CN113214255A - Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof - Google Patents
Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof Download PDFInfo
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- CN113214255A CN113214255A CN202110434953.9A CN202110434953A CN113214255A CN 113214255 A CN113214255 A CN 113214255A CN 202110434953 A CN202110434953 A CN 202110434953A CN 113214255 A CN113214255 A CN 113214255A
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- 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
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Abstract
The invention discloses a synthetic method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate, which comprises the following steps: firstly, carrying out substitution reaction on a compound 1 and 1-bromo-3-chloropropane under the action of a first reaction solvent and alkali in an inert atmosphere to obtain a compound 2; secondly, the compound 2 is reduced by a reducing agent in a second reaction solvent in an inert atmosphere and automatically generates intramolecular cyclization reaction to obtain a compound 3; thirdly, starting Boc protecting group in a third reaction solvent for the compound 3 to obtain a compound 4; in the fourth step, compound 4 is catalytically hydrogenated to remove the protecting group, thus obtaining compound 5. The method has the advantages of easily obtained raw materials, convenient operation, safe reaction, easy control, suitability for amplification, short route, higher overall yield, suitability for industrial production and the like.
Description
Technical Field
The invention relates to the field of chemical synthesis methods, in particular to a synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salts thereof.
Background
The compound 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester (CAS:885272-17-3) and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate is only reported in documents.
Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate or a salt thereof, which has the advantages of readily available raw materials, convenient operation, safe reaction, easy control, suitability for amplification, 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, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester comprises the following steps:
firstly, carrying out substitution reaction on a compound 1 and 1-bromo-3-chloropropane under the action of a first reaction solvent and alkali in an inert atmosphere to obtain a compound 2;
secondly, the compound 2 is reduced by a reducing agent in a second reaction solvent in an inert atmosphere and automatically generates intramolecular cyclization reaction to obtain a compound 3;
thirdly, starting Boc protecting group in a third reaction solvent for the compound 3 to obtain a compound 4;
fourthly, the compound 4 is catalyzed and hydrogenated to remove the protecting group, and a compound 5, namely 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate is obtained;
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 anhydrous 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 anhydrous tetrahydrofuran, methyl tert-butyl ether or toluene;
the reducing agent is selected from lithium aluminum hydride;
the third reaction solvent is selected from any one or more of methanol, ethanol, isopropanol, tert-butanol, dichloromethane, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether, toluene or N, N-dimethylformamide;
the catalyst for catalytic hydrogenation is a palladium catalyst;
the fourth reaction solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran or toluene.
Specifically, the synthesis method further comprises:
and step five, mixing the compound 5 obtained in the step four with acid in an organic solvent, stirring for reaction, and precipitating to obtain a salt of the compound 5.
Specifically, in the first step, the hydrogen protons of carbon atoms of cyano groups are removed from the compound 1 at the temperature of between 80 ℃ below zero and 0 ℃ under the action of alkali, then 1-bromo-3-chloropropane is dripped at the temperature of between 20 ℃ below zero and 10 ℃, and then the mixture is stirred and reacts at the temperature of between 10 ℃ below zero and 25 ℃.
Preferably, the base is lithium diisopropylamide. Lithium diisopropylamide can be prepared in situ from diisopropylamine and n-butyllithium, followed by addition of compound 1.
Specifically, in the first step, 1-bromo-3-chloropropane is added dropwise and reacted while stirring.
Specifically, in the first step, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1-3): (1-10); preferably, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1.05-2): (1.05-5); more preferably, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1.1-1.5): (1.1-2).
Preferably, in the first step, when the compound 1 reacts with alkali, the reaction temperature is-80 ℃ to-20 ℃; more preferably, the reaction temperature is from-80 ℃ to-50 ℃.
Specifically, in the first step, the reaction time of the compound 1 and the alkali is 30-90 min; preferably, the reaction time is 45min to 75 min; more preferably, the reaction time is 60 min.
Preferably, in the first step, when the 1-bromo-3-chloropropane is dripped, the reaction temperature is controlled to be-10-5 ℃; more preferably, the reaction temperature is from 0 ℃ to 5 ℃.
Preferably, in the first step, after the dropwise addition of the 1-bromo-3-chloropropane is finished, the reaction temperature is controlled to be 0-25 ℃; more preferably, the reaction temperature is from 10 ℃ to 25 ℃.
Specifically, in the first step, after 1-bromo-3-chloropropane is added, the reaction time is 1-24 h; preferably, the reaction time is 2-20 h; more preferably, the reaction time is 4-16 h. Reaction time can be monitored by TLC.
Preferably, the first reaction solvent is selected from anhydrous tetrahydrofuran.
Specifically, in the second step, a reducing agent is added to a solution of the second reaction solvent of the compound 2, the reaction temperature is controlled to be-20 ℃ to 5 ℃, and the reaction is stirred.
Specifically, in the second step, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1-5); preferably, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1.1-3); 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-10 ℃ to 5 ℃; more preferably, the reaction temperature is from 0 ℃ to 5 ℃.
Specifically, in the second step, the reaction time is 1-12 h; preferably, the reaction time is 2-8 h; more preferably, the reaction time is 2-4 h. Reaction time can be monitored by TLC.
Preferably, the second reaction solvent is anhydrous tetrahydrofuran.
Specifically, in the third step, Boc is added2O is added into the solution of the third reaction solvent of the compound 3 and stirred for reaction at the temperature of 10-35 ℃.
Specifically, in the third step, compound 3 is reacted with Boc2The feeding molar ratio of O is 1: (1-5); preferably, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1.1-3); more preferably, the compound 2 and the reducing agent are fed in a molar ratio of 1: (1.2-2).
Preferably, in the third step, the reaction temperature is 20 ℃ to 30 ℃.
Specifically, in the third step, the reaction time is 1-12 h; preferably, the reaction time is 2-6 h. Reaction time can be monitored by TLC.
Preferably, the third reaction solvent is methanol or ethanol.
Specifically, in the fourth step, the compound 4 is subjected to catalytic hydrogenation reaction under the hydrogen pressure of 20-100 psi and the temperature of 20-50 ℃.
Preferably, in the fourth step, acetic acid is added into the reaction system to activate the reaction.
Specifically, the palladium catalyst is 2 to 10 percent palladium carbon; preferably, the palladium catalyst is 5% palladium on carbon.
Preferably, the amount of the palladium catalyst is 5-20% of the mass of the compound 4; more preferably, the amount of palladium catalyst used is 5% to 10% by mass of compound 4.
Specifically, in the fourth step, the reaction time is 1-24 h; preferably, the reaction time is 4-20 h. Reaction time can be monitored by TLC.
Preferably, the fourth reaction solvent is methanol or ethanol.
Specifically, in the fifth step, the acid is selected from hydrogen chloride, hydrogen bromide, acetic acid, maleic acid, citric acid, or fumaric acid; the organic solvent is selected from methanol, ethanol, dichloromethane, ethyl acetate, methyl tert-butyl ether, or tetrahydrofuran. Preferably, in the fifth step, the acid and the organic solvent are a hydrochloric acid methanol solution.
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.).
Some abbreviated Chinese definitions in this application: TLC, thin layer chromatography; boc2O is di-tert-butyl dicarbonate.
The beneficial effects of the invention include:
1) the target product is prepared by adopting the commercial cheap and easily-obtained raw materials of 1-benzhydryl-3-cyanoazetidine and 1-bromo-3-chloropropane, so that the raw material cost is saved.
2) The invention has reasonable reaction process design, obtains the 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate through four-step reaction synthesis, and has short synthetic route and higher yield.
3) In the second step, the cyano reduction reaction and the intramolecular cyclization reaction are completed through one-step reaction, and the reaction design is ingenious.
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 first step is as follows: diisopropylamine (183g,1.81mol) was added dropwise to a solution of n-butyllithium in n-heptane (605ml,2.5M,1.51mol) at-50 ℃ and stirred at-50 ℃ for 0.5 h. A solution of Compound 1(250g,1.01mol) in tetrahydrofuran (1000mL) was added dropwise, 1-bromo-3-chloropropane (189g,1.20mol) was added dropwise, and the reaction was allowed to return to room temperature for 16 hours. TLC (petroleum ether/ethyl acetate 5/1) showed complete reaction, the reaction solution was washed with water (500mL) and saturated brine (500mL), the separated organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 2(200g, 61%) as a white solid.
The second step is that: a solution of Compound 2(162g,0.498mol) in tetrahydrofuran (1000mL) was added dropwise to lithium aluminum hydride (23g,0.606mol) in tetrahydrofuran (1500mL) at-50 ℃ to return to room temperature and stirred for 16 hrs. TLC (petroleum ether/ethyl acetate 4/1) monitored the completion of the starting material reaction. The reaction was quenched by the addition of aqueous sodium hydroxide (23g, 15%). Filtration, soaking the filter cake in ethanol (1000mL), filtration, combining the filtrates and concentrating to give crude compound 3(128 g).
The third step: to a solution of Compound 3(100g) in methanol (305mL) was added Boc at room temperature2O (79.27g), and stirred at room temperature for 2 hours. TLC (dichloromethane/methanol 10/1) monitored the starting material for completion of the reaction. The reaction solution was concentrated and purified by column chromatography (silica, petroleum ether/ethyl acetate 100/1-50/1) to give compound 4(97g, 72.7%) as a white solid.
The fourth step, in N2To a solution of compound 4(80g,0.203mol) in ethanol (700mL) was added a solution of palladium on carbon (10g) and acetic acid (36g) in ethanol (100mL) under protection, and H was replaced2Heating to 50 deg.C in H2The reaction was carried out at 50psi for 16 hours. TLC (petroleum ether/ethyl acetate 6/1) monitored the completion of the starting material reaction. The reaction solution was cooled and filtered, the filtrate was concentrated, and then 10% aqueous hydrochloric acid (150mL) was added to the filtrate, followed by extraction with methyl tert-ether (50mL × 3) to remove impurities, the aqueous phase was separated, the pH was adjusted to 10, the organic phase was dried over methyl tert-ether (100mL × 4), and the organic phase was concentrated to remove most of the solvent, whereby compound 5 was obtained. The diluted HCl/EtOAc (diluted to 0.4M with methyl tert-ether) was then added directly and the solid precipitated with stirring and was filtered and dried to give compound 5(40g, 75% yield) as the hydrochloride salt as a white solid.
Example two
The first step is as follows: sodium hydride (2.42g, 60%, 60.41mmol) was added to a solution of compound 1(10g,40.27mmol) in tetrahydrofuran (100mL) at 0 ℃ and stirred at 0 ℃ for 0.5 h. 1-bromo-3-chloropropane (7.61g,48.32mmol) was added dropwise and the reaction was allowed to return to room temperature for 16 hours. TLC (petroleum ether/ethyl acetate-5/1) showed a small amount of starting material remaining, the reaction solution was quenched with saturated ammonium chloride (100mL), extracted with ethyl acetate (200mL), the organic phase separated and dried over anhydrous sodium sulfate and concentrated to give compound 2(10g) as a white solid.
EXAMPLE III
The third step: to a solution of Compound 3(10g) in ethyl acetate (50mL) was added Boc at room temperature2O (7.9g), and the mixture was stirred at room temperature for 16 hours. TLC (dichloromethane/methanol 10/1) monitored the starting material for completion of the reaction. The reaction was concentrated and purified by column chromatography (silica, petroleum ether/ethyl acetate 100/1-50/1) to give compound 4(9g, 67.1%) as a white solid.
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 (11)
1. A method for synthesizing 2, 6-diazaspiro [3.5] nonane-6-carboxylic acid tert-butyl ester is characterized by comprising the following steps:
firstly, carrying out substitution reaction on a compound 1 and 1-bromo-3-chloropropane under the action of a first reaction solvent and alkali in an inert atmosphere to obtain a compound 2;
secondly, the compound 2 is reduced by a reducing agent in a second reaction solvent in an inert atmosphere and automatically generates intramolecular cyclization reaction to obtain a compound 3;
thirdly, starting Boc protecting group in a third reaction solvent for the compound 3 to obtain a compound 4;
fourthly, the compound 4 is catalyzed and hydrogenated to remove the protecting group, and a compound 5 is obtained;
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 anhydrous 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 anhydrous tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene;
the reducing agent is selected from lithium aluminum hydride;
the third reaction solvent is selected from any one or more of methanol, ethanol, isopropanol, tert-butanol, dichloromethane, ethyl acetate, tetrahydrofuran, methyl tert-butyl ether, toluene or N, N-dimethylformamide;
the catalyst for catalytic hydrogenation is a palladium catalyst;
the fourth reaction solvent is selected from any one or more of methanol, ethanol, tetrahydrofuran or toluene.
2. The method of claim 1, further comprising:
and a fifth step of mixing the compound 5 obtained in the fourth step with an acid in an organic solvent to obtain a salt of the compound 5.
3. The process according to claim 1 or 2, wherein in the first step, the hydrogen protons of the carbon atom of the cyano group are removed from the compound 1 at-80 ℃ to 0 ℃ under the action of a base, 1-bromo-3-chloropropane is added dropwise at-20 ℃ to 10 ℃, and then the reaction is carried out with stirring at-10 ℃ to 25 ℃.
4. The process according to claim 3, characterized in that in the first step, the compound 1, the base and the 1-bromo-3-chloropropane are fed in a molar ratio of 1: (1-3): (1-10); preferably, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1.05-2): (1.05-5); more preferably, the feeding molar ratio of the compound 1, the alkali and the 1-bromo-3-chloropropane is 1: (1.1-1.5): (1.1-2).
5. The method of claim 3, wherein in the first step, the reaction temperature of the compound 1 with the base is-80 ℃ to-20 ℃; more preferably, the reaction temperature is from-80 ℃ to-50 ℃.
6. The method according to claim 1 or 2, wherein in the second step, a reducing agent is added to a solution of the compound 2 in the second reaction solvent, the reaction temperature is controlled to-20 ℃ to 5 ℃, and the reaction is stirred.
7. The method of claim 6, wherein in the second step, the molar ratio of compound 2 to reducing agent charged is 1: (1-5); preferably, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1.1-3); more preferably, the compound 2 and the reducing agent are fed in a molar ratio of 1: (1.1-1.5).
8. The method of claim 1 or 2, wherein in the third step, Boc is introduced2O is added into the solution of the third reaction solvent of the compound 3 and stirred for reaction at the temperature of 10-35 ℃.
9. The method of claim 8, wherein in the third step, compound 3 is reacted with Boc2The feeding molar ratio of O is 1: (1-5); preferably, the feeding molar ratio of the compound 2 to the reducing agent is 1: (1.1-3); more preferably, the compound 2 and the reducing agent are fed in a molar ratio of 1: (1.2-2).
10. The process according to claim 1 or 2, wherein in the fourth step, the compound 4 is catalytically hydrogenated under a hydrogen pressure of 20 to 100psi and at a temperature of 20 to 50 ℃.
11. The method according to claim 2, wherein in the fifth step, the acid is selected from the group consisting of hydrogen chloride, hydrogen bromide, acetic acid, maleic acid, citric acid, and fumaric acid; the organic solvent is selected from methanol, ethanol, dichloromethane, ethyl acetate, methyl tert-butyl ether, or tetrahydrofuran.
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