CN113292568B - Synthetic method of 3-hydroxymethyl-1, 2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester - Google Patents
Synthetic method of 3-hydroxymethyl-1, 2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester Download PDFInfo
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Abstract
The invention relates to a synthesis method of 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester, which comprises four steps, wherein in the first step, a compound 1 reacts with a compound 2 under the action of an alkyl lithium reagent to obtain a compound 3, and in the second step, the compound 3 and the compound 4 undergo a cyclization reaction in water to obtain a compound 5; thirdly, intramolecular cyclization of the compound 5 under the action of alkali is carried out to obtain a compound 6; in the fourth step, the ester group of the compound 6 is reduced by lithium aluminum hydride to obtain a compound 7. The method has the advantages of easily obtained raw materials, short synthetic route, suitability for amplification, higher yield and the like, and solves the technical problem that no industrial synthetic method is available at present.
Description
Technical Field
The invention relates to the field of chemical synthesis methods, in particular to a synthesis method of 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester.
Background
The compound 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester (CAS:1250997-43-3) and related derivatives have wide application in medicinal chemistry and organic synthesis. At present, few reports exist about the synthesis method of 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester.
Therefore, aiming at the need of developing a synthesis method which has the advantages of easily obtained 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 application is to provide a method for synthesizing 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester, which has the advantages of readily available raw materials, short synthetic route, suitability for amplification, high yield and the like. Mainly solves the technical problem that the compound has no preparation method at present.
In order to solve the technical problem, the application provides the following technical scheme:
a method for synthesizing 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester comprising the steps of:
the first step, in an inert atmosphere and a first reaction solvent, reacting a compound 1 with a compound 2 under the action of an alkyl lithium reagent to obtain a compound 3;
secondly, reacting the compound 3 and the compound 4 in a second reaction solvent under heating and stirring, and directly cyclizing to obtain a compound 5;
thirdly, carrying out intramolecular cyclization on the compound 5 in a third reaction solvent under the action of alkali to obtain a compound 6;
fourthly, reducing the ester group of the compound 6 in a fourth reaction solvent by lithium aluminum hydride to obtain a compound 7, namely 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester;
the reaction formula is as follows:
wherein the first reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene; the alkyl group in the alkyllithium reagent is selected from methyl, ethyl, propyl or butyl; x in said Compound 11Selected from chlorine or bromine; x in said Compound 22Selected from chlorine or bromine, R is selected from methyl, ethyl, propyl or butyl; the second reaction solvent is water; the third reaction solvent is selected from one or more of tetrahydrofuran, dioxane, methyl tert-butyl ether, N-dimethylformamide or toluene; the alkali is selected from sodium hydrogen, sodium carbonate or potassium carbonate; the fourth reaction solvent is selected from one or more of tetrahydrofuran, dioxane, methyl tert-butyl ether, N-dimethylformamide or toluene.
Specifically, in the first step, alkynyl hydrogen is removed from the compound 1 under the action of an alkyl lithium reagent, and then the compound 2 is added for reaction.
Specifically, in the first step, the feeding molar ratio of the compound 1, the alkyl lithium reagent and the halogenated ethyl formate is 1: (1-3): (1-10). Preferably, the feeding molar ratio of the compound 1, the alkyl lithium reagent and the halogenated ethyl formate is 1: (1.1-2): (1.5-5); more preferably, the feeding molar ratio of the compound 1, the alkyl lithium reagent and the halogenated ethyl formate is 1: (1.1-1.5): (2-5).
Specifically, in the first step, when the compound 1 reacts with an alkyl lithium reagent, the reaction temperature is minus 78 ℃ +/-5 ℃; preferably, the reaction temperature is-78 ℃.
Specifically, in the first step, the reaction time of the compound 1 and an alkyl lithium reagent is 30-90 min; preferably, the reaction time is 45min to 75 min; more preferably, the reaction time is 60 min.
Specifically, in the first step, the compound 2 is added for reaction, and the reaction temperature is-25-0 ℃; preferably, the reaction temperature is-20 ℃ to-10 ℃.
Specifically, in the first step, after the compound 2 is added, the reaction time is 2-12 h; preferably, the reaction time is 2-8 h; more preferably, the reaction time is 4-6 h. 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 or methyl tert-butyl ether.
Specifically, in the second step, the feeding molar ratio of the compound 3 to the compound 4 is (1-3): 1; preferably, the feeding molar ratio of the compound 3 to the compound 4 is (1.1-2): 1; more preferably, the feeding molar ratio of the compound 3 to the compound 4 is (1.1-1.5): 1.
specifically, in the second step, the reaction temperature of the compound 3 and the compound 4 is 60-90 ℃; preferably, the reaction temperature is 70-80 ℃; more preferably, the reaction temperature is 85 ℃.
Specifically, in the second step, the reaction time of the compound 3 and the compound 4 is 6-24 hours; preferably, the reaction time is 8-16 h; more preferably, the reaction time is 10-12 h. The reaction time was monitored by TLC.
Specifically, in the third step, the feeding molar ratio of the compound 5 to the base is 1: (1-5); preferably, the compound 5 and the base are fed in a molar ratio of 1: (1.1-3); more preferably, the compound 5 and base are fed in a molar ratio of 1: (1.5-2).
Specifically, in the third step, the alkali is sodium hydrogen, and a solution of the third reaction solvent of the compound 5 is added dropwise to a solution of the third reaction solvent of sodium hydride, and the dropwise addition and the stirring reaction are performed simultaneously; the reaction temperature is-10-5 ℃, and the reaction time is 1-12 h. Preferably, in the third step, when the alkali is sodium hydrogen, the reaction temperature is-5-0 ℃.
Preferably, in the third step, when the alkali is sodium hydrogen, the reaction time is 1-8 h; more preferably, the reaction time is 2-6 h. Reaction time can be monitored by TLC.
Preferably, when the base is sodium hydrogen, the third reaction solvent is an anhydrous solvent or is subjected to anhydrous treatment in advance.
Preferably, when the base is sodium hydrogen, the third reaction solvent is selected from N, N-dimethylformamide.
Preferably, when the base is sodium hydrogen, the third step is carried out under an inert atmosphere.
Specifically, in the third step, the alkali is sodium carbonate or potassium carbonate, the alkali is added into the solution of the third reaction solvent of the compound 5, the solution is heated to 50-66 ℃ for reaction, and the reaction time is 8-24 hours.
Preferably, in the third step, when the alkali is sodium carbonate or potassium carbonate, the reaction temperature is 55-60 ℃.
Preferably, in the third step, when the alkali is sodium carbonate or potassium carbonate, the reaction time is 12-20 h. Reaction time can be monitored by TLC.
Preferably, when the base is sodium carbonate or potassium carbonate, the third reaction solvent is selected from tetrahydrofuran.
Specifically, in the fourth step, a solution of the fourth reaction solvent of compound 6 is added dropwise to a solution of the fourth reaction solvent of lithium aluminum hydride, and the reaction is carried out while stirring the dropwise addition.
Specifically, in the fourth step, the feeding molar ratio of the compound 6 to the lithium aluminum hydride is 1: (1-5); preferably, the feeding molar ratio of the compound 3 to the compound 4 is 1: (1.1-3); more preferably, the feed molar ratio of compound 3 to compound 4 is 1: (1.5-2).
Specifically, in the fourth step, the reaction temperature is-10-5 ℃; preferably, the reaction temperature is-5 to 0 ℃.
Specifically, in the fourth step, the reaction time is 1-12 h; preferably, the reaction time is 1-8 h; more preferably, the reaction time is 2-6 h. Reaction time can be monitored by TLC.
Preferably, the fourth reaction solvent is an anhydrous solvent or is subjected to anhydrous treatment in advance.
Preferably, the fourth reaction solvent is selected from tetrahydrofuran.
Preferably, the fourth 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 target product is prepared from 3-halopropyne (compound 1), haloformate (compound 2) and reported tert-butyl (3-azidopropyl) aminomethyl (compound 4), and the raw materials are cheap and easy to obtain.
2) The reaction process is reasonable in design, 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester is synthesized through four-step reaction, and the synthesis route is short.
3) The four-step reaction involved in the application is a very mature reaction type in chemical production in the field, and is easy to be produced in an enlarged scale.
4) The synthesis method has high yield.
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(20g,268.42mmol,20.83mL,1.00eq) was dissolved in methyl tert-ether (200mL), N2The temperature is reduced to-78 ℃ under protection, a solution of methyllithium (1.6M,184.54mL,1.10eq) is added dropwise, the temperature is kept at-78 ℃ and stirred for 1 hour, compound 2 ethyl chloroformate (145.64g,1.34mol,5.00eq) is added dropwise, and the temperature is increased to-20 ℃ for reaction for 4 hours. TLC (petroleum ether/ethyl acetate 3/1) monitored the completion of the starting material reactionThe reaction was quenched by the addition of water (500mL) to the reaction mixture slowly, tert-methyl ether (500 mL. times.3) was added, the combined organic phases were washed with saturated brine (500mL), the separated organic phase was dried over anhydrous sodium sulfate and concentrated, the reaction was filtered through celite, and the filtrate was concentrated to give crude compound 3(40 g).
The second step is that: compound 4(18g,69.22mmol,1eq) and compound 3(14g,95.52mmol,1.38eq) were added to water (180mL), warmed to 80 ℃ and stirred for 12 hours. TLC (petroleum ether/ethyl acetate 3/1) monitored the completion of the starting material reaction. The reaction solution was extracted with ethyl acetate (50mL × 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by column chromatography to give compound 5(9g,25.95mmol, 37.49%) as a white solid.
The third step: a solution of compound 5(9g,25.95mmol,1eq) in DMF (30mL) was added dropwise to a solution of sodium hydride (1.66g,41.52mmol, 60% purity,1.6eq) in DMF (58.5mL) at 0 ℃ and stirred for 2h at 0 ℃. TLC (dichloromethane/methanol 10/1) monitored the starting material for completion of the reaction. The reaction was quenched by slowly adding water (30 mL). Extraction with dichloromethane (15mL × 3) combined organic phases were washed with saturated brine, the organic phases were concentrated and purified by column chromatography (silica, petroleum ether/ethyl acetate 50/1-0/1) to give compound 6(3.4g,10.96mmol, 42.22%) as a white solid.
The fourth step: a solution of compound 6(2g,6.44mmol,1eq) in THF (20mL) was added dropwise to a solution of lithium aluminum hydride (511.62mg,13.48mmol,2.09eq) in THF (10mL) at 0 ℃ and stirred for 2 hours at 0 ℃. TLC (dichloromethane/methanol 10/1) monitored the starting material for completion of the reaction. Adding Na into the reaction system2SO4.10H2O (1g), stirred for 30 mins. Filtration and concentration of the filtrate followed by column chromatography purification (silica, petroleum ether/ethyl acetate 50/1-0/1) gave compound 7(1g,3.73mmol, 57.83%) as a white solid.
Example two
The reaction formula of this example is as follows:
compound 1(20g,268.42mmol,20.83mL,1.00eq) was dissolved in tetrahydrofuran (200mL), N2The temperature was reduced to-78 ℃ under protection, a solution of n-butyllithium (2.5M,118mL,1.10eq) was added dropwise while maintaining at-78 ℃ and stirring for 1 hour, the compound ethyl 2 chloroformate (145.64g,1.34mol,5.00eq) was added dropwise, and the temperature was raised to-20 ℃ for reaction for 4 hours. TLC (petroleum ether/ethyl acetate-3/1) monitored completion of the starting material reaction water (500mL) was added slowly to the reaction solution to quench the reaction, methyl tert-ether (500mL × 3), the combined organic phases were washed with saturated brine (500mL), the separated organic phase was dried over anhydrous sodium sulfate and concentrated, the reaction was filtered through celite, and the filtrate was concentrated to give crude compound 3(35 g).
EXAMPLE III
The reaction formula of this example is as follows:
compound 1(20g,168mmol,14.49mL,1.00eq) was dissolved in tetrahydrofuran (200mL), N2The temperature is reduced to-78 ℃ under protection, n-butyllithium solution (2.5M,74mL,1.10eq) is added dropwise, the temperature is kept at-78 ℃ and stirred for 1 hour, compound 2 ethyl chloroformate (91.22g,840.6mol,5.00eq) is added dropwise, and the temperature is increased to-20 ℃ for reaction for 4 hours. TLC (petroleum ether/ethyl acetate-3/1) monitored completion of the starting material reaction water (500mL) was added slowly to the reaction solution to quench the reaction, methyl tert-ether (500mL × 3), the combined organic phases were washed with saturated brine (500mL), the separated organic phase was dried over anhydrous sodium sulfate and concentrated, the reaction was filtered through celite, and the filtrate was concentrated to give crude compound 3(30 g).
Example four
The reaction formula of this example is as follows:
sodium carbonate (2.2g,20.7mmol,1.6eq) was added to a solution of compound 5(4.5g,13.0mmol,1.0eq) in THF (30mL) at 20 deg.C, and the mixture was stirred at 50 deg.C for 16 hours. TLC (dichloromethane/methanol 10/1) monitored that a small amount of starting material remained. The reaction was quenched by slowly adding water (30 mL). Extraction with dichloromethane (15mL × 3) combined organic phases were washed with saturated brine, and the organic phases were concentrated and purified by column chromatography (silica, petroleum ether/ethyl acetate 50/1-0/1) to give compound 6(1.5g,4.84mmol, 37.25%) 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 (25)
1. A method for synthesizing 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester, comprising the steps of:
the first step is as follows: reacting the compound 1 with the compound 2 under the action of an alkyl lithium reagent in an inert atmosphere and a first reaction solvent to obtain a compound 3;
the second step is that: reacting the compound 3 and the compound 4 in a second reaction solvent under heating and stirring, and directly cyclizing to obtain a compound 5;
the third step: carrying out intramolecular cyclization on the compound 5 in a third reaction solvent under the action of alkali to obtain a compound 6;
the fourth step: reducing the ester group of the compound 6 in a fourth reaction solvent by lithium aluminum hydride to obtain a compound 7, namely 3-hydroxymethyl-7, 8-dihydro-4H, 6H-1,2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester;
the reaction formula is as follows:
wherein the first reaction solvent is selected from one or more of tetrahydrofuran, methyl tert-butyl ether, N-dimethylformamide or toluene;
the alkyl group in the alkyllithium reagent is selected from methyl, ethyl, propyl or butyl;
x in said Compound 11Selected from chlorine or bromine;
x in said Compound 22Selected from chlorine or bromine, R is selected from methyl, ethyl, propyl or butyl;
the second reaction solvent is water;
the third reaction solvent is selected from one or more of tetrahydrofuran, dioxane, methyl tert-butyl ether, N-dimethylformamide or toluene;
the alkali is selected from sodium hydrogen, sodium carbonate or potassium carbonate;
the fourth reaction solvent is selected from one or more of tetrahydrofuran, dioxane, methyl tert-butyl ether, N-dimethylformamide or toluene.
2. The method of claim 1, wherein in the first step, compound 1 is subjected to an alkyllithium reagent to remove alkynylhydrogens, and compound 2 is added to the reaction.
3. The synthesis method according to claim 2, wherein in the first step, the feeding molar ratio of the compound 1, the alkyl lithium reagent and the halogenated ethyl formate is 1: (1-3): (1-10).
4. The method of claim 3, wherein the molar ratio of the compound 1, the alkyl lithium reagent, and the ethyl haloformate is 1: (1.1-2): (1.5-5).
5. The method of claim 4, wherein the molar ratio of the compound 1, the alkyl lithium reagent, and the ethyl haloformate is 1: (1.1-1.5): (2-5).
6. The method of claim 2, wherein in the first step, compound 1 is reacted with the alkyllithium reagent at a temperature of-78 ℃ ± 5 ℃.
7. The method of synthesis according to claim 6, wherein the reaction temperature is-78 ℃.
8. The method of claim 2, wherein the reaction temperature of the first step is-25 to 0 ℃ when the compound 2 is added.
9. The synthesis method according to claim 8, wherein the reaction temperature is-20 ℃ to-10 ℃.
10. The synthesis method according to claim 1, wherein in the second step, the feeding molar ratio of the compound 3 to the compound 4 is (1-3): 1.
11. the synthesis method according to claim 10, wherein the feeding molar ratio of the compound 3 to the compound 4 is (1.1-2): 1.
12. the synthesis method according to claim 11, wherein the feeding molar ratio of the compound 3 to the compound 4 is (1.1-1.5): 1.
13. the method of claim 1, wherein in the second step, the reaction temperature of compound 3 and compound 4 is 60 to 90 ℃.
14. The synthesis method according to claim 13, wherein the reaction temperature is 70-80 ℃.
15. The method of synthesis according to claim 13, wherein the reaction temperature is 85 ℃.
16. The synthesis method according to claim 1, wherein in the third step, the feeding molar ratio of the compound 5 to the base is 1: (1-5).
17. The method of synthesis according to claim 16, wherein the compound 5 and the base are fed in a molar ratio of 1: (1.1-3).
18. The synthesis method of claim 17, wherein the compound 5 and the base are fed in a molar ratio of 1: (1.5-2).
19. The synthesis method according to claim 16, wherein in the third step, the base is sodium hydrogen, and a solution of the compound 5 in the third reaction solvent is added dropwise to a solution of sodium hydride in the third reaction solvent while stirring to react; the reaction temperature is-10-5 ℃, and the reaction time is 1-12 h.
20. The synthesis method of claim 16, wherein in the third step, the base is sodium carbonate or potassium carbonate, the base is added into the solution of the compound 5 in the third reaction solvent, and the reaction is carried out at 50-66 ℃ for 8-24 h.
21. The method according to claim 1, wherein in the fourth step, a solution of the compound 6 in the fourth reaction solvent is added dropwise to a solution of lithium aluminum hydride in the fourth reaction solvent, and the reaction is stirred while the dropwise addition is performed.
22. The method of claim 21, wherein in the fourth step, the molar ratio of compound 6 to lithium aluminum hydride is 1: (1-5); the feeding molar ratio of the compound 3 to the compound 4 is 1: (1.1-3).
23. The method of claim 22, wherein the feed molar ratio of compound 3 to compound 4 is 1: (1.5-2).
24. The synthesis method according to claim 21, wherein in the fourth step, the reaction temperature is-10 to 5 ℃.
25. The synthetic method of claim 24 wherein the reaction temperature is-5 to 0 ℃.
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| CN107216332A (en) * | 2017-06-29 | 2017-09-29 | 上海药明康德新药开发有限公司 | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 |
| CN111533745A (en) * | 2020-05-20 | 2020-08-14 | 成都药明康德新药开发有限公司 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
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| CN107216332A (en) * | 2017-06-29 | 2017-09-29 | 上海药明康德新药开发有限公司 | The synthetic method of (6H) the formic acid base ester of 7 methylol of the tert-butyl group, 7,8 dihydro 4H pyrazolos diazepine 5 |
| CN111533745A (en) * | 2020-05-20 | 2020-08-14 | 成都药明康德新药开发有限公司 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
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