CN116514811A - Synthesis method of 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate - Google Patents
Synthesis method of 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 4
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 title abstract description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 title abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZWSWUDWUDLAILP-UHFFFAOYSA-N tert-butyl 4-(chloromethyl)-4-cyanopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(CCl)(C#N)CC1 ZWSWUDWUDLAILP-UHFFFAOYSA-N 0.000 claims abstract description 21
- HWLNKJXLGQVMJH-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21CCNCC2 HWLNKJXLGQVMJH-UHFFFAOYSA-N 0.000 claims abstract description 20
- UQADQTBQNVARAP-UHFFFAOYSA-N tert-butyl 4-cyanopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(C#N)CC1 UQADQTBQNVARAP-UHFFFAOYSA-N 0.000 claims abstract description 17
- -1 lithium aluminum hydride Chemical compound 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 14
- PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 10
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 239000000047 product Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 2
- 230000003321 amplification Effects 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- 238000007039 two-step reaction Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- MDXMRUQPSOETSG-UHFFFAOYSA-N acetic acid piperidine Chemical compound C(C)(=O)O.N1CCCCC1.C(C)(=O)O MDXMRUQPSOETSG-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 238000012512 characterization method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- NZVZVGPYTICZBZ-UHFFFAOYSA-N 1-benzylpiperidine Chemical class C=1C=CC=CC=1CN1CCCCC1 NZVZVGPYTICZBZ-UHFFFAOYSA-N 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- ZBCMUHWEHQJMNT-UHFFFAOYSA-N tert-butyl 2-methylnonanoate Chemical compound CCCCCCCC(C)C(=O)OC(C)(C)C ZBCMUHWEHQJMNT-UHFFFAOYSA-N 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, which is characterized by comprising the following reaction steps: s1, reacting N-Boc-4-cyanopiperidine with chloroiodomethane under the catalysis of lithium diisopropylamide to obtain 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester; s2, reacting the 4- (chloromethyl) -4-cyano piperidine-1-carboxylic acid tert-butyl ester synthesized in the step S1 with lithium aluminum hydride to obtain 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester in a ring closure mode. The synthesis method has the advantages of short route, short reaction period, high product yield, low reaction cost, easy amplification of reaction and convenient operation, and can prepare the target product through two-step reaction.
Description
Technical Field
The invention relates to the technical field of organic synthesis of medical intermediates, in particular to a method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate.
Background
The 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester (CAS: 896464-16-7) is an important organic synthesis intermediate and medical intermediate, can be used for synthesizing a plurality of derivative products, is a main structure of various active medicaments, and is commonly used in medicament design.
At present, few reports are reported on a synthetic method of 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, namely, the article "synthesis of 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate" published by Yangtze pharmaceutical industry group Co., ltd Hu Tao and published in fine chemical intermediate, which takes bis (2-chloroethyl) amine hydrochloride (1) as a starting material, 4-disubstituted N-benzyl piperidine (3) is produced by bis-alkylation with ethyl cyanoacetate after nitrogen benzylation, piperidine acetic acid acetate (3) is reduced into hydroxyl compound (4) by sodium borohydride, then p-toluenesulfonylation is carried out into sulfonate (5), cyano is cyclized into 2-azaspirobutane (6) by intramolecular synergistic reaction after reduction by aluminum lithium hydride, is reacted with tert-butyl dicarbonate to produce 2-N-Boc product (7), and finally final target compound 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate is obtained by 7 steps such as hydrogenolysis debenzolization. The synthetic route has more reaction steps, the total reaction yield is about 36 percent, and the product yield is not high.
Therefore, there is a need to develop a method for synthesizing tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate, which has the advantages of short synthetic route, low reaction cost, short reaction period, high product yield and convenient operation.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, which can solve the problems of long synthetic route, long preparation period, high cost and low total yield of products of 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate in the prior art.
In order to solve the problems, the invention adopts the following technical scheme:
the invention provides a method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, which comprises the following reaction steps:
s1, reacting N-Boc-4-cyanopiperidine with chloroiodomethane under the catalysis of lithium diisopropylamide to obtain 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester;
s2, performing ring closure on the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester synthesized in the step S1 and lithium aluminum hydride to obtain 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester;
the overall reaction formula is as follows:
specifically, in the step S1, the feeding molar ratio of the N-Boc-4-cyanopiperidine to the lithium diisopropylamide is 1: (1-2), the feeding mole ratio of the N-Boc-4-cyanopiperidine to chloroiodomethane is 1: (1-2).
Specifically, in the step S1, the reaction solvent is tetrahydrofuran, and the reaction temperature is-70 ℃ to-20 ℃.
Specifically, in the step S1, after the reaction is completed, water is added for quenching reaction, and the product of 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester is obtained through liquid separation, water phase extraction, organic phase combination, washing, drying, concentration and filtration.
Specifically, in the step S2, the feeding molar ratio of the tert-butyl 4- (chloromethyl) -4-cyanopiperidine-1-carboxylate to the lithium aluminum hydride is 1: (1-3).
Specifically, in the step S2, the reaction solvent is tetrahydrofuran, and the reaction temperature is-30 ℃.
Specifically, in the step S2, after the reaction is completed, the reaction is quenched, the organic phase is concentrated after filtration and liquid separation, the concentrate is treated, the filtrate is filtered and dried to obtain the product of the 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a synthetic method of 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, which has the advantages of short route, short reaction period, high product yield, low reaction cost, easy amplification of reaction and convenient operation.
Detailed Description
The present invention will be described more fully hereinafter with reference to the preferred embodiments for the purpose of facilitating understanding of the present invention, but the scope of protection of the present invention is not limited to the specific embodiments described below.
Unless defined otherwise, all technical and scientific terms used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the scope of the present invention.
The various reagents and materials used in the present invention are commercially available or may be prepared by known methods unless otherwise specified.
The invention provides a method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, which comprises the following reaction steps:
s1, reacting N-Boc-4-cyanopiperidine with chloroiodomethane under the catalysis of lithium diisopropylamide to obtain 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester;
s2, performing ring closure on the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester synthesized in the step S1 and lithium aluminum hydride to obtain 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester;
the overall reaction formula is as follows:
in the step S1, the feeding molar ratio of the N-Boc-4-cyanopiperidine to the lithium diisopropylamide is 1: (1-2), the feeding mole ratio of the N-Boc-4-cyanopiperidine to chloroiodomethane is 1: (1-2).
In the step S1, the reaction solvent is tetrahydrofuran, and the reaction temperature is-70 ℃ to-20 ℃.
In the step S1, after the reaction is finished, adding water to quench the reaction, separating liquid, extracting water phase, combining organic phases, washing, drying, concentrating and filtering to obtain the product of the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester.
Wherein in the step S2, the feeding mole ratio of the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the lithium aluminum hydride is 1: (1-3).
In the step S2, the reaction solvent is tetrahydrofuran, and the reaction temperature is-30 ℃.
In the step S2, after the reaction is finished, quenching the reaction, filtering, separating liquid, concentrating an organic phase, treating the concentrate, filtering, and drying the filtrate to obtain the product of the 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate.
Example 1
The synthetic method of the 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester in the embodiment comprises the following reaction steps:
synthesis of S1, 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester
THF (1000 ml) was added to a three-necked flask, cooled to below-50 ℃, lithium diisopropylamide (700 ml,2mol/L,1.4 eq.) was added, a THF solution (700 ml) of N-Boc-4-cyanopiperidine (210 g,1.0 eq.) was added dropwise, the mixture was stirred at-50 ℃ for 1 hour after the dropwise addition, chloroiodomethane (282 g,1.6 eq.) was added dropwise thereto, and the mixture was stirred for 10 minutes and then naturally warmed to room temperature to continue the stirring reaction for 1 hour;
then adding water (1L) into a three-mouth bottle to quench the reaction, stirring and separating the liquid, extracting the water phase with ethyl acetate (400 ml) twice, merging and collecting the organic phase, washing the organic phase with saturated brine (300 ml), drying and concentrating, adding petroleum ether (400 ml) to pulp and filter, and drying to obtain the product, wherein the weight is 200g, and the yield is 81%.
The product obtained in this step was analyzed by LCMS (liquid chromatography-mass spectrometry) and the molecular weight of the product was tested to be 259[ m+h ] +, which corresponds to the molecular weight of the target product, tert-butyl 4- (chloromethyl) -4-cyanopiperidine-1-carboxylate.
The structural characterization data of the product obtained in the step are as follows: 1 H NMR(400MHz，CDCl3)δ4.20(s，2H)，3.57(s，2H)，3.05(s，2H)，2.06(dd，J＝13.4，2.1Hz，2H)，1.58–1.40(m，11H)。
the product obtained in this step was shown to be tert-butyl 4- (chloromethyl) -4-cyanopiperidine-1-carboxylate.
Synthesis of S2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester
THF (1000 ml) and lithium aluminum hydride tetrahydrofuran solution (460 ml,2.5mol/L,1.5 eq.) were added to a three-necked flask, the temperature was lowered to 0℃or lower, and 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester (200 g,1.0 eq.) was added dropwise to the flask as THF solution (700 ml), followed by stirring for 10 minutes and then naturally heating to room temperature for reaction for 4 hours;
then water (15 ml) and 10% sodium hydroxide (15 ml) are added into a three-mouth bottle in turn, water (45 ml) is used for quenching reaction, stirring and filtering are carried out, filtrate is separated, organic phase is concentrated, 1L ethanol is added into concentrate, oxalic acid is added for regulating pH value to 5-6, stirring is carried out overnight, filtering is carried out, filter cake is dried to obtain 186g product, and yield is 76%.
The product obtained in this step was analyzed by LCMS (liquid chromatography-mass spectrometry) and the molecular weight of the product was tested to be 227[ M+H ] + ], which was consistent with the molecular weight of the target product, tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate.
The structural characterization data of the product obtained in the step are as follows: 1 H NMR(400MHz，CDCl 3 )δ3.83(s，4H)，3.43–3.27(m，4H)，1.93–1.80(m，4H)，1.44(s，9H)。
the product obtained in this step was shown to be tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate.
Example 2
The synthesis of tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate in this example was identical to example 1, except that:
in step S1, N-Boc-4-cyanopiperidine and chloroiodomethane are prepared according to a formula of 1:2, the molar ratio of N-Boc-4-cyanopiperidine to lithium diisopropylamide is 1:2, the reaction temperature is-70 ℃,4- (chloromethyl) -4-cyano piperidine-1-carboxylic acid tert-butyl ester is obtained by reaction in tetrahydrofuran, and the reaction yield in the step is 72%;
in the step S2, the feeding mole ratio of the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the lithium aluminum hydride is 1:3, a step of; the reaction temperature was-30℃and the reaction yield in this step was 72%.
Example 3
The synthesis of tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate in this example was identical to example 1, except that:
in step S1, N-Boc-4-cyanopiperidine and chloroiodomethane are prepared according to a formula of 1:1, the molar ratio of N-Boc-4-cyanopiperidine to lithium diisopropylamide is 1:1, the reaction temperature is-20 ℃,4- (chloromethyl) -4-cyano piperidine-1-carboxylic acid tert-butyl ester is obtained by reaction in tetrahydrofuran, and the reaction yield in the step is 63%;
in the step S2, the feeding mole ratio of the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the lithium aluminum hydride is 1:2; the reaction temperature was-5℃and the reaction yield in this step was 70%.
Example 4
The synthesis of tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate in this example was identical to example 1, except that:
in step S1, N-Boc-4-cyanopiperidine and chloroiodomethane are prepared according to a formula of 1:1.2, N-Boc-4-cyanopiperidine and lithium diisopropylamide in a molar ratio of 1:1.8 molar ratio of material feeding, the reaction temperature is-40 ℃,4- (chloromethyl) -4-cyano piperidine-1-carboxylic acid tert-butyl ester is obtained by reaction in tetrahydrofuran, and the reaction yield in the step is 70%;
in the step S2, the feeding mole ratio of the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester to the lithium aluminum hydride is 1:1, a step of; the reaction temperature was 30℃and the reaction yield in this step was 59%.
In summary, the invention provides a method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-tert-butyl formate, which has the advantages of short route, short reaction period, high product yield, low reaction cost, easy amplification of reaction and convenient operation.
The foregoing description of the invention has been presented for purposes of illustration and description, and is not intended to be limiting. Several simple deductions, modifications or substitutions may also be made by a person skilled in the art to which the invention pertains, based on the idea of the invention.
Claims (7)
1. The synthesis method of the 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester is characterized by comprising the following reaction steps:
s1, reacting N-Boc-4-cyanopiperidine with chloroiodomethane under the catalysis of lithium diisopropylamide to obtain 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester;
s2, performing ring closure on the 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester synthesized in the step S1 and lithium aluminum hydride to obtain 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester;
the overall reaction formula is as follows:
2. the method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester according to claim 1, wherein in the step S1, the molar ratio of N-Boc-4-cyanopiperidine to lithium diisopropylamide is 1: (1-2), the feeding mole ratio of the N-Boc-4-cyanopiperidine to chloroiodomethane is 1: (1-2).
3. The method for synthesizing tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate according to claim 2, wherein in the step S1, the reaction solvent is tetrahydrofuran, and the reaction temperature is-70 ℃ to-20 ℃.
4. The method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester according to claim 3, wherein in the step S1, after the reaction is completed, water is added for quenching reaction, and the product 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester is obtained through liquid separation, water phase extraction, organic phase combination, washing, drying concentration and filtration.
5. The method for synthesizing 2, 7-diaza-spiro [3,5] nonane-2-carboxylic acid tert-butyl ester according to claim 1, wherein in the step S2, the feeding molar ratio of 4- (chloromethyl) -4-cyanopiperidine-1-carboxylic acid tert-butyl ester to lithium aluminum hydride is 1: (1-3).
6. The method for synthesizing tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate according to claim 5, wherein in the step S2, the reaction solvent is tetrahydrofuran, and the reaction temperature is-30 ℃ to 30 ℃.
7. The method for synthesizing tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate according to claim 6, wherein in the step S2, after the reaction is completed, the reaction is quenched, filtered, separated into liquid, the organic phase is concentrated, the concentrate is treated, filtered, and the filtrate is dried to obtain the product tert-butyl 2, 7-diaza-spiro [3,5] nonane-2-carboxylate.
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