CN1740172A - Abacavin preparing process - Google Patents
Abacavin preparing process Download PDFInfo
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- CN1740172A CN1740172A CN 200510029670 CN200510029670A CN1740172A CN 1740172 A CN1740172 A CN 1740172A CN 200510029670 CN200510029670 CN 200510029670 CN 200510029670 A CN200510029670 A CN 200510029670A CN 1740172 A CN1740172 A CN 1740172A
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Abstract
The present invention provides abacavin preparing process. The process includes the reaction between 4-chloro-2-amino-purine and [(4-bromo)-cyclopentyl-2-ene-1-radical] methanol to prepare the key intermediate {(1R, 4S)-4-(2-amino-6-chloro-9H-purine-9 radical) -cyclopentyl-2-ene-1-radical} methanol; and subsequent known process to prepare abacavin. The present invention has less reaction steps, simple operation and easy-to-obtain material, and is suitable for industrial production.
Description
Technical field:
The invention belongs to the pharmaceutical chemistry technical field.Be specifically related to a kind of method of making Abacavir.
Background technology:
Abacavir (ABACAVIR) is a kind of anti-AIDS (AIDS) new drug that the U.S. developed in recent years, belongs to nucleoside HIV RT Depressant class, is used for retrovirus, and it is splendid to have result of treatment.
Acquired immune deficiency syndrome (AIDS) is very harmful to the mankind, and development trend is extremely serious again, replaces in the past comparatively primary medicine with novel drugs, increases drug effect, and effectively checking state of an illness expansion is that thing is in the thing that must go.U.S. Ge Lansu company makes great efforts research through for many years, and develop anti-AIDS of new generation (AIDS) ucleosides new drug---Abacavir (ABACAVIR), and register patent in the world, the patent No.: US5034394, former operational path is as follows:
The starting raw material of making Abacavir in the above-mentioned United States Patent (USP) is a 2-amino-4,6-dichloro pyrimidine and [4-(kharophen) ring penta-2-alkene-1-yl] methyl acetate.Need six-step process altogether from the starting raw material to the finished product, each step process such as diazonium, coupling, reduction is arranged, technology is too loaded down with trivial details.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the method that is suitable for suitability for industrialized production that research and design is new.
The invention provides a kind of method of making Abacavir, this method be with 4-chloro-2-amino-purine with
[(4-bromine)-ring penta-2-alkene-1-bromo-base] methyl alcohol reacts, make (1R, 4S)-4-(2-amino-6-chloro-9H-purine-9-yl) ring penta-2-alkene-1-yl } methyl alcohol.And then by above-mentioned United States Patent (USP) method and cyclopropylamine condensation manufacturing Abacavir.
Above-mentioned reaction is to be starting raw material from 4-chloro-2-amino-purine, omitted need p-Chlorobenzoic acid amide diazotization in the former operational path after, a few step process processes such as coupling again, reduction, decomposition, only need one step of condensation promptly to finish the process products that just can finish through four-step reaction in the former operational path, obviously the important intermediate { (1R that more helps Abacavir through the technology after improving, 4S)-and 4-(2-amino-6-chloro-9H--9-yl) ring penta-2-alkene-1-yl } methyl alcohol synthetic, amino-purine market is on sale for its starting raw material 4-chloro-2-.Another raw material [(4-bromine)-ring penta-2-alkene-1-yl] methyl alcohol can be used [(4-amino)-ring penta-2-alkene-1-yl] methyl alcohol manufacturing, and [(4-amino)-ring penta-2-alkene-1-yl] methyl alcohol can be consulted United States Patent (USP): US4, and 268,672 described methods are made.Solvent for use is ethers or alcohols among the present invention.As: glycol dimethyl ether, methyl alcohol, ethanol or Virahol, tetrahydrofuran (THF) or dioxane also can.The solvent for use amount be reaction raw materials weight 5-20 doubly, doubly measuring with 9-12 is optimum quantity, the ratio of starting raw material 4-chloro-2-amino-purine and [(4-bromine)-ring penta-2-alkene-1-yl] methyl alcohol is a mol ratio 1: 1 for well.Temperature of reaction can be controlled in the reaction solvent reflux temperature, and the reaction times is not wait in 3～20 hours, is good with 7～10 hours wherein.
The synthetic Abacavir of making of method of the present invention, saved the many loaded down with trivial details processing step in the former patent, only promptly finish four-step reaction in the former patent with a step condensation reaction, saved more than half step, the reaction times shortens greatly, thereby has reduced energy consumption and cost, the patent medicine cost is reduced greatly, the inventive method raw material is easy to get, and makes industrial production more become to rationalizing, and the content's index of final product and effective ingredient and former patent are described quite.
Below, by example actual process of the present invention is described once, need to prove: the present invention is wherein part experiment just, does not comprise the whole examples of the present invention.
Example:
The A:[(4-bromine)-and ring penta-2-alkene-1-yl] methyl alcohol synthetic
With 11.3 grams (0.1 mole) [(4-amino)-ring penta-2-alkene-1-yl] methyl alcohol (synthetic) by relevant patent, add in 250 milliliters of four-necked bottles, cooling is stirred, and slowly adds 50 milliliter of 48% Hydrogen bromide, is cooled to about 0 ℃.Slowly drip the 40 gram aqueous solution that are made into by 6.9 gram (0.1 mole) Sodium Nitrites again.A bottle interior reaction temperature is maintained about 0 ℃, detect the diazotization terminal point with starch-potassium iodide starch paper before dripping off.Doazo reaction liquid behind the terminal point still places cryosel.
Be furnished with prolong, in the 500ml four-hole bottle of agitator and thermometer, adding 10 gram cuprous bromides, 20 gram 48% Hydrogen bromides and 0.5 gram thiodiphenylamine (resistance is poly-).The nearly boiling of heating.Under vigorous stirring, continue heating, drip above-mentioned diazotization reaction liquid.Dripped off in about 15 minutes, and dripped off the back and continue in little reaction down 1 hour of boiling.Cool to room temperature.With dichloromethane extraction three times (each 50 milliliters).Combined dichloromethane extraction liquid, water are given a baby a bath on the third day after its birth inferior, and 5% sodium carbonate solution is washed once for 50 milliliters.Wash neutrality again, tell organic layer, use anhydrous magnesium sulfate drying, and add 0.1 gram thiodiphenylamine.Elimination solid after 24 hours.Methylene dichloride is removed in liquid decompression evaporation below 40 ℃.Lean on the cut of about 60 ℃ of following collections again at 10 millimeters mercury, get 12.5 gram products.Yield 70%.Chromatogram content is more than 98%.(it is stand-by to preserve refrigerator)
B:{ (1R, 4S)-4-(2-amino-6-chloro-9H-9-yl) ring penta-2-alkene-1-yl } methyl alcohol synthetic
Is furnished with prolong at a 500mL; agitator; addition funnel; in the four-hole bottle of thermometer; add 8.4 gram (0.05 mole) 4-chloro-2-amino-purine; 8.9 gram [(4-bromine)-ring penta-2-alkene-1-yl] methyl alcohol; the 120ml dioxane; under nitrogen protection, stir; be heated to and boil; by splashing into the 20 gram solution that 5.6 gram potassium hydroxide and water are made in the dropping funnel; drip off in 5 minutes; drip off again and reflux; stirring reaction 2 hours, PH are about 7, if PH continues reaction greater than 7.5; after reaction finishes; reaction solution is poured in the 500-1000ml water, and solid product is separated out; suction filtration; wash three times; drain, use ethyl alcohol recrystallization; get 9.5 gram crystallizations; yield 75%, fusing point is: 138-139 ℃, chromatogram content is more than 98%.
C:{ (1R, 4S)-4-[2-amino-6-(cyclopropyl amino)-9H-purine-9-yl]-ring penta-2-alkene-1-yl } methyl alcohol is synthetic
The above-mentioned product of dissolving 1 gram in 80mL ethanol; add the 1.3ml cyclopropylamine; and under nitrogen protection; this group reaction thing was refluxed 6 hours; add the 1.3ml cyclopropylamine afterwards again; continued back flow reaction 6 hours, the vacuum precipitation adds the saturated sodium hydrogen carbonate solution of 25ml chloroform and 50ml again; again with chloroform with above-mentioned water layer extracted several times; promptly get crude product, merge organic phase, the methyl alcohol-ethyl acetate with 3% on silicagel column is purified; get 0.85 gram { (1R behind the desolventizing; 4S)-4-[2-amino-6-(cyclopropyl amino)-9H-purine-9-yl]-ring penta-2-alkene-1-yl } methyl alcohol, get 0.66 with the acetonitrile recrystallization and restrain the meal that is white in color, melting range: 93-96 ℃.
Claims (4)
1, a kind of method of making Abacavir, it is characterized in that this method makes key intermediate { (1R with 4-chloro-2-amino-purine and [(4-bromine)-ring penta-2-alkene-1-yl] methyl alcohol reaction, 4S)-and 4-(2-amino-6-chloro-9H-purine-9-yl) ring penta-2-alkene-1-yl } methyl alcohol, make Abacavir by known method and cyclopropylamine condensation then.
2, according to the described a kind of method of making Abacavir of claim 1, it is characterized in that making { (1R, 4S)-and 4-(2-amino-6-chloro-9H-purine-9-yl) ring penta-2-alkene-1-yl } in the reaction of methyl alcohol, 4-chloro-2-amino-purine is 1: 1 with the consumption mol ratio of [(4-bromine)-ring penta-2-alkene-1-yl] methyl alcohol; The reaction solvent amount is that the 5-20 of 4-chloro-2-amino-purine weight doubly measures; Temperature of reaction is the reflux temperature of solvent; Reaction times is 3-20 hour.
3, according to the described a kind of method of making Abacavir of claim 1, it is characterized in that making { (1R, 4S)-and 4-(2-amino-6-chloro-9H-purine-9-yl) ring penta-2-alkene-1-yl } in the reaction of methyl alcohol, described solvent is ether or alcohols: glycol dimethyl ether, methyl alcohol, ethanol or Virahol, tetrahydrofuran (THF) or dioxane.
4,, it is characterized in that wherein said [(4-bromine)-ring penta-2-alkene-1-yl] methyl alcohol synthesizes with Hydrogen bromide by [(4-amino)-ring penta-2-alkene-1-yl] methyl alcohol to make according to the described a kind of method of making Abacavir of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510029670 CN1740172A (en) | 2005-09-15 | 2005-09-15 | Abacavin preparing process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510029670 CN1740172A (en) | 2005-09-15 | 2005-09-15 | Abacavin preparing process |
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| Publication Number | Publication Date |
|---|---|
| CN1740172A true CN1740172A (en) | 2006-03-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510029670 Pending CN1740172A (en) | 2005-09-15 | 2005-09-15 | Abacavin preparing process |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100465174C (en) * | 2006-06-13 | 2009-03-04 | 中国科学院上海有机化学研究所 | Process for preparing optics pure abacavir |
| CN101284811B (en) * | 2008-06-11 | 2010-06-16 | 常州恩滋生物科技有限公司 | Synthetic method for chiral carbocyclic ring intermediate of abacavir |
-
2005
- 2005-09-15 CN CN 200510029670 patent/CN1740172A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100465174C (en) * | 2006-06-13 | 2009-03-04 | 中国科学院上海有机化学研究所 | Process for preparing optics pure abacavir |
| CN101284811B (en) * | 2008-06-11 | 2010-06-16 | 常州恩滋生物科技有限公司 | Synthetic method for chiral carbocyclic ring intermediate of abacavir |
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