| Title of Invention | "PREPARATION OF PROSTAMIDES" |
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| Abstract | The present invention provides a process for the preparation of a prostamide which comprises the steps of (d) reacting first intermediate having the general formula I wherein Z is a protecting group and the dotted line represents the presence or 10 absence of a double bond to yield a second intermediate having the general Formula (b) reacting said second intermediate with Na(TMS)2N and (C6H5)3P+(CH2)6 CONR2 X wherein R is a C1-5 alkyl or hydrogen and X' is an anion to yield a third intermediate having the general formula III (c) reacting said third intermediate with a protecting agent to yield a fourth intermediate having the general formula TV (e) reacting said fourth intermediate to remove said protecting groups and yield a prostamide having the general formula V |
| Full Text | WO 03/07-1481 PCT/US03/06071 PREPARATION OF KROSTAMIDES BACKGROUND OF THE INVENTION Cross Reference to Related Applications This application claims priority under 35 U.S.C. §119(e)(l) to provisional application number 60/360,84? which was filed on March 1,2002. 1. Field of the Invention This invention relates to the synthesis of prostamides, which may be useful as pharmaceutical compounds, e.g. as medicinal compounds usefiil for treating 15 glaucoma and/or lower elevated intraocular pressure. 2. Description of Related Art The syntheses of various N-substituted prostaglandin carboxamldes by condensation of a hemiacetal with ylide derived from a substituted phosphonium salt has been reported in the prior art viz. Journal of Medicinal Chemistry 22(11),1346,1979 and US patent 3 954 741, The method of preparation of PGF2a compound is disclosed in US patent 4 195 383. A process for the preparation of latanoprost, an isopropyl ester of PGF2a is disclosed in PCT 20 patent WO01/55101. BRIEF SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a prostamide which, comprises the steps of 25 (a) o reacting first intermediate having the general formula I $& WO 1)3/074481 PCT/US03/I16071 wherein Z is a protecting group and the dotted line represents the presence or absence of a double bond to yield a second intermediate having the general Formula n (b) reacting said second intermediate with Na(TMS)3N and (C6H5)3P+(CH2)6 CONR2 X wherein R is a C1-5 alkyl or hydrogen and X* is an anion to yield a third 10 intermediate having the general formula ID WO 03/0744X1 PCT/US03/06071 3 (c) reacting said third intermediate with a protecting agent to yield a fourth intermediate having the general formula TV (d) reacting said fourth intermediate to remove said protecting groups and yield 5 a prostamide having the general formula V WO 03/074481 PCT/US03AXS071 A DETAILED DESCRIPTION OF THE INVENTION Preferably the present invention provides a process for the preparation of a prostamide which comprises the steps of (a) reacting first intermediate having the general formula T with Diisobutylaluminum (DEBAL) wherein Z is a protecting group and the dotted line represent the presence or absence of double bond. The reaction step(a) involves reduction of a lactone to lactol iinder standard 10 diisobutylaluminum hydride(T>IBAL)conditions as described in the literature (Organic Syntheses by A Armstrong). The reaction is carried out by reacting the first intermediate with general formula I with one equivalent of DXBAL at a temperature of 20'C or less in ah inert solvent e.g toluene and stirring for at least 1 hour. The reaction of step (a) yields a second intermediate having the general formula II. WO 03/074481 PCT/US03/"fi071 5 This reaction step is a Wittig reaction, wellknown to person ordinarily skilled in the art, with a lactol. The second intermediate of genera! formula II reacted under stirring condition with sodiumbistrimethylsilylamide and CC6H5)3P+(CH2)CONR2X at a temperature of -15°C or less for at least 2 hours in an inert solvent e.g. toluene, under an inert atmosphere e.g. Nitrogen wherein R is C1-C5 alkyl or hydrogen and X" is an anion to yield a third intermediate having the genera! formula III. 10 This step involves conversion of free hydroxyl group to a trimethylsilyl protected group. This is achieved by reacting the third.intermediate of general formula HI with a protecting agent Treimethylsilyl chloride (TMSC1) at a temperature of 5*C or less and increasing the temperature over minimum of 1 hour to 20° to 25'C to protect free hydroxyl and yield a fourth intermediate having a general formula IV. WO 03/074481 PCT/US03/(16071 6 (d) The fourth intermediate of general formula IV is subsequently reacted with DimethylsulfoxidepMSO) and aqueous LiCl to remove said protecting group and yield prostamide having genera! formula V. 10 More preferably at least one R is hydrogen and the other is ethyl. More preferably Z is IMS. WO 03/074481 7 PCT/OS03/1W071 The acronyms used in the description and appended claims have the following meanings: D]BAL is diisolutylalumium hydride. TMS is trimethylsilyl. TMSCI is trimethylsilyl chloride orchJorotrimethyl silane. TMSO is trimethylsilyloxy. DMSO is dimethylsulfoxide. 5 DESCRIPTION OF THE PREFERRED EMBODIMENT This step of the synthesis produces the crude bimatoprost API by introduction of the upper side chain. The Iactone moiety is first reduced to the lactol under standard diisobutylaluminum hydride conditions. The lactol is not isolated, but is treated directly in situ with Wittig reagent. The crude bimatoprost is 10 a mixture of cis and trans isoxners about the 5,6-double bond. The cis isomeris the major project. The trans isomer is controlled in the crude bimatoprost specifications by a limit not more than 8% on each individual impurity. WO 03/07J4S3 PCT/US03/0fi071 8 What is claimed is: 1. A process, for the preparation of a prostamide which comprises the steps of (a) reacting fTrst intermediate having the general formula I with Diisobutylaluminum (DIBAL) at a temperature of 20°C or less in an inert solvent e.g. toluene wherein Z is a protecting group and the dotted line represents the presence or 10 absence of a double bond to yield a second intermediate having the general Formula JL 1 reacting said second intetm.ediate.with NaOrimemyisilyOsN and (C^3^(CH2)6 CONR2 X" at a temperature of 15°C or less 15 in an inert solvent e.g. toluene under an inert atmosphere e.g. nitrogen wherein R is a C1-5 alkyi or hydrogen and X" is an anion to yield a third intermediate having the general formula Hf VVO 03/074481 PCT/USO3/ttfiO7i (C) 9 10 15 combining said third intermediate with a protecting agent TMSCI at a temperature of 5°C or less and increasing the temperature over a minimum of one(1) hour to 20 to 25°C to protect the free hydroxyl and yield a fourth intermediate having the general formula IV reacting said fourth intermediate at a temperature of 40°C or below, in an inert solvent, e.g. hexane, by sequentially reacting said fourth intermediate with DMSO and aqueous LiCI to remove said protecting groups and yield a prostamide having the general formula V. WO 03/074481 PCT/US"3/O6"?1 10 2. The process of claim 1 wherein one R is hydrogen and the other R is ethyl. 3. The process of claim 1 wherein Z is trimethyJsily! (TMS). The present invention provides a process for the preparation of a prostamide which comprises the steps of (d) reacting first intermediate having the general formula I wherein Z is a protecting group and the dotted line represents the presence or 10 absence of a double bond to yield a second intermediate having the general Formula (b) reacting said second intermediate with Na(TMS)2N and (C6H5)3P+(CH2)6 CONR2 X wherein R is a C1-5 alkyl or hydrogen and X' is an anion to yield a third intermediate having the general formula III (c) reacting said third intermediate with a protecting agent to yield a fourth intermediate having the general formula TV (e) reacting said fourth intermediate to remove said protecting groups and yield a prostamide having the general formula V |
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01243-kolnp-2004-assignment.pdf
01243-kolnp-2004-correspondence.pdf
01243-kolnp-2004-description(complete).pdf
01243-kolnp-2004-letters patent.pdf
01243-kolnp-2004-reply f.e.r .pdf
1243-KOLNP-2004-(13-08-2012)-CORRESPONDENCE.pdf
1243-KOLNP-2004-(13-08-2012)-REQUEST FOR PAGES FOR PHOTOCOPY.pdf
1243-KOLNP-2004-(14-05-2012)-CORRESPONDENCE.pdf
1243-KOLNP-2004-(27-12-2012)-CORRESPONDENCE.pdf
1243-KOLNP-2004-(27-12-2012)-OTHERS.pdf
1243-KOLNP-2004-ASSIGNMENT.pdf
1243-KOLNP-2004-CORRESPONDENCE 1.1.pdf
1243-KOLNP-2004-CORRESPONDENCE 1.3.pdf
1243-KOLNP-2004-CORRESPONDENCE 1.5.pdf
1243-KOLNP-2004-CORRESPONDENCE-1.2.pdf
1243-KOLNP-2004-CORRESPONDENCE-1.4.pdf
1243-KOLNP-2004-EXAMINATION REPORT.pdf
1243-KOLNP-2004-GRANTED-ABSTRACT.pdf
1243-KOLNP-2004-GRANTED-CLAIMS.pdf
1243-KOLNP-2004-GRANTED-DESCRIPTION (COMPLETE).pdf
1243-KOLNP-2004-GRANTED-FORM 1.pdf
1243-KOLNP-2004-GRANTED-LETTER PATENT.pdf
1243-KOLNP-2004-GRANTED-SPECIFICATION.pdf
1243-KOLNP-2004-OTHERS 1.1.pdf
1243-KOLNP-2004-REPLY TO EXAMINATION REPORT.pdf
| Patent Number | 202661 | ||||||||||||||||||||||||
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| Indian Patent Application Number | 1243/KOLNP/2004 | ||||||||||||||||||||||||
| PG Journal Number | 09/2007 | ||||||||||||||||||||||||
| Publication Date | 02-Mar-2007 | ||||||||||||||||||||||||
| Grant Date | 02-Mar-2007 | ||||||||||||||||||||||||
| Date of Filing | 25-Aug-2004 | ||||||||||||||||||||||||
| Name of Patentee | ALLERGAN,INC | ||||||||||||||||||||||||
| Applicant Address | 2525 DUPONT DRIVE,T2-7H IRVINE ,CA92612 | ||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C 07 C 405/00 | ||||||||||||||||||||||||
| PCT International Application Number | PCT/US2003/006071 | ||||||||||||||||||||||||
| PCT International Filing date | 2003-02-28 | ||||||||||||||||||||||||
PCT Conventions:
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