CS266349B2 - Process for preparing new intermediate produts of prostaglandine - Google Patents

Abstract

The invention relates to the preparation of compounds of formula (I), wherein R means a straight or branched chain C1-6 alkyl group optionally substituted by a cyclopentyl or cyclohexyl group; or a cyclopentyl or cyclohexyl group; and R<1> stands for a C1-4 alkyl group. The invention relates also to the new intermediates of formula (II), formula (III), formula (IV) and formula (V).

Description

Many PGE derivatives are known to significantly suppress the cytoprotective effect. Such compounds are the secretion of gastric juices and have other misoprostol of the formula

COOCH 3 (VIII) and rioprostyl IX

(IX), (Drugs of the Future 2nd _f (12), p. 817 (1977) ibid (3), pp. 207 (1985)).

The compounds are carried out by methods

48, 4217 (1975); US Patent No. 4,132,738)

Production of the above

Lett. The reaction is carried out between a cyclopent-1-ene-alkanoic acid ester of the formula XI known from the literature (Tetrahedron according to Reaction Scheme A conjugate).

COOCH +

ó THP (XI.)

COOCH3 (Vlil.)

XH ₂ 0THP (XII.)

OTHP

/ j к. ik лк ...> 14 tea. ’

CS 266 349 B2

(XI) optionally, between a cyclopent-1-en-alkanol of formula XII protected by a tetrahydropyranyl group (THP group) and a vinyl group reagent of formula XIII

HMP

The preparation of the vinyl acetate reagent of formula XIII is known from the literature (J. Med. Chem. 20 (9) _r . 1152 (1977); BE Patent No. 827,127 and US Patent No. 4,087,447) and is carried out according to scheme B.

According to Reaction Scheme B, a 4-methyl-1-octin-4 (RS) -ol containing a trimethylsilyl protecting group and having the formula 4 (4)

OSiMe ₃

Reaction scheme V

MgBr ClSiMe ₃

OSiMe.

Bu ₃ SnM

CS 266 349 B2, which can be obtained by trimethylsilylation after Grignard reaction with propyl magnesium magnesium bromide from 2-hexanone, converts by stereoselective hydroboration, hydroalumination or hydrostannation reactions to the corresponding trans-vinyl-borane-, -alan- or stannane compounds of formulas (5), (6) , (7)

(5)

from which the corresponding trans-iodoalkane of formula 8 is obtained by the action of elemental iodine

(8)

From the obtained iodoalkane of formula 8 or the vinylstannane compound of formula 7, the corresponding trans-vinyl lithium compound of formula 9 is prepared by transmetallation reaction with n-butyllithium.

From a tetrahydrofuran solution of a vinyl lithium compound of formula 9, a vinyl reagent of formula XIII can be obtained by treatment with an ethereal solution of a copper pentine derivative solvated with hexamethylphosphoric acid triamide (HMP). The performance of this reaction requires, besides its complexity, high precision, in particular conditions, as well as the extreme purity and absolute absence of water in the reagents and solvent. New synthesis of compounds of formulas VIII and IX as well as of formula XIV

can be performed as follows (Tetrahedron Lett. 23 (10), p. 1 067 (1982)): The authors have created an omega-chain reaction of compounds of formulas XV and XVI (xiv)

CS 266 349 B2

O

with phosphorous formula la nit *

transselective Wittig reaction.

Phosphorane of formula Ia can be prepared according to Reaction Scheme C ', wherein all of the intermediates of the reaction sequence are non-insulable reactive substances, which excludes any possibility of purification.

As is evident, the known solutions have considerable disadvantages in terms of feasibility. In order to overcome these disadvantages, new methods have been sought for the production of intermediates of formulas Ia and I, respectively.

Reaction Scheme C

Θ Θ

Me ₃ SI n-BuLi.

CH

CH / S = CH ₂

^rn \ ®Br® 57 °

Ph-P-CH ₃ ¹¹ - Ph-P = CH ₂

^From Ph Ph ^Ph ^ \ ^-рь-р ф -осг Ph ^ ° ^A nBuLi

Ph _x

Ph — P = / Yy \

Ph ^ZZ OLi

Iq

Surprisingly, it has been found that when the oxo compound of formula VII is reacted

(VII) wherein R is optionally a cyclopentyl or cyclohexyl group substituted with a straight or branched C 1-6 alkyl group or a cyclopentyl or cyclohexyl group, R ¹ is a C 1-6 alkyl group with a C 1-6 alkyl ester of bromoacetic acid and a zinc metal ( Reformat synthesis), the obtained compound of formula VI

CS 266 349 B2 (VI) wherein R and R ¹ are as defined above, are reacted with a metal hydride of formula V to obtain the compound obtained.

OH

AND-*

CH ₂ -CH ₂ -OH (V) wherein R and R ¹ are as defined above are reacted with triphenylphosphine and tetrabromomethane, the compound of formula IV obtained

OH l

C ------ ------ R R (IV) ₂ сн -сн -вг ₂ wherein R and R are as defined above - with an inorganic iodine compound, this reaction is obtained iodine compound of the formula III

OH i}

R ------- C ------- R (III)

CH ₂ -CH ₂ -J where R and R ¹ are as defined above - with triphenylphosphine a new phosphonium salt of formula II is then obtained

^J I ^R CH2 'CH2 C = OH

R '(II) which is reacted with two equivalents of a lithiumalkyl- or lithiumalkylamide type compound in one step to an intermediate of formula (I).

A preferred embodiment of the process of the invention is as follows: The compounds of formula VII are reacted in tetrahydrofuran or other solvent suitable for Reformat synthesis with zinc metal or ethyl bromoacetate or another C _1-6 alkyl ester. Compounds of formula VI are reduced with a complex metal hydride, preferably lithium aluminum. hydride (LAH) in tetrahydrofuran or another suitable metal hydride reaction solvent. The primary hydroxyl group of the compounds of formula (V) is replaced with a bromine atom by the tetrabromomethane-triphenylphosphine in acetonitrile solvent, and the bromine of the compounds of formula (IV) is further exchanged in an acetonic medium by alkali metal iodide, preferably sodium iodide. Compounds of formula III are converted to the phosphonium salt of formula II by refluxing in acetonitrile in the presence of 10 to 15 molar equivalents of triphenylphosphine. The compounds of the general formulas prepared according to the invention,

CS 266 349 B2

VI, V, IV, III and II are stable, insulatable and easy to clean. Compounds of formulas n1 to vi can be purified by distillation or chromatographic methods, salts of formula II by chromatography or recrystallization.

The compounds of Formulas II-V prepared according to the invention are novel.

A further unexpected advantage of the process according to the invention is that the compounds of formula V can be extremely selectively brominated (almost quantitatively), the tertiary hydroxyl group remaining unchanged.

As already mentioned, compounds of formula II can be converted by reaction with molar equivalents of lithiumalkyl or lithium alkylamide compounds to compounds of formula I. The lithium iodide formed as a by-product increases the trans selectivity in the next step of the Wittig reaction, e.g. XVI or XVII

and compounds of formula I (Tetrahedron Lett. 26 (3), p. 311 (1985), J. Am. Chem. Soc. 103, p. 2823 (1981); Liebigs Ann. Chem. vol. 708, p. 1). (1967)).

The invention is illustrated by the following non-limiting examples. Example 1

Preparation of 3-methyl-3 (R, S) -hydroxyheptanoic acid ethyl ester _m.p.

To a suspension of 17.5 g of dry zinc powder and 150 ml of absolute tetrahydrofuran, 27.5 ml of ethyl bromoacetate and 35 ml of 2-hexanone are added in parallel over 30 minutes (the reaction is exothermic). The reaction mixture is then boiled for an additional 90 minutes, cooled to room temperature and quenched with a mixture of 100 ml of water and 20 ml of acetic acid added at such a rate that the temperature of the mixture does not exceed 30 ° C. After decomposition, the two phases are separated, the aqueous phase is extracted three times with 80 ml of ethyl acetate. The solvent was then removed from the combined organic phases and distilled fractionated.

Yield: 35.3 g (76%). Boiling point 68-70 ° C (0.26 kPa).

1 H-NMR: (CDCl ₃ , on TMS) δ 0.9 t (3H); SS = 1-1.5 m (PN), SS = 2.5 S (3H); S S 3,5 3.5 S (1H); λ = 4.2 q (2H).

Example 2 (R, S) -2-hydroxy-2- (2-hydroxyethyl) hexane.

9 g of 3-methyl-3 (R, S) -hydroxyheptanoic acid ethyl ester are dissolved in 50 ml of absolute tetrahydrofuran, then 2 g of lithium aluminum hydride (LAH) is carefully added in small portions at room temperature. Then the temperature of the reaction mixture was allowed to rise to 40 ° C and the reaction was monitored by chromatography (eluent: 4 volumes of hexane, 1 volume of ethyl acetate; silica gel 60 F ₂ 54 < ^Merck ®) developing agent 5% ethanolic solution of phosphformolybdic acid (150 ° C) starting material: R f at 0.4, product R f at 0.1). As soon as no starting material can be detected in the reaction mixture, the reaction mixture is stripped of excess LAH with 10 ml of ethyl acetate, then carefully diluted with 50 ml of water. The precipitated aluminum and lithium salts are then filtered off and the biphasic mother liquor is isolated. The aqueous phase is shaken three times with 20 ml of ethyl acetate, then the combined organic phases are freed from the solvent. The product was purified by column chromatography.

EN 266 349 02

Yield: 5.7 g (82%).

replaced by ¹³ C-NMR: (CDCl ₃ on TMS)? S = 14.1, 23.3; 26.3; 26.5; 41.4; 42.3; 59.4; 73.8 pptu.

Example 3

Preparation of 2- (R, S) -hydroxy-2- (2-bromoethyl) hexane

2.4 g of 2- (R, S) -hydroxy-2- (2'-hydroxyethyl) -hexane are dissolved in 10 ml of acetonitrile, then 4.7 g of triphenylphosphine are added to the reaction mixture. The suspension obtained is kept at room temperature and 5.1 g of tetrabromomethane are added thereto, and the solution is stirred for 3 hours. The reaction is monitored by chromatography. (Conditions as described in Example 2, the product has an Rf at 0.5). After completion of the reaction, the product was freed from the solvent, then purified by chromatography (2 cm diameter column, 20 cm height, silica gel 60 F ₂ → (Merck), eluent: hexane / ethyl acetate 4: 1 v / v, pressure 0.26 kPa).

Yield: 3.3 g (97%).

¹H-NMR: (CDC1 ₃ / TMS) <= 5 (ppm 0.9 t / 34); 1.2 S (ЗН); 1.2-1.5 m (7H); 1.95-2.2 m (2H);

3.4-3.6 m (2H).

Example 4

2-R, S-hydroxy-2- (2'-iodoethyl) hexane

2.1 g of 2- (R, S) -hydroxy-2- (2'-bromoethyl) hexane are dissolved in 10 ml of sodium iodide saturated with sodium iodide. The reaction mixture is boiled for 30 minutes, then the acetone is distilled off. The residue was taken up in 15 ml of n-hexane and the filtered salt was washed three times with 10 ml of n-hexane on the filter. The combined n-hexane phases are then freed of solvent.

Yield: 2.3 g (90%).

^X H-NMR (CDC1 ₃ / TMS) </ ppm / = 0.92 t / 3H /; 1.17 S (3H); 1.2-1.6 m (7H); 2.03-2.22 m (2H); 3.15-3.35 m (2H).

¹ H replaced by ¹³ C-NMR: (CDCl ₃ / TMS): δ (ppm)? -0.55; 14.0; 23.1; 25.0; 25.3; 41.6; 46.8; 74.0.

Example 5

Preparation of 3- (R, S) -hydroxy-3-methyl-1-heptyltriphenylphosphonium iodide

A mixture of 2 g of 2- (R, S) -hydroxy-2- (2'-iodoethyl) hexane, 20 g of triphenylphosphine and 20 ml of acetonitrile was boiled for 8 hours. After the reaction time, the iodine starting compound is tested. (Control under conditions given in Example 2; Rf starting iodine compound at 0.5).

After the reaction was completed, the mixture was cooled to room temperature, the triphenylphosphine was filtered off and washed twice with 20 ml of acetonitrile on the filter. The mother liquor and the acetonitrile wash solution may be combined and de-solvented. The product is freed from excess triphenylphosphine by chromatography; on the column described in Example 3, triphenylphosphine was eluted with ethyl acetate and the product was 2: 1 acetone-ethyl acetate. The solvent is then distilled gently (in vacuo) from the product, and crystallization is carried out from hexane at room temperature.

Yield: 3.4 g (84%).

Mp 128-130 ° C.

¹ H-NMR: (CDCl ₃ / TSM): δ (ppm): 0.85 t (3H); 1.3 S (3H); 1.4-1.9 m (8H); 3.4-3.85 m (3H);

7.7-8 m (15H).

^{X is} H, C replaced by ^13: (CDC1 ₃ / TMS /: <5 / ppm / 14.1 / _C? /; 17.5; 19.6 / C ₂ /, 23.0 / CG /;

26.1? 25.2 (C _methyl ); 33.9; 34.0 (Сд); 41.5 (Cg); 71.8; 72.3 (C ₃ ); 116.4;

119.8 / C ₁ / x 130.4; 130.8; 133.3; 133.7; 135.1; 135,2 (C _aromatic ):

Claims (6)

A process for the preparation of novel prostaglandin derivatives of the general formula I ' -CH ₂ -C-OL 1 (I) wherein R represents an optionally cyclopentyl or cyclohexyl substituted alkyl group in a straight or branched carbon chain or a cyclopentyl or cyclohexyl group, R ¹ represents a C ^^ alkyl group, characterized by being of formula VII is reacted obecnéR ¹ Compound (VII) wherein R and R * are as defined above, with a C ^ alkyl ester of bromoacetic acid and zinc metal, the resulting compound of Formula VI common R ¹ Λ ' ^ЧЧч СН _о -С-О-СН - СН _{: 1} ² I! ²³ О (VI) where R and r! are as defined above, reacted with In the metal hydride, the obtained compound R ¹ OH AND-" CH ₂ -CH ₂ -OH (V) wherein R and R ¹ are to be reacted with triphenylphosphine and carbon tetrabromide, the compound of formula (IV) obtained above as defined above; R ¹ ----- 1 ----- R AND CH ₂ -CH ₂ -Br where R a is as defined above, is reacted with an inorganic iodine compound and an iodine compound of formula III prepared by this reaction OH R ¹ ----- C ----- R ₂ -ch ₂ -j wherein R and R ¹ are as defined above, are reacted with triphenylphosphine, the phosphonium salt of formula II thus obtained CS 266 349 B2 where R and r! are as defined above and reacted with a lithiumalkyl- or lithiumalkylamide-type compound to give a compound of formula I. 2. A process according to claim 1 wherein the compound of formula (VII) is reacted with ethyl bromoacetate and zinc metal in an anhydrous organic solvent. 3. The process of claim 1 wherein the metal hydride is lithium aluminum hydride. -X. 4. The process of claim 1 wherein the compound of formula V is reacted with triphenylphosphine and tetrabromomethane in an organic solvent, preferably acetonitrile. 5. The process according to claim 1, wherein the inorganic iodine compound is an alkali metal iodide, preferably sodium iodide. 6. The method of claim 1, wherein the compound of formula II is converted to a compound of formula I by reaction with an alkyllithium compound containing C ^ _ ₆ alkyl or C ^^^ glithiumalkylamidem or -cykloalkylalkylamidem.