CN101195622A - Process for the preparation of famciclovir - Google Patents
Process for the preparation of famciclovir Download PDFInfo
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- CN101195622A CN101195622A CNA2007101915934A CN200710191593A CN101195622A CN 101195622 A CN101195622 A CN 101195622A CN A2007101915934 A CNA2007101915934 A CN A2007101915934A CN 200710191593 A CN200710191593 A CN 200710191593A CN 101195622 A CN101195622 A CN 101195622A
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- China
- Prior art keywords
- amino
- purine
- chloro
- under
- catalysis
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960004396 famciclovir Drugs 0.000 title claims abstract description 12
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 8
- KXPSHSVVYGZKAV-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1Cl KXPSHSVVYGZKAV-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- FSJCDRZLIWVLEH-UHFFFAOYSA-N 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]propane-1,3-diol Chemical compound NC1=NC(Cl)=C2N=CN(CCC(CO)CO)C2=N1 FSJCDRZLIWVLEH-UHFFFAOYSA-N 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 4
- 238000006298 dechlorination reaction Methods 0.000 claims abstract description 3
- 238000003408 phase transfer catalysis Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- -1 1-ethyl Chemical group 0.000 abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminum chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 239000003638 chemical reducing agent Substances 0.000 abstract 2
- 239000003054 catalyst Substances 0.000 abstract 1
- 230000007613 environmental effect Effects 0.000 abstract 1
- 230000002349 favourable effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of famciclovir, which comprises a catalyst and a reaction bottle, wherein 2-amino-6-chloropurine is used as a raw material and condensed with 3-bromopropane-1, 1, 1-ethyl triformate under phase transfer catalysis to obtain 2-amino-6-chloro-9- (2, 2-diethoxycarbonyl ethyl butyrate-4-yl) purine, decarboxylation is carried out by using sodium ethoxide solution to obtain 2-amino-6-chloro-9- (2-ethoxycarbonyl ethyl butyrate-4-yl) purine, and NaBH is used for catalyzing by aluminum chloride4The method for preparing famciclovir by using hydrogen as a reducing agent to reduce 2-amino-6-chloro-9- (4-hydroxy-3-hydroxymethyl butyl) purine to obtain 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methylbutyl) purine, reacting with acetic anhydride under the catalysis of 4-dimethylaminopyridine to obtain 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methylbutyl) purine, and finally carrying out hydrogenation dechlorination under the catalysis of Pd-C has the advantages of simple and convenient operation, high yield and low cost, can realize industrial production, is favorable for environmental protection by using hydrogen as a reducing agent, and also improves the quality of products.
Description
Technical field
The present invention relates to a kind of medical preparation method, especially a kind of preparation method of Famciclovir.
Background technology
The Famciclovir synthetic method has a lot; practical mainly contain two kinds of methods: one; adopt 2; 2-amino-6-chloropurine and 2-ethanoyl methyl-4-iodine butylacetic acid ester condensation; hydrogenation makes 1; wherein the synthetic of 2-ethanoyl methyl 4-iodine butylacetic acid ester needs to adopt Lithium Aluminium Hydride to reduce; Lithium Aluminium Hydride uses dangerous; dangerous; the cost height; simultaneously can produce by product when 2-amino-6-chloropurine and 2-ethanoyl methyl-4-iodine butylacetic acid ester condensation reaction; utilize the method for recrystallization to be difficult to separate, must adopt the method for column chromatography to separate, thereby be unsuitable for suitability for industrialized production.Method two is raw material and 3-N-PROPYLE BROMIDE-1,1 with 2-amino-6-chloropurine, and 1-tricarboxylic acid ethyl ester is through condensation, Pd-C/HCOONH
4Under reduce Na/C
2H
5Decarboxylation under the OH, NaBH
4Esterification gets 1 under following reduction, the aceticanhydride, and total recovery only is 8.1%.
Summary of the invention
The present invention is directed to the defective of prior art, a kind of high efficiency Famciclovir preparation method is provided.
To achieve these goals, the present invention takes following measure to realize:
A kind of preparation method of Famciclovir, comprise catalyzer, reaction flask, it is characterized in that with 2-amino-6-chloropurine (2) be raw material under phase-transfer catalysis with 3-N-PROPYLE BROMIDE-1,1, the condensation of 1-tricarboxylic acid ethyl ester gets 2-amino-6-chloro-9-(2,2-diethoxy carbonyl ethyl butyrate-4-yl) purine, get 2-amino-6-chloro-9-(2-ethoxycarbonyl ethyl butyrate-4-yl) purine with the alcohol sodium solution decarboxylation again, under aluminum chloride-catalyzed, use NaBH then
4As reductive agent reduce 2-amino-6-chloro-9-(4-hydroxyl-3 methylol-butyl) purine, under 4-dimethylaminopyridine catalysis, with aceticanhydride react 2-amino-6-chloro-9-(4-acetoxy-3-acetoxy-methyl butyl) purine, under Pd-C catalysis, the hydrogenation dechlorination gets the method for Famciclovir at last.
The present invention has following characteristics with respect to prior art: the present invention is through the technology after improving, and is easy and simple to handle, the yield height, and cost is low, can realize suitability for industrialized production, wherein uses hydrogen to help environment protection as reductive agent, has also improved the quality of product.
Embodiment
Concrete steps are as follows:
1. amino-6-chloro-9-(2,2-diethoxy carbonyl ethyl butyrate-4-yl) purine: in reaction flask, drop into 17g (0.10mol) 2-amino-6-chloropurine, 150mL dimethyl formamide, 38g (0.11mol) 98%3-N-PROPYLE BROMIDE-1,1,1-tricarboxylic acid ethyl ester, 17.9g (0.13mol) Anhydrous potassium carbonate, 1.61g (0.005mol) Tetrabutyl amonium bromide stir down in 60 ~ 70 ℃ of reactions 24 hours.Reaction finishes, and is cooled to room temperature, filters, and filter cake washs with a small amount of dimethyl formamide, and merging filtrate removes solvent under reduced pressure, resistates propyl carbinol recrystallization.
2.2-amino-6-chloro-9-(2-ethoxycarbonyl ethyl butyrate-4-yl) purine: in reaction flask, drop into 37.3g (0.087mol) amino-6-chloro-9-(2,2-diethoxy carbonyl ethyl butyrate-4-yl) purine, 300mL ethanol, stir down and drip 18.8g (0.05mol 18% alcohol sodium solution in 20 ~ 25 ℃, drip off insulation 1h, be cooled to 10 ℃ of suction filtrations then, filter cake is dried with a small amount of cold washing with alcohol.
3.2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine: the diethylene glycol dimethyl ether that in reaction flask, adds 4.3g (0.125mol) sodium borohydride and 12mL, stirring and dissolving, slowly add 35.6g (0.1mol) 2-amino-6-chloro-9-(2-ethoxycarbonyl ethyl butyrate-4-yl) purine then, under vigorous stirring, drip 21mL (2.0mol/L) and contain the diethylene glycol dimethyl ether solution of aluminum chloride 0.041mol, rate of addition makes temperature of reaction be no more than 50 ℃, at room temperature stir 1h then, 50-55 ℃ of reaction 0.5h is chilled to room temperature and pours in the 250g trash ice that contains the 25mL concentrated hydrochloric acid.The precipitation that filtration is separated out is through frozen water washing, the compound that press dry wetly.
4.2-amino-6-chloro-9-(4-acetoxy-3-acetoxy-methyl butyl) purine: in reaction flask, add all wet 2-amino-6-chloro-9-(4-hydroxyl-3-methylol-butyl) purine that makes, 17.8mL (0.126mol) triethylamine, 0.94g (7.7mmol) 4-Dimethylamino pyridine, the 180mL methylene dichloride, under little backflow, Dropwise 5 1g (0.5mol) aceticanhydride, drip off back flow reaction 1h, be chilled to room temperature, be neutralized to pH6.5 with 10%NaOH, tell dichloromethane layer, water 100mL dichloromethane extraction, merge organic phase, washing, organic phase are steamed and are desolventized remaining solid 75mL dehydrated alcohol recrystallization.
5. Famciclovir: in reaction flask, add 10.7g (0.03mol) 2-amino-6-chloro-9-(4-acetoxy-3-acetoxy-methyl butyl) purine, 100mL ethyl acetate, 4g (0.04mol) triethylamine, 1g5% palladium carbon, at 48 ~ 58 ℃ of logical hydrogen reaction 12h, intact to raw material reaction.Reaction finishes, and filters, and filter cake washs with amount of ethyl acetate.Merging filtrate is used the 15mL water washing, divides the phase of anhydrating, and organic phase removes ethyl acetate under reduced pressure, with the mixed solution (V of ethyl acetate, sherwood oil
Ethyl acetate: V
Sherwood oil=3: 7) recrystallization.
In the reality, the present invention is used for infecting with the HBV of prevention and treatment liver transplantation, prolongs patient's lifetime.
Claims (1)
1. the preparation method of a Famciclovir, comprise catalyzer, reaction flask, it is characterized in that with 2-amino-6-chloropurine (2) be raw material under phase-transfer catalysis with 3-N-PROPYLE BROMIDE-1,1, the condensation of 1-tricarboxylic acid ethyl ester gets 2-amino-6-chloro-9-(2,2-diethoxy carbonyl ethyl butyrate-4-yl) purine, get 2-amino-6-chloro-9-(2-ethoxycarbonyl ethyl butyrate-4-yl) purine with the alcohol sodium solution decarboxylation again, under aluminum chloride-catalyzed, use NaBH then
4As reductive agent reduce 2-amino-6-chloro-9-(4-hydroxyl-3 methylol-butyl) purine, under 4-dimethylaminopyridine catalysis, with aceticanhydride react 2-amino-6-chloro-9-(4-acetoxy-3-acetoxy-methyl butyl) purine, under Pd-C catalysis, the hydrogenation dechlorination gets the method for Famciclovir at last.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101915934A CN101195622A (en) | 2007-12-13 | 2007-12-13 | Process for the preparation of famciclovir |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101915934A CN101195622A (en) | 2007-12-13 | 2007-12-13 | Process for the preparation of famciclovir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101195622A true CN101195622A (en) | 2008-06-11 |
Family
ID=39546264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007101915934A Pending CN101195622A (en) | 2007-12-13 | 2007-12-13 | Process for the preparation of famciclovir |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101195622A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496991A (en) * | 2014-11-04 | 2015-04-08 | 常州康丽制药有限公司 | Preparation method for high-quality 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbutyl)purine |
| CN104744472A (en) * | 2015-03-12 | 2015-07-01 | 常州康丽制药有限公司 | Preparation method of high-quality 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine |
| CN112979653A (en) * | 2019-12-12 | 2021-06-18 | 上药康丽（常州）药业有限公司 | Method for synthesizing famciclovir by using microchannel reactor |
-
2007
- 2007-12-13 CN CNA2007101915934A patent/CN101195622A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496991A (en) * | 2014-11-04 | 2015-04-08 | 常州康丽制药有限公司 | Preparation method for high-quality 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbutyl)purine |
| CN104744472A (en) * | 2015-03-12 | 2015-07-01 | 常州康丽制药有限公司 | Preparation method of high-quality 2-amino-6-chloro-9-(4-hydroxyl-3-hydroxymethylbutyl) purine |
| CN112979653A (en) * | 2019-12-12 | 2021-06-18 | 上药康丽（常州）药业有限公司 | Method for synthesizing famciclovir by using microchannel reactor |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
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Open date: 20080611 |