Process for the production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation

Information

  • Patent Grant
  • 7468433
  • Patent Number
    7,468,433
  • Date Filed
    Tuesday, November 6, 2001
    22 years ago
  • Date Issued
    Tuesday, December 23, 2008
    15 years ago
  • Inventors
  • Original Assignees
  • Examiners
    • Badio; Barbara P
    Agents
    • The Nath Law Group
    • Goldberg; Joshua B.
    • McGee; Sheldon M.
Abstract
The invention relates to a process for the preparation of 16,17-[(cyclohexylmethylene)bis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione[11β,16α(R)] and similar compounds, by reaction of an appropriate 16,17-ketal with cyclohexanealdehyde.
Description

This application was filed under 35 U.S.C. 371 as a national stage of PCT/EP01/12808, filed Nov. 6, 2001.


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 process 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 preparation. The process comprises reacting pregna-1,4-diene-3,20-dione-16,17-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,




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in which

  • R is hydrogen (H) or isobutyryl [CO—CH(CH3)2], in predominantly epimerically 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 epimeric purity when, rather than the 16,17-dihydroxy compound or the 16,17-diester, the corresponding 16,17-ketal, in particular the 16,17-acetonide derivative, is used as a starting material.


The invention thus relates to a process for the preparation of the compounds of the formula 1 in predominantly epimerically pure form, which comprises reacting compounds of the formula 2,




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in which

  • R is hydrogen (H) or isobutyryl [CO—CH(CH3)2],
  • R1 is 1-4C-alkyl and
  • R2 is 1-4C-alkyl,
  • with cyclohexanealdehyde.


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, esters, e.g. ethyl acetate, halogenated hydrocarbons, e.g. methylene chloride, chloroform, nitrated hydrocarbons, e.g. nitromethane, 2-nitropropane or preferably 1-nitropropane, or without solvents, 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 epimer mixture. Surprisingly, the reaction, however, is controlled according to the 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 epimerically puree form” thus means that the R-epimer (based on the absolute configuration at C-22) in the compound 1 where R=hydrogen (H) results to at least 90%, preferably at least 95%, in particular at least 97%, based on the 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 hydrocarbons (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% strength, perchloric acid (at temperatures from 0° C. to 40° C., preferably 15° C. to 30° C., in particular 20° C. to 25° C.).


If the R-epimer is desired in purer form than is achievable on account of the reaction conditions, suitable separation and purification steps—such as, for example, preparative HPLC, or fractional crystallization such as described in international patent application WO 9809982—may follow the reaction.


The following example serves to illustrate the invention in greater detail:


EXAMPLE
16,17-[(Cyclohexylmethylene)bis(oxy)]-11,21-dihydroxypregna-1,4diene-3,20-dione[11β,16α(R)]

20 g of desonide are suspended in 70 ml of 1-nitropropane and treated slowly with ice-cooling with 12.6 ml of 70% strength perchloric acid and 6.6 g of cyclohexanealdehyde. The reaction mixture is stirred overnight at room temperature and then filtered. The filter cake is dissolved in 90 ml of DMF and the solution is added dropwise with stirring to sodium hydrogencarbonate solution. The precipitate is filtered off with suction, washed with water and dried. 19 g of the title compound having an R-/S-epimer ratio of 97.8/2.2 are obtained.

Claims
  • 1. A process for the preparation of a compound of the formula 1
  • 2. The process as claimed in claim 1, wherein the solvent is nitromethane, 2-nitropropane or 1-nitropropane.
  • 3. The process according to claim 1, wherein the solvent is 1-nitropropane.
  • 4. The process according to claim 1, wherein the perchloric acid is 60% to 70% in strength.
  • 5. The process according to claim 1, wherein the compound of the formula 1 is 16,17-[(Cyclohexylmethylene)bis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-diene[11β,16α(R)].
Priority Claims (1)
Number Date Country Kind
00124626 Nov 2000 EP regional
PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/EP01/12808 11/6/2001 WO 00 8/4/2003
Publishing Document Publishing Date Country Kind
WO02/38584 5/16/2002 WO A
US Referenced Citations (2)
Number Name Date Kind
4925933 Jakupovic et al. May 1990 A
5733901 Gutterer Mar 1998 A
Foreign Referenced Citations (8)
Number Date Country
41 29 535 Mar 1992 DE
0 164 636 Dec 1985 EP
164636 Dec 1985 EP
0 262 108 Mar 1988 EP
0 508 900 Oct 1992 EP
527509 Aug 1985 ES
9422899 Oct 1994 WO
9809982 Mar 1998 WO
Related Publications (1)
Number Date Country
20050080063 A1 Apr 2005 US