CN111484527A - Preparation method of tenofovir alafenamide intermediate - Google Patents
Preparation method of tenofovir alafenamide intermediate Download PDFInfo
- Publication number
- CN111484527A CN111484527A CN201910072169.0A CN201910072169A CN111484527A CN 111484527 A CN111484527 A CN 111484527A CN 201910072169 A CN201910072169 A CN 201910072169A CN 111484527 A CN111484527 A CN 111484527A
- Authority
- CN
- China
- Prior art keywords
- reaction
- solvent
- hours
- compound
- halogenating agent
- Prior art date
- 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.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims description 9
- LDEKQSIMHVQZJK-CAQYMETFSA-N tenofovir alafenamide Chemical compound O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 LDEKQSIMHVQZJK-CAQYMETFSA-N 0.000 title abstract description 10
- 229960004946 tenofovir alafenamide Drugs 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 229940126214 compound 3 Drugs 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 28
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 28
- 230000002140 halogenating effect Effects 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 8
- 229940011051 isopropyl acetate Drugs 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000003759 ester based solvent Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 2
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 claims description 2
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 230000026030 halogenation Effects 0.000 abstract 1
- 238000005658 halogenation reaction Methods 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 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 description 6
- 239000007858 starting material Substances 0.000 description 4
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 4
- 239000002994 raw material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- -1 phenolic ester Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 125000000848 adenin-9-yl group Chemical group [H]N([H])C1=C2N=C([H])N(*)C2=NC([H])=N1 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 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
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
The present invention provides a method suitable for the industrial production of tenofovir alafenamide, and the inventors have found that in the reaction for preparing compound 3, the solvent is distilled off halfway, and the halogenation reagent and the reaction solvent are added again to continue the reaction, so that high-purity compound 3 which is a non-corresponding isomer can be obtained in a short time.
Description
Technical Field
The invention relates to a preparation process of a drug intermediate, in particular to a synthesis process of a tenofovir alafenamide intermediate.
Background
Tenofovir Alafenamide (TAF), which was approved by the FDA at 11 months of 2016, was marketed as the best drug for treating hepatitis B to date, wherein the chemical name is N- [ (S) - [ (1R) -2- (6-amino-9H-purin-9-yl) -1-methylethoxy ] methyl ] phenoxyphosphinyl ] -L-alanine-1-methylethyl ester hemifumarate, the structural formula is as follows:
at present, the methods suitable for large-scale production of tenofovir alafenamide all use tenofovir (PMPA) as a starting material, and the method comprises the following steps of halogenating the starting material to form phenolic ester, halogenating the starting material, and amidating the starting material:
the patents which take the route as the main design idea mainly include:
in patent CN103842366B, PMPA is used as a raw material to prepare a high-purity chiral compound 3, wherein the chiral purity reaches over 90 percent. The main defect of the patent is that the preparation efficiency is not high, and in the process of configuration transformation, a relatively long reaction time is needed, and the requirement can be met only in 48-96 hours; compound 2 is prepared by treating PMPA with triphenyl phosphite in the presence of a suitable base; triphenyl phosphite is expensive and a toxic, harmful, pungent odor substance; the yield is at most 81%, see example 5 of the patent specification.
Patent CN201710005963.4, PMPA is used as raw material, after double chlorination of PMPA, phenol ester and amidation are constructed by one-step method, the patent shortens the operation process, but when constructing the chirality of compound TAF, half of racemization product is generated, and the preparation efficiency is not high.
Disclosure of Invention
From the above analysis, it is known that compound 3 is an important intermediate for the preparation of tenofovir alafenamide. The invention aims to provide a method for preparing a tenofovir alafenamide intermediate, which is simple to operate, cheap in raw materials and mild in reaction, and is suitable for industrial production, so as to overcome the defects of the prior art.
The inventors have surprisingly found that, in the reaction for preparing the compound 3, the time for obtaining the compound 3 having a high purity of the diastereomer can be greatly shortened by distilling off the solvent halfway and continuing the reaction by adding the halogenating agent and the reaction solvent again.
In order to achieve the aim, the invention adopts the following technical scheme:
synthesis of Compound 3
A process for preparing compound 3, wherein X is halo,
the method comprises the following steps: (1) treating compound 2 with a halogenating agent in the presence of a reaction solvent; (2) evaporating the solvent; (3) adding the halogenating reagent and the reaction solvent again; the reaction was continued to give compound 3 which was at least 90% non-corresponding isomer.
In some embodiments of the present invention for preparing compound 3, the total reaction time is less than 48 hours, preferably the total reaction time is 18 to 24 hours.
In some embodiments of the present invention for preparing compound 3, the solvent may be distilled off when the reaction proceeds for 1 to 18 hours, preferably, the solvent may be distilled off when the reaction proceeds for 1 to 5 hours, and more preferably, the solvent may be distilled off when the reaction proceeds for 3 to 5 hours.
In some embodiments of the present invention for preparing compound 3, the halogenating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosgene, triphosgene, phosphorus oxychloride, oxalyl bromide, phosphorus tribromide, phosphorus oxybromide, and phosphorus pentabromide, preferably, the halogenating agent is thionyl chloride.
In some embodiments of the present invention for preparing compound 3, the halogenating agent uses 1.5-10 times the equivalent of thionyl chloride.
In some embodiments of the present invention for preparing compound 3, the reaction solvent is selected from one or more of ester solvents and aromatic solvents, optionally, the ester solvents are selected from one or more of ethyl acetate, isopropyl acetate, ethyl formate, isopropyl formate, and the aromatic solvents are selected from one or more of toluene, xylene, and anisole; preferably, the reaction solvent is toluene or a mixture of toluene and isopropyl acetate.
Compared with the prior art, the invention mainly has the following advantages:
the preparation method of the compound 3 can obviously shorten the reaction time, has high chiral purity and obviously improves the industrial production efficiency.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
Compound 2(140g), toluene (1.4L), thionyl chloride (229.5g, 5eq) were added to a 2L three-necked flask, stirred, heated to 80 ℃, stirred and reacted for 3 hours, the solvent was distilled off under reduced pressure, thionyl chloride (229.5g, 5eq) and toluene (1.4L) were added again, the reaction was continued for 16 hours under stirring, and the solvent was distilled off under reduced pressure to obtain compound 3 having an isomer ratio of 95: 5.
In the reaction process, based on 0h of the initial reaction, after 3h of the reaction, the solvent is distilled off under reduced pressure, the ratio of the isomers detected by HP L C is 79:21, after 7h of the reaction, the ratio of the isomers detected by HP L C is 88:12, after 19h of the reaction, the solvent is distilled off under reduced pressure, and the ratio of the isomers detected by HP L C is 95: 5.
Example 2
Compound 2(50g), isopropyl acetate (0.5L) and thionyl chloride (82g, 5eq) were added to a 2L three-necked flask, stirred, heated to 80 ℃, stirred and reacted for 1 hour, the solvent of the reaction solution was distilled off under reduced pressure, thionyl chloride (82g, 5eq) and isopropyl acetate (0.5L) were added, the reaction was continued for 40 hours under stirring, and after the solvent was distilled off, compound 3 having an isomer ratio of 90.5:9.5 was obtained.
In the reaction process, by starting reaction for 0h, after the solvent of the reaction solution is evaporated under reduced pressure for 1h, sampling is carried out, the ratio of HP L C detected isomer is 75:25, sampling is carried out for 7h, the ratio of HP L C detected isomer is 86:14, sampling is carried out for 18h, the ratio of HP L C detected isomer is 90: 10, and the ratio of HP L C detected isomer is 90.5:9.5 after 41h of reaction is finished.
Example 3
Compound 2(50g), toluene/isopropyl acetate (0.4/0.1L) and thionyl chloride (50g, 3eq) were added to a 2L three-necked flask, stirred, heated to 80 ℃, stirred for 5 hours, the solvent was distilled off under reduced pressure, thionyl chloride (16.5g, 1eq) and toluene/isopropyl acetate (0.4/0.1L) were added again, and the reaction was continued for 40 hours with an isomer ratio of 92:8.
In the reaction process, by starting reaction for 0h, after the solvent is evaporated under reduced pressure for 5h, sampling is carried out, the ratio of HP L C detected isomer is 76:24, sampling is carried out for 10h, the ratio of HP L C detected isomer is 88:12, sampling is carried out for 24, the ratio of HP L C detected isomer is 91:9, and the ratio of HP L C detected isomer is 92:8 after 45h of reaction is finished.
Example 4
Compound 1(50g), acetonitrile/xylene (0.4/0.1L) and thionyl chloride (150g, 9eq) were added to a 2L three-necked flask, stirred, heated to 70 ℃, stirred and reacted for 5 hours, the solvent was distilled off under reduced pressure, thionyl chloride (16.5g, 1eq) and acetonitrile/xylene (0.4/0.1L) were added again, the reaction was continued for 30 hours with stirring, and after the solvent was distilled off, the isomer ratio was 92:8.
In the reaction process, the ratio of HP L C detected isomer is 80:20 after reaction for 5h, the ratio of HP L C detected isomer is 87:13 after reaction for 10h, the ratio of HP L C detected isomer is 90.5:9.5 after reaction for 20h, and the ratio of HP L C detected isomer is 92:8 after reaction for 35 h.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. A process for the preparation of compound 3,
wherein X is a halogen group, comprising the steps of: (1) reacting compound 2 with a halogenating agent in the presence of a reaction solvent; (2) evaporating the solvent; (3) the halogenating agent and the reaction solvent are added again and the reaction is continued to give compound 3 which is at least 90% diastereomer.
2. The process of claim 1, wherein the total reaction time is less than 48 hours, preferably the total reaction time is from 18 to 24 hours.
3. The production method of claim 1 or 2, wherein the solvent is distilled off when the reaction is carried out for 1 to 18 hours, preferably, when the reaction is carried out for 1 to 5 hours, more preferably, when the reaction is carried out for 3 to 5 hours.
4. The process according to any one of claims 1 to 3, wherein said halogenating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosgene, triphosgene, phosphorus oxychloride, oxalyl bromide, phosphorus tribromide, phosphorus oxybromide, phosphorus pentabromide, preferably said halogenating agent is thionyl chloride.
5. The process according to claim 4, wherein the halogenating agent is thionyl chloride in an equivalent amount of 1.5 to 10 times.
6. The production method according to any one of claims 1 to 5, wherein the reaction solvent is selected from one or more of ester solvents and aromatic solvents.
7. The preparation method of claim 6, wherein the ester solvent is selected from one or more of ethyl acetate, isopropyl acetate, ethyl formate and isopropyl formate, and the aromatic solvent is selected from one or more of toluene, xylene and anisole.
8. The process according to claim 6, wherein the reaction solvent is toluene or a mixture of toluene and isopropyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910072169.0A CN111484527A (en) | 2019-01-25 | 2019-01-25 | Preparation method of tenofovir alafenamide intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910072169.0A CN111484527A (en) | 2019-01-25 | 2019-01-25 | Preparation method of tenofovir alafenamide intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111484527A true CN111484527A (en) | 2020-08-04 |
Family
ID=71793843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910072169.0A Pending CN111484527A (en) | 2019-01-25 | 2019-01-25 | Preparation method of tenofovir alafenamide intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111484527A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114671915A (en) * | 2021-12-31 | 2022-06-28 | 浙江车头制药股份有限公司 | Preparation method of high diastereoisomer phosphonyl chloride |
| CN115651023A (en) * | 2022-12-28 | 2023-01-31 | 成都苑东生物制药股份有限公司 | Preparation method of key intermediate of propamol fumarate tenofovir alafenamide |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103842366A (en) * | 2011-10-07 | 2014-06-04 | 吉联亚科学公司 | Methods for preparing anti-viral nucleotide analogs |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
| CN106632484A (en) * | 2017-01-05 | 2017-05-10 | 上海厚璞生物科技有限公司 | Preparation method of tenofovir alafenamide |
| WO2017203395A1 (en) * | 2016-05-21 | 2017-11-30 | Shilpa Medicare Limited | Crystalline forms of tenofovir alafenamide hemi fumarate |
| CN108409790A (en) * | 2018-03-30 | 2018-08-17 | 南京哈柏医药科技有限公司 | A kind of tenofovir Chinese mugwort draws the easy synthesis technology of phenol amine hemifumarate |
| CN108822149A (en) * | 2018-06-01 | 2018-11-16 | 成都苑东生物制药股份有限公司 | A kind of fumaric acid tenofovir Chinese mugwort draws the preparation method of phenol amine key intermediate |
-
2019
- 2019-01-25 CN CN201910072169.0A patent/CN111484527A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103842366A (en) * | 2011-10-07 | 2014-06-04 | 吉联亚科学公司 | Methods for preparing anti-viral nucleotide analogs |
| WO2015161781A1 (en) * | 2014-04-21 | 2015-10-29 | 四川海思科制药有限公司 | Method for preparing nucleoside analogue and intermediate thereof |
| WO2017203395A1 (en) * | 2016-05-21 | 2017-11-30 | Shilpa Medicare Limited | Crystalline forms of tenofovir alafenamide hemi fumarate |
| CN106632484A (en) * | 2017-01-05 | 2017-05-10 | 上海厚璞生物科技有限公司 | Preparation method of tenofovir alafenamide |
| CN108409790A (en) * | 2018-03-30 | 2018-08-17 | 南京哈柏医药科技有限公司 | A kind of tenofovir Chinese mugwort draws the easy synthesis technology of phenol amine hemifumarate |
| CN108822149A (en) * | 2018-06-01 | 2018-11-16 | 成都苑东生物制药股份有限公司 | A kind of fumaric acid tenofovir Chinese mugwort draws the preparation method of phenol amine key intermediate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114671915A (en) * | 2021-12-31 | 2022-06-28 | 浙江车头制药股份有限公司 | Preparation method of high diastereoisomer phosphonyl chloride |
| CN114671915B (en) * | 2021-12-31 | 2024-04-09 | 浙江车头制药股份有限公司 | Preparation method of high diastereoisomer phosphonochloride |
| CN115651023A (en) * | 2022-12-28 | 2023-01-31 | 成都苑东生物制药股份有限公司 | Preparation method of key intermediate of propamol fumarate tenofovir alafenamide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101719011B1 (en) | Method for synthesis of (1S, 2R)-MILNACIPRAN | |
| CA2600008A1 (en) | Improved process for the synthesis of enantiomeric indanylamine derivatives | |
| JP2012519677A (en) | Process for producing cinacalcet and salts thereof, and intermediate used in the process | |
| CN111484527A (en) | Preparation method of tenofovir alafenamide intermediate | |
| CN111233829A (en) | Preparation method of nicotine with optical activity | |
| EP1442006B1 (en) | Preparation of amphetamines from phenylpropanolamines | |
| KR20110028647A (en) | Process for preparing cinacalcet and pharmaceutically acceptable salts thereof | |
| US9000205B2 (en) | Process for the preparation of 2-cyanophenylboronic acid and esters thereof | |
| CN110372749B (en) | Preparation method of phenyl PMPA (Permethoprim Perofovir) key intermediate | |
| CA2790519A1 (en) | Improved resolution methods for isolating desired enantiomers of tapentadol intermediates and use thereof for the preparation of tapentadol | |
| CN107827755B (en) | Synthesis method of ticagrelor intermediate (1R,2S) -2- (3, 4-difluorophenyl) cyclopropylamine | |
| US8779192B2 (en) | Process of preparing an alkylamine derivative | |
| CN107602382B (en) | Method for synthesizing chiral aryl allyl ether compound through organic catalysis | |
| CN111689852B (en) | Preparation method of 2,3,5,6-tetrachlorobenzoyl chloride | |
| WO2012146978A2 (en) | A novel process for the preparation of tapentadol or a pharmaceutically acceptable salt thereof | |
| CN104693025B (en) | A kind of method preparing 1,3-propanedicarboxylic acid list L-menthyl ester | |
| KR20100118747A (en) | Improved preparation method of sarpogrelate hydrochloride | |
| EP3230258B1 (en) | Process for the preparation of (1s,2r)-milnacipran | |
| KR101070721B1 (en) | Method for producing (z)-1-phenyl-1-diethylaminocarbonyl-2-hydroxymethyl cyclopropane | |
| WO2014009964A1 (en) | Process for enantiomeric enrichment of 2 ', 6 ' - pipecoloxylidide | |
| EP2814806B1 (en) | An improved process for the preparation of aliskiren | |
| EP2805936A1 (en) | Process for preparing levomilnacipran HCL | |
| CN113045468A (en) | Preparation method of brivaracetam intermediate | |
| CN1668586A (en) | Method for preparing 13 5-triaminobenzene and hydrolyzing it into high-purity phloroglucinal | |
| JPH07278077A (en) | Production of 1-aminocyclopropanecarboxylic acid hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200804 |