CN101531680B - Method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine - Google Patents
Method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine Download PDFInfo
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- CN101531680B CN101531680B CN 200810034579 CN200810034579A CN101531680B CN 101531680 B CN101531680 B CN 101531680B CN 200810034579 CN200810034579 CN 200810034579 CN 200810034579 A CN200810034579 A CN 200810034579A CN 101531680 B CN101531680 B CN 101531680B
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Abstract
The invention provides a method for synthesizing (R)-9(2-(diethyl phosphonyl methoxyl) propyl)-adenine. The method includes the following steps of: implementing condensation reaction of (R)-hydroxypropyl adenine and tosyloxy methyl diethyl phosphate in solvent under the catalysis of catalytic amount of dialkyl magnesium, and then collecting generated PMPA diethyl ester from the reaction product. By using the method to produce the PMPA diethyl ester, the yield rate and the purity can be improved to over 80 percent, the used agent is safe, and the process operation is easy to control.
Description
Technical field
The present invention relates to synthesize (R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-method of VITAMIN B4.
Background technology
Tenofovir (PMPA) is first by the nucleotide analog that HIV-1 infects that is used for the treatment of of drugs approved by FDA, and the indication of approval be and other antiretroviral drugs combined utilization treatments HIV-1 infection.Its chemistry (R)-9-[2-(phosphonium mesitoyl methoxy) propyl group by name]-VITAMIN B4, structural formula is as follows:
(R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-VITAMIN B4 (abbreviation PMPA diethyl ester; be the key intermediate of synthetic PMPA down together); and the main method of synthetic PMPA diethyl ester is at present: be raw material with the VITAMIN B4; generate (R)-hydroxypropyl VITAMIN B4 with the condensation of (R)-propylene carbonate; again under the catalysis of lithium hydride (sodium) or trimethyl carbinol lithium with the ester condensation of tolysulfonyl oxygen ylmethyl p diethylaminobenzoic acid; generate PMPA diethyl ester (latter can further generate PMPA under the effect of trimethylammonium iodine (bromine) silane); see EP206459; US5733788, US5935946.Its synthetic route is as follows:
In the said synthesis route, the condensation reaction EP206459 in second step, the basic catalyst of US5733788 report usefulness is lithium hydride or sodium hydride, and these two kinds of reagent are met water, the wet air releasing hydrogen gas is flammable, can be quick-fried, production operation is difficulty relatively, and the reaction molar yield has only 20～30%, and the purity of the PMPA diethyl ester that obtains has only 40～45%.Though and the yield molar yield has brought up to 40～45% behind the US5935946 report use trimethyl carbinol lithium, product purity has also brought up to 60～65%, but commercially available the costing an arm and a leg of reagent trimethyl carbinol lithium, the production cost of therefore present PMPA diethyl ester is than higher, simultaneously, suitability for industrialized production also has problems.
Summary of the invention
The purpose of this invention is to provide a kind of synthetic (R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-method of VITAMIN B4, to overcome the deficiency of above-mentioned technology, so that suitability for industrialized production.
Method of the present invention comprises the steps:
(R)-hydroxypropyl VITAMIN B4 in solvent, is carried out condensation reaction with tolysulfonyl oxygen ylmethyl diethyl phosphoric acid under the dialkyl magnesium catalysis of catalytic amount, from reaction product, collect the PMPA diethyl ester that generates then;
Temperature of reaction is 25～100 ℃, preferred 35～70 ℃;
Reaction times is 3～6 hours;
Preferably, the mol ratio of each raw material is:
(R)-and the hydroxypropyl VITAMIN B4: dialkyl magnesium: tolysulfonyl oxygen ylmethyl diethyl phosphoric acid=1: 1～10: 1～10, preferred 1: 1～2: 2～3;
The alkyl of said dialkyl magnesium is fatty alkyl or aralkyl, and preferred dialkyl magnesium is di-n-butyl magnesium or magnesium ethide;
Said (R)-hydroxypropyl VITAMIN B4 can adopt the EP206459 disclosed method synthetic.
Preferred DMF of said solvent or DMA;
Preferably, (R)-hydroxypropyl VITAMIN B4 is dissolved in the solvent, adds dialkyl magnesium under protection of inert gas, the back drips tolysulfonyl oxygen ylmethyl diethyl phosphoric acid, divides 2～4 addings, each 0.5～1.5 hour at interval.
Use method of the present invention to produce the PMPA diethyl ester, molar yield and purity all can be brought up to more than 80%, agents useful for same safety, and technological operation is easy to control.
Embodiment
Embodiment 1
(R)-the hydroxypropyl VITAMIN B4
Under nitrogen protection; in reaction flask, drop into VITAMIN B4 10.0g, sodium hydroxide 0.12g, (R)-propylene carbonate 8.3g, DMF 70ml; the mixture stage is heated: 90 ℃, 110 ℃ and 125 ℃; midfeather 1 hour; in 125 ℃ of left and right sides insulation reaction of interior temperature 28 hours; after TLC shows reaction end, obtain (R)-hydroxypropyl VITAMIN B4, cooling stores.Area normalization HPLC purity assay is 83%.
Embodiment 2
(R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-VITAMIN B4 (PMPA diethyl ester)
Under nitrogen protection, in the complete soln that embodiment 1 obtains, add di-n-butyl magnesium 12.0g, the back drips tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 38.0g and (divides three addings, each 1 hour at interval), after adding for the first time system temperature is raised to 65 ℃, for the second time, add and fashionablely all be controlled at 65 ℃ for the third time;
Added the back insulation reaction 3 hours, TLC follows the tracks of reaction (TLC condition: chloroform: methyl alcohol=6: 1, volume).Cool to 20 ℃ after reacting completely, add glacial acetic acid 20ml, temperature is no more than 25 ℃, pH=5 in the control.The pressure reducing and steaming solvent.Add 30ml water in the resistates, use the 300ml dichloromethane extraction.Dichloromethane layer washes with water 3 times, each water 30ml.Evaporated under reduced pressure behind the organic layer anhydrous sodium sulfate drying obtains orange target product 25.6g, and area normalization HPLC purity assay is 83%, and yield is 83.7%.
Embodiment 3
(R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-VITAMIN B4 (PMPA diethyl ester)
Under nitrogen protection, in the complete soln that obtains according to embodiment 1 method, add di-n-butyl magnesium 20.0g, the back drips tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 40.0g and (divides three addings, each 1 hour at interval), after adding for the first time system temperature is raised to 35 ℃, for the second time, add and fashionablely all be controlled at 35 ℃ for the third time; Added the back insulation reaction 6 hours, TLC follows the tracks of reaction.Aftertreatment is the same, obtains orange 21.2g, and area normalization HPLC purity assay is 81%, and yield is 67.7%.
Embodiment 4
(R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-VITAMIN B4 (PMPA diethyl ester)
Under nitrogen protection, in the complete soln that obtains according to embodiment 1 method, add magnesium ethide 8.0g, the back drips tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 38.0g and (divides three addings, each 1 hour at interval) system temperature is raised to 60 ℃ after adding for the first time, for the second time, add and fashionablely all be controlled at 60 ℃ for the third time; Added the back insulation reaction 4 hours, added the back insulation reaction 4 hours, TLC follows the tracks of reaction.Aftertreatment obtains orange 18.8g with embodiment 2, and area normalization HPLC purity assay is 82%, and yield is 60.7%.
Embodiment 5
(R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-VITAMIN B4 (PMPA diethyl ester)
Under nitrogen protection, in the complete soln that obtains according to embodiment 1 method, add di-n-butyl magnesium 15.0g, the back drips tolysulfonyl oxygen ylmethyl diethyl phosphoric acid 57.0g and (divides three addings, each 1 hour at interval), after adding for the first time system temperature is raised to 45 ℃, for the second time, add and fashionablely all be controlled at 45 ℃ for the third time; Added the back insulation reaction 4 hours, TLC follows the tracks of reaction.Aftertreatment obtains orange 20.3g with embodiment 2, and area normalization HPLC purity assay is 80%, and yield is 64.0%.
Claims (5)
1. synthetic (R)-9-[2-(diethyl phosphonyl methoxyl base) propyl group]-method of VITAMIN B4, it is characterized in that, comprise the steps: (R)-hydroxypropyl VITAMIN B4 in solvent, under the dialkyl magnesium catalysis of catalytic amount, carry out condensation reaction, from reaction product, collect the PMPA diethyl ester that generates then with tolysulfonyl oxygen ylmethyl diethyl phosphoric acid;
The chemistry of PMPA is called (R)-9-[2-(phosphonium mesitoyl methoxy) propyl group]-VITAMIN B4;
Described dialkyl magnesium is di-n-butyl magnesium or magnesium ethide.
2. method according to claim 1 is characterized in that, temperature of reaction is 25～100 ℃, and the reaction times is 3～6 hours.
3. method according to claim 1 is characterized in that, the mol ratio of each raw material is:
(R)-and the hydroxypropyl VITAMIN B4: dialkyl magnesium: tolysulfonyl oxygen ylmethyl diethyl phosphoric acid=1: 1～10: 1～10.
4. method according to claim 3 is characterized in that, the mol ratio of each raw material is:
(R)-and the hydroxypropyl VITAMIN B4: dialkyl magnesium: tolysulfonyl oxygen ylmethyl diethyl phosphoric acid=1: 1～2: 2～3.
5. method according to claim 1 is characterized in that, (R)-hydroxypropyl VITAMIN B4 is dissolved in the solvent; under protection of inert gas, add dialkyl magnesium; the back drips tolysulfonyl oxygen ylmethyl diethyl phosphoric acid, divides 2～4 addings, each 0.5～1.5 hour at interval.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374039A (en) * | 2012-04-20 | 2013-10-30 | 上海益生源药业有限公司 | Synthesis method of tenofovir |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102219805A (en) * | 2011-03-10 | 2011-10-19 | 苏州腾龙生物医药技术有限公司 | Novel production process of tenofovir |
| CN103665043B (en) | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | A kind of tenofovir prodrug and its application in medicine |
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2008
- 2008-03-13 CN CN 200810034579 patent/CN101531680B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| Karine Barral et al..Synthesis,in Vitro Antiviral Evaluation,and Stability Studies of Novel α-Borano-Nucleotide Analogues of 9-[2-(Phosphonomethoxy)ethyl]adenine and (R)-9-[2-(Phosphonomethoxy)propyl]adenine.《Journal of Medicinal Chemistry》.2006,第49卷 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103374039A (en) * | 2012-04-20 | 2013-10-30 | 上海益生源药业有限公司 | Synthesis method of tenofovir |
| CN103374039B (en) * | 2012-04-20 | 2015-11-18 | 上海益生源药业有限公司 | The synthetic method of tynofovir |
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Address after: 201203 Shanghai Guo Shou Jing Road, Zhangjiang High Tech Park of Pudong New Area No. 351 Building No. 2 room 687-21 Patentee after: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co.,Ltd. Patentee after: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. Address before: 201203 Zhang Heng road Shanghai, Pudong New Area Zhangjiang hi tech Park No. 1479 Patentee before: Shanghai Desano Pharmaceutical Holding Co.,Ltd. Patentee before: SHANGHAI DESANO CHEMICAL PHARMACEUTICAL Co.,Ltd. |
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Effective date of registration: 20221101 Address after: 224145 South District of Marine Economic Development Zone, Dafeng District, Yancheng City, Jiangsu Province Patentee after: YANCHENG DESANO PHARMACEUTICAL Co.,Ltd. Patentee after: JIANGSU PUXIN PHARMACEUTICAL Co.,Ltd. Address before: 201203 room 687-21, 2 building, No. 351, Guo Shou Jing Road, Zhangjiang hi tech park, Pudong New Area, Shanghai. Patentee before: SHANGHAI ACEBRIGHT PHARMACEUTICALS GROUP Co.,Ltd. Patentee before: YANCHENG DESANO PHARMACEUTICAL Co.,Ltd. Patentee before: JIANGSU PUXIN PHARMACEUTICAL Co.,Ltd. |