CN117049998A - Method for preparing nemaltevir intermediate by using methyl cardiac sulfonate - Google Patents
Method for preparing nemaltevir intermediate by using methyl cardiac sulfonate Download PDFInfo
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- CN117049998A CN117049998A CN202210479003.2A CN202210479003A CN117049998A CN 117049998 A CN117049998 A CN 117049998A CN 202210479003 A CN202210479003 A CN 202210479003A CN 117049998 A CN117049998 A CN 117049998A
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- compound
- azabicyclo
- hexane
- dimethyl
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- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000000747 cardiac effect Effects 0.000 title claims abstract description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 title claims abstract description 11
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 title claims description 4
- 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
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 229940125782 compound 2 Drugs 0.000 claims abstract description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 30
- 229940126214 compound 3 Drugs 0.000 claims description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 12
- 238000007254 oxidation reaction Methods 0.000 claims description 10
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 238000007142 ring opening reaction Methods 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 7
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 229940125898 compound 5 Drugs 0.000 claims description 4
- 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 claims description 3
- FSNCEEGOMTYXKY-JTQLQIEISA-N Lycoperodine 1 Natural products N1C2=CC=CC=C2C2=C1CN[C@H](C(=O)O)C2 FSNCEEGOMTYXKY-JTQLQIEISA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 230000009435 amidation Effects 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 238000006264 debenzylation reaction Methods 0.000 claims description 2
- 230000002140 halogenating effect Effects 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 1
- 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 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 229940125904 compound 1 Drugs 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 3
- 239000003513 alkali Substances 0.000 abstract description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- -1 lithium aluminum hydride Chemical compound 0.000 description 5
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-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
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid 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
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 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
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-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
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000032798 delamination Effects 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
- 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 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
- 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
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 238000005070 sampling 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
- 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
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by using methyl cardiac benzoate, wherein (1) the methyl cardiac benzoate of a compound 1 is cyclized and halogenated to obtain a compound 2, wherein X is Cl, br or I; (2) The Nemactetvir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is prepared by a compound 2. Further, the step (1) comprises the following reaction conditions that the compound 2 reacts with an aqueous alkali solution, sulfuric acid and an organic solvent are added, and then a halogen reagent is added; solves the defect of high cost of using the caronic anhydride as the raw material in the prior art. The reaction operation is simple and easy to obtain, and the yield is high.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a preparation method for preparing a nemrotevir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by using methyl cardiac sulfonate.
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:
nemactetvir
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.
6, 6-dimethyl-3-azabicyclo [3.1.0] hexane
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 and has high price, so that the cost for preparing the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is high, and the preparation method of the caronic anhydride is dangerous and is not friendly to the environment due to the use of a large amount of manganese-containing reagents.
Even if a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane without using caronic anhydride is disclosed, the method has the defects of difficult raw material acquisition, overlong route and complex reaction.
Disclosure of Invention
In order to solve the problem that the method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by using methyl cardiac acid disclosed by the invention solves the defect that the prior art has high cost by using caronic anhydride as a raw material. The reaction operation is simple and easy to obtain, and the yield is high.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a process for preparing a nemrotevir intermediate using methyl cardiac pavilion, comprising the steps of:
(1) Cyclizing and halogenating methyl cardiac maleate of the compound 1 to obtain a compound 2, wherein X is Cl, br or I;
(2) The Nemactetvir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is prepared by a compound 2.
Further, the step (1) comprises the following reaction conditions that the compound 2 reacts with an aqueous alkali solution, sulfuric acid and an organic solvent are added, and then a halogen reagent is added;
preferably, the bromine reagent is bromine, chlorine, NBS, NCS, TCCA, dibromohydantoin, preferably, the halogen reagent is bromine, NBS; preferably dibromohydantoin.
The first step of preparing intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane via compound 2:
(11) Preparing a compound 3 from the compound 2, wherein X is Cl, br or I;
(12) Ring opening of the compound 3, amidation and cyclization to obtain intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Further, the reaction condition of the step (11) is that the compound 2 is dissolved in an organic solvent, and an alkaline reagent is added for reaction.
Further, the alkaline reagent comprises sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium hydrogen and calcium hydride. Sodium tert-butoxide is preferred.
Further, the preparation of the intermediate of the compound 3 comprises the following steps of
Reacting the compound 3 with borohydride and boron trifluoride diethyl etherate, and reducing and ring-opening to obtain a compound I; reacting the compound I with thionyl chloride to obtain a compound II; the compound II is subjected to oxidation reaction to obtain a compound III; the compound III reacts with ammonia, and cyclizes to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Further, the preparation of the intermediate of the compound 3 may further comprise the steps of:
reacting the compound 3 with ammonia, and ring-opening to obtain a compound IV; carrying out substitution and oxidation reaction on the compound IV and a halogenated reagent to obtain a compound V; the compound V is subjected to substitution reaction to obtain a compound VI; the compound VI is substituted and cyclized to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
A third way of preparing an intermediate by Compound 3 is by the following steps
Reacting the compound 3 with ammonia, and ring-opening to obtain a compound IV; carrying out substitution and oxidation reaction on the compound IV and a halogenated reagent to obtain a compound V; the compound V is subjected to oxidation reaction to obtain a compound VII; the compound VII is substituted and cyclized to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
The second disclosed procedure for the preparation of intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane via compound 2 is as follows:
(a) The compound 2 reacts with benzylamine to obtain a compound 4,
(b) The hydroxyl protecting group on the compound 4 to obtain a compound 5, wherein R is Ms and Ts,
(c) Deprotection and oxidation of compound 5 to give compound 6,
(d) Debenzylation and reduction of the compound 6 to obtain intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
Compared with the prior art, the invention has the following technical effects:
the methyl cardiac acid is used as the raw material, the raw material is easy to obtain, the preparation method is simple, the yield is high, the use of the carone anhydride to prepare the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is avoided, the cost is reduced, and the industrialization is convenient.
Drawings
FIG. 1A profile of Compound 2 in example 1;
figure 2 a profile of compound 3 in example 2.
Examples
The technical means adopted by the invention and the effects thereof are further described below with reference to the examples and the attached drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting thereof.
The specific techniques or conditions are not identified in the examples and are described in the literature in this field or are carried out in accordance with the product specifications. The reagents or apparatus used were conventional products commercially available through regular channels, with no manufacturer noted.
Example 1
200g of Compound 1, 280g of 30% aqueous sodium hydroxide solution, and concentrated sulfuric acid (98%) were added to the flask, the mixture was heated to 80℃and reacted for 2 hours, the temperature was lowered to-5℃and 100g of DCM800g was then added thereto, followed by 223.4g of dibromohydantoin in portions. And (3) finishing the dibromohydantoin addition, and carrying out heat preservation reaction for 1 hour. 100g of aqueous sodium sulfite solution was added to quench. And (5) filtering. The filtrate is separated, the organic layer is concentrated to obtain 285g of compound 2 with the yield of 97.8%, and the mass spectrum of the compound 2 is shown in figure 1.
Example 2
165 g of the obtained compound 2 is added into 800g of toluene, 115 g of sodium tert-butoxide is added in batches at about-5 ℃, the mixture is stirred for 1 hour after being cooled to room temperature, then the mixture is heated to 110 ℃ for reaction for 2-3 hours, and the temperature is reduced. Quenched with 600 grams of 2N hydrochloric acid. Layering. The organic layer was concentrated to dryness to afford 392.5 g of compound in 92% yield. The mass spectrum of the compound 3 is shown in figure 2.
Example 3
20g of the compound 3 prepared according to example 2 were dissolved in dry 200ml of THF, 7.2g of sodium borohydride was added, and then 22.4g of boron trifluoride etherate was added dropwise, the dropwise addition was completed at a temperature of not more than 30℃and the reaction was carried out at a temperature of 70℃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. Obtaining the compound I, extracting with isopropyl acetate, drying, filtering, and directly using the filtrate for the next reaction.
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. Compound II was obtained and then washed 3 times with 50g of water. The organic layer was used directly for the next reaction.
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. To obtain the compound III.
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, 7.3g of TM was obtained as an oily substance, which was the target product (CAS: 943516-54-9). The total yield was 41.4%.
Example 4
20g of compound 3 prepared as in example 4 was charged into a 500ml autoclave, 200g of 20% aminoalcohol solution was added thereto, and the temperature was raised to 110℃and the reaction was 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. The compound IV was obtained and used directly in the next step of synthesis.
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 50 ℃, and the reaction is kept for 3 hours until no bubbles are generated. 50g of water was added, stirred for 60 minutes, left to stand for 30 minutes, and layered. The organic layer was washed with 50g of water and then concentrated to no fraction. The compound V was obtained and used directly in the next synthesis.
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 VI: 1 H(CDCl3,600MHz)1.19(s,3H),1.34(s,3H),2.90(m,2H),1.38(m,1H),1.27(dd，1H)
10g of nickel catalyst was added to the reaction mixture of the above step, followed by H 2 Pressurizing to 1MPa, and controlling the temperature to 80 ℃ for reaction for 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, 7.8g of TM was obtained as an oily substance, which was the target product (CAS: 943516-54-9). The total yield was 44.3%.
Example 5
A concentrate of Compound V was prepared as in example 5, and was added to a mixture of 9.5g of sodium hydroxide and 200g of water, and the mixture was reacted at 50℃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 delamination and concentration of the organic layer to dryness gave compound VII.
The compound VII obtained in the previous step is added into 50g of ammonia water, 9g of nickel catalyst is added, and then the mixture is pressurized to 1MPa, and the temperature is controlled to 80 ℃ for reaction for 10 hours. 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, 7.7g of TM was obtained as an oily substance, which was the target product (CAS: 943516-54-9). The total yield was 43.7%.
The applicant states that the detailed method of the present invention is illustrated by the above examples, but the present invention is not limited to the detailed method described above, i.e. it does not mean that the present invention must be practiced in dependence upon the detailed method described above. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (10)
1. A process for the preparation of a nemrotevir intermediate using methyl cardiac sulfonate, characterized by: the method comprises the following steps:
(1) Cyclizing and halogenating methyl cardiac pavilion to obtain a compound 2, wherein X is Cl, br or I;
(2) The Nemactetvir intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is prepared by a compound 2.
2. The method according to claim 1, characterized in that: the step (1) comprises the following reaction conditions that a compound 2 reacts with an alkaline aqueous solution, sulfuric acid and an organic solvent are added, and a halogen reagent is added;
preferably, the halogen reagent is bromine, chlorine, NBS, NCS, TCCA.
3. The method according to claim 1, characterized in that: the intermediate is prepared through the following steps:
(11) Preparing a compound 3 from the compound 2, wherein X is Cl, br or I;
(12) Ring opening of the compound 3, amidation and cyclization to obtain intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
4. The method according to claim 2, characterized in that: the reaction condition of the step (11) is that the compound 2 is dissolved in an organic solvent, and an alkaline reagent is added for reaction.
5. A method according to claim 3, characterized in that: the alkaline reagent comprises sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, sodium hydrogen and calcium hydride.
6. A method according to claim 3, characterized in that: the step (12) comprises the following steps of
Reacting the compound 3 with borohydride and boron trifluoride diethyl etherate, and reducing and ring-opening to obtain a compound I; reacting the compound I with thionyl chloride to obtain a compound II; the compound II is subjected to oxidation reaction to obtain a compound III; the compound III reacts with ammonia, and cyclizes to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
7. A method according to claim 3, characterized in that: the step (12) comprises the following steps of
Reacting the compound 3 with ammonia, and ring-opening to obtain a compound IV; carrying out substitution and oxidation reaction on the compound IV and a halogenated reagent to obtain a compound V; the compound V is subjected to substitution reaction to obtain a compound VI; the compound VI is substituted and cyclized to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
8. The method according to claim 5, wherein: the step (12) comprises the following steps of
Reacting the compound 3 with ammonia, and ring-opening to obtain a compound IV; carrying out substitution and oxidation reaction on the compound IV and a halogenated reagent to obtain a compound V; the compound V is subjected to oxidation reaction to obtain a compound VII; the compound VII is substituted and cyclized to obtain an intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
9. The method according to claim 1, characterized in that: the intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is obtained through the following steps:
(a) The compound 2 reacts with benzylamine to obtain a compound 4,
(b) The hydroxyl protecting group on the compound 4 to obtain a compound 5, wherein R is Ms and Ts,
(c) Deprotection and oxidation of compound 5 to give compound 6,
(d) Debenzylation and reduction of the compound 6 to obtain intermediate 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane,
10. compounds of formula (I)
Wherein R is Ms or Ts.
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