Title of Invention	PROCESS FOR THE PRODUCTION OF 16, 17 - [(CYCLOHEXYLMETHYLEN) BIS (OXY)] - 11, 21 - DIHY - DROXY - PREGNA - 1, 4 - DIEN - 3, 20 DION OR ITS 21 - ISOBUTYRAT BY TRANSKETALISATION
Abstract	A process for the preparation of the compounds of the formula 1, in which R is hydrogen (H), in over 95 % epimerically pure form, which comprises reacting compounds of the formula 2, in which R is hydrogen (H), Rl is methyl (CH3) and R2 is methyl (CH3), with cyclohexanealdehyde using perchloric acid as a catalyst and a nitrated hydrocarbon as a solvent at a temperature between 0°C and 40°C.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) PROCESS FOR THE PRODUCTION OF 16, 17-£(CYCLOHEXYLMETHYLEN)BIS(OXY)]-l1, 21-DIHY-DR0XY-PREGNA~i,4-DIEN-3.20-DI0N OR ITS 21-ISQBUTYRAT BY TRANSKETALISATION We ALTANA PHARMA AG of BYK-6ULDEN-STRASSE 2, D-78467 KONSTANZ, DEUTSCHLAND, GERMANY, GERMAN Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed : - 387/MUMNP/2003 07-04-03 PROCESS FOR THE PRODUCTION OF IS,17-l (CYCLOHEXYLMETHYLEN)BIS(OXY) !-11, 21-DIHYDROXY-PREGNA~1,4-DIEN-3,2 0-DION OR ITS 21-ISOBUTYRAT BY TRANSKHTALISATION Technical field The invention relates to a novel process for the preparation of a known glucocorticoid, which is used in the pharmaceutical industry for the production of medicaments. Prior art The International patent application WO 9422899 describes novel prednisolone derivatives and a proc¬ess for their preparation. In this process, 16-hydroxyprednisolone Is reacted with cyclohexanealdehyde, German patent application DE 41 29 535 discloses novel glucocorticoids and a process for their prepa¬ration. The process comprises reacting pregna-1,4-diene-3,20-dione-l6,17-dihydroxy compounds, in the form of their 16,17-diester derivatives, with aldehydes (e.g. with cyclohexanealdehyde) to give the desired final products. Description of the Invention The.invention relates to a process for the preparation of the compounds of the formula 1, in which R is hydrogen (H) or Isobutyryl [CO-CH(CH3)2], in predominantly epimerlcally pure form, It has now been found that the compounds of the formula 1 are obtained in a simple manner in good yield and surprisingly high epimorlc purity when, rather than tho 16,17-dlhydroxy compound or tho 16,17-diester, the corresponding 16,17-ketal, In particular the 16,17-acotonlde derivative, is used as a starting material. • The invention thus relates to a process for the preparation of the compounds of (he formula 1 in pre¬dominantly epimorically pure form, which comprises reacting compounds of the formula 2, in which R is hydrogen (H) or isobulyryl [CO-CH(CH3)2], R1 is 1-4C-alkyl and R2is1-4C-alkyl, with cyclohexanoaldehyde. Preferably, the process Is carried out using those compounds of the formula 2 in which R1 and R2 are in each case methyl (CH3). The reaction is carried out in suitable solvents such as, for example, ethers, e.g. dioxane, diisopropyl ether, asters, e.g. ethyl acetate, halogenated hydrocarbons, e.g. methylene chloride, chloroform, ni¬trated hydrocarbons, e.g. nitromethane, 2-nitropropane or preferably 1-nitropropane, or without sol¬vents, with addition of catalytic or else relatively large amounts of acid, such as mineral acids, e.g. tetrafluoroboric acid or in particular perchloric acid, or sulfonic acids, in particular methanesulfonic acid, at temperatures of advantageously 0°C to 60°C. The reaction of the 16-hydroxyprednisolone ketal of the formula 2 with cyclohexanealdehyde normally yields an eplmer mixture. Surprisingly, the reaction, however, is controlled according to tho invention by means of suitable reaction conditions such that the R-epimer desired and indicated in formula 1 results. According to the Invention, "in predominantly epimorically pure form" thus means that the R-epimer (based on the absolute configuration at C-22) in the compound 1 where R = hydrogen (H) re¬sults to at least 90%, preferably at least 95%, In particular at least 97%, based on tho total yield. For the predominant preparation of the R-epimer, the following conditions, for example, are preferred: as solvents, halogenated hydrocarbons (such as methylene chloride or chloroform) or nitrated hydro¬carbons (such as nitromethane, 2-nitropropane or preferably 1-nitropropane) and, as a catalyst, methanesulfonic acid (at temperatures from 10°C to 40°C) or 35-70% strength, In particular 60-70% We Claim: 1. A process for the preparation of the compounds of the formula 1, in which R is hydrogen (H), in over 95 % epimerically pure form, which comprises reacting compounds of the formula 2, in which R is hydrogen (H), Rl is methyl (CH3) and R2 is methyl (CH3), with cyclohexanealdehyde using perchloric acid as a catalyst and a nitrated hydrocarbon as a solvent at a temperature between 0°C and 40°C. 2. The process as claimed in claim 1, wherein the solvent is nitromethane, 2-nitropropane or 1-nitropropane. 3. The process as claimed in claim 1, wherein the solvent is 1-nitropropane. 4. The process as claimed in claim 1, wherein the perchloric acid is 60% to 70% in strength. 5. The process as claimed in claim 1, wherein the temperature is between 15°C and 30°C. 6. The process as claimed in claim 1, wherein the temperature is between 20°C and 25°C. 7. The process as claimed in claim 1, wherein the compound of the formula 1 is 16,17-[(Cyclohexylmethylene)bis(oxy)]-ll,21-dihydroxypregna-l,4-diene-3,20-dione[lip,16a(R)]. Dated this 5th day of April, 2003. HIRAL CHANDRAKANT JOSHI AGENT FOR ALT ANA PHARMA AG

Documents:

387-mumnp-2003-cancelled pages(26-9-2006).pdf

387-mumnp-2003-claims(7-4-2003).pdf

387-mumnp-2003-claims(amended)-(26-9-2006).pdf

387-mumnp-2003-claims(granted)-(13-8-2007).pdf

387-mumnp-2003-claims(granted)-(26-9-2006).doc

387-mumnp-2003-claims(granted)-(26-9-2006).pdf

387-mumnp-2003-correspondece(27-9-2006).pdf

387-mumnp-2003-correspondece(ipo)-(21-9-2006).pdf

387-mumnp-2003-correspondence(2-9-2002).pdf

387-MUMNP-2003-CORRESPONDENCE(5-11-2008).pdf

387-mumnp-2003-correspondence(ipo)-(15-10-2007).pdf

387-mumnp-2003-description(complete)-(7-4-2003).pdf

387-mumnp-2003-description(granted)-(13-8-2007).pdf

387-mumnp-2003-form 13(5-11-2008).pdf

387-mumnp-2003-form 18 (22-11-2005).pdf

387-mumnp-2003-form 18(22-11-2005).pdf

387-mumnp-2003-form 1a (7-4-2003).pdf

387-mumnp-2003-form 2(complete)-(7-4-2003).pdf

387-mumnp-2003-form 2(granted)-(13-8-2007).pdf

387-mumnp-2003-form 2(granted)-(26-07-2006).doc

387-mumnp-2003-form 2(granted)-(26-9-2006).pdf

387-mumnp-2003-form 2(title page)-(7-4-2003).pdf

387-mumnp-2003-form 2(title page)-(granted)-(13-8-2007).pdf

387-mumnp-2003-form 3 (5-4-2003).pdf

387-mumnp-2003-form 3(7-4-2003).pdf

387-mumnp-2003-form 5 (5-4-2003).pdf

387-mumnp-2003-form 5(7-4-2003).pdf

387-mumnp-2003-general power of attorney(29-8-2002).pdf

387-MUMNP-2003-GENERAL POWER OF ATTORNEY(5-11-2008).pdf

387-mumnp-2003-pct-ipea-409(7-4-2003).pdf

387-mumnp-2003-pct-isa-210(7-4-2003).pdf

387-mumnp-2003-power of attorney(20-9-2007).pdf

387-mumnp-2003-wo international publication report(7-4-2003).pdf