CN105017244A - Cis/trans-tert-butyl-4-O-hexahydro-1H-pyrrole[3,4-c]pyridine-2(3H)-tert-butyl carboxylate synthesis method - Google Patents
Cis/trans-tert-butyl-4-O-hexahydro-1H-pyrrole[3,4-c]pyridine-2(3H)-tert-butyl carboxylate synthesis method Download PDFInfo
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- CN105017244A CN105017244A CN201410151952.3A CN201410151952A CN105017244A CN 105017244 A CN105017244 A CN 105017244A CN 201410151952 A CN201410151952 A CN 201410151952A CN 105017244 A CN105017244 A CN 105017244A
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- butyl
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- 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
- C07D471/04—Ortho-condensed systems
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- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
The present invention relates to a cis-trans-tert-butyl-4-O-hexahydro-1H-pyrrole[3,4-c]pyridine-2(3H)-tert-butyl carboxylate synthesis method. A purpose of the present invention is mainly to solve the technical problem of lack of the industrial compound synthesis method in the prior art. The synthesis method comprises that trans-1-tert-butyl-3-ethyl-4-(cyanomethyl)pyrrolidine-1,3-carboxylate is adopted as a raw material and Raney nickel is respectively adopted as a catalyst to achieve one-step ring closure to obtain trans-tert-butyl-4-O-hexahydro-1H-pyrrole[3,4-c]pyridine-2(3H)-tert-butyl carboxylate, or Pd/C is adopted as a catalyst to reduce cyano and then sodium ethoxide is adopted as an alkali to carry out a ring closure reaction so as to synthesize the cis-tert-butyl-4-O-hexahydro-1H-pyrrole[3,4-c]pyridine-2(3H)-tert-butyl carboxylate.
Description
Technical field
The present invention relates to the tertiary butyl-4 along anti-two kinds of structures
-the practicality synthetic method of oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester.
Background technology
For the tertiary butyl-4
-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester (CAS, cis: 1273568-51-6 is trans: 1251012-56-2) is a kind of useful organic synthesis intermediate, is often reduced, by acid amides to secondary amine, market sale is better.The present invention uses same starting raw material by different synthetic methods, develop a kind of synthesizing cis and the trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] novel method of pyridine-2 (3H)-carboxylic acid tert-butyl ester, avoid and just adopt different this shortcoming of configuration raw material from synthesis, shorten synthetic route, reduce cost, the starting raw material of synthesis can be obtained by simple synthesis.
Summary of the invention
Object of the present invention: use the identical raw material anti-form-1-tertiary butyl-3-ethyl-4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters is by diverse ways synthesizing cis and the trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester.Mainly solve the technical problem that this compound lacks Industrialized synthesis method at present.
Technical scheme of the present invention: the present invention is with the anti-form-1-tertiary butyl-3-ethyl-4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters is raw material, the different compound trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl esters and the cis tertiary butyl-4 is finally obtained respectively by two kinds of different approach
-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester.
The concrete route of the present invention is as follows:
In above-mentioned technique, the synthesis of trans tertiary butyl-4
-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-one
,with the anti-form-1-tertiary butyl-3-ethyl-4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters for raw material, with methyl alcohol or ethanol as solvent, with Raney's nickel as catalyzer, realize a step and close ring, temperature of reaction is 20-60 DEG C.
The synthesizing cis tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester, the first step, with the anti-form-1-tertiary butyl-3-ethyl-4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters is raw material, with methyl alcohol or ethanol as solvent, temperature of reaction is 20-60 DEG C, by cyano reduction; Second step, solvent is ethanol or methyl alcohol, and temperature of reaction is by room temperature to backflow, and back flow reaction obtains the cis tertiary butyl-4 in 5 hours
-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester.
Beneficial effect of the present invention: present invention process is reasonable in design, by different approach, has synthesized the compound along anti-two kinds of different structures.
Embodiment
embodiment 1
The synthesis of the trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester
1 gram of Raney's nickel (Raney Ni) is joined in the hydrogenation bottle of 250 mL, adds a small amount of ethanol wet; By 10 grams of (3S, 4S)-1-tertiary butyl 3-ethyl 4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters and 10 mL ammoniacal liquor dissolve in 100 mL ethanol, join in hydrogenation bottle, with hydrogen exchange repeatedly after, reaction is in 50 psi hydrogen-pressure, reaction 5 hours at 50 DEG C in bottle.TLC(petrol ether/ethyl acetate=1/1 volume ratio, Rf=0.5) detect raw material reaction completely, system is cooled to room temperature, and cross and filter Raney Ni, filtrate is spin-dried for and obtains 3.6 grams of trans tertiary butyls-4 by column chromatography
-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-one: (3.6 grams, productive rate: 42.3%).
1H-NMR (MeOD): δ3.727-3.659 (m, 2H), 3.470-3.359 (m, 2H), 3.262-3.191 (m, 1H), 3.033-2.948 (m, 1H), 2.584-2.536 (m, 1H), 2.199-2.100 (m, 2H), 1.729-1.511 (m, 1H), 1.410-1.406 (d,
J= 1.6 Hz, 9H)。
embodiment 2
The synthesis of the anti-form-1-tertiary butyl-3-ethyl-4-(2-amine ethyl) pyrroles-1,3-carboxylicesters
1 gram of Pd/C is joined in the hydrogenation bottle of 250 mL, adds a small amount of ethanol wet; By 10 grams of (3S, 4S)-1-tertiary butyl 3-ethyl 4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters dissolves in 100 mL ethanol, joins in hydrogenation bottle, with hydrogen exchange repeatedly after, reaction is in 50 psi hydrogen-pressure, reaction 5 hours at 50 DEG C in bottle.TLC(petrol ether/ethyl acetate=11, Rf=0.5) raw material reaction is detected complete, system is cooled to room temperature, cross and filter Pd/C, filtrate is spin-dried for and obtains 7.3 grams of (3S by column chromatography, the 4S)-1-tertiary butyl-3-ethyl-4-(2-amine ethyl) pyrroles-1,3-carboxylicesters: (7.3 grams, productive rate: 72%).
embodiment 3
The synthesis of the cis tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester
7.3 grams of (3S, 4S)-1-tertiary butyl-3-ethyl-4-(2-amine ethyl) pyrroles-1,3-carboxylicesterss are added in 100 mL ethanol, at room temperature, add sodium ethylate 3.7 grams in batches, reflux 5 hours.TLC(petrol ether/ethyl acetate=1/1, Rf=0.3) detect raw material reaction completely, system is cooled to room temperature.Be spin-dried for by solvent, add diluted ethyl acetate, removed by filtration solid, filtrate is spin-dried for, and obtains 2.3 grams of cis tertiary butyls-4 by column chromatography
-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-one: (2.3 grams, productive rate: 37.5%).
1H-NMR (CDCl
3): δ6.582-6.538 (d, 1H), 3.796-3.746 (t, 1H), 3.568-3.477 (m, 2H), 3.999-3.291 (m, 3H), 3.017-2.949 (m, 1H), 2.595-2.514 (m, 1H), 1.880-1.848 (m, 1H), 1.747-1.649 (m, 1H), 1.439 (s, 9H)。
Claims (5)
1. a trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] synthetic method of pyridine-2 (3H)-carboxylic acid tert-butyl ester, it is characterized in that, with the anti-form-1-tertiary butyl-3-ethyl-4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters for raw material, with methyl alcohol or ethanol as solvent, with Raney's nickel as catalyzer, realize a step and close ring, obtain the trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester.
2. a cis tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] synthetic method of pyridine-2 (3H)-carboxylic acid tert-butyl ester, it is characterized in that, the first step, with the anti-form-1-tertiary butyl-3-ethyl-4-(cyanogen methyl) tetramethyleneimine-1,3-carboxylicesters is raw material, with methyl alcohol or ethanol as solvent, by cyano reduction; Second step, solvent is ethanol or methyl alcohol, obtains the cis tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester.
3. the synthetic method of the trans tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester according to claim 1, is characterized in that: temperature of reaction is 20-60 DEG C.
4. the cis tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3 according to claim 2,4-c] synthetic method of pyridine-2 (3H)-carboxylic acid tert-butyl ester, it is characterized in that, the first step temperature of reaction is 20-60 DEG C, and second step temperature of reaction is by room temperature extremely backflow.
5. the synthetic method of the cis tertiary butyl-4-oxygen hexahydro--1H-pyrroles [3,4-c] pyridine-2 (3H)-carboxylic acid tert-butyl ester according to claim 4, is characterized in that, back flow reaction 5 hours.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831774A (en) * | 2017-02-07 | 2017-06-13 | 上海合全药业股份有限公司 | It is a kind of（6S,7S）9 tertbutyloxycarbonyls 7（Trifluoromethyl）2,9 diaza spiros [5.5] undecanoic synthetic method |
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2014
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Patent Citations (5)
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| WO1998011090A2 (en) * | 1996-09-16 | 1998-03-19 | Warner-Lambert Company | 3-alkyl-3-phenyl-piperidines |
| CN1564806A (en) * | 2001-08-29 | 2005-01-12 | 妇女第一健康关怀公司 | Processes for the production of alpha-difluoromethyl ornithine (DFMO) |
| CN101903386A (en) * | 2007-12-21 | 2010-12-01 | 株式会社Lg生命科学 | Dipeptidyl peptidase-IV inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as active agent |
| WO2010071575A1 (en) * | 2008-12-16 | 2010-06-24 | Astrazeneca Ab | Quaternary piperidine derivatives and uses thereof |
| WO2013185082A2 (en) * | 2012-06-08 | 2013-12-12 | Biogen Idec Ma Inc. | Inhibitors of bruton's tyrosine kinase |
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| AHMED E. AHMED等: "Conformationally Restricted Analogs of Histamine Hi Receptor Antagonists: trans- and cis-1 -Benzyl-3-dimeth ylamino-6-ph enylpiperidine", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831774A (en) * | 2017-02-07 | 2017-06-13 | 上海合全药业股份有限公司 | It is a kind of（6S,7S）9 tertbutyloxycarbonyls 7（Trifluoromethyl）2,9 diaza spiros [5.5] undecanoic synthetic method |
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