The present invention relates to an improved process for the preparation of pure celiprolol base in monohydrate form by crystallizing crude celiprolol base in carboxylic acid ester solvent and its conversion to pharmaceutically acceptable acid addition salts of celiprolol base particularly celiprolol hydrochloride Form I in high purity.
Celiprolol, a beta-blocker class of antihypertensive agent, is chemically N'- (3-acetyl-4- (3-((l,l-dimethylethyl) amino)-2-hydroxypropoxy) phenyl)-N, N- diethyl urea and is known from U.S. Pat. No. 4,034,009. Celiprolol is represented by formula (I)
(FORMULA REMOVED)

The aryloxy-propanolamines of very high purity should be prepared in the view of their medical use. In particular the preparations, which are used in human medicine, should either contain no by-products at all from the synthesis, or only the slightest traces of these products. It has been observed that when the known synthesis processes for the preparation of l-aryloxy-3-amino-2-propanols are carried out industrially; for example preparation of crude products of aryloxy-propanolamines by reaction of a corresponding l-aryloxy-2, 3-epoxy-propane with an amine as described in J. Med. Chem. 1971, 14, (6), 511-513; crude products containing many impurities are obtained and removal of which is very difficult.
Various synthesis processes are available for the preparation of celiprolol in U.S. Pat. No. US 4,034,009, CA 1,061,342 and CA 1,061,341. The above references disclose the extraction of reaction mixture, in which celiprolol base is formed, with different solvents, evaporation of solvent followed by triturating with ether.
The major disadvantage of the 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 by produced or remain with the desired celiprolol base in the above-mentioned processes. These impurities are, for instance,
(FORMULA REMOVED)

Impurity B: 1,3-bis [3-acetyl-4- [3-[(l,l-dimethylethyl) amino]-2-hydroxy- propoxy] phenyl] urea.
(FORMULA REMOVED)

Impurity C: Rl=CO-NH-C (CH3)3, R2=NH-C (CH3)3; l-{3-acetyl-4- [(2RS)-3-[(l,l-dimethylethyl) amino]-2-hydroxypropoxy] phenyl]-3-(l,l-dimethylethyl) urea.
(FORMULA REMOVED)

Impurity E: 1,1'-[[(1,1 -dimethylethyl) imino] bis [(2-hydroxypropane-l, 3-diyl) oxy (3-acetyl-l, 4-phenylene)]] bis (3,3-diethylurea)
Various purification processes are available for the preparation of aryloxy-propanolamines. U.S. Pat. No. 4,849,530 describes the purification of celiprolol base via diphenyl acetate salt of celiprolol. The method further involves the step to convert the salt into base, which in any case usually comprises many stages, so this method is also not recommended in the preparation of the compounds on an industrial scale.
It has been found that use of celiprolol base having melting point 110-117°C for the preparation of celiprolol hydrochloride does not give Form I consistently. Surprisingly, it was observed that the use of celiprolol base which has been dried at a temperature below 70°C, more preferably below 55°C with a moisture content of less than 5% w/w and having melting point 80-100°C, leads to consistency in achieving Form I celiprolol hydrochloride. Such a base is characterized by its distinct infrared spectrum, melting point and x-ray powder diffraction pattern differing from the celiprolol base melting above 110°C. 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). This has been reported in PCT application WO 01/08633.
There is therefore still a need for improved purification process for celiprolol base which are technically easy to carry out and, in particular, should enable relatively large amounts of

impurities and by-products formed in the synthesis to be removed without trace in a simple manner.
It is an object of the present invention to provide a highly selective method for preparation of celiprolol base in high purity, substantially free of impurities, which is simple, industrially advantageous, convenient and cost effective and more importantly does not suffer from the limitations associates with the prior art methods.
The process provides obvious benefits with respect to economics and convenience to operate on a commercial scale by allowing solvents to be used, which are more compatible with, environmental and health concerns.
The present invention relates to an improved process for the preparation of pure celiprolol base in monohydrate form by crystallizing crude celiprolol base in carboxylic acid ester solvent and its conversion to pharmaceutically acceptable acid addition salts of celiprolol base particularly celiprolol hydrochloride Form I in high purity.
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 the European pharmacopoeia requirements.
Accordingly, first aspect of the present invention provides a process for the preparation of pure celiprolol base in monohydrate form comprises:
a. providing a solution of crude celiprolol base in a carboxylic acid ester solvent at about
ambient temperature
b. recovering the celiprolol base in monohydrate form.
A second aspect of the present invention provides conversion of celiprolol base monohydrate to pharmaceutically acceptable acid addition salts of celiprolol base particularly celiprolol hydrochloride Form I in high purity.
The solution of crude celiprolol base may be obtained by extracting the reaction mixture of the last step of a process, in which celiprolol base is formed, by carboxylic acid esters solvent.
The crude celiprolol base may be obtained from any of the synthetic routes described in the prior art, including those described in US 4,034,009, CA 1,061,342 and CA 1,061,341, which are herein incorporated by the references.
Examples of carboxylic acid esters solvent include methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture thereof.
The ambient temperature may be in the range of about 10 to about 40°C.
Isolation of celiprolol base may be accomplished by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof
The crystallization / precipitation may be performed at temperatures of from about 0°C to about 25°C for 2 hours to 15 hours in some particular embodiments.
For the crystallization, seed crystals may be added in order to improve the yield of celiprolol base.
The drying of celiprolol base may be carried out at a temperature from about ambient temperature to about 80°C.
The celiprolol base obtained by the present process is in the form of monohydrate having water content 4-5 %.
The amount of impurity 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 followed, celiprolol base substantially free of impurities may be isolated with 0.20 % or less total impurity content including impurity B.
The process of the present invention provides celiprolol base substantially free of impurities that contains no more than 0.20 % of total impurities, however, the processes known in the prior art, give celiprolol base having impurity levels of about 1 to 2 %.
The qualitative results as monitored by HPLC after crystallization of celiprolol base are tabulated herein below:

(TABLE REMOVED)

The celiprolol base obtained by the present process may be converted to pharmaceutical ly acceptable acid addition salts of celiprolol base.
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 WO 01/08633.
The following example, which will further illustrate the invention, but is not intended to limit the scope of the invention as defined hereinabove or as claimed below.
Reference Example
Tert Butyl amine (68.05 gms) was added in water (109 ml) at 5° to 10°C. N- [3-acetyl-4- (2'-hydroxy-3'-bromo)-propoxy]-phenyl-N'-diethylurea (40 gms) was then added to this mixture at 10° to 17°C.The reaction contents were stirred at 15° to 20° for 10 to 12 hours, more DI Water (45 ml) was added and reaction solution was evaporated under reduced pressure. To the resulting slurry ethyl acetate and dilute hydrochloric acid were added to adjust pH 1.5 -2.0. The aqueous layer was separated and washed again with ethyl acetate. The aqueous layer was charcoaled, rendered alkaline, the base 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 15°C for 30 minutes. The solid was filtered and washed to afford 37.4 gms of base. Yield: 37.4 gms (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:
Tert Butyl amine (170.12 gm) and N- [3-acetyl-4- (2-hydroxy-3'-bromo)-propoxy]-phenyl-N'-diethylurea (l00gm) were added in water (272 ml) at a temperature of about 5°C. The reaction mixture was stirred at a temperature of 15-30°C for 5-10 hours. After completion of the reaction the reaction mixture was concentrated under reduced pressure at 20-25°C. The residue was diluted with ethyl acetate (200 ml) at 20-25°C and cooled to 10°C. The pH was adjusted to 1.5 to 2.0 with dilute hydrochloric acid (~ 50 ml) at 10 -15°C. The aqueous layer was washed with
ethyl acetate (100ml) and was given activated carbon treatment (5 gm). The pH of aqueous layer
was adjusted to above 10 with sodium hydroxide solution (37 %). The resulting solution was
extracted twice with ethyl acetate (1000ml and 200ml) and washed with water (150 ml). The
organic layer was stirred at 2-5°C for 12 hours and the resultant solid was filtered off, to afford
celiprolol base. The celiprolol base was dried at 30 - 35°C.
Yield: 79 gm (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 gm) having water content 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 and filtered. The hyflo bed was washed with acetone (114 ml). The filtrate was cooled to 15 - 20°C and seeded with 1.7 gm of Celiprolol hydrochloride (Form-I). Concentrated hydrochloric acid (11.5 gm) 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°C. Celiprolol hydrochloride was filtered and dried under vacuum. Yield: 41 gm Total impurities: 0.05 %

WE CLAIM:
1. A process for the preparation of pure celiprolol base in monohydrate form comprises:
a. providing a solution of crude celiprolol base in a carboxylic acid ester solvent at
about ambient temperature.
b. recovering the celiprolol base.
2. The process according to claim 1, wherein solution of crude celiprolol base is obtained by extracting the reaction mixture of the last step of a process, in which celiprolol base is formed.
3. The process according to claim 1, wherein carboxylic acid ester solvent is selected from the group consisting of methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate or mixture thereof.
4. The process according to claim 1, wherein ambient temperature is in the range of about 10 to about 40°C.
5. The process according to claim 1, wherein recovery of celiprolol base is accomplished by concentration, crystallization, precipitation, cooling, filtration, centrifugation or a combination thereof.
6. The process according to claim 1 or 5, wherein the crystallization / precipitation is performed at temperatures of from about 0°C to about 25°C.
7. The process according to claim 1, wherein drying of celiprolol base is carried out at a temperature from about ambient temperature to about 80°C.
8. The process according to claim 1, wherein celiprolol base obtained is substantially free of impurities having no more than 0.20 % of total impurities.
9. The process according to claim 1, further comprising the conversion of celiprolol base monohydrate to pharmaceutically acceptable acid addition salts of celiprolol base.
10. The process according to claim 2, wherein acid addition salts of celiprolol base is prepared by adding respective acid in the mixture of celiprolol base and solvent.
11. The process according to claim 9 or 10, wherein acids which are suitable for salt formation are selected from the group consisting of, 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.
12. The process according to claim 9, wherein acid addition salt of celiprolol base is celiprolol hydrochloride Form I.
13. A process for the preparation of Celiprolol Hydrochloride From I comprising:
a. providing a solution of crude Celiprolol base in a carboxylic acid ester solvent at
about ambient temperature.
b. recovering the Celiprolol base having essentially free of impurity C and E and
c. converting celiprolol base into celiprolol hydrochloride Form I.
14. A process according to claim 13, wherein obtained Celiprolol Hydrochloride From I has
total impurities less than 0.1 %.
15. A process for the preparation of pure celiprolol base as herein described and illustrated by the example.