WO2007029155A2 - An improved process for preparation of pure celiprolol base - Google Patents

An improved process for preparation of pure celiprolol base Download PDF

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WO2007029155A2
WO2007029155A2 PCT/IB2006/053073 IB2006053073W WO2007029155A2 WO 2007029155 A2 WO2007029155 A2 WO 2007029155A2 IB 2006053073 W IB2006053073 W IB 2006053073W WO 2007029155 A2 WO2007029155 A2 WO 2007029155A2
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celiprolol
acid
base
crude
acetate
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PCT/IB2006/053073
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French (fr)
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WO2007029155A3 (en
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Naresh Kumar
Sandeep Nayyar
Manu Mahendru
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
    • C07C273/189—Purification, separation, stabilisation, use of additives

Definitions

  • the present invention relates to an improved process for preparing pure celiprolol base in monohydrate form by crystallizing crude celiprolol base in one or more carboxylic acid ester solvents and its conversion to pharmaceutically acceptable acid addition salts, for example, celiprolol hydrochloride Form I in high purity.
  • Celiprolol a beta-blocker class antihypertensive agent, is chemically N'-(3-acetyl-4- (3-((l,l-dimethylethyl)amino)-2-hydroxypropoxy)phenyl)-N,N-diethyl urea and is disclosed in U.S. Patent No. 4,034,009. Celiprolol is represented by Formula (I)
  • Medically used aryloxy-propanolamines should be prepared in high purity levels.
  • medical preparations containing aryloxy-propanolamines should either contain no or only traces of by-products from its synthesis.
  • Current industrial synthetic processes for the preparation of l-aryloxy-3-amino-2-propanols form crude products containing many impurities, the removal of which is very difficult.
  • Such industrial synthetic processes include, for example, reacting a corresponding l-aryloxy-2, 3 -epoxy -propane with an amine as described in /. Med. Chem. 1971, 14(6), 511-513.
  • Impurity B 1,3-bis [3-acetyl-4- [3-[(l,l-dimethylethyl) amino] -2-hydroxy- propoxy] phenyl] urea.
  • Impurity E l,l'-[[(l,l-dimethylethyl) imino] bis [(2-hydroxypropane-l, 3-diyl) oxy (3- acetyl-1, 4-phenylene)]] bis (3,3-diethylurea)
  • Various processes are disclosed in purifying aryloxy-propanolamines.
  • U.S. Patent No. 4,849,530 describes the purification of celiprolol base via diphenyl acetate salt of celiprolol. The method involves converting the salt into the base, which comprises multiple stages, rendering this method undesirable in preparing such compounds on an industrial scale.
  • celiprolol base having a melting point of 110-117 0 C for the preparation of celiprolol hydrochloride does not consistently result in Form I.
  • celiprolol base which has been dried at a temperature below 70 0 C, more preferably below 55 0 C with a moisture content of less than 5 % w/w and having melting point 80-100 0 C, leads to consistently forming Form I celiprolol hydrochloride.
  • Such a celiprolol base is characterized by its distinct infrared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 110 0 C.
  • the moisture content in the celiprolol base may vary from 2-5 % w/w but it generally remains as a monohydrate (4.5 % w/w water content).
  • a process for the preparation of pure celiprolol base in monohydrate form comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature, and isolating the celiprolol base.
  • the process can include one or more of the following embodiments.
  • the solution of crude celiprolol base can be obtained by extracting a reaction mixture taken from the last step of a process in which crude celiprolol base is formed using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base.
  • the one or more carboxylic acid ester solvents can be selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof.
  • ambient temperature can be between about 10 0 C to about 40 0 C.
  • the celiprolol base can be isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof.
  • crystallization or precipitation can be carried out at a temperature from about 0 0 C to about 25 0 C.
  • the celiprolol base can be dried at a temperature from ambient temperature to about 80 0 C.
  • the celiprolol base can be substantially free of impurities having less than 0.20 % of total impurities, preferably less than about 0.1 % of total impurities.
  • the process further comprises the conversion of celiprolol base monohydrate to a pharmaceutically acceptable acid addition salts of celiprolol base by contacting celiprolol base monohydrate with one or more acids.
  • the one or more acids can be selected from hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids or mixtures thereof.
  • the acid addition salt of celiprolol base is celiprolol hydrochloride Form I.
  • From I comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; isolating the celiprolol base having essentially free of impurity C and E and converting celiprolol base into celiprolol hydrochloride Form I.
  • the celiprolol hydrochloride Form I has total impurities of less than about 0.1 %.
  • a process for preparing pure celiprolol base in monohydrate form comprising the steps of: a. providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; b. isolating the celiprolol base in monohydrate form.
  • Acid addition salts provided by such processes include, for example, celiprolol hydrochloride Form I in high purity.
  • a reaction mixture taken from the last step of a process in which crude celiprolol base is formed can be extracted using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base.
  • the extracted solution may be used as such without any further isolation steps.
  • Crude celiprolol base may be obtained from any synthetic route described in the prior art, including those described in, for example, U.S. Patent No. 4,034,009 and Canadian Patent Nos. 1,061,342 and 1,061,341, which are incorporated herein by the reference.
  • Suitable carboxylic acid ester solvents include, for example, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof.
  • Ambient temperatures are temperatures in the range of about 10 0 C to about 40 0 C.
  • Celiprolol base can be isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. Crystallization or precipitation may be performed at a temperature from about 0 0 C to about 25 0 C over about 2 hours to about 15 hours in some embodiments.
  • seed crystals may be added in order to improve the yield of celiprolol base.
  • Celiprolol base can be dried at temperatures from ambient temperature to about 80 0 C.
  • Celiprolol base obtained by the processes described herein is in monohydrate form having water content of about 4-5 %.
  • the amount of impurities B, C and E, as well as other impurities present in the final product vary with the solvent of crystallization.
  • celiprolol base substantially free of impurities may be isolated with about 0.20 % or less total impurity content including impurity B.
  • Processes described herein provides celiprolol base substantially free of impurities that contains no more than 0.20 % of total impurities. In contrast, previously known processes provide celiprolol base having impurity levels of about 1 to 2 %.
  • Celiprolol base obtained by the process described herein may be converted to its corresponding pharmaceutically acceptable acid addition salts.
  • Acids which are suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids and the like.
  • acid addition salts of celiprolol base may be prepared by adding respective acid in the mixture of celiprolol base and solvent followed by isolation.
  • Celiprolol hydrochloride Form I may be obtained by the process given in PCT Application No. WO 01/08633, which is incorporated herein by reference.
  • the European pharmacopoeia specifications for related substances of celiprolol hydrochloride are as follows: any one specified impurity: NMT 0.2%; any other impurity (known/unknown): NMT 0.1 %; total impurities: NMT 0.5 %.
  • Celiprolol hydrochloride obtained by celiprolol base prepared by present process has total impurities less than 0.1 %, which meets/exceeds the European pharmacopoeia requirements.
  • aqueous layer was washed with ethyl acetate (100 mL) and was mixed with activated carbon (5 g).
  • the pH of aqueous layer was adjusted to above 10 with sodium hydroxide solution (37 %).
  • the resulting solution was extracted twice with ethyl acetate
  • celiprolol base was dried at 30-35 0 C.
  • Example-2 Preparation of Celiprolol hydrochloride Form I: Celiprolol base (44 g) having water content of 4-5% was dissolved in a mixture of acetone (695 mL) and water (13.5 mL). The resulting clear solution was treated with activated carbon, filtered on a hyflo bed, which was washed with acetone (114 mL). The filtrate was cooled to 15-20 0 C and seeded with 1.7 g of celiprolol hydrochloride (Form-I). Concentrated hydrochloric acid (11.5 g) was then added to the reaction mixture to adjust the pH to 5.8-6.3 and the reaction mixture was stirred for 30 minutes at 15-20 0 C. Celiprolol hydrochloride was filtered and dried under vacuum.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an improved process for preparing pure celiprolol base in monohydrate form by crystallizing crude celiprolol base in one or more carboxylic acid ester solvents and its conversion to pharmaceutically acceptable acid addition salts, for example, celiprolol hydrochloride Form I in high purity.

Description

AN IMPROVED PROCESS FOR PREPARATION OF PURE CELIPROLOL BASE
Field Of The Invention The present invention relates to an improved process for preparing pure celiprolol base in monohydrate form by crystallizing crude celiprolol base in one or more carboxylic acid ester solvents and its conversion to pharmaceutically acceptable acid addition salts, for example, celiprolol hydrochloride Form I in high purity.
Background Of The Invention
Celiprolol, a beta-blocker class antihypertensive agent, is chemically N'-(3-acetyl-4- (3-((l,l-dimethylethyl)amino)-2-hydroxypropoxy)phenyl)-N,N-diethyl urea and is disclosed in U.S. Patent No. 4,034,009. Celiprolol is represented by Formula (I)
Figure imgf000002_0001
(I) Medically used aryloxy-propanolamines should be prepared in high purity levels. In particular, medical preparations containing aryloxy-propanolamines should either contain no or only traces of by-products from its synthesis. Current industrial synthetic processes for the preparation of l-aryloxy-3-amino-2-propanols form crude products containing many impurities, the removal of which is very difficult. Such industrial synthetic processes include, for example, reacting a corresponding l-aryloxy-2, 3 -epoxy -propane with an amine as described in /. Med. Chem. 1971, 14(6), 511-513.
Various synthesis processes for preparing celiprolol are disclosed in U.S. Patent No. 4,034,009 and Canadian Patent Nos. 1,061,342 and 1,061,341. In particular, these references disclose the extraction of a reaction mixture in which celiprolol base is formed with different solvents and evaporation of such solvents followed by triturating with ether. One major disadvantage of such a method is the use of ether solvent, which is prone to explosion, difficult to handle on an industrial scale and cause environmental problems. Also various impurities having analogous structures are produced or cannot be separated from the celiprolol base. These impurities include, for example, Impurities B, C and E:
Figure imgf000003_0001
Impurity B: 1,3-bis [3-acetyl-4- [3-[(l,l-dimethylethyl) amino] -2-hydroxy- propoxy] phenyl] urea.
and βnantiomer
Figure imgf000003_0002
Impurity C: Rl=CO-NH-C (CH3)3, R2=NH-C (CH3)3; l-{3-acetyl-4- [(2RS)-3-[(l,l- dimethy lethy 1) amino] -2-hy droxypropoxy ] phenyl] -3 -( 1 , 1 -dimethy lethy 1) urea.
Figure imgf000003_0003
Impurity E: l,l'-[[(l,l-dimethylethyl) imino] bis [(2-hydroxypropane-l, 3-diyl) oxy (3- acetyl-1, 4-phenylene)]] bis (3,3-diethylurea) Various processes are disclosed in purifying aryloxy-propanolamines. For example, U.S. Patent No. 4,849,530 describes the purification of celiprolol base via diphenyl acetate salt of celiprolol. The method involves converting the salt into the base, which comprises multiple stages, rendering this method undesirable in preparing such compounds on an industrial scale.
It has been observed that use of celiprolol base having a melting point of 110-117 0C for the preparation of celiprolol hydrochloride does not consistently result in Form I. However, it was observed that the use of celiprolol base which has been dried at a temperature below 70 0C, more preferably below 55 0C with a moisture content of less than 5 % w/w and having melting point 80-100 0C, leads to consistently forming Form I celiprolol hydrochloride. Such a celiprolol base is characterized by its distinct infrared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 110 0C. Depending on the drying time and technique for drying, the moisture content in the celiprolol base may vary from 2-5 % w/w but it generally remains as a monohydrate (4.5 % w/w water content). These observations are disclosed in PCT Application No. WO 01/08633.
Thus, there remains a need for improved purification processes for celiprolol base which are technically easy to carry out, effectively remove impurities and by-products, and provide highly pure product.
Summary Qf The Invention
Generally provided is a highly selective process for preparing highly pure celiprolol base substantially free of impurities. Such methods are simple, industrially advantageous, convenient and cost effective and more importantly does not suffer from the limitations associated with previously known methods. In addition, such a process is economically and commercially beneficial by employing solvents that minimize environmental and health concerns.
Thus provided herein is a process for the preparation of pure celiprolol base in monohydrate form comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature, and isolating the celiprolol base. The process can include one or more of the following embodiments. For example, the solution of crude celiprolol base can be obtained by extracting a reaction mixture taken from the last step of a process in which crude celiprolol base is formed using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base. In another embodiment, the one or more carboxylic acid ester solvents can be selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof. In yet another embodiment, ambient temperature can be between about 10 0C to about 40 0C.
In another embodiment, the celiprolol base can be isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. In another embodiment, crystallization or precipitation can be carried out at a temperature from about 0 0C to about 25 0C. In yet another embodiment, the celiprolol base can be dried at a temperature from ambient temperature to about 80 0C.
In other embodiments, the celiprolol base can be substantially free of impurities having less than 0.20 % of total impurities, preferably less than about 0.1 % of total impurities. In another embodiment, the process further comprises the conversion of celiprolol base monohydrate to a pharmaceutically acceptable acid addition salts of celiprolol base by contacting celiprolol base monohydrate with one or more acids. The one or more acids can be selected from hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids or mixtures thereof. Preferably, the acid addition salt of celiprolol base is celiprolol hydrochloride Form I. In another aspect, provided is a process for the preparation of celiprolol hydrochloride
From I comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; isolating the celiprolol base having essentially free of impurity C and E and converting celiprolol base into celiprolol hydrochloride Form I.
In one embodiment, the celiprolol hydrochloride Form I has total impurities of less than about 0.1 %. Detailed Description Qf The Invention
Thus, provided is a process for preparing pure celiprolol base in monohydrate form comprising the steps of: a. providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; b. isolating the celiprolol base in monohydrate form.
In another aspect, provided is a process of converting celiprolol base monohydrate to a pharmaceutically acceptable acid addition salt thereof. Acid addition salts provided by such processes include, for example, celiprolol hydrochloride Form I in high purity.
A reaction mixture taken from the last step of a process in which crude celiprolol base is formed can be extracted using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base. The extracted solution may be used as such without any further isolation steps.
Crude celiprolol base may be obtained from any synthetic route described in the prior art, including those described in, for example, U.S. Patent No. 4,034,009 and Canadian Patent Nos. 1,061,342 and 1,061,341, which are incorporated herein by the reference.
Suitable carboxylic acid ester solvents include, for example, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof.
Ambient temperatures are temperatures in the range of about 10 0C to about 40 0C. Celiprolol base can be isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. Crystallization or precipitation may be performed at a temperature from about 0 0C to about 25 0C over about 2 hours to about 15 hours in some embodiments.
For the crystallization, seed crystals may be added in order to improve the yield of celiprolol base.
Celiprolol base can be dried at temperatures from ambient temperature to about 80 0C. Celiprolol base obtained by the processes described herein is in monohydrate form having water content of about 4-5 %. The amount of impurities B, C and E, as well as other impurities present in the final product, vary with the solvent of crystallization. As demonstrated in the examples that follow, celiprolol base substantially free of impurities may be isolated with about 0.20 % or less total impurity content including impurity B.
Processes described herein provides celiprolol base substantially free of impurities that contains no more than 0.20 % of total impurities. In contrast, previously known processes provide celiprolol base having impurity levels of about 1 to 2 %.
Qualitative results as monitored by HPLC after crystallization of celiprolol base are tabulated herein below:
Figure imgf000007_0001
Celiprolol base obtained by the process described herein may be converted to its corresponding pharmaceutically acceptable acid addition salts.
Acids which are suitable for salt formation are, for example, hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids and the like.
In general, acid addition salts of celiprolol base may be prepared by adding respective acid in the mixture of celiprolol base and solvent followed by isolation.
Celiprolol hydrochloride Form I may be obtained by the process given in PCT Application No. WO 01/08633, which is incorporated herein by reference.
The European pharmacopoeia specifications for related substances of celiprolol hydrochloride are as follows: any one specified impurity: NMT 0.2%; any other impurity (known/unknown): NMT 0.1 %; total impurities: NMT 0.5 %. Celiprolol hydrochloride obtained by celiprolol base prepared by present process has total impurities less than 0.1 %, which meets/exceeds the European pharmacopoeia requirements.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Examples
Reference Example
7e?t-butylamine (68.05 g) was added in water (109 mL) at 5 0C to 10 0C. N- [3- acetyl-4- (2'-hydroxy-3'-bromo)-propoxy]-phenyl-N'-diethylurea (40 g) was then added to the mixture at 10 0C to 17 0C. The reaction mixture was stirred at 15 0C to 20 0C for 10 to 12 hours. Additional water (45 mL) was added and the solvent was evaporated under reduced pressure. To the resulting slurry, ethyl acetate was added and the pH was adjusted to 1.5 -2.0 by adding dilute hydrochloric acid. The aqueous layer was separated and washed again with ethyl acetate. The aqueous layer was mixed with charcoal, made alkaline by adding NaOH and the solid which separates out was extracted with ethyl acetate and evaporated under reduced pressure. The solid residue was stirred in diethyl ether (320 mL) at 10 to 150C for 30 minutes. The solid was filtered and washed to afford 37.4 g of celiprolol base. Yield: 37.4 g (91.2 %) Impurity B: 0.102 % Impurity C: 0.217 % Impurity E: 0.933 %
Total unknown Impurities: 0.198 %.
Example-1 Preparation of celiprolol base monohydrate:
7e?t-butylamine (170.12 g) and N-[3-acetyl-4-(2-hydroxy-3'-bromo)-propoxy]- phenyl-N'-diethylurea (100 g) were added in water (272 mL) at a temperature of about 5 0C. The reaction mixture was stirred at a temperature of 15-30 0C for 5-10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at 20-25 0C. The resulting residue was diluted with ethyl acetate (200 mL) at 20-25 0C and cooled to 10 0C. The pH was adjusted to 1.5 to 2.0 with dilute hydrochloric acid (~ 50 mL) at 10-15 0C. The aqueous layer was washed with ethyl acetate (100 mL) and was mixed with activated carbon (5 g). The pH of aqueous layer was adjusted to above 10 with sodium hydroxide solution (37 %). The resulting solution was extracted twice with ethyl acetate
(1000 mL and 200 mL) and washed with water (150 mL). The organic layer was stirred at 2- 5 0C for 12 hours and the resultant solid was filtered off, to yield celiprolol base. The celiprolol base was dried at 30-35 0C.
Yield: 79 g (77.1 %) Impurity B: 0.0765%
Impurity C: Nil
Impurity E: Nil
Total unknown Impurities: 0.08 %.
Example-2 Preparation of Celiprolol hydrochloride Form I: Celiprolol base (44 g) having water content of 4-5% was dissolved in a mixture of acetone (695 mL) and water (13.5 mL). The resulting clear solution was treated with activated carbon, filtered on a hyflo bed, which was washed with acetone (114 mL). The filtrate was cooled to 15-20 0C and seeded with 1.7 g of celiprolol hydrochloride (Form-I). Concentrated hydrochloric acid (11.5 g) was then added to the reaction mixture to adjust the pH to 5.8-6.3 and the reaction mixture was stirred for 30 minutes at 15-20 0C. Celiprolol hydrochloride was filtered and dried under vacuum.
Yield: 41 g
Total impurities: 0.05 %

Claims

We Claim: L A process for the preparation of pure celiprolol base in monohydrate form comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature, and isolating the celiprolol base. 2. The process of claim 1, wherein the solution of crude celiprolol base is obtained by extracting a reaction mixture taken from the last step of a process in which crude celiprolol base is formed using one or more carboxylic acid ester solvents to obtain a solution of crude celiprolol base. 3. The process of claim 1, wherein the one or more carboxylic acid ester solvents are selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixtures thereof. 4. The process of claim 1, wherein ambient temperature is between about 10 0C to about 40 0C. 5. The process of claim 1, wherein the celiprolol base is isolated by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof. 6. The process of claim 5, wherein crystallization or precipitation is carried out at a temperature from about 0 0C to about 25 0C. 7. The process of claim 1, wherein the celiprolol base is dried at a temperature from ambient temperature to about 80 0C. 8. The process of claim 1, wherein celiprolol base is substantially free of impurities having less than 0.20 % of total impurities. 9. The process of claim 1, wherein celiprolol base is substantially free of impurities having less than about 0.1 % of total impurities. 10. The process according to claim 1, further comprising the conversion of celiprolol base monohydrate to a pharmaceutically acceptable acid addition salts of celiprolol base by contacting celiprolol base monohydrate with one or more acids. 11. The process of claim 8, wherein the one or more acids are selected from hydrochloric acid, hydrobromic acid, hydriodic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid and perchloric acid, formic acid, acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, glycolic acid, lactic acid, malic acid, benzoic acid, salicylic acid, nicotinic acid, cyclohexylsulfonic acid, diphenylacetic acid, methanesulfonic acid, amidosulfonic acids or mixtures thereof. 12. The process according to claim 8, wherein acid addition salt of celiprolol base is celiprolol hydrochloride Form I. 13. A process for the preparation of celiprolol hydrochloride From I comprising: providing a solution of crude celiprolol base in one or more carboxylic acid ester solvents at ambient temperature; isolating the celiprolol base having essentially free of impurity C and E and converting celiprolol base into celiprolol hydrochloride Form I. 14. The process of claim 12, wherein the celiprolol hydrochloride Form I has total impurities of less than about 0.1 %.
PCT/IB2006/053073 2005-09-05 2006-09-01 An improved process for preparation of pure celiprolol base WO2007029155A2 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034009A (en) * 1973-12-20 1977-07-05 Chemie Linz Aktiengesellschaft 4-Ureido-2-acyl phenoxypropanolamine
WO2001008633A2 (en) * 1999-07-30 2001-02-08 Ranbaxy Laboratories Limited An improved form of form i celiprolol hydrochloride

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4034009A (en) * 1973-12-20 1977-07-05 Chemie Linz Aktiengesellschaft 4-Ureido-2-acyl phenoxypropanolamine
WO2001008633A2 (en) * 1999-07-30 2001-02-08 Ranbaxy Laboratories Limited An improved form of form i celiprolol hydrochloride

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JOSHI, RAMESH A. ET AL: "A New and Improved Process for Celiprolol Hydrochloride" ORGANIC PROCESS RESEARCH & DEVELOPMENT , 5(2), 176-178 CODEN: OPRDFK; ISSN: 1083-6160, 2001, XP002429670 *
SMITH, LESLIE HAROLD ET AL: ".beta.-Adrenergic blocking agents. 10. (3-Amino-2- hydroxypropoxy)anilides" JOURNAL OF MEDICINAL CHEMISTRY, 14(6), 511 -13 CODEN: JMCMAR; ISSN: 0022-2623, 1971, XP002429671 cited in the application *

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