CN104557677A - Chemical resolution preparation method for optical pure 2-pipecolic acid - Google Patents

Chemical resolution preparation method for optical pure 2-pipecolic acid Download PDF

Info

Publication number
CN104557677A
CN104557677A CN201410846424.XA CN201410846424A CN104557677A CN 104557677 A CN104557677 A CN 104557677A CN 201410846424 A CN201410846424 A CN 201410846424A CN 104557677 A CN104557677 A CN 104557677A
Authority
CN
China
Prior art keywords
pipecolic acid
acid
pipecolic
mandelate
amygdalic
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
Application number
CN201410846424.XA
Other languages
Chinese (zh)
Inventor
刘经红
刘启宾
郑鹏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ALLYCHEM Co Ltd DALIAN CHINA
Original Assignee
ALLYCHEM Co Ltd DALIAN CHINA
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by ALLYCHEM Co Ltd DALIAN CHINA filed Critical ALLYCHEM Co Ltd DALIAN CHINA
Priority to CN201410846424.XA priority Critical patent/CN104557677A/en
Publication of CN104557677A publication Critical patent/CN104557677A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a preparation method for (R)-(+)-2-pipecolic acid and (S)-(-)-2-pipecolic acid enantiomers. According to the method, optical pure mandelic acid is taken as a resolving agent for chemically resolving racemic 2-pipecolic acid, a single enantiomer is obtained and is subjected to alkaline hydrolysi, and optical pure 2-pipecolic acid is obatained. The preparation method is mild in reaction condition, simple and convenient to carry out, high in yield, low in cost and easy for industrialization.

Description

The chemical resolution preparation method of optically pure Pipecolic Acid
Technical field
The present invention relates to the chemical resolution preparation method of optically pure Pipecolic Acid, belong to organic chemicals synthesis and preparation technical field.
Background technology
Optically pure 2-piperidine carboxylic acid is a kind of important rigid annular nonprotein amino acid, it both can limit the conformation of polypeptide, also can be used as the multi-functional skeleton in different compou nd synthesis storehouse, so be widely used in the preparation of many chiral drugs and biologically active substance, if local anaesthetics ropivacaine, antipsychotics thioridazine etc. are all for main raw material obtains with optically pure 2-piperidine carboxylic acid.
At present, optically active (R)-(+)-Pipecolic Acid or (S)-(-)-Pipecolic Acid are separated: Watanabe etc. take diethyl acetamido as raw material, adopt chemosynthesis-biological resolution integrated process finally to obtain having optically active L-nipecotic acid and D-nipecotic acid; J. tartrate is adopted to be resolving agent in Med. Chem. 33 (1998) 23-31, through twice recrystallization purifying preparation (R)-(+)-Pipecolic Acid or (S)-(-)-Pipecolic Acid optical antipode.
Summary of the invention
The present invention take optically pure mandelic acid as resolving agent, chemical resolution is carried out to the Pipecolic Acid of racemization, a step can directly obtain the dextrorotation of high-optical-purity or left-handed Pipecolic Acid mandelate, without the need to purifying, through basic hydrolysis, obtain optically pure (R)-(+)-Pipecolic Acid or (S)-(-)-Pipecolic Acid.Concrete technical scheme is as follows.
The method that the application provides is: take optically pure mandelic acid as resolving agent, chemical resolution is carried out to the Pipecolic Acid of racemization, directly the dextrorotation of high-optical-purity or left-handed Pipecolic Acid mandelate is obtained without the need to purifying, again through basic hydrolysis, obtain optically pure (R)-(+)-Pipecolic Acid and (S)-(-)-Pipecolic Acid; Described amygdalic acid is D-amygdalic acid and L-amygdalic acid, and structural formula is as follows:
D-amygdalic acid L-amygdalic acid
Described have optically pure Pipecolic Acid for (S)-(-)-Pipecolic Acid and (R)-(+)-Pipecolic Acid, and structural formula is as follows:
(S)-(-)-Pipecolic Acid (R)-(+)-Pipecolic Acid.
Further, described in the application, method comprises the steps:
(1) be 1:0.5 ~ 0.7 in molar ratio by the Pipecolic Acid of described racemization and optically pure D-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (-)-Pipecolic Acid mandelate and the mother liquor thereof of high-optical-purity;
(2) above-mentioned mother liquor concentrations is to dry, dissociate the Pipecolic Acid of partial resolution, be 1:0.5 ~ 0.7 in molar ratio with L-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (+)-Pipecolic Acid mandelate of high-optical-purity;
(3) optically active Pipecolic Acid mandelate that step (1) and (2) obtain prepares optically pure (S)-(-)-Pipecolic Acid and (R)-(+)-Pipecolic Acid through basic hydrolysis in methyl alcohol.
Further, described method can also realize as follows:
(1) be 1:0.5 ~ 0.7 in molar ratio by the Pipecolic Acid of described racemization and optically pure L-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (+)-Pipecolic Acid mandelate and the mother liquor thereof of high-optical-purity;
(2) above-mentioned mother liquor concentrations is to dry, dissociate the Pipecolic Acid of partial resolution, be 1:0.5 ~ 0.7 in molar ratio with D-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (-)-Pipecolic Acid mandelate of high-optical-purity;
(3) optically active Pipecolic Acid mandelate that step (1) and (2) obtain prepares optically pure (S)-(-)-Pipecolic Acid and (R)-(+)-Pipecolic Acid through basic hydrolysis in methyl alcohol.
Preferably, (+)-Pipecolic Acid mandelate described in above-mentioned steps (3) or (-)-Pipecolic Acid mandelate and highly basic methanol mixed, stir at 0 ~ 80 DEG C, filter, be washed to neutrality, purification obtains (R)-(+)-Pipecolic Acid or (S)-(-)-Pipecolic Acid.
Preferably, highly basic described in the application is sodium hydroxide or potassium hydroxide.
Preferably, above-mentioned steps (1) and (2) middle fractionation organic solvent used are methyl alcohol or ethanol.
Beneficial effect:
1, the application is by carrying out chemical resolution to the Pipecolic Acid of racemization, a step can directly obtain the left-handed of high-optical-purity or dextrorotation Pipecolic Acid mandelate, and without the need to through recrystallization purifying, therefore reaction yield is high;
2, preparation method of the present invention will can also split mother liquor concentrations to dry for the first time, be hydrolyzed the Pipecolic Acid of the partial resolution that dissociates, be dissolved in organic solvent with the amygdalic acid of another configuration, place the diastereoisomeric salt of the Pipecolic Acid-amygdalic acid of separating out high-optical-purity, again through alkaline hydrolysis, obtain optically pure (R)-(+)-Pipecolic Acid or (S)-(-)-Pipecolic Acid;
3, raw material of the present invention is easy to get, low price, reaction conditions be gentle; Post-reaction treatment process operation is easy; Process safety is reliable, is suitable for suitability for industrialized production.
Embodiment
Below by specific examples, the present invention is further detailed.
embodiment 1(S) preparation of-(-)-Pipecolic Acid
50.0g racemization Pipecolic Acid (0.387mol) is dissolved in 50g methyl alcohol, and nearly reflux heat dissolves, and drips the mixing solutions of 40.6g D-amygdalic acid (0.270mol) and 180ml methyl alcohol, be incubated 0.5 hour, slow cooling, to room temperature, is placed 12 hours, filter, collect filtrate.Filter cake cold methanol washs, dry white solid 44.8g(-)-Pipecolic Acid mandelate, yield 83.0%, [ɑ] d 20=-19.2 ° of (C=2, H 2o);
Add in 44.8g(-)-Pipecolic Acid mandelate in 224g methyl alcohol, 20%NaOH is dissolved in adjust ph 10, separates out white solid, add 112g water to stir, filter, be washed to neutrality, dry 14.1g white solid (S)-(-)-Pipecolic Acid, yield 68.1%, [ɑ] d 20=-25 ° of (C=2, H 2o), ee value > 99.0%.
embodiment 2(R) preparation of-(+)-Pipecolic Acid
In embodiment 1, gained fractionation mother liquor concentrations adds 150g dissolve with methanol to dry gained solid; 20%NaOH is dissolved in adjust ph 10; separate out white solid; add 75g water to stir; filter; be washed to neutrality, dry (R)-(+) the Pipecolic Acid 26.9g that must contain a small amount of (S)-(-)-Pipecolic Acid;
26.9g(R)-(+) Pipecolic Acid crude product, is dissolved in 27g methyl alcohol, and nearly reflux heat dissolves, drip the mixing solutions of 40.6g L-amygdalic acid (0.270mol) and 180ml methyl alcohol, be incubated 0.5 hour, slow cooling is to room temperature, place 12 hours, filter, collect filtrate.Filter cake cold methanol washs, dry white solid 47.1g(+)-Pipecolic Acid mandelate, yield 87.2%, [ɑ] d 20=+20 ° of (C=1.5, H 2o).
Add in 47.1g(+)-Pipecolic Acid mandelate in 236g methyl alcohol, 20%NaOH is dissolved in adjust ph 10, separates out white solid, add 118g water to stir, filter, be washed to neutrality, dry 15.7g white solid (R)-(+)-Pipecolic Acid, yield 72.0%, [ɑ] d 20=+25.8 ° of (C=2, H 2o), ee value > 99.0%.
embodiment 3(R) preparation of-(+)-Pipecolic Acid
By the method for embodiment 1,50.0g racemization Pipecolic Acid (0.387mol) is dissolved in 70g ethanol, nearly reflux heat dissolves, drip the mixing solutions of 40.6g L-amygdalic acid (0.270mol) and 250ml ethanol, be incubated 0.5 hour, slow cooling, to room temperature, is placed 12 hours, filter, collect filtrate.Filter cake cold methanol washs, dry white solid 45.4g(+)-Pipecolic Acid mandelate, yield 84.2%, [ɑ] d 20=+20.4 ° of (C=1.5, H 2o);
Add in 45.4g(+)-Pipecolic Acid mandelate in 227g methyl alcohol, 20%NaOH is dissolved in adjust ph 10, separates out white solid, add 114g water to stir, filter, be washed to neutrality, dry 14.5g white solid (R)-(+)-Pipecolic Acid, yield 69.0%, [ɑ] d 20=+25 ° of (C=1.5, H 2o), ee value > 99.0%.
embodiment 4(S) preparation of-(-)-Pipecolic Acid
In embodiment 3, gained fractionation mother liquor concentrations adds 150g dissolve with methanol to dry gained solid, 20%NaOH is dissolved in adjust ph 10, separate out white solid, add 75g water to stir, filter, be washed to neutrality, dry (S)-(-) the Pipecolic Acid 25.8g that must contain a small amount of (R)-(+)-Pipecolic Acid.
25.8g(S)-(-) Pipecolic Acid crude product, is dissolved in 36g ethanol, and nearly reflux heat dissolves, drip the mixing solutions of 40.6g D-amygdalic acid (0.270mol) and 250ml ethanol, be incubated 0.5 hour, slow cooling is to room temperature, place 12 hours, filter, collect filtrate.Filter cake cold methanol washs, dry white solid 45.8g(-)-Pipecolic Acid mandelate, yield 84.8%, [ɑ] d 20=-19.8 ° of (C=2, H 2o);
Add in 45.8g(-)-Pipecolic Acid mandelate in 229g methyl alcohol, 20%NaOH is dissolved in adjust ph 10, separates out white solid, add 115g water to stir, filter, be washed to neutrality, dry 14.9g white solid (S)-(-)-Pipecolic Acid, yield 70.6%, [ɑ] d 20=+24 ° of (C=2, H 2o), ee value > 99.0%.
The above; be only the present invention's preferably embodiment; but protection scope of the present invention is not limited thereto; anyly be familiar with those skilled in the art in the technical scope that the present invention discloses; be equal to according to technical scheme of the present invention and inventive concept thereof and replace or change, all should be encompassed within protection scope of the present invention.

Claims (6)

1. prepare the method for optical purity Pipecolic Acid for one kind, it is characterized in that, take optically pure mandelic acid as resolving agent, chemical resolution is carried out to the Pipecolic Acid of racemization, directly the dextrorotation of high-optical-purity or left-handed Pipecolic Acid mandelate is obtained without the need to purifying, again through basic hydrolysis, obtain optically pure (R)-(+)-Pipecolic Acid and (S)-(-)-Pipecolic Acid; Described amygdalic acid is D-amygdalic acid and L-amygdalic acid, and structural formula is as follows:
D-amygdalic acid L-amygdalic acid
Described have optically pure Pipecolic Acid for (S)-(-)-Pipecolic Acid and (R)-(+)-Pipecolic Acid, and structural formula is as follows:
(S)-(-)-Pipecolic Acid (R)-(+)-Pipecolic Acid.
2. a kind of method preparing optical purity Pipecolic Acid according to claim 1, is characterized in that, comprise the steps:
(1) be 1:0.5 ~ 0.7 in molar ratio by the Pipecolic Acid of described racemization and optically pure D-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (-)-Pipecolic Acid mandelate and the mother liquor thereof of high-optical-purity;
(2) above-mentioned mother liquor concentrations is to dry, dissociate the Pipecolic Acid of partial resolution, be 1:0.5 ~ 0.7 in molar ratio with L-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (+)-Pipecolic Acid mandelate of high-optical-purity;
(3) optically active Pipecolic Acid mandelate that step (1) and (2) obtain prepares optically pure (S)-(-)-Pipecolic Acid and (R)-(+)-Pipecolic Acid through basic hydrolysis in methyl alcohol.
3. a kind of method preparing optical purity Pipecolic Acid according to claim 1, is characterized in that, comprise the steps:
(1) be 1:0.5 ~ 0.7 in molar ratio by the Pipecolic Acid of described racemization and optically pure L-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (+)-Pipecolic Acid mandelate and the mother liquor thereof of high-optical-purity;
(2) above-mentioned mother liquor concentrations is to dry, dissociate the Pipecolic Acid of partial resolution, be 1:0.5 ~ 0.7 in molar ratio with D-amygdalic acid resolving agent, be dissolved at 0 ~ 80 DEG C in organic solvent, then place at 0 ~ 50 DEG C and separate out solid, obtain (-)-Pipecolic Acid mandelate of high-optical-purity;
(3) optically active Pipecolic Acid mandelate that step (1) and (2) obtain prepares optically pure (S)-(-)-Pipecolic Acid and (R)-(+)-Pipecolic Acid through basic hydrolysis in methyl alcohol.
4. according to the method in claim 2 or 3, it is characterized in that, (+)-Pipecolic Acid mandelate described in step (3) or (-)-Pipecolic Acid mandelate and highly basic methanol mixed, pH value is 9-11, stir under the condition of 0 ~ 80 DEG C, filter, be washed to neutrality, purification obtains (R)-(+)-Pipecolic Acid or (S)-(-)-Pipecolic Acid.
5. method according to claim 4, is characterized in that, described highly basic is sodium hydroxide or potassium hydroxide, and concentration is 20-40%.
6. according to the method in claim 2 or 3, it is characterized in that, step (1) and (2) middle fractionation organic solvent used are methyl alcohol or ethanol.
CN201410846424.XA 2014-12-31 2014-12-31 Chemical resolution preparation method for optical pure 2-pipecolic acid Pending CN104557677A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410846424.XA CN104557677A (en) 2014-12-31 2014-12-31 Chemical resolution preparation method for optical pure 2-pipecolic acid

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410846424.XA CN104557677A (en) 2014-12-31 2014-12-31 Chemical resolution preparation method for optical pure 2-pipecolic acid

Publications (1)

Publication Number Publication Date
CN104557677A true CN104557677A (en) 2015-04-29

Family

ID=53074854

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410846424.XA Pending CN104557677A (en) 2014-12-31 2014-12-31 Chemical resolution preparation method for optical pure 2-pipecolic acid

Country Status (1)

Country Link
CN (1) CN104557677A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104710373A (en) * 2015-03-06 2015-06-17 上海晓明检测技术服务有限公司 Preparation method for high-purity cyproconazole isomer
CN106831540A (en) * 2017-03-09 2017-06-13 爱斯特（成都）生物制药股份有限公司 It is a kind of（S）The preparation method of 3 piperidine carboxylic acids
CN107216278A (en) * 2016-03-21 2017-09-29 广东东阳光药业有限公司 A kind of improved method for preparing Lei Dipawei optics intermediates

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1146029A1 (en) * 2000-04-13 2001-10-17 Nissan Chemical Industries Ltd. Method for optical resolution of piperidine carboxylic acid derivative
CN1442407A (en) * 2003-04-11 2003-09-17 中国科学院上海有机化学研究所 Chemical resolution preparation method of optically pure fesufenadin and its hydrochloride salt
CN101209990A (en) * 2006-12-26 2008-07-02 江苏天汁化学有限公司 Resolution method for 3-piperidine formic acid ester

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1146029A1 (en) * 2000-04-13 2001-10-17 Nissan Chemical Industries Ltd. Method for optical resolution of piperidine carboxylic acid derivative
CN1442407A (en) * 2003-04-11 2003-09-17 中国科学院上海有机化学研究所 Chemical resolution preparation method of optically pure fesufenadin and its hydrochloride salt
CN101209990A (en) * 2006-12-26 2008-07-02 江苏天汁化学有限公司 Resolution method for 3-piperidine formic acid ester

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BIN HO ET AL.: "Synthesis of 2-piperidinecarboxylic acid derivatives as potential anticonvulsants", 《EUR.J.MED.CHEM.》 *
PHILIP MAGNUS ET AL.: "Synthesis of the vinblastine-like antitumor bis-indole alkaloid navelbine analog desethyldihydronavelbine", 《J.ORG.CHEM.》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104710373A (en) * 2015-03-06 2015-06-17 上海晓明检测技术服务有限公司 Preparation method for high-purity cyproconazole isomer
CN107216278A (en) * 2016-03-21 2017-09-29 广东东阳光药业有限公司 A kind of improved method for preparing Lei Dipawei optics intermediates
CN106831540A (en) * 2017-03-09 2017-06-13 爱斯特（成都）生物制药股份有限公司 It is a kind of（S）The preparation method of 3 piperidine carboxylic acids

Similar Documents

Publication Publication Date Title
CN105175339B (en) A kind of method for preparing dexmedetomidine hydrochloride
CN109400556A (en) A kind of synthetic method of D- (-)-pantoic acid lactone
CN104557677A (en) Chemical resolution preparation method for optical pure 2-pipecolic acid
CN102241555A (en) Method for preparing photoactived amino acid through resolution
CN101659622A (en) Method for splitting valine
CN104193635A (en) Synthesis method of pregabalin
CN103420845B (en) One prepares the method for cinacalcet intermediate R-(+)-1-(1-naphthyl) ethamine
CN104151249B (en) Medetomidine industrialization method for splitting
CN102010327B (en) Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid
CN102351764A (en) Method for preparing high optical purity D-cystine
CN110642765A (en) Synthesis method of D-p-methylsulfonyl phenyl serine ethyl ester
CN102603592B (en) Preparation method for (R)-1-benzyl-3-aminopyrrolidine and (S)-1-benzyl-3-aminopyrrolidine
CN102010345B (en) Method for preparing D-phenylalanine through dynamic kinetic resolution
CN103467350B (en) (S) preparation method of-AzeOH
CN112961070A (en) Preparation method of L-2-aminobutanamide hydrochloride
CN103086877B (en) A kind of method for splitting of 2 hydracrylic acid class racemoid
CN104725259B (en) Preparation method for levodopa intermediate derivative
CN104876856A (en) Method for preparing (R)-(+)-3-piperidinamine dihydrochloride by using resolution method
CN100391934C (en) Method for preparing L-glutamic acid
CN102628075A (en) Method for producing chiral amino acid by penicillin acylase resolution and product thereof
CN104592046A (en) Optically active valine compound and production method thereof
CN102093284B (en) Method for enriching piperidine-2-formanilide optically active compound
CN101735070A (en) Resolution method of R-(+)-1-(1-naphthyl) ethylamine
CN103131747A (en) Method for synthesizing (S)-3-(4-hydroxyl phenyl)-3-methylamino propionic acid by using biological enzymes through chiral resolution
CN106316873A (en) Novel method for preparing L-carnitine

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20150429

RJ01 Rejection of invention patent application after publication