WO2014141092A2 - Improved process for the preparation of tenofovir - Google Patents
Improved process for the preparation of tenofovir Download PDFInfo
- Publication number
- WO2014141092A2 WO2014141092A2 PCT/IB2014/059675 IB2014059675W WO2014141092A2 WO 2014141092 A2 WO2014141092 A2 WO 2014141092A2 IB 2014059675 W IB2014059675 W IB 2014059675W WO 2014141092 A2 WO2014141092 A2 WO 2014141092A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tenofovir disoproxil
- preparation
- tenofovir
- triphenylphosphonium
- isopropyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 229960004556 tenofovir Drugs 0.000 title claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 claims abstract description 16
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 23
- 229960001355 tenofovir disoproxil Drugs 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 21
- JFVZFKDSXNQEJW-CQSZACIVSA-N tenofovir disoproxil Chemical compound N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N JFVZFKDSXNQEJW-CQSZACIVSA-N 0.000 claims description 21
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 10
- JHYNXXBAHWPABC-UHFFFAOYSA-N chloromethyl propan-2-yl carbonate Chemical compound CC(C)OC(=O)OCCl JHYNXXBAHWPABC-UHFFFAOYSA-N 0.000 claims description 8
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000012024 dehydrating agents Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- XMQSELBBYSAURN-UHFFFAOYSA-M triphenyl(propyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCC)C1=CC=CC=C1 XMQSELBBYSAURN-UHFFFAOYSA-M 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- HHBXWXJLQYJJBW-UHFFFAOYSA-M triphenyl(propan-2-yl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C)C)C1=CC=CC=C1 HHBXWXJLQYJJBW-UHFFFAOYSA-M 0.000 claims description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 3
- JHYNXXDQQHTCHJ-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 JHYNXXDQQHTCHJ-UHFFFAOYSA-M 0.000 claims description 2
- SLAFUPJSGFVWPP-UHFFFAOYSA-M ethyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CC)C1=CC=CC=C1 SLAFUPJSGFVWPP-UHFFFAOYSA-M 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- JNDAAZVYZSEWCG-UHFFFAOYSA-M tert-butyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C)(C)C)C1=CC=CC=C1 JNDAAZVYZSEWCG-UHFFFAOYSA-M 0.000 claims description 2
- KRPZTRZZTNJZNM-UHFFFAOYSA-M tert-butyl(triphenyl)phosphanium;iodide Chemical compound [I-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C(C)(C)C)C1=CC=CC=C1 KRPZTRZZTNJZNM-UHFFFAOYSA-M 0.000 claims description 2
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 claims description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 239000001110 calcium chloride Substances 0.000 claims 1
- 229910001628 calcium chloride Inorganic materials 0.000 claims 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims 1
- 239000000292 calcium oxide Substances 0.000 claims 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims 1
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 239000000395 magnesium oxide Substances 0.000 claims 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- 150000003839 salts Chemical class 0.000 description 12
- 229940086542 triethylamine Drugs 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 230000003197 catalytic effect Effects 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- GNJZAZRKAUNBQQ-UHFFFAOYSA-N 7h-purin-6-amine;hydrate Chemical compound O.NC1=NC=NC2=C1NC=N2 GNJZAZRKAUNBQQ-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- PINIEAOMWQJGBW-FYZOBXCZSA-N tenofovir hydrate Chemical compound O.N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N PINIEAOMWQJGBW-FYZOBXCZSA-N 0.000 description 4
- -1 Tenofovir disoproxil fumaric acid salt Chemical class 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 0.000 description 1
- UUZYBYIOAZTMGC-UHFFFAOYSA-M benzyl(trimethyl)azanium;bromide Chemical compound [Br-].C[N+](C)(C)CC1=CC=CC=C1 UUZYBYIOAZTMGC-UHFFFAOYSA-M 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000003786 synthesis reaction 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
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- GRVPDGGTLNKOBZ-UHFFFAOYSA-M triethyl(methyl)azanium;bromide Chemical compound [Br-].CC[N+](C)(CC)CC GRVPDGGTLNKOBZ-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Definitions
- the invention generally relates to a novel process for the preparation of Tenofovir. More specifically, the invention relates to process for the preparation of Tenofovir disoproxil Fumarate using catalytic amount of Wittig reagent which can be practiced on an industrial scale.
- Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil fumaric acid salt, chemically known as 9-[(R)-2-[[bis [[(isopropoxycarbonyl) oxy]methoxy] phosphinyl] methoxy] propyl] adenine Fumarate is represented by the following structure of Formula:
- Tenofovir disoproxil Fumarate is a highly potent antiviral agent and is available in the market under the brand name VIREAD® in the form of 300mg of oral tablets and in combination with other antiviral agents.
- U.S. Pat. No. 5,922,695 discloses phosphonomethoxy nucleotide analogs such as Tenofovir disoproxil and the salts, hydrates, tautomers and solvates thereof.
- the '695 patent further discloses a process for preparation of Tenofovir disoproxil by esterification of Tenofovir with chloromethyl isopropyl carbonate using 1 -methyl-2-pyrrolidinone and triethylamine.
- Tenofovir Disoproxil is converted into its Fumarate salt without isolation.
- WO 2011/111074 describes a process for the preparation of Tenofovir Disoproxil which involves esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, phase transfer catalyst optionally dehydrating agent and converting Tenofovir Disoproxil into its pharmaceutically acceptable salts.
- phase transfer catalyst quaternary ammonium
- the present invention provides a process for the preparation of Tenofovir disoproxil Fumarate using a catalytic amount of wittig reagent which enhances the rate of reaction.
- the process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.
- the process for the preparation of Wittig salts especially phosphonium salts has been disclosed in the prior art patents i.e., US3932485, US4122123, US6169209, US6187959 and US6423873. So far the use of Wittig reagent as a phase transfer catalyst is not used in any prior art processes for the preparation of Tenofovir disoproxil Fumarate.
- the main object of the invention is to provide a novel process for the preparation of Tenofovir Disoproxil Fumarate using Wittig reagent.
- Another object of the invention is to provide a simple, cost effective process for the preparation of Tenofovir Disoproxil Fumarate with high purity and without the formation of undesired impurities.
- Yet another object of the present invention is to provide an efficient process which avoids the use of large quantities of catalysts.
- Further object of the invention is to provide a process for preparation of Tenofovir Disoproxil Fumarate in high yield and purity in short span of time, thereby substantially minimize the product degradation.
- the present invention encompasses a process for the preparation of Tenofovir Disoproxil and its conversion to pharmaceutically acceptable salts using catalytic amount of Wittig reagent.
- Wittig salts are Quaternary phosphonium salts and the same can be defined with the general formula as given below:
- One aspect of the invention provides a novel process by employing additives which can be used in catalytic amount. Also, it has now surprisingly been found that the catalytic amount of additives with dehydrating agent has overcome all the long felt need of an industrial viable process for the preparation of Tenofovir.
- the present invention relates to an improved process for the preparation of Tenofovir Disoproxil and its pharmaceutically acceptable salts comprising the steps of:
- the esterification of Tenofovir monohydrate is carried out in the presence of a base and Wittig reagent, wherein base is selected from organic amine like trialkyl amine such as triethylamine, diisopropyl ethyl amine preferably triethylamine and the wittig reagent is selected from the group comprising Isopropyl triphenylphosphonium iodide, triphenylphosphonium bromide, n-propyl triphenyl phosphonium bromide, -propyl triphenyl phosphonium iodide, ethyl triphenylphosphonium iodide, ethyl triphenylphosphonium bromide, tert-butyl triphenylphosphonium iodide, tert-butyl triphenylphosphonium bromide.
- base is selected from organic amine like trialkyl amine such as triethylamine, diis
- esterification of Tenofovir monohydrate is carried out in the presence of a dehydrating agent.
- the dehydrating agent is selected from silylated dehydrating agent such as trialkylsilylhalides, bis(trimethylsilyl)acetamide (BSA) and hexamethyldisilazane (HMDS), preferably trialkly silyl halides, more preferably trimethyl silyl chloride.
- esterification of Tenofovir monohydrate is carried out in a solvent selected from Acetonitrile, dimethyl formamide, N-methyl pyrrolidine, cyclohexane, ethyl acetate, isopropyl acetate, n-hepatne, isopropyl alcohol and water or mixtures thereof, preferably N-methyl pyrrolidine.
- Tenofovir Disoproxil is converted into its pharmaceutically acceptable salt preferably Fumarate salt by the conventional methods.
- Example-1 illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
- Example-1
- Cyclohexane (350ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (50.0g) were taken at 30 ⁇ 5°C under nitrogen atmosphere.
- triethyl amine (33 g) was added and heated to 80 ⁇ 5°C. Water was collected azeotropically at 80 ⁇ 5°C. After completion of water removal, NMP (150ml), trimethyl silyl chloride (3.56 g) was charged and stirred for 30 mins at 30° ⁇ 5.
- Triethylamine (79.57g) was added and heated the reaction mass to 52 ⁇ 2°C.
- Cyclohexane (1400ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (200.0g) were taken at 30°C to 35 °C under nitrogen atmosphere.
- Triethyl amine (132.0g) was added and heated to 80°C to 85°C. Water was collected azeotropically at 80°C to 85°C. Cyclohexane was distilled off completely after removal of water.
- NMP 700ml
- trimethyl silyl chloride 14.24g
- Tenofovir free base (50.0g), fumaric acid (15.2g) were charged into isopropyl alcohol (440ml) and heated to 53 ⁇ 2°C to get a clear solution.
- Reaction mass was filtered through micron filter paper. The filtrate was allowed to crystallize out gradually by natural cooling for 12.0hrs ⁇ 2hrs to 25 ⁇ 5°C.
- the reaction mass was maintained at 25 ⁇ 5°C for 1.0hr ⁇ 5min and cooled to 10 ⁇ 2°C under nitrogen atmosphere. Then it was maintained for 4 hours ⁇ 5 min at 10 ⁇ 2°C.
- the reaction mass was further cooled slowly to 0 ⁇ 2°C and maintained for 1.0hr ⁇ 5min.
- the wet material was isolated by filtration and washed with isopropyl alcohol and dried completely under vacuum at 38 ⁇ 2°C to yield Tenofovir disoproxil Fumarate.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
An improved process for the preparation of Tenofovir disoproxil Fumarate using Wittig reagents as phase transfer catalyst.
Description
IMPROVED PROCESS FOR THE PREPARATION OF TENOFOVIR
FIELD OF THE INVENTION: The invention generally relates to a novel process for the preparation of Tenofovir. More specifically, the invention relates to process for the preparation of Tenofovir disoproxil Fumarate using catalytic amount of Wittig reagent which can be practiced on an industrial scale.
BACKGROUND OF THE INVENTION:
Tenofovir is approved for commercial use as in the form of Tenofovir disoproxil fumaric acid salt, chemically known as 9-[(R)-2-[[bis [[(isopropoxycarbonyl) oxy]methoxy] phosphinyl] methoxy] propyl] adenine Fumarate is represented by the following structure of Formula:
Tenofovir disoproxil Fumarate is a highly potent antiviral agent and is available in the market under the brand name VIREAD® in the form of 300mg of oral tablets and in combination with other antiviral agents.
U.S. Pat. No. 5,922,695 ("the '695 patent") discloses phosphonomethoxy nucleotide analogs such as Tenofovir disoproxil and the salts, hydrates, tautomers and solvates thereof. The '695 patent further discloses a process for preparation of Tenofovir disoproxil by esterification of Tenofovir with chloromethyl isopropyl carbonate using 1 -methyl-2-pyrrolidinone and triethylamine. In this patent Tenofovir Disoproxil is converted into its Fumarate salt without isolation.
Various processes for the synthesis of tenofovir disoproxil and its salts has been disclosed in the patent/ patent applications i.e., US2004/0018150, US6465649, US5935946, US5977089. US 20130005969 describes the process for the preparation of Tenofovir which involves the usage of phase transfer catalyst and it describes the phase transfer catalysts as tertramethyl ammonium bromide, tetrabutyl ammonium bromide, methyl triethyl ammonium bromide, benzyl trimethyl ammonium bromide, benzyl triethyl ammonium bromide, molecular sieves and crown ethers.
WO 2011/111074 describes a process for the preparation of Tenofovir Disoproxil which involves esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, phase transfer catalyst optionally dehydrating agent and converting Tenofovir Disoproxil into its pharmaceutically acceptable salts.
In the above mentioned prior art processes, it is found that a relatively large amount of quaternary ammonium, as a phase transfer catalyst, has been used to proceed up the reaction rapidly. Moreover, a portion of the phase transfer catalyst is usually converted to by-products which often difficult and may be carry over in the final product.
It would be desirable to provide a process for the preparation of Tenofovir disoproxil Fumarate, which is simple, convenient and cost effective manner and on commercial scale using catalytic amount of wittig reagent. The present invention provides a process for the preparation of Tenofovir disoproxil Fumarate using a catalytic amount of wittig reagent which enhances the rate of reaction. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield. The process for the preparation of Wittig salts especially phosphonium salts has been disclosed in the prior art patents i.e., US3932485, US4122123, US6169209, US6187959 and US6423873.
So far the use of Wittig reagent as a phase transfer catalyst is not used in any prior art processes for the preparation of Tenofovir disoproxil Fumarate.
OBJECTIVE OF THE INVENTION:
The main object of the invention is to provide a novel process for the preparation of Tenofovir Disoproxil Fumarate using Wittig reagent.
Another object of the invention is to provide a simple, cost effective process for the preparation of Tenofovir Disoproxil Fumarate with high purity and without the formation of undesired impurities.
Yet another object of the present invention is to provide an efficient process which avoids the use of large quantities of catalysts.
Further object of the invention is to provide a process for preparation of Tenofovir Disoproxil Fumarate in high yield and purity in short span of time, thereby substantially minimize the product degradation.
SUMMARY OF THE INVENTION:
The present invention encompasses a process for the preparation of Tenofovir Disoproxil and its conversion to pharmaceutically acceptable salts using catalytic amount of Wittig reagent. Wittig salts are Quaternary phosphonium salts and the same can be defined with the general formula as given below:
RPPh X Where R=alkyl, benzyl, allylic and aryl and X is halogens.
One aspect of the invention provides a novel process by employing additives which can be used in catalytic amount. Also, it has now surprisingly been found that the catalytic amount of additives with dehydrating agent has overcome all the long felt need of an industrial viable process for the preparation of Tenofovir.
This process is valuable as well as viable for the production of Tenofovir with minimal reaction time and less by-products.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS:
The present invention relates to an improved process for the preparation of Tenofovir Disoproxil and its pharmaceutically acceptable salts comprising the steps of:
a) Esterifying Tenofovir with chloromethyl isopropyl carbonate in presence of a base, Wittig reagent and dehydrating reagent in a suitable solvent.
b) Optionally purifying Tenofovir disoproxil
c) Converting Tenofovir disoproxil into its pharmaceutically acceptable salts.
In one embodiment of the present invention, the esterification of Tenofovir monohydrate is carried out in the presence of a base and Wittig reagent, wherein base is selected from organic amine like trialkyl amine such as triethylamine, diisopropyl ethyl amine preferably triethylamine and the wittig reagent is selected from the group comprising Isopropyl triphenylphosphonium iodide, triphenylphosphonium bromide, n-propyl triphenyl phosphonium bromide, -propyl triphenyl phosphonium iodide, ethyl triphenylphosphonium iodide, ethyl triphenylphosphonium bromide, tert-butyl triphenylphosphonium iodide, tert-butyl triphenylphosphonium bromide.
In another embodiment of the present invention esterification of Tenofovir monohydrate is carried out in the presence of a dehydrating agent. The dehydrating agent is selected from silylated dehydrating agent such as trialkylsilylhalides, bis(trimethylsilyl)acetamide (BSA) and hexamethyldisilazane (HMDS), preferably trialkly silyl halides, more preferably trimethyl silyl chloride.
In another embodiment of the present invention esterification of Tenofovir monohydrate is carried out in a solvent selected from Acetonitrile, dimethyl formamide, N-methyl pyrrolidine, cyclohexane, ethyl acetate, isopropyl acetate, n-hepatne, isopropyl alcohol and water or mixtures thereof, preferably N-methyl pyrrolidine.
In another embodiment of the present invention, Tenofovir Disoproxil is converted into its pharmaceutically acceptable salt preferably Fumarate salt by the conventional methods.
During the esterification reaction it has been observed that due to prolonged heating of the reaction mass product starts degrading resulting impurities such as monoester. In view of this observation it is important to complete the esterification reaction in minimum possible time. Probably the esterification reaction takes place through the formation of triethyl amine salt of Tenofovir. The triethyl amine salt of Tenofovir is very limited solubility in the reaction media resulting in the formation of heterogenous reaction system. We have observed that addition of Wittig reagent such as n-propyl triphenylphosphonium bromide, Isopropyl triphenylphosphonium Iodide etc., improved the rate of reaction.
According to the present invention, by using Wittig reagent along with dehydrating agents the yield of Tenofovir Disoproxil and its pharmaceutically acceptable salts is increased from 50% to 90%. The dimer impurity formed by the prior art processes is minimized by using this invention.
The following are the advantages of the present invention over the prior art process:
• Less catalytic amounts of Wittig salts are used which is tenfold less than the prior art processes
• Reaction completes within short span of time
• Ease of handling and recycling of Wittig salts
The following non limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.
Example-1
Preparation of Tenofovir disoproxil free base Cyclohexane (700ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (lOO.Og, (1.0X)) were taken at 30±5°C under nitrogen atmosphere. To this triethyl amine (66.0g) was added and heated to 80±5°C. Water was collected azeotropically at 80±5°C. After completion of water removal, NMP (350ml), trimethyl silyl chloride (7.12g) was charged and stirred for 30 mins at 30°±5. Triethylamine (79.57g) was added and heated the reaction mass to 52±2°C. To the reaction mass, Chloromethyl isopropyl carbonate (250.0g) and n-propyl triphenylphosphonium bromide (12.62g, O.leq) was added and maintained for 5.0hrs±lhr. The reaction was monitored by HPLC (Conversion usually 84.3%). Pre-cooled process water (12.0 X) was added after reaction completion and isolated by filtration and wet cake washed with water & followed by cyclohexane. The wet Tenofovir disoproxil was charged into methylene dichloride (600ml) and again washed with water at 12± 3°C and treated with sodium sulphate. The dried organic layer was concentrated under vacuum below 35 °C. MDC traces are removed by adding cyclohexane and followed by distillation under vacuum below 35°C. To this reaction mass ethyl acetate was added and maintained for 1.0hrs±5min at 22±2°C. Then cooled to - 3±2°C, maintained for 3.0hrs±5min. Reaction mass was filtered and washed with pre-cooled ethyl acetate and Cyclohexane mixture. The isolated wet product was dried completely under vacuum at 32.5 ± 2.5°C.
Yield: 145.0g; HPLC Purity: 99.58%
Example-2
Preparation of Tenofovir disoproxil free base
Cyclohexane (350ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (50.0g) were taken at 30±5°C under nitrogen atmosphere. To this triethyl amine (33 g) was added and heated to 80±5°C. Water was collected azeotropically at 80±5°C. After completion of water removal, NMP (150ml), trimethyl silyl chloride (3.56 g) was charged and stirred for 30 mins at
30°±5. Triethylamine (79.57g) was added and heated the reaction mass to 52±2°C. Chloromethyl isopropyl carbonate (125.0 g), and Isopropyl triphenylphosphonium Iodide (7.08 g, O.leq) were added to the reaction mass and maintained for 5.0hrs±lhr. The reaction was monitored by HPLC (Conversion usually 80-85%). Pre-cooled process water (12.0 X) was added after reaction completion and isolated by filtration and wet cake was washed with water & followed by cyclohexane. The wet Tenofovir Disoproxil was charged into methylene dichloride (6.0 X) and again washed with water at 12± 3°C and treated with sodium sulphate. The dried organic layer was concentrated under vacuum below 35°C. MDC traces are removed by adding cyclohexane and followed by distillation under vacuum below 35 °C. To this reaction mass ethyl acetate was added and maintained for 1.0hrs±5min at 22±2°C. Cyclohexane was added and maintained for 1.0hrs±5min at 22±2°C, cooled to -3±2°C; maintained for 4.0hrs±5min. Reaction mass was filtered and washed with pre-cooled cyclohexane and ethyl acetate mixture followed by Cyclohexane. The isolated wet product was dried completely under vacuum at 32.5 ± 2.5°C. Yield: 61.0g; HPLC Purity: 93.07%
Example-4
Preparation of Tenofovir disoproxil free base Cyclohexane (28 L) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (4.0kg) were taken at 30±5°C under nitrogen atmosphere. Triethyl amine (2.64 kg) was added and heated to 80±5°C. Water was collected azeotropically at 80±5°C. After completion of water removal, NMP (14.4kg), trimethyl silyl chloride (0.285 kg) was charged and stirred for 30 mins at 30°±5. Triethylamine (3.18Kg) was added and heated the reaction mass to 52±2°C. To the reaction mass added chloromethyl isopropyl carbonate (10.0 kg), n-propyl triphenylphosphonium bromide (0.505kg, O.leq) and maintained for 5.0hrs±lhr. The reaction was monitored by HPLC (Conversion usually 80-85%). Pre-cooled process water (12.0 X) was added after reaction completion and isolated by filtration and wet cake washed with water & followed by cyclohexane. The wet Tenofovir Disoproxil was charged into methylene dichloride (6.0 lit X) and again washed with water at 12± 3°C and then dilute Aq. Ammonia washed to remove the MonoPOC PMPA impurity and treated with sodium sulphate. The dried organic
layer was concentrated under vacuum below 35°C. MDC traces are removed by adding cyclohexane and followed by distillation under vacuum below 35°C. To this reaction mass ethyl acetate was added and maintained for 1.0hrs±5min at 22±2°C. Then added Cyclohexane and maintained for 1.0hrs±5min at 22±2°C, cooled to -3±2°C; maintained for 4.0hrs±5min. Reaction mass was filtered and washed with pre-cooled cyclohexane and ethyl acetate mixture followed by Cyclohexane. The isolated wet product was dried completely under vacuum at 32.5 ± 2.5°C. Yield: 5.30 kg; HPLC Purity: 98.20%
Example-4
Preparation of Tenofovir disoproxil Fumarate
Cyclohexane (1400ml) and 9-[(R)-2-(Phoshonomethoxy) propyl] adenine monohydrate (200.0g) were taken at 30°C to 35 °C under nitrogen atmosphere. Triethyl amine (132.0g) was added and heated to 80°C to 85°C. Water was collected azeotropically at 80°C to 85°C. Cyclohexane was distilled off completely after removal of water. NMP (700ml) and trimethyl silyl chloride (14.24g) was charged and stirred for 30mins.Triethyl amine (66.0g) was added and the reaction mass was heated to 52°C to 54°C. To the reaction mass added chloromethyl isopropyl carbonate (500 g), n-propyl triphenylphosphonium bromide (25.2 g, O.leq) and maintained for 4.0hrs±5min. The reaction mass was monitored by HPLC (Conversion usually 80-85%). Pre- cooled process water (2400 ml) was added after reaction completion and isolated by filtration and wet cake slurry with Pre-chilled water & followed by cyclohexane wash (800ml). The wet Tenofovir Disoproxil was charged into methylene dichloride (300ml) and again washed with water at 12±3°C and then dilute Aq. Ammonia wash to remove the MonoPOC PMPA impurity and finally washed with dilute fumaric acid solution treated with sodium sulphate. The dried organic layer was added to the Isopropyl alcohol/Fumaric acid solution at 52±3°C. The methylene dichloride/Isopropyl alcohol was distilled out (4.0X) and cooled to 25-35°C, reaction mass was stirred for lhr. The reaction mass was cooled to 8±2°C and maintained for 4hrs at 8±2°C. Then cooled to 2±3°C and maintained for lhr.Filtered the product and washed with Isopropyl alcohol. The wet product was dried at 38°C to 40°C under reduced pressure to provide the title compound.
Yield: 250 g; HPLC Purity: 99.11 %
Example-5 Preparation of Tenofovir disoproxil Fumarate
Tenofovir free base (50.0g), fumaric acid (15.2g) were charged into isopropyl alcohol (440ml) and heated to 53±2°C to get a clear solution. Reaction mass was filtered through micron filter paper. The filtrate was allowed to crystallize out gradually by natural cooling for 12.0hrs±2hrs to 25±5°C. The reaction mass was maintained at 25±5°C for 1.0hr±5min and cooled to 10±2°C under nitrogen atmosphere. Then it was maintained for 4 hours ± 5 min at 10±2°C. The reaction mass was further cooled slowly to 0±2°C and maintained for 1.0hr±5min. The wet material was isolated by filtration and washed with isopropyl alcohol and dried completely under vacuum at 38±2°C to yield Tenofovir disoproxil Fumarate.
Yield: 53.0 g, HPLC Purity: 99.70%
Claims
A novel process for the preparation of Tenofovir disoproxil Fumarate using wittig reagents.
An improved method for the preparation of Tenofovir disoproxil Fumarate which comprises of the following steps.
a) Condensation of Tenofovir with chloromethyl isopropyl carbonate in the presence of base, Wittig reagent and a dehydrating agent in a solvent.
b) Optionally purifying Tenofovir Disoproxil and
c) Reacting Tenofovir disoproxil with fumaric acid and isopropyl alcohol to obtain Tenofovir disoproxil Fumarate.
The wittig reagent according to claim 1 is selected from Isopropyl triphenylphosphonium iodide, triphenylphosphonium bromide, n-propyl triphenyl phosphonium bromide, - propyl triphenyl phosphonium iodide, ethyl triphenylphosphonium iodide, ethyl triphenylphosphonium bromide, tert-butyl triphenylphosphonium iodide, tert-butyl triphenylphosphonium bromide.
The dehydrating agent according to claim 2 is selected from Trimethyl sillyl chloride, acetic anhydride, Magnesium oxide, Calcium Oxide, Calcium chloride.
The solvent according to claim 2 is selected from Acetonitrile, dimethyl formamide, N- methyl pyrrolidine, cyclohexane, ethyl acetate, isopropyl acetate, n-heptane, isopropyl alcohol and water or mixtures thereof.
Use of Wittig reagent as a Phase transfer catalyst for the preparation of Tenofovir Disoproxil Fumarate.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1035CH2013 | 2013-03-12 | ||
IN1035/CHE/2013 | 2013-03-12 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2014141092A2 true WO2014141092A2 (en) | 2014-09-18 |
WO2014141092A3 WO2014141092A3 (en) | 2014-12-24 |
Family
ID=51538226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2014/059675 WO2014141092A2 (en) | 2013-03-12 | 2014-03-12 | Improved process for the preparation of tenofovir |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2014141092A2 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105440076A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate |
CN105440077A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate |
CN105440078A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate conveniently |
CN105481897A (en) * | 2015-12-31 | 2016-04-13 | 苏州弘森药业有限公司 | New method for preparing tenofovir disoproxil fumarate |
CN105481898A (en) * | 2015-12-31 | 2016-04-13 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir fumarate by two-step process |
CN105566393A (en) * | 2015-12-31 | 2016-05-11 | 苏州弘森药业有限公司 | Synthetic method of tenofovir disoproxil fumarate |
CN111171076A (en) * | 2019-12-26 | 2020-05-19 | 合肥启旸生物科技有限公司 | Preparation method of tenofovir dimer |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5498787A (en) * | 1994-04-20 | 1996-03-12 | Standard Chemical & Pharmaceutical Co., Ltd. | Method for preparing cephalosporin derivatives |
US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
WO2010026603A2 (en) * | 2008-09-05 | 2010-03-11 | Matrix Laboratories Limited | Novel amine salts of tenofovir, process for producing the same and use thereof in production of tenofovir dioproxil |
US20110112292A1 (en) * | 2008-04-25 | 2011-05-12 | Cipla Limited | Crystalline Form of Tenofovir Disoproxil and a Process for Its Preparation |
-
2014
- 2014-03-12 WO PCT/IB2014/059675 patent/WO2014141092A2/en active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5498787A (en) * | 1994-04-20 | 1996-03-12 | Standard Chemical & Pharmaceutical Co., Ltd. | Method for preparing cephalosporin derivatives |
US5922695A (en) * | 1996-07-26 | 1999-07-13 | Gilead Sciences, Inc. | Antiviral phosphonomethyoxy nucleotide analogs having increased oral bioavarilability |
US20110112292A1 (en) * | 2008-04-25 | 2011-05-12 | Cipla Limited | Crystalline Form of Tenofovir Disoproxil and a Process for Its Preparation |
WO2010026603A2 (en) * | 2008-09-05 | 2010-03-11 | Matrix Laboratories Limited | Novel amine salts of tenofovir, process for producing the same and use thereof in production of tenofovir dioproxil |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105440076A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for preparing tenofovir disoproxil fumarate |
CN105440077A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate |
CN105440078A (en) * | 2015-12-31 | 2016-03-30 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir disoproxil fumarate conveniently |
CN105481897A (en) * | 2015-12-31 | 2016-04-13 | 苏州弘森药业有限公司 | New method for preparing tenofovir disoproxil fumarate |
CN105481898A (en) * | 2015-12-31 | 2016-04-13 | 苏州弘森药业有限公司 | Method for synthesizing tenofovir fumarate by two-step process |
CN105566393A (en) * | 2015-12-31 | 2016-05-11 | 苏州弘森药业有限公司 | Synthetic method of tenofovir disoproxil fumarate |
CN111171076A (en) * | 2019-12-26 | 2020-05-19 | 合肥启旸生物科技有限公司 | Preparation method of tenofovir dimer |
Also Published As
Publication number | Publication date |
---|---|
WO2014141092A3 (en) | 2014-12-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2014141092A2 (en) | Improved process for the preparation of tenofovir | |
TWI709567B (en) | Methods for preparing anti-viral nucleotide analogs | |
US8759515B2 (en) | Process for the preparation of tenofovir disoproxil fumarate | |
WO2012081032A1 (en) | Process for the preparation of tenofovir | |
CN102143967B (en) | Purification method for adefovir dipivoxil | |
CA2628098A1 (en) | Process for the preparation of (.omega.-aminoalkylamino)alkyl halides and conversion to amifostine | |
WO2014118805A1 (en) | Process for the preparation of ivacaftor and solvates thereof | |
US9056882B2 (en) | Process for the preparation of tenofovir | |
KR20100103427A (en) | Improved process for preparing meropenem using zinc powder | |
WO2010026603A2 (en) | Novel amine salts of tenofovir, process for producing the same and use thereof in production of tenofovir dioproxil | |
ES2836118T3 (en) | Procedure for the Preparation of a Nitric Oxide Donor Prostaglandin Analog | |
WO2014097306A1 (en) | Stable and pure polymorphic form of bortezomib | |
WO2009075776A1 (en) | Process for the preparation of retapamulin and its intermediates | |
CN103804414A (en) | Intermediate compound for preparing rosuvastatin calcium and method for preparing rosuvastatin calcium from rosuvastatin calcium | |
KR101909570B1 (en) | Preparation method for highly pure tenofovir disoproxil | |
JP4511368B2 (en) | Phosphorodiamidite production method | |
KR101195631B1 (en) | New Synthetic Method of 9-[2-phosphonomethoxyethyl]adenine | |
JP4178378B2 (en) | Method for producing chlorosilane compound | |
AU2016228317B2 (en) | Methods for preparing anti-viral nucleotide analogs | |
WO2005009970A1 (en) | An improved process for the preparation of gatifloxacin | |
JP2020521764A (en) | Pyrazole amine reactive crystallization | |
WO2011158259A1 (en) | Novel process for the preparation of (3s)-tetrahydrofuran-3-yl (is, 2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-(phosphonooxy) propylcarbamate and its pharmaceutically acceptable salts thereof | |
HU184819B (en) | Process for preparing o,o-dialkyl-s-/benzazimido-methyl/-thiol-phosphoric acid esters | |
WO2012114280A1 (en) | An improved process for the preparation of pyrrolidine thiol derivatives useful in the synthesis of carbapenem compounds | |
WO2005030781A1 (en) | Process for the preparation of 3-amino-2-hydroxypropylphosphinic acid derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14765180 Country of ref document: EP Kind code of ref document: A2 |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14765180 Country of ref document: EP Kind code of ref document: A2 |