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WO2007042848A2 - Procede de preparation de carbidopa - Google Patents

Procede de preparation de carbidopa Download PDF

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Publication number
WO2007042848A2
WO2007042848A2 PCT/HU2006/000092 HU2006000092W WO2007042848A2 WO 2007042848 A2 WO2007042848 A2 WO 2007042848A2 HU 2006000092 W HU2006000092 W HU 2006000092W WO 2007042848 A2 WO2007042848 A2 WO 2007042848A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
methyl ester
hydrazino
dihydroxyphenyl
reaction
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.)
Ceased
Application number
PCT/HU2006/000092
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English (en)
Other versions
WO2007042848A3 (fr
Inventor
Katalin Kataine Fadgyas
János FARKAS
Gyula Lukacs
Ferenc Lang
Ferenc Jurak
Istvánné CSALA
Tamásné KOROKNAI
Marta Porcs-Makkay
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.)
Egis Pharmaceuticals PLC
Original Assignee
Egis Pharmaceuticals PLC
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 Egis Pharmaceuticals PLC filed Critical Egis Pharmaceuticals PLC
Publication of WO2007042848A2 publication Critical patent/WO2007042848A2/fr
Publication of WO2007042848A3 publication Critical patent/WO2007042848A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings

Definitions

  • the invention relates to a new process for the preparation of carbidopa. More specifically, the invention relates to the preparation of carbidopa by using 3,3- pentamethylene oxaziridine, a new intermediate useful for the said process , and to the preparation of this intermediate.
  • optically active (-)-(L)- 3- (3 , 4-dihydroxyphenyl) -2-hydrazino-2-methyl- propionic acid (German patent specification Ho . 1,173,487) .
  • the aim of the improved processes is to avoid resolution as the final step of the synthesis.
  • the optically active amino acids obtained by resolution during the preceding steps of the synthesis or disposable in industrial quantities or the derivatives thereof are applied in the course of these processes .
  • L- ⁇ - methyldopa is L- ⁇ - methyldopa or the intermediates thereof.
  • the chemical structure of carbidopa of the formula (II) is highly similar to that of L- ⁇ - methyldopa.
  • This latter substance is a generally applied hypertensive drug, which has been on the market for a long time and which is manufactured on an industrial scale.
  • the structural difference between the two compounds is that while carbidopa contains a hydrazino group at the carbon atom adjacent to the carboxylic acid, L- ⁇ -methyldopa contains an amino group of the same steric position.
  • the compound is first diazotated to obtain L- ⁇ -bromocarboxylic acid.
  • the bromine atom can be exchanged directly for a hydrazino group by reacting said compound with hydrazine, but because of the inversion occurring in the course of the reaction the isomer having the undesired steric position is formed.
  • the bromine atom is exchanged for an iodine atom by a reaction with sodium iodide, which reaction also involves an inversion.
  • reaction scheme 1 The thus-obtained D-iodocarboxylic acid is then reacted with hydrazine resulting in an inversion to obtain L-carbidopa of the appropriate steric position.
  • the reaction is illustrated in reaction scheme 1. During the reaction carried out with sodium iodide a partial racemization occurs because of the iodine-iodine exchange under the circumstances of the bromine-iodine exchange. The low yield of the process and the insufficient optical purity of the thus-obtained product can in part be explained by this fact.
  • the hydrazino group is formed from the amino group by N- amination. This reaction namely does not affect the optical centre, consequently no racemization takes place.
  • Several methods have been provided for the conversion of the amino group into hydrazino group. S. Karady at al. (J.Org.Chem. 36, 1949-1951 (1971)) have published three processes applying as starting substance the optically active intermediate of L- ⁇ -methyldopa. In this starting substance the two aromatic hydroxyl groups are protected by dimethoxy groups. According to one of these processes dimethoxy- ⁇ -methyldopa is reacted with hydroxylamine O- sulphonic acid.
  • the amino group of the dimethoxy derivative of L-ot-methyldopa is acylated, a salt is formed with sodium hydride from the thus-obtained optically active L-acetamide, the salt is reacted with chloro- amine, and carbidopa of the formula (II) is obtained by the acidic hydrolysis of the acetyl group.
  • reaction scheme 3 A serious drawback of this process is that it requires the application of very expensive reagents (sodium hydride, chloro- amine) , special reaction circumstances and equipment, furthermore the thus-obtained product is to be purified by chromatography. This process is also unsuitable for an industrial scale production.
  • the dimethoxy derivative of L- ⁇ -methyldopa is reacted with potassium cyanate, the thus-obtained carbamide derivative is converted into the dimethoxy derivative of carbidopa of the formula (II) by treatment with sodium hypochlorite, which is then demethylated in the final reaction step with concentrated aqueous hydrogen bromide solution.
  • reaction scheme 3 This process requires a chromatographic purification, and the total yield following the purification of the product by chromatography is only 27%. Due to the low yield and the purification by chromatography the process is unsuitable for an industrial scale production.
  • reaction scheme 5 A drawback of the process is that the N-amination with the oxaziridine derivative of the formula (IV) is carried out by using a starting substance containing protected phenolic hydroxy1 groups .
  • This protected compound can be the appropriate dialkoxy derivative (generally dimethoxy derivative) , diacetoxy derivative or iso- propylenedioxy derivative.
  • the protecting groups of the phenolic hydroxy groups are usually removed in a later phase of the synthesis, often under drastic reaction conditions (concentrated aqueous hydrogen bromide, high temperature) . Consequently, side- products may be formed, which reduce the quality of the compound of the formula (II) , and the removal thereof is expensive and causes losses.
  • side-products (4-hydroxy-3- methoxyphenyl, 3-hydroxy-4-mehtoxyphenyl derivatives, furthermore L- ⁇ -methyldopa) are formed with structures and properties similar to those of the end-product of the formula (II) , consequently the removal thereof is cumbersome and expensive.
  • the amount of the decomposition product to be kept mostly in view that is L-oc-methyldopa being formed in the course of the vigorous hydrolysis , can be kept below the limit of 0.5 w/w% specified in the pharmacopoeiae only after several purification procedures .
  • the phenolic hydroxyl groups of L- ⁇ -methyldopa ester are protected with a boron compound suitable for the formation of a transitional complex.
  • ortho-boronic acid or ortho-boronic acid derivatives (such as sodium tetraborate) are applied.
  • the desired carbidopa of the formula (II) is produced according to reaction scheme 6 by starting from the methyl ester of L- ⁇ - methyldopa (the compound of the formula III) in a biphasic reaction mixture (toluene and aqueous phase) .
  • the boronic acid complex of the formula (3) is prepared first from the starting substance of the formula (III),
  • the amination reaction is carried out in a biphasic reaction mixture.
  • the boronic acid complex of the formula (3) being in the aqueous phase is reacted with a solution of 3,3- pentamethylene oxaziridine of the formula (IV) in toluene.
  • the drawback of this process resides in the fact that the reaction between the boronic acid complex of the formula (3) soluble in the aqueous phase and 3,3- pentamethylene oxaziridine of the formula (IV) being in the toluene phase takes place in a heterogeneous phase.
  • the contact between the two phases is promoted by strong stirring and the application of a phase transfer catalyst. Due to the two phases the process is complicated.
  • the aim of the invention was to elaborate a method suitable for an industrial scale preparation of carbidopa of the formula (II) , which eliminates the drawbacks of the aforementioned processes and provides said compound in a high yield and in high purity.
  • the invention is based on the recognition that
  • a particular advantage of the process according to this invention resides in the fact that - contrary to the biphase reaction mixture consisting of toluene and an aqueous phase - it can be carried out in a homogeneous reaction medium. Namely, in the applied organic solvent boiling at a temperature of higher than 80 0 C - preferably in toluene - both L- ⁇ -methyldopa methyl ester of the formula (III) and 3,3- pentamethylene oxaziridine of the formula (IV) can be dissolved.
  • the reaction can be carried out at a temperature between 80 0 C and 130 0 C depending on the boliling point of the solvent. It is preferable to carry out the reaction at a temperature between 100 0 C and 105 0 C.
  • the reaction is accomplished within a short period of time, usually within 1 - 2 hour(s) .
  • the thus-obtained compound of the formula (I) can be isolated from the reaction mixture by filtration or centrifugation .
  • the compound of the formula (I) separates from the reaction mixture in a highly pure crystalline form.
  • the side-products and the unreacted starting substances are contained in the organic mother liquor .
  • the thus-obtained compound of the formula (I) is then converted into (-) - (L) -3- (3,4- dihydroxyphenyl) -2-hydrazino-2-methylpropionic acid of the formula (II) by acidic hydrolysis.
  • the hydrolysis is preferably carried out with hydrogen chloride, particularly with 20 % hydrogen chloride solution.
  • the hydrolysis is carried out at a temperature between 90 0 C and 100 0 C, preferably at 93-95 0 C.
  • the reaction takes place in a few hours (generally between 3 and 6 hours, preferably in 5 hours) .
  • a process for the preparation of (+) - (L) -2- (N' -cyclohexylidene- hydrazino) -3- (3,4-dihydroxyphenyl) -2-methylpropionic acid methyl ester of the formula (I) which comprises reacting L-oc-methyldopa methyl ester of the formula (III) with 3,3-penta- methylene oxaziridine of the formula (IV) and isolating the thus-obtained compound of the formula (I) .

Landscapes

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

Abstract

L'invention concerne un procédé permettant la préparation d'acide (-) - (L) -3- (3, 4-dihydroxyphényl) - 2 -hydrazino-2 -méthylpropionique (carbidopa) représenté par la formule (II), comprenant l'utilisation d'une 3, 3 -pentaméthylène oxaziridine de formule (IV). Ce procédé consiste à faire réagir un ester L-a-méthyldopa méthyle de formule (III) avec la 3,3-penta- méthylene oxaziridine de formule (IV), à isoler l'ester méthylique d'acide (+) - (L) -2- (N' - cyclohexylidène-hydrazino) -3- (3, 4-dihydroxyphényl) -2 -méthylpropionique de formule (I), et à le soumettre à une hydrolyse avec un acide. L'ester méthylique d'acide (+) - (L) -2- (N' -cyclohexylidène-hydrazino) -3- (3, 4-dihydroxyphényl) -2-méthylpropionique de formule (I) est un nouvel intermédiaire. L'acide (-) - (L) -3- (3, 4-dihydroxyphényl) -2-hydrazino-2- méthyl propionique (carbidopa) de (XI) obtenu par ce procédé est un ingrédient actif thérapeutique utile possédant la dénomination internationale commune carbidopa.
PCT/HU2006/000092 2005-10-12 2006-10-12 Procede de preparation de carbidopa Ceased WO2007042848A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU0500940A HU227283B1 (en) 2005-10-12 2005-10-12 Process for the preparation of carbidopa
HUP0500940 2005-10-12

Publications (2)

Publication Number Publication Date
WO2007042848A2 true WO2007042848A2 (fr) 2007-04-19
WO2007042848A3 WO2007042848A3 (fr) 2007-05-31

Family

ID=89986337

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2006/000092 Ceased WO2007042848A2 (fr) 2005-10-12 2006-10-12 Procede de preparation de carbidopa

Country Status (2)

Country Link
HU (1) HU227283B1 (fr)
WO (1) WO2007042848A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432496A (zh) * 2011-12-23 2012-05-02 浙江手心医药化学品有限公司 一种卡比多巴的精制方法
CN102702019A (zh) * 2012-06-16 2012-10-03 山东新华制药股份有限公司 卡比多巴的合成方法
CN114478303A (zh) * 2022-02-23 2022-05-13 浙江野风药业股份有限公司 一种卡比多巴的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DD240818A3 (de) * 1981-02-10 1986-11-19 Ernst Schmitz Verfahren zur herstellung von hydrazinocarbonsaeurederivaten durch n-aminierung von aminocarbonsaeurederivaten
DD230865B1 (de) * 1982-08-09 1987-05-20 Dresden Arzneimittel Verfahren zur herstellung von hydrazinocarbonsaeurederivaten durch n-aminierung von aminocarbonsaeurederivaten
DE19700061A1 (de) * 1997-01-03 1998-07-09 Hoechst Schering Agrevo Gmbh Verfahren zur Herstellung von cyclischen N-Aminosulfonamiden

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102432496A (zh) * 2011-12-23 2012-05-02 浙江手心医药化学品有限公司 一种卡比多巴的精制方法
CN102702019A (zh) * 2012-06-16 2012-10-03 山东新华制药股份有限公司 卡比多巴的合成方法
CN114478303A (zh) * 2022-02-23 2022-05-13 浙江野风药业股份有限公司 一种卡比多巴的合成方法

Also Published As

Publication number Publication date
WO2007042848A3 (fr) 2007-05-31
HU0500940D0 (en) 2005-12-28
HU227283B1 (en) 2011-01-28
HUP0500940A2 (en) 2007-05-29

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