CN115490626B - 一种pf-07321332的关键手性化合物及其制备方法 - Google Patents
一种pf-07321332的关键手性化合物及其制备方法 Download PDFInfo
- Publication number
- CN115490626B CN115490626B CN202111422350.3A CN202111422350A CN115490626B CN 115490626 B CN115490626 B CN 115490626B CN 202111422350 A CN202111422350 A CN 202111422350A CN 115490626 B CN115490626 B CN 115490626B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- alkali
- preparation
- trimethylsilyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 title abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 229940126214 compound 3 Drugs 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 9
- 229940125904 compound 1 Drugs 0.000 claims abstract description 6
- 229940125782 compound 2 Drugs 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 6
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- QNSPKWUAZQIIGZ-QMMMGPOBSA-N dimethyl (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate Chemical compound COC(=O)CC[C@@H](C(=O)OC)NC(=O)OC(C)(C)C QNSPKWUAZQIIGZ-QMMMGPOBSA-N 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical group [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 229940011051 isopropyl acetate Drugs 0.000 claims description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 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 3
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims 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 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 238000005915 ammonolysis reaction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 210000001503 joint Anatomy 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 150000003839 salts Chemical class 0.000 abstract description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 abstract description 2
- 238000004176 ammonification Methods 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 238000004321 preservation Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical group FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000711573 Coronaviridae Species 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 238000001308 synthesis method Methods 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- XCZYYPNBFOATIK-WDSKDSINSA-N (2S)-2-amino-3-[(3S)-2-oxopyrrolidin-3-yl]propanenitrile Chemical compound N[C@@H](C[C@H](CCN1)C1=O)C#N XCZYYPNBFOATIK-WDSKDSINSA-N 0.000 description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- -1 butyrolactam compound Chemical class 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229940125675 paxlovid Drugs 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229950009390 symclosene Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HTNPEHXGEKVIHG-ZJTJHKMLSA-N molnupiravir Chemical compound CC(C)C(=O)OC[C@H]1O[C@H](C(O)C1O)N1C=C\C(NC1=O)=N\O HTNPEHXGEKVIHG-ZJTJHKMLSA-N 0.000 description 1
- 229940075124 molnupiravir Drugs 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- MDDUHVRJJAFRAU-YZNNVMRBSA-N tert-butyl-[(1r,3s,5z)-3-[tert-butyl(dimethyl)silyl]oxy-5-(2-diphenylphosphorylethylidene)-4-methylidenecyclohexyl]oxy-dimethylsilane Chemical compound C1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C(=C)\C1=C/CP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 MDDUHVRJJAFRAU-YZNNVMRBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明提供了一种PF‑07321332的关键手性化合物7的制备方法，包括以BOC‑L‑谷氨酸二甲酯化合物1为起始原料，利用强碱拔氢后与1,2,3‑噁噻唑烷‑3‑甲酸苄酯2,2‑二氧化物化合物2对接得到化合物3；再经过一锅法氢化并环合得到化合物4；化合物4通过氨化反应、脱水反应，最后酸解成盐反应，以甲基磺酸盐的形式得到目标产物化合物7；该关键手性化合物7具有纯度高，性质稳定利于保存的特点，可以十分方便地应用于合成PF‑07321332后续工艺中，可利于降低工艺成本，适宜工业化生产。
Description
技术领域
本发明属于医药化工领域，具体涉及用于合成抗病毒药物PF-07321332的中间体手性丁内酰胺化合物及其制备方法。
背景技术
PF-07321332是一款由美国辉瑞制药研发的一种新型口服新冠病毒3CL蛋白酶抑制剂。它的作用机制有别于已经获批的抗新冠病毒药物瑞德西韦和Molnupiravir，它能通过抑制新冠病毒切割长多肽链从达到抑制病毒的效果。2021年11月5日，辉瑞公司宣布，新型口服在抗病毒药物Paxlovid用于治疗新冠病毒肺炎的II/III期临床试验中，能显著降低新冠患者住院和死亡风险。而PF-07321332作为Paxlovid的主要成分，Paxlovid一旦获批，市场前景极其巨大。
PF-07321332化学名为：(1R,2S,5S)-N-((S)-1-氰基-2-((S)-2-氧代吡咯啉-3-基)乙基)-3-((S)-3,3-二甲基-2-(2,2,2-三氟乙酰氨基)丁酰基)-6,6-二甲基-3-氮杂双环[3.1.0]己-2-甲酰胺，其关键片段之一为(S)-2-氨基-3-((S)-2-氧代吡咯啉-3-基)丙腈，它们结构式分别如下：
目前仍未有专利对化合物(S)-2-氨基-3-((S)-2-氧代吡咯啉-3-基)丙腈的合成进行报道，已知的文献或专利仅报道了其骨架分子化合物的合成，WO2001014329报道了(S)-2-((叔丁氧羰基)氨基)-3-((S)-2-氧代吡咯啉-3-基)丙酸甲酯的合成方法，路线如下：
Science 2020年第368卷6497期1331页报道了利用硼氢化钠还原一步合环的方法，路线如下：
这两种方法仅合成出了(S)-2-氨基-3-((S)-2-氧代吡咯啉-3-基)丙腈的骨架分子，酯基转化为氰基仍然需要经过多步反应，这部分工作仍然没有文献报道。另外，这两种方法需都要使用强刺激性化合物溴乙腈作为烷基化试剂，储存和放大都具有一定安全隐患；中间体都涉及氰基的还原，氢化或硼氢化钠还原的难度较大，路线1使用钯碳催化时钯负载量较高，路线成本较高，而路线2则反应收率较低，也不太适合放大生产。
总之，这两种方法用于放大生产收率较低，工艺成本较高，仍然需要找到工艺路线简单、成本低廉、适宜工业化生产的合成方法。
发明内容
针对现有技术的不足，本发明的目的是提供一种用于合成PF-07321332的手性丁内酰胺化合物及其制备方法，该制备工艺路线简单、收率较高、成本低廉、适宜工业化生产。
本发明目的之一是提供一种PF-07321332的关键手性化合物7及其合成方法：
PF-07321332的关键手性化合物7，其结构式为：
一种PF-07321332的关键手性化合物7的制备方法，包括如下步骤：
(1)将化合物4经过氨解反应得到化合物5；
(2)将化合物5经过脱水反应得到化合物6；
(3)将化合物6经过甲基磺酸酸解脱Boc并一步成盐反应得到化合物7；
作为优选，所述步骤(1)中的用到的反应溶剂选自甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯或甲苯。
作为优选，所述步骤(2)的脱水反应中，脱水剂选自三氟甲磺酸酐、三氯氧膦、三氟乙酸酐、三氯异氰尿酸(TCCA)或Burgess试剂；不加碱或加入有机碱，有机碱选自三乙胺、二异丙基乙胺、吡啶、2,6-二甲基吡啶或DBU；反应溶剂选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氯甲烷、四氢呋喃、2-甲基四氢呋喃、乙腈、甲苯、二甲苯或氯苯；反应结束后加水淬灭，乙酸乙酯萃取，有机相浓缩，加石油醚，冷却析晶，过滤得化合物6。
作为优选，所述步骤(3)中用到的反应溶剂选自甲醇、乙醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯、甲苯或水以及这些溶剂任意两种形成的混合溶剂。
本发明目的之二是提供化合物4的合成方法，采取如下的技术方案：
一种化合物4的制备方法，包括如下步骤：
(1)将化合物1在碱作用下与化合物2反应得到化合物3；
(2)将化合物3在催化剂作用下进行氢化反应脱CBZ并一步成环得到化合物4；
作为优选，所述步骤(1)中碱选自二异丙基氨基锂、双(三甲基硅基)胺基锂、双(三甲基硅基)胺基钠、双(三甲基硅基)胺基钾或正丁基锂；反应溶剂选自四氢呋喃、2-甲基四氢呋喃或甲苯；反应结束后加入氯化铵淬灭，乙酸乙酯萃取，有机相浓缩，加石油醚，冷却析晶，过滤得化合物3。
作为优选，所述步骤(2)中催化剂选自钯碳或氢氧化钯；不加碱或加入碱促进关环反应，碱选自三乙胺、二异丙基乙胺、碳酸钾、碳酸钠、醋酸钠或醋酸钾；反应溶剂选甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或醋酸异丙酯。
本发明目的之三是提供一种PF-07321332的关键手性化合物7的制备方法，包括如下步骤：
(1)以BOC-L-谷氨酸二甲酯化合物1为起始原料，利用强碱拔氢后与1,2,3-噁噻唑烷-3-甲酸苄酯2,2-二氧化物化合物2对接得到化合物3；
(2)所得化合物3经过一锅法氢化并环合得到化合物4；
(3)化合物4通过氨化反应、脱水反应，最后酸解成盐反应，以甲基磺酸盐的形式得到目标产物化合物7；
本发明提供了用于合成PF-07321332的关键手性化合物7具有纯度高，性质稳定利于保存的特点，可以十分方便地应用于合成PF-07321332后续工艺中。另外，开发了化合物4的合成方法，其提高了路线总收率，烷基化反应收率较高，且有效减少了副产物的生成，氢化脱CBZ也降低了还原反应的难度，并显著降低了贵金属催化剂的用量。本方法提供的用于PF-07321332的关键手性化合物7，可利于降低工艺成本，适宜工业化生产。
具体实施方式
下面对本发明的实施例作详细说明，本实施例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于下述的实施例。
实施例1
三口烧瓶中加入化合物1(27.53g,100mmol)和四氢呋喃(135mL)，搅拌溶解，并真空切换氮气3次并冷至-55～-50℃，氮气保护下将二异丙基氨基锂(2.0M四氢呋喃/正庚烷溶液,105mL)缓慢滴入反应瓶中，滴完后保温反应1小时，缓慢将化合物2的溶液(28.30g,110mmol,溶于140mL四氢呋喃)滴入反应瓶中，缓慢升温至室温反应。反应结束加入饱和氯化铵淬灭反应(270mL)淬灭反应，水相用乙酸乙酯(135mL)萃取3次，合并有机相水洗1次(135mL)，浓缩至小体积，缓慢滴入270mL石油醚，缓慢冷却至0～10℃并保温析晶1小时，过滤，收集滤饼干燥得中间体3(39.59g,收率87.5％)。
MS(ESI)m/z＝453.2[M+H]+。
1H NMR(400MHz,CDCl3)δ7.32-7.37(m,4H),7.28-7.32(m,1H),5.05-5.16(br,2H),5.08(s,2H),4.31-4.38(m,1H),3.72(s,3H),3.66(s,3H),3.22-3.31(m,1H),3.12-3.22(m,1H),2.52-2.59(m,1H),1.93-2.02(m,2H),1.76-1.90(m,2H),1.41(s,9H)。
实施例1中，溶剂四氢呋喃可用2-甲基四氢呋喃或甲苯代替；二异丙基氨基锂可用双(三甲基硅基)胺基锂、双(三甲基硅基)胺基钠、双(三甲基硅基)胺基钾或正丁基锂代替。
实施例2
将中间体3(45.25g,100mmol)和无水甲醇(226mL)，加入醋酸钠(8.20g,100mmol)，加入3％钯碳(0.45g干计)，水泵抽真空切换氢气3次，40～45℃常压加氢反应10～16小时。反应结束过滤除去钯碳和盐，浓缩蒸出部分溶剂，加热至55～60℃，缓慢加入水270mL，缓慢冷至0～10℃打浆1小时，过滤，得化合物4(26.69g,收率93.2％)。
实施例2中，醋酸钠可不加，或可用三乙胺、二异丙基乙胺、碳酸钾、碳酸钠或醋酸钾代替；钯碳可用氢氧化钯代替；溶剂甲醇可用乙醇、异丙醇、四氢呋喃、乙酸乙酯或醋酸异丙酯代替。
实施例3
三口烧瓶中加入化合物4(28.63g,100mmol)和乙醇(143mL)，加入氨水(28％,125.2g)，加热回流6～8小时。反应结束旋去部分溶剂后加入水(172mL)，缓慢冷却至0～5℃结晶，过滤，收集固体干燥得化合物5(25.10g,92.5％)。
实施例3中，乙醇可用甲醇、异丙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯或甲苯代替。
实施实例4
往反应瓶中加入化合物5(27.13g，100mmol)和四氢呋喃(135mL)，搅拌溶解后冷却至0～5℃，加入三乙胺(30.36g,300mmol)，缓慢滴入三氟甲磺酸酐(33.86g,120mmol)，保温反应4～6小时，反应结束后缓慢加入水(270mL)淬灭反应，水相用乙酸乙酯(135mL)萃取3次，合并有机相水洗1次(135mL)，浓缩后缓慢加入石油醚271mL，缓慢冷却至0～5℃析晶，过滤，收集滤饼干燥得中间体化合物6(23.26g,91.8％)。
MS(EI)m/z＝276.2[M+Na]+。
1H NMR(400MHz,CDCl3)δ6.56(s,1H),6.32(br,0.18H),6.00(br,0.82H),4.61-4.79(m,1H),3.34-3.43(m,2H),2.47-2.57(m,1H),2.39-2.47(m,1H),2.26-2.34(m,1H),1.90-1.97(m,1H),1.82-1.90(m,1H),1.48(s,9H)。
实施例4中，三乙胺可不加，或者也可用二异丙基乙胺、吡啶、2,6-二甲基吡啶或DBU代替；三氟甲磺酸酐可用三氯氧膦、三氟乙酸酐、三氯异氰尿酸TCCA或Burgess试剂代替；溶剂四氢呋喃可用N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二氯甲烷、2-甲基四氢呋喃、乙腈、甲苯、二甲苯或氯苯代替。
实施例5
三口烧瓶中加入化合物6(25.33g,100mmol)和异丙醇(127mL)，加入甲基磺酸(14.41g,150mmol)，加热至55～60℃反应3～5小时。旋去部分溶剂后加入乙酸乙酯(200mL)，缓慢冷却至0～5℃，过滤，收集滤饼真空干燥得目标化合物7(23.36g,93.7％)。
MS(ESI)m/z(游离碱)＝154.2[M+H]+。
1H NMR(400MHz,CD3OD)δ4.73(t,J＝5.6Hz,1H),3.29-3.34(m,2H),2.65-2.73(m,1H),2.64(s,3H),2.33-2.41(m,1H),2.10-2.19(m,2H),1.78-1.88(m,1H)。
实施例5中，异丙醇可用甲醇、乙醇、丙酮、甲基叔丁醚、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯、醋酸异丙酯、甲苯或水以及这些溶剂任意两种形成的混合溶剂代替。
Claims (4)
1.化合物4的制备方法，其特征在于包括如下步骤：
(1)将化合物1在碱作用下与化合物2反应得到化合物3；
(2)将化合物3在催化剂作用下进行氢化反应脱CBZ并一步成环得到化合物4；
2.根据权利要求1所述的化合物4的制备方法，其特征在于所述步骤(1)中碱选自二异丙基氨基锂、双(三甲基硅基)胺基锂、双(三甲基硅基)胺基钠、双(三甲基硅基)胺基钾或正丁基锂；反应溶剂选自四氢呋喃、2-甲基四氢呋喃或甲苯。
3.根据权利要求1所述的化合物4的制备方法，其特征在于所述步骤(2)中催化剂选自钯碳或氢氧化钯；不加碱或加入碱促进关环反应，碱选自三乙胺、二异丙基乙胺、碳酸钾、碳酸钠、醋酸钠或醋酸钾；反应溶剂选甲醇、乙醇、异丙醇、四氢呋喃、乙酸乙酯或醋酸异丙酯。
4.化合物7的制备方法，其特征在于包括如下步骤：
(1)以BOC-L-谷氨酸二甲酯化合物1为起始原料，利用强碱拔氢后与1,2,3-噁噻唑烷-3-甲酸苄酯-2,2-二氧化物化合物2对接得到化合物3；
(2)将化合物3在催化剂作用下进行氢化反应脱CBZ并一步成环得到化合物4；
(3)将化合物4经过氨解反应得到化合物5；
(4)将化合物5经过脱水反应得到化合物6；
(5)将化合物6经过甲基磺酸酸解脱Boc并一步成盐反应得到化合物7；
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111422350.3A CN115490626B (zh) | 2021-11-26 | 2021-11-26 | 一种pf-07321332的关键手性化合物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111422350.3A CN115490626B (zh) | 2021-11-26 | 2021-11-26 | 一种pf-07321332的关键手性化合物及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115490626A CN115490626A (zh) | 2022-12-20 |
| CN115490626B true CN115490626B (zh) | 2024-08-23 |
Family
ID=84465357
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111422350.3A Active CN115490626B (zh) | 2021-11-26 | 2021-11-26 | 一种pf-07321332的关键手性化合物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115490626B (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11174231B1 (en) * | 2020-06-09 | 2021-11-16 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| CN114466838A (zh) * | 2020-09-03 | 2022-05-10 | 辉瑞大药厂 | 含腈的抗病毒化合物 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6774243B2 (en) * | 1999-08-24 | 2004-08-10 | Agouron Pharmaceuticals, Inc. | Efficient synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates |
| CN106928206B (zh) * | 2015-12-31 | 2022-02-18 | 中国科学院上海药物研究所 | 醛基类化合物及其制法和用途 |
-
2021
- 2021-11-26 CN CN202111422350.3A patent/CN115490626B/zh active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11174231B1 (en) * | 2020-06-09 | 2021-11-16 | Pardes Biosciences, Inc. | Inhibitors of cysteine proteases and methods of use thereof |
| CN114466838A (zh) * | 2020-09-03 | 2022-05-10 | 辉瑞大药厂 | 含腈的抗病毒化合物 |
Non-Patent Citations (2)
| Title |
|---|
| Crystal structure of SARS-CoV-2 main proteasein complex with protease inhibitor PF-07321332;Yao Zhao，等;《Protein & Cell》;第13卷;第689-693页及Supplementary Information * |
| Yao Zhao，等.Crystal structure of SARS-CoV-2 main proteasein complex with protease inhibitor PF-07321332.《Protein & Cell》.2021,第13卷第689-693页及Supplementary Information. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115490626A (zh) | 2022-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112125805B (zh) | 水溶性厚朴酚衍生物及和厚朴酚衍生物和其中间体的制备方法、和相关的单羟基保护中间体 | |
| CN108586465B (zh) | 一种巴瑞替尼的制备方法 | |
| CN113999142B (zh) | 一种手性N-Boc-反式-1,2-环己二胺的制备方法 | |
| CN109096122B (zh) | 制备亚精胺的方法 | |
| CN115490626B (zh) | 一种pf-07321332的关键手性化合物及其制备方法 | |
| WO2011082506A1 (zh) | 一种制备阿利克伦及其中间体的方法 | |
| CN111518110B (zh) | 一种海鞘素化合物及其中间体的制备方法 | |
| CN111217791A (zh) | 依鲁司他中间体及其制备方法 | |
| CN112174837B (zh) | 一种合成(R)-4-甲氧基-α-甲基苯乙胺的方法 | |
| CN112920053B (zh) | 一种手性α-甲基芳乙胺的制备方法 | |
| CN111646991B (zh) | 一种阿维巴坦钠中间体的制备方法 | |
| KR20240024937A (ko) | Cyp11a1 억제제 및 그의 중간체의 제조 방법 | |
| CN113072514B (zh) | 轮环藤宁及其中间体的制备方法 | |
| CN110092726B (zh) | 一种Bictegravir中间体的合成方法 | |
| CN109265385B (zh) | 一种手性催化剂的合成工艺 | |
| CN115557871B (zh) | 一种抗病毒化合物pf-07321332的合成方法 | |
| JP2020070296A (ja) | リナグリプチンの製造法 | |
| CN114105848B (zh) | 一种顺式-d-羟脯氨酸衍生物的制备方法 | |
| CN111217709A (zh) | 一种（1-氟环丙基）甲胺盐酸盐的制备方法 | |
| CN116396290B (zh) | 一种制备莫西沙星中间体(s,s)-2,8-二氮杂双环[4,3,0]壬烷的方法 | |
| CN111087405A (zh) | 一种不对称合成石蒜科生物碱(+)-γ-lycorane的方法 | |
| CN109503430B (zh) | 一种邻氟邻亚胺基苯甲酸中间体化合物及其制备方法和应用 | |
| CN114736186B (zh) | 一种由氨基甲酸叔丁酯合成维兰特罗中间体的方法 | |
| CN117777048B (zh) | 一种手性2-羟甲基吗啉-4-羧酸叔丁酯的制备方法 | |
| CN109400553B (zh) | 阿利克仑中间体的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |