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
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- compound
- aminomethyl
- butyl
- dihydro
- triazolodiazepine
- 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.)
- Pending
Links
Classifications
-
- 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
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111533745A true CN111533745A (en) | 2020-08-14 |
Family
ID=71972105
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010428553.2A Pending CN111533745A (en) | 2020-05-20 | 2020-05-20 | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111533745A (en) |
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 |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1337736A (en) * | 1969-11-18 | 1973-11-21 | Takeda Chemical Industries Ltd | Benzodiazepine derivatives |
| CA2016550A1 (en) * | 1990-05-09 | 1991-11-11 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R .A.S.) | Preparation process of thieno-triazolo-diazepine derivatives |
| FR2779652B1 (en) * | 1998-06-15 | 2001-06-08 | Sod Conseils Rech Applic | USE OF DIAZEPINES FOR THE PREPARATION OF MEDICINES FOR THE TREATMENT OF CONDITIONS OR DISEASES IN WHICH ONE OF THE SOMATOSTATIN RECEPTORS IS INVOLVED |
| CN101014578A (en) * | 2004-09-16 | 2007-08-08 | 安斯泰来制药有限公司 | Triazole derivative or salt thereof |
| CN101863886A (en) * | 2002-09-04 | 2010-10-20 | 百时美施贵宝公司 | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
| 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 |
| CN106715439A (en) * | 2014-10-02 | 2017-05-24 | 葛兰素史克知识产权第二有限公司 | Compound |
| 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 |
-
2020
- 2020-05-20 CN CN202010428553.2A patent/CN111533745A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1337736A (en) * | 1969-11-18 | 1973-11-21 | Takeda Chemical Industries Ltd | Benzodiazepine derivatives |
| CA2016550A1 (en) * | 1990-05-09 | 1991-11-11 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R .A.S.) | Preparation process of thieno-triazolo-diazepine derivatives |
| FR2779652B1 (en) * | 1998-06-15 | 2001-06-08 | Sod Conseils Rech Applic | USE OF DIAZEPINES FOR THE PREPARATION OF MEDICINES FOR THE TREATMENT OF CONDITIONS OR DISEASES IN WHICH ONE OF THE SOMATOSTATIN RECEPTORS IS INVOLVED |
| CN101863886A (en) * | 2002-09-04 | 2010-10-20 | 百时美施贵宝公司 | Heterocyclic aromatic compounds useful as growth hormone secretagogues |
| CN101014578A (en) * | 2004-09-16 | 2007-08-08 | 安斯泰来制药有限公司 | Triazole derivative or salt thereof |
| 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 |
| CN106715439A (en) * | 2014-10-02 | 2017-05-24 | 葛兰素史克知识产权第二有限公司 | Compound |
| 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 |
Non-Patent Citations (6)
| Title |
|---|
| ACS: "RN:1251000-46-0", 《STN-REGISTRY数据库》 * |
| EDWARD C. LAWSON等: "Synthesis and Biological Evaluation of 1,2,4-Triazolo[2,3-a]pyrrole Derivatives as Alpha-4(α4) Integrin Antagonists", 《LETTERS IN DRUG DESIGN & DISCOVERY》 * |
| RICHARD S.P. HSI等: "SYNTHESIS OF ADINAZOLAM MESYLATE MULTIPLY LABELED WITH CARBON-13 AND DEUTERIUM", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICAL》 * |
| 宁永成: "《有机化合物结构鉴定与有机波谱学》", 28 February 1989, 清华大学出版社 * |
| 朴凤玉: "三唑并苯并氮卓衍生物的合成及其抗惊厥活性研究", 《中国优秀博硕士学位论文全文数据库(博士)工程科技Ⅰ辑》 * |
| 杜彩云等: "《有机化学》", 31 December 2015, 武汉大学出版社 * |
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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111620869B (en) | Synthesis method of tert-butyl-1, 7-diazaspiro [3.5] nonane-1-formyloxy ester | |
| CN114181191B (en) | Synthesis method of cyclic sulfate | |
| CN111533745A (en) | Process for preparing tert-butyl-3- (aminomethyl) dihydro-5H-triazolodiazepine-8 (9H) -carboxylic acid ester | |
| CN110551133A (en) | Process for preparing tert-butyl-5- (hydroxymethyl) -7-oxa-2-azaspiro [3.5] nonane-2-carboxylic acid ester | |
| CN111548356B (en) | Process for preparing tert-butyl-1, 8-dioxa-4, 11-diazaspiro [5.6] dodecane-11-carboxylic acid ester | |
| CN111675659B (en) | Synthesis method of (5-fluoropyrimidine-4-yl) methanol | |
| KR101769204B1 (en) | New method for preparation of chiral chromanol derivatives | |
| CN111606905B (en) | Preparation of di-tert-butyl-2- (2-ethoxy-2-oxoethylidene) dihydro-3H-imidazopyridine diformate | |
| CN113214255B (en) | Synthesis method of 2, 6-diazaspiro [3.5] nonane-6-tert-butyl formate and salt thereof | |
| CN111662287B (en) | Preparation of 5-tert-butyl-4-ethyl-3-methyl-dihydro-3H-imidazopyridine- (4H) -diformyl ester | |
| CN110551129B (en) | Preparation method of 4, 5-dihydro-1H, 3H-pyrrolo [1,2-A ] [1,4] diazepine-2, 4-dicarboxylic acid-2-tert-butyl ester | |
| CN110627686A (en) | Synthesis method of fluorenylmethyloxycarbonyl-O-trityl-L-threonine | |
| CN110483534B (en) | Preparation method of (2,4,5, 7-tetrahydropyrano [3,4-c ] pyrazol-7-yl) methanol | |
| CN111574524B (en) | 2- (tert-butoxycarbonyl) -7-oxyylidene-2, 6-diazaspiro [3.4] octane-5-carboxylic acid preparation method | |
| CN114524815B (en) | 8-alkoxypurine derivative and preparation method and application thereof | |
| CN113214290B (en) | Synthesis method of 2, 5-dioxa-8-azaspiro [3.5] nonane and salt thereof | |
| CN113149891B (en) | Preparation method of 2-amino-2- (1-methyl-4-piperidinyl) ethanol | |
| CN111620877B (en) | Process for preparing 1-benzyl-5- (tert-butyloxycarbonyl) octahydropyrrolopyrrole-2-carboxylic acid | |
| JP5561967B2 (en) | Glucose compounds, methods for producing them, and methods for producing davidin | |
| CN107383033A (en) | The synthetic method of cis 5 tertbutyloxycarbonyl tetrahydrofuran simultaneously [3,4 c] pyrroles's 3A carboxylate methyl esters | |
| CN110563687B (en) | Preparation method of 4- (aminomethyl) chroman-3-ol | |
| CN111533740A (en) | Process for preparing tert-butyl-1- (hydroxymethyl) -3-oxoidene-2, 8-diazaspiro [4.5] decane formylic ester | |
| CN115785122A (en) | Indole derivative piperidine compound and synthetic method thereof | |
| CN111518015A (en) | Preparation method of tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester | |
| CN116986969A (en) | Synthesis method of fluoroallyl alcohol |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20200814 |
|
| WD01 | Invention patent application deemed withdrawn after publication |