CN100465174C - Process for preparing optics pure abacavir - Google Patents
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- CN100465174C CN100465174C CNB2006100276498A CN200610027649A CN100465174C CN 100465174 C CN100465174 C CN 100465174C CN B2006100276498 A CNB2006100276498 A CN B2006100276498A CN 200610027649 A CN200610027649 A CN 200610027649A CN 100465174 C CN100465174 C CN 100465174C
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Abstract
A process for preparing the optical-purity (99.9% ee) Abakawei features that its initial raw materials are (1S,4R)-4-amino-2-cyclopentyl-1-methanol and 2,5-diamino- 4,6-dichloropyrimidine.
Description
Technical field
The present invention relates to a kind of preparation method of optics pure abacavir, and promptly (1S, 4R)-preparation method of 4-(2-amino-6-cyclopropyl amino-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol.
Background technology
Acquired immune deficiency syndrome (AIDS) (Acquired Immunodefkiency Syndrome is called for short AIDS) is the communicable disease that is caused by human immunodeficiency virus (Human ImmunodefIcierlcy Virus is called for short HIV).Approach such as trafficability characteristic contact, blood transfusion are propagated.At present, acquired immune deficiency syndrome (AIDS) (AIDS) worldwide is widely current, and has caused the great attention of countries in the world government and relevant international organization, becomes great public health and social concern highly visible.
From zidovudine (AZT)--first treatment HIV infections/AIDS medicine in 1987 by the drugs approved by FDA listing after, the researchdevelopment of anti-AIDS medicine is advanced by leaps and bounds, external at present existing tens medicines go on the market.Wherein Abacavir (Abacavir) is a kind of homocyclic nucleus glycoside hiv reverse transcriptase inhibitor, chemistry (1S by name, 4R)-4-(2-amino-6-cyclopropyl amino-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol, its English [(1S by name, 4R)-4-[2-amino-6-cyclopropylamino-9H-purin-yl]-2-cyclopentene-1-methanol], be called for short Abacavir, be in publicly traded a kind of new anti HIV-1 virus medicine on December 17th, 1998 by Glaxo Wellcome company, this medicine is called Ziagen in the registration of US and European, and has obtained passing through of U.S. FDA.Chemical structural formula is as follows,
Patent US 5034394 has reported 2-amino-4, and the reaction of 6-dichloro pyrimidine and 4-acetylaminohydroxyphenylarsonic acid (2-cyclopentenes-1-yl) methyl acetate obtains Abacavir through complicated technologies such as a series of diazonium, couplings again.
Patent US 5917042 has reported 2-amino-4, and 6-two chloro-, 5 formamido groups and 4-amino-2-cyclopentenyl-1-methyl alcohol reaction obtains Abacavir through a series of conversions again.
Aforesaid method all has complicated operation and produces shortcoming such as a large amount of three wastes, therefore, needs development gentle more, more the method for environmental protection.
Summary of the invention
The purpose of this invention is to provide a kind of optical purity (1S that might use as treatment HIV infection/AIDS medicine, 4R) the preparation method of Abacavir, promptly (1S, 4R)-preparation method of 4-(2-amino-6-cyclopropyl amino-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol.
The invention provides a kind of simple and cheap method and prepare optical purity enantiomorph (1S, 4R)-4-(2-amino-6-cyclopropyl amino-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol, with (1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol and 2,5-diamino-4, the 6-dichloro pyrimidine is a starting raw material, can access optical purity (1S, 4R) Abacavir of 99.9% ee value.Method of the present invention may further comprise the steps:
In the existence of organic solvent, (1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol and 2,5-diamino-4, the 6-dichloro pyrimidine add or do not add alkali in the presence of ,-20 ℃ to 120 ℃ reactions 1～24 hour; The reaction back adds or does not add alkali cancellation reaction; Purified (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino that obtains solid form]-2-cyclopentenyl-1-methyl alcohol;
Described (1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol, 2,5-diamino-4, the mol ratio of 6-dichloro pyrimidine and alkali is 0.1～4:0.1～4:0～8;
Or not in organic solvent, (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol and ortho-formiate, in the presence of moisture or water-free acid ,-20 ℃ to 60 ℃ reactions 1～24 hour; The reaction back adds or does not add alkali cancellation reaction; Purified obtain solid form (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol;
Described (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-mol ratio of 2-cyclopentenyl-1-methyl alcohol, ortho-formiate, acid and water is 0.1～2:0.1～20:0.1～2:0～2;
In the existence of organic solvent, (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol and cyclopropylamine ,-20 ℃ to 120 ℃ reactions 1～24 hour; The reaction back adds or does not add alkali cancellation reaction; Purified obtain solid form (1S, 4R)-Abacavir, ee value for example 99.9%;
Described (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-mol ratio of 2-cyclopentenyl-1-methyl alcohol and cyclopropylamine is 0.1～2:0.1～2;
The organic solvent that the present invention describes is methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF), dioxane, N, dinethylformamide, methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol, acetone or their mixture are preferably ethanol.
The alkali that the present invention describes is sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, ammoniacal liquor, triethylamine, pyridine or their mixture, is preferably triethylamine.
The ortho-formiate that the present invention describes is trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate or their mixture, is preferably triethyl orthoformate.
The method that the present invention describes is easy and simple to handle, can access the optics pure abacavir of 99.9% ee value, and can use ethanol as reaction solvent, has protected environment to greatest extent.
Embodiment
Below the embodiment by the embodiment form is described in further detail foregoing of the present invention again.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1 (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol synthetic
(1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol (113mg, 1mmol), 2,5-diamino-4, the 6-dichloro pyrimidine (358mg, 2mmol), 1mL triethylamine, 10mL methyl alcohol, reflux, the point plate tracks to reaction to be finished, steaming desolventizes, silicagel column separate the white plates solid (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol 109mg, productive rate is 43%.
Embodiment 2 (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol synthetic
(1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol (226mg, 2mmol), 2,5-diamino-4, and the 6-dichloro pyrimidine (179mg, 1mmol), 2mL triethylamine, 10mL N, dinethylformamide, reflux, some plate track to reaction and finish, and steaming desolventizes, silicagel column separate white plates solid (1S, 4R)-and 4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol 144mg, productive rate is 57%.
Embodiment 3 (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol synthetic
(1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol (113mg, 1mmol), 2,5-diamino-4, the 6-dichloro pyrimidine (179mg, 1mmol), 1mL triethylamine, 10mL methylene dichloride, reflux, the point plate tracks to reaction to be finished, steaming desolventizes, silicagel column separate the white plates solid (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol 71mg, productive rate is 28%.
Embodiment 4 (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol synthetic
(1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol (113mg, 1mmol), 2,5-diamino-4, the 6-dichloro pyrimidine (179mg, 1mmol), 1mL triethylamine, 10mL ethanol, reflux, the point plate tracks to reaction to be finished, steaming desolventizes, silicagel column separate the white plates solid (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol 198mg, productive rate 78%.
Embodiment 5 (1S, 4R)-synthetic (1S of 4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol (834mg, 3.26mmol), the 10mL triethyl orthoformate, 1.15mL the vitriol oil, room temperature reaction, some plate track to reaction to be finished, and steaming desolventizes, silicagel column separates, obtain white solid (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol 90mg, productive rate 9%.
Embodiment 6 (1S, 4R)-synthetic (1S of 4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol (834mg, 3.26mmol), the 15mL triethyl orthoformate, and tosic acid (1.72g, 10mmol), the 10mL ether, back flow reaction, some plate track to reaction and finish, and steaming desolventizes, silicagel column separates, obtain white solid (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol 30mg, productive rate 30%.
Embodiment 7 (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol synthetic
(1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol (834mg, 3.26mmol), the 17mL triethyl orthoformate, the 1.15mL concentrated hydrochloric acid is heated to 60 ℃ of reactions, the point plate tracks to reaction to be finished, steaming desolventizes, and silicagel column separates, and obtains white solid (1S, 4R)-and 4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol 900mg, productive rate 92%.[α]
D 25＝-107.5(c0.28MeOH)。
Embodiment 8 (1S, 4R)-Abacavir synthetic
(1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol (502mg, 1.66mmol), 0.9mL cyclopropylamine, methyl alcohol 20mL, room temperature reaction, the point plate tracks to reaction to be finished, and steaming desolventizes, and the silicagel column separation obtains (1S, 4R)-and Abacavir 220mg, productive rate 46%.
Embodiment 9 (1S, 4R)-Abacavir synthetic
(1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol (1g, 3.32mmol), 1.8mL cyclopropylamine, tetrahydrofuran (THF) 20mL, reflux, the point plate tracks to reaction to be finished, and steaming desolventizes, and the silicagel column separation obtains (1S, 4R)-and Abacavir 109mg, productive rate 23%.
Embodiment 10 (1S, 4R)-Abacavir synthetic
(1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol (502mg, 1.66mmol), 1.8mL cyclopropylamine, ethanol 20mL, reflux, the point plate tracks to reaction to be finished, and steaming desolventizes, and the silicagel column separation obtains (1S, 4R)-and Abacavir 450mg, productive rate 95%.[α]
D 25=-49.5 (c0.15MeOH), chirality HPLC analytical results are 99.9% ee.
Claims (7)
1. one kind prepares optical purity (1S 4R)-synthetic method of Abacavir, is characterized in that being with (1S, 4R)-and 4-amino-2-cyclopentenyl-1-methyl alcohol and 2,5-diamino-4,6-dichloro pyrimidine are starting raw material, obtain optical purity (1S, 4R)-Abacavir, this method comprises following three steps:
(1) in the existence of organic solvent, (1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol and 2,5-diamino-4, the 6-dichloro pyrimidine add or do not add alkali in the presence of ,-20 ℃ to 120 ℃ reactions 1～24 hour; The reaction back adds or does not add alkali cancellation reaction; Purified (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino that obtains solid form]-2-cyclopentenyl-1-methyl alcohol; Described (1S, 4R)-4-amino-2-cyclopentenyl-1-methyl alcohol, 2,5-diamino-4, the mol ratio of 6-dichloro pyrimidine and alkali is 0.1～4:0.1～4:0～8;
(2) not in organic solvent, (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol and orthoformic acid C
1～C
6Alkyl ester, in the presence of aqueous acid ,-20 ℃ to 60 ℃ the reaction 1～24 hour; The reaction back adds or does not add alkali cancellation reaction; Purified obtain solid form (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol; Described (1S, 4R)-4-[(2,5-diamino-6-chloro-4-pyrimidyl) amino]-2-cyclopentenyl-1-methyl alcohol, orthoformic acid C
1～C
6The mol ratio of alkyl ester, acid and water be 0.1～2:0.1～2:0.1～2:0～2;
(3) in the existence of organic solvent, (1S, 4R)-4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol and cyclopropylamine ,-20 ℃ to 120 ℃ reactions 1～24 hour; The reaction back adds or does not add alkali cancellation reaction; Purified obtaining (1S, 4R)-Abacavir; Described (1S, 4R)-mol ratio of 4-(2-amino-6-chloro-9-hydrogen-9-purine radicals)-2-cyclopentenyl-1-methyl alcohol and cyclopropylamine is 0.1～2:0.1～2.
2. the method for claim 1, it is characterized in that described organic solvent is methylene dichloride, chloroform, tetracol phenixin, hexane, benzene, toluene, chlorobenzene, oil of mirbane, dimethylbenzene, ether, tertbutyl ether, tetrahydrofuran (THF), dioxane, N, dinethylformamide, methyl alcohol, ethanol, propyl alcohol, the trimethyl carbinol, acetone or their mixture.
3. the method for claim 1 is characterized in that described alkali is sodium hydroxide, potassium hydroxide, sodium bicarbonate, yellow soda ash, ammoniacal liquor, triethylamine, pyridine or their mixture.
4. the method for claim 1 is characterized in that described orthoformic acid C
1～C
6Alkyl ester be trimethyl orthoformate, triethyl orthoformate, tripropyl orthoformate or their mixture.
5. the method for claim 1 is characterized in that the acid in the described aqueous acid is hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, formic acid, acetate, methylsulfonic acid, tosic acid or their mixture.
6. the method for claim 1, it is characterized in that described optical purity (1S, 4R)-the ee value of Abacavir is 99.9%.
7. the method for claim 1 is characterized in that described organic solvent is an ethanol.
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| CN102603652A (en) * | 2011-12-27 | 2012-07-25 | 河南师范大学 | 5-formacylpyrimidine carbocyclic nucleoside and preparation method thereof |
| CN104788451A (en) * | 2014-01-21 | 2015-07-22 | 浙江九洲药业股份有限公司 | Preparation method of abacavir |
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| US5034394A (en) * | 1988-06-27 | 1991-07-23 | Burroughs Wellcome Co. | Therapeutic nucleosides |
| CN1139924A (en) * | 1994-02-04 | 1997-01-08 | 惠尔康基金会集团公司 | Chloropyrimide intermediates |
| CN1281457A (en) * | 1997-10-14 | 2001-01-24 | 葛兰素集团有限公司 | process for synthesis of chloropurine intermediates |
| CN1740172A (en) * | 2005-09-15 | 2006-03-01 | 上海玛耀化学技术有限公司 | Abacavin preparing process |
| CN1763040A (en) * | 2005-09-15 | 2006-04-26 | 上海玛耀化学技术有限公司 | Abacavir production method |
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2006
- 2006-06-13 CN CNB2006100276498A patent/CN100465174C/en active Active
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| US5034394A (en) * | 1988-06-27 | 1991-07-23 | Burroughs Wellcome Co. | Therapeutic nucleosides |
| CN1139924A (en) * | 1994-02-04 | 1997-01-08 | 惠尔康基金会集团公司 | Chloropyrimide intermediates |
| US5917042A (en) * | 1994-02-04 | 1999-06-29 | Glaxo Wellcome Inc. | Process for the preparation of 2,5-diamino-4,6-dichloropyrimidine |
| CN1281457A (en) * | 1997-10-14 | 2001-01-24 | 葛兰素集团有限公司 | process for synthesis of chloropurine intermediates |
| CN1740172A (en) * | 2005-09-15 | 2006-03-01 | 上海玛耀化学技术有限公司 | Abacavin preparing process |
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