CN111484528A - Preparation method of tenofovir alafenamide intermediate - Google Patents
Preparation method of tenofovir alafenamide intermediate Download PDFInfo
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- CN111484528A CN111484528A CN201910072336.1A CN201910072336A CN111484528A CN 111484528 A CN111484528 A CN 111484528A CN 201910072336 A CN201910072336 A CN 201910072336A CN 111484528 A CN111484528 A CN 111484528A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 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 description 9
- 229960004946 tenofovir alafenamide Drugs 0.000 title description 9
- 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 claims abstract description 26
- 229940125782 compound 2 Drugs 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 19
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 15
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 13
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000002140 halogenating effect Effects 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000001704 evaporation Methods 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 4
- 150000002825 nitriles Chemical class 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940011051 isopropyl acetate Drugs 0.000 claims description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 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
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-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
- 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
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229960004556 tenofovir Drugs 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 22
- 239000007787 solid Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 238000001035 drying Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- -1 phenolic ester Chemical class 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 238000004537 pulping Methods 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
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-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
- 125000004429 atom Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 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
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 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
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 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
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- 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 relates to a preparation method of a tenofovir alafenac intermediate, which comprises the steps of (1) taking PMPA as a raw material, reacting with a first halogenating reagent in a first reaction solvent to obtain a compound 1, (2) detecting that the PMPA as the raw material is completely converted and evaporating the solvent by HP L C, and (3) reacting the compound 1 with phenol in a second reaction solvent to obtain a compound 2.
Description
Technical Field
The invention relates to a preparation process of a drug intermediate, in particular to a preparation method 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 method suitable for large-scale production of tenofovir alafenamide takes tenofovir (PMPA) as a starting material, and comprises the following steps of chlorination to form phenolic ester, chlorination and amidation:
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, hazardous, pungent odor substance.
Patent CN201710005963.4, PMPA is used as raw material, and 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 low.
Patent CN201610414329.1, provides a process for preparing compound 2, which provides a scheme to remove water from raw materials and add alkali, which is on one hand reagent increase, cost increase and waste generation increase, and on the other hand, thionyl chloride and phenol systems are easy to generate impurities, resulting in low conversion of PMPA.
Disclosure of Invention
From the analysis, the preparation of tenofovir alafenamide and the compound 2 are important intermediates, and the invention aims to provide the method which is simple to operate, cheap in raw materials and mild in reaction, is suitable for industrial production of the tenofovir alafenamide intermediate and overcomes the defects of the prior art.
In order to achieve the aim, the invention adopts the following technical scheme:
synthesis of Compound 2
A preparation method of a compound 2, which comprises the following steps,
wherein X is halogen group, the method comprises the steps of (1) taking PMPA as a raw material, reacting with a first halogenating reagent in a first reaction solvent to obtain a compound 1, (2) detecting that the PMPA as the raw material is completely converted by HP L C, and evaporating the solvent, and (3) reacting the compound 1 with phenol in a second reaction solvent to obtain a compound 2.
In some embodiments of the process for the preparation of compound 2 of the present invention, the first halogenating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosgene, triphosgene, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, and oxalyl bromide, preferably, the first halogenating agent is thionyl chloride.
In some embodiments of the process for the preparation of compound 2 of the present invention, the first halogenating agent uses 1.5-10 equivalents of thionyl chloride, more preferably 3 equivalents of thionyl chloride.
In some embodiments of the method for producing compound 2 of the present invention, the first reaction solvent may be selected from one or more of aromatic solvents, ether solvents and nitrile solvents.
In some embodiments of the method for producing compound 2 of the present invention, wherein the aromatic solvent is selected from one or more of toluene, xylene, anisole or chlorobenzene, for example; the ether solvent is selected from, for example, tetrahydrofuran, methyltetrahydrofuran or dioxane, etc.; said nitrile solvents are for example selected from acetonitrile and/or propionitrile; preferably, the first reaction solvent is toluene.
In some embodiments of the process for the preparation of Compound 2 of the present invention, the first reaction solvent uses 5 to 50ml/g of toluene, preferably 10ml/g of toluene.
In some embodiments of the process for the preparation of compound 2 of the present invention, phenol is used in an amount of 1.0 to 10 times the molar equivalent relative to PMPA.
In some embodiments of the process for the preparation of compound 2 of the present invention, the second reaction solvent may be selected from one or more of chlorinated hydrocarbons or esters, more preferably from one or more of chloroform, N-methylpyrrolidone (NMP) and isopropyl acetate.
Compared with the prior art, the invention has the following advantages:
the preparation method of the compound 2 optimizes reaction conditions, eliminates unnecessary reagents such as alkali or condensing agents, has high atom utilization efficiency and is environment-friendly; in addition, the used materials are cheap, the yield is high, the operability is strong, and the method is suitable for industrial production.
Detailed Description
The present invention will be described in detail with reference to specific examples.
EXAMPLE 1 preparation of Compound 1
PMPA (25g,0.082mol, containing one molecule of water) and acetonitrile (170ml) are added into a three-necked bottle with the diameter of 500m L, stirred at room temperature, added with thionyl chloride (48.8,0.41mol), heated to 70-80 ℃, stirred for reaction for 3h, sampled and dissolved in methanol, and HP L C detects that the raw material PMPA is completely converted, cooled to the ambient temperature, and decompressed to evaporate the solvent, thus obtaining light yellow solid which is directly used in the next step.
EXAMPLE 2 preparation 2 of Compound 1
Adding PMPA (10g, 0.033mol) and anisole (500ml) into a three-necked bottle of 1L, stirring at room temperature, adding thionyl chloride (32.0g), heating to 90-100 ℃, stirring for reaction for 3 hours, detecting that the PMPA as a raw material is completely converted by HP L C, cooling to the ambient temperature, performing suction filtration, washing with anisole to obtain a white solid, and directly using the white solid in the next step.
EXAMPLE 3 preparation 3 of Compound 1
PMPA (10g, 0.033mol) and chlorobenzene (500ml) are added into a three-necked flask of 1L, stirred at room temperature, added with thionyl chloride (64.0g), heated to 120 ℃ at 100 ℃, stirred for reaction for 3h, and HP L C detects that the raw material PMPA is completely converted, cooled to the ambient temperature, filtered by suction, washed by toluene to obtain white solid which is directly used in the next step.
EXAMPLE 4 preparation 4 of Compound 1
PMPA (10g, 0.033mol), xylene (100ml) were added to a three-necked flask of 5L, stirred at 0-5 deg.C, e.g. triphosgene (6.6g) was added in portions, stirred, naturally warmed to room temperature, reacted for 3 hours, HP L C detected complete conversion of the starting material PMPA, and the solvent was distilled off to give a white solid which was used directly in the next step.
EXAMPLE 5 preparation of Compound 15
PMPA (250g) and toluene (1.7L) are added into a three-necked flask of 5L, the mixture is stirred at room temperature, thionyl chloride (618.0g) is added, the temperature is increased to 80-90 ℃, the mixture is stirred for reaction for 6 hours, HP L C detects that the PMPA as a raw material is completely converted, the mixture is cooled to room temperature and is rapidly filtered, and filter cake toluene (0.5L x2) is washed to obtain white solid (310g, overweight) which is directly used in the next step.
EXAMPLE 6 preparation 1 of Compound 2
Adding a solid of the compound 1 (31.0g of crude product, theoretical value: 28.1g) and acetonitrile (125ml) into a 500ml three-neck flask, stirring, adding phenol (10.0g), heating to 60-75 ℃, sampling and monitoring after 8h, completely converting raw materials, stopping reaction, directly spin-drying reaction liquid, adding ice water (50ml), dissolving, controlling the internal temperature below 40 ℃, adjusting the pH value to 12 by saturated sodium hydroxide, stirring for half an hour, extracting by dichloromethane (2X100ml), adjusting the pH value of a water phase by concentrated hydrochloric acid to 3, filtering, drying a filter cake to obtain a crude product, crushing the crude product, thermally pulping by methanol for 5h, naturally cooling to room temperature, performing suction filtration, and drying to obtain an off-white solid compound 2(25.3g), wherein the yield is 80.0%, and the purity is 98.5%.
H NMR(D2O,400MHz)8.200(s,1H),8.113(s,1H),7.113-7.094(td,2H),6.987(m,1H),6.580-6.600(td,2H),4.294-4.162(AB,2H),3.965(m,1H)，3.965-3.453(AB,2H),1.183-1.168(d,3H).MS：[M-1]-:362.11。
EXAMPLE 7 preparation 2 of Compound 2
2L three-necked flask, adding compound 1 solid (155g crude product, theory value: 140.5g) and chloroform (750ml), adding phenol (75g) in batches, stirring for 30min at room temperature, heating to 50-55 ℃, sampling and monitoring after 8h, completely converting raw materials, stopping reaction, directly spin-drying reaction liquid, adding ice water (200ml), dissolving, controlling the internal temperature below 40 ℃, adjusting the pH value to 12 with saturated sodium hydroxide, stirring for 2h, separating liquid, adjusting the pH value of water phase with concentrated hydrochloric acid to 3, separating out solid, stirring for 2h, ice-water bath, stirring for 1h, filtering, drying filter cake to obtain crude product, crushing the crude product, hot-pulping with methanol for 5h, naturally cooling to room temperature, suction filtering, drying to obtain white solid compound 2(143.0g, two-step yield 90.5%), and purity: 99.0%.
EXAMPLE 8 preparation 3 of Compound 2
Adding a solid of the compound 1 (31.0g of crude product, theoretical value: 28.1g) and NMP (50ml) into a 250ml three-neck flask, stirring, adding phenol (20g), stirring, dissolving the solid, heating to 90 ℃, sampling and monitoring after 3h, stopping reaction after the raw materials are completely converted, adding ice water (80ml), dissolving clearly, controlling the internal temperature to be below 40 ℃, adjusting the pH value to 12 by saturated sodium hydroxide, stirring for 2h, separating liquid, adjusting the pH value of a water phase by concentrated hydrochloric acid to 3, separating out the solid, stirring for 2h, carrying out ice water bath, stirring for 1h, filtering, drying a filter cake to obtain a crude product, crushing the crude product, carrying out hot pulping for 5h by methanol, naturally cooling to room temperature, carrying out suction filtration, and drying to obtain a white solid compound 2(19.0g, and the yield of two steps is 60%). Purity: 97.5 percent.
EXAMPLE 9 preparation 4 of Compound 2
2L three-necked flask, adding compound 1 solid (155g crude product, theory value: 140.5g) and isopropyl acetate (750ml), stirring, adding phenol (125g) in batches, stirring, heating to 80-90 ℃, sampling and monitoring after 16h, completely converting raw materials, stopping reaction, removing solvent by rotary evaporation, adding ice water (50ml), dissolving, controlling the internal temperature below 40 ℃, adjusting the pH value to 12 by saturated sodium hydroxide, stirring for 2h, separating liquid, adjusting the pH value of water phase by concentrated hydrochloric acid to 3, separating out solid, stirring for 2h, water bathing filter cake, stirring for 1h, filtering, drying to obtain crude product, crushing the crude product, beating with methanol for 5h, naturally cooling to room temperature, filtering, drying to obtain white solid compound 2(221.4g, two-step yield 72.0%) 95.5%.
EXAMPLE 10 preparation of Compound 25
2L Tri-necked flask, adding compound 1 solid (155g crude product, theory value: 140.5g) and dichloromethane (1000ml), adding phenol (75g) in batches, stirring for 30min at room temperature, heating to 35-40 ℃, sampling and monitoring after 24h, stopping reaction when raw material conversion is complete, adding ice water (200ml), dissolving, controlling internal temperature below 40 ℃, adjusting pH value 12 with saturated sodium hydroxide, stirring for 2h, separating liquid, adjusting pH value 3 of water phase with concentrated hydrochloric acid, precipitating solid, stirring for 2h, ice water bath, stirring for 1h, filtering, drying filter cake to obtain crude product, crushing crude product, hot-pulping with methanol for 5h, naturally cooling to room temperature, suction-filtering, and drying to obtain white solid compound 2(134.5g, two-step yield 85.0%), purity is 98.8%.
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 preparation method of a compound 2, which comprises the following steps,
the method comprises the steps of (1) taking PMPA as a raw material to react with a first halogenating reagent in a first reaction solvent to obtain a compound 1, (2) detecting that the PMPA as the raw material is completely converted by HP L C and evaporating the solvent, and (3) reacting the compound 1 with phenol in a second reaction solvent to obtain a compound 2.
2. The process according to claim 1, wherein said first halogenating agent is selected from one or more of thionyl chloride, oxalyl chloride, phosgene, triphosgene, phosphorus oxychloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxybromide, oxalyl bromide, preferably said first halogenating agent is thionyl chloride.
3. The process according to claim 2, wherein the first halogenating agent is used in an amount of 1.5 to 10 equivalents of thionyl chloride, preferably 3 equivalents of thionyl chloride.
4. The production method according to any one of claims 1 to 3, wherein the first reaction solvent is one or more selected from an aromatic solvent, an ether solvent and a nitrile solvent.
5. The production process according to claim 4, wherein the aromatic solvent is selected from one or more of toluene, xylene, anisole or chlorobenzene, the ether solvent is selected from one or more of tetrahydrofuran, methyltetrahydrofuran or dioxane, and the nitrile solvent is selected from acetonitrile and/or propionitrile; preferably, the first reaction solvent is toluene.
6. The production process according to claim 5, wherein the first reaction solvent is toluene in an amount of 5 to 50ml/g, preferably 10 ml/g.
7. The production process according to any one of claims 1 to 6, wherein the phenol is used in an amount of 1.0 to 10-fold molar equivalent relative to PMPA.
8. The production process according to any one of claims 1 to 7, wherein the second reaction solvent is selected from one or more of chlorinated hydrocarbons or esters, preferably, the second reaction solvent is selected from one or more of acetonitrile, chloroform, N-methylpyrrolidone (NMP), isopropyl acetate and dichloromethane.
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|---|---|---|---|---|
| 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 (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
| 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 |
| WO2017221189A1 (en) * | 2016-06-22 | 2017-12-28 | Laurus Labs Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts thereof |
| 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 CN201910072336.1A patent/CN111484528A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817593A (en) * | 2015-04-27 | 2015-08-05 | 广州同隽医药科技有限公司 | Synthetic process of key intermediate of hemifumarate tenofovir alafenamide |
| WO2017221189A1 (en) * | 2016-06-22 | 2017-12-28 | Laurus Labs Limited | An improved process for the preparation of tenofovir alafenamide or pharmaceutically acceptable salts 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 |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 刘浩 等: "替诺福韦前药的设计、合成及初步代谢", 《精细化工》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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