CN110229174A - The synthetic method of Bictegravir bulk pharmaceutical chemicals genotoxicity impurity - Google Patents
The synthetic method of Bictegravir bulk pharmaceutical chemicals genotoxicity impurity Download PDFInfo
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- CN110229174A CN110229174A CN201910430937.5A CN201910430937A CN110229174A CN 110229174 A CN110229174 A CN 110229174A CN 201910430937 A CN201910430937 A CN 201910430937A CN 110229174 A CN110229174 A CN 110229174A
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- 231100000025 genetic toxicology Toxicity 0.000 title claims abstract description 63
- 230000001738 genotoxic effect Effects 0.000 title claims abstract description 63
- 239000012535 impurity Substances 0.000 title claims abstract description 54
- 229950004159 bictegravir Drugs 0.000 title claims abstract description 29
- SOLUWJRYJLAZCX-LYOVBCGYSA-N bictegravir Chemical compound C([C@H]1O[C@@H]2CC[C@@H](C2)N1C(=O)C1=C(C2=O)O)N1C=C2C(=O)NCC1=C(F)C=C(F)C=C1F SOLUWJRYJLAZCX-LYOVBCGYSA-N 0.000 title claims abstract description 29
- 239000000126 substance Substances 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title claims abstract description 24
- 150000003939 benzylamines Chemical class 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 claims abstract description 19
- 230000017858 demethylation Effects 0.000 claims abstract description 10
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 10
- 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 claims abstract description 6
- 239000000539 dimer Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 150000001875 compounds Chemical class 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003480 eluent Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- -1 hexamethyldisilane amine Chemical class 0.000 claims description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 6
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 5
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 238000010828 elution Methods 0.000 claims 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 239000002574 poison Substances 0.000 claims 1
- 231100000614 poison Toxicity 0.000 claims 1
- 229910052700 potassium Inorganic materials 0.000 claims 1
- 239000011591 potassium Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 238000012827 research and development Methods 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 235000010894 Artemisia argyi Nutrition 0.000 description 2
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100034343 Integrase Human genes 0.000 description 2
- 108010061833 Integrases Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 244000030166 artemisia Species 0.000 description 2
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
- 239000012964 benzotriazole Substances 0.000 description 2
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960000366 emtricitabine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000008450 motivation Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960004556 tenofovir Drugs 0.000 description 2
- 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 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical class CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 108700020129 Human immunodeficiency virus 1 p31 integrase Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- DDFGTVSLZJLQEV-UHFFFAOYSA-N [C](C1CCCCC1)C1CCCCC1 Chemical compound [C](C1CCCCC1)C1CCCCC1 DDFGTVSLZJLQEV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- 229940124525 integrase strand transfer inhibitor Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 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
- 229960004946 tenofovir alafenamide Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides the synthetic methods of Bictegravir bulk pharmaceutical chemicals genotoxicity impurity, specifically include the synthetic method for preparing genotoxicity impurity A and B, first using three fluorin benzyl amines as raw material, reaction obtains three fluorin benzyl amine dimers under alkaline condition, then the three fluorin benzyl amines dimer and compound C are condensed to yield genotoxicity impurity A, the genotoxicity impurity A carries out demethylation and handles to obtain genotoxicity impurity B.
Description
Technical field
The invention belongs to impurity of the drug to synthesize field, in particular to genotoxicity is miscellaneous in a kind of Bictegravir bulk pharmaceutical chemicals
The synthetic method of matter A and genotoxicity impurity B.
Background technique
Biketarvy is the treatment human immunodeficiency virus type 1 (Human researched and developed by Ji Leadd B.V, the U.S.
Immunodeficiency Virus-1, hereinafter referred to as HIV-1) infection drug, on 2 7th, 2018 by U.S.'s food and medicine
Surveillance Authority (Food and Drug Administration, abbreviation FDA) approval listing, significant in efficacy, market manifestation
Well, clinical data shows that Biketarvy and conventional inverase do not find side effect and resistance to during treating within 3 months at present
Pharmacological property.Biketarvy is by Bictegravir (50mg), emtricitabine (Emtricitabine, 200mg), tenofovir Chinese mugwort
Three kinds of drawing phenol amine fumarate (Tenofovir Alafenamide, 25mg) is at the compound preparation being grouped as.Wherein, grace it is bent he
It is the active drug treated HIV-1 and infect clinical application many years that shore and tenofovir Chinese mugwort, which draw phenol amine fumarate all, and
Bictegravir is then main new chemical molecular entity in drug Biketarvy, is a kind of chain tra nsfer of HIV-1 integrase
Inhibitor (Integrase Strand Transfer Inhibitor, abbreviation INSTI), and integrase is a kind of HIV-1 coding
Virus replication necessary to a kind of enzyme, Bictegravir can inhibit integrase activity, prevent HIV-1 be integrated into place
Main DNA, and then prevent conversion and the virus progression of HIV-1 virus.
Biketarvy is developed to first have to that the active constituent Bictegravir to conform to quality requirements is prepared；And
In Bictegravir preparation process, the preparation work of impurity reference substance is also even more important, and researcher needs in preparation process
The various impurity generated are studied in detail, and the impurity reference substance of acquisition is to active medicaments object ingredient (Active
Pharmaceutical Ingredient, hereinafter referred to as API) production technology exploitation, analysis method exploitation and quality standard formulation
There are significant impacts.And in all impurity reference substances, genotoxicity impurity (including latent gene toxic impurities) is even more important,
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (International Council for Harmonization, with
Lower abbreviation ICH) guideline in, the metering of the permission daily ingestion of genotoxicity impurity (including latent gene toxic impurities) is
1.5 micrograms/day.During the technique research and development of drug, research staff needs to pay close attention to genotoxicity impurity, understands synthesis base
Because of the method for toxic impurities, genotoxicity impurity and the suitable analysis method of exploitation are removed to develop suitable preparation process
Genotoxicity impurity is detected, genotoxicity impurity is no more than limit specified in ICH guideline in final control API；However,
In the prior art for type, structure or the synthesis side of related gene toxic impurities in Bictegravir bulk pharmaceutical chemicals preparation process
Method is short in understanding.
Summary of the invention
In order to solve Bictegravir bulk pharmaceutical chemicals in the prior art genotoxicity impurity type and synthesis be short in understanding
The technical issues of, the invention discloses genotoxicity impurity A in a kind of Bictegravir bulk pharmaceutical chemicals and genotoxicity impurity Bs
Synthetic method and its synthetic product.
The synthetic method of genotoxicity impurity A in a kind of Bictegravir bulk pharmaceutical chemicals, which comprises 2,4,6- tri-
Fluorin benzyl amine reacts under alkaline condition obtains three fluorin benzyl amine dimers；The three fluorin benzyl amines dimer and compound C are dissolved in two
One of chloromethanes, tetrahydrofuran or ethyl acetate or multi-solvents obtain mixed liquor I；Contracting is added in the mixed liquor I
Mixture and alkali, and it is heated to 20-40 DEG C of reaction 7-8 hours, obtain mixed liquor II；Decompression is carried out to the mixed liquor II to be spin-dried for obtaining
Residue, add the mixture of methylene chloride and methanol as eluant, eluent to residue column chromatography for separation, collection is isolated
Main component, the solvent being spin-dried in the main component obtains genotoxicity impurity A.
Further, described 2,4,6- tri- fluorin benzyl amines react under alkaline condition obtain three fluorin benzyl amine dimers include: by
Described 2,4,6- tri- fluorin benzyl amines are dissolved in one or more solvents in tetrahydrofuran or methylene chloride, obtain mixed liquor III；Described
It is added in hexamethyldisilazide lithium, hexamethyldisilane amine base sodium or potassium hexamethyldisilazide at least in mixed liquor III
A kind of alkali obtains mixed liquor IV；The mixed liquor IV is heated to 25-40 DEG C and is reacted 14 hours, 10% chlorine is added after reaction
Change aqueous ammonium and carry out quenching reaction, vacuum rotary steam removes solvent, obtains mixed liquor V；Dichloromethane is added in the mixed liquor V
Alkane aqueous phase extracted, and organic phase is collected, after carrying out evaporated under reduced pressure to the organic phase, obtain residue；To the residue into
Row column chromatographic purifying is added methylene chloride as eluant, eluent, collects primary product, be spin-dried for solvent, obtain three fluorin benzyl amine dimers.
Further, the three fluorin benzyl amines dimeric structure are as follows:
Further, the compound C-structure are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
Further, the condensing agent is 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid
One of salt, dicyclohexylcarbodiimide or 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride are a variety of.
Further, the alkali is one of n,N-diisopropylethylamine or triethylamine or a variety of.
A kind of genotoxicity impurity A of the synthesis of synthetic method described in any one of -6 according to claim 1, feature exist
In the structure of the genotoxicity impurity A are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
A kind of synthetic method of genotoxicity impurity B in Bictegravir bulk pharmaceutical chemicals, which is characterized in that the method packet
Include: genotoxicity impurity A being obtained with synthetic method described in any one of claim 1-6 or as claimed in claim 7 is original
Material, is dissolved in one of acetonitrile or dioxane or multi-solvents for the genotoxicity impurity A, obtains mixed liquor VI；Institute
The demethylation reagent that 2.0-4.0 molar equivalent is added in mixed liquor VI is stated, and is heated to 40-50 DEG C of reaction 4-6 hours, obtains base
Because of toxic impurities B.
Further, the demethylation reagent is one of magnesium bromide or lithium bromide or a variety of.
A kind of genotoxicity impurity B of the synthesis of the synthetic method according to any one of claim 8-9, feature exist
In the structure of the genotoxicity impurity B are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
The present invention is using three fluorin benzyl amines as raw material, and reaction obtains three fluorin benzyl amine dimers under alkaline condition, then will be described
Three fluorin benzyl amine dimers and compound C are condensed to yield genotoxicity impurity A, and the genotoxicity impurity A carries out demethylation processing
Obtain genotoxicity impurity B.The genotoxicity impurity synthetic method of Bictegravir bulk pharmaceutical chemicals of the present invention, not only can be with
The genotoxicity impurity A and B of purity is high are prepared, and synthesis route is simple and convenient to operate, selectivity is good；Synthesis obtains
Genotoxicity impurity A and B can be used for the quality research of Bictegravir bulk pharmaceutical chemicals and quality control experiment, control
The purity of Bictegravir bulk pharmaceutical chemicals or its preparation.Other features and advantages of the present invention will be explained in the following description
It states, also, partly as will become apparent from the description, or understand through the implementation of the invention.The purpose of the present invention and
Other advantages can be achieved and obtained by structure pointed in the specification, claims and drawings.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is this hair
Bright some embodiments for those of ordinary skill in the art without creative efforts, can be with root
Other attached drawings are obtained according to these attached drawings.
Fig. 1 shows the process of genotoxicity impurity A in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram；
Fig. 2 shows the processes of genotoxicity impurity B in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, technical solution in the embodiment of the present invention clearly and completely illustrated, it is clear that described embodiment is
A part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
Fig. 1 shows the process of genotoxicity impurity A in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram.As shown, first 2,4,6- tri- fluorin benzyl amines react under alkaline condition obtains three fluorin benzyl amine dimers, described in preparation
It is raw material, using tetrahydrofuran, methylene chloride as solvent that three fluorin benzyl amine dimer steps, which include: with 2,4,6- tri- fluorin benzyl amines, then plus
Enter hexamethyldisilazide lithium (Lithium Hexamethyldisilazide, hereinafter referred to as LiHMDS), two silicon of hexamethyl
Base amido sodium (Na Hexamethyldisilazide, hereinafter referred to as NaHMDS), potassium hexamethyldisilazide (K
Hexamethyldisilazide, hereinafter referred to as KHMDS) alkali is done, it is heated to 25~40 DEG C and reacts 14 hours；After completion of the reaction,
10% aqueous ammonium chloride solution is added and carries out quenching reaction, vacuum rotary steam removes solvent, adds methylene chloride aqueous phase extracted, collects
Organic phase after organic phase carries out evaporated under reduced pressure, obtains residue；Column chromatographic purifying, eluant, eluent two are carried out to the residue
Chloromethanes collects primary product, is spin-dried for solvent, obtains yellow solid, as three fluorin benzyl amine dimers.Wherein, described 2,4,6- tri-
The solvent of fluorin benzyl amine is preferably tetrahydrofuran, the three fluorin benzyl amines dimeric structure being prepared are as follows:
Then, using the three fluorin benzyl amines dimer and compound C as raw material, with methylene chloride, tetrahydrofuran or acetic acid second
Ester is solvent, with 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate (HATU), dicyclohexyl carbon
Diimine (Dicyclohexylcarbodiimide, abbreviation DCC) or 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide salt
Hydrochlorate (EDCI) is condensing agent, with n,N-diisopropylethylamine (DIEA) or triethylamine does alkali, be heated to 20~40 DEG C of reactions 7~
8 hours, obtain mixed liquor II；After the reaction was completed, decompression is carried out to the mixed liquor II to be spin-dried for obtaining residue, add dichloro
The mixture of methane and methanol carries out column chromatography for separation to residue as eluant, eluent, collects the main component isolated, is spin-dried for
Solvent in the main component obtains faint yellow solid, as genotoxicity impurity A.Wherein, the three fluorin benzyl amines dimer
Solvent with compound C is preferably tetrahydrofuran；The condensing agent is preferably that 1- (3- dimethylamino-propyl) -3- ethyl carbon two is sub-
Amine hydrochlorate (EDCI)；The alkali is preferably N, N- diisopropylethylamine (DIEA)；Reaction temperature described in synthetic method is preferably
30~40 DEG C；The eluant, eluent for synthesizing the genotoxicity impurity A is preferably methylene chloride: methanol=50:1 mixture；
The compound C-structure are as follows:
R, S respectively indicates the chiral configuration of compound；
The structure of the genotoxicity impurity A are as follows:
R, S respectively indicates the chiral configuration of compound；The genotoxicity impurity A is a kind of new compound, has no text
Report is offered, can be used for the experiment of the quality research of Bictegravir bulk pharmaceutical chemicals and quality control, to control Bictegravir original
Expect medicine or the purity of its preparation；Meanwhile the genotoxicity impurity A is analysed in depth, convenient also can be research and development people
Member improves Bictegravir bulk pharmaceutical chemicals preparation process and provides relevant technical motivation.
Illustratively, 2,4,6- tri- fluorin benzyl amine 6.4g, tetrahydrofuran 10mL are added in 100mL reaction flask, are added
LiHMDS 20mL is heated to 25~40 DEG C and reacts 14 hours；10% aqueous ammonium chloride solution 15mL is added, stirs 10 minutes, subtracts
Pressure is evaporated off tetrahydrofuran, methylene chloride 20mL aqueous phase extracted is added simultaneously carries out liquid separation and collect organic phase, to organic phase evaporated under reduced pressure,
Again to residue column chromatographic purifying, methylene chloride is added as solvent is spin-dried for after eluant, eluent, obtains yellow solid 4.0g, as three
Fluorin benzyl amine dimer；Then, compound C2.0g, tetrahydrofuran 14mL and three fluorin benzyl amines two are added in 100ml reaction flask
Aggressiveness 2.2g, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI) 4g, N, N- diisopropylethylamine
(DIEA) 1.2g is heated to 30~40 DEG C of 7~8h of reaction, then is spin-dried for reaction product, methylene chloride is added later: methanol
The eluant, eluent of=50:1 obtains faint yellow solid, i.e. genotoxicity impurity A 1.2g, purity to residue column chromatography for separation is spin-dried for
It is 98%, mass spectrum (Mass Spectrum, hereinafter referred to as MS): [M+H]+=605.
Fig. 2 shows the processes of genotoxicity impurity B in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram.As shown, genotoxicity impurity B using the genotoxicity impurity A as raw material, carries out demethylation processing, to close
At obtaining genotoxicity impurity B, comprising: using the genotoxicity impurity A as raw material, with acetonitrile, dioxane is solvent, and is added
Entering magnesium bromide or lithium bromide is demethylation reagent, and demethylation reagent dosage is 2.0~4.0 molar equivalents, it is then heated to 40~
50 DEG C are reacted 4~6 hours；To which appropriate hydrochloric acid is added after completion of the reaction, in reaction product and stirs 30 minutes, then it is spin-dried for mixing
Liquid carries out residue column chromatographic purifying, the mixture of methylene chloride and methanol is added as eluant, eluent, synthesis obtains pale yellow colored solid
Body, as genotoxicity impurity B.Wherein, the solvent of the genotoxicity impurity A is preferably 2- methyltetrahydrofuran；It is described de-
Methylating reagent is preferably magnesium bromide；And the demethylation reagent dosage is preferably 3.0 molar equivalents；It is miscellaneous to synthesize the genotoxicity
The eluant, eluent of matter B is preferably methylene chloride: methanol=20:1 mixture；The structure of the genotoxicity impurity B are as follows:
R, S respectively indicates the chiral configuration of compound；The genotoxicity impurity B is also a kind of new compound, has no
Document report can be used for the experiment of the quality research of Bictegravir bulk pharmaceutical chemicals and quality control, to control Bictegravir
The purity of bulk pharmaceutical chemicals or its preparation；Meanwhile the genotoxicity impurity B is analysed in depth, convenient also can be research and development
Personnel improve Bictegravir bulk pharmaceutical chemicals preparation process and provide relevant technical motivation.
Illustratively, genotoxicity impurity A 1.0g, magnesium bromide 0.52g and acetonitrile are added in 50mL reaction flask
10mL, heating mixed liquor to 40~50 DEG C react 4~6 hours；To which the hydrochloric acid that concentration is 2 mol/Ls after completion of the reaction, is added
2mL is simultaneously stirred 30 minutes；Then, be spin-dried for reaction solution, add using methylene chloride: methanol=20:1 mixture is as eluant, eluent
Column chromatographic purifying is carried out to residue, collects the main component that purifying obtains, the solvent being spin-dried in the main component obtains light
Yellow solid 0.7g, as impurity B, purity 98%, mass spectrum MS:[M+H]+=591.
Although the present invention is described in detail referring to the foregoing embodiments, those skilled in the art should manage
Solution: it is still possible to modify the technical solutions described in the foregoing embodiments, or to part of technical characteristic into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The spirit and scope of scheme.
Claims (10)
1. the synthetic method of genotoxicity impurity A in a kind of Bictegravir bulk pharmaceutical chemicals, which is characterized in that the described method includes:
Tri- fluorin benzyl amine of 2,4,6- reacts under alkaline condition obtains three fluorin benzyl amine dimers；
The three fluorin benzyl amines dimer and compound C are dissolved in one of methylene chloride, tetrahydrofuran or ethyl acetate or more
Kind solvent, obtains mixed liquor I；
Condensing agent and alkali are added in the mixed liquor I, and is heated to 20-40 DEG C of reaction 7-8 hours, obtains mixed liquor II；
Decompression is carried out to the mixed liquor II to be spin-dried for obtaining residue, adds the mixture of methylene chloride and methanol as elution
Agent collects the main component isolated to residue column chromatography for separation, the solvent being spin-dried in the main component, obtains gene poison
Property impurity A.
2. synthetic method according to claim 1, which is characterized in that described 2,4,6- tri- fluorin benzyl amines are anti-under alkaline condition
Should obtain three fluorin benzyl amine dimers includes:
Described 2,4,6- tri- fluorin benzyl amines are dissolved in one or more solvents in tetrahydrofuran or methylene chloride, obtain mixed liquor III；
Hexamethyldisilazide lithium, two silicon substrate amine of hexamethyldisilane amine base sodium or hexamethyl are added in the mixed liquor III
At least one of base potassium alkali, obtains mixed liquor IV；
The mixed liquor IV is heated to 25-40 DEG C and is reacted 14 hours, 10% aqueous ammonium chloride solution is added after reaction and quenches
It goes out reaction, vacuum rotary steam removes solvent, obtains mixed liquor V；
Methylene chloride aqueous phase extracted is added in the mixed liquor V, and collects organic phase, evaporated under reduced pressure is carried out to the organic phase
Afterwards, residue is obtained；
Column chromatographic purifying is carried out to the residue, methylene chloride is added as eluant, eluent, collects primary product, is spin-dried for solvent,
Obtain three fluorin benzyl amine dimers.
3. synthetic method according to claim 1 or 2, which is characterized in that the three fluorin benzyl amines dimeric structure are as follows:
4. synthetic method according to claim 1, which is characterized in that the compound C-structure are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
5. synthetic method according to claim 1, which is characterized in that the condensing agent is that (7- aoxidizes three nitrogen of benzo to 2-
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide or 1- (3- dimethylamino-propyl) -3- ethyl
One of carbodiimide hydrochloride is a variety of.
6. synthetic method according to claim 1, which is characterized in that the alkali is n,N-diisopropylethylamine or triethylamine
One of or it is a variety of.
7. a kind of genotoxicity impurity A of the synthesis of synthetic method described in any one of -6 according to claim 1, which is characterized in that
The structure of the genotoxicity impurity A are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
8. the synthetic method of genotoxicity impurity B in a kind of Bictegravir bulk pharmaceutical chemicals, which is characterized in that the described method includes:
Genotoxicity impurity A being obtained with synthetic method described in any one of claim 1-6 or as claimed in claim 7 is original
Material, is dissolved in one of acetonitrile or dioxane or multi-solvents for the genotoxicity impurity A, obtains mixed liquor VI；
The demethylation reagent of 2.0-4.0 molar equivalent is added in the mixed liquor VI, and it is small to be heated to 40-50 DEG C of reaction 4-6
When, obtain genotoxicity impurity B.
9. synthetic method according to claim 8, which is characterized in that the demethylation reagent is in magnesium bromide or lithium bromide
It is one or more.
10. a kind of genotoxicity impurity B of the synthesis of the synthetic method according to any one of claim 8-9, which is characterized in that
The structure of the genotoxicity impurity B are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104995198A (en) * | 2012-12-21 | 2015-10-21 | 吉里德科学公司 | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
| WO2018005328A1 (en) * | 2016-06-27 | 2018-01-04 | Concert Pharmaceuticals, Inc. | Deuterated bictegravir |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104995198A (en) * | 2012-12-21 | 2015-10-21 | 吉里德科学公司 | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
| WO2018005328A1 (en) * | 2016-06-27 | 2018-01-04 | Concert Pharmaceuticals, Inc. | Deuterated bictegravir |
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