CN104788451A - Preparation method of abacavir - Google Patents
Preparation method of abacavir Download PDFInfo
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- CN104788451A CN104788451A CN201410027146.5A CN201410027146A CN104788451A CN 104788451 A CN104788451 A CN 104788451A CN 201410027146 A CN201410027146 A CN 201410027146A CN 104788451 A CN104788451 A CN 104788451A
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- Prior art keywords
- abacavir
- preparation
- acid
- base
- purine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
Abstract
The invention relates to a preparation method of abacavir. According to the preparation method, (1S,4R)-4-(2-amino-6-chloro-9H-purine-9-yl)cyclopentene-2-ene-1-yl methanol or a hydrochloride of (1S,4R)-4-(2-amino-6-chloro-9H-purine-9-yl)cyclopentene-2-ene-1-yl methanol is reacted with cyclopropylamine, and then an obtained product and an alcohols solvent of acid are subjected to salt forming reaction so as to obtain abacavir. Abacavir free alkali with high purity and properties can be obtained via simple dissociation. The preparation method is suitable for industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to a kind of preparation method of Abacavir.
Background technology
Abacavir, chemical name is (1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purine-9-base]-2-cyclopentenyl-1-methyl alcohol.Structural formula is as follows:
It belongs to efabirenz anti-hiv drug, for the competitive inhibitor of HIV-1RT substrate, suppress RT active, obstruction proviral DNA synthesizes, and due to structurally 3 ' lack hydroxyl, when they are attached to 3 ' end of proviral DNA chain, the combination of 5 ' to 3 ' phosphodiester bond can not be carried out again, terminate the prolongation of viral DNA chain.By above-mentioned mechanism of action, suppress HIV to copy, and with HIV-1RT avidity more than strong with normal DNA polysaccharase avidity in cell, therefore there is certain therapeutic index.
Patent application WO9939691 and patent application EP1857458 has reported the chloro-9H-purine of (1S, 4R)-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate and cyclopropylamine react and prepare abacavir free base.
Patent application EP0434450 has reported the chloro-9H-purine of (1S, 4R)-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methyl alcohol and cyclopropylamine react and prepare abacavir free base.
Patent application WO9852949 has reported the chloro-9H-purine of (1S, 4R)-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate and cyclopropylamine react after and benzoic acid prepare Abacavir benzoate.
EP2305680 has reported the chloro-9H-purine of (1S, 4R)-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate and cyclopropylamine react and prepare abacavir free base.Reported abacavir free base and propanedioic acid to react and prepare Abacavir malonate simultaneously.
The method general character of above-mentioned patent report all utilizes (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methyl alcohol (hydrochloride) and cyclopropylamine react, because reaction mechanism is all identical, all there is the problem that impurity is difficult to remove when preparing Abacavir.As the impurity of following structural formula can be generated in reaction process:
According to above-mentioned existing report technique, this impurity does not remove.
Consider Abacavir good medicinal application prospect in treatment acquired immune deficiency syndrome (AIDS), be necessary to develop impurity is few, purity is high Abacavir preparation technology for suitability for industrialized production.
Summary of the invention
The invention provides a kind of preparation method of Abacavir, the method can remove the impurity being difficult in existing method remove, and prepares the Abacavir that purity is high, combustion is good.
Technical scheme provided by the invention is: with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methyl alcohol or its hydrochloride be raw material, further with the alcoholic solvent generation salt-forming reaction of acid prepares Abacavir salt after reacting with cyclopropylamine.After can prepare abacavir free base through alkali is free.
Described reaction formula is as follows:
Described X can be 1 or 2.
Described acid can be mineral acid or organic acid.
Described mineral acid is hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid or oxalic acid etc.
Described organic acid is phenylformic acid or propanedioic acid etc.
The preferred hydrochloric acid of described mineral acid.
Described alcoholic solvent is the alkanol of C1-C8.
Further, described alkanol is preferably methyl alcohol, ethanol, n-propyl alcohol and Virahol.
Described alkali is preferably alkali metal base or carbonate;
Described alkali metal base is preferably sodium hydroxide, potassium hydroxide or lithium hydroxide;
Described carbonate is preferably sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus.
One embodiment of the present invention is: with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methyl alcohol or its hydrochloride be raw material, after reacting with cyclopropylamine further with the alcoholic solvent generation salt-forming reaction of halogen acid, dissociate through alkali after preparing Abacavir X halogen hydrochlorate and obtain Abacavir
Described X is 1 or 2.
The preferred a kind of embodiment of the present invention is: with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate is raw material, after reacting with cyclopropylamine further with the alcoholic solvent generation salt-forming reaction of hydrochloric acid, dissociate through alkali after preparing Abacavir dihydrochloride and obtain Abacavir
The preferred a kind of embodiment of the present invention is: with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate is raw material, further with alcohol hydrochloric acid generation salt-forming reaction prepares Abacavir dihydrochloride after reacting with cyclopropylamine.After can prepare abacavir free base through the free of alkali,
The preparation method of Abacavir provided by the invention, react time further with sour salify, through simple aftertreatment, the impurity removing following structural formula can be separated easily:
The Abacavir salt that purity is high can be obtained like this, after can obtain the high Abacavir of purity through simply free.
Embodiment
In order to understand the present invention further, below in conjunction with embodiment, the preparation method to a kind of Abacavir provided by the invention is described in detail.It is to be appreciated that these embodiments describe just for further describing feature of the present invention, instead of the restriction to the scope of the invention or the claims in the present invention scope.
Embodiment 1: the preparation of Abacavir dihydrochloride
By (1S, 4R) ?4 ?(2 ?ammonia base ?6 ?chlorine ?9H ?fast purine ?9 ?yl) ring penta ?2 ?alkene ?1 ?base methylate hydrochlorate (30g, 0.1mol) with cyclopropylamine (22.6g, 0.4mol) drop in 180g ethanol, after reflux to reaction terminates, drop into sodium carbonate (11g, 0.1mol), after boiling off partial solvent, filtered while hot, filtrate is concentrated into dry, drop into 200g fresh ethanol be heated to molten clear after, be cooled to 40 ~ 45 DEG C, dripping content is 35.5% acidic alcohol (20.5g, 0.2mol), drip after finishing and be warming up to 50 ~ 55 DEG C, be incubated 0.5 ?after 1 hour, be down to room temperature, filter, obtain Abacavir dihydrochloride 32.6g, yield is 91.4%.
Embodiment 2: the preparation of Abacavir dihydrobromide
By (1S, 4R) ?4 ?(2 ?ammonia base ?6 ?chlorine ?9H ?fast purine ?9 ?yl) ring penta ?2 ?alkene ?1 ?base methylate hydrochlorate (30g, 0.1mol) with cyclopropylamine (22.6g, 0.4mol) drop in 180g Virahol, after reflux to reaction terminates, drop into sodium carbonate (11g, 0.1mol), after boiling off partial solvent, filtered while hot, filtrate is concentrated into dry, drop into 200g fresh isopropanol be heated to molten clear after, be cooled to 40 ~ 45 DEG C, dripping content is 25% Hydrogen bromide Virahol (64.8g, 0.2mol), drip after finishing and be warming up to 50 ~ 55 DEG C, be incubated 0.5 ?after 1 hour, be down to room temperature, filter, obtain Abacavir dihydrobromide 40.1g, yield is 90.1%.
Embodiment 3: the preparation of Abacavir dibenzoate
By (1S, 4R) ?4 ?(2 ?ammonia base ?6 ?chlorine ?9H ?fast purine ?9 ?yl) ring penta ?2 ?alkene ?1 ?base methylate hydrochlorate (30g, 0.1mmol) with cyclopropylamine (22.6g, 0.4mol) drop in 180g Virahol, after reflux to reaction terminates, drop into sodium carbonate (11g, 0.1mol), after boiling off partial solvent, filtered while hot, filtrate is concentrated into dry, drop into 400g fresh isopropanol be heated to molten clear after, be cooled to 40 ~ 45 DEG C, add phenylformic acid (24.4g, 0.2mol), drip after finishing and be warming up to 50 ~ 55 DEG C, be incubated 0.5 ?after 1 hour, be down to room temperature, filter, obtain Abacavir dibenzoate 48.76g, yield is 92.6%.
Embodiment 4: the preparation of Abacavir oxalate
By (1S, 4R) ?4 ?(2 ?ammonia base ?6 ?chlorine ?9H ?fast purine ?9 ?yl) ring penta ?2 ?alkene ?1 ?base methylate hydrochlorate (30g, 0.1mol) with cyclopropylamine (22.6g, 0.4mol) drop in 180g Virahol, after reflux to reaction terminates, drop into sodium carbonate (11g, 0.1mol), after boiling off partial solvent, filtered while hot, filtrate is concentrated into dry, drop into 400g fresh isopropanol be heated to molten clear after, be cooled to 40 ~ 45 DEG C, add oxalic acid (14.2g, 0.1mol), drip after finishing and be warming up to 50 ~ 55 DEG C, be incubated 0.5 ?after 1 hour, be down to room temperature, filter, obtain Abacavir oxalate 33.46g, yield is 89.0%.
Embodiment 5: the preparation of Abacavir
Abacavir dihydrochloride (the 30g that embodiment 1 is prepared, 0.084mol), gac 1g and sodium carbonate (26.6g, 0.251mol) drop in Virahol 180g, be heated to 80 ?85 DEG C, be incubated and start air distillation, steam a certain amount of after, filtered while hot, after filtrate is concentrated into and does, drop into Virahol 180g crystallization and obtain Abacavir 21.5g, yield is 89.9%.
Embodiment 6: the preparation of Abacavir
The Abacavir dihydrobromide (35g, 0.078mol) embodiment 2 prepared and sodium carbonate (24.8g, 0.23mol) drop in Virahol 210g, be heated to 40 ?45 DEG C, be incubated 0.5 ?after 1 hour, drop into gac 1g, be warming up to 80 ?85 DEG C, be incubated while start air distillation, steam a certain amount of after, filtered while hot, filtrate be concentrated into dry after, drop into Virahol 45g crystallization and obtain Abacavir 20g, yield is 89.4%.
Embodiment 7: the preparation of Abacavir
The Abacavir dibenzoate (30g, 0.057mol) embodiment 3 prepared and sodium bicarbonate (16.8g, 0.2mol) drop in Virahol 210g, be heated to 40-45 DEG C, be incubated after 0.5-1 hour, drop into gac 1g, be warming up to 80-85 DEG C, be incubated while start air distillation, steam a certain amount of after, filtered while hot, filtrate be concentrated into dry after, drop into Virahol 45g crystallization and obtain Abacavir 14.4g, yield is 88.9%.
Embodiment 8: the preparation of Abacavir
The Abacavir oxalate (30g, 0.07mol) embodiment 4 prepared and sodium hydroxide (8.4g, 0.21mol) drop in Virahol 210g, be heated to 40 ?45 DEG C, be incubated 0.5 ?after 1 hour, drop into gac 1g, be warming up to 80 ?85 DEG C, be incubated while start air distillation, steam a certain amount of after, filtered while hot, filtrate be concentrated into dry after, drop into Virahol 45g crystallization and obtain Abacavir 18.2g, yield is 90.8%.
Claims (10)
1. the preparation method of an Abacavir, it is characterized in that, with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methyl alcohol or its hydrochloride be raw material, after reacting with cyclopropylamine further with the alcoholic solvent generation salt-forming reaction of acid, carry out dissociating with alkali after preparing Abacavir X hydrochlorate and obtain Abacavir
Described X is 1 or 2.
2. preparation method according to claim 1, described acid is mineral acid or organic acid.
3. preparation method according to claim 2, described mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid or oxalic acid; Described organic acid is phenylformic acid or propanedioic acid.
4. preparation method according to claim 2, described acid is hydrochloric acid.
5. preparation method according to claim 1, described alcohol is the alkanol of C1-C8.
6. preparation method according to claim 5, described alcohol is methyl alcohol, ethanol, n-propyl alcohol or Virahol.
7. preparation method according to claim 1, described alkali is alkali metal base or carbonate.
8. preparation method according to claim 7, described alkali metal base sodium hydroxide, potassium hydroxide or lithium hydroxide; Described carbonate is sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus.
9. the preparation method of an Abacavir, it is characterized in that, with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate is raw material, after reacting with cyclopropylamine further with the alcoholic solvent generation salt-forming reaction of hydrochloric acid, Abacavir is obtained through free after preparing Abacavir dihydrochloride
10. the preparation method of an Abacavir, it is characterized in that, with (1S, 4R) the chloro-9H-purine of-4-(2-amino-6--9-base) ring penta-2-alkene-1-base methylate hydrochlorate is raw material, after reacting with cyclopropylamine further with alcohol hydrochloric acid generation salt-forming reaction, Abacavir is obtained through free after preparing Abacavir dihydrochloride
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| CN201410027146.5A CN104788451A (en) | 2014-01-21 | 2014-01-21 | Preparation method of abacavir |
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| CN201410027146.5A CN104788451A (en) | 2014-01-21 | 2014-01-21 | Preparation method of abacavir |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1054981A (en) * | 1989-12-22 | 1991-10-02 | 惠尔康基金会集团公司 | The treatment nucleosides |
| CN1263529A (en) * | 1997-05-17 | 2000-08-16 | 葛兰素集团有限公司 | Carbocyclic nucleoside hemisulfate and its use in treating viral infectiosn |
| CN1296406A (en) * | 1998-02-06 | 2001-05-23 | 葛兰素集团有限公司 | Pharmaceutial compositions |
| CN1861601A (en) * | 2006-06-13 | 2006-11-15 | 中国科学院上海有机化学研究所 | Process for preparing optics pure abacavir |
| CN101563346A (en) * | 2006-12-21 | 2009-10-21 | 埃斯特维化学股份有限公司 | Process for the preparation of abacavir |
| EP2305680A2 (en) * | 2009-09-30 | 2011-04-06 | Aurobindo Pharma Limited | Novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol |
-
2014
- 2014-01-21 CN CN201410027146.5A patent/CN104788451A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1054981A (en) * | 1989-12-22 | 1991-10-02 | 惠尔康基金会集团公司 | The treatment nucleosides |
| CN1263529A (en) * | 1997-05-17 | 2000-08-16 | 葛兰素集团有限公司 | Carbocyclic nucleoside hemisulfate and its use in treating viral infectiosn |
| CN1296406A (en) * | 1998-02-06 | 2001-05-23 | 葛兰素集团有限公司 | Pharmaceutial compositions |
| CN1861601A (en) * | 2006-06-13 | 2006-11-15 | 中国科学院上海有机化学研究所 | Process for preparing optics pure abacavir |
| CN101563346A (en) * | 2006-12-21 | 2009-10-21 | 埃斯特维化学股份有限公司 | Process for the preparation of abacavir |
| EP2305680A2 (en) * | 2009-09-30 | 2011-04-06 | Aurobindo Pharma Limited | Novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol |
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Application publication date: 20150722 |