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WO2019167058A1 - An improved process for the preparation of propiomazine maleate - Google Patents

An improved process for the preparation of propiomazine maleate Download PDF

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Publication number
WO2019167058A1
WO2019167058A1 PCT/IN2019/050128 IN2019050128W WO2019167058A1 WO 2019167058 A1 WO2019167058 A1 WO 2019167058A1 IN 2019050128 W IN2019050128 W IN 2019050128W WO 2019167058 A1 WO2019167058 A1 WO 2019167058A1
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WIPO (PCT)
Prior art keywords
formula
propiomazine
preparation
maleate
base
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/IN2019/050128
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French (fr)
Inventor
Kannasani RAVI KUMAR
Kasa Mallik Yadav
Mula SREENU
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RA Chem Pharma Ltd
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RA Chem Pharma Ltd
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Publication date
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Priority to EP19760246.9A priority Critical patent/EP3759081A4/en
Publication of WO2019167058A1 publication Critical patent/WO2019167058A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
    • C07D279/24—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
    • C07D279/28—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom with other substituents attached to the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

  • Propiomazine maleate of formula-I is a phenothiazine derivative, chemically known as 1-[10-(2-dimethylaminopropyl)-10H-phenothiazin-2-yl]propan-1-one maleate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an improved process for the preparation of highly pure Propiomazine Maleate of formula-I. More particularly, the invention relates to a cost-effective process, which provides Propiomazine maleate of formula-I with high purity, which is free from isomeric impurity of formula-III, specifically isopropiomazine. The isomeric impurity is controlled during the preparation of Propiomazine maleate. (I)

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF PROPIOMAZINE MALEATE
The present invention relates to an improved process for the preparation of Propiomazine maleate. More particularly, the invention relates to a cost-effective process, which provides Propiomazine maleate of formula-I with high purity, which is free from isomeric impurity, specifically isopropiomazine.
[Chem .1]
Figure pctxmlib-appb-I000002
Propiomazine maleate of formula-I is a phenothiazine derivative, chemically known as 1-[10-(2-dimethylaminopropyl)-10H-phenothiazin-2-yl]propan-1-one maleate.
[Chem .2]
Figure pctxmlib-appb-I000003
Propiomazine is an antihistamine drug, which acts by blocking H1 receptors. It is used to treat insomnia, and to produce sleepiness or drowsiness and to relieve anxiety before or during surgery or other procedures and in combination with analgesics also during labor. Propiomazine is a derivative of Phenothiazine.
The process for preparation of Propiomazine has been discussed in “Kathleen B. Crombie and Leo F. Cullen. Analytical profiles of drug substances., pp 439-466 (1973)” which reported two synthetic routes for the preparation of Propiomazine hydrochloride.
According to the above review artic le, one of the two synthetic routes is illustrated in Scheme-1 discloses the preparation of Propiomazine base by reacting 2-dimethylaminopropyl chloride with 2-propionylphenothiazine in the presence of sodium amide as the condensing agent, and subsequently converting the base form to the hydrochloride.
[Chem .3]
Figure pctxmlib-appb-I000004
The other synthesis route is illustrated in Scheme-2, which was developed by Establissements Clin-RylaB for the preparation of Propiomazine hydrochloride is based on the decarboxylation by heating of the aminoalkyl ester of the N-carboxyphenothiazine. Specifically 2-propionylphenothiazine is converted in to its N-carbonyl chloride derivative by reacting with phosgene. Reaction of the chloride with 2-dimethylamino-1-propanol yields the ester hydrochloride, which is decarboxylated by heating to obtain Propiomazine hydrochloride.
[Chem .4]
Figure pctxmlib-appb-I000005
The above mentioned routes for Propiomazine hydrochloride have considerable disadvantages, which involve multiple steps for the synthesis and use of expensive starting materials.
Synthesis of Propiomazine maleate has not been disclosed in any literature which is available in the public domain.
The present inventors have now found a simple, cost-effective process, which provides propiomazine maleate with high purity and free from isopropiomazine impurity.
Object of the Invention
The main object of the present invention is to provide simple, cost-effective and industrially viable method for the preparation of Propiomazine maleate of formula-I on commercial scale.
The main aspect of the present invention is to provide an improved process for the preparation of Propiomazine maleate of formula-I.
[Chem .5]
Figure pctxmlib-appb-I000006
The first aspect of the present invention is to provide an improved process for the preparation of 1-[10-(2-dimethylaminopropyl)-10H-phenothiazin-2-yl]propan-1-one of formula-II comprises the steps of reacting hydrochloride salt of 2-dimethylaminoisopropyl chloride with 2-propionyl phenothiazine in presence of a base and suitable solvent which is selected from the group comprising of toluene, xylene, preferably toluene.
[Chem .6]
Figure pctxmlib-appb-I000007
The second aspect of the present invention is process for preparation of Propiomazine maleate with high purity which is free from isomeric impurity of formula-III. The isomeric impurity produced during the preparation of Propiomazine base of formula II is controlled during the preparation of Propiomazine maleate. The Propiomazine base of formula II is dissolved in alcoholic media to get a clear solution. Addition of maleic acid to the above clear solution produces Propiomazine maleate of formula-I which is free from isomeric impurity.
[Chem .7]
Figure pctxmlib-appb-I000008
The present invention relates to an improved process for the preparation of Propiomazine maleate of formula-I and its purification from the undesired isomeric impurity. i.e., isopropiomazine of formula-III.
The first embodiment of the present invention is an improved process for the preparation of 1-[10-(2-dimethylaminopropyl)-10H-phenothiazin-2-yl]propan-1-one of formula-II, which comprises condensing 2-propionyl phenothiazine of formula –IV
Figure pctxmlib-appb-C000001
with hydrochloride salt of 2-dimethylaminoisopropyl chloride of formula-V
[Chem .9]
Figure pctxmlib-appb-I000009

in presence of a base and suitable solvent to obtain the compound of Propiomazine base of formula-II.
The process is schematically represented as below:
[Chem .10]
Figure pctxmlib-appb-I000010
Further embodiment of the present invention relates to process for preparation of Propiomazine maleate with high purity and free from isopropiomazine impurity of formula-III. The isomeric impurity is controlled during the preparation of Propiomazine maleate. The crude Propiomazine base obtained in the above condensation step contains isomeric impurity of 20-25%. The Propiomazine base of formula II is dissolved in alcoholic media to get a clear solution. Addition of maleic acid to the above clear solution produces Propiomazine maleate of formula-I which is free from isomeric impurity.
The process is schematically represented as below:
[Chem .11]
Figure pctxmlib-appb-I000011

According to one embodiment of the present invention the base used in condensation step is selected from potassium hydroxide, sodium hydroxide, potassium tertiary butoxide, preferably potassium hydroxide.
According to another embodiment of the present invention solvent used in condensation step is selected from the group comprising of toluene, xylene, preferably toluene.
According to yet another embodiment of the present invention alcoholic media used in purification step is selected from methanol, ethanol, isopropyl alcohol, preferably methanol.
The present invention can be illustrated in the following non- limiting example.
Examples
Preparation of Propiomazine maleate: To a stirred solution of 2-dimethylaminoisopropyl chloride hydrochloride (67.5 gm, 0.427 mole) in water (50 ml) and Toluene (250 ml) mixture was basified with aqueous sodium hydroxide solution at below 10oC and separate the organic layer. To obtained base toluene layer was added 2-propionyl phenothiazine (50 gm, 0.171 mole) and potassium hydroxide flakes (19 gm, 0.342 mole) at below 10oC. Reaction mixture temperature was slowly heated to reflux and maintained for 5-6 hrs under azeotropic condition. Progress of the reaction was monitored/ confirmed by HPLC. After completion of reaction, the reaction mixture was cooled to 25-30oC and water (200 ml) was added and stirred for 10-15 minutes. The organic layer was separated and concentrated to get Propiomazine crude compound. Crude compound was dissolved in methanol (200 ml) and stirred for 10-15 minutes at 25-30oC to get clear solution, Maleic acid (20 gm) was added to the above clear solution and stirring was continued for another 4-5 hrs at 25-30oC and the precipitated solid was filtered and dried to get Propiomazine maleate in pure form. Yield: 34 gms.
Purity: greater than 99.5% and isopropiomazine content below 0.10% by HPLC.

Claims (9)

  1. An improved process for the preparation of Propiomazine of formula-II, comprising condensing 2-propionyl phenothiazine of formula –IV.
    Figure pctxmlib-appb-C000002
    with hydrochloride salt of 2-dimethylaminoisopropyl chloride of formula-V
    Figure pctxmlib-appb-C000003
    in presence of a base and suitable solvent to obtain the compound of Propiomazine of formula II.
    Figure pctxmlib-appb-C000004
  2. Process for the preparation of Propiomazine Maleate of formula-I, comprising condensing 2-propionyl phenothiazine of formula –IV
    Figure pctxmlib-appb-C000005
    with hydrochloride salt of 2-dimethylaminoisopropyl chloride of formula-V
    Figure pctxmlib-appb-C000006
    in presence of a base and suitable solvent to obtain the compound of Propiomazine
    of formula II.
    Figure pctxmlib-appb-C000007
    which is further dissolved in alcoholic media to get clear solution and added maleic acid to obtain the compound of Propiomazine maleate of formula-I,
    Figure pctxmlib-appb-C000008
    which is free from isomeric impurity of formula-III.
    Figure pctxmlib-appb-C000009
  3. An improved process for the preparation of Propiomazine of formula-II, comprising condensing 2-propionyl phenothiazine of formula –IV
    Figure pctxmlib-appb-C000010
    with hydrochloride salt of 2-dimethylaminoisopropyl chloride of formula-V
    Figure pctxmlib-appb-C000011
    in presence of a base and toulene to obtain the compound of Propiomazine of formula II.
    Figure pctxmlib-appb-I000012
  4. An improved process for the preparation of Propiomazine of formula-II, comprising condensing 2-propionyl phenothiazine of formula –IV
    Figure pctxmlib-appb-C000012
    with hydrochloride salt of 2-dimethylaminoisopropyl chloride of formula-V
    Figure pctxmlib-appb-C000013
    in presence of a potassium hydroxide and suitable solvent to obtain the compound of Propiomazine of formula II.
    Figure pctxmlib-appb-C000014
  5. The process claimed in claim 1, 2 and 3 base is selected from group comprising of Potassium hydroxide, sodium hydroxide, potassium tertiary butoxide.
  6. The process claimed in claim 1, 2 and 4 solvent is selected from the group comprising of Toluene, xylene.
  7. The process for the preparation of Propiomazine maleate, comprising Propiomazine base of formula II is dissolved in alcoholic media to get a clear solution and added maleic acid to obtain the compound of Propiomazine maleate of formula I, which is free from isomeric impurity of formula-III.
    Figure pctxmlib-appb-C000015
    Figure pctxmlib-appb-C000016
  8. Propiomazine maleate having purity of greater than 99.5% wherein the isomeric impurity of formula III is below 0.10% by HPLC.
  9. The process claimed in claim 7, alcoholic media is selected from the group comprising methanol, ethanol, isopropyl alcohol preferably methanol.
PCT/IN2019/050128 2018-02-27 2019-02-18 An improved process for the preparation of propiomazine maleate Ceased WO2019167058A1 (en)

Priority Applications (1)

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EP19760246.9A EP3759081A4 (en) 2018-02-27 2019-02-18 IMPROVED PROCESS FOR THE PREPARATION OF PROPIOMAZINE MALEATE

Applications Claiming Priority (2)

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IN201841007386 2018-02-27
IN201841007386 2018-02-27

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118598824A (en) * 2024-06-03 2024-09-06 海南海和制药有限公司 A kind of synthetic method of promethazine hydrochloride

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KATHLEEN B CROMBIE , LEO F CULLEN : "Propiomazine Hydrochloride", ANALYTICAL PROFILES OF DRUG SUBSTANCES , vol. 2, 30 November 1973 (1973-11-30), pages 439 - 466, XP009523596, ISSN: 0099-5428, DOI: 10.1016/S0099-5428(08)60050-7 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118598824A (en) * 2024-06-03 2024-09-06 海南海和制药有限公司 A kind of synthetic method of promethazine hydrochloride

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EP3759081A1 (en) 2021-01-06

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