CN116751153A - Preparation method of Nemactetvir intermediate - Google Patents
Preparation method of Nemactetvir intermediate Download PDFInfo
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- CN116751153A CN116751153A CN202210217711.9A CN202210217711A CN116751153A CN 116751153 A CN116751153 A CN 116751153A CN 202210217711 A CN202210217711 A CN 202210217711A CN 116751153 A CN116751153 A CN 116751153A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 121
- BGOMFPZIMJCRDV-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(C)(C)C21 BGOMFPZIMJCRDV-UHFFFAOYSA-N 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 229910021529 ammonia Inorganic materials 0.000 claims description 33
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 230000035484 reaction time Effects 0.000 claims description 16
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 10
- -1 aminomethyl alcohol Chemical compound 0.000 claims description 10
- 239000004973 liquid crystal related substance Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 230000001590 oxidative effect Effects 0.000 claims description 8
- 239000007858 starting material Substances 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 238000007142 ring opening reaction Methods 0.000 claims description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical group ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical group [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 239000007868 Raney catalyst Substances 0.000 claims description 5
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 5
- 229910052759 nickel Inorganic materials 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 150000001414 amino alcohols Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical group [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 239000012670 alkaline solution Substances 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims 2
- 230000018044 dehydration Effects 0.000 claims 2
- 238000006297 dehydration reaction Methods 0.000 claims 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 230000007547 defect Effects 0.000 abstract description 2
- 150000008064 anhydrides Chemical class 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 229940125675 paxlovid Drugs 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000006481 deamination reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 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 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- HEMYJVAMSVISRT-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane;hydrochloride Chemical compound Cl.C1NCC2C(C)(C)C21 HEMYJVAMSVISRT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/48—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of 2,2-dimethylcyclopropane rings, e.g. nitrile of chrysanthemumic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/28—Saturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings
- C07C47/353—Saturated compounds having —CHO groups bound to carbon atoms of rings other than six—membered aromatic rings containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
- C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of a Nemactetr intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and an enantiomer thereof, wherein the Nemactetr intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or the salt and the enantiomer thereof are obtained by substituting a compound shown in a formula I or the salt and the enantiomer thereof and cyclizing, and the defect of high cost of using Carlong anhydride as a raw material in the prior art is overcome.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method of a Nemactetvir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane and a novel compound for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Background
Paxlovid belongs to small molecule oral medicine, and is suitable for adult patients with new coronaries, including patients with high risk factors such as cardiovascular diseases, diabetes, chronic lung diseases, etc. The fei company discloses Paxlovid clinical data showing that Paxlovid can reduce the risk of hospitalization and death by 89%. Paxlovid is an oral drug from a combination of Nemactetavir tablet/ritonavir tablet. Wherein the structure of the nemaltevir is as follows:
the preparation of nemrotevir is disclosed in the pyroxene patent WO 2021250648:
6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is a key intermediate for the preparation of nemaltevir.
The disclosed preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is mainly prepared by using caronic anhydride.
For example, patent WO2007075790a discloses a process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride by reduction of lithium aluminum hydride using caron anhydride as starting material:
WO2008082508A discloses a process for the preparation of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by reduction of lithium aluminum hydride using caron anhydride as starting material and deprotection:
patent WO2009073380A, US7723531B also discloses a process using the preparation of caronic anhydride.
The caronic anhydride is used as a raw material, so that the cost for preparing the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is high, and the lithium aluminum hydride used in the route is unsafe and is not beneficial to large-scale industrial production.
Disclosure of Invention
The invention discloses a preparation method of a Nemactetvir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane and a novel compound for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane. Solves the defect of high cost of using the caronic anhydride as the raw material in the prior art.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
wherein:
the first technical scheme is as follows:
R 1 is-CHO, -CH 2 OH、-CN、-CH 2 X，
R 2 is-CHO, -CH 2 OH、-CN、-CH 2 X, X is F, cl, br, I.
Preferably, the compound of formula I is substituted with ammonia and cyclized to the intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt, enantiomer thereof, further, the ammonia is an ammonia reagent, further an ammonia alcohol, ammonia water; further aminoalcohols include aminomethyl alcohol and aminoethanol; the concentration of ammonia water is 25-30%, and can be 25%, 26%, 27%, 28%, 29%, 30%.
Preferably, the compound I is catalytically reacted with ammonia, and the catalyst is nickel catalyst, further nickel and Raney nickel. Preferably, the compound of the formula I is catalyzed by hydrogen to prepare an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and enantiomer thereof, and the catalyst is a nickel catalyst, and further is nickel or Raney nickel.
Preferably, the reaction temperature is 50-110 ℃, further 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃.
Preferably, the reaction time is 4 to 10 hours, further 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours.
The second scheme is as follows:
R 3 is that
Preferably, the compound of formula I-a is reacted with ammonia, further ammonia being an ammonia reagent, further ammonia methanol.
Preferably, the reaction temperature is 90-110 ℃;
preferably, the reaction time is 4 to 6 hours, further 4 hours, 5 hours, 6 hours.
Third scheme:
R 21 is-CHO, -CH 2 OH、-CHX 1 ，X 1 F, cl, br, I.
The compound of formula I is selected from the following compounds:
preferably, R 21 A compound selected from the group consisting of:
preferably, the reaction temperature is: 50-80 ℃, further 50 ℃, 60 ℃, 70 ℃ and 80 ℃.
Preferably, the reaction time is: 8-10 hours, further 8 hours, 9 hours, 10 hours.
Also disclosed are methods of preparing compounds of formula I:
wherein, the liquid crystal display device comprises a liquid crystal display device,
1)R 1、 is-CHO, -CH 2 OH、-CN、-CH 2 X，R 2 is-CHO, -CH 2 OH、-CN、-CH 2 X；
2)R 1 is-CHO-, R 2 is-CHO-, and R 1、 R 2 Are connected into a ring as shown in the formula I-a
R 3 Is thatX is F, cl, br, I;
R 4 is-CH 2 OH、-CH 2 X、-CHONH 2 、-CHOOR 6 ,
R 5 is-CH 2 OH、-CH 2 X 2 、-CHONH 2 、-CHOOR 6 ,
R 6 Methyl, ethyl, propyl, isopropyl;
1)R 7 is-CH 2 OH、-CH 2 X 3 、-CN
R 8 is-CH 2 OH、-CH 2 X 3 、-CN；
2)R 7 is-CHO-, R 8 The structure of the compound of the formula II-a is-CHO-, and the structure is shown as follows:
R 9 is thatX 3 F, cl, br, I;
preferably, the compound of formula II is selected from the following compounds:
wherein X is 4 F, cl, br, I.
Preferably, the compound of formula III is selected from the following compounds:
disclosed are processes for preparing intermediates using compounds of formula 1 as starting materials:
preferably, the compound of formula 1 reacts with borohydride and boron trifluoride diethyl etherate, and the compound of formula 2 is obtained through reduction ring opening; further, the reaction temperature is 55-70 ℃; further, the reaction time is 10 to 14 hours, further 10 hours, 12 hours and 14 hours; further, the molar ratio of the compound of formula 1, borohydride and boron trifluoride diethyl etherate is 1:1-1.2: 0.9 to 1, and the molar ratio of the compound of formula 1, borohydride and boron trifluoride etherate is 1:1.2:1.
Preferably, the compound of formula 2 is reacted with thionyl chloride to give the compound of formula 3; further reacting under alkaline condition, wherein the alkaline solution is triethylamine; further, the organic solvent is acetonitrile.
Preferably, the compound of formula 3 is oxidized to provide a compound of formula 4; the further oxidant is sodium periodate, and the further catalyst is ruthenium chloride.
Preferably, the compound of formula 4 is reacted with ammonia and cyclized to provide an intermediate; the ammonia is further ammonia reagent, such as ammonia methanol and ammonia water.
Another process for preparing an intermediate using a compound of formula 1 as starting material is disclosed:
preferably, the compound of formula 1 is reacted with ammonia as a starting material to give a compound of formula 5 via ring opening; the further reaction temperature is 100-120 ℃, and the further reaction temperature is 100 ℃, 110 ℃ and 120 ℃; further, the reaction time is 25-35 hours, and further, the reaction time is 25 hours, 30 hours and 35 hours.
Preferably, the compound of formula 5 is substituted with a halogenating agent and oxidized to give a compound of formula 6; the oxidant is phosphorus oxychloride, the reaction temperature is 30-40 ℃, and the reaction temperature is 30 ℃, 35 ℃ and 40 ℃.
Preferably, the compound of formula 6 undergoes a substitution reaction to give a compound of formula 7; the reaction temperature is further 90-110deg.C, further 90 deg.C, 100 deg.C, and 110 deg.C.
Preferably, the compound of formula 7 is substituted and cyclized to obtain an intermediate, and further, the catalyst is nickel or Raney nickel; further, the reaction temperature is 50-80 ℃; the further reaction time is 8-10 hours.
A third method for preparing an intermediate using a compound of formula 1 as starting material is disclosed:
preferably, the compound of formula 6 is oxidized to provide a compound of formula 8; further, the reaction temperature is 40-60 ℃, and further 40 ℃,50 ℃ and 60 ℃; the reaction time is 25-35 hours, 25 hours, 30 hours and 35 hours.
Preferably, the compound of formula 8 is substituted and cyclized to provide an intermediate; further, the compound of formula 8 reacts with ammonia, further an ammonia reagent, further aqueous ammonia, an ammonia alcohol solution; further, the reaction temperature is 50-80 ℃; further, the reaction time is 8-10 hours.
Also disclosed are methods of preparing intermediates using compounds of formula III as starting materials:
preferably, the compound of formula III-1 is reduced by ketone under borohydride, lewis acid or borane conditions to obtain the compound of formula II-1; oxidizing the compound II-1 to obtain a compound I-1; reacting the formula I-1 with ammonia, and cyclizing to obtain an intermediate.
The invention has the following beneficial effects:
1. the operation is simple, the later reduction is safe, and the method is suitable for industrial production;
2. the raw materials are easy to obtain, and the preparation cost is reduced.
Detailed Description
The invention is further defined in the following examples, which are to be understood as being given by way of illustration only and not as limiting the claims of the invention, although these examples are given to give preferred embodiments of the invention.
Example 1
1-1 Synthesis examples of Compounds of formula 2:
20g of the compound of formula 1 are dissolved in dry 200ml of THF, 7.2g of sodium borohydride is added, then 22.4g of boron trifluoride diethyl etherate is added dropwise, the dropwise addition process is not more than 30 ℃, the dropwise addition is completed, and the temperature is raised to 55-70 ℃ for reaction for 12 hours. And after sampling and central control are qualified. Quenched with 10g of water. Then adding 30% hydrogen peroxide to raise the temperature to 70 ℃ to eliminate the intermediate state of the reaction. Extracting with isopropyl acetate, drying, and filtering to obtain filtrate for the next reaction.
1-2 Synthesis examples of Compounds of formula 3:
18.9g of triethylamine and 12.6g of acetonitrile are added into the isopropyl acetate extract in the last step, and then 17g of thionyl chloride is added dropwise at the temperature of 10 ℃ until the dropwise addition is finished. The reaction was stirred for 1 hour. Cooling to below 0 ℃, adding 50g of water for quenching. Then washed 3 times with 50g of water. The organic layer was used directly for the next reaction.
1-3 Synthesis examples of Compounds of formula 4:
adding 0.5g of ruthenium chloride into the organic layer obtained in the previous step, slowly adding sodium periodate, then dropwise adding 30% hydrogen peroxide, stirring and reacting for 1 hour after the addition, and layering. The organic layer was washed with sodium sulfite. And (5) washing with water. Concentrating until no fraction is present.
1-4 intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane synthesis example:
the above concentrate was added to 100mL of 17% methanolic ammonia solution, stirred for 30 minutes, and then heated to 100deg.C for reaction for 5 hours. Cooling, concentrating under reduced pressure to evaporate excessive ammonia and methanol. The pH was adjusted to 10-11 with 7g of 5% sodium hydroxide and extracted with MTBE. After concentrating MTBE under reduced pressure, TM4.3g of an oily substance was obtained as the target product (CAS: 943516-54-9). The total yield was 24%.
Example 2.
2-1 Synthesis example of Compound of formula 5:
20g of the compound of formula 1 are introduced into a 500ml autoclave, 200g of a 20% amino alcohol solution are added, and the temperature is raised to 110℃and the reaction is stirred for 30 hours. Cooling to room temperature, and removing excessive ammonia. The reaction solution was concentrated under reduced pressure until no fraction was obtained. Directly used for the next synthesis.
2-2 Synthesis examples of Compounds of formula 6:
200g of chloroform was added to the concentrate obtained in the above step, the temperature was raised to 35℃and 40g of phosphorus oxychloride was added dropwise. A large amount of hydrogen chloride gas is generated during the dropping process. The drop was completed for about 3 hours. After the dripping is finished, the temperature is raised to 40-50 ℃, and the reaction is carried out for 1-3 hours under the heat preservation until no bubbles are generated. 50g of water was added, stirred for 30 minutes, left to stand for 30 minutes, and layered. The organic layer was washed with 50g of water and then concentrated to no fraction. Directly used for the next synthesis.
2-3 Synthesis examples of Compounds of formula 7:
the concentrated solution obtained in the previous step is added into 100g of strong ammonia water, and the temperature is raised to 100 ℃ for reaction for 5 hours. And then directly used in the next reaction. Compound 7: 1 H(CDCl3,600MHz)1.19(s,3H),1.34(s,3H),2.90(m,2H),1.38(m,1H),1.27(dd，1H)
synthesis of 2-4 intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane:
10g of nickel catalyst was added to the reaction mixture of the above step, followed by H 2 Pressurizing to 0.8-1 MPa, controlling the temperature to 50-80 ℃ and reacting for 8-10 hours. Then deamination is carried out by distillation under reduced pressure. 8g of sodium hydroxide was added and the mixture was extracted with MTBE. After concentrating MTBE under reduced pressure, 6.5g of TM was obtained as an oily substance, which was the target product (CAS: 943516-54-9). The total yield was 36.8%.
Example 3:
example 3-1 Synthesis example of Compound of formula 8:
a concentrated solution of Compound 6 was prepared in accordance with examples 2-1 and 2-2, and was added to a mixture of 9.5g of sodium hydroxide and 200g of water, and the temperature was raised to 50℃for reaction for 30 hours. Then ethyl acetate was added for extraction. 10g of concentrated brine and 30g of water were then added. 20g of TCCA was slowly added, and the mixture was centrally controlled until the material disappeared. Filtration and separation, concentration of the organic layer to dryness gives 8g of the compound of formula 8.
Example 3-2 synthesis of intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane:
12.3g of compound 7 of formula 7, 50g of ammonia water and 9g of nickel catalyst are added, and then the mixture is pressurized to 0.8 MPa-1 MPa and reacted for 8-10 hours at a temperature of 50-80 ℃. Then deamination is carried out by distillation under reduced pressure. 6g of sodium hydroxide was added and the mixture was extracted with MTBE. After concentrating MTBE under reduced pressure, 5.6g of TM was obtained as an oily substance, which was the target product (CAS: 943516-54-9). The total yield was 31.8%.
Claims (10)
1. A method for preparing a nemaltevir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and an enantiomer thereof, which is characterized in that:
the Nemactetvir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt thereof, and enantiomer is obtained by substituting a compound shown in a formula I or a salt thereof and enantiomer and cyclizing,
wherein, the liquid crystal display device comprises a liquid crystal display device,
1)R 1 is-CHO, -CH 2 OH、-CN、-CH 2 X，
R 2 is-CHO, -CH 2 OH、-CN、-CH 2 X；
2)R 1 is-CHO-, R 2 is-CHO-, and R 1 、R 2 Are connected into a ring as shown in the formula I-a
R 3 Is thatX is F, cl, br, I.
2. A method for preparing a nemaltevir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and an enantiomer thereof, which is characterized in that:
the Nemactevir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or salt, enantiomer thereof is obtained by the substitution of a compound of the formula I-b or salt, enantiomer and cyclization
R 21 is-CHO, -CH 2 OH、-CHX 1 ，X 1 F, cl, br, I.
3. The preparation method of the nemaltevir intermediate is characterized by comprising the following steps of:
the compound of formula I or the salt and enantiomer thereof react with ammonia, and then cyclize to obtain 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or the salt and enantiomer thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
1)1)R 1 is-CHO, -CH 2 OH、-CN、-CH 2 X，
R 2 is-CHO, -CH 2 OH、-CN、-CH 2 X；
2)R 1 is-CHO-, R 2 is-CHO-, and R 1 、R 2 Are connected into a ring as shown in the formula I-a
R 3 Is thatX is F, cl, br, I;
preferably, the compound of formula I is substituted with ammonia and cyclized to the intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt, enantiomer thereof, further, the ammonia is an ammonia reagent, further an ammonia alcohol, ammonia water; further aminoalcohols include aminomethyl alcohol and aminoethanol; the concentration of ammonia water is 25-30%, which can be 25%, 26%, 27%, 28%, 29%, 30%;
preferred compounds of formula I are catalytically reacted with ammonia, the catalyst being a nickel catalyst, further being nickel, raney nickel. Preferably, the compound of the formula I is catalyzed by hydrogen to prepare an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and enantiomer thereof, and the catalyst is a nickel catalyst, and further is nickel and Raney nickel;
preferably, the reaction temperature is 50-110deg.C, further 50 deg.C, 60 deg.C, 70 deg.C, 80 deg.C, 90 deg.C, 100 deg.C, 110 deg.C;
preferably, the reaction time is 4 to 10 hours, further 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours.
4. A process for the preparation of a compound of formula I or a salt, enantiomer thereof, characterized in that: the preparation of the compound of formula I comprises the steps of:
(1) Reducing and ring-opening by taking a compound shown in a formula 1 or salt and enantiomer thereof as raw materials to obtain a compound shown in a formula III;
R 4 is-CH 2 OH、-CH 2 X、-CHONH 2 、-CHOOR 6 ,
R 5 is-CH 2 OH、-CH 2 X 2 、-CHONH 2 、-CHOOR 6 ,
R 6 Methyl, ethyl, propyl, isopropyl;
(2) Oxidizing the compound of formula III to obtain the compound of formula II or salt, enantiomer thereof,
1)R 7 is-CH 2 OH、-CH 2 X 3 、-CN，
R 8 is-CH 2 OH、-CH 2 X 3 、-CN；
2)R 7 is-CHO-, R 8 The structure of the compound of the formula II-a is-CHO-, and the structure is shown as follows:
R 9 is thatX 3 F, cl, br, I;
(3) The compound of the formula II is substituted to obtain the compound of the formula I or salt, enantiomer thereof,
wherein, the liquid crystal display device comprises a liquid crystal display device,
1)R 1 is-CHO, -CH 2 OH、-CN、-CH 2 X，
R 2 is-CHO, -CH 2 OH、-CN、-CH 2 X；
2)R 1 is-CHO-, R 2 is-CHO-, and R 1 、R 2 Are connected into a ring as shown in the formula I-a
R 3 Is thatX is F, cl, br, I.
5. A process for the preparation of a nemaltevir intermediate, characterized by:
the method comprises the following steps:
(1) The compound of formula 1 or the salt and enantiomer thereof are used as raw materials to be subjected to reduction ring opening to obtain the compound of formula 2,
the reducing agent is borohydride;
(2) Cyclizing a compound of formula 2 to a compound of formula 3 by reacting a compound of formula 2 with thionyl chloride
(3) Oxidizing the compound of formula 3 to obtain the compound of formula 4
(4) Reacting the compound shown in the formula 4 to obtain an intermediate of Nemactetvir, namely 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and an enantiomer thereof;
preferably, the compound of formula 1 reacts with borohydride and boron trifluoride diethyl etherate, and the compound of formula 2 is obtained through reduction ring opening; further, the reaction temperature is 55-70 ℃; further, the reaction time is 10 to 14 hours, further 10 hours, 12 hours and 14 hours; further, the molar ratio of the compound of formula 1, borohydride and boron trifluoride diethyl etherate is 1:1-1.2: 0.9 to 1, and the molar ratio of the compound of the formula 1, the borohydride and the boron trifluoride diethyl etherate is 1:1.2:1;
preferably, the compound of formula 2 is reacted with thionyl chloride to give the compound of formula 3; further reacting under alkaline condition, wherein the alkaline solution is triethylamine; further, the organic solvent is acetonitrile;
preferably, the compound of formula 3 is oxidized to provide a compound of formula 4; the further oxidant is sodium periodate, and the further catalyst is ruthenium chloride;
preferably, the compound of formula 4 is reacted with ammonia and cyclized to provide an intermediate; the ammonia is further ammonia reagent, such as ammonia methanol and ammonia water.
6. A process for the preparation of a nemaltevir intermediate, characterized by:
the method comprises the following steps:
(1) Ring-opening the compound of formula 1 as raw material to obtain the amide compound of formula 5,
(2) The compound of formula 5 and halogenated reagent are subjected to substitution reaction and dehydration to obtain the compound of formula 6,
wherein X is 4 F, cl, br, I;
(3) The compound of the formula 6 is subjected to substitution reaction to obtain a compound of the formula 7,
(4) The compound of formula 7 is substituted and cyclized to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and an enantiomer thereof;
preferably, the compound of formula 1 is reacted with ammonia as a starting material to give a compound of formula 5 via ring opening; the further reaction temperature is 100-120 ℃, and the further reaction temperature is 100 ℃, 110 ℃ and 120 ℃; further, the reaction time is 25-35 hours, and the further reaction time is 25 hours, 30 hours and 35 hours;
preferably, the compound of formula 5 is substituted with a halogenating agent and oxidized to give a compound of formula 6; further, the oxidant is phosphorus oxychloride, the further reaction temperature is 30-40 ℃, and the further reaction temperature is 30 ℃, 35 ℃ and 40 ℃;
preferably, the compound of formula 6 undergoes a substitution reaction to give a compound of formula 7; further, the reaction temperature is 90-110 ℃, further 90 ℃, 100 ℃ and 110 ℃;
preferably, the compound of formula 7 is substituted and cyclized to obtain an intermediate, and further, the catalyst is nickel or Raney nickel; further, the reaction temperature is 50-80 ℃; the further reaction time is 8-10 hours.
7. A process for the preparation of a nemaltevir intermediate, characterized by:
the method comprises the following steps:
(1) Reacting the compound of formula 1 with ammonia to obtain an amide compound of formula 5,
(2) Carrying out substitution reaction and dehydration on the halogenated reagent of the compound of the formula 5 to obtain a compound of the formula 6,
wherein X is 4 F, cl, br, I;
(3) The compound of formula 6 is oxidized to obtain a compound of formula 8,
(4) The compound of formula 8 is substituted and cyclized to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and an enantiomer thereof;
preferably, the compound of formula 6 is oxidized to provide a compound of formula 8; further, the reaction temperature is 40-60 ℃, and further 40 ℃,50 ℃ and 60 ℃; the further reaction time is 25-35 hours, further 25 hours, 30 hours and 35 hours;
preferably, the compound of formula 8 is substituted and cyclized to provide an intermediate; further, the compound of formula 8 reacts with ammonia, further an ammonia reagent, further aqueous ammonia, an ammonia alcohol solution; further, the reaction temperature is 50-80 ℃; further, the reaction time is 8-10 hours.
8. A process for the preparation of a nemaltevir intermediate, characterized by:
(1) The compound of the formula III-1 is taken as a raw material and is reduced by ketone to obtain the compound of the formula II-1;
wherein R is 6 Methyl, ethyl, propyl, isopropyl.
(2) Reducing the compound of the formula II-1 to obtain a compound of the formula I-1;
(3) Cyclizing the compound shown in the formula I-1 to obtain a Nemactetavir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane or a salt and enantiomer thereof,
preferably, the compound of formula III-1 is reduced by ketone under borohydride, lewis acid or borane conditions to obtain the compound of formula II-1; oxidizing the compound II-1 to obtain a compound I-1; reacting the formula I-1 with ammonia, and cyclizing to obtain an intermediate.
9. The following compounds or salts, enantiomers thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,
1)R 1 is-CHO, -CH 2 OH、-CN、-CH 2 X，
R 2 is-CHO, -CH 2 OH、-CN、-CH 2 X；
2)R 1 is-CHO-, R 2 is-CHO-, and R 1 、R 2 Are connected into a ring as shown in the formula I-a
R 3 Is thatX is F, cl, br, I.
10. The following compounds or salts, enantiomers thereof:
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