CN103864674B - (R) preparation method of-3-amino piperidine dihydrochloride - Google Patents

(R) preparation method of-3-amino piperidine dihydrochloride Download PDF

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CN103864674B
CN103864674B CN201410097492.0A CN201410097492A CN103864674B CN 103864674 B CN103864674 B CN 103864674B CN 201410097492 A CN201410097492 A CN 201410097492A CN 103864674 B CN103864674 B CN 103864674B
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adds
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CN103864674A (en
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李朝艳
宋伟
徐雪丽
闫卫红
曹英寒
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Nanyang Institute of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

The invention discloses the preparation method of one (R)-3-amino piperidine dihydrochloride; D-Glu is starting raw material; through 1. hydroxy esterification and amido Boc protect, 2. ester group reduces, 3. hydroxy activated, 4. cyclisation, 5. amido take off Boc protection; five step reactions, obtain (R)-3-amino piperidine dihydrochloride.Preparation method's synthetic route of the present invention is short, and cost is low, can realize suitability for industrialized production.

Description

(R) preparation method of-3-amino piperidine dihydrochloride
Technical field
The invention belongs to field of medicaments, in particular to the preparation method of medicine intermediate (R)-3-amino piperidine dihydrochloride.
Background technology
(R)-3-amino piperidine dihydrochloride is mainly used in the synthesis of dipeptidyl peptidase-IV (DPP-IV) inhibitor, is a kind of novel high added value medicine intermediate, expensive.
(R)-3-amino piperidine dihydrochloride prior synthesizing method, is generally through the racemic 3-amino piperidine of synthesis and hydrochloride splits, or directly synthesizes (R)-3-amino piperidine and hydrochloride thereof by chiral raw material.By the retrieval of domestic and foreign literature, its synthetic method is mainly as follows:
Route one: with 3-amino piperidine for starting raw material, obtains (R)-3-amino piperidine dihydrochloride through hydrogenating reduction, fractionation and salify.
Route two: be that raw material is protected by hydro-reduction, amido Boc, Homfnan degrades, split and de-amido Boc protects salify five step to be obtained by reacting (R)-3-amino piperidine dihydrochloride with niacinamide.
Route three: racemic N-benzyl one 3-piperidyl urea obtains (R)-N-benzyl one 3-piperidyl urea by fractionation, obtains (R)-3-amino piperidine dihydrochloride through hofmann rearrangement, hydrogenolysis disconnection salinization.
Route four: take ethyl nipecotate as starting raw material, obtains (R)-3-amino piperidine dihydrochloride by amido protection, ammonia solution, Homfnan degraded, fractionation, Deprotection salify.
Route five: this route is with D mono-ornithine hydrochloride for starting raw material, and acidylate, cyclisation, reduction, salify obtain (R)-3-amino piperidine dihydrochloride.
Route six: take D-Glu as starting raw material, protects through carboxyl acetify, amido Cbz, ester group reduction, hydroxy activated, cyclisation, amido takes off Cbz protection, amido Boc protects, hydrogenolysis takes off benzyl, amido takes off obtained (the R)-3-amino piperidine dihydrochlorides of 9 steps reaction such as Boc protection.
But, there is following problem in the existing technology of preparing of (R)-3-amino piperidine dihydrochloride: 1. need in building-up process to use method for splitting, affect productive rate.2. expensive raw material price.3. reaction conditions carries out under needing low temperature, improves the requirement to production unit, increases production cost.Therefore how to provide a kind of synthetic route short, cost is low, and can realize the preparation method of (R)-3-amino piperidine dihydrochloride of suitability for industrialized production, be technical problem urgently to be resolved hurrily to one skilled in the art.
Summary of the invention
The object of this invention is to provide a kind of synthetic route short, cost is low, can realize the preparation method of (R)-3-amino piperidine dihydrochloride of suitability for industrialized production, in order to realize object of the present invention, intends adopting following technical scheme:
One aspect of the present invention relates to the preparation method of one (R)-3-amino piperidine dihydrochloride, it is characterized in that comprising following reactions steps:
The synthesis of 1. N-tertbutyloxycarbonyl-D-Glu dimethyl ester (APD1):
2. the synthesis of (R)-2-tertbutyloxycarbonyl-1,5-PD (APD2)
3. the synthesis of (R)-2-tertbutyloxycarbonyl-1,5 penta bis-mesylate (APD3)
4. the synthesis of (R)-3-t-butoxycarbonylamino piperidines (APD4)
5. the synthesis of (R)-3-amino piperidine dihydrochloride (APD5)
In a preferred embodiment of the present invention, step is 1.: 20 weight part D-Glus are dissolved in the MeOH of 80-100 weight part under stirring, carry out ice bath, add 32 weight part SOCl2 and keep temperature lower than 30 DEG C, after adding, be warming up to 30 ± 5 DEG C, stir 6 ± 0.5h, sample and tested by high performance liquid chromatography, treat that monomer conversion is more than 95% stopped reaction, decompression desolventizing, adds 50 weight part H 2o and 40-50 weight part Dioxane(dioxan), be placed in ice bath and cool, add 25-30 weight part TEA(trolamine) and 30-35 weight part (Boc) 2o(tert-Butyl dicarbonate), add complete, remove ice bath and be heated to 30 ± 5 DEG C, stir 5 ~ 6h, detect intermediate reaction by LC-MS complete, stopped reaction, removes organic solvent, uses EA(ethyl acetate) extraction, by salt water washing, Na 2sO 4(sodium sulfate) is dry, obtains oily matter.
In a preferred embodiment of the present invention, step is 2.: 30 weight part APD1 are dissolved in 160-180 weight part EtOH(ethanol), 30min is cooled in ice-water bath, substep adds 10-15 weight part sodium borohydride, when precipitation appears in reaction, remove refrigerating unit, reactant reflux 2 hours, complete by LC-MS detection reaction, be cooled to 25 DEG C, pour 180-220 weight part saline into dissolving, filter, filtrate is concentrated into 90-110 weight part, use MTBE(methyl tertiary butyl ether) extraction, undissolved solids stirs extraction 2h in MTBE, extract is dry by MgSO4, filter, concentrate and obtain colorless oil, leave standstill crystallization.
In a preferred embodiment of the present invention, step 3.: 13-15 weight part APD2 is dissolved in 90-110 weight part DCM(methylene dichloride), add 18-20 weight part TEA and stir 30min in 0 DEG C of ice bath.Drip MsCl(methane sulfonyl chloride), in 0 DEG C of ice bath, stir 30min after dropwising, be then heated to 30 ± 5 DEG C, continue to stir 30-60min, detected by LC-MS, after reacting completely, use water, saturated NaHCO successively 3(sodium bicarbonate) solution, normal saline washing, dry concentrating obtains yellow oil.
In a preferred embodiment of the present invention, step 4.: 8-12 weight part APD3 stir under be dissolved in 80-100 weight part CAN(acetonitrile) in, add 90-95 weight part 25%NH 3h 2o, is incubated 30 ± 5 DEG C, continues stirring 2 days, is disappeared by LC-MS detecting reactant, and mixture concentrates, with EA extraction, and salt water washing, Na 2sO 4drying, concentrates and obtains white solid.
In a preferred embodiment of the present invention, step 5.: 30-34 weight part APD4 adds 170-180 weight part MeOH(methyl alcohol) in, control temperature less than 30 DEG C drips SOCl 2(thionyl chloride), drips after terminating, and control temperature is at 30 ± 5 DEG C, and reaction 10h, detects reactionless thing, cooling discharge, adds EA extraction, washing, vacuum drying product.
It is short that synthesis method involved in the present invention has synthetic route, and cost is low, without the need to carrying out the advantage split, can realize (R)-3-amino piperidine dihydrochloride of suitability for industrialized production.
Embodiment
Embodiment 1
A kind of preparation method of (R)-3-amino piperidine dihydrochloride, comprises following reactions steps:
The synthesis of 1. N-tertbutyloxycarbonyl-D-Glu dimethyl ester (APD1):
20gD-L-glutamic acid is dissolved in 120mlMeOH(ice bath under stirring), add 32gSOCl 2keep temperature lower than 30 DEG C, after adding, be warming up to 30 ± 5 DEG C, stir 6 ± 0.5h, sample and tested by high performance liquid chromatography, treat that monomer conversion is more than 95% stopped reaction, decompression desolventizing.Add 50mlH 2o and 50mlDioxane, is placed in ice bath and cools, add 27.3gTEA and 32.2g(Boc) 2o, adds complete, removes ice bath and is heated to 30 ± 5 DEG C, stirs 5 ~ 6h, detects intermediate reaction complete, stopped reaction by LC-MS.Remove organic solvent, extract with 2 × 150mlEA.By salt water washing, Na 2sO 4drying, obtains oily matter.Yield 99%, purity 95%.
2. the synthesis of (R)-2-tertbutyloxycarbonyl-1,5-PD (APD2)
30gAPD1 is dissolved in 200mlEtOH, 30min is cooled in ice-water bath, substep adds 12.3g sodium borohydride, when precipitation appears in reaction, remove refrigerating unit, reactant reflux 2 hours, complete by LC-MS detection reaction, be cooled to 25 DEG C, pour 200ml saline into dissolving, filter, filtrate is concentrated into 100ml, and with 3 × 150mlMTBE extraction, undissolved solids stirs extraction 2h in MTBE, extract is dry by MgSO4, filter, concentrate and obtain 22.5ml colorless oil, leave standstill crystallization.Productive rate 90%, purity 94%.
3. the synthesis of (R)-2-tertbutyloxycarbonyl-1,5 penta bis-mesylate (APD3)
14.1gAPD2 is dissolved in 100mlDCM, adds 19.4gTEA and stir 30min in 0 DEG C of ice bath.Drip MsCl, in 0 DEG C of ice bath, stir 30min after dropwising, be then heated to 30 ± 5 DEG C, continue to stir 30-60min, detected by LC-MS, after reacting completely, with 80ml water, saturated NaHCO 3, normal saline washing, dry concentrated obtains yellow oil.Productive rate 82%, purity 96%.
4. the synthesis of (R)-3-t-butoxycarbonylamino piperidines (APD4)
10gAPD3 is dissolved in 90mlACN under stirring, and adds 92g25%NH 3h 2o, is incubated 30 ± 5 DEG C, and continue stirring 2 days, disappeared by LC-MS detecting reactant, mixture is concentrated into 50ml.With 3 × 100mlEA extraction, salt water washing, Na 2sO 4drying, concentrates and obtains white solid.Productive rate 74%, purity 98%.
5. the synthesis of (R)-3-amino piperidine dihydrochloride (APD5)
32gAPD4 adds in 175.9gMeOH, and control temperature less than 30 DEG C drips SOCl 2, drip after terminating, control temperature is at 30 ± 5 DEG C, and reaction 10h, detects reactionless thing, cooling discharge, adds EA extraction, washing, vacuum drying product.Yield 94%, purity 98%.
Should be understood that; the specific embodiment of the present invention is only the object for exemplary illustration; it limits protection scope of the present invention never in any form; those skilled in the art can be improved according to the above description or be converted, and all these improve and convert the protection domain that all should belong to claims of the present invention.

Claims (1)

1. a preparation method for (R)-3-amino piperidine dihydrochloride, is characterized in that comprising following reactions steps:
The synthesis of 1. N-tertbutyloxycarbonyl-D-Glu dimethyl ester (APD1):
2. the synthesis of (R)-2-tertbutyloxycarbonyl-1,5-PD (APD2)
3. the synthesis of (R)-2-tertbutyloxycarbonyl-1,5 penta bis-mesylate (APD3)
4. the synthesis of (R)-3-t-butoxycarbonylamino piperidines (APD4)
5. the synthesis of (R)-3-amino piperidine dihydrochloride (APD5)
Specifically comprise the following steps:
1) 20 weight part D-Glus are dissolved in the MeOH of 80-100 weight part under stirring, and carry out ice bath, add 32 weight part SOCl 2keep temperature lower than 30 DEG C, after adding, be warming up to 30 ± 5 DEG C, stir 6 ± 0.5h, sample and tested by high performance liquid chromatography, treat that monomer conversion is more than 95% stopped reaction, decompression desolventizing, adds 50 weight part H 2o and 40-50 weight part Dioxane, is placed in ice bath and cools, and adds 25-30 weight part TEA and 30-35 weight part (Boc) 2o, adds complete, removes ice bath and is heated to 30 ± 5 DEG C, stirs 5 ~ 6h, and detect intermediate reaction by LC-MS complete, stopped reaction, removes organic solvent, with EA extraction, by salt water washing, and Na 2sO 4drying, obtains oily matter APD1;
2) 30 weight part APD1 are dissolved in 160-180 weight part EtOH, in ice-water bath, cool 30min, and substep adds 10-15 weight part sodium borohydride, when precipitation appears in reaction, remove refrigerating unit, reactant reflux 2 hours, complete by LC-MS detection reaction, be cooled to 25 DEG C, pour 180-220 weight part saline into dissolving, filtering, filtrate is concentrated into 90-110 weight part, with MTBE extraction, undissolved solids stirs extraction 2h in MTBE, and extract passes through MgSO 4drying, filters, and concentrates and obtains colorless oil APD2, leaves standstill crystallization;
3) 13-15 weight part APD2 is dissolved in 90-110 weight part DCM, adds 18-20 weight part TEA and stir 30min in 0 DEG C of ice bath; Drip MsCl, in 0 DEG C of ice bath, stir 30min after dropwising, be then heated to 30 ± 5 DEG C, continue to stir 30-60min, detected by LC-MS, after reacting completely, use water, saturated NaHCO successively 3solution, normal saline washing, dry concentrating obtains yellow oil APD3;
4) 8-12 weight part APD3 is dissolved in 80-100 weight part ACN under stirring, and adds 90-95 weight part 25%NH 3h 2o, is incubated 30 ± 5 DEG C, continues stirring 2 days, is disappeared by LC-MS detecting reactant, and mixture concentrates, with EA extraction, and salt water washing, Na 2sO 4drying, concentrates and obtains white solid APD4;
5) 30-34 weight part APD4 adds in 170-180 weight part MeOH, and control temperature less than 30 DEG C drips SOCl 2, drip after terminating, control temperature is at 30 ± 5 DEG C, and reaction 10h, detects reactionless thing, cooling discharge, adds EA extraction, washing, vacuum drying product.
CN201410097492.0A 2014-03-17 2014-03-17 (R) preparation method of-3-amino piperidine dihydrochloride Expired - Fee Related CN103864674B (en)

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CN105330591A (en) * 2014-08-15 2016-02-17 南通书创药业科技有限公司 Preparation method of medical intermediate R-3-aminopiperidine dihydrochloride
CN108358845A (en) * 2018-02-02 2018-08-03 广州仁恒医药科技股份有限公司 A kind of new synthetic method of R-3- amino-hexahydro azepan hydrochloride
CN110372573A (en) * 2019-08-01 2019-10-25 苏州汉德创宏生化科技有限公司 The synthesis technology of antihyperglycemic drug intermediate R-3- amino-piperadine dihydrochloride
CN113121414B (en) * 2020-01-15 2024-03-29 鲁南制药集团股份有限公司 Synthesis method of trelagliptin intermediate
CN111807994A (en) * 2020-07-27 2020-10-23 四川嘉瑛莱科技有限责任公司 L-glutamic acid derivative and synthesis method and application thereof

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