CN108822149B - Preparation method of tenofovir alafenamide fumarate key intermediate - Google Patents
Preparation method of tenofovir alafenamide fumarate key intermediate Download PDFInfo
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- CN108822149B CN108822149B CN201810555169.1A CN201810555169A CN108822149B CN 108822149 B CN108822149 B CN 108822149B CN 201810555169 A CN201810555169 A CN 201810555169A CN 108822149 B CN108822149 B CN 108822149B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 title claims abstract description 27
- 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 title claims abstract description 27
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 24
- 230000035484 reaction time Effects 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 23
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 23
- 239000008096 xylene Substances 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 230000002140 halogenating effect Effects 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 5
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 4
- 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 3
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 7
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- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 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 17
- 238000003756 stirring Methods 0.000 description 16
- -1 (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] adenine Chemical compound 0.000 description 11
- 229930024421 Adenine Natural products 0.000 description 11
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 11
- 229960000643 adenine Drugs 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 229960004693 tenofovir disoproxil fumarate Drugs 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000001914 filtration Methods 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 229960004556 tenofovir Drugs 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229940126656 GS-4224 Drugs 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010029155 Nephropathy toxic Diseases 0.000 description 2
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007694 nephrotoxicity Effects 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000008085 renal dysfunction Effects 0.000 description 2
- SGOIRFVFHAKUTI-ZCFIWIBFSA-N tenofovir (anhydrous) Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(O)=O)C=NC2=C1N SGOIRFVFHAKUTI-ZCFIWIBFSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229910006121 SOBr2 Inorganic materials 0.000 description 1
- 229960001997 adefovir Drugs 0.000 description 1
- 229960003205 adefovir dipivoxil Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 208000028659 discharge Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 231100000380 osteotoxicity Toxicity 0.000 description 1
- 239000012466 permeate Substances 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
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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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 belongs to the field of drug synthesis, relates to a preparation method of a drug intermediate, and particularly relates to a preparation method of a tenofovir alafenamide fumarate key intermediate. The invention provides a novel method for preparing a tenofovir alafenamide fumarate key intermediate 2 with high diastereoisomer purity, which has the characteristics of short reaction time, few byproducts, simple operation, good product quality, high reaction yield, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a preparation method of a drug intermediate, and particularly relates to a preparation method of a tenofovir alafenamide fumarate key intermediate.
Background
The chemical name of tenofovir (PMPA, TFV) is (R) -9- (2-phosphomethoxypropyl) -adenine, which has antiviral and anti-hepatitis B activity and far lower toxicity than adefovir. Tenofovir has strong acidity and large polarity, is difficult to permeate cell membranes, has poor bioavailability, and has certain toxicity to bone due to strong acidity. Tenofovir can increase the osmotic burden on the glomeruli, especially in patients with renal dysfunction.
Tenofovir Disoproxil Fumarate (TDF), chemical name: 9- [ (R) -2- [ [ bis [ [ (isopropoxycarbonyl) oxy ] methoxy ] phosphinyl ] methoxy ] -propyl ] adenine fumarate (1: 1), a novel Nucleotide Reverse Transcriptase Inhibitor (NRTIs) produced by Gilead Sciences, USA, is a new tenofovir prodrug superior to adefovir dipivoxil, was approved by the U.S. Food and Drug Administration (FDA) for first-line drug treatment of HIV and HBV infection in 2001 and 2008, and was approved by the national Food and Drug Administration (FDA) for formal marketing in 2013 in 7 months. Compared with tenofovir and Tenofovir Disoproxil Fumarate (TDF) as a TFV diester prodrug, the preparation method has the advantages of greatly improving the penetrability and bioavailability of cells, having high anti-HIV and HBV activity, and having better advantages in drug resistance and safety. TDF still has some disadvantages, such as being easily metabolized to TFV in plasma, and, for patients with renal dysfunction, the risk of causing nephrotoxicity.
Tenofovir Alafenamide Fumarate (TAF), also developed by Gilead Sciences, in the United states, was approved by the FDA in the United states for marketing on 10/11/2016 for the treatment of chronic Hepatitis B (HBV) infection with compensated liver disease. The drug is a nucleoside reverse transcriptase inhibitor, and is a tenofovir prodrug which is newer than Tenofovir Disoproxil Fumarate (TDF). Compared with TDF, the product has stronger antiviral activity and can enter lymphatic tissue more effectively. Tenofovir Alafenamide Fumarate (TAF) can achieve high anti-HIV and anti-HBV activity with a very low dose clinically, and can significantly reduce nephrotoxicity and bone toxicity caused by TDF. The structure of TAF is as follows:
the prior literature reports that the main synthetic routes of Tenofovir Alafenamide Fumarate (TAF) mainly comprise the following two routes.
Synthetic route 1(CN1443189A)
In the route, the prepared intermediate A is a mixture of diastereoisomers at a phosphorus center, the intermediate B obtained by further carrying out substitution reaction with L-isopropyl alanine is still a mixture of diastereoisomers at the phosphorus center, and subsequent purification needs to be carried out by methods such as column chromatography, chiral resolution, induced crystallization and the like.
Synthesis scheme 2(US20130090473A1)
The synthesis route 2 is realized by synthesizing the intermediate 2 with high diastereoisomer purity when preparing the intermediate C with high diastereoisomer purity, firstly, the intermediate 1 and thionyl chloride are subjected to acyl chlorination reaction in a toluene solvent, the reaction time is 48 to 96 hours, the configuration inversion is carried out during the reaction to obtain the intermediate 2 with high diastereoisomer purity, and further the intermediate 3 with high diastereoisomer purity is generated, thereby avoiding the purification means such as column chromatography or chiral resolution, but the reaction time is long, some difficultly removed byproducts are generated, the color of the obtained key intermediate 2 is relatively deepened, and the intermediate 2 which does not have great influence on the subsequent reaction can be obtained only by completely decompressing, concentrating and drying the post-treatment, under the condition, the configuration transformation is difficult along with the batch amplification, the intermediate 2 with high diastereoisomer purity is difficult to obtain, and the industrial production is difficult.
In addition, patent CN105531281B reports the synthesis of intermediate 2:
the route is similar to the route of the patent US20130090473A1, except that the material 1' with the protecting group is used, the other reaction conditions are the same, and the protecting group is additionally added, so that the reaction steps of raw material obtaining are increased, the cost is increased, the discharge treatment of waste liquid is increased, the pressure of environmental protection is increased, and no substantial advantageous effect is generated.
Therefore, it is necessary to develop a new and more industrialized and lower-cost method for preparing Tenofovir Alafenamide Fumarate (TAF) key intermediate 2. The method has the characteristics of short reaction time, few byproducts, simple operation, good product quality, high reaction yield and the like, and is more suitable for industrial production.
Disclosure of Invention
The invention provides a novel method for preparing a Tenofovir Alafenamide Fumarate (TAF) key intermediate 2 with high diastereoisomer purity, which has the characteristics of short reaction time, few byproducts, simple operation, good product quality, high reaction yield, suitability for industrial production and the like.
The specific technical scheme is as follows:
a preparation method of a tenofovir alafenamide fumarate key intermediate 2 comprises the following steps of carrying out acyl halogenation reaction on an intermediate 1 and a halogenating agent in a solvent to obtain the tenofovir alafenamide fumarate key intermediate 2 with at least 80% of diastereoisomer purity:
wherein X is halogen;
wherein the solvent is xylene, xylene/acetonitrile, xylene/toluene/acetonitrile or xylene/chlorobenzene, preferably xylene;
wherein the halogenating agent is thionyl chloride (SOCl2), oxalyl chloride (C2O2Cl2), phosphorus trichloride (PCl3), dibromosulfoxide (SOBr2), oxalyl bromide (C2O2Br2) and phosphorus tribromide (PBr 3);
wherein the diastereoisomeric purity of intermediate 2 is monitored during the reaction by HPLC, and based on the stability of intermediate 2, intermediate 2 can be esterified to C in methanol before monitoring:
further, the reaction time is 12 hours to 36 hours.
Further, the reaction yielded tenofovir alafenamide fumarate key intermediate 2 of at least 80% diastereomeric purity.
Further, the reaction temperature is 60 ℃ to 110 ℃, preferably 70 ℃ to 95 ℃.
Further, the feeding molar ratio of the halogenating agent to the intermediate 1 is (1.5-10): 1-fold, preferably (2.5-5): 1.
further, the feeding mass ratio of the xylene to the intermediate 1 is (4-20): 1, preferably (5-10): 1.
further, the preparation method comprises the following steps: taking the intermediate 1, the halogenating agent and the reaction solvent according to the proportion, heating to 60-110 ℃, reacting for 12-36 hours, cooling, and separating solids to obtain the intermediate 2.
The invention also provides application of the preparation method in synthesis of tenofovir alafenamide fumarate.
The present invention also provides a process for preparing tenofovir alafenamide fumarate, comprising the step of preparing intermediate 2 according to the above process.
The intermediate 2 prepared by the method reacts with L-isopropyl alanine, and finally forms a salt with fumaric acid to obtain tenofovir alafenamide fumarate, and the yield and the purity of the prepared tenofovir alafenamide fumarate are improved.
The preparation process of the invention has the following beneficial effects:
1. compared with methods such as chromatographic separation, chiral resolution, induced crystallization and the like in the prior art, the method has the advantages of simple operation, high yield, low cost, contribution to industrial production and the like;
2. compared with the configuration transformation method in the prior art, the method has the characteristics of short reaction time, simple operation, less by-products, excellent quality of the intermediate 2 and the like, and the reaction time is greatly prolonged after the batch amplification in the prior art, the by-products are inevitably increased, and the effect of small batch is difficult to achieve.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to the following examples, which are provided for illustration only and are not intended to limit the scope of the present invention, and any equivalent replacement in the field made in the light of the present disclosure is included in the scope of the present invention.
The structure of the compound is nuclear magnetic resonance (1H NMR) or MS.
The NMR spectrometer (1H NMR) was Bruker AVANCE-400, the NMR (1H NMR) shifts () are given in parts per million (ppm) and the solvent determined was d6-DMSO or D2O, internal standard Tetramethylsilane (TMS), chemical shift is 10‐6(ppm) is given as a unit.
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Ultimate AQ C18).
The term "room temperature" in the present invention means a temperature of 10 to 25 ℃.
The invention will be further illustrated with reference to the following specific examples:
EXAMPLE 1 preparation of intermediate 2 with high diastereomeric purity
(1) Preparation of intermediate 1-1:
preparation of 9- [ (R) -2 [ [ (S) - [ di- (phenoxy) phosphinyl ] methoxy ] propyl ] adenine
Adding 25L of acetonitrile into a 100L glass lining reaction kettle at room temperature, starting stirring, adding tenofovir (5kg, 17.4mol) and thionyl chloride (6.2kg, 52.1mol), replacing nitrogen for protection (nitrogen replacement is performed for 3 times, the vacuum degree of the reaction kettle is less than or equal to-0.080 MPa, stirring is performed for 3-5 min, and nitrogen is backfilled to normal pressure and stirred for 3-5 min for one-time nitrogen replacement). After the addition, the temperature is raised to 70 ℃, the reaction is carried out for 2h under the temperature, the reduced pressure concentration is carried out, 25L of acetonitrile and phenol (6.6kg, 69.6mol) are added into a glass lining reaction kettle after the concentration is dried, the stirring is started, the temperature is raised to about 80 ℃, the reaction is carried out for 13h, the reduced pressure concentration is carried out, 25L of ethyl acetate is added into a 100L glass lining reaction kettle containing the concentrated residue, after the mixture is heated to 50 ℃ for dissolution, 25L of n-heptane is slowly added into the system, the mixture is cooled to room temperature for crystallization, the filtration and the drying are carried out, 6.5kg of white-like solid is obtained, namely the intermediate 1, the yield is 85 percent, and.
The nuclear magnetic data of the product are as follows:
1H NMR(400MHz，d6‐DMSO):1.13(d，3H)，4.04‐4.11(m，1H)，4.15‐4.33(m，4H)，7.05‐7.07(d，2H)，7.12‐7.14(d，2H)，7.20‐7.25(m，4H)，7.34‐7.41(m，4H)，8.05(s，1H)，8.15(s，1H)。
(2) preparation of intermediate 1:
preparation of 9- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] adenine
Adding 25L of tetrahydrofuran and 5L of water into a 100L glass lining reaction kettle at room temperature, magnetically stirring, adding a compound 1(5.0kg, 11.4mol) and potassium hydroxide (0.77kg, 13.7mol), reacting for 5 hours at room temperature, adding 35L of water and 30L of ethyl acetate into the system, extracting and separating liquid, extracting the water phase once with 25L of ethyl acetate, regulating the pH of the water phase to 3 with 6N hydrochloric acid in an ice water bath, separating out solid, filtering, and drying in vacuum to obtain 3.7kg of white solid, namely an intermediate 2, the yield is 89%, and the liquid phase purity is 99.58%.
The nuclear magnetic data of the product are as follows:
1HNMR(400MHz，D2O):1.13(d，3H)，3.42‐3.45(q，2H)，3.67‐3.70(q，2H)，4.97‐4.03(m，2H)，4.18‐4.24(q，2H)，4.28‐4.35(dd，2H)，6.60‐6.64(d，2H)，7.03‐7.05(t，1H)，7.13‐7.18(t，2H)，8.16(s，1H)，8.23(s，1H)；31PNMR15.3。
(3) preparation of intermediate 2:
a250 ml three-necked flask is added with intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene (100.0 g) and thionyl chloride (16.4g, 137.5mmol), magnetically stirred, replaced with nitrogen (1L volume of a balloon filled with nitrogen is used for replacing nitrogen protection, the same procedures are adopted in subsequent experimental examples), the temperature is raised to 70 ℃, the reaction is kept for 30h, the temperature is reduced to room temperature, and the mixture is filtered and vacuum dried to obtain white-like solid 10.4g, namely intermediate 2, the yield is 99%, and the purity of the diastereoisomer is 92.16%.
Note: when the purity of the non-enantiomer and the confirmation of the structure are determined based on the high activity of the intermediate 2, the detection is extended to methyl ester detection, namely, a small amount of sample is dissolved in methanol and then the sample detection is carried out.
Nuclear magnetic data of the product (according to compound C after extension):
1HNMR(400MHz，d6‐DMSO):1.23(d，3H)，3.72‐3.83(m，4H)，3.95‐4.04(m，2H)，4.11‐4.17(q，1H)，4.33‐4.39(m，1H)，6.24(s，2H)，7.07‐7.09(d，1H)，7.13‐7.18(m，2H)，7.27‐7.34(m，2H)，7.90(s，1H)，8.33(s，1H)。
examples 2 to 5: preparation of intermediate 2 with high diastereomeric purity
The procedure for the preparation of intermediate 2 in example 1 was followed by fixing the charge of intermediate 1 (10.0g, 27.5mmol), varying the amount of xylene, the amount of thionyl chloride, the reaction temperature, the reaction time and the results shown in Table 1:
table 1: production results of intermediate 2
The nuclear magnetic data for examples 2-5 are consistent with the results of example 1.
Example 6 preparation of intermediate 2 with high diastereomeric purity
Adding intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene 200.0g, acetonitrile 20.0g and oxalyl chloride (34.9g, 275.0mmol) into a 250ml three-neck flask, magnetically stirring, replacing nitrogen for protection, heating to 60 ℃, keeping the temperature for reaction for 30h, cooling to room temperature, decompressing and concentrating to remove oxalyl chloride, filtering, and vacuum drying to obtain white solid 9.9g, namely intermediate 2 with yield of 94%. The diastereomeric purity is 91.59%. The nuclear magnetic data are consistent with the results of example 1.
Example 7 preparation of intermediate 2 with high diastereomeric purity
Adding an intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene 40.0g, toluene 10.0g and phosphorus trichloride (18.9g, 68.8mmol) into a 250ml three-neck flask, magnetically stirring, replacing nitrogen for protection, heating to 70 ℃, keeping the temperature for reaction for 24 hours, cooling to room temperature, decompressing and concentrating to remove phosphorus trichloride, filtering, and drying in vacuum to obtain 10.3g of white-like solid, namely the intermediate 2, with the yield of 98%. The diastereomeric purity is 93.11%. The nuclear magnetic data are consistent with the results of example 1.
Example 8 preparation of intermediate 2 with high diastereomeric purity
Adding intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene 50.0g, toluene 10.0g, acetonitrile 10.0g and dibromosulfoxide (11.4g, 55.0mmol) into a 250ml three-necked flask, magnetically stirring, replacing nitrogen protection, heating to 70 ℃, keeping the temperature for reaction for 30h, cooling to room temperature, filtering, and drying in vacuum to obtain white-like solid 10.8g, namely intermediate 2 with the yield of 92%. The diastereomer purity was 91.73%. The nuclear magnetic data are consistent with the results of example 1.
Example 9 preparation of intermediate 2 with high diastereomeric purity
Adding intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene 75.0g and oxalyl bromide (23.7g, 110.0mmol) into a 250ml three-necked bottle, magnetically stirring, replacing nitrogen for protection, heating to 70 ℃, preserving heat for reaction for 30h, cooling to room temperature, filtering, and drying in vacuum to obtain white-like solid 10.9g, namely intermediate 2 with the yield of 93%. The diastereomeric purity is 90.93%. The nuclear magnetic data are consistent with the results of example 1.
Example 10 preparation of intermediate 2 with high diastereomeric purity
Adding intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene 60.0g, chlorobenzene 10.0g, phosphorus tribromide (11.2g, 41.3mmol) into a 250ml three-necked bottle, magnetically stirring, replacing nitrogen for protection, heating to 80 ℃, keeping the temperature for reaction for 30h, cooling to room temperature, filtering, and drying in vacuum to obtain 11.1g of white-like solid, namely intermediate 2 with the yield of 95%. The diastereomer was 92.88% pure. The nuclear magnetic data are consistent with the results of example 1.
Example 11 preparation of intermediate 2 with high diastereomeric purity
Adding intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), xylene 100.0g and thionyl chloride (16.4g, 137.5mmol) into a 250ml three-necked flask, magnetically stirring, replacing nitrogen for protection, heating to 70 ℃, preserving heat for reaction for 24h, cooling to room temperature, filtering, and drying in vacuum to obtain white-like solid 10.0g, namely intermediate 2 with the yield of 95%. The diastereomer was 90.16% pure. The nuclear magnetic data are consistent with the results of example 1.
Example 12 preparation of intermediate 2 with high diastereomeric purity
Under the condition of room temperature, 15kg of dimethylbenzene, an intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (3.0kg, 8.3mol) are added into a 100L glass lining reaction kettle, stirring is started, thionyl chloride (2.5kg, 21.0mol) is added, nitrogen replacement is carried out for 3 times (the vacuum degree of the reaction kettle is less than or equal to-0.080 MPa, stirring is carried out for 3-5 min, nitrogen is backfilled to the normal pressure, stirring is carried out for 3-5 min for one time of nitrogen replacement), the temperature is raised to 80 ℃, the reaction is carried out for 24h, the reaction is carried out for reducing the temperature to the room temperature, thionyl chloride is removed through decompression concentration, centrifugation is carried out under the nitrogen protection, and vacuum drying is carried out, so that 3.1kg of white-like solid is obtained, the yield is 99. The nuclear magnetic data are consistent with the results of example 1.
Comparative example 1 the intermediate 2 was prepared with a high degree of diastereomeric purity according to the method reported in patent US20130090473A
A250 mL three-necked flask was charged with intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (10.0g, 27.5mmol), toluene 60mL, and thionyl chloride (4.9g, 41.3mmol), magnetically stirred, purged with nitrogen, warmed to 70 ℃ and reacted with heat preservation. The content of diastereoisomers was monitored by HPLC, the results are given in the following table:
from the above table, it can be seen that at 48h, the content of the diastereomer is less than 80%, increasing with the increase of the reaction time, approaching the 90% content reported in patent US 20130090473A.
Comparative example 2 following the procedure reported in patent US20130090473A, both the starting material and the reaction solvent were amplified 100 times to prepare intermediate 2 with a high diastereomeric purity:
adding 5.2kg of toluene and 1.0kg of intermediate 19- [ (R) -2- [ [ (hydroxyphenoxyphosphono) methoxy ] propyl ] ] adenine (2.8 mol) into a 20L glass lining reaction kettle at room temperature, starting stirring, adding 0.5kg of thionyl chloride (4.2 mol), replacing nitrogen for protection (nitrogen is replaced for 3 times, the vacuum degree of the reaction kettle is less than or equal to-0.080 MPa, stirring for 3-5 min, backfilling nitrogen to the normal pressure, stirring for 3-5 min for nitrogen replacement), heating to 70 ℃, preserving heat for reaction for 96h, cooling to room temperature, decompressing and concentrating to remove thionyl chloride, centrifuging under the protection of nitrogen, and drying in vacuum to obtain 1.0kg of light yellow solid, the yield is 95%, the liquid phase purity is 94.51, and the diastereoisomer purity is 76.64%.
It can be seen that the process reported in US20130090473A is not prone to inversion of configuration during batch scale-up, and even if the reaction time is as long as 96 hours, the non-enantiomeric purity is only 76.64% and less than 80%, and the liquid phase purity is low and less than 95%. In the embodiment 12 of the invention, the reaction time is short, the content of the non-corresponding isomer is up to 91.79 percent, and the liquid phase purity is 98.35 percent. Therefore, compared with the method reported in US20130090473A, the method of the invention has the advantages of high efficiency, less by-products, excellent quality of the intermediate 2, suitability for industrial production and the like.
Claims (12)
1. A preparation method of a tenofovir alafenamide fumarate intermediate 2 is characterized in that the intermediate 1 and a halogenating agent are subjected to an acyl halogenation reaction in a solvent to obtain the tenofovir alafenamide fumarate intermediate 2 with at least 80% of diastereoisomer purity:
wherein X is halogen;
wherein the solvent is xylene, xylene/acetonitrile, xylene/toluene/acetonitrile or xylene/chlorobenzene;
wherein the halogenating agent is thionyl chloride, oxalyl chloride, phosphorus trichloride, thionyl bromide, oxalyl bromide or phosphorus tribromide.
2. The method of claim 1, wherein the reaction time is 12 to 36 hours.
3. The method of claim 1, wherein the solvent is xylene.
4. The process of claim 1 wherein the reaction yields tenofovir alafenamide fumarate intermediate 2 of at least 90% diastereomeric purity.
5. The method of claim 1, wherein the reaction temperature is 60 ℃ to 110 ℃.
6. The method of claim 5, wherein the reaction temperature is 70 ℃ to 95 ℃.
7. The process according to claim 1, wherein the molar ratio of the halogenating agent to the intermediate 1 is (1.5-10): 1.
8. the process according to claim 7, wherein the molar ratio of the halogenating agent to the intermediate 1 is (2.5-5): 1.
9. the preparation method according to claim 1, wherein the feed mass ratio of the xylene to the intermediate 1 is (4-20): 1.
10. the preparation method according to claim 9, wherein the feed mass ratio of xylene to intermediate 1 is (5-10): 1.
11. the preparation method of any one of claims 1 to 10, comprising the steps of taking the intermediate 1, the halogenating agent and the reaction solvent in proportion, heating to 60 ℃ to 110 ℃, reacting for 12 to 36 hours, cooling, and separating solids to obtain the intermediate 2.
12. Use of the preparation method of any one of claims 1-11 in the synthesis of tenofovir alafenamide fumarate.
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