WO2014060908A1 - Improved process for preparation of revaprazan hydrochloride - Google Patents

Improved process for preparation of revaprazan hydrochloride Download PDF

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Publication number
WO2014060908A1
WO2014060908A1 PCT/IB2013/059225 IB2013059225W WO2014060908A1 WO 2014060908 A1 WO2014060908 A1 WO 2014060908A1 IB 2013059225 W IB2013059225 W IB 2013059225W WO 2014060908 A1 WO2014060908 A1 WO 2014060908A1
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methyl
process according
tetra
butyl
revaprazan
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PCT/IB2013/059225
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French (fr)
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Shahid Akhtar Ansari
Hitin Maganbhai HIRPARA
Nikhil Shashikant BHATT
Ashok Keshavlal YADAV
Jitendrakumar Shantilal PRAJAPATI
Reenaben Ratansing Baria
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Lupin Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to improved process for preparation of revaprazan hydrochloride in a high yield and purity.
  • Revaprazan hydrochloride is chemically known as 4-(3,4-dihydro-l-mefhyl-2(lH)- isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine hydrochloride and represented by formula I.
  • Revaprazan hydrochloride (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and, therefore, can be used as an anti-ulcer agent.
  • Revaprazan hydrochloride (I) was first disclosed in patent US 5,750,531 , along with its process for preparation as depicted in scheme 1.
  • the synthesis involve reaction of 5, 6- dimethyl-2, 4-dichloro pyrimidine (II) and 1 -methyl- 1, 2, 3,4-tetrahydroisoquinoline (III) to produce 5, 6-dimethyl-4-(l -methyl- l ,2,3,4-tetrahydroisoquinolin-2-yl)-2- chloropyrimidine (IV) which is purified by column chromatography. Pure compound (IV) is reacted with 4-fluorophenyl amine (V) to obtain revaprazan (VI).
  • Scheme 1 Process for preparation ofrevaprazan hydrochloride (I) as given in US 5,750,531.
  • Scheme 2 Process for preparation ofrevaprazan hydrochloride as given in US 6,252,076.
  • Figure 1 X-ray powder diffraction pattern of revaprazan hydrochloride.
  • the present invention provides process for preparation of revaprazan hydrochloride (I) comprising reaction of l-methyl-l ,2,3,4-tetrahydroisoquinoline (III) compound (VII)
  • R is a good leaving group selected from in presence of phase transfer catalyst and solvent to give revaprazan (VI) and followed by treatment with hydrochloride acid.
  • Revaprazan hydrochloride (I) can be optionally purified.
  • the present invention provides process for preparation of revaprazan hydrochloride (I) comprising reaction of 1 -methyl- 1,2,3,4- tetrahydroisoquinoline (III) with compound (VII) wherein R is a good leaving group selected from is F, CI, Br, I,
  • the phase transfer catalyst is selected from tetrabutylarmnomurn bromide ⁇ ⁇ tetra butyl ammonium chloride, benzyl tri butyl ammonium chloride, benzyl tri ethyl ammonium chloride, tetra ethyl ammonium bromide, tetra ethyl ammonium chloride, tetra propyl ammonium bromide, cetyltrimethyl ammonium bromide, ethyl tri phenyl phosphonium bromide, tetra butyl phosphonium chloride, tetra butyl phosphonium bromide, tetra phenyl phosphonium bromide and methyl tri phenyl phosphonium bromide, polyethylene glycol; preferably TBAB.
  • the reaction can be carried out in solvent selected form esters such as ethyl acetate, butyl acetate etc.; chlorinated hydrocarbons such as dichlorome thane, chloroform, ethylene dichloride etc.; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc., nitriles such as acetonitrile, propionitrile etc.; ether such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxan etc.; alcohols such as tert-butyl alcohol etc.; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone etc.; dimethyl sulfoxide, sulfolane; aromatic hydrocarbons such as benzene, toluene, xylene etc.; or mixtures thereof; preferably methyl isobutyl
  • the phase transfer catalyst can be employed in the range of 5 to 20%, preferably 10-20%, weight/weight of4-halide-2-(4-fluorophenylamino)-5, 6- dimethylpyrimidine (VII).
  • the compound 1 -methyl- 1, 2, 3,4-tetrahydroisoquinoline (III) can be used in slight molar excess, preferably 1.1 to 1.5 moles, of 4-halide-2-(4- fluorophenylamino)-5,6-dimethylpyrimidine (VII).
  • Revaprazan (VI) is converted to revaprazan hydrochloride (I) by treating with hydrochloride acid.
  • Revaprazan hydrochloride (I) can be isolated from the reaction mixture by techniques known in art like filtration, concentration, evaporation of the solvent etc. Yield of revaprazan hydrochloride (I) was 97-100%.
  • Revaprazan hydrochloride (I) can be optionally purified by crystallization froman alcoholic solvent like methanol, isopropanol, tert-butanol etc., preferably methanol.
  • the present invention provides revaprazan hydrochloride (I) with purity of >99.9%, by HPLC.
  • the X-ray powder diffraction pattern of revaprazan hydrochloride (I) is as depicted in figure- 1. It shows characteristic peaks at 7.41, 10.33, 12.26, 13.34, 16.34, 16.97, 17.66, 19.66, 20.84, 22.22, 23.35, 24.26, 25.51, 25.73, 26.05, 27.12 ⁇ °2Theta.
  • the X-ray diffraction pattern was measured using PANalytical, X'pert PRO machine with parameters as: scan axis: gonio; step size: 0.0083°; scan mode: continuous; anode material: Cu; radiation type: K-alpha 1 and scan angle (°): 3.5 to 39.98.
  • Revaprazan hydrochloride (I) obtained by the present invention exhibit a particle size of d(0.5) of about 20-30 micron and d(0.9) of about 120-130 micron.
  • the micronized revaprazan hydrochloride exhibit a particle size of d(0.5) of about 2-5 micron and d(0.9) of about 6-8 micron.
  • the manufacture of revaprazan hydrochloride (I) as per the process of present invention is advantageous in that the process iseconomical due to high yield, provides revaprazan hydrochloride with high purity and is commercially viable.
  • the present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
  • Example 1 process for preparation of revaprazan hydrochloride (I):
  • revaprazan hydrochloride (I) (4.58 Kg) and methanol (27.5 L) was heated to 60-65°C to get clear solution.
  • the solution was filtered through hyflo bed.
  • the solution was heated to 60-65°C and methanol (about 22 L) was distilled out under atmospheric pressure.
  • the mixture was cooled to 0-5°C.
  • the solid was filtered, washed with methanol and dried under vacuum. Yield: 3.72 Kg (81%); HPLC purity: 99.95%.

Abstract

The present invention provides improved process for preparation of revaprazan hydrochloride (I) comprising reaction of l-methyl-l,2,3,4-tetrahydroisoquinoline (III) withcompound (VII) wherein R is a good leaving group selected from F, Cl, Br, I, (1), (2), (3) in presence of phase transfer catalyst and solvent to give revaprazan (VI) and followed by treatment with hydrochloride acid.

Description

IMPROVED PROCESS FOR PREPARATION OF REVAPRAZAN
HYDROCHLORIDE
FIELD OF INVENTION
The present invention relates to improved process for preparation of revaprazan hydrochloride in a high yield and purity. BACKGROUND OF THE INVENTION
Revaprazan hydrochloride is chemically known as 4-(3,4-dihydro-l-mefhyl-2(lH)- isoquinolinyl)-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine hydrochloride and represented by formula I.
Figure imgf000002_0001
Revaprazan hydrochloride (I) inhibits gastric acid secretion by means of a reversible proton-pump inhibiting effect and, therefore, can be used as an anti-ulcer agent.
Revaprazan hydrochloride (I) was first disclosed in patent US 5,750,531 , along with its process for preparation as depicted in scheme 1. The synthesis involve reaction of 5, 6- dimethyl-2, 4-dichloro pyrimidine (II) and 1 -methyl- 1, 2, 3,4-tetrahydroisoquinoline (III) to produce 5, 6-dimethyl-4-(l -methyl- l ,2,3,4-tetrahydroisoquinolin-2-yl)-2- chloropyrimidine (IV) which is purified by column chromatography. Pure compound (IV) is reacted with 4-fluorophenyl amine (V) to obtain revaprazan (VI).
Figure imgf000003_0001
(VI) (IV)
Scheme 1: Process for preparation ofrevaprazan hydrochloride (I) as given in US 5,750,531.
Another patent US 6,252,076 provides process for preparation of revaprazan hydrochloride (I) as depicted in scheme 2. Reaction of 1 -methyl- 1,2,3,4- tetrahydroisoquinoline (III) and 4-chloro-2-(4-fluorophenylamino)-5,6- dimethylpyrimidine (VII, R=C1) is carried out in presence of base and solvent to give revaprazan (VI) followed by treatmentwith hydrochloride acid to provide revaprazan hydrochloride (I) in a yield upto91%.
Figure imgf000003_0002
Scheme 2: Process for preparation ofrevaprazan hydrochloride as given in US 6,252,076.
The synthesis of US 5,750,531, suffers a severe drawback of side reactions which leads to formation of contaminants like 2-(4-chloro-5,6-dimethylpyrimidin-2-yl)-l-methyl- 1 ,2,3,4-tetrahydroisoquinoline (VIII); 2,2'-(5,6-dimethylpyrimidine-2,4-diyl)bis(l- methyl-l ,2,3,4-tetrahydroisoquinoline) (IX) and the patent US 6,252,076 does not disclose purit of revaprazan hydrochloride (I) obtained.
Figure imgf000004_0001
In our hand, when reaction of compound (III) and (VII) was carried out in absence of base and presence of a phase transfer catalyst surprisingly revaprazan hydrochloride was obtained in very high yield and high HPLC purity.
DESCRIPTION OF DRAWING
Figure 1 :X-ray powder diffraction pattern of revaprazan hydrochloride.
SUMMARY OF THE INVENTION
The present invention provides process for preparation of revaprazan hydrochloride (I) comprising reaction of l-methyl-l ,2,3,4-tetrahydroisoquinoline (III) compound (VII)
Figure imgf000004_0002
(vii) wherein R is a good leaving group selected from
Figure imgf000004_0003
in presence of phase transfer catalyst and solvent to give revaprazan (VI) and followed by treatment with hydrochloride acid. Revaprazan hydrochloride (I) can be optionally purified. DETAILED DES CRIPTION OF THE INVENTION
In a preferred embodiment, the present invention provides process for preparation of revaprazan hydrochloride (I) comprising reaction of 1 -methyl- 1,2,3,4- tetrahydroisoquinoline (III) with compound (VII) wherein R is a good leaving group selected from is F, CI, Br, I,
Figure imgf000005_0001
in presence of phase transfer catalyst and solvent to give revaprazan (VI) andfollowed by treatment with hydrochloride acid, wherein R is a good
The phase transfer catalyst is selected from tetrabutylarmnomurn bromide Π ΗΛΗ tetra butyl ammonium chloride, benzyl tri butyl ammonium chloride, benzyl tri ethyl ammonium chloride, tetra ethyl ammonium bromide, tetra ethyl ammonium chloride, tetra propyl ammonium bromide, cetyltrimethyl ammonium bromide, ethyl tri phenyl phosphonium bromide, tetra butyl phosphonium chloride, tetra butyl phosphonium bromide, tetra phenyl phosphonium bromide and methyl tri phenyl phosphonium bromide, polyethylene glycol; preferably TBAB.
The reaction can be carried out in solvent selected form esters such as ethyl acetate, butyl acetate etc.; chlorinated hydrocarbons such as dichlorome thane, chloroform, ethylene dichloride etc.; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone etc., nitriles such as acetonitrile, propionitrile etc.; ether such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxan etc.; alcohols such as tert-butyl alcohol etc.; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone etc.; dimethyl sulfoxide, sulfolane; aromatic hydrocarbons such as benzene, toluene, xylene etc.; or mixtures thereof; preferably methyl isobutyl ketone and xylene. Thereaction is carried out at a temperature of 75 to 200°C, preferably 100 to 150°C.
In the reaction, the phase transfer catalyst can be employed in the range of 5 to 20%, preferably 10-20%, weight/weight of4-halide-2-(4-fluorophenylamino)-5, 6- dimethylpyrimidine (VII). The compound 1 -methyl- 1, 2, 3,4-tetrahydroisoquinoline (III) can be used in slight molar excess, preferably 1.1 to 1.5 moles, of 4-halide-2-(4- fluorophenylamino)-5,6-dimethylpyrimidine (VII).
Revaprazan (VI) is converted to revaprazan hydrochloride (I) by treating with hydrochloride acid. Revaprazan hydrochloride (I) can be isolated from the reaction mixture by techniques known in art like filtration, concentration, evaporation of the solvent etc. Yield of revaprazan hydrochloride (I) was 97-100%.
Revaprazan hydrochloride (I) can be optionally purified by crystallization froman alcoholic solvent like methanol, isopropanol, tert-butanol etc., preferably methanol.
The present invention provides revaprazan hydrochloride (I) with purity of >99.9%, by HPLC. The X-ray powder diffraction pattern of revaprazan hydrochloride (I) is as depicted in figure- 1. It shows characteristic peaks at 7.41, 10.33, 12.26, 13.34, 16.34, 16.97, 17.66, 19.66, 20.84, 22.22, 23.35, 24.26, 25.51, 25.73, 26.05, 27.12 ±°2Theta.The X-ray diffraction pattern was measured using PANalytical, X'pert PRO machine with parameters as: scan axis: gonio; step size: 0.0083°; scan mode: continuous; anode material: Cu; radiation type: K-alpha 1 and scan angle (°): 3.5 to 39.98.
Revaprazan hydrochloride (I) obtained by the present invention exhibit a particle size of d(0.5) of about 20-30 micron and d(0.9) of about 120-130 micron. The micronized revaprazan hydrochloride exhibit a particle size of d(0.5) of about 2-5 micron and d(0.9) of about 6-8 micron. The manufacture of revaprazan hydrochloride (I) as per the process of present invention is advantageous in that the process iseconomical due to high yield, provides revaprazan hydrochloride with high purity and is commercially viable. The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.
EXAMPLES:
Example 1: process for preparation of revaprazan hydrochloride (I):
A mixture of4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine (VII) (1.5 Kg), 1- methyl-l,2,3,4-tetrahydroisoquinoline (III) (1.32 Kg),and TBAB (0.15 Kg) in methyl isobutyl ketone (12 L) was heated to 115-119°C for 48 hours. The reaction mixture was cooled to 25-30°C and water (3.2 L) was added to it. The pH of the reaction mixture was adjusted to about 0.6 with cone. HC1. The reaction mixture was cooled to 0-5°C and stirred for 3 hours. The solid was filtered, washed with water and dried under vacuum. Yield: 2.31 Kg (97.46%); HPLC purity: 98.34%.
Example 2: process for preparation of revaprazan hydrochloride (I):
A mixture of4-chloro-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine (VII) (50 g), 1- methyl-l,2,3,4-tetrahydroisoquinoline (III) (43.86 g),and TBAB (5 g) in xylene (400 ml) was heated to 135-140°C for 33 hours. The reaction mixture was cooled to 25-30°C and water (100 ml) was added to it. The pH of the reaction mixture was adjusted to about 0.6 with cone. HC1. The reaction mixture was cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with water and dried under vacuum. Yield: quantitative.
Example 3: purification of revaprazan hydrochloride (I):
A mixture of revaprazan hydrochloride (I) (4.58 Kg) and methanol (27.5 L) was heated to 60-65°C to get clear solution. The solution was filtered through hyflo bed. The solution was heated to 60-65°C and methanol (about 22 L) was distilled out under atmospheric pressure. The mixture was cooled to 0-5°C. The solid was filtered, washed with methanol and dried under vacuum. Yield: 3.72 Kg (81%); HPLC purity: 99.95%.

Claims

CLAIMS :
1. A process for preparation of revaprazan hydrochloride (I)
Figure imgf000008_0001
comprising reaction of l-methyl-l,2,3,4-tetrahydroisoquinoline (III)
Figure imgf000008_0002
(HI)
with 4-halide-2-(4-fluorophenylamino)-5,6-dimethylpyrimidine (VII)
Figure imgf000008_0003
(vi i)
from is F, CI, Br, I,
Figure imgf000008_0004
in presence of phase transfer catalyst and solvent to give revaprazan (VI)
Figure imgf000009_0001
(VI) and followed by treatment with hydrochloride acid.
A process according to claim 1 wherein, the phase transfer catalyst is selected from tetra butyl ammonium bromide, tetra butyl ammonium chloride, benzyl tri butyl ammonium chloride, benzyl tri ethyl ammonium chloride, tetra ethyl ammonium bromide, tetra ethyl ammonium chloride, tetra propyl ammonium bromide, cetyl tri methyl ammonium bromide, ethyl tri phenyl phosphonium bromide, tetra butyl phosphonium chloride, tetra butyl phosphonium bromide, tetra phenyl phosphonium bromide and methyl tri phenyl phosphonium bromide, polyethylene glycol.
A process according to claim 2 wherein, the phase transfer catalyst istetra butyl ammonium bromide.
A process according to claim 1 wherein, solvent is selected form esters such as ethyl acetate, butyl acetate; chlorinated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles such as acetonitrile, propionitrile; ether such as diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxan; alcohols such as tert-butyl alcohol; amides such as dimethylformamide, dimethylacetamide, N-methyl pyrrolidone; dimethyl sulfoxide; sulfolane; aromatic hydrocarbons such as benzene, toluene, xylene; or mixtures thereof.
A process according to claim 4 wherein, solvent is methyl isobutyl ketone or xylene. A process according to claim 1 wherein,reaction is carried out at a temperature of 75 to 200°C.
A process according to claim 1 wherein, the phase transfer catalyst is employed as 5 to 20% weight/weight of 4-halide-2-(4-fluorophenylamino)-5, 6- dimethylpyrimidine (VII).
A process according to claim 1 wherein, 1 -methyl- 1, 2, 3, 4- tetrahydroisoquinoline (III) is employed in 1.1 to 1.5 moles of 4-halide-2-(4- fluorophenylamino)-5,6-dimethylpyrimidine (VII).
A process according to claim 1 wherein, revaprazan hydrochloride can be optionally purified by crystallization from an alcoholic solvent like methanol, isopropanol, tert-butanol.
A process according to claim 9 wherein, revaprazan hydrochloride is purified by crystallizationfrom methanol.
PCT/IB2013/059225 2012-10-17 2013-10-09 Improved process for preparation of revaprazan hydrochloride WO2014060908A1 (en)

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Cited By (8)

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CN105399727A (en) * 2015-12-02 2016-03-16 芷威（上海）化学科技有限公司 Novel revaprazan hydrochloride crystalline form
CN105601611A (en) * 2014-11-19 2016-05-25 江苏天士力帝益药业有限公司 Revaprzan hydrochloride polymorphic substance and preparation method thereof
WO2016078542A1 (en) * 2014-11-19 2016-05-26 江苏天士力帝益药业有限公司 Preparation method for revaprazan hydrochloride
CN106995431A (en) * 2016-01-25 2017-08-01 广东华南药业集团有限公司 A kind of auspicious pula life hydrate crystal forms and its production and use
CN106995432A (en) * 2016-01-25 2017-08-01 广东华南药业集团有限公司 A kind of auspicious pula life is without hydrate crystal forms and its production and use
CN107759562A (en) * 2016-08-21 2018-03-06 常州四药制药有限公司 A kind of preparation method of hydrochloric acid revaprzan
WO2019221522A1 (en) * 2018-05-18 2019-11-21 Yuhan Corporation Novel processes for preparing a diaminopyrimidine derivative or acid addition salt thereof
JP7474754B2 (en) 2018-05-18 2024-04-25 ユーハン・コーポレイション Novel process for producing diaminopyrimidine derivatives or acid addition salts thereof

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