CN103664743B - The preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester - Google Patents
The preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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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 the preparation method of the highly-solid selectively of one (3S, 4R) 3 amido 4 methyl piperidine 1 carboxylic acid tert-butyl ester.Mainly solve previous literature and report synthetic route length and the problem of stereo selectivity difference of this compounds.The present invention is with compound R) 1 (1 tertbutyloxycarbonyl) 4 oxo 3 piperidyl hydrazine 1,2 dicarboxylic acids dibenzyl esters are initiation material, Ylide reaction is occurred to obtain (S) 1 (1 tertbutyloxycarbonyl) 4 methylene 3 piperidyl hydrazine 1,2 dicarboxylic acids dibenzyl ester in the basic conditions.Under metal hydrogenation catalyst and hydrogen effect, catalytic hydrogenation obtains (3S afterwards, 4R) 3 diazanyl 4 methyl piperidine base 1 carboxylic acid tert-butyl ester, last under the effect of metal hydrogenation catalyst and hydrogen, reduction obtains (3S, 4R) 3 amido 4 methyl piperidine base 1 carboxylic acid tert-butyl ester.Total recovery is 34.5%.
Description
Technical field
The present invention relates to the preparation method that compound (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester is new.
Background technology
Piperidines and substituted piperidines the most extremely synthesize the concern of chemist, for a long time, organic chemist
It is devoted to develop new method and effectively synthesizes piperidines.Because it is complicated that piperidines is widely used in other
Organic heterocyclic molecule and the synthetic intermediate of medicine.And some molecules containing piperidines unit have the most biological living
Property.But, to only having a few effectively synthetic method synthesis 3-substituted piperidines of amido-4-up to now.
Document organic chemistry communication (Org. Lett., 2002,25,4499-4502) such as reports a kind of synthesis
The method of trans-(3S)-amido-4-substituted piperidine, the method utilizes the serine of protection for raw material through the method for RCM cyclization
Tetrahydrobiopterin synthesis piperidines, then by catalytic hydrogenation, the method for deprotection obtains based on trans-(3S)-amido-4-substituted piperidine
Want product (as shown in formula-1).But the method has route long, different protection group conversion ratios limits on an equal basis.
Formula-1
Document tetrahedron bulletin (Tetrahedron Lett., 2002,43,4289-4293) report is pointed out, utilization has
Machine metallic compound obtains trans 3-amido-4-alkyl to the 3,4-aziridine of protection on N the nucleophilic addition of piperidines
Piperidines (shown in formula-2).
Formula-2
But to pass through from tetrahydrochysene piperidines through epoxidation, epoxy addition, intramolecular nucleophilic for raw material N heterocycle propane
Replace the step such as cyclization to obtain, in terms of the source of raw material, have the biggest restriction and regioselectivity not in this way
High.
Have been reported that aldehyde ketone reacts with azodicarboxylate under the catalysis of proline very early and can directly obtain α-diazanyl aldehyde
Ketone, document tetrahedron bulletin (Tetrahedron Lett., 2006,47,1117-1119) report Ketohexamethylene and DEAD or
DBAD effect is worth to α-diazanyl Ketohexamethylene (shown in formula-3) with high yield and high ee.This intermediate is further converted to α-amine
Base aldehyde ketone.
Formula-3
Document organic chemistry communication (Org. Lett., 2011,13,2638-2641) reports at organic chiral catalyst
Effect under α-dibasic aldehyde react with azodicarboxy tert-butyl acrylate, obtain the substituted carbonyl of alpha-amido high enantioselectivity
Compound (shown in formula-4).
Formula-4
The importance in organic synthesis based on above Literature Consult and 3-amido-4-Alkylpiperidine, in order to overcome
Many restrictions such as route length and the stereo selectivity of synthesis 3-amido-4-Alkylpiperidine were poor in the past, we have invented a kind of Gao Li
Body optionally synthesizes the method for 3-amido-4-methyl piperidine.
Summary of the invention
It is an object of the invention to the system being to provide a kind of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester
Preparation Method.Mainly solve previous literature and report synthetic route length and the problem of stereo selectivity difference of this compounds.
Technical scheme is: the preparation method of (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, including following
Step: with compound (R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester 1 for initial former
Material, occurs ylide (Witting) reaction to obtain (S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperazine in the basic conditions
Piperidinyl hydrazine-1,2-dicarboxylic acids dibenzyl ester 2.Then compound 2 obtain under metal hydrogenation catalyst and hydrogen effect (3S, 4R)-
3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester 3.Compound 3 is under metal hydrogenation catalyst effect, and hydrogen reducing obtains
(3S, 4R)-3-amido-4-methyl piperidine base-1-carboxylic acid tert-butyl ester is end product.Dominant response formula is as follows:
Wherein there is Witting reaction in first step reaction in the presence of base, and alkaline matter used is potassium tert-butoxide, hydrogen
One in potassium oxide, Feldalat NM or sodium hydrogen etc..Solvent used be a kind of in dichloromethane, chloroform or oxolane or
Several, the response time used is 4～20 hours, is wherein preferred alkaline matter with potassium tert-butoxide, and oxolane is optimum solvent,
Response time is optimal with 10 hours.
Second step reacts under metal hydrogenation catalyst and hydrogen atmosphere, and reduction obtains (3S, 4R)-3-diazanyl-4-methyl
Piperidyl-1-carboxylic acid tert-butyl ester.Metal hydrogenation catalyst used is in palladium dydroxide, palladium carbon, Raney's nickel or Lithium Aluminium Hydride etc.
One, organic solvent used is one or more in alcohols solvent or esters solvent, and reaction temperature used is 20 ~ 50 to take the photograph
Family name's degree, the response time used is 24 ~ 75 hours, and the preferably response time is 24 hours, wherein with palladium carbon as optimum catalyst, with
Methanol is optimum solvent, and reaction temperature is best with room temperature (20-30 DEG C).
Three-step reaction is under metal hydrogenation catalyst and hydrogen atmosphere, and reduction obtains (3S, 4R)-3-amido-4-methyl
Piperidines-1-carboxylic acid tert-butyl ester.Metal hydrogenation catalyst used is palladium dydroxide, palladium carbon, Raney's nickel, Lithium Aluminium Hydride, sodium borohydride/
One in Nickel Chloride or red aluminum etc., organic solvent used is one or more in alcohols solvent or esters solvent, institute
Stating esters solvent ethyl acetate, the preferred methanol of described alcohols solvent or ethanol, reaction temperature used is 20 ~ 50 Celsius
Degree, the response time used is 24 ~ 75 hours, and the preferred response time is 24 ~ 50 hours, and wherein with Raney's nickel, methanol is made molten
Agent, under room temperature (20-30 DEG C), reaction is optimum reaction condition.
By our trial, the method selecting hydro-reduction, first public report (3S, 4R)-3-amido-4-first
The synthetic method of the highly-solid selectively of phenylpiperidines-1-carboxylic acid tert-butyl ester, has weight to its further property Quality Research and application
Want meaning.
Beneficial effects of the present invention: present invention firstly discloses one (3S, 4R)-3-amido-4-methyl piperidine-1-carboxylic
The synthetic method of tert-butyl acrylate, owing to this compound has two chiral centres, document report synthetic route all not to have directly to take
To single compound, the present invention controls stereoselective purpose by selective reduction, provides single for subsequent reactions
The basis of configuration of compound.Existing document (Tetrahedron Lett, 2002,43,4289-4293) reports such and changes
The synthetic method of compound.Through contrast route, it has been found that such compou nd synthesis route of document report is long, three-dimensional selection
Property is poor, and the product finally given is racemization, the compound of position isomery.And the present invention can obtain single change well
Compound, and there is higher ee value.Solve its as the many problem of the configuration of intermediate, provide for follow-up reaction and application
Facility.
Detailed description of the invention
Enumerate embodiment so that the present invention to be described in detail, but the present invention is not limited to these embodiments.
(S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperidyl hydrazine-1, the preparation of 2-dicarboxylic acids dibenzyl ester
Embodiment 1: operating procedure: in the single port bottle of 100 milliliters, and triphenylmethylphospbromide bromide (1.3 grams, 3.6 mmoles
You) it is dissolved in the chloroform of 20 milliliters, add potassium hydroxide (0.37 gram 6.63 mMs) under zero degrees celsius.(R)-1-
(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester is dissolved in (1.5 grams, 3.01 mMs) 15 milli
Being slowly added in reaction bulb in the chloroform risen, room temperature (20-30 DEG C) stirs 20 hours, and reactant liquor is poured in frozen water and quenched
Going out, add methylene chloride extraction, and organic facies uses saturated aqueous common salt washing, and anhydrous sodium sulfate is dried, column chromatography purification, and eluant is
Petroleum ether: ethyl acetate=5:1, obtains 0.25 gram of white solid product, yield 16%.
Embodiment 2: operating procedure: in the single port bottle of 100 milliliters, and triphenylmethylphospbromide bromide (1.3 grams, 3.6 mmoles
You) it is dissolved in the chloroform of 20 milliliters of l, add Feldalat NM (0.36 gram 6.63 mMs) under zero degrees celsius.(R)-1-(1-
Tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester is dissolved in (1.5 grams, 3.01 mMs) 15 milliliters
Chloroform in be slowly added in reaction bulb, room temperature (20-30 DEG C) stir 20 hours, reactant liquor pours cancellation in frozen water into,
Adding ethyl acetate extraction, organic facies uses saturated aqueous common salt washing, and anhydrous sodium sulfate is dried, column chromatography purification, and eluant is stone
Oil ether: ethyl acetate=5:1, obtains 0.15 gram of white solid product, yield 10.6%.
Embodiment 3: operating procedure: in the there-necked flask of 100 milliliters, and triphenylmethylphospbromide bromide (2.6 grams, 7.2 mmoles
You) it is dissolved in the oxolane of 36 milliliters, add sodium hydrogen (0.26 gram 6.63 mMs) under zero degrees celsius.(R)-1-(the tertiary fourth of 1-
Oxygen carbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester be dissolved in the oxolane of 50 milliliters be slowly added into anti-
Answering in bottle, room temperature (20-30 DEG C) stirs 4 hours, and reactant liquor pours cancellation in frozen water into, adds ethyl acetate extraction, and organic facies uses
Saturated aqueous common salt washs, and anhydrous sodium sulfate is dried, column chromatography purification, and eluant is petroleum ether: ethyl acetate=5:1, obtains 0.5
Gram white solid product, yield 30%.
Embodiment 4: operating procedure: in the single port bottle of 250 milliliters, and triphenylmethylphospbromide bromide (2.6 grams, 7.2 mmoles
You) it is dissolved in the oxolane of 36 milliliters, add potassium tert-butoxide (1.49 grams, 13.3 mMs) under zero degrees celsius.(R)-1-
(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester (3 grams, 6.03 mMs) is dissolved in 50 milliliters
Oxolane in be slowly added in reaction bulb, room temperature (20-30 DEG C) stir 10 hours, reactant liquor pours cancellation in frozen water into,
Adding ethyl acetate extraction, organic facies uses saturated aqueous common salt washing, and anhydrous sodium sulfate is dried, column chromatography purification, and eluant is stone
Oil ether: 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: operating procedure: by (S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperidyl hydrazine-1,2-dicarboxyl
Acid dibenzyl ester (0.5 gram, 1.01 mMs) and palladium dydroxide (0.3 gram, palladium weight percentage is 10%) add in reaction bulb,
Add the ethyl acetate of 10 milliliters, filter after room temperature (20-30 DEG C) stirs 75 hours in the hydrogen atmosphere of 1 atmospheric pressure, use
Methanol thoroughly washs filter cake, and the filtrate of gained obtains colorless oil 0.90 gram, yield 36% after removing solvent methanol.
Embodiment 6: operating procedure: by (S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperidyl hydrazine-1,2-dicarboxyl
Acid dibenzyl ester (0.5 gram, 1.01 mMs) and Raney's nickel (0.5 gram) add in reaction bulb, add the ethanol of 10 milliliters, at 1
In the hydrogen atmosphere of atmospheric pressure, 50 DEG C of stirrings were filtered after 24 hours, thoroughly washed filter cake with methanol, and the filtrate of gained removes molten
Agent.Nuclear-magnetism display reaction is the most miscellaneous, does not has obvious product.
Embodiment 7: operating procedure: by (S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperidyl hydrazine-1,2-dicarboxyl
(0.3 gram, (palladium weight percentage is 10%) adds in reaction bulb, adds for acid dibenzyl ester (0.5 gram, 1.01 mMs) and palladium carbon
The methanol of 10 milliliters, filters after room temperature (20-30 DEG C) stirs 5 hours in the hydrogen atmosphere of 1 atmospheric pressure, thoroughly washes with methanol
Washing filter cake, the filtrate of gained obtains colorless oil 0.17 gram, 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: operating procedure: by (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester (0.15 gram,
0.65 mM) and palladium carbon (0.1 gram, palladium weight percentage is 10%) add in reaction bulb, add the methanol of 10 milliliters, 1
In the hydrogen atmosphere of individual atmospheric pressure, stirring in 50 hours was filtered after 50 hours, thoroughly washed filter cake with methanol, and the filtrate of gained removes
Colorless oil 0.01 gram, yield 7% is obtained after solvent methanol.
Embodiment 9: operating procedure: by (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester (0.15 gram,
0.65 mM) and palladium dydroxide (0.3 gram, palladium weight percentage is 10%) add in reaction bulb, add the acetic acid of 10 milliliters
Ethyl ester, filters after room temperature (20-30 DEG C) stirs 75 hours in the hydrogen atmosphere of 1 atmospheric pressure, thoroughly washs filter cake with methanol,
The filtrate of gained obtains colorless oil 0.02 gram, yield 12% after removing solvent ethyl acetate.
Embodiment 10: operating procedure: by (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester (0.15 gram,
0.65 mM) and sodium borohydride/Nickel Chloride adds in reaction bulb, adds the ethanol of 10 milliliters, at the hydrogen of 1 atmospheric pressure
In atmosphere, 50 DEG C of stirrings were filtered after 24 hours, thoroughly washed filter cake with methanol, and the filtrate of gained removes solvent.Nuclear-magnetism shows instead
Should be the most miscellaneous, there is not obvious product.
Embodiment 11: operating procedure: by (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester (0.15 gram,
0.65 mM) and Raney's nickel (0.3 gram) add in reaction bulb, add the methanol of 20 milliliters, at the hydrogen gas of 1 atmospheric pressure
Filtering after room temperature (20-30 DEG C) stirs 24 hours in atmosphere, thoroughly wash filter cake with methanol, the filtrate of gained is evaporated off solvent through rotation
White solid 70 milligrams, yield 50% is obtained after methanol.
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, including following step
Rapid:
The first step: be with compound (R)-1-(1-tertbutyloxycarbonyl)-4-oxo-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester
Initiation material, occurs Ylide reaction to obtain (S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperidines in the basic conditions
Base hydrazine-1,2-dicarboxylic acids dibenzyl ester；
Second step: (S)-1-(1-tertbutyloxycarbonyl)-4-methylene-3-piperidyl hydrazine-1,2-dicarboxylic acids dibenzyl ester is at metallic hydrogen
Change and obtain (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester under the effect of catalyst and hydrogen；
3rd step: (3S, 4R)-3-diazanyl-4-methyl piperidine base-1-carboxylic acid tert-butyl ester is at metal hydrogenation catalyst and the work of hydrogen
Under with, reduction obtains (3S, 4R)-3-amido-4-methyl piperidine base-1-carboxylic acid tert-butyl ester.
The preparation method of (3S, 4R) the most according to claim 1-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, its
Feature is, the alkaline matter used by the reaction of the described first step is potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium acetate, ethanol
One in potassium, Feldalat NM or Feldalat KM；Solvent used is a kind of or several in dichloromethane, chloroform or oxolane
Kind, the response time used is 4 ~ 20 hours.
The preparation method of (3S, 4R) the most according to claim 2-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, its
Feature is, alkaline matter used is potassium tert-butoxide, and solvent used is oxolane, and the response time used is 10 hours.
The preparation method of (3S, 4R) the most according to claim 1-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, its
Feature is, described second step reaction metal hydrogenation catalyst used is in palladium dydroxide, palladium carbon, Raney's nickel or Lithium Aluminium Hydride
Kind, organic solvent used is one or more in alcohols solvent or esters solvent, and reaction temperature used is 20 ~ 50 DEG C,
Response time used is 24 ~ 75 hours.
The preparation method of (3S, 4R) the most according to claim 4-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, its
Feature is, metal hydrogenation catalyst used is palladium carbon, and solvent used is methanol, and the response time used is 24 hours, instead
Answering temperature is room temperature.
The preparation method of (3S, 4R) the most according to claim 1-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, its
Feature is, metal hydrogenation catalyst used by described three-step reaction is palladium dydroxide, palladium carbon, Raney's nickel, Lithium Aluminium Hydride, hydroboration
One in sodium/Nickel Chloride or red aluminum, organic solvent used is one or more in alcohols solvent or esters solvent, institute
Being 20 ~ 50 DEG C by reaction temperature, the response time used is 24 ~ 75 hours.
The preparation method of (3S, 4R) the most according to claim 6-3-amido-4-methyl piperidine-1-carboxylic acid tert-butyl ester, its
Feature is, metal hydrogenation catalyst used is Raney's nickel；Organic solvent used is methanol, and reaction temperature is room temperature, used instead
It is 24 ~ 50 hours between Ying Shi.
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| Title |
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| Direct Asymmetric α-Amination of Cyclic Ketones Catalyzed by Siloxyproline;Yujiro Hayashi，等;《Chem. Asian J》;20071228;第3卷;第225-232页 * |
| Highly Efficient and Practical Pyrrolidine–Camphor-Derived Organocatalysts for the Direct α-Amination of Aldehydes;Pang-Min Liu，等;《Eur. J. Org. Chem.》;20100824;第29卷;第5705–5713页 * |
| Potent, selective MCH-1 receptor antagonists;Shawn D. Erickson，等;《Bioorganic & Medicinal Chemistry Letters》;20080108;第18卷;第1402–1406页 * |
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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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