃, cooling to 50 ℃, adding 65 parts of ethanol solution, heating to 100 ℃ in a sealed environment, reacting for 3 hours, stopping heating, and cooling to room temperature to obtain a substrate 2;
6) and (3) uniformly mixing the matrix 1 prepared in the step (4) and the matrix 2 prepared in the step (2), adding a catalyst, performing coupling reaction for 0.5 hour, stopping the reaction, and filtering large-particle impurities to obtain fine powder, namely the required darunavir.
The purity of ferric nitrite in 65 parts of ferric nitrite solution is ninety-eight percent, and the purity of ethanol in 65 parts of ethanol solution is ninety-five percent.
The metal base is one or two of lithium hydroxide, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
Example three: a preparation method of darunavir comprises the following steps:
1) taking 30 parts of cobalt, 20 parts of triethylamine, 20 parts of ferrous oxide, 20 parts of zinc oxide, 5 parts of 1.2 equivalent weight of methyl hamine, 30 parts of zinc, 80 parts of ferric nitrite solution, 40 parts of metal alkali, 50 parts of aluminum oxide, 20 parts of silicon dioxide, 5 parts of p-acetamidobenzoyl chloride, 5 parts of precipitator, 80 parts of ethanol solution and 30 parts of nickel for later use;
2) placing 80 parts of an iron nitrite solution in a reaction container, adding 30 parts of nickel, 30 parts of cobalt and 30 parts of zinc into the iron nitrite solution 80, adjusting the reaction temperature to be fifty ℃, stirring for 1-2 hours by using stirring equipment, and setting the stirring frequency to be one hundred twenty revolutions per minute to prepare a mixed solution 1;
3) adding 50 parts of aluminum oxide and 20 parts of silicon dioxide into the mixed solution 1 prepared in the step 2, uniformly mixing, adding 5 parts of precipitator, adding 20 parts of ferrous oxide and 20 parts of zinc oxide after precipitation is generated, keeping the reaction temperature at thirty ℃, and standing for 5 hours to obtain a mixed solution 2;
4) putting the mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 12 hours at 450 ℃ for 3 hours in a hydrogen state, and finally heating the mixed solution to 600 ℃ to obtain a matrix 1;
5) placing 20 parts of triethylamine, 5 parts of 1.2 equivalent weight of methyl bihydrogen, 40 parts of metal base and 5 parts of p-acetamidobenzoyl chloride in a container, uniformly stirring, heating to 200 ℃, cooling to 50 ℃, adding 80 parts of ethanol solution, heating to 100 ℃ in a sealed environment, reacting for 3 hours, stopping heating, and cooling to room temperature to obtain a substrate 2;
6) and (3) uniformly mixing the matrix 1 prepared in the step (4) and the matrix 2 prepared in the step (2), adding a catalyst, performing coupling reaction for 0.5 hour, stopping the reaction, and filtering large-particle impurities to obtain fine powder, namely the required darunavir.
The purity of ferric nitrite in 80 parts of ferric nitrite solution is ninety-eight percent, and the purity of ethanol in 80 parts of ethanol solution is ninety-five percent.
The metal base is one or two of lithium hydroxide, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
The invention has the beneficial effects that: the preparation method of darunavir comprises the steps of taking 20-30 parts of cobalt, 10-20 parts of triethylamine, 10-20 parts of ferrous oxide, 10-20 parts of zinc oxide, 3-5 parts of 1.2 equivalent weight of methyl hamine, 20-30 parts of zinc, 50-80 parts of ferric nitrite solution, 30-40 parts of metal alkali, 40-50 parts of aluminum oxide, 10-20 parts of silicon dioxide, 3-5 parts of p-acetamidobenzoyl chloride, 3-5 parts of precipitator, 50-80 parts of ethanol solution and 20-30 parts of nickel for later use, taking 50-80 parts of ferric nitrite solution, placing 20-30 parts of nickel, 20-30 parts of cobalt and 20-30 parts of zinc into 50-80 parts of ferric nitrite solution, adjusting the reaction temperature to fifty ℃ and stirring for 1-2 hours by using a stirring device, setting the stirring frequency to be one hundred twenty revolutions per minute to prepare a mixed solution 1, wherein the price of reaction materials used in the method is low, the requirement on the reaction environment is low, correspondingly, the preparation cost of the darunavir is greatly reduced, patients can use the darunavir, the darunavir can really reach patients, the mixed solution 2 is dried in an infrared drying oven, the drying temperature is eighty ℃, the mixed solution is reduced for 3 hours at 450 ℃ in a hydrogen state after being dried for 12 hours, finally the mixed solution is heated to 600 ℃ to obtain a matrix 1, 10-20 parts of triethylamine, 3-5 parts of 1.2 equivalent weight of methyl hamine, 30-40 parts of metal alkali and 3-5 parts of p-acetamidobenzoyl chloride are placed in a container, the mixed solution is uniformly stirred and heated to 200 ℃, the mixed solution is cooled to 50 ℃ and then added with 50-80 parts of ethanol solution, the mixed solution is heated to 100 ℃ in a sealed environment, stopping heating after reacting for 3 hours, cooling to room temperature to obtain a matrix 2, uniformly mixing the matrix 1 prepared in the step 4 and the matrix 2 prepared in the step 2, adding a catalyst, stopping the reaction after coupling reaction for 0.5 hour, and filtering large-particle impurities to obtain fine powder, namely the required darunavir.
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 (3)
1. A preparation method of darunavir is characterized by comprising the following steps:
1) taking 20-30 parts of cobalt, 10-20 parts of triethylamine, 10-20 parts of ferrous oxide, 10-20 parts of zinc oxide, 3-5 parts of 1.2 equivalent weight of methyl hamine, 20-30 parts of zinc, 50-80 parts of ferric nitrite solution, 30-40 parts of metal alkali, 40-50 parts of alumina, 10-20 parts of silicon dioxide, 3-5 parts of p-acetamidobenzoyl chloride, 3-5 parts of precipitator, 50-80 parts of ethanol solution and 20-30 parts of nickel for later use;
2) placing 50-80 parts of an iron nitrite solution in a reaction container, adding 20-30 parts of nickel, 20-30 parts of cobalt and 20-30 parts of zinc into 50-80 parts of the iron nitrite solution, adjusting the reaction temperature to be fifty ℃, stirring for 1-2 hours by using stirring equipment, and setting the stirring frequency to be one hundred twenty revolutions per minute to prepare a mixed solution 1;
3) adding 40-50 parts of aluminum oxide and 10-20 parts of silicon dioxide into the mixed solution 1 prepared in the step 2, uniformly mixing, adding 3-5 parts of precipitator, adding 10-20 parts of ferrous oxide and 10-20 parts of zinc oxide after precipitation is generated, keeping the reaction temperature at thirty ℃, and standing for 3-5 hours to obtain a mixed solution 2;
4) putting the mixed solution 2 into an infrared drying oven for drying, setting the drying temperature to eighty ℃, reducing the mixed solution for 12 hours at 450 ℃ for 3 hours in a hydrogen state, and finally heating the mixed solution to 600 ℃ to obtain a matrix 1;
5) 10-20 parts of triethylamine, 3-5 parts of 1.2 equivalent weight of methyl hydrogen carbonate, 30-40 parts of metal alkali and 3-5 parts of p-acetamido-benzoyl-sulfonyl chloride are placed in a container, stirred uniformly and heated to 200 ℃, cooled to 50 ℃, added with 50-80 parts of ethanol solution, heated to 100 ℃ in a sealed environment, stopped heating after reacting for 3 hours, and cooled to room temperature to obtain a substrate 2;
6) and (3) uniformly mixing the matrix 1 prepared in the step (4) and the matrix 2 prepared in the step (2), adding a catalyst, performing coupling reaction for 0.5 hour, stopping the reaction, and filtering large-particle impurities to obtain fine powder, namely the required darunavir.
2. The process of claim 1, wherein the purity of ferric nitrite in 50-80 parts of ferric nitrite solution is ninety-eight percent, and the purity of ethanol in 50-80 parts of ethanol solution is ninety-five percent.
3. The process of claim 1, wherein the metal base is one or a mixture of two of lithium hydroxide, sodium bicarbonate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium bicarbonate, sodium carbonate and potassium carbonate.
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| CN111039951A (en) * | 2019-12-16 | 2020-04-21 | 上海雅本化学有限公司 | Preparation method of darunavir |
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