CN111484529A - Method for synthesizing tenofovir monophenyl ester - Google Patents
Method for synthesizing tenofovir monophenyl ester Download PDFInfo
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- CN111484529A CN111484529A CN201910078783.8A CN201910078783A CN111484529A CN 111484529 A CN111484529 A CN 111484529A CN 201910078783 A CN201910078783 A CN 201910078783A CN 111484529 A CN111484529 A CN 111484529A
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- China
- Prior art keywords
- tenofovir
- diphenyl iodonium
- monophenyl ester
- synthesizing
- solvent
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- 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 60
- 229960004556 tenofovir Drugs 0.000 title claims abstract description 45
- ITAMCOCNZJPJDF-UHFFFAOYSA-N 1-(6-aminopurin-9-yl)propan-2-yloxymethyl-phenoxyphosphinic acid Chemical compound C1=NC2=C(N)N=CN=C2N1CC(C)OCP(O)(=O)OC1=CC=CC=C1 ITAMCOCNZJPJDF-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000007787 solid Substances 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000010410 layer Substances 0.000 claims abstract description 17
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012044 organic layer Substances 0.000 claims abstract description 10
- OZLBDYMWFAHSOQ-UHFFFAOYSA-N diphenyliodanium Chemical class C=1C=CC=CC=1[I+]C1=CC=CC=C1 OZLBDYMWFAHSOQ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 239000003021 water soluble solvent Substances 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- -1 diphenyl iodonium hexafluoroarsenate Chemical compound 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- SBQIJPBUMNWUKN-UHFFFAOYSA-M diphenyliodanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.C=1C=CC=CC=1[I+]C1=CC=CC=C1 SBQIJPBUMNWUKN-UHFFFAOYSA-M 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LGPSGXJFQQZYMS-UHFFFAOYSA-M diphenyliodanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[I+]C1=CC=CC=C1 LGPSGXJFQQZYMS-UHFFFAOYSA-M 0.000 claims description 3
- ZCQCKDXLBKERRC-UHFFFAOYSA-M diphenyliodanium;fluoride Chemical compound [F-].C=1C=CC=CC=1[I+]C1=CC=CC=C1 ZCQCKDXLBKERRC-UHFFFAOYSA-M 0.000 claims description 3
- VFLZSOJENDKXJE-UHFFFAOYSA-M diphenyliodanium;methanesulfonate Chemical compound CS([O-])(=O)=O.C=1C=CC=CC=1[I+]C1=CC=CC=C1 VFLZSOJENDKXJE-UHFFFAOYSA-M 0.000 claims description 3
- CQZCVYWWRJDZBO-UHFFFAOYSA-N diphenyliodanium;nitrate Chemical compound [O-][N+]([O-])=O.C=1C=CC=CC=1[I+]C1=CC=CC=C1 CQZCVYWWRJDZBO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- UMIKAXKFQJWKCV-UHFFFAOYSA-M diphenyliodanium;4-methylbenzenesulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1.C=1C=CC=CC=1[I+]C1=CC=CC=C1 UMIKAXKFQJWKCV-UHFFFAOYSA-M 0.000 claims description 2
- RSJLWBUYLGJOBD-UHFFFAOYSA-M diphenyliodanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[I+]C1=CC=CC=C1 RSJLWBUYLGJOBD-UHFFFAOYSA-M 0.000 claims description 2
- WQIRVUAXANLUPO-UHFFFAOYSA-M diphenyliodanium;iodide Chemical compound [I-].C=1C=CC=CC=1[I+]C1=CC=CC=C1 WQIRVUAXANLUPO-UHFFFAOYSA-M 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003799 water insoluble solvent Substances 0.000 claims 1
- 239000000706 filtrate Substances 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 description 3
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.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.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 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 description 3
- 229960001355 tenofovir disoproxil Drugs 0.000 description 3
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- KUMNEOGIHFCNQW-UHFFFAOYSA-N diphenyl phosphite Chemical compound C=1C=CC=CC=1OP([O-])OC1=CC=CC=C1 KUMNEOGIHFCNQW-UHFFFAOYSA-N 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- MZTPSHAQKGUMBY-UHFFFAOYSA-N n,n-diethylethanamine;phenol Chemical compound CCN(CC)CC.OC1=CC=CC=C1 MZTPSHAQKGUMBY-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960004946 tenofovir alafenamide Drugs 0.000 description 1
- 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 description 1
- 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 description 1
- OJAJJFGMKAZGRZ-UHFFFAOYSA-N trimethyl(phenoxy)silane Chemical compound C[Si](C)(C)OC1=CC=CC=C1 OJAJJFGMKAZGRZ-UHFFFAOYSA-N 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 invention discloses a method for synthesizing tenofovir monophenyl ester, which comprises the following steps: adding tenofovir (PMPA), diphenyl iodonium salt, an acid-binding agent and a solvent into a reaction bottle, detecting after reacting for a period of time, adding dilute hydrochloric acid to adjust the pH to be below 1 when the reaction is complete, layering, adding sodium carbonate into a water layer to neutralize to 2-3, separating out solids, and filtering. If the solvent is a water-soluble solvent, dichloromethane and dilute hydrochloric acid are added to adjust the pH value to be below 1, an organic layer is extracted and separated, sodium carbonate is added into a water layer to neutralize the water layer to 2-3, solid is separated out, and the filtrate is filtered and dried to obtain tenofovir monophenyl ester.
Description
Technical Field
The invention relates to a method for synthesizing tenofovir monophenyl ester, and belongs to the technical field of pharmaceutical chemicals.
Background
Tenofovir Alafenamide Fumarate (TAF) is a novel Nucleoside Reverse Transcriptase Inhibitor (NRTI), and in clinical trials, it has been shown that it has a very high antiviral effect at a dose less than one tenth of the dose of Viread (Viread, TDF) which is a commercially available drug in Gilidard, and can improve renal and skeletal parameters. By analysis and comparison of published patent and journal literature, we summarize the main synthetic routes for TAF as follows:
The route takes tenofovir (PMPA) as a raw material, and tenofovir alafenamide is obtained by phenoxy esterification and chiral phosphoramidite. The synthesis of a key intermediate tenofovir monophenyl ester mainly comprises the following methods:
Patent US7390791 provides a process in which anhydrous PMPA and phenol are subjected to a dehydration reaction in NMP by DCC, and tenofovir monophenyl ester is obtained by post-treatment after the reaction is completed, the process yield is low, and a large amount of salt is generated by post-treatment.
Patent WO2002008241 provides a method, anhydrous PMPA is firstly reacted with thionyl chloride in sulfolane and DMF, then phenoxy trimethylsilane is added, and the tenofovir monophenyl ester is obtained after the reaction is finished and post-treatment.
Patent US8664386 provides a method, which comprises reacting anhydrous PMPA with triethylamine and DMAP in acetonitrile, adding triphenyl phosphite, and post-treating after the reaction to obtain tenofovir monophenyl ester, which has a high yield, but we have found that the removal of diphenyl phosphite and triethylamine phenol, which are by-products of the reaction, is difficult, and very complicated post-treatment is required to obtain qualified tenofovir monophenyl ester.
By analyzing the existing literature data, a new method for synthesizing tenofovir monophenyl ester is researched and developed to replace the existing synthetic route with low yield and large environmental protection pressure, and the industrial production is better realized.
Disclosure of Invention
The invention aims to provide a method for synthesizing tenofovir monophenyl ester, which can improve the reaction yield while solving the technical problems.
The invention provides a method for preparing tenofovir monophenyl ester, which comprises the following steps:
The method comprises the following steps: adding tenofovir (PMPA), diphenyl iodonium salt, an acid-binding agent and a solvent into a reaction bottle, detecting after reacting for a period of time, adding dilute hydrochloric acid to adjust the pH to be below 1 when the reaction is complete, layering, adding sodium carbonate into a water layer to neutralize to 2-3, separating out solids, and filtering. And if the solvent is a water-soluble solvent, adding dichloromethane and dilute hydrochloric acid to adjust the pH value to be below 1, extracting and removing an organic layer, adding sodium carbonate into a water layer to neutralize the water layer to 2-3, separating out solids, filtering and drying to obtain tenofovir monophenyl ester.
The diphenyliodonium salts are diphenyliodonium salts such as diphenyliodonium hexafluoroarsenate, diphenyliodonium hexafluorophosphate, diphenyliodonium hexafluoroantimonate, diphenyliodonium nitrate, diphenyliodonium p-toluenesulfonate, diphenyliodonium tetrafluoroborate, diphenyliodonium fluoride, diphenyliodonium chloride, diphenyliodonium bromide, diphenyliodonium iodide, diphenyliodonium trifluoromethanesulfonate and diphenyliodonium methanesulfonate, and preferably are diphenyliodonium trifluoromethanesulfonate.
The acid-binding agent is base such as triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, potassium tert-butoxide, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate and the like, and triethylamine is preferred.
The molar ratio of the PMPA to the diphenyl iodonium salt to the acid-binding agent is 1: 1-2: 1 to 2.
The solvent is a single solvent or a mixed solvent such as tetrahydrofuran, dichloromethane, N, N-Dimethylformamide (DMF), N, N-Dimethylformamide (DMA), N-methylpyrrolidone (NMP), butyl acetate, dimethyl sulfoxide, toluene, acetonitrile, water and the like, and toluene is preferred.
The reaction temperature is 20-130 ℃.
further, the amount concentration of PMPA material as the raw material is generally 2.0 mol/L to 10.0 mol/L.
Compared with the reported method for synthesizing tenofovir monophenyl ester, the synthesis method has the advantages of high yield, simple operation, less three wastes and the like.
Detailed Description
The examples given are merely intended to be illustrative of the products or methods of the invention in general terms, and are intended to facilitate a better understanding of the invention, and not to limit the scope of the invention. The experimental methods described in the following examples are all conventional methods unless otherwise specified; the materials are commercially available, unless otherwise specified.
Example 1
adding 28.7g (0.10mol,1.0equiv) of tenofovir, 43.0g (0.10mol,1.0equiv) of diphenyl iodonium trifluoromethanesulfonate, 11.1g (0.11mol,1.1equiv) of triethylamine and 500ml of toluene into a reaction kettle under the protection of nitrogen, heating to reflux, detecting by using a T L C to control the reaction end point, reducing the temperature to 0 ℃ after the reaction is finished, adding dilute hydrochloric acid to adjust the pH to be less than 1, separating a toluene layer, slowly adding a sodium carbonate solid into a water layer to adjust the pH to be 2-3, stirring for half an hour, filtering, and drying to obtain 32.1g of white solid tenofovir monophenyl ester, wherein the molar yield is 88.3%, and the purity of the HP L C is 97.5%.
Example 2
under the protection of nitrogen, 28.7g (0.10mol,1.0equiv) of tenofovir, 36.8g (0.10mol,1.0equiv) of diphenyliodonium tetrafluoroborate, 14.6g (0.12mol,1.2equiv) of 4-dimethylaminopyridine and 300ml of butyl acetate are added into a reaction kettle, the mixture is heated to reflux, the reaction end point is controlled by TLC detection, the temperature is reduced to 0 ℃, dilute hydrochloric acid is added to adjust the pH to be below 1, an organic layer is removed, sodium carbonate solid is slowly added into a water layer to adjust the pH to be 2-3, the mixture is stirred for half an hour, filtered and dried to obtain 31.6g of white solid tenofovir monophenyl ester, the molar yield is 87.0%, and the purity of HP L C is 98.2%.
Example 3
under the protection of nitrogen, 28.7g (0.10mol,1.0equiv) of tenofovir, 36.8g (0.10mol,1.0equiv) of diphenyl iodonium hexafluorophosphate, 14.2g (0.11mol,1.1equiv) of diisopropylethylamine and 200ml of acetonitrile are added into a reaction kettle, the mixture is heated to reflux, the T L C detects and controls the reaction end point, when the reaction is finished, the temperature is reduced to 0 ℃, 150ml of dichloromethane is added, dilute hydrochloric acid is added to adjust the pH to be below 1, an organic layer is removed, sodium carbonate solid is slowly added into a water layer to adjust the pH to be 2-3, the mixture is stirred for half an hour, filtered and dried to obtain 30.6g of white solid tenofovir monophenyl ester, the molar yield is 84.2%, and the purity of HP L C is 97.8%.
Example 4
under the protection of nitrogen, 28.7g (0.10mol,1.0equiv) of tenofovir, 47.0g (0.10mol,1.0equiv) of diphenyl iodonium hexafluoroarsenate, 9.5g (0.12mol,1.2equiv) of pyridine and 100ml of N-methylpyrrolidone are added into a reaction kettle, the mixture is heated to 60 ℃, the T L C detection controls the reaction end point, when the reaction is finished, the temperature is reduced to 0 ℃, diluted hydrochloric acid is added to adjust the pH to be less than 1, 200ml of water is added, 250ml of dichloromethane is added to extract twice, organic layers are removed, sodium carbonate solid is slowly added into a water layer to adjust the pH to be 2-3, the mixture is stirred for half an hour, filtered and dried, 26.2g of white solid tenofovir monophenyl ester is obtained, the molar yield is 72.1%, and the purity of the L C is 99.2%.
Example 5
adding 28.7g (0.10mol,1.0equiv) of tenofovir, 68.6g (0.20mol,2.0equiv) of diphenyl iodonium nitrate, 22.4g (0.20mol,2.0equiv) of potassium tert-butoxide and 400ml of dichloromethane into a reaction kettle under the protection of nitrogen, heating to reflux, detecting by using a T L C to control the reaction end point, reducing the temperature to 0 ℃ after the reaction is finished, adding diluted hydrochloric acid to adjust the pH to be less than 1, separating an organic layer, slowly adding a sodium carbonate solid into a water layer to adjust the pH to be 2-3, stirring for half an hour, filtering, and drying to obtain 29.2g of white solid tenofovir monophenyl ester, wherein the molar yield is 80.1%, and the purity of the HP L C is 97.2%.
Example 7
adding 28.7g (0.10mol,1.0equiv) of tenofovir, 30.0g (0.10mol,1.0equiv) of diphenyl iodonium fluoride salt, 21.2g (0.10mol,1.0equiv) of potassium phosphate and 150ml of N, N-dimethylformamide into a reaction kettle under the protection of nitrogen, heating to 80 ℃, detecting and controlling the reaction end point by using TL C, reducing the temperature to 0 ℃, adding diluted hydrochloric acid to adjust the pH to be less than 1, adding 200ml of water, adding 250ml of dichloromethane and 2 for extraction twice, removing an organic layer, slowly adding a sodium carbonate solid into a water layer to adjust the pH to 2-3, stirring for half an hour, filtering and drying to obtain 26.9g of white solid tenofovir monophenyl ester, wherein the molar yield is 74.1%, and the purity of HP L C is 98.9%.
Example 7
adding 28.7g (0.10mol,1.0equiv) of tenofovir disoproxil, 15.2g (0.15mol,1.5equiv) of triethylamine and 200ml of drinking water into a reaction kettle under the protection of nitrogen, stirring for half an hour, adding 56.4g (0.15mol,1.5equiv) of diphenyl iodonium methanesulfonate, reacting at room temperature, detecting by TLC to control the reaction end point, reducing the temperature to 0 ℃, adding dilute hydrochloric acid to adjust the pH to be less than 1, adding 250ml of dichloromethane to 2, extracting for two times, separating an organic layer, slowly adding a sodium carbonate solid into a water layer to adjust the pH to 2-3, stirring for half an hour, filtering, and drying to obtain 22.9g of white solid tenofovir HP monophenyl ester, wherein the molar yield is 63.0%, and the purity of L C is 97.8%.
Example 8
under the protection of nitrogen, 28.7g (0.10mol,1.0equiv) of tenofovir, 36.0g (0.10mol,1.0equiv) of diphenyliodonium bromide salt, 10.6g (0.10mol,1.0equiv) of sodium carbonate, 150ml of toluene and 150ml of butyl acetate are added into a reaction kettle, the mixture is heated to 80 ℃, the reaction end point is controlled by TLC detection, the temperature is reduced to 0 ℃, dilute hydrochloric acid is added to adjust the pH to be below 1 after the reaction is finished, an organic layer is removed, sodium carbonate solid is slowly added into a water layer to adjust the pH to be 2-3, the mixture is stirred for half an hour, filtered and dried to obtain 31.3g of white solid tenofovir monophenyl ester, the molar yield is 86.3%, and the purity C of HP L is 97.9%.
Claims (8)
1. A method for synthesizing tenofovir monophenyl ester is characterized by comprising the following steps: adding tenofovir (PMPA), diphenyl iodonium salt, an acid-binding agent and a water-insoluble solvent into a reaction vessel, reacting completely, adding dilute hydrochloric acid to adjust the pH to be below 1, layering, adding sodium carbonate into a water layer to neutralize the pH to 2-3, separating out solids, and filtering to obtain tenofovir monophenyl ester.
2. A method for synthesizing tenofovir monophenyl ester is characterized by comprising the following steps: adding tenofovir (PMPA), diphenyl iodonium salt, an acid-binding agent and a water-soluble solvent into a reaction vessel, reacting completely, adding dichloromethane and dilute hydrochloric acid to adjust the pH to be below 1, extracting and removing an organic layer, adding sodium carbonate into a water layer to neutralize to 2-3, separating out solids, filtering and drying to obtain tenofovir monophenyl ester.
3. The method for synthesizing tenofovir monophenyl ester according to claim 1 or 2, characterized in that: the diphenyl iodonium salts are diphenyl iodonium triflate, diphenyl iodonium hexafluoroarsenate, diphenyl iodonium hexafluorophosphate, diphenyl iodonium hexafluoroantimonate, diphenyl iodonium nitrate, diphenyl iodonium p-toluenesulfonate, diphenyl iodonium tetrafluoroborate, diphenyl iodonium fluoride, diphenyl iodonium chloride, diphenyl iodonium bromide, diphenyl iodonium iodide and diphenyl iodonium methanesulfonate, preferably diphenyl iodonium triflate.
4. The method for synthesizing tenofovir monophenyl ester according to claim 1 or 2, characterized in that: the acid-binding agent is triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, potassium tert-butoxide, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and potassium bicarbonate, and triethylamine is preferred.
5. The method for synthesizing tenofovir monophenyl ester according to claim 1 or 2, characterized in that: the molar ratio of the PMPA to the diphenyl iodonium salt to the acid-binding agent is 1: 1-2: 1 to 2.
6. The method for synthesizing tenofovir monophenyl ester according to claim 1, characterized in that: the solvent is tetrahydrofuran, dichloromethane, N, N-Dimethylformamide (DMF), N, N-Dimethylformamide (DMA), N-methylpyrrolidone (NMP), butyl acetate, dimethyl sulfoxide, toluene or acetonitrile; the solvent is a single solvent or a mixed solvent, and toluene is preferred.
7. The method for synthesizing tenofovir monophenyl ester according to claim 1 or 2, characterized in that: the reaction temperature is 20-130 ℃.
8. the method for synthesizing tenofovir monophenyl ester according to claim 1 or 2, characterized in that the substance concentration of the raw material PMPA is 2.0 mol/L to 10.0 mol/L.
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|---|---|---|---|---|
| US20060116356A1 (en) * | 2004-04-14 | 2006-06-01 | Cai Zhenhong R | Phosphonate analogs of HIV integrase inhibitor compounds |
| CN107021984A (en) * | 2017-04-28 | 2017-08-08 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
| CN107522743A (en) * | 2017-09-30 | 2017-12-29 | 深圳科兴生物工程有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method |
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| US20060116356A1 (en) * | 2004-04-14 | 2006-06-01 | Cai Zhenhong R | Phosphonate analogs of HIV integrase inhibitor compounds |
| CN107021984A (en) * | 2017-04-28 | 2017-08-08 | 福建广生堂药业股份有限公司 | A kind of Preparation Method And Their Intermediate of TAF nucleoside derivates |
| CN107522743A (en) * | 2017-09-30 | 2017-12-29 | 深圳科兴生物工程有限公司 | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method |
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