WO2018134836A1 - Nouveau procédé rentable et faisable pour la fabrication de d-pénicillamine - Google Patents

Nouveau procédé rentable et faisable pour la fabrication de d-pénicillamine Download PDF

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Publication number
WO2018134836A1
WO2018134836A1 PCT/IN2017/050354 IN2017050354W WO2018134836A1 WO 2018134836 A1 WO2018134836 A1 WO 2018134836A1 IN 2017050354 W IN2017050354 W IN 2017050354W WO 2018134836 A1 WO2018134836 A1 WO 2018134836A1
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WO
WIPO (PCT)
Prior art keywords
formula
acid
compound
penicillamine
base
Prior art date
Application number
PCT/IN2017/050354
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English (en)
Inventor
Guruprasad Manohar KULKARNI
Shweta KULKARNI
Neelu SHARMA
Original Assignee
Synven Shree Life Sciences Pvt. Ltd.
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 Synven Shree Life Sciences Pvt. Ltd. filed Critical Synven Shree Life Sciences Pvt. Ltd.
Publication of WO2018134836A1 publication Critical patent/WO2018134836A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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
    • C07D263/36—One oxygen atom
    • C07D263/42—One oxygen atom attached in position 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to a process for the manufacture of D Penicillamine (DEPEN) of formula I, in good yield and purity.
  • D Penicillamine is a valuable therapeutic compound useful in the treatment of rhuematoid arthritis, chronic hepatitis and multiple sclerosis.
  • D-Penicillamine having the following formula I is known to be useful in the treatment of rhuematoid arthritis, chronic hepatitis and multiple sclerosis, which produces less serious side-effects than the L(+)-penicillamine.
  • US3888923 discloses process for preparation of Penicillamine which comprises the reaction of 2- isopropyl-S,S-dimethyl- thiazolidine with a carbonyl reagent (such as hydrazine, phenylhydrazine, 2,4- dinitrophenylhydrazine, semicarbazide, Thiosemicarbazide and hydroxylamine) in the presence of water and a water immiscible inert solvent.
  • a carbonyl reagent such as hydrazine, phenylhydrazine, 2,4- dinitrophenylhydrazine, semicarbazide, Thiosemicarbazide and hydroxylamine
  • US3960940 discloses another process, wherein, D(-)-Penicillamine and its salts are prepared by reacting a 6-amino or blocked 6-amino penicillin e.g. penicillin G or penicillin V, or a salt thereof, with a hydrazine having two -- NH-groups, or a salt or solvate thereof in presence of a mineral acid.
  • a 6-amino or blocked 6-amino penicillin e.g. penicillin G or penicillin V, or a salt thereof
  • a hydrazine having two -- NH-groups, or a salt or solvate thereof in presence of a mineral acid.
  • the reaction takes place in two stages; firstly, the hydrazine compound reacts with the penicillin compound to cleave the ⁇ -lactam ring to yield penicilloic acid hydrazide.
  • US'461 discloses a process for converting penicillins to penicillamine by hydrolysis of penicillin to penicilloic acid, decarboxylating the penicilloic acid to penilloic acid, treating the penilloic acid with a mercuric salt to yield a solution of penicillamine-mercuric salt complex and a byproduct penilloaldehyde, and converting said complex to penicillamine.
  • the process further comprises separating the by-product penilloaldehyde from the penicillamine mercuric salt complex by acidifying said solution to a pH within the range of about 1.3 to about 1.8 and precipitating the by-product penilloaldehyde from this acidified solution with a reagent selected from the group consisting of hydroxylamine, semicarbazide, thiosemicarbazide, benzohydrazide, phenylhydrazine and substituted phenylhydrazine, wherein the substituent is a member of the group consisting of nitro, dinitro, halo and dihalo.
  • a reagent selected from the group consisting of hydroxylamine, semicarbazide, thiosemicarbazide, benzohydrazide, phenylhydrazine and substituted phenylhydrazine, wherein the substituent is a member of the group consisting of nitro, dinitro, halo and dihalo.
  • Another object of the invention is to employ a chiral moiety containing multiple acid functional groups to convert them into multiple oxazolones containing molecule as a precursor for making amino acids in general sulphur containing amino acids in particular and more particularly D - penicillamine.
  • the present invention provides substantially pure D - penicillamine, compound of formula 1, and the process for its preparation and purification.
  • substantially pure D - penicillamine' is D - penicillamine of purity greater than 99 %.
  • the inventiveness of the present invention lies in the employment of a chiral acid for the preparation of the D - penicillamine in high yields by employing mild and simple procedures.
  • the novel process converts the starting material to the intended product in an efficient manner and the starting material can be recovered and recycled for use in subsequent batches.
  • the present invention discloses novel chiral acid based oxazolones which has been designed for asymmetric synthesis of D-penicillamine.
  • Oxazolones are well known chiral auxiliaries and are well documented in chemical literature.
  • the novel chiral acid moiety as used in the invention hosts two to three oxazolones which in fact leads to doubling or tripling the yields and thus boost the economics of the synthesis.
  • the salient features of present invention involves elegant chemistry, asymmetric synthesis with well- known oxazolone systems but on a new molecular system, which facilitates the process with versatile chiral auxiliaries, low effluent load, excellent economics thereby opens up new vista for amino acid synthesis.
  • the chiral auxiliary as designed in the present invention is novel.
  • the process of the present invention is more chemistry intensive and less equipment intensive.
  • the effluent loads are very high in the existing Degussa process.
  • the yields can get doubled and the lead time also gets halved.
  • the process is economically viable as there are two oxazolones on the same template.
  • the same auxiliary or similar bis and tri carboxylic acid containing chiral auxiliaries from the chiral pool can be employed for the synthesis of unnatural D amino acid.
  • chiral acids that can be used in the process of the present invention may be selected from the group consisting of:
  • the chiral acid is D- camphoric acid.
  • the invention provides a process for the preparation of substantially pure D - penicillamine which comprises;
  • Formula 5 e) optionally purifying the D - penicillamine of formula 1 by salting out the product or by employing suitable organic solvents to precipitate the product from water.
  • the preparation of dimethyl 2,2'- ⁇ [(lR,3R)- l,2,2-trimethylcyclopentane-l,3-diyl]bis(carbonylazanediyl) ⁇ diacetate which comprises reaction of D-camphoric acid with Glycine methyl ester hydrochloride in the presence of a dehydrating agent and a base in methylene dichloride as a solvent.
  • the dehydrating reagents used in the preparation of amido ester (2) are selected from the group consisting of EDC HC1, DCC and HOBt.
  • the dimethyl 2,2'- ⁇ [(lR,3R)-l,2,2-trimethylcyclopentane-l,3- diyl]bis(carbonylazanediyl) ⁇ diacetate(2) is hydrolyzed by treating with a base in a hydroxylic solvent at room temperature for about 10 to 14 hrs to afford 2,2'- ⁇ [(lR,3R)-l,2,2-trimethylcyclopentane-l,3diyl]bis(carbonylazanediyl) ⁇ diacetic acid (3).
  • the base employed for the hydrolysis of amido ester(2) may be an inorganic base selected from sodium hydroxide, potassium hydroxide, and other alkaline earth hydroxides, or an organic base selected from triethylamine or diisopropylethylamine.
  • the hydroxylic solvent may be selected from the group consisting of methanol, ethanol, isopropanol and water or a combination thereof.
  • a preferable hydroxylic solvent may be a mixture of water and methanol or ethanol or isopropanol.
  • the 2,2'- ⁇ [(lR,3R)-l,2,2-trimethylcyclopentane- l,3diyl]bis(carbonylazanediyl) ⁇ diacetic acid(3) thus obtained in acetic acid is reacted with a dehydrating agent in presence of a base at a temperature of 65 ° C for 12 hours.
  • the product bis - oxazolone (4) is isolated by extracting into methylene dichloride.
  • the dehydrating agents used in the preparation of compound of formula 4 (Oxazolones) is selected from the group consisting of phosphoric acid, polyphosphoric acid, sodium sulphate, and organic anhydrides.
  • the base is selected from sodium acetate or potassium acetate.
  • D - penicillamine is prepared by condensing the bis-oxazolone (4) thus obtained with acetone in the presence of a base to obtain intermediate compound of formula 5.
  • the condensed product (formula 5) thus obtained is either isolated or insitu reacted with a sulphur transfer agent to open the oxazolone rings followed by acid hydrolysis to obtain the product, D - penicillamine.
  • the sulphur transfer reagents employed in the preparation of D - penicillamine of formula 1 is selected from the group consisting of sodium thioacetate, potassium thioacetate, benzyl triethylammonium tetrathiomolybdate, hydrogen sulphide and phosphorous penta sulphide.
  • the base is selected from sodium acetate or potassium acetate and the acid employed in the hydrolysis are selected from HC1, acetic acid, sulphuric acid.
  • the intermediate 5 can also be prepared directly by treating the compound of formula 3 by employing acetone as solvent in the presence of dehydrating agents selected from phosphoric acid, polyphosphoric acid, sodium sulphate, organic anhydrides and the base selected from sodium acetate or potassium acetate.
  • dehydrating agents selected from phosphoric acid, polyphosphoric acid, sodium sulphate, organic anhydrides and the base selected from sodium acetate or potassium acetate.
  • the final product, D - penicillamine is purified by employing organic solvents selected from the group consisting of methanol, ethanol, isopropanol, acetic acid and mixture thereof or a combination of toluene with ethers selected from DIPE or MTBE.
  • the present invention provides a process for synthesis of D - penicillamine (formula 1) involving the following novel intermediates; a) dimethyl 2,2'- ⁇ [(lR,3R)-l,2,2-trimethylcyclopentane-l,3- diyl]bis(carbon lazanediyl) ⁇ diacetate (amido ester of formula 2);

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

Abstract

L'invention concerne une nouvelle synthèse pour la fabrication de pénicillamine D par l'intermédiaire de nouveaux auxiliaires chiraux en tant que composés intermédiaires. Le procédé comprend la conversion d'acide camphorique D en un ester amido par réaction de celui-ci avec du chlorhydrate de glycine d'ester de méthyle suivi d'une conversion en son bis-acide par réaction avec une base appropriée. Selon l'invention, le bis-acide est en outre converti en son bis-oxazolone qui est condensé avec de l'acétone en présence d'une base pour obtenir un intermédiaire 5 suivi d'une réaction avec un agent de transfert de soufre et une hydrolyse consécutive pour obtenir de la pénicillamine D.
PCT/IN2017/050354 2017-01-23 2017-08-21 Nouveau procédé rentable et faisable pour la fabrication de d-pénicillamine WO2018134836A1 (fr)

Applications Claiming Priority (2)

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IN201721002477 2017-01-23
IN201721002477 2017-01-23

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WO2018134836A1 true WO2018134836A1 (fr) 2018-07-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909067A (zh) * 2020-08-28 2020-11-10 浙江凯普化工有限公司 一种d-青霉胺的有机全合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960940A (en) * 1973-08-22 1976-06-01 Glaxo Laboratories Limited Process for the preparation of D(-)-penicillamine and salts thereof
US20030130349A1 (en) * 1997-06-23 2003-07-10 Tanabe Seiyaku Co., Ltd. Inhibitors of alpha 4beta1 mediated cell adhesion

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3960940A (en) * 1973-08-22 1976-06-01 Glaxo Laboratories Limited Process for the preparation of D(-)-penicillamine and salts thereof
US20030130349A1 (en) * 1997-06-23 2003-07-10 Tanabe Seiyaku Co., Ltd. Inhibitors of alpha 4beta1 mediated cell adhesion

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AHMED EL-MEKABATY: "Erlenmeyer Azlactones: Synthesis, Reactions and Biological Activity", INTERNATIONAL JOURNAL OF MODERN ORGANIC CHEMISTRY, 1 April 2013 (2013-04-01), pages 40 - 66, XP055518098, Retrieved from the Internet <URL:http://modernscientificpress.com/Journals/ViewArticle.aspx?pd2T1QECjbDHPPMZhNX7727I2QqqYjFklXrClTSBlBPixnFhdfp/wCsbf1zpU/aH> *
CHARVILLE , HAYLEY: "Direct Amide Formation Between Carboxylic Acids and Amines: Mechanism and Development of Novel Catalytic Solutions", THESIS DPH, 6 March 2012 (2012-03-06), Durham University, pages 1 - 195, XP055518089, Retrieved from the Internet <URL:http://etheses.dur.ac.uk/3416/1/HCharvilleThesis.pdf?DDD7+> *
RATAN KUMAR KAR: "Fundamentals of Organic Synthesis, THE RETROSYNTHETIC ANALYSIS", vol. II, 1 January 2008, ISBN: 81-7381-532-1, pages: 81 - 82 *
ROBERT THORNTON MORRISON ET AL.: "Organic Chemistry", 1 January 2008, ISBN: 978-81-7758-169-0, pages: 1260 *
SHARMA, N. ET AL.: "A REVIEW ON OXAZOLONE, IT’ S METHOD OF SYNTHESIS AND BIOLOGICAL ACTIVITY", EUROPEAN JOURNAL OF BIOMEDICAL AND PHARMACEUTICAL SCIENCES (EJBPS), vol. 2, no. 3, 11 June 2015 (2015-06-11), pages 964 - 987, XP055518103, Retrieved from the Internet <URL:https://www.researchgate.net/publication/280882247_A_REVIEW_ON_OXAZOLONE_IT'_S_METHOD_OF_SYNTHESIS_AND_BIOLOGICAL_ACTIVITY> *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909067A (zh) * 2020-08-28 2020-11-10 浙江凯普化工有限公司 一种d-青霉胺的有机全合成方法
CN111909067B (zh) * 2020-08-28 2022-03-15 浙江凯普化工有限公司 一种d-青霉胺的有机全合成方法

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