CN111518015A - Preparation method of tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester - Google Patents
Preparation method of tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester Download PDFInfo
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- CN111518015A CN111518015A CN202010428560.2A CN202010428560A CN111518015A CN 111518015 A CN111518015 A CN 111518015A CN 202010428560 A CN202010428560 A CN 202010428560A CN 111518015 A CN111518015 A CN 111518015A
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- decane
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- azaspiro
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- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 4
- 239000007858 starting material Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- -1 tert-butyl dicarbonyl anhydride Chemical class 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WZWQNWWFCHNJON-UHFFFAOYSA-N 1,4-dioxaspiro[4.5]decane-8-carbonitrile Chemical compound C1CC(C#N)CCC21OCCO2 WZWQNWWFCHNJON-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- C07D209/54—Spiro-condensed
Abstract
The invention relates to tert-butyl-8-oxoidene-2-azaspiro [4.5]The invention relates to a preparation method of decane-2-formic acid ester, which mainly solves the technical problems of high raw material cost, difficult reaction control, inconvenient experimental operation and the like in the existing synthesis process, and uses cheap and easily obtained 1, 4-dioxaspiro [4.5]]Preparing tert-butyl-8-oxylidene-2-azaspiro [4.5] by four-step reaction by taking decane-8-ketone as a starting material]Decane-2-carboxylic acid ester. The reaction formula is as follows:
Description
Technical Field
The invention relates to a synthesis method of tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester.
Background
The tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester and related derivatives have important application in pharmaceutical chemistry and organic synthesis, and have good prospect. However, the synthesis routes reported at present generally have low yield and are not suitable for amplification. Therefore, the development of a synthesis method which has the advantages of cheap raw materials, easy obtainment of raw materials, convenient operation, easy batch production control and proper overall yield is very significant.
Disclosure of Invention
The invention aims to develop a preparation method of tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester, which has the advantages of cheap raw materials, convenient operation, amplification and high yield in four steps. Mainly solves the technical problem that the compound is not suitable for an industrial preparation method at present.
The technical scheme of the invention is as follows: tert-butyl-8-oxylidene-2-azaspiro [4.5]The preparation method of decane-2-formic acid ester comprises the following steps: synthesized by a 4-step method, and the first step is 1, 4-dioxaspiro [4.5]]Decane-8-one as starting material 1, 4-dioxaspiro [4.5] obtained by p-methylsulfonylmethylisocyanitrile and potassium tert-butoxide]Decane-8-carbonitrile; second, 1, 4-dioxaspiro [4.5]]Decane-8-carbonitrile is reacted with 1-bromo-2-chloroethane under the action of lithium diisopropylamide to produce 8- (2-chloroethyl) -1, 4-dioxaspiro [4.5]]Decane-8-carbonitrile; in the third step, 8- (2-chloroethyl) -1, 4-dioxaspiro [4.5]]Decane-8-carbonitrile is subjected to cyclization after reduction by hydrogen and Raney nickel and then reacts with tert-butyl dicarbonyl anhydride to generate tert-butyl-1, 4-dioxa-10-aza-dispiro [4.2.48.25]Tetradecane-10-carboxylic acid ester. In the fourth step, compound 4 is deprotected with pyridinium p-toluenesulfonate to give t-butyl-8-oxoidene-2-azaspiro [4.5]]Decane-2-carboxylic acid ester; the reaction formula is as follows:
in the process, the first step is as follows: the solvent is the mixed solution of glycol dimethyl ether and ethanol, and the reaction temperature is 0-20 ℃; secondly, the solvent is toluene, the reaction temperature is 0-20 ℃, and the reaction time is 13 hours; step three, taking methanol as a solvent, controlling the reaction temperature to be 50 ℃, controlling the pressure to be 50 Psi, and controlling the reaction time to be 6 hours; the fourth step is that the solvent is the mixed solution of acetone and water, the reaction temperature is 70 ℃, and the reaction time is 15 hours.
The invention has the beneficial effects that: the invention has reasonable reaction process design, adopts the raw material 1, 4-dioxaspiro [4.5] decane-8-ketone which is cheap and easy to obtain and can be produced in a large scale, synthesizes tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-formic acid ester by four steps, saves the synthesis cost and can be produced in a large scale.
Detailed Description
Example 1
Synthesis of 1, 4-dioxaspiro [4.5] decane-8-carbonitrile
500 g of Compound 1 are placed in a 10L reactor, 7.5L of ethylene glycol dimethyl ether and 400 mL of ethanol are added, followed by addition of 812 g of p-methylsulfonylmethylisocyanitrile and 826 g of potassium tert-butoxide in portions at 0 ℃. Stirring was carried out at 0 ℃ for 1 hour and then at 20 ℃ for 3 hours. The reaction solution was slowly poured into 3L of aqueous solution, extracted with 2L of ethyl acetate three times, the organic phases were combined, washed with 2L of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column to give 400 g of product with a yield of 74.76%.
Synthesis of 8- (2-chloroethyl) -1, 4-dioxaspiro [4.5] decane-8-carbonitrile
Adding 300 mL of 129 g of compound 2 in toluene slowly into 1.2L of lithium diisopropylamide solution at 0 ℃, stirring the reaction solution at 0 ℃ for 30 minutes, slowly heating to 20 ℃, stirring for 30 minutes, and dropwise adding 331 g of 1-bromo-2-chloroethane. After the completion of the dropwise addition, the reaction mixture was stirred at 20 ℃ for 12 hours. The reaction solution was poured into 1L of saturated ammonium chloride solution, extracted 3 times with 300 mL of ethyl acetate, the organic phases were combined, concentrated under reduced pressure and purified by silica gel column to give 90 g of pale yellow oily product, yield: 50.78 percent.
Tert-butyl-1, 4-dioxa-10-azadispiro [4.2.48.25]Synthesis of tetradecane-10-formic acid ester
Adding 1 gram of Raney nickel into a 250 mL hydrogenation bottle, adding 50 mL of methanol and 3 grams of compound 3, pumping gas for 3 times, reacting at 50 ℃ for 4 hours under the atmosphere of 50 Psi hydrogen, filtering the reaction solution, adding 12 grams of tert-butyl dicarbonyl anhydride into the filtrate, and continuing to react at 50 ℃ for 2 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column to obtain 3.1 g of pure product with a yield of 80%.
Synthesis of tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-carboxylic acid ester
31 g of Compound 4 was dissolved in a mixed solution of 225 mL of acetone and 150 mL of water, and 39 g of pyridinium p-toluenesulfonate was added at 20 ℃. The reaction solution was heated to 70 ℃ and stirred for 15 hours. The reaction solution turned into a yellow solution. The reaction mixture was concentrated to remove acetone and extracted 3 times with 50 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and recrystallized from petroleum ether to give 13 g of pure white product, and the mother liquor was concentrated and purified through a silica gel column to give 5 g of white solid, giving a total of 18 g of pure product, yield: 68.16 percent.
H NMR (400MHz, CHLOROFORM-d) = 3.46 - 3.17 (m, 4H), 2.34 - 2.25 (m,4H), 1.79 (br t,J=7.2 Hz, 6H), 1.40 (s, 9H)。
Example 2
Synthesis of 1, 4-dioxaspiro [4.5] decane-8-carbonitrile
10 g of Compound 1 and 17 g of p-methylsulfonylmethylisocyanitrile were added to 10 mL of ethylene glycol dimethyl ether, 18 g of potassium tert-butoxide was added to the reaction mixture at 0 ℃ and the mixture was stirred at 20 ℃ for 12 hours. The reaction solution was poured into a saturated ammonium chloride solution, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column to give 6.7 g of compound 2 with a yield of 50%.
Synthesis of 8- (2-chloroethyl) -1, 4-dioxaspiro [4.5] decane-8-carbonitrile
60 mL of tetrahydrofuran solution of 6.7 g of compound 2 was slowly added to 40 mL of lithium diisopropylamide solution at-50 ℃, the reaction solution was stirred at-50 ℃ for 30 minutes, then slowly heated to 20 ℃, stirred for 30 minutes, and 6.8 g of 1-bromo-2-chloroethane was added dropwise. After the completion of the dropwise addition, the reaction mixture was stirred at 20 ℃ for 12 hours. The reaction solution was poured into 200 mL of a saturated ammonium chloride solution, extracted 3 times with 100 mL of ethyl acetate, the organic phases were combined, concentrated under reduced pressure and purified by a silica gel column to give 4.45 g of a pale yellow oily product, yield: 48.66 percent.
Tert-butyl-1, 4-dioxa-10-azadispiro [4.2.48.25]Synthesis of tetradecane-10-formic acid ester
15 g of lithium aluminum hydride was added to 500 mL of anhydrous tetrahydrofuran, and 250 mL of a solution of 47 g of Compound 3 in anhydrous tetrahydrofuran was slowly added dropwise to the reaction solution at 10 ℃. After the completion of the dropwise addition, the reaction was carried out at 20 ℃ for 15 hours. 5 mL of water was added dropwise to the reaction mixture at 0 ℃ and stirred at 20 ℃ for 1 hour, then 53 g of t-butyldicarbonyl anhydride was added and the reaction mixture was stirred at 20 ℃ for 3 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate. The filtrates were combined, concentrated under reduced pressure and recrystallized from 100 mL of petroleum ether to give 31 g of a white solid, and the mother liquor was passed through a column to give 15 g of a white solid, giving a total of 46 g of pure product, yield: 75.6 percent.
Synthesis of tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-carboxylic acid ester
3 g of Compound 4 was dissolved in a mixed solution of 20 mL of tetrahydrofuran and 15 mL of water, and 4 g of pyridinium p-toluenesulfonate was added at 20 ℃. The reaction solution was heated to 70 ℃ and stirred for 15 hours. The reaction solution turned into a yellow solution. The reaction mixture was concentrated to remove acetone and extracted 3 times with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated and purified through a silica gel column to give 1.4 g of a white solid. Yield: 54.8 percent.
H NMR (400MHz, CHLOROFORM-d) = 3.46 - 3.17 (m, 4H), 2.34 - 2.25 (m,4H), 1.79 (br t,J=7.2 Hz, 6H), 1.40 (s, 9H)。
Claims (5)
1. Tert-butyl-8-oxylidene-2-azaspiro [4.5]The preparation method of decane-2-formic acid ester is characterized by comprising the following steps: synthesized by a 4-step method, and the first step is 1, 4-dioxaspiro [4.5]]Decane-8-one as starting material 1, 4-dioxaspiro [4.5] obtained by p-methylsulfonylmethylisocyanitrile and potassium tert-butoxide]Decane-8-carbonitrile; second, 1, 4-dioxaspiro [4.5]]Decane-8-carbonitrile is reacted with 1-bromo-2-chloroethane under the action of lithium diisopropylamide to produce 8- (2-chloroethyl) -1, 4-dioxaspiro [4.5]]Decane-8-carbonitrile; in the third step, 8- (2-chloroethyl) -1, 4-dioxaspiro [4.5]]Decane-8-carbonitrile is subjected to cyclization after reduction by hydrogen raney nickel and then reacts with tert-butyl dicarbonyl anhydride to generate tert-butyl-1, 4-dioxa-10-aza-dispiro [4.2.4 ]8.25]Tetradecane-10-carboxylic acid ester; in the fourth step, compound 4 is deprotected with pyridinium p-toluenesulfonate to give t-butyl-8-oxoidene-2-azaspiro [4.5]]Decane-2-carboxylic acid ester.
2. The process for preparing tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-carboxylic acid ester according to claim 1, which comprises: the first step solvent is the mixture of glycol dimethyl ether and ethanol, and the reaction temperature is 0-20 ℃.
3. The process for preparing tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-carboxylic acid ester according to claim 1, which comprises: the second step solvent is toluene, the reaction temperature is 0-20 ℃, and the reaction time is 12.5 hours.
4. The process for preparing tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-carboxylic acid ester according to claim 1, which comprises: and step three, the solvent is methanol, the reaction temperature is 50 ℃, and the reaction time is 6 hours.
5. The process for preparing tert-butyl-8-oxoidene-2-azaspiro [4.5] decane-2-carboxylic acid ester according to claim 1, which comprises: the fourth step is that the solvent is the mixed solution of acetone and water, the reaction temperature is 70 ℃, and the reaction time is 15 hours.
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| WO2007024113A1 (en) * | 2005-08-25 | 2007-03-01 | Rstech Corporation | Process for the preparation of chiral 3-hydroxy pyrrolidine compound and derivatives thereof having high optical purity |
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2020
- 2020-05-20 CN CN202010428560.2A patent/CN111518015A/en active Pending
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Application publication date: 20200811 |