CN115304537B - Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane - Google Patents
Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane Download PDFInfo
- Publication number
- CN115304537B CN115304537B CN202210978219.3A CN202210978219A CN115304537B CN 115304537 B CN115304537 B CN 115304537B CN 202210978219 A CN202210978219 A CN 202210978219A CN 115304537 B CN115304537 B CN 115304537B
- Authority
- CN
- China
- Prior art keywords
- dimethyl
- hexane
- azabicyclo
- preparing
- oxo
- 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
- BGOMFPZIMJCRDV-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2C(C)(C)C21 BGOMFPZIMJCRDV-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title abstract description 15
- CTLLMXVSHAUPFO-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one Chemical compound C1OC(=O)C2C(C)(C)C21 CTLLMXVSHAUPFO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 14
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- NOEANOXILSYOIN-UHFFFAOYSA-N 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2-one Chemical compound C1NC(=O)C2C(C)(C)C21 NOEANOXILSYOIN-UHFFFAOYSA-N 0.000 claims description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 230000003113 alkalizing effect Effects 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 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 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000002360 preparation method Methods 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 abstract description 2
- 229960000623 carbamazepine Drugs 0.000 abstract description 2
- 150000002466 imines Chemical class 0.000 abstract description 2
- 150000002596 lactones Chemical class 0.000 abstract description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract 5
- 238000004176 ammonification Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 11
- 239000007789 gas Substances 0.000 description 6
- 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 6
- 229940125675 paxlovid Drugs 0.000 description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 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 description 3
- 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 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- -1 lithium aluminum hydride Chemical compound 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 230000002034 xenobiotic effect Effects 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)
- Indole Compounds (AREA)
Abstract
The invention provides a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane by using lactone, which is obtained by three steps of ammonification, cyclization and reduction, wherein the cost of the raw material 6, 6-dimethyl-2-oxo-3-oxabicyclo [3.1.0] hexane of the process is lower than that of caronic anhydride, and the preparation method is simpler than that of the caronic anhydride. In addition, only one amide needs to be reduced during reduction, compared with the prior art of the carbazepine Long Xian imine, the method has the advantages of easier reduction, reduction of the consumption of reducing agent, higher safety, great reduction of the cost of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, simplicity and easiness in industrialization, and great economic and social values.
Description
Technical Field
The invention relates to a method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, belonging to the technical field of organic synthesis.
Background
6, 6-Dimethyl-3-azabicyclo [3.1.0] hexane (compound I) is a key intermediate for preparing anti-neocrown drug Paxlovid.
Paxlovid was developed by the company xenobiotic, and was first approved by the U.S. Food and Drug Administration (FDA) for marketing at 22, 12, 2021, and this drug was only prescribed and should be taken as soon as possible within five days after the symptoms had developed in the patient to prevent the exacerbation of the condition to a severe condition.
Clinical trial data published as "Paxlovid" on day 12 and 14 of the year of the best 2021 show that the drug is 89% effective in preventing hospitalization and death of severe high risk patients. The current laboratory data also shows that "Paxlovid" is "still effective" against the amikappaphrons variant strain, since it blocks an enzyme involved in the replication process of the amikappaphrons virus in the experiment.
At present, the global new crown epidemic situation is very severe, and the production task of new crown medicine is urgent. Paxlovid has very broad market prospect.
Compound I is a key intermediate of Paxlovid, and the literature reports a synthetic method thereof, and the specific route is as follows:
The method has the advantages of high price of the starting material of the carbolic anhydride or the carbolic acid, long production steps, reduction by using red aluminum, lithium aluminum hydride or a large amount of sodium borohydride/Lewis acid during reduction, more than 20 times of THF (tetrahydrofuran) required by a solvent, high solvent cost, low kettle efficiency, extremely high risk during use of a large amount of reducing agent, high industrial production cost and high product price.
Aiming at the defects, a great deal of research is carried out on the production of the compound I, a simple and easy method for preparing the compound I is invented, and the production cost of the compound I is greatly reduced.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention aims to provide a brand-new synthesis method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, which can effectively reduce the cost of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
The method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane comprises the following steps:
(1) Adding 6, 6-dimethyl-2-oxo-3-oxabicyclo [3.1.0] hexane (compound II) and ammonia water into an alcohol solvent, reacting for 10-15 hours at 100-120 ℃ and 1.5-2MPa in an autoclave, concentrating under reduced pressure after the reaction is finished, dissolving with ethyl acetate, adding n-hexane, crystallizing, filtering, and drying to obtain cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide (compound III); the mass ratio of the 6, 6-dimethyl-2-oxo-3-oxabicyclo [3.1.0] hexane to the ammonia water is 1:1-1:1.5.
(2) Dissolving cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide (compound III) in methyl tert-butyl ether (MTBE), adding a catalyst N, N-Diisopropylethylamine (DIPEA), adding p-toluenesulfonyl chloride or methanesulfonyl chloride at 0-5 ℃ and reacting for 2-4 hours at the temperature, heating to 55-60 ℃ and refluxing for 4-6 hours, adding water, layering, extracting a water layer by using methyl tert-butyl ether, merging organic phases, washing, concentrating under reduced pressure to obtain 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane (compound IV); the mass ratio of cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide to p-toluenesulfonyl chloride or methanesulfonyl chloride is 1:1-1.5:1; the mass ratio of cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide to N, N-diisopropylethylamine is 1:2-1:2.5.
(3) Dissolving 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane (compound IV) in tetrahydrofuran, adding sodium borohydride serving as a reducing agent, adding boron trifluoride tetrahydrofuran solution serving as a catalyst or trimethylchlorosilane (preferably trimethylchlorosilane) under the protection of nitrogen, reacting for 1-3 hours at 50-60 ℃, after the reaction is finished, using a hydrochloric acid acidification system PH < 2, heating to 50-60 ℃, stirring, distilling under reduced pressure, alkalizing an aqueous phase to PH >13 by using liquid alkali, extracting by using methyl tert-butyl ether, merging organic phases, distilling under normal pressure, and collecting 130-140 ℃ components to obtain a target product 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane (compound I); the mass ratio of the 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane to the sodium borohydride is 1.5:1-2:1; the mass ratio of the 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane to the boron trifluoride tetrahydrofuran solution or the trimethylchlorosilane is 1:1-1:2.
The synthetic route is as follows:
the invention has the beneficial effects that:
the invention takes lactone 6, 6-dimethyl-2-oxo-3-oxabicyclo [3.1.0] hexane as a raw material, and the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane is prepared by three steps of reaction of ammoniation, cyclization and reduction, the cost of a raw material compound II of the process is lower than that of caronic anhydride, and compared with the caronic anhydride, the preparation method is simpler. In addition, only one amide needs to be reduced during reduction, compared with the prior art of the carbazepine Long Xian imine, the method has the advantages of easier reduction, reduction of the consumption of reducing agent, higher safety, great reduction of the cost of the 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane, simplicity and easiness in industrialization, and great economic and social values.
Drawings
FIG. 1 is a gas chromatogram of a sample of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane synthesized in accordance with the present invention;
FIG. 2 is a gas chromatogram of a 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane standard sample.
Detailed Description
In order to better understand the technical scheme of the present invention, the method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane according to the present invention will be further described with reference to the following examples.
Example 1
(1) Adding 126.16g of compound II into a 1L autoclave, adding 150g of ammonia water and 400g of methanol, heating to 110-120 ℃/1.5-2MPa, stirring for 12 hours, cooling to room temperature, decompressing, transferring into a 1000L single-mouth bottle, decompressing, spin-drying solvent and water, taking dry ammonia gas with methanol, adding 126g of ethyl acetate, heating to dissolve, dropwise adding 252g of n-hexane at 50-60 ℃, cooling to 0-5 ℃ after adding, crystallizing, filtering, blowing and drying at 30-40 ℃ to obtain 130.5g of intermediate III, and obtaining off-white solid with yield: 91.1%.
(2) 120G of compound III is added into 600g of MTBE, 258g of DIPEA is added, the temperature is controlled to be 0-5 ℃, 105.5g of methanesulfonyl chloride is added dropwise, the reaction is carried out for 3 hours after the addition is finished, the temperature is increased to be 55-60 ℃ and reflux is carried out for 5 hours, 1000g of water is added, the mixture is stood for layering, the water layer is extracted for 2 times by using MTBE (300 g), the organic phases are combined, the mixture is washed once by 200g of saturated brine, and the organic layer is concentrated to be dried under reduced pressure to obtain 92.5g of compound IV as yellow oily substance. Yield: 88.2%.
(3) Dissolving 62.6g of compound IV in 313g of THF, adding 38g of sodium borohydride, protecting with nitrogen after the addition, heating to 50-60 ℃, dropwise adding 103g of trimethylchlorosilane, keeping the temperature at 50-60 ℃ for 2 hours after the addition, detecting no raw materials by GC, flushing the system into 500g of tap water, keeping the temperature less than 40 ℃, acidifying the system with concentrated hydrochloric acid until the pH value is less than 2 after the addition is completed, heating to 50-60 ℃ and stirring for 1 hour, decompressing and steaming to remove tetrahydrofuran, alkalizing the water phase with liquid alkali until the pH value is more than 13, extracting 2 times with MTBE (200 g), merging organic phases, distilling at normal pressure, and collecting components at 130-140 ℃ to obtain 50.9g of compound I as colorless liquid. Yield: 91.7%. The gas chromatogram of the prepared target product compound I is shown in figure 1, the gas chromatogram of the standard sample of the compound I is shown in figure 2, and the gas chromatogram of the application is compared with the standard sample, and the peak positions of the gas chromatograms are consistent, so that the preparation of the compound I is successful.
Example 2
The methanesulfonyl chloride in step (2) was changed to equimolar p-toluenesulfonyl chloride to give 91.3g of compound IV as a yellow oil, yield: 87.1%. The rest of the procedure is the same as in example 1.
Example 3
Changing the trimethylchlorosilane in the step (3) into equimolar boron trifluoride tetrahydrofuran solution to obtain 48.7g of compound I as colorless liquid; yield: 87.7%. The rest of the procedure is the same as in example 1.
Claims (6)
1. A process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane comprising the steps of:
(1) Adding 6, 6-dimethyl-2-oxo-3-oxabicyclo [3.1.0] hexane and ammonia water into a methanol solvent, reacting for 10-15 hours at 100-120 ℃, concentrating under reduced pressure after the reaction is finished, dissolving with ethyl acetate, adding n-hexane, crystallizing, filtering and drying to obtain cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide;
(2) Dissolving cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide in methyl tertiary butyl ether, adding N, N-diisopropylethylamine, adding p-toluenesulfonyl chloride or methanesulfonyl chloride at 0-5 ℃ and reacting for 2-4 hours at the temperature, heating to 55-60 ℃ and refluxing for 4-6 hours, adding water, layering, extracting a water layer by using methyl tertiary butyl ether, merging organic phases, washing, concentrating under reduced pressure to obtain 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane;
(3) Dissolving 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane in tetrahydrofuran, adding sodium borohydride serving as a reducing agent, adding boron trifluoride tetrahydrofuran solution or trimethylchlorosilane serving as a catalyst, reacting for 1-3 hours at 50-60 ℃ under the protection of nitrogen, acidifying with hydrochloric acid after the reaction is finished, distilling under reduced pressure to remove a solvent, alkalizing an aqueous phase, extracting with methyl tert-butyl ether, distilling under normal pressure, and collecting 130-140 ℃ components to obtain a target product 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane.
2. A process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane according to claim 1, wherein: in the step (1), the mass ratio of the 6, 6-dimethyl-2-oxo-3-oxabicyclo [3.1.0] hexane to the ammonia water is 1:1-1:1.5.
3. A process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane according to claim 1, wherein: in the step (2), the mass ratio of cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide to p-toluenesulfonyl chloride or methanesulfonyl chloride is 1:1-1.5:1.
4. A process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane according to claim 1, wherein: in the step (2), the mass ratio of cis-3, 3-dimethyl-2-hydroxymethyl cyclopropyl-1-formamide to N, N-diisopropylethylamine is 1:2-1:2.5.
5. A process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane according to claim 1, wherein: in the step (3), the mass ratio of the 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane to the sodium borohydride is 1.5:1-2:1.
6. A process for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane according to claim 1, wherein: in the step (3), the mass ratio of the 6, 6-dimethyl-2-oxo-3-azabicyclo [3.1.0] hexane to the boron trifluoride tetrahydrofuran solution or the trimethylchlorosilane is 1:1-1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210978219.3A CN115304537B (en) | 2022-08-16 | 2022-08-16 | Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210978219.3A CN115304537B (en) | 2022-08-16 | 2022-08-16 | Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115304537A CN115304537A (en) | 2022-11-08 |
| CN115304537B true CN115304537B (en) | 2024-06-14 |
Family
ID=83862058
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210978219.3A Active CN115304537B (en) | 2022-08-16 | 2022-08-16 | Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115304537B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031542A (en) * | 2021-12-10 | 2022-02-11 | 浙江新和成股份有限公司 | Novel preparation method of azabicyclo medical intermediate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110183445B (en) * | 2019-06-28 | 2021-08-24 | 昆明学院 | Synthetic method of moxifloxacin and derivatives thereof |
| CN114085181B (en) * | 2022-01-18 | 2022-05-06 | 南京桦冠生物技术有限公司 | Synthetic method and application of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane |
| CN114605308B (en) * | 2022-03-18 | 2023-12-19 | 阜新孚隆宝医药科技有限公司 | Preparation method of azabicyclo medicine intermediate of Pa Luo Weide and intermediate |
| CN114644587A (en) * | 2022-03-22 | 2022-06-21 | 兰州大学 | Synthesis process of intermediate bicyclic imine of anti-novel coronavirus pneumonia medicine Paxlovid |
-
2022
- 2022-08-16 CN CN202210978219.3A patent/CN115304537B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114031542A (en) * | 2021-12-10 | 2022-02-11 | 浙江新和成股份有限公司 | Novel preparation method of azabicyclo medical intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115304537A (en) | 2022-11-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR102653443B1 (en) | Preparation method of artificially synthesized racemic nicotine salt | |
| CN105859670B (en) | A kind of preparation method of high purity butylene phthalide | |
| CN102911022A (en) | Method for artificially synthesizing natural curcumin compound | |
| CN104892614B (en) | A kind of synthetic method of 6H iso-indoles simultaneously ketone derivatives of [2,1 α] indoles 6 | |
| CN114436924B (en) | Synthesis method of hydroxy pinacolone retinoic acid ester | |
| CN115304537B (en) | Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN111116490A (en) | Preparation and purification method of oxalagogri intermediate salicylate | |
| CN106748630A (en) | A kind of synthetic method of antalgesic intermediate Bromomethylcyclobutane | |
| CN103601708B (en) | Preparation method of prostaglandin medicine impurity | |
| CN103333110B (en) | Production method of medicinal laurocapram | |
| CN103183592B (en) | The preparation method of chloro-1,1, the 1-tri-alkoxy ethane of 2- | |
| CN109503477B (en) | Triarylmethane compound and high-efficiency catalytic synthesis method thereof | |
| CN102234253A (en) | Method for preparing febuxostat intermediate | |
| CN102617329A (en) | Preparation method of ibuprofen arginine salt | |
| CN106117204A (en) | The preparation method of Lei Dipawei intermediate (1R, 3S, 4S) 2 Boc 2 azabicyclo [2.2.1] pentane 3 carboxylic acid | |
| CN110668922A (en) | Refining method of musk medulla | |
| CN102008978B (en) | Chiral catalyst and preparation method and application thereof | |
| CN110128303B (en) | Method for synthesizing musk extract (2R,5R) -Musclide-A1 | |
| CN115304538B (en) | Method for preparing 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane | |
| AU2021380304B2 (en) | Preparation method for cannflavin compounds | |
| CN103214496A (en) | Simple and rapid preparation process of dihydroartemisinin | |
| CN116836107B (en) | Carbazol eight-membered ring large conjugated structure OLED material and preparation method thereof | |
| CN103408423A (en) | Nature active product L-cichoric acid synthesis process | |
| CN112457235B (en) | Preparation method of 7-methylindole |
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 |