Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
1999-10-15
2002-09-10
Bernhardt, Emily (Department: 1609)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C514S254050
Reexamination Certificate
active
06448404
ABSTRACT:
DESCRIPTION
1. Field of the Invention
The present invention relates to a crystalline form of nefazodone and to a process for the preparation thereof.
More particularly, the invention relates to the crystalline nefazodone hydrochloride dihydrate, having the chemical name of 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one hydrochloride dihydrate, of formula
and to a process for the preparation thereof.
Nefazodone is a well-known therapeutical agent having an antidepressant activity. For therapeutical purposes, it is preferably used in the hydrochloride form. Two forms of this compound are known: Polymorph A (m.p. 186-187° C.) and Polymorph B (m.p. 181-182° C.) and the former is the preferred product in the pharmaceutical field.
2. Prior Art
The purification of nefazodone still presents a number of difficulties.
U.S. Pat. No. 4,338,317 describes the preparation of nefazodone and a process for purifying same. To be precise, Example 2 (col. 9, lines 17-47, describes the purification of the free base by acidification in ethanol with ethanolic hydrogen chloride and crystallisation to provide a hydrated form (0.25 mole water) of nefazodone hydrochloride, melting at 175-177°C. The description continues to say that a non-hydrated sample obtained according to that process also melted at 175-177° C.
Example 6 of U.S. Pat. No. 4,487,773 describes a method of purifying crude nefazodone hydrochloride in methylene chloride, with filtration and concentration of the filtrate at reduced pressure. Crystallisation of the residue from isopropanol affords a still crude product (yield 62.5%) which is further crystallised from water and then from isopropanol to afford nefazodone hydrochloride melting at 180-182.5° C.
Gary D. Madding (J. Het. Chem., 22, 1121, 1985) describes an even more time-consuming method of purification. In fact, the method described on page 1125, left hand column, lines 38-51, comprises a first purification of the free base with isopropanol/heptane, with a yield of 84% of theory. The thus obtained nefazodone base is dissolved in isopropanol. 12N HCl is added to this solution and the volatiles are removed under vacuum. The resulting mass is crystallised from isopropanol to give nefazodone hydrochloride (yield, 94%). The product is subsequently dissolved in methylene chloride in an attempt to remove the insoluble impurity, 1,1′-trimethylene-bis-[4-(3-chlorophenyl)piperazine]hydrochloride, by filtration. After removal of the solvent, the nefazodone hydrochloride is crystallised again from isopropanol to give a product melting at 181.0-182.00 C. Since the final yield is not clearly stated, it is estimated, in view of the type and number of treatments contemplated, that it is approximately 74% or less.
In view of the above, it is obvious that, for the time being, the purification of nefazodone is very time-consuming and that this has a considerable influence on the production cost thereof, either with regard to the labour involved or with regard to the inevitable reduction of the final yield as a result of each of the said steps. It is also obvious that the preferred treatment for removing, at least in part, the 1,1′-trimethylene-bis-[4-(3-chlorophenyl)piperazine]hydrochloride (to be called hereinafter “bis-chloro base” for brevity) is the one using methylene chloride. Nevertheless, methylene chloride is rather toxic and entails the use of special security measures.
Therefore, the need for a new way to eliminate or, at least, drastically to reduce the impurities of crude nefazodone to below the respective limit of acceptability, in a low number of steps and using solvents representing fewer drawbacks than methylene chloride, is still very current.
SUMMARY OF THE INVENTION
The research conducted by the present inventors has lead to the surprising discovery that when nefazodone is purified through the formation of the crystalline hydrochloride dihydrate thereof, not only the “bis-chloro base” but also other impurities are practically quantitatively eliminated or, in any case, drastically reduced. Typical examples of such impurities are: 1-(3-hydroxypropyl)-4-(3-chlorophenyl)piperazine (which is hereinafter called “hydroxy base” for brevity), a mass 470 isomer of nefazodone, the 4-chloro isomer of nefazodone (which is hereinafter called “para-chloro isomer” for brevity) and 1-(3-chloropropyl)-4-(3-chlorophenyl)piperazine (hereinafter called “chloro base” for brevity.
In the first aspect thereof, the present invention relates therefore to crystalline nefazodone hydrochloride dihydrate.
Typically, the crystalline nefazodone hydrochloride dihydrate according to the present invention comprises less than 0.5% impurities. Preferably, it comprises less than 0.2% and more preferably still, less that 0.1% impurities.
REFERENCES:
patent: 4338317 (1982-07-01), Temple, Jr. et al.
patent: 4487773 (1984-12-01), Temple, Jr. et al.
patent: 5256664 (1993-10-01), Mayol et al.
patent: 5886004 (1999-03-01), Audia et al.
Artús Surroca Juan J.
Bonet Montserrat Jané
Jané LlorençRafecas
Bernhardt Emily
Finaf 92, S.A.
Scully Scott Murphy & Presser
LandOfFree
Crystalline form of nefazodone and process for the... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Crystalline form of nefazodone and process for the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Crystalline form of nefazodone and process for the... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2845784