CN116082359A - Method for preparing 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester - Google Patents
Method for preparing 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester Download PDFInfo
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- CN116082359A CN116082359A CN202211392568.3A CN202211392568A CN116082359A CN 116082359 A CN116082359 A CN 116082359A CN 202211392568 A CN202211392568 A CN 202211392568A CN 116082359 A CN116082359 A CN 116082359A
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- ZBCMUHWEHQJMNT-UHFFFAOYSA-N tert-butyl 2-methylnonanoate Chemical compound CCCCCCCC(C)C(=O)OC(C)(C)C ZBCMUHWEHQJMNT-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 108
- 238000006243 chemical reaction Methods 0.000 claims abstract description 106
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 35
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229940125782 compound 2 Drugs 0.000 claims abstract description 26
- 229940126214 compound 3 Drugs 0.000 claims abstract description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229940125898 compound 5 Drugs 0.000 claims abstract description 24
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 229940125904 compound 1 Drugs 0.000 claims abstract description 15
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 12
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 12
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 27
- KUSYIGBGHPOWEL-UHFFFAOYSA-N 2-methyl nonaoic acid Chemical compound CCCCCCCC(C)C(O)=O KUSYIGBGHPOWEL-UHFFFAOYSA-N 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- -1 tert-butyl 3-cyano-3- (trimethylsilyloxy) azetidine-1-carboxylic acid Chemical compound 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 claims description 3
- GUQHMHLZZUYGNC-UHFFFAOYSA-N 3-hydroxy-1-methylazetidine-3-carboxylic acid Chemical compound CN1CC(O)(C(O)=O)C1 GUQHMHLZZUYGNC-UHFFFAOYSA-N 0.000 claims description 2
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 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
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 150000003413 spiro compounds Chemical class 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 238000001514 detection method Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000009987 spinning Methods 0.000 description 10
- 239000003814 drug Substances 0.000 description 8
- 238000011161 development Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000003760 magnetic stirring Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- 238000013461 design Methods 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WEFREESWPHICPL-UHFFFAOYSA-N tert-butyl 3-cyanoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(C#N)C1 WEFREESWPHICPL-UHFFFAOYSA-N 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention discloses a preparation method of 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester, which comprises the following steps: dissolving the compound 1 in tetrahydrofuran, and adding trimethylcyano silane to react to obtain a compound 2; dissolving the compound 2 into methanol, and adding thionyl chloride to react to obtain a compound 3; dissolving the compound 3 in methanol, adding triethylamine and di-tert-butyl dicarbonate, and reacting to obtain a compound 4; dissolving the compound 4 into N, N-dimethylformamide, and then adding cesium carbonate and bromoacetonitrile to obtain a compound 5; the compound 5 is dissolved in methanol, a catalyst Raney nickel is added, the compound 6 is obtained by reaction in hydrogen, and the synthesis method suitable for industrial production is obtained by continuously optimizing the structure of the spiro compound.
Description
Technical field:
the invention relates to a method for synthesizing a compound, in particular to a method for preparing a compound of 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester.
The background technology is as follows:
compared with foreign competitors, chinese medicine enterprises frequently suffer from the problems of technology, funds and the like, new medicine development work cannot be effectively carried out, foreign patent expired medicines can be simply and repeatedly produced or imitated, the product lacks international competitiveness, the domestic market is also severely threatened by imported western medicines, and the discovery of lead compounds is a necessary way for discovering innovative medicines. Because of long development period (8-10 years) and high cost (8-10 hundred million dollars), most developed countries currently adopt a method of 'many, fast, high and saving' which is a combined chemical technology platform to accelerate development and production of small molecular prodrugs, the development period of the new drugs can be shortened by 5-7 years, and the foundation and cradle which can bring the platform into play are various high-quality template compounds. Through years of research, novel spiro drug template compounds are found to have a plurality of biological activities with wide prospects, but few compounds which can be screened by novel drugs can be collected nationally, so that the needs of innovative drug development cannot be met. The document report of the spiro template compound is less, and no pharmaceutical enterprises basically have technical capability in China for design, research and development and production. These novel spiro compounds are essential in the development of new drugs.
The compound tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate is a novel spiro compound which we have devised autonomously. No literature report exists on the current synthesis method. Therefore, a synthetic method which has the advantages of easily available raw materials, convenient operation, easy control of reaction and proper overall yield and is suitable for industrial production needs to be developed. The novel spiro compound structure is designed independently, a synthetic route is designed, and a synthetic method suitable for industrial production is found through continuous optimization. The breakthrough of the key technology of the project has important practical significance for the research and development of new medicines in China, and can have profound influence on the development of the new medicines.
Disclosure of Invention
The invention aims to solve the problem that novel spiro template compounds in China are few, so that the screening of new drugs is limited. The invention develops a preparation method of 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester, which has the advantages of easily obtained raw materials, convenient operation, easy control of reaction and higher yield, and is suitable for industrial production.
In order to solve the technical problems, the invention provides the following technical scheme:
a process for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate comprising the steps of:
firstly, dissolving 1- (tert-butoxycarbonyl) -3-azetidinone (compound 1) into tetrahydrofuran, and then adding trimethylcyanosilane to react to obtain a compound tert-butyl 3-cyano-3- (trimethylsilyloxy) azetidine-1-formyloxy ester (compound 2);
secondly, dissolving a compound tert-butyl 3-cyano-3- (trimethylsilyloxy) azetidine-1-formylic ester into methanol, adding acid, and carrying out hydrolysis reaction to obtain a compound methyl 3-hydroxyazetidine-3-formylic ester (a compound 3);
thirdly, dissolving the compound methyl 3-hydroxyazetidine-3-formylic acid ester into methanol, and adding alkali and di-tert-butyl dicarbonate to obtain the compound 1-tert-butyl 3-methyl 3-hydroxyazetidine-1, 3-dicarboxylic acid ester (compound 4);
fourthly, dissolving the compound 1-tertiary-butyl 3-methyl 3-hydroxyazetidine-1, 3-dimethyl formamide, adding alkali and bromoacetonitrile to obtain the compound 1-tertiary-butyl 3-methyl 3- (cyanomethoxy) azetidine-1, 3-dimethyl formamide (compound 5);
and fifthly, dissolving the compound 1-tertiary-butyl 3-methyl 3- (cyanomethoxy) azetidine-1, 3-dimethyl ester into methanol, adding a catalyst, and reacting under hydrogen to obtain the final compound 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tertiary butyl ester (compound 6).
As a preferred embodiment of the present invention, 1 to 1.1 molar equivalent of trimethylcyanosilane is added per 1 molar equivalent of compound 1 in the first step.
As a preferred embodiment of the present invention, 2 to 5 molar equivalents of acid are added per 1 molar equivalent of compound 2 in the second step.
As a preferred embodiment of the present invention, the acid in the second step is at least one selected from thionyl chloride and hydrochloric acid.
As a preferred embodiment of the present invention, the base in the third step is at least one selected from triethylamine and diisopropylethylamine.
As a preferred embodiment of the present invention, 1 to 3 molar equivalents of di-tert-butyl dicarbonate are added per 1 molar equivalent of compound 3 in the third step.
As a preferred embodiment of the present invention, the base in the fourth step is at least one selected from cesium carbonate, potassium t-butoxide and sodium hydrogen.
As a preferred embodiment of the present invention, bromoacetonitrile is added in the fourth step in an amount of 1 to 2 molar equivalents per 1 molar equivalent of compound 4.
As a preferred embodiment of the present invention, the catalyst in the fifth step is at least one selected from palladium on carbon, palladium hydroxide, platinum dioxide and raney nickel.
As a preferable technical scheme of the invention, the reaction condition in the first step is that the temperature is 15-65 ℃ and the reaction is carried out for 6-16 hours.
As a preferable technical scheme of the invention, the reaction condition in the second step is that the temperature is 15-70 ℃ and the reaction lasts for 6-16 hours.
As a preferable technical scheme of the invention, the reaction condition in the third step is that the temperature is 15-40 ℃ and the reaction lasts for 6-16 hours.
As a preferable technical scheme of the invention, the reaction condition in the fourth step is that the temperature is 15-40 ℃ and the reaction lasts for 6-16 hours.
As a preferable technical scheme of the invention, the reaction condition in the fifth step is 15-50 ℃ and the pressure is 40-50Psi under hydrogen for 6-16 hours.
As a preferred technical scheme of the present invention, in the fifth step, the preparation method of the compound 6 comprises the following steps:
step A, dissolving the compound 1 in tetrahydrofuran, and adding trimethylcyano silane to react to obtain a compound 2;
step B, dissolving the compound 2 into methanol, and adding thionyl chloride to react to obtain a compound 3;
step C, dissolving the compound 3 in methanol, adding triethylamine and di-tert-butyl dicarbonate, and reacting to obtain a compound 4;
step D, dissolving the compound 4 into N, N-dimethylformamide, and then adding cesium carbonate and bromoacetonitrile to obtain a compound 5;
and E, dissolving the compound 5 into methanol, adding a catalyst Raney nickel, and reacting in hydrogen to obtain the compound 6.
In the step A, the compound 1 is dissolved in tetrahydrofuran, and then the trimethyl cyanosilane is added to react for 6 to 16 hours at the temperature of 16 to 65 ℃ to obtain the compound 2.
In the step B, the compound 2 is dissolved in methanol, and then the thionyl chloride is added to react for 6 to 16 hours at a temperature of between 15 and 70 ℃ to obtain the compound 3.
In the step C, the compound 3 is dissolved in methanol, and then triethylamine and di-tert-butyl dicarbonate are added to react for 6 to 16 hours at a temperature of between 15 and 40 ℃ to obtain the compound 4
In the step D, the compound 4 is dissolved in N, N-dimethylformamide, cesium carbonate and bromoacetonitrile are added, and the reaction condition is 15-40 ℃ and the reaction is carried out for 6-16 hours to obtain the compound 5.
In the step E, the compound 5 is dissolved in methanol, raney nickel is added, the reaction condition is 15-50 ℃, the pressure is 40-50Psi, and the compound 6 is obtained after the reaction for 6-16 hours under hydrogen.
The invention has the advantages that: the reaction process of the invention has reasonable design, adopts easily available raw material tert-butyl 3-oxo-azetidine-1-formylic acid ester which can be produced in large scale, synthesizes 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester by five steps, and has short route, easy reaction amplification and convenient operation.
Description of the drawings:
FIG. 1 is a reaction scheme of a preparation method; 1 is: 1- (tert-butoxycarbonyl) -3-azetidinone, 2 is: tert-butyl 3-cyano-3- (trimethylsilyloxy) azetidine-1-carboxylic acid ester, 3 is: methyl 3-hydroxyazetidin-3-carboxylic acid ester, 4 is: 1-tert-butyl 3-methyl 3-hydroxyazetidino-1, 3-dicarboxyl ester, 5 is: 1-tert-butyl 3-methyl 3- (cyanomethoxy) azetidine-1, 3-dicarboxyl ester, 6 is: 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester.
Detailed Description
The following description of the present invention will be made clearly and fully, and it is apparent that the embodiments described are some, but not all, of the embodiments of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The compounds or reagents used in the examples below are all commercial compounds or reagents, unless otherwise specified.
The Chinese paraphrasing of the abbreviations of the present invention: TLC: thin layer chromatography; LCMS: high performance liquid chromatograph.
Example 1:
the reaction scheme of example 1 is shown in FIG. 1:
the embodiment adopts the following steps:
the first step: a 500 ml three-necked flask, magnetic stirring, thermometer, condenser tube was prepared. Compound 1 (50 g, 292 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (250 ml) and trimethylcyanosilane (31 g, 313 mmol, 1.07 eq.) was slowly added and the reaction heated to 65 ℃ and stirred for 16 hours. TLC showed complete reaction of starting material. The reaction was quenched with saturated aqueous sodium bicarbonate (200 ml) and then extracted three times with ethyl acetate (300 ml 3). The organic phases were combined, washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin to give compound 2 (64 g, crude) as a pale yellow oil.
And a second step of: compound 2 (64 g, 323 mmol, 1.00 eq.) was dissolved in methanol (350 ml) and thionyl chloride (92.2 g, 775 mmol, 2.40 eq.) was added dropwise and heated to 70 ℃ and stirred for 16 hours. The nuclear magnetic detection reaction is complete. The reaction solution was dried by spin to give compound 3 (60 g, hydrochloride salt, crude).
And a third step of: compound 3 (60 g, 358 mmol, 1.00 eq) was dissolved in methanol (300 ml) and triethylamine and di-tert-butyl dicarbonate were added at room temperature. The reaction was dried by spinning, water (500 ml) was added and extracted three times with ethyl acetate (500 ml x 3). The combined organic phases were washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 4 (25 g, 108 mmol, 30.2% yield) as a yellow oil.
Fourth step: compound 4 (368 g, 1.59 mol, 1.00 eq) was dissolved in N, N-dimethylformamide (2000 ml), then cesium carbonate (1.04 kg, 3.18 mol, 2.00 eq) was added, and after stirring for 20 minutes bromoacetonitrile (286 g, 2.39 mol, 1.50 eq) was added. The reaction solution was stirred at 40℃for 16 hours. TLC detection reaction was complete. The reaction was poured into ice water (3000 ml) and extracted three times with ethyl acetate (2000 ml 3). The combined organic phases were washed once with saturated brine (1000 ml), dried over magnesium sulfate, filtered and dried by spinning. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 5 (130 g, 481 mmol, 30.2% yield) as a white solid.
Fifth step: compound 5 (45 g, 186 mmol, 1.00 eq.) was dissolved in methanol (2000 ml) and raney nickel (15.9 g, 18.6 mmol, 10% purity) was added under nitrogen. The reaction solution was replaced with hydrogen three times and stirred at 50℃for 16 hours. LCMS detected complete reaction. The reaction solution was allowed to stand at room temperature for a while, and the supernatant was decanted and dried by spin-drying to give Compound 6 (40 g, crude product) as a yellow solid.
Example 2:
the reaction scheme of example 2 is shown in FIG. 1:
the embodiment adopts the following steps:
the first step: a 500 ml three-necked flask, magnetic stirring, thermometer, condenser tube was prepared. Compound 1 (50 g, 292 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (250 ml) and trimethylcyanosilane (31 g, 313 mmol, 1.07 eq.) was slowly added and the reaction heated to 65 ℃ and stirred for 16 hours. TLC showed complete reaction of starting material. The reaction was quenched with saturated aqueous sodium bicarbonate (200 ml) and then extracted three times with ethyl acetate (300 ml 3). The organic phases were combined, washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin to give compound 2 (64 g, crude) as a pale yellow oil.
And a second step of: compound 2 (64 g, 323 mmol, 1.00 eq.) was dissolved in methanol (350 ml) and thionyl chloride (92.2 g, 775 mmol, 2.40 eq.) was added dropwise and heated to 70 ℃ and stirred for 16 hours. The nuclear magnetic detection reaction is complete. The reaction solution was dried by spin to give compound 3 (60 g, hydrochloride salt, crude).
And a third step of: compound 3 (60 g, 358 mmol, 1.00 eq) was dissolved in methanol (300 ml) and triethylamine and di-tert-butyl dicarbonate were added at room temperature. The reaction was dried by spinning, water (500 ml) was added and extracted three times with ethyl acetate (500 ml x 3). The combined organic phases were washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 4 (25 g, 108 mmol, 30.2% yield) as a yellow oil.
Fourth step: compound 4 (368 g, 1.59 mol, 1.00 eq) was dissolved in N, N-dimethylformamide (2000 ml), then cesium carbonate (1.04 kg, 3.18 mol, 2.00 eq) was added, and after stirring for 20 minutes bromoacetonitrile (286 g, 2.39 mol, 1.50 eq) was added. The reaction solution was stirred at 40℃for 16 hours. TLC detection reaction was complete. The reaction was poured into ice water (3000 ml) and extracted three times with ethyl acetate (2000 ml 3). The combined organic phases were washed once with saturated brine (1000 ml), dried over magnesium sulfate, filtered and dried by spinning. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 5 (130 g, 481 mmol, 30.2% yield) as a white solid.
Fifth step: compound 5 (45 g, 186 mmol, 1.00 eq.) was dissolved in methanol (2000 ml) and raney nickel (15.9 g, 18.6 mmol, 10% purity) was added under nitrogen. The reaction solution was replaced with hydrogen three times and stirred at 50℃for 16 hours. LCMS detected complete reaction. The reaction solution was allowed to stand at room temperature for a while, and the supernatant was decanted and dried by spin-drying to give Compound 6 (40 g, crude product) as a yellow solid.
Example 3:
the reaction scheme of example 3 is shown in FIG. 1:
the embodiment adopts the following steps:
the first step: a 500 ml three-necked flask, magnetic stirring, thermometer, condenser tube was prepared. Compound 1 (50 g, 292 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (250 ml) and trimethylcyanosilane (31 g, 313 mmol, 1.07 eq.) was slowly added and the reaction heated to 65 ℃ and stirred for 16 hours. TLC showed complete reaction of starting material. The reaction was quenched with saturated aqueous sodium bicarbonate (200 ml) and then extracted three times with ethyl acetate (300 ml 3). The organic phases were combined, washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin to give compound 2 (64 g, crude) as a pale yellow oil.
And a second step of: compound 2 (64 g, 323 mmol, 1.00 eq.) was dissolved in methanol (350 ml) and thionyl chloride (92.2 g, 775 mmol, 2.40 eq.) was added dropwise and heated to 70 ℃ and stirred for 16 hours. The nuclear magnetic detection reaction is complete. The reaction solution was dried by spin to give compound 3 (60 g, hydrochloride salt, crude).
And a third step of: compound 3 (60 g, 358 mmol, 1.00 eq) was dissolved in methanol (300 ml) and triethylamine and di-tert-butyl dicarbonate were added at room temperature. The reaction was dried by spinning, water (500 ml) was added and extracted three times with ethyl acetate (500 ml x 3). The combined organic phases were washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 4 (25 g, 108 mmol, 30.2% yield) as a yellow oil.
Fourth step: compound 4 (368 g, 1.59 mol, 1.00 eq) was dissolved in N, N-dimethylformamide (2000 ml), then cesium carbonate (1.04 kg, 3.18 mol, 2.00 eq) was added, and after stirring for 20 minutes bromoacetonitrile (286 g, 2.39 mol, 1.50 eq) was added. The reaction solution was stirred at 40℃for 16 hours. TLC detection reaction was complete. The reaction was poured into ice water (3000 ml) and extracted three times with ethyl acetate (2000 ml 3). The combined organic phases were washed once with saturated brine (1000 ml), dried over magnesium sulfate, filtered and dried by spinning. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 5 (130 g, 481 mmol, 30.2% yield) as a white solid.
Fifth step: compound 5 (45 g, 186 mmol, 1.00 eq.) was dissolved in methanol (2000 ml) and raney nickel (15.9 g, 18.6 mmol, 10% purity) was added under nitrogen. The reaction solution was replaced with hydrogen three times and stirred at 50℃for 16 hours. LCMS detected complete reaction. The reaction solution was allowed to stand at room temperature for a while, and the supernatant was decanted and dried by spin-drying to give Compound 6 (40 g, crude product) as a yellow solid.
Example 4:
the reaction scheme of example 4 is shown in FIG. 1:
the embodiment adopts the following steps:
the first step: a 500 ml three-necked flask, magnetic stirring, thermometer, condenser tube was prepared. Compound 1 (50 g, 292 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (250 ml) and trimethylcyanosilane (31 g, 313 mmol, 1.07 eq.) was slowly added and the reaction heated to 65 ℃ and stirred for 16 hours. TLC showed complete reaction of starting material. The reaction was quenched with saturated aqueous sodium bicarbonate (200 ml) and then extracted three times with ethyl acetate (300 ml 3). The organic phases were combined, washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin to give compound 2 (64 g, crude) as a pale yellow oil.
And a second step of: compound 2 (64 g, 323 mmol, 1.00 eq.) was dissolved in methanol (350 ml) and thionyl chloride (92.2 g, 775 mmol, 2.40 eq.) was added dropwise and heated to 70 ℃ and stirred for 16 hours. The nuclear magnetic detection reaction is complete. The reaction solution was dried by spin to give compound 3 (60 g, hydrochloride salt, crude).
And a third step of: compound 3 (60 g, 358 mmol, 1.00 eq) was dissolved in methanol (300 ml) and triethylamine and di-tert-butyl dicarbonate were added at room temperature. The reaction was dried by spinning, water (500 ml) was added and extracted three times with ethyl acetate (500 ml x 3). The combined organic phases were washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 4 (25 g, 108 mmol, 30.2% yield) as a yellow oil.
Fourth step: compound 4 (368 g, 1.59 mol, 1.00 eq) was dissolved in N, N-dimethylformamide (2000 ml), then cesium carbonate (1.04 kg, 3.18 mol, 2.00 eq) was added, and after stirring for 20 minutes bromoacetonitrile (286 g, 2.39 mol, 1.50 eq) was added. The reaction solution was stirred at 40℃for 16 hours. TLC detection reaction was complete. The reaction was poured into ice water (3000 ml) and extracted three times with ethyl acetate (2000 ml 3). The combined organic phases were washed once with saturated brine (1000 ml), dried over magnesium sulfate, filtered and dried by spinning. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 5 (130 g, 481 mmol, 30.2% yield) as a white solid.
Fifth step: compound 5 (45 g, 186 mmol, 1.00 eq.) was dissolved in methanol (2000 ml) and raney nickel (15.9 g, 18.6 mmol, 10% purity) was added under nitrogen. The reaction solution was replaced with hydrogen three times and stirred at 50℃for 16 hours. LCMS detected complete reaction. The reaction solution was allowed to stand at room temperature for a while, and the supernatant was decanted and dried by spin-drying to give Compound 6 (40 g, crude product) as a yellow solid.
Example 5:
the reaction scheme of example 5 is shown in FIG. 1:
the embodiment adopts the following steps:
the first step: a 500 ml three-necked flask, magnetic stirring, thermometer, condenser tube was prepared. Compound 1 (50 g, 292 mmol, 1.00 eq.) was dissolved in tetrahydrofuran (250 ml) and trimethylcyanosilane (31 g, 313 mmol, 1.07 eq.) was slowly added and the reaction heated to 65 ℃ and stirred for 16 hours. TLC showed complete reaction of starting material. The reaction was quenched with saturated aqueous sodium bicarbonate (200 ml) and then extracted three times with ethyl acetate (300 ml 3). The organic phases were combined, washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin to give compound 2 (64 g, crude) as a pale yellow oil.
And a second step of: compound 2 (64 g, 323 mmol, 1.00 eq.) was dissolved in methanol (350 ml) and thionyl chloride (92.2 g, 775 mmol, 2.40 eq.) was added dropwise and heated to 70 ℃ and stirred for 16 hours. The nuclear magnetic detection reaction is complete. The reaction solution was dried by spin to give compound 3 (60 g, hydrochloride salt, crude).
And a third step of: compound 3 (60 g, 358 mmol, 1.00 eq) was dissolved in methanol (300 ml) and triethylamine and di-tert-butyl dicarbonate were added at room temperature. The reaction was dried by spinning, water (500 ml) was added and extracted three times with ethyl acetate (500 ml x 3). The combined organic phases were washed once with saturated brine (300 ml), dried over magnesium sulfate, filtered and dried by spin. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 4 (25 g, 108 mmol, 30.2% yield) as a yellow oil.
Fourth step: compound 4 (368 g, 1.59 mol, 1.00 eq) was dissolved in N, N-dimethylformamide (2000 ml), then cesium carbonate (1.04 kg, 3.18 mol, 2.00 eq) was added, and after stirring for 20 minutes bromoacetonitrile (286 g, 2.39 mol, 1.50 eq) was added. The reaction solution was stirred at 40℃for 16 hours. TLC detection reaction was complete. The reaction was poured into ice water (3000 ml) and extracted three times with ethyl acetate (2000 ml 3). The combined organic phases were washed once with saturated brine (1000 ml), dried over magnesium sulfate, filtered and dried by spinning. Purification on a silica gel column (petroleum ether: ethyl acetate=3:1) afforded compound 5 (130 g, 481 mmol, 30.2% yield) as a white solid.
Fifth step: compound 5 (45 g, 186 mmol, 1.00 eq.) was dissolved in methanol (2000 ml) and raney nickel (15.9 g, 18.6 mmol, 10% purity) was added under nitrogen. The reaction solution was replaced with hydrogen three times and stirred at 50℃for 16 hours. LCMS detected complete reaction. The reaction solution was allowed to stand at room temperature for a while, and the supernatant was decanted and dried by spin-drying to give Compound 6 (40 g, crude product) as a yellow solid.
In conclusion, the preparation method of the 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester has reasonable reaction process design, adopts the readily available and large-scale production raw material 3-cyano azetidine-1-carboxylic acid tert-butyl ester, synthesizes the 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester through five steps, and has the advantages of short route, easy reaction amplification and convenient operation.
The foregoing describes specific embodiments of the invention. It is to be understood that the invention is not limited to the specific embodiments described above, wherein devices and structures not described in detail are to be understood as being implemented in a manner common in the art; numerous variations, changes, or substitutions of light can be made by one skilled in the art without departing from the spirit of the invention and the scope of the claims.
Claims (20)
1. A process for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, comprising the steps of:
1) Dissolving the compound 1 into tetrahydrofuran, and then adding trimethylcyano silane to react to obtain a compound 2;
2) Dissolving the compound 2 into methanol, adding acid, and carrying out hydrolysis reaction to obtain a compound 3;
3) Dissolving the compound 3 into methanol, and adding alkali and di-tert-butyl dicarbonate to obtain a compound 4;
4) Dissolving the compound 4 into N, N-dimethylformamide, and adding alkali and bromoacetonitrile to obtain a compound 5;
5) Dissolving the compound 5 into methanol, adding a catalyst, and reacting under hydrogen to obtain a final compound 6;
the compound 1 was 1- (tert-butoxycarbonyl) -3-azetidinone, the compound 2 was tert-butyl 3-cyano-3- (trimethylsilyloxy) azetidine-1-carboxylic acid ester, the compound 3 was methyl 3-hydroxyazetidine-3-carboxylic acid ester, the compound 4 was 1-tert-butyl 3-methyl 3-hydroxyazetidine-1, 3-dicarboxylic acid ester, the compound 5 was 1-tert-butyl 3-methyl 3- (cyanomethoxy) azetidine-1, 3-dicarboxylic acid ester, and the compound 6 was 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylic acid tert-butyl ester.
2. A process for preparing tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate according to claim 1, characterized in that: 1 to 1.1 molar equivalents of said trimethylcyanosilane are added per 1 molar equivalent of said compound 1 in step 1).
3. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the acid in the step 2) is thionyl chloride and/or hydrochloric acid.
4. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: 2 to 5 molar equivalents of the acid are added per 1 molar equivalent of the compound 2 in step 2).
5. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the base in step 3) is triethylamine and/or diisopropylethylamine.
6. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: 1 to 3 molar equivalents of said di-tert-butyl dicarbonate are added per 1 molar equivalent of said compound 3 in step 3).
7. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the base in the step 4) is at least one of cesium carbonate, potassium tert-butoxide and sodium hydrogen.
8. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: 1 to 2 molar equivalents of bromoacetonitrile are added per 1 molar equivalent of compound 4 in step 4).
9. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the catalyst in the step 5) is at least one of palladium carbon, palladium hydroxide, platinum dioxide and Raney nickel.
10. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the reaction condition in the step 1) is that the temperature is 15-65 ℃ and the reaction is 6-16 hours.
11. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the reaction condition in the step 2) is that the temperature is 15-70 ℃ and the reaction lasts for 6-16 hours.
12. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the reaction condition in the step 3) is that the temperature is 15-40 ℃ and the reaction lasts for 6-16 hours.
13. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the reaction condition in the step 4) is that the temperature is 15-40 ℃ and the reaction is carried out for 6-16 hours.
14. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the reaction condition in the step 5) is that the temperature is 15-50 ℃, the pressure is 40-50Psi, and the reaction is carried out for 6-16 hours under hydrogen.
15. A process according to claim 1 or 2 for the preparation of tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate, characterized in that: the preparation method of the compound 6 comprises the following steps:
step A, dissolving the compound 1 in tetrahydrofuran, and adding trimethylcyano silane to react to obtain a compound 2;
step B, dissolving the compound 2 into methanol, and adding thionyl chloride to react to obtain a compound 3;
step C, dissolving the compound 3 in methanol, adding triethylamine and di-tert-butyl dicarbonate, and reacting to obtain a compound 4;
step D, dissolving the compound 4 into N, N-dimethylformamide, and then adding cesium carbonate and bromoacetonitrile to obtain a compound 5;
and E, dissolving the compound 5 into methanol, adding a catalyst Raney nickel, and reacting in hydrogen to obtain the compound 6.
16. A process for preparing tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate according to claim 15, characterized in that: in the step A, the compound 1 is dissolved in tetrahydrofuran, and then trimethylcyano silane is added, the reaction condition is that the temperature is 16-65 ℃, and the reaction is carried out for 6-16 hours, so as to obtain the compound 2.
17. A process for preparing tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate according to claim 15, characterized in that: in the step B, the compound 2 is dissolved in methanol, then thionyl chloride is added, the reaction condition is 15-70 ℃, and the compound 3 is obtained after the reaction for 6-16 hours.
18. A process for preparing tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate according to claim 15, characterized in that: in the step C, the compound 3 is dissolved in methanol, and then triethylamine and di-tert-butyl dicarbonate are added, the reaction condition is 15-40 ℃, and the compound 4 is obtained after the reaction for 6-16 hours.
19. A process for preparing tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate according to claim 15, characterized in that: in the step D, the compound 4 is dissolved in N, N-dimethylformamide, cesium carbonate and bromoacetonitrile are added, the reaction condition is 15-40 ℃, and the reaction is carried out for 6-16 hours to obtain the compound 5.
20. A process for preparing tert-butyl 9-carbonyl-5-oxo-2, 8-aza [3.5] nonane-2-carboxylate according to claim 15, characterized in that: in the step E, the compound 5 is dissolved in methanol, then Raney nickel is added, the reaction condition is 15-50 ℃, the pressure is 40-50Psi, and the compound 6 is obtained after the reaction for 6-16 hours under hydrogen.
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| WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
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