CN113121537B - Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate - Google Patents
Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate Download PDFInfo
- Publication number
- CN113121537B CN113121537B CN202110391999.7A CN202110391999A CN113121537B CN 113121537 B CN113121537 B CN 113121537B CN 202110391999 A CN202110391999 A CN 202110391999A CN 113121537 B CN113121537 B CN 113121537B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- synthesis
- bromo
- synthesis method
- 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
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
Abstract
The invention discloses a synthetic method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate, which comprises the following steps: step one, in a first reaction solvent, reacting a compound 1 with 1-bromo-2-chloroethane under the action of alkali to obtain a compound 2; and step two, in a second reaction solvent, the compound 2 is reduced by a reducing agent and then automatically undergoes a cyclization reaction to obtain a compound 3. The method has the advantages of easily available raw materials, convenient operation, short route, high overall yield, suitability for industrial production and the like, and mainly solves the technical problem that no industrial synthesis method is available at present.
Description
Technical Field
The invention relates to the field of chemical synthesis methods, in particular to a simple and convenient synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate.
Background
The compound 2, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (CAS: 236406-39-6) and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. Although a few documents report the existing 2, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester synthesis method, the synthesis route is long, and the total yield is not high.
Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, short route, high overall yield and suitability for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide the method for synthesizing the 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate, which has the advantages of easily obtained raw materials, convenient operation, short route, high overall yield, suitability for industrial production and the like.
In order to solve the technical problems, the invention provides the following technical scheme:
a method for synthesizing 2, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester comprises the following steps:
step one, in a first reaction solvent, reacting a compound 1 with 1-bromo-2-chloroethane under the action of alkali to obtain a compound 2;
secondly, in a second reaction solvent, the compound 2 is reduced by a reducing agent and then automatically undergoes a cyclization reaction to obtain a compound 3;
the reaction formula is as follows:
wherein the content of the first and second substances,
the first reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene;
the base is selected from lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or sodium hydride;
the second reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene;
the reducing agent is selected from lithium aluminum hydride.
Specifically, in the first step, hydrogen protons of carbon atoms of a cyano group are removed from the compound 1 under the action of alkali, and then 1-bromo-2 chloroethane is added for reaction.
Specifically, in the first step, 1-bromo-2-chloroethane is added dropwise and reacted with stirring.
Specifically, in the first step, the feeding molar ratio of the compound 1, alkali and 1-bromo-2-chloroethane is 1: (1-3): (1-10); preferably, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-2 chloroethane is 1: (1.05-2): (1.05-5); more preferably, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-2-chloroethane is 1: (1.1-1.5): (1.1-2).
Specifically, in the first step, when the compound 1 reacts with alkali, the reaction temperature is-80 ℃ to-70 ℃; preferably, the reaction temperature is-78 ℃.
Specifically, in the first step, the reaction time of the compound 1 and alkali is 30-90 min; preferably, the reaction time is 45min to 75min; more preferably, the reaction time is 60min.
Specifically, in the first step, 1-bromo-2-chloroethane is added for reaction, and the reaction temperature is-10-5 ℃; preferably, the reaction temperature is from-5 ℃ to 0 ℃.
Specifically, in the first step, after the compound 2 is added, the reaction time is 1-12 h; preferably, the reaction time is 2 to 8 hours; more preferably, the reaction time is 4 to 6 hours. Reaction time can be monitored by TLC.
Preferably, the first reaction solvent is an anhydrous solvent or is subjected to anhydrous treatment in advance.
Preferably, the first reaction solvent is selected from tetrahydrofuran.
Preferably, the first step is carried out under an inert atmosphere.
Specifically, in the second step, a reducing agent is added to a solution of compound 2 in the second reaction solvent to carry out a reaction.
Specifically, in the second step, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1-5); preferably, the molar ratio of compound 2 to reducing agent is 1: (1.1 to 3); more preferably, the compound 2 and the reducing agent are fed in a molar ratio of 1: (1.1-1.5).
Specifically, in the second step, the reaction temperature is-20 ℃ to 5 ℃; preferably, the reaction temperature is-10 to 5 ℃; more preferably, the reaction temperature is 0 to 5 ℃.
Specifically, in the second step, the reaction time is 1-12 h; preferably, the reaction time is 2 to 8 hours; more preferably, the reaction time is 2 to 4 hours. The reaction time was monitored by TLC.
Preferably, the second reaction solvent is an anhydrous solvent or is subjected to anhydrous treatment in advance.
Preferably, the second reaction solvent is selected from tetrahydrofuran.
Preferably, the second step is carried out under an inert atmosphere.
In the present application, the inert atmosphere refers to that the reaction is carried out under the protection of nitrogen or inert gas (such as helium, argon, etc.).
The beneficial effects of the invention include:
1) The reaction process of the invention has reasonable design, obtains the 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate through two-step reaction synthesis, and has short synthetic route.
2) The target product is prepared by adopting cheap and easily-obtained raw materials of 1-Boc-4-cyanopiperidine and 1-bromo-2 chloroethane, so that the raw material cost is saved.
3) In the second step, the cyano-group reduction reaction and the cyclization reaction are completed through one-step reaction, and the reaction design is ingenious.
4) The reaction type related to the application can be matured and can be produced on a large scale.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Example one
The reaction formula of this example is as follows:
the first step is as follows: compound 1 (350g, 1.66mol, 1.00eq) was dissolved in anhydrous tetrahydrofuran (2000 mL), cooled to-70 ℃ and LDA (266.73g, 2.49mol, 1.50eq) was added dropwise, and stirred at-70 ℃ for 1 hour. 1-bromo-2-chloroethane (285.67g, 1.99mol,165.13mL, 1.20eq) was added dropwise at-70 ℃ and the reaction was allowed to warm to 0 ℃ for 3 hours. TLC monitored the completion of the reaction, quenched the reaction by addition of saturated ammonium chloride solution, quenched with ethyl acetate (500 mL. Times.2), combined organic phases dried over anhydrous sodium sulfate and concentrated, and the crude product purified by column chromatography to give compound 2 (188g, 41.4%) as a yellow oil.
The second step is that: the three-pot reaction was carried out in parallel. To an anhydrous tetrahydrofuran solution of compound 2 (70g, 256.63mmol, 1.00eq) was added lithium aluminum hydride (19.48g, 513.25mmol, 2.00eq) at 0 ℃ and stirred at 0 ℃ for 2 hours. TLC monitored completion of the starting material reaction, quenched by slow addition of water (70 mL) and 10% aqueous sodium hydroxide (70 mL), filtered, and the filtrate was dried over anhydrous sodium sulfate and concentrated to give compound 3 (185g, 769.74mmol, 99.98%) as a yellow oil.
Example two
The reaction formula of this example is as follows:
the first step is as follows: compound 1 (3.50g, 16.6mmol, 1.00eq) was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to 0 ℃ and added with sodium hydride (998.6mg, 60%,24.97mmol, 1.5eq) and stirred at 0 ℃ for 1 hour. 1-bromo-2-chloroethane (2.87g, 19.98mmol, 1.20eq) was added dropwise at 0 ℃ and the reaction was warmed to room temperature for 5 hours. TLC monitored the completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution, quenched with ethyl acetate (50 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to give Compound 2 (1.0 g, 22.03%) as a yellow oil.
EXAMPLE III
The reaction formula for this example is as follows:
the first step is as follows: compound 1 (4.00g, 19.0mmol, 1.00eq) was dissolved in anhydrous tetrahydrofuran (24 mL), cooled to-75 ℃ and lithium hexamethyldisilazide (1M, 28.53mL,28.53mol, 1.5eq) was added, stirring was carried out at-75 ℃ for 1 hour. 1-bromo-2-chloroethane (3.27g, 22.83mmol, 1.20eq) was added dropwise at-75 ℃ and the temperature was raised to 0 ℃ to react for 1 hour. TLC was used to monitor the completion of the reaction, and the reaction solution was quenched by addition of saturated ammonium chloride solution, quenched with ethyl acetate (40 mL. Times.2), the combined organic phases were dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to give compound 2 (1.8g, 34.69%) as a yellow oil.
In summary, the above embodiments are merely preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalents, improvements, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (21)
1. A method for synthesizing 2, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
step one, in a first reaction solvent, reacting a compound 1 with 1-bromo-2 chloroethane under the action of alkali to obtain a compound 2;
step two, in a second reaction solvent, the compound 2 is reduced by a reducing agent and then automatically generates cyclization reaction to obtain a compound 3;
thirdly, quenching the reaction;
the reaction formula is as follows:
wherein, the first and the second end of the pipe are connected with each other,
the first reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene;
the base is selected from lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, or sodium hydride;
the reaction time of the compound 1 and alkali is 30-90 min;
the second reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene;
the reducing agent is selected from lithium aluminum hydride;
the third step quench reagent was equal volume of water and 10% aqueous naoh.
2. The synthesis process as claimed in claim 1, wherein in the first step, compound 1 is subjected to base to remove hydrogen protons from the carbon atom of cyano group, and 1-bromo-2-chloroethane is added for reaction.
3. The synthesis method according to claim 2, wherein in the first step, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-2 chloroethane is 1: (1-3): (1-10).
4. The synthesis method according to claim 2, wherein in the first step, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-2 chloroethane is 1: (1.05-2): (1.05-5).
5. The synthesis method according to claim 2, wherein in the first step, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-2 chloroethane is 1: (1.1-1.5): (1.1-2).
6. The method of claim 2, wherein in the first step, the reaction temperature of compound 1 with the base is from-80 ℃ to-70 ℃.
7. The synthesis process according to claim 2, characterized in that in the first step the reaction temperature is-78 ℃.
8. The synthesis process according to claim 2, characterized in that in the first step the reaction time is from 45min to 75min.
9. The synthesis process according to claim 2, characterized in that in the first step the reaction time is 60min.
10. The synthesis method according to claim 2, wherein in the first step, 1-bromo-2-chloroethane is added for reaction, and the reaction temperature is-10-5 ℃.
11. The synthesis process according to claim 2, characterized in that in the first step the reaction temperature is between-5 ℃ and 0 ℃.
12. The synthesis method according to claim 1, wherein in the second step, a reducing agent is added to a solution of compound 2 in the second reaction solvent to carry out the reaction.
13. The synthesis method according to claim 12, wherein in the second step, the molar ratio of compound 2 to the reducing agent is 1: (1-5).
14. The synthesis method according to claim 12, wherein in the second step, the molar ratio of compound 2 to the reducing agent is 1: (1.1-3).
15. The synthesis method according to claim 12, wherein in the second step, the molar ratio of compound 2 to the reducing agent is 1: (1.1-1.5).
16. The synthesis process according to claim 12, characterized in that, in the second step, the reaction temperature is between-20 ℃ and 5 ℃.
17. The synthesis process according to claim 12, characterized in that in the second step, the reaction temperature is between-10 and 5 ℃.
18. The synthesis process according to claim 12, characterized in that in the second step, the reaction temperature is between 0 and 5 ℃.
19. The synthesis process according to claim 1, characterized in that the first reaction solvent and/or the second reaction solvent are anhydrous solvents or have been subjected to anhydrous treatment beforehand.
20. The synthesis method according to claim 1, wherein the first reaction solvent and/or the second reaction solvent is selected from tetrahydrofuran.
21. The method of synthesis according to claim 1, characterized in that the reaction of the first and/or second step is carried out under an inert atmosphere.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110391999.7A CN113121537B (en) | 2021-04-13 | 2021-04-13 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110391999.7A CN113121537B (en) | 2021-04-13 | 2021-04-13 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113121537A CN113121537A (en) | 2021-07-16 |
| CN113121537B true CN113121537B (en) | 2022-11-08 |
Family
ID=76775867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110391999.7A Active CN113121537B (en) | 2021-04-13 | 2021-04-13 | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113121537B (en) |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5756743A (en) * | 1996-04-10 | 1998-05-26 | Hoechst Marion Roussel Inc. | Spiro cyclopent b!indole-piperidines! |
| CN103442568A (en) * | 2010-10-08 | 2013-12-11 | Abbvie公司 | Furo[3,2-d]pyrimidine compounds |
| CN103304572A (en) * | 2012-03-09 | 2013-09-18 | 上海医药集团股份有限公司 | 3-cyanoquinoline compound as well as pharmaceutical composition and application thereof |
| TWI633113B (en) * | 2013-10-17 | 2018-08-21 | 美國禮來大藥廠 | Novel urea compounds |
| WO2016065582A1 (en) * | 2014-10-30 | 2016-05-06 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
| CN111285874A (en) * | 2018-12-07 | 2020-06-16 | 广东东阳光药业有限公司 | RET inhibitors, pharmaceutical compositions thereof and uses thereof |
| CN109608460A (en) * | 2018-12-17 | 2019-04-12 | 上海合全药业股份有限公司 | A kind of synthetic method of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate |
| CN109651368A (en) * | 2018-12-17 | 2019-04-19 | 武汉药明康德新药开发有限公司 | The preparation method of 4- methyl formate -2- oxygen -1,8- diaza spiro [4.5] decane -8- t-butyl formate |
| US20220079951A1 (en) * | 2018-12-20 | 2022-03-17 | Saint Louis University | Bet inhibitors for modulating dux4 expression in fshd |
| AU2020348849A1 (en) * | 2019-09-19 | 2022-04-07 | The Regents Of The University Of Michigan | Spirocyclic androgen receptor protein degraders |
-
2021
- 2021-04-13 CN CN202110391999.7A patent/CN113121537B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113121537A (en) | 2021-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6949668B2 (en) | Process for producing 5-(3-cyanophenyl)-3-formylbenzoic acid compound | |
| CN107778383B (en) | Refining method of sugammadex sodium | |
| EP3847157A1 (en) | Process for the preparation of methyl 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylate | |
| KR20200123151A (en) | Method for preparing nitric oxide-providing prostaglandin analogs | |
| CN113121537B (en) | Synthesis method of 2, 8-diazaspiro [4.5] decane-8-tert-butyl formate | |
| Couret et al. | Dimesitylneopentylgermene, a new stable germene | |
| CN112300072A (en) | High-yield synthesis method of 5-iodoisoquinoline compounds | |
| CN101155820B (en) | Processes for preparing 6,7,8-trihydroxy-1-(hydroxymethyl)-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane | |
| KR100355916B1 (en) | New manufacturing method of diisopinocampal chloroborane | |
| CN107915653B (en) | Method for preparing amide by catalyzing ester and amine to react | |
| CN112480172A (en) | Use of borane-pyridine complexes for the preparation of pharmaceutical compounds | |
| CN112521421A (en) | Preparation method of pharmaceutical compound | |
| KR101113791B1 (en) | Novel potassium azidoaryltrifluoroborate derivatives and method for producing the same | |
| CN113214255B (en) | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof | |
| CN115260103B (en) | Preparation method of 4,5-dihalogen-1- (difluoromethyl) -1H-imidazole | |
| CN114805017B (en) | Preparation method of 2-fluoro-1, 5-hexadiene compound | |
| CA3059585A1 (en) | Process for the preparation of deuterated ethanol from d2o | |
| JP7081698B2 (en) | Method for manufacturing a coupling compound | |
| JPH0586940B2 (en) | ||
| JPS62126164A (en) | 4-alkoxy-2-oxo-pyrrolidine-1 acetic acid alkyl ester and manufacture | |
| JPS63246370A (en) | Production of amine compound | |
| CN113214257A (en) | Synthesis method of 1-oxyidene-2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate | |
| CN117820065A (en) | Gamma-aryl substituted gem-difluoro olefin compound and preparation method thereof | |
| CN116239623A (en) | Preparation method and application of boric acid ester | |
| CN114262292A (en) | Pyridine derivative and preparation method and application thereof |
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 |