FR2515643A1 - PROCESS FOR PREPARING -2,3 AND -3,4 PROSTAGLANDINS - Google Patents

Abstract

The invention relates to a new process for producing -2,3 and -3,4 prostaglandins; TO FORM USEFUL COMPOUNDS, A DOUBLE BINDING IN THE -2,3,3 OR -3,4 POSITION OF PROSTAGLANDINS E IS INTRODUCED BY THIS METHOD; THE PROCESS REDUCES THE NUMBER OF STAGES AND PROPORTIONALLY INCREASES COMPOUND PREPARATION PERFORMANCE.

Description

The invention relates to a novel method for

  prepare desti-2,3 and A-3,4 prostaglandins.

  More particularly, the invention relates to a new method for introducing a double bond on the 2,3 or 3,4 position of type E prostaglandins of the general formulas I, II and III.

  For example, we can refer to Prostatic

  In particular, the new process can be used to prepare useful compounds of the type described in US Pat.

  U.S. Patent No. 4,312,994 in the name of the

  The method is useful in that it reduces the number of stages and increases the yield compared to previous methods of producing type A-2,3 and 3,4-prostaglandins E. The E-series prostaglandins are

  known to have various therapeutic applications.

  See for example E W Horton in "Chemistry, Bioche-

  mistry and Pharmacological Activity of Prostanoids "

Pergamon Press (1979).

  In particular, the invention provides a method for producing d-2,3-type prostaglandin E which comprises: a) preparing a higher trialkylsilyl enolether of a C-9 ketone;

  b) the treatment of the higher trialkylsilyl enol-ether

  with lithium dialkylamide followed by a selenium or sulfur reagent; (c) oxidation of the product of (b); and d) hydrolyzing the product of c) with a weak acid to

  produce the desired A -2,3 prostaglandins.

  The invention also provides in particular a method for producing type 4-3,4 prostaglandins E which comprises

  a) the preparation of a higher trialkylsilyl enol-ether

1564 of a C-9 ketone;

  b) the treatment of the higher trialkylsilyl enol-ether

  with lithium dialkylamide followed by a selenium or sulfur reagent; (c) oxidation of the product of (b); d) treating the product of c) with lithium dialkylamide; e) treating the product of d) with a proton source and f) hydrolyzing the product of e) with a weak acid

  to produce the desired 4-3,4 prostaglandins.

  The higher trialkylsilyl enol-ether varies according to the compound to be prepared. In general, this process is a competition reaction in which it is possible for protons to be torn off from many sites and consequently there is great diversity.

  potential end products The trialkyl ether-trialkyl ether

  The use should be such that it protects other sites against the removal of protons There is no general formula for determining the size

  relative to constant factors

  conques but for example to prepare the (-) - dihydroxy-

  , 16 (RS) methyl-16-oxo-9-prostatriene EZ, 5Z, 13E

  methyl oate, the enol-ether dimethyl-tert-butyl-silyli-

  On the contrary, tri-enol ethers

  alkylsilyl relatively smaller or less

  are poorly suited Examples of ineffective compounds

  caces in and example are the trimethylol enol ethers

  silyl, triethylsilyl (which has the same molecular weight

  only dimethyl-tert-butyl-silyl) or even dimethylbutylsilyl which is a chain isomer

  It seems, therefore, that a certain degree of ramification

  the side chain is necessary to ob-

  keep the desired results; the exact degree can be 8

determined for each compound.

  The general scheme of the invention as applied to the compounds of the aforementioned U.S. Patent Application No. 06 / 245,453 is illustrated by diagrams B and C The ether compound (formula XI) R 4 is O-tetrahydropyranyl or O-silyltrialkyl and R 2 and R 3 are hydrogen or alkyl reacts with the appropriate cuprate and then with a higher trialkylchlorosilane in the presence of HMPT The compound obtained (formula XII) is then treated with a lithium dialkylamide such as

  lithium diisopropylamide or isopropylcyclohexyl-

  lithium amide and the reaction is stopped with a selenium or sulfur reagent such as diphenyl diselenide, phenylselenium chloride or diphenyl disulfide, of which diphenyl diselenide is preferred, to obtain a compound of formula XIII The compound of formula XIII is then oxidized, for example with hydrogen peroxide or sodium periodate to provide compound XIV or compound XXI The compound of formula XXI can be hydrolyzed with a weak acid such as acetic acid

  to provide the compound of formula XXII of the invention.

  Otherwise the compound of formula XXII can be treated with a lithium dialkylamide and the reaction stopped with a source of protons such as a weak acid or an alcohol, among which is preferred acetic acid

  to provide the compounds of formula XXIII of the invention.

  The compounds of formula XXIII can be hydrolysed with a weak acid such as acetic acid for

  provide the compounds of formula XXIV.

  Other features and advantages of the invention will be better understood when reading the

  following description of several examples of

non-limiting realization.

  EXAMPLE I (T & trahydropyranyl-2-oxy-3 (RS) oxo-5

  cyclopentene-1) -7-heptene-5-methyl ester.

  To a solution of 2.88 g of methyl (3-hydroxy (RS) oxo-5-cyclopenten-1) heptene methyl ester and 35 ml of ether, 50 mg of p-toluenesulphonic acid and 1.1 g of dihydropyran are added. The reaction mixture was allowed to stand at room temperature for about 24 hours, then diluted with ether, washed successively with 5% aqueous potassium carbonate and water, dried over anhydrous sodium sulfate. and the solvent is removed under reduced pressure

  chromatography the residue on silica gel using

  reading 25% ethyl acetate in hexane as

  eluent to obtain the desired product.

  EXAMPLE II E- (tri-n-butylstannyl) -1-methyl-4-trimethyl-

silyloxy-4-octene-1.

  2.12 g of trimethylsilyloxy-4 (RS) -4-methyloctyl-1 and 3.0 g of tributyltin hydride are mixed and irradiated under argon with an OC solar lamp for 2 hours and then at 55.degree. hours We use

  the desired compound obtained directly in Example III.

  EXAMPLE III Z (2) (4 (RS) -trimethyl) -detrahydropyranyloxy

  4-silyloxy-4-methyloctene-1-yl) -2-tert-butyldimethyl-

  5-silyloxy cyclopentene-1 (5) -7 heptene-5-Z oate-loc

racemic methyl.

  11.5 g of the compound of Example II are dissolved in 30 ml of anhydrous tetrahydrofuran and cooled to -60 ° C. in argon. 14.5 ml of a 1.55 M solution of butyllithium are added. This solution is stirred for about 45 minutes In a separate flask, 3.0 g of penty-1-ylure copper and 7.4 g of hexamethylphosphoric triamide were dissolved with stirring in 30 ml of ether.

  this solution is then added to the reaction mixture.

  The mixture obtained is stirred for 10 minutes at -60 ° C. and then a solution of the product of Example I is added.

  (3.7 g) in 30 ml of ether. The reaction mixture is stirred

  at -60 ° C. for about 1 hour and then treated successively with 40 ml of hexamethylphosphorotriamide and 5 g of tertbutyldimethylchlorosilane dissolved in 10 ml of ether. The temperature of the reaction mixture is allowed to rise to -20 ° C. and it is added thereto. The reaction mixture is poured on a mixture of 1 N hydrochloric acid and ether. The ether layer is separated and washed twice with water, filtered and dried over sodium sulfate. The residue is then chromatographed in a solvent system consisting of 2% ethyl acetate in

  hexane to obtain the pure desired product.

  EXAMPLE IV Tetrahydropyranyloxy-3c (4 (RS) -trimethyl)

  4-silyloxy-4-methyl-octene-1-yl) -2-tert-butyldimethyl-

  5-silyloxy-cyclopentene-1 (5) 7-phenylselenyl-2-heptene

  Reacted methyl ester A solution of 550 mg of cyclohexylisopropylamine in 15 ml of anhydrous tetrahydrofuran was cooled to about -30 ° C. under argon and treated with 2.31 ml of a 1.55 M solution of Butyllithium After about 1.5 hours of stirring at -30 ° to -20 ° C., the solution is cooled to -60 ° C. and treated dropwise with a solution of 2.1 g of the enol ether produced in the reaction mixture. Example III in 20 ml of tetrahydrofuran When the addition is complete, a solution of 1 g of diphenyl diselenide in 10 ml of tetrahydrofuran is added dropwise. The reaction mixture is diluted with ether and washed twice with water. the water is dried and the solvent is removed The residue is chromatographed in a solvent system consisting of acetate

  2% ethyl in hexane to obtain the desired product.

sire.

  EXAMPLE V Tetrahydropyranyloxy-3 (4 (RS) -trimethyl)

  4-silyloxy-4-methyl-octene-1-yl) -20-tert-butyldimethyl

  5-silyloxy-cyclopentene-1 (5) -7-heptadiene-2-ene

of racemic methyl.

  A solution of 1 g of the product of Example IV in 50 ml of methylene chloride containing 500 mg of pyridine is treated with a solution of 5 g of 30% hydrogen peroxide in 5 ml of water and stirred vigorously. this two-phase system for about 4 hours at room temperature The solution is poured into ether and washed once with 1 N hydrochloric acid and twice with water, then dried over sodium sulfate. The residue is chromatographed with a solvent system consisting of 2% ethyl acetate in hexane.

to obtain the desired product.

  EXAMPLE VI / 3-Tetrahydropyranyloxy-4 (RS) -trimethyl

  4-silyloxy-4-methyl-octene-1-yl) -2-tert-butyldimethyl

  5-silyloxy cyclopentene-1 (5 L 7-7 heptadiene-3 EZ, SZ oate-

1 o (racemic methyl.

  A solution of 165 mg of cyclohexylis: opropylamine and 4 ml of dried THF was cooled to -30 ° C. under argon and treated with 0.75 ml of a 1.55 M solution of butyllithium. This solution was stirred between about -30.degree. -20 C for one hour and then cooled to -600 C.

  A solution of 230 mg of hexamethylphosphoric acid is added

  triamide in 1 ml of tetrahydrofuran A solution of 630 mg of the product of Example V in 6 ml of anhydrous tetrahydrofuran is added dropwise over one hour. When the addition is complete, 1 ml is added.

  a solution of 90 mg of acetic acid in the tetra-

  hydrofuran The reaction mixture is poured into ether and water. The organic layer is washed with water, dried over sodium sulfate and the solvent is removed. The residue is used directly in Example VII. EXAMPLE VII (-) - dihydroxy-11 O <16 (RS) methyl-16 oxo-9

  prostatriene-3 EZ, 5% Z, 13 Methyl ester.

  The product of Example VI (630 mg) is dissolved

  by stirring in 10 ml of a 3/1/1 mixture of acetic acid.

  tick, water and tetrahydrofuran.

  until the mixture becomes homogeneous.

  This solution is then allowed to stand at room temperature for 24-48 hours. The solution is diluted with ether, washed four times with water,

  dried over sodium sulphate and the solvent is removed.

  The residue is chromatographed in a 70% mixture

  of ethyl acetate and 30% of hexane to obtain the

desired posture.

EXAMPLE VIII

  In Example III it is possible to use a higher molecular weight trialkylsilyl chloride and to treat the product as in Examples IV

  to VII to obtain the desired product of Example VII.

EXAMPLE IX

  The procedures of the examples are used

  II to VII, except that a triethyl radical is

  silyl in position C-11 instead of the radical tetrahydro-

  pyrannyl to give the desired compound of Example VII.

  EXAMPLE X (+) - dihydroxy-10 ', 16 (RS) methyl-16 oxo-9

  prostatriene-2 E, 5 Z, 13 Methyl ester.

  The product obtained in Example V is used in the procedure of Example VII to obtain

this compound.

  Of course, various modifications can be made by those skilled in the art to the devices or processes which have just been described as non-limiting examples.

  without departing from the scope of the invention.

-DIAGRAME A

I ÈH PGE 1 II

PGE 2

III -1 - O PGE 3

DIAGRAMIME B

COOP 2

  xi R 4 i Cup Drate 2. Triailkylsilyl, Cl higher Hexamethylphosphoramide (iÄPT Si (alkyl)

X-N COQ R 2

  R 3 R 4 N R 4 OS 1 (alkyl) 3 1 Dialkylamide of Li 2 Ph Se 2 Si (alkyl) V

COOR 2

R 3 54

  O Si (alkyl) 3 Si (alkyl) -O 3 v Oxidising agent, for example H 202 R 4 O Si (alkyl) XII xiii XIV i kylamidul, Li 60 ec 2 Acetic acid 600 C

L>

1 5 6 4 3

1.0 C

S i (a, f k yl -A - -

C ,, 1 C) e j, z

Pl 4 IM l, It? yl C) -

i -'o

C O CI) R 2

OH

X: -, 1 1

  Vxx, Yi IZO Si (alkyl) R R 'O Si (alkyl) 3 \ V il O

1 C

OOR 2 HO-, -ll OH xxi v

Claims (4)

  A process for producing type A-2,3 prostaglandins E, characterized in that it comprises: a) preparing a higher trialkylsilyl enol-ether of a C-9 ketone;   b) the treatment of a higher trialkylsilyl enol-ether   with lithium dialkylamide followed by a selenium or sulfur reagent; c) the oxidation of the product of (b) and d) the hydrolysis of the product of (c) with a weak acid   to provide the desired 4-2,3-prostaglandin.   Process for producing type 4-3,4 prostaglandins E, characterized in that it comprises:   a) the preparation of a higher trialkylsilyl enol-ether less than a C-9 ketone;   b) the treatment of the higher trialkylsilyl enol-ether   with a dialkylamid of lithium then a selenium or sulfur reagent; c) the oxidation of the product of (b);   d) treating the product of (c) with a dialkyl-   lithium amide; e) treating the product of (d) with a proton source and f) hydrolyzing the product of (e) with a weak acid   to produce the desired 4-3,4 prostaglandins.   Process according to Claim 2, characterized   in that the (+) - dihydroxy-1lo, 16 (RS) methyl is produced   16 9-oxo-3-prostatriene EZ, 5 Z, 13 methyl E-oate.