CN111533745A - Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester - Google Patents
Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester Download PDFInfo
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- CN111533745A CN111533745A CN202010428553.2A CN202010428553A CN111533745A CN 111533745 A CN111533745 A CN 111533745A CN 202010428553 A CN202010428553 A CN 202010428553A CN 111533745 A CN111533745 A CN 111533745A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The invention relates to a preparation method of tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -formic acid ester, which mainly solves the technical problem that no industrial synthesis method is available at present. The method comprises three steps, firstly, adding triethyloxonium tetrafluoroborate into a solvent dichloromethane for reaction to obtain a compound 2 from a compound 1, secondly, reacting the compound 2 with benzyl (2-hydrazino-2-oxyylideneethyl) aminomethyl in toluene to obtain a compound 3, and thirdly, reacting the compound 3 with palladium carbon hydroxide in methanol to obtain a final compound 4, wherein the reaction formula is as follows:
Description
Technical Field
The invention relates to a synthetic method of a compound tert-butyl-3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-A ] [1,4] diazepin-8 (9H) -formic ether, which is abbreviated as: a process for the preparation of tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester.
Background
The compound tert-butyl-3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-A ] [1,4] diazepine-8 (9H) -formate ester (CAS: 1251000-46-0) and related derivatives have wide application in medicinal chemistry and organic synthesis. At present, the synthesis method of tert-butyl-3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-A ] [1,4] diazepine-8 (9H) -formic acid ester is reported in a few 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 invention aims to develop a synthetic method of tert-butyl-3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-A ] [1,4] diazepin-8 (9H) -formic acid ester, which has the advantages of easily obtained raw materials, convenient operation, easily controlled reaction and higher yield. Mainly solves the technical problem that no industrial synthesis method is available at present.
The technical scheme of the invention is as follows: the invention relates to a synthesis method of tert-butyl-3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-A ] [1,4] diazepin-8 (9H) -formate, which comprises the following three steps, wherein in the first step, compound 1 is added with triethyloxonium tetrafluoroborate in solvent dichloromethane to react to obtain compound 2, in the second step, compound 2 and benzyl (2-hydrazino-2-oxoethylidene ethyl) aminomethyl ester are reacted in toluene to obtain compound 3, and in the third step, compound 3 and palladium hydroxide carbon are reacted in methanol to obtain final compound 4. The reaction formula is as follows:
the first step is reaction temperature is room temperature, and reaction time is 12 hours; the second step is that the reaction temperature is 110 ℃ and the reaction time is 2 hours; the third step is carried out at room temperature overnight.
The Chinese explanation of the invention is as follows: TLC: thin layer chromatography.
The invention has the beneficial effects that: the reaction process is reasonable in design, the raw material tert-butyl-3-oxyylidene-1, 4-diazo-heptylcyclo-1-formyloxy ester which is easy to obtain and can be produced in a large scale is adopted, and tert-butyl-3- (aminomethyl) -6, 7-dihydro-5H- [1,2,4] triazolo [4,3-A ] [1,4] diazepine-8 (9H) -formyloxy ester is synthesized by three steps.
Detailed Description
The reaction formula of the invention is as follows:
example (b):
the first step is as follows: compound 1(20 g,0.94mol) was dissolved in anhydrous dichloromethane (2L), triethyloxonium tetrafluoroborate (20 g, 0.11mol) was added at 25 ℃ under nitrogen protection, and the reaction was stirred at this temperature for 12 hours. The mixture was then washed with saturated sodium bicarbonate solution (200mL x 3), brine (200mL), dried over anhydrous sodium sulfate and filtered. The solvent was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column (petroleum ether/ethyl acetate volume ratio =10/1) to give compound 2(13g, yield 61.0%) as a colorless oil.
1(400 M; CDCl3)
5.254 (1 H, s), 4.097 (2 H, s), 3.983-3.917 (2 H, m), 3.501-3.451 (4 H,m), 1.804 (2 H, s), 1.405 (9 H, s), 1.216-1.154 (3 H, m)。
The second step is that: compound 2(10 g,0.041 mol) and benzyl (2-hydrazino-2-oxoethylidene) aminomethyl ester were dissolved in anhydrous toluene (200mL) and refluxed at 110 ℃ for 2 hours, TLC (petroleum ether/ethyl acetate volume ratio =1/1, Rf =0.7) showed complete consumption of starting material. The mixture was filtered. The filtrate was concentrated in vacuo to give Compound 3 (7.1 g, yield: 42.8%) as a white solid.
1(400 M; CDCl3)
5.254 (1 H, s), 5.038 (2 H, s), 4.578 (2 H, s), 4.449-4.434 (2 H, d,J=6 Hz), 4.081-4.071 (2 H, d,J= 4 Hz), 1.805 (2 H, s), 1.347 (9 H, s)。
The third step: compound 3(12 g,0.03 mol) was reacted with palladium hydroxide on carbon (containing 50% H)2O,6 g) was placed in methanol (150 mL) and stirred at room temperature with hydrogen (40 Psi) overnight. The catalyst was filtered, the filtrate was concentrated, and the obtained crude product was added to methyl t-butyl ether (150 mL), stirred for 2h, filtered, and dried under vacuum to obtain Compound 4(5.12 g, yield: 64%) as a white solid.
1(400 M; CDCl3)
4.662 (s, 2H,), 4.164-4.141 (t,J= 9.2 Hz, 2H), 3.999 (s, 2H,), 3.172(s, 2H), 1.973-1.952 (t,J= 8.4 Hz, 2H), 1.407 (s, 9H)。
Claims (4)
1. A preparation method of tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -formic acid ester is characterized by comprising the following steps: the method comprises the following steps of firstly adding triethyloxonium tetrafluoroborate into a solvent dichloromethane from a compound 1 to react to obtain a compound 2, secondly reacting the compound 2 with benzyl (2-hydrazino-2-oxyylideneethyl) aminomethyl in toluene to obtain a compound 3, and thirdly reacting the compound 3 with palladium carbon hydroxide in methanol to obtain a final compound 4, wherein the reaction formula is as follows:
2. a process for the preparation of tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester according to claim 1, wherein: the first step was carried out at room temperature for 12 hours.
3. A process for the preparation of tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester according to claim 1, wherein: the second step reaction temperature is 110 ℃, and the reaction time is 2 hours.
4. A process for the preparation of tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester according to claim 1, wherein: and the third step is carried out at room temperature overnight.
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| CN202010428553.2A CN111533745A (en) | 2020-05-20 | 2020-05-20 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
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| CN202010428553.2A CN111533745A (en) | 2020-05-20 | 2020-05-20 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608315A (en) * | 2020-12-14 | 2021-04-06 | 承德医学院 | Triazolodiazepine compound and preparation method and medical application thereof |
| CN113292568A (en) * | 2021-04-13 | 2021-08-24 | 南通药明康德医药科技有限公司 | Synthetic method of 3-hydroxymethyl-1, 2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester |
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| GB1337736A (en) * | 1969-11-18 | 1973-11-21 | Takeda Chemical Industries Ltd | Benzodiazepine derivatives |
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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 |
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2020
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| CN101970415A (en) * | 2008-01-09 | 2011-02-09 | 阵列生物制药公司 | 5h-cyclopenta[d]pyrimidines as akt protein kinase inhibitors |
| CN102216305A (en) * | 2008-11-13 | 2011-10-12 | 弗·哈夫曼-拉罗切有限公司 | Spiro-5,6-dihydro-4h-2,3,5,10b-tetraaza-benzo[e]azulenes |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608315A (en) * | 2020-12-14 | 2021-04-06 | 承德医学院 | Triazolodiazepine compound and preparation method and medical application thereof |
| CN112608315B (en) * | 2020-12-14 | 2021-11-30 | 承德医学院 | Triazolodiazepine compound and preparation method and medical application thereof |
| CN113292568A (en) * | 2021-04-13 | 2021-08-24 | 南通药明康德医药科技有限公司 | Synthetic method of 3-hydroxymethyl-1, 2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester |
| CN113292568B (en) * | 2021-04-13 | 2022-04-19 | 南通药明康德医药科技有限公司 | Synthetic method of 3-hydroxymethyl-1, 2,5, 8A-tetraaza-azulene-5-carboxylic acid tert-butyl ester |
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