CN103664743A - Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate - Google Patents
Preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a high-stereoselectivity preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate, which is mainly used for solving the problems that compounds reported by conventional documents have long synthesis routes and poor stereoselectivity. The preparation method comprises the following steps: carrying out ylide reaction under an alkaline condition by taking a compound R)-1-(1-tert-butyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dibenzyl dicarboxylate as a starting material to obtain (S)-1-(1-tert-butyloxycarbonyl)-4-methylene -3-piperidyl hydrazine-1,2-dibenzyl dicarboxylate; then, obtaining (3S, 4R)-3- diazanyl-4-methyl piperidine-1-tertiary butyl carboxylate by catalytic hydrogenation under action of a metal hydrogenation catalyst and hydrogen gas; and finally, reducing under action of the metal hydrogenation catalyst and hydrogen gas to obtain the (3S, 4R)-3-amido-4-methyl piperidine-1-tertiary butyl carboxylate. And the total yield is 34.5%.
Description
Technical field
The present invention relates to the new preparation method of compound (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester.
Background technology
The long-term extremely concern of synthetic chemistry man of piperidines of piperidines and replacement, for a long time, organic chemist is devoted to develop effectively synthetic piperidines of new method.Because piperidines is widely used in the synthetic intermediate of other complicated organic heterocyclic molecules and medicine.And some molecules that contain piperidines unit have good biological activity.But, to only having up to now a few effectively synthetic method to synthesize the piperidines that 3-amido-4-replaces.
Document organic chemistry communication (Org. Lett. for example; 2002; 25; 4499-4502), reported the method for a kind of synthesis of trans-(3S)-amido-4-substituted piperidine; the Serine of the method utilization protection is the method tetrahydrobiopterin synthesis piperidines of raw material through RCM pass ring; then by catalytic hydrogenation, the method for deprotection obtains take, and trans-(3S)-amido-4-substituted piperidine is primary product (shown in-1).But the method has route long, different protecting group transformation efficiencys is restriction on an equal basis not.
Formula-1
Document tetrahedron wall bulletin (Tetrahedron Lett.; 2002,43,4289-4293) report is pointed out; utilize organometallic compound to protect on N 3, the nucleophilic addition(Adn) of 4-ethylenimine piperidines obtains trans 3-amido-4-alkyl piperidines (shown in formula-2).
Formula-2
But for raw material N heterocycle propane, to pass through from tetrahydrochysene piperidines process epoxidation, epoxy addition, the steps such as intramolecular nucleophilic substitution Guan Huan obtain, so the method is having very large restriction and regioselectivity not high aspect the source of raw material.
There is very early report aldehyde ketone to react with azodicarboxylate and can directly obtain α-diazanyl aldehyde ketone under the catalysis of proline(Pro), document tetrahedron wall bulletin (Tetrahedron Lett., 2006,47,1117-1119) report pimelinketone and DEAD or DBAD do to obtain α-diazanyl pimelinketone (shown in formula-3) in order to high yield and high ee value.This intermediate is further converted to α-amido aldehyde ketone.
Formula-3
Document organic chemistry communication (Org. Lett., 2011,13,2638-2641) reported that α under the effect of organic chiral catalyzer-dibasic aldehyde reacts with azodicarboxy tert-butyl acrylate, obtain the carbonyl compound (shown in formula-4) that alpha-amino group replaces high enantioselectivity.
Formula-4
Literature Consult based on above and the importance of 3-amido-4-Alkylpiperidine in organic synthesis, in order to overcome in the past, many restrictions of synthetic 3-amido-4-Alkylpiperidine are as long in route and stereoselectivity is poor, and we have invented a kind of method of synthetic 3-amido-4-methyl piperidine of highly-solid selectively.
Summary of the invention
The object of the invention is to be to provide a kind of (3S, 4R)-3-amido-4-methyl piperidine-1-preparation method of carboxylic acid tert-butyl ester.Mainly solve previous literature and report synthetic route length and the poor problem of stereoselectivity of this compounds.
Technical scheme is: the preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, comprises the following steps: with compound (R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester
1for starting raw material, at alkaline condition, issue raw ylide (Witting) reaction and obtain (S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester
2.Then compound
2under metal hydrogenation catalyst and hydrogen effect, obtain (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester
3.Compound
3under metal hydrogenation catalyst effect, it is final product that hydrogen reducing obtains (3S, 4R)-3-amido-4-methyl piperidine base-1-carboxylic acid tert-butyl ester.Principal reaction formula is as follows:
There is Witting reaction in the first step reaction wherein under the existence of alkali, and alkaline matter used is a kind of in potassium tert.-butoxide, potassium hydroxide, sodium methylate or sodium hydrogen etc.Solvent used is one or more in methylene dichloride, trichloromethane or tetrahydrofuran (THF), and the reaction times used is 4～20 hours, wherein take potassium tert.-butoxide as preferred alkaline matter, and tetrahydrofuran (THF) is optimum solvent, and the reaction times was with 10 hours the bests.
Second step reaction is under metal hydrogenation catalyst and hydrogen atmosphere, and reduction obtains (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester.Metal hydrogenation catalyst used is a kind of in palladium hydroxide, palladium carbon, Raney's nickel or Lithium Aluminium Hydride etc., organic solvent used is one or more in alcoholic solvent or esters solvent, temperature of reaction used is 20 ~ 50 degrees Celsius, reaction times used is 24 ~ 75 hours, the preferred reaction time is 24 hours, wherein take palladium carbon as optimum catalyst, take methyl alcohol as optimum solvent, temperature of reaction is best with room temperature (20-30 ℃).
Three-step reaction is under metal hydrogenation catalyst and hydrogen atmosphere, and reduction obtains (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester.Metal hydrogenation catalyst used is palladium hydroxide, palladium carbon, Raney's nickel, a kind of in Lithium Aluminium Hydride, sodium borohydride/Nickel Chloride or red aluminium etc., organic solvent used is one or more in alcoholic solvent or esters solvent, described esters solvent ethyl acetate, described alcoholic solvent particular methanol or ethanol, temperature of reaction used is 20 ~ 50 degrees Celsius, reaction times used is 24 ~ 75 hours, the preferred reaction times is 24 ~ 50 hours, wherein with Raney's nickel, methyl alcohol is made solvent, and the lower reaction of room temperature (20-30 ℃) is optimum reaction condition.
By our trial, select the method for hydro-reduction, openly reported first the synthetic method of the highly-solid selectively of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, to the research of its further character with apply significant.
Beneficial effect of the present invention: the present invention discloses a kind of (3S first, the synthetic method of 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, because this compound has two chiral centres, bibliographical information synthetic route does not all have directly to take single compound, the present invention controls stereoselective object by selective reduction, for subsequent reactions provides the basis of single configuration of compound.Existing document (Tetrahedron Lett, 2002,43,4289-4293) reported the synthetic method of this compounds.Through contrast route, we find, such compou nd synthesis route of bibliographical information is long, and stereoselectivity is poor, and the product finally obtaining is racemization, the compound of position isomerism.And the present invention can obtain single compound well, and there is higher ee value.Solved the problem that its configuration as intermediate is many, for follow-up reaction and application are provided convenience.
Embodiment
Enumerate embodiment so that the present invention is described in detail, but the present invention is not limited to these embodiment.
(S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1, the preparation of 2-dicarboxylic acid dibenzyl ester
embodiment 1: operation steps: in the single port bottle of 100 milliliters, bromination three phenyl methyl Phosphonium (1.3 grams, 3.6 mmoles) are dissolved in the trichloromethane of 20 milliliters, add potassium hydroxide (0.37 gram of 6.63 mmole) under zero degrees celsius.(R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester is dissolved in (1.5 grams, 3.01 mmoles) in the trichloromethane of 15 milliliters, slowly join in reaction flask, room temperature (20-30 ℃) stirs 20 hours, reaction solution is poured cancellation in frozen water into, extraction adds methylene chloride, organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purifying, eluent is sherwood oil: ethyl acetate=5:1, obtains 0.25 gram of white solid product, yield 16%.
embodiment 2: operation steps: in the single port bottle of 100 milliliters, bromination three phenyl methyl Phosphonium (1.3 grams, 3.6 mmoles) are dissolved in the trichloromethane of 20 milliliters of l, add sodium methylate (0.36 gram of 6.63 mmole) under zero degrees celsius.(R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester is dissolved in (1.5 grams, 3.01 mmoles) in the trichloromethane of 15 milliliters, slowly join in reaction flask, room temperature (20-30 ℃) stirs 20 hours, reaction solution is poured cancellation in frozen water into, add ethyl acetate extraction, organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purifying, eluent is sherwood oil: ethyl acetate=5:1, obtains 0.15 gram of white solid product, yield 10.6%.
embodiment 3: operation steps: in the there-necked flask of 100 milliliters, bromination three phenyl methyl Phosphonium (2.6 grams, 7.2 mmoles) are dissolved in the tetrahydrofuran (THF) of 36 milliliters, add sodium hydrogen (0.26 gram of 6.63 mmole) under zero degrees celsius.(R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester is dissolved in and slowly joins in reaction flask in the tetrahydrofuran (THF) of 50 milliliters, room temperature (20-30 ℃) stirs 4 hours, and reaction solution is poured cancellation in frozen water into, adds ethyl acetate extraction, organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purifying, eluent is sherwood oil: ethyl acetate=5:1, obtain 0.5 gram of white solid product, yield 30%.
embodiment 4: operation steps: in the single port bottle of 250 milliliters, bromination three phenyl methyl Phosphonium (2.6 grams, 7.2 mmoles) are dissolved in the tetrahydrofuran (THF) of 36 milliliters, add potassium tert.-butoxide (1.49 grams, 13.3 mmoles) under zero degrees celsius.(R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1, (3 grams of 2-dicarboxylic acid dibenzyl esters, 6.03 mmoles) be dissolved in and slowly join in reaction flask in the tetrahydrofuran (THF) of 50 milliliters, room temperature (20-30 ℃) stirs 10 hours, reaction solution is poured cancellation in frozen water into, add ethyl acetate extraction, organic phase is used saturated common salt water washing, anhydrous sodium sulfate drying, column chromatography purifying, eluent is sherwood oil: ethyl acetate=5:1, obtains 1.5 grams of white solid product, yield 50%.
The preparation of (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester
embodiment 5: operation steps: by (S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1, (0.5 gram of 2-dicarboxylic acid dibenzyl ester, 1.01 mmoles) and (0.3 gram of palladium hydroxide, palladium weight percentage is 10%) add in reaction flask, the ethyl acetate that adds 10 milliliters, in 1 atmospheric hydrogen atmosphere, room temperature (20-30 ℃) stirs after 75 hours and filters, with the thorough washing leaching cake of methyl alcohol, the filtrate of gained obtains 0.90 gram of colorless oil, yield 36% after removing solvent methanol.
embodiment 6: operation steps: by (S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1, (0.5 gram of 2-dicarboxylic acid dibenzyl ester, 1.01 mmoles) and (0.5 gram of Raney's nickel,) add in reaction flask, the ethanol that adds 10 milliliters, in 1 atmospheric hydrogen atmosphere, 50 ℃ are stirred filtration after 24 hours, and with the thorough washing leaching cake of methyl alcohol, the filtrate of gained is except desolventizing.Nuclear-magnetism shows that reaction is very assorted, does not have obvious product.
embodiment 7: operation steps: by (S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1, (0.5 gram of 2-dicarboxylic acid dibenzyl ester, 1.01 mmoles) and (0.3 gram, palladium carbon, (palladium weight percentage is 10%) adds in reaction flask, the methyl alcohol that adds 10 milliliters, in 1 atmospheric hydrogen atmosphere, room temperature (20-30 ℃) stirs after 5 hours and filters, with the thorough washing leaching cake of methyl alcohol, the filtrate of gained obtains 0.17 gram of colorless oil, yield 73% after removing solvent methanol.
The preparation of (3S, 4R)-3-amido-4-methyl piperidine base-1-carboxylic acid tert-butyl ester
embodiment 8: operation steps: by (3S, 4R)-(0.15 gram of 3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester, 0.65 mmole) and (0.1 gram, palladium carbon, palladium weight percentage is 10%) add in reaction flask, the methyl alcohol that adds 10 milliliters, stirs after 50 hours and filters, with the thorough washing leaching cake of methyl alcohol for 50 hours in 1 atmospheric hydrogen atmosphere, the filtrate of gained obtains 0.01 gram of colorless oil, yield 7% after removing solvent methanol.
embodiment 9: operation steps: by (3S, 4R)-(0.15 gram of 3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester, 0.65 mmole) and (0.3 gram of palladium hydroxide, palladium weight percentage is 10%) add in reaction flask, the ethyl acetate that adds 10 milliliters, in 1 atmospheric hydrogen atmosphere, room temperature (20-30 ℃) stirs after 75 hours and filters, with the thorough washing leaching cake of methyl alcohol, the filtrate of gained obtains 0.02 gram of colorless oil, yield 12% after removing solvent ethyl acetate.
embodiment 10: operation steps: by (3S, 4R)-(0.15 gram of 3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester, 0.65 mmole) and sodium borohydride/Nickel Chloride add in reaction flask, the ethanol that adds 10 milliliters, in 1 atmospheric hydrogen atmosphere, 50 ℃ are stirred filtration after 24 hours, with the thorough washing leaching cake of methyl alcohol, the filtrate of gained is except desolventizing.Nuclear-magnetism shows that reaction is very assorted, does not have obvious product.
embodiment 11: operation steps: by (3S, 4R)-(0.15 gram of 3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester, 0.65 mmole) and Raney's nickel (0.3 gram) add in reaction flask, the methyl alcohol that adds again 20 milliliters, in 1 atmospheric hydrogen atmosphere, room temperature (20-30 ℃) stirs after 24 hours and filters, with the thorough washing leaching cake of methyl alcohol, the filtrate of gained obtains 70 milligrams of white solids, yield 50% through revolving after solvent methanol is removed in steaming.
1H?NMR?(400?MHz?CD3OD)?δ?4.09~4.13?(m,?1H),?3.95~3.99?(m,?1H),?2.33~3.01?(m,?3H),?1.60~1.70?(m,?1H),?1.43?(s,?9H),?1.30~1.44?(m,?1H),?1.01~1.19?(m,?1H),?0.91?(d,?
J?=?2.0?Hz?3H)。
Claims (7)
1. the preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, is characterized in that, comprises the following steps:
The first step: with compound (R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester is starting raw material, at alkaline condition, issue raw Ylide reaction and obtain (S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester;
Second step: (S)-1-(1-tertbutyloxycarbonyl)-4-methylene radical-3-piperidyl hydrazine-1,2-dicarboxylic acid dibenzyl ester obtains (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester under the effect of metal hydrogenation catalyst and hydrogen;
The 3rd step: (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester is under the effect of metal hydrogenation catalyst and hydrogen, and reduction obtains (3S, 4R)-3-amido-4-methyl piperidine base-1-carboxylic acid tert-butyl ester.
2. (3S according to claim 1, the preparation method of 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, it is characterized in that, the alkaline matter that the described the first step is reacted used is a kind of in potassium tert.-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, potassium ethylate, sodium methylate or potassium methylate; Solvent used is one or more in methylene dichloride, trichloromethane or tetrahydrofuran (THF), and the reaction times used is 4 ~ 20 hours.
3. the preparation method of (3S, 4R) according to claim 2-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, is characterized in that, alkaline matter used is potassium tert.-butoxide, and solvent used is tetrahydrofuran (THF), and the reaction times used is 10 hours.
4. (3S according to claim 1, the preparation method of 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, it is characterized in that, it is a kind of in palladium hydroxide, palladium carbon, Raney's nickel or Lithium Aluminium Hydride that described second step reacts metal hydrogenation catalyst used, organic solvent used is one or more in alcoholic solvent or esters solvent, temperature of reaction used is 20 ~ 50 degrees Celsius, and the reaction times used is 24 ~ 75 hours.
5. the preparation method of (3S, 4R) according to claim 4-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, is characterized in that, metal hydrogenation catalyst used is palladium carbon, solvent used is methyl alcohol, and the reaction times used is 24 hours, and temperature of reaction is room temperature.
6. (3S according to claim 1, the preparation method of 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, it is characterized in that, described three-step reaction metal hydrogenation catalyst used is a kind of in palladium hydroxide, palladium carbon, Raney's nickel, Lithium Aluminium Hydride, sodium borohydride/Nickel Chloride or red aluminium etc., organic solvent used is one or more in alcoholic solvent or esters solvent, temperature of reaction used is 20 ~ 50 ℃, and the reaction times used is 24 ~ 75 hours.
7. (3S, 4R) according to claim 6-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, is characterized in that, metal hydrogenation catalyst used is Raney's nickel; Organic solvent used is methyl alcohol, and temperature of reaction is room temperature, and the reaction times used is 24 ~ 50 hours.
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| WO2018013867A1 (en) | 2016-07-13 | 2018-01-18 | Marineau Jason J | Inhibitors of cyclin dependnt kinase 7 (cdk7) |
| CN114853662A (en) * | 2021-02-05 | 2022-08-05 | 四川青木制药有限公司 | Preparation method of chiral hydrazinylpiperidine derivative |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018013867A1 (en) | 2016-07-13 | 2018-01-18 | Marineau Jason J | Inhibitors of cyclin dependnt kinase 7 (cdk7) |
| EP4295852A2 (en) | 2016-07-13 | 2023-12-27 | Syros Pharmaceuticals, Inc. | Piperidine derivatives as inhibitors of cyclin dependent kinase 7 (cdk7) |
| CN114853662A (en) * | 2021-02-05 | 2022-08-05 | 四川青木制药有限公司 | Preparation method of chiral hydrazinylpiperidine derivative |
| CN114853662B (en) * | 2021-02-05 | 2024-01-12 | 四川青木制药有限公司 | Process for preparing chiral hydrazinopiperidine derivatives |
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Effective date of registration: 20141216 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant after: Wuhan AppTec New Drug Development Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Wuhan AppTec New Drug Development Co., Ltd. Applicant before: Shanghai SynTheAll Pharmaceutical Co., Ltd. |
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Effective date of registration: 20160727 Address after: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant after: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Address before: 200131 Shanghai City, Pudong New Area Waigaoqiao Free Trade Zone Foote Road No. 288 Applicant before: Shanghai Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Tianjin Yaoming Kangde New Medicine Development Co., Ltd. Applicant before: Wuhan AppTec New Drug Development Co., Ltd. |
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