CS201029B2 - Method of producing bis/tetrahydropyranyl/ethers of prostenoic acid derivatives - Google Patents

Description

The invention relates to a process for the preparation of bis (tetrahydropyranyl) ethers which are useful as intermediates for the preparation of certain novel analogs of natural prostaglandins. In particular, the invention relates to a process for the preparation of intermediate bis (tetrahydropyranyl) ethers of prostenoic acid derivatives used in the preparation of the prostaglandins described in co-pending U.S. Patent No. 201,027.

The present invention provides a process for the preparation of bis (tetrahydropyranyl) ethers of prostenoic acid derivatives of formula (I)

in which

Ar is alpha-furyl or beta-furyl, alpha-thienyl or beta-thienyl, alpha-naphthyl or beta-naphthyl, 3,4-dimethoxyphenyl or phenyl optionally monosubstituted by phenyl, methyl or methoxy n is an integer of 0 to 5, wherein when Ar is a phenyl group optionally substituted by the above method or a naphthyl group, n is 0 or 1,

R represents a hydrogen atom or a methyl group,

THP represents a 2-tetrahydropyranyl group,

W represents a single bond or a cis-double bond and

Z represents a single bond or a trans-double bond, characterized in that the compound of formula (II) is present

in which

Ar, n, R, Z and THP are as defined above, is reacted with an ylide of formula ^(C 6 H _{5) 3} P = C ^H - ^CH 2- ^CH 2- ^CH 2- ^c °° ^(>

to form a compound of formula I wherein Ar, n, R, THP, and Z are as defined above and W is a cis double bond, and the resulting product is optionally converted by hydrogenation to a compound of formula I wherein Ar, n, R, THP and Z are as defined above and W represents a single bond.

An example of one embodiment of the reaction according to the invention can be illustrated, for example, by the following reaction scheme;

Scheme A

HIM

As shown in Scheme A, the reaction consists of a Wittig condensation in which the heaiacetal of formula (II) is not reacted with (4-carboxybutyl) triphenylphosphonium bromide in dimethylsulfoxide, in the presence of sodium methylsulfinylmethide. The product of formula (i ') is then optionally purified by column chromatography. Cyclopentatb] furan derivatives of formula II 'and their preparation are described in the description of the invention to U.S. Pat. No. 20,027.

The following Scheme B illustrates the preparation of the starting materials and those compounds of the invention wherein one or both of W and Z are single bonds, which compounds are useful starting materials for the preparation of the prostaglandins described in U.S. Pat. No. 20,027.

201029 '

Scheme Β

(13)

The starting materials of formula (9) and their preparation are described in the description of the invention to U.S. Pat. patent δ. 201 027 and reaction step (9) - (12) is carried out by first carrying out base hydrolysis to remove the p-biphenylcarbonyl protecting group as described in U.S. Pat. patent δ. 201 027, the resulting compound is treated with dihydropyran and an acid catalyst, for example p-toluenesulfonic acid, in anhydrous medium to introduce 2-tetra-; hydropyranyl protecting groups in place of the two free hydroxyl groups, the resulting lactone is reduced to the corresponding hemiacetal and the hemiacetal is subjected to a condensation analogous to that described in Reaction Step II '- * I * in Scheme A. These steps for preparing a compound of formula (12) from formulas (9) are described in the description of the invention to US. No. 201,027 and intermediate lactones and hemiacetals are described in this patent.

The compound of formula (12) can be used either as a precursor for the preparation of 13,14-dihydroprostaglandins of series 2 or as an intermediate for the preparation of the compound of formula (13) which is a precursor for the production of 13,14-dihydroprostaglandins of series 1. Said prostaglandins are described in Description of the Invention No. 201,027.

The reaction of step (12) - (13) is carried out by catalytic hydrogenation using a cell of a homogeneous catalyst such as triphenylphosphine rhodium chloride or a heterogeneous catalyst such as palladium or rhodium.

Compounds of the type represented by formula (11) are prepared by selective hydrogenation of a 5,6-cis-double bond in a compound of formula (i ') at low temperature using the catalysts described above. For this hydrogenation, palladium on carbon is particularly preferably used as the catalyst and is operated at -20 ° C. Compounds of the type represented by formula (11) are not only precursors of prostaglandins of series 1, but also precursors of compounds corresponding to formula (13), which are prepared therefrom as described above in connection with reaction step (12) - (13).

The C-epimers of the compounds of formulas (11), (12) and (13) may be used as precursors of the 15-epi-prostaglandin derivatives described in the description of the invention to U.S. Pat. 201 027 and the 15-methylprostaglandins hydrogenated at the 5,6 and / or 13,14 position and their C 1 -epimers can be prepared from appropriately substituted analogs of formula I ', synthesized as described above.

13,14-Dihydro-15-methylprostaglandins can be prepared from appropriately substituted starting materials according to Scheme B.

If chromatographic purification is desirable or desirable in the above-described procedures, suitable chromatographic supports, including neutral alumina and silica gel, are used, with silica gel having a particle size of 60 to 200 mesh is generally preferred. The chromatography is conveniently carried out in inert solvents such as diethyl ether, ethyl acetate, benzene, chloroform, methylene chloride, cyclohexane or n-hexane, and is further illustrated in the examples.

The invention is illustrated by the following non-limiting examples. In the examples, all temperatures are given in degrees Celsius and the melting and boiling points are not corrected.

For example,

9alpha-hydroxy-11 alpha, 15alpha-bis- (2-tetrahydropyranyloxy) -16- (2-thienyl) -cis-5-trans-13-omega-tetranorprostadienoic acid d ')

To a solution of 2.6 g (6 mmol) of (4-carboxybutyl) triphenylphosphonium bromide in 5.0 mL of dry dimethyl sulfoxide was added 5.7 mL (11.4 mmol) of a 2.2 M solution of sodium methylsulfinylmethylide in dimethylsulfoxide under a dry nitrogen atmosphere. . A solution of 1.03 g (2.2 mol) of gamma-hemiacetal 2- [5alpha-hydroxy-3alpha- (2-tetrahydropyranyloxy) -2beta- (3alpha- (2-tetrahydropyranyloxy)) was added dropwise to the resulting red ylide solution over 20 minutes. -4- (2-thienyl) -trans-1-buten-1-yl) -1α-cyclopentyl] acetaldehyde in 5.0 mL of dry dimethylsulfoxide. After stirring for another 2 hours at room temperature, the reaction mixture was poured into ice-water, the basic aqueous solution was washed twice with 20 ml of ethyl acetate each time and acidified to pH ca. 3 with 10% hydrochloric acid. the extracts were washed once with 10 ml of water, dried over magnesium sulphate and evaporated. The solid residue was triturated with ethyl acetate and the filtrate was concentrated to give 1.02 g of 9alpha-hydroxy-11 alpha, 15alpha-bs- (2-tetrhydropyranyloxy) -16- (2-thienyl) -e-5- trans-13-omega-tranorprostadienoic acid d ').

The IR spectrum of the product contains a thick band at 1700 cm ", along with absorptions between 2,800 and 2,600 cm " corresponding to the carboxyl group.

The corresponding beta-thienyl derivatives are prepared in an analogous manner.

15alpha-tetrahydropyranyl ether ID: 1 710, 970 cm ”’

15beta-tetrahydropyranyl ether IR: 1 710, 970 cm ''.

Example 2

9alpha-hydroxy-11 alpha, 15alpha-bis- (2-tetrahydropyranyloxy) -16- (2-thienyl) -is-5-omega-tetranorprostenoic acid (12)

To a solution of 5150 mg (11.6 mmol) of (4-carboxybutyl) triphenylphosphonium bromide in 10.1 mL of dry dimethylsulfoxide was added 10.8 mL (21.1 mmol) of a 1.96 M solution of sodium methylsulfinylmethylide in dimethylsulfoxide under a dry nitrogen atmosphere. . A solution of 1,300 mg (2.6 mmol) of gamma-hemiacetal 2- [5alpha-hydroxy-3alpha- (2-tetrahydropyranyloxy) -2beta- (3alpha- / 2-) - was added dropwise to the resulting red ylide solution over 20 minutes. tetrahydropyranyloxy (-4- (2-thienyl) -1-butyl) -,. alpha.-cyclopentyl] acetaldehyde in 7.0 mL of dry dimethyl sulfoxide. After stirring for another 2 hours at room temperature, the reaction mixture was poured into ice-water, the basic aqueous solution was acidified to about pH 3 with 10% hydrochloric acid, the acidic aqueous solution was extracted three times with 100 ml of ethyl acetate each time. , dried over magnesium sulphate and evaporated. The solid residue was triturated with ethyl acetate, the mixture was filtered, and the filtrate was subjected to silica gel column chromatography (60 to 200 mesh) using ethyl acetate as eluent. After removal of high impurities, 9α-hydroxy-11α, -15α-bis- (2-tetrahydropyranyloxy) -, 6- (2-thienyl) -cis-5-omega-tetranorprostenoic acid (12) is obtained.

Example 3

9alpha-hydroxy-11alpha, 15alpha-bis- (2-tetrahydropyranyloxy) -17- (2-thienyl) -cis-5-trans-13-omega-trinorprostadienoic acid

To a solution of 1.8 g (4.04 mmol) of (4-carboxybutyl) triphenylphosphonium bromide in 8.0 mL of dry dimethylsulfoxide was added 3.5 mL (7.8 mmol) of a 2.2 M solution of sodium methylsulfinylmethylide in dry nitrogen. dimethylsulfoxide. A solution of 717 mg (1.5 mmol) of gamma-hemiacetal 2- [5α-hydroxy-3α- (2-tetrahydropyranyloxy) -2beta- (3α-α-2-tetrahydropyranyloxy) -5] is added dropwise to the resulting red ylide solution over 20 minutes. - (2-Thienyl) -trans-1-penten-1-yl) -1α-cyclopentyl] acetaldehyde in 5.0 mL of dry dimethylsulfoxide. After stirring for another 2 hours at room temperature, the reaction mixture was poured into ice water, the basic aqueous solution was washed twice with 20 ml of ethyl acetate and acidified to about pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted three times with 20 ml of ethyl acetate. the organic extracts were washed once with 10 ml of water, dried over magnesium sulphate and evaporated to a solid residue which was triturated with ethyl acetate and then filtered. The filtrate was subjected to silica gel column chromatography (60 to 200 mesh) using ethyl acetate as eluent. Removal of impurities of high R @ 1 yielded 260 mg of 9a-hydroxy-11a, 15a-labis- (2-tetrahydropyranyloxy) -17- (2-thienyl) -cis-5-trans-13-omega-trinoroprostadienoic acid.

In a similar manner, the corresponding 16- (p-biphenylyl) - (i.e., 1,705,

970 cm ^-1 ), 16- (beta-naphthyl) - (IR 1710, 970 cm ^-1 ) and 16- (alpha-naphthyl) -derivatives (IR 1795,

970 cm ^-1 ).

Example 4

9alpha-hydroxy-11 alpha, 15alpha-bis- (2-tetrahydropyranyloxy) -17- (2-thienyl) -cis-5-trans-13-omega-trinorprostadienoic acid

To a solution of 1.8 g (4.05 mmol) of (4-carboxybutyl) triphenylphosphonium bromide in 5.0 mL of dry dimethyl sulfoxide was added 3.2 mL (7.0 mmol) of a 2.2 M solution of sodium methylsulfinylmethylide in dry nitrogen. dimethylsulfoxide. A solution of 717 mg (1.34 mmol) of 2-L5alpha-hydroxy-3alpha- (2-tetrahydropyranyloxy) -2beta- (3alpha- (2-tetrahydropyranyloxy) -5-) - is added dropwise to the resulting red colored ylide solution over 20 minutes. (2-Thienyl) -trans-1-penten-1-yl) -1α-cyclopentyl] -acetaldehyde in 5.0 mL of dry dimethylsulfoxide.

After stirring at room temperature for 2 hours, the reaction mixture is poured into ice-water, the basic aqueous solution is washed twice with 20 ml of ethyl acetate and acidified to about pH 3 with 10% aqueous hydrochloric acid. The acidic solution is extracted three times with 20 ml of ethyl acetate. The mixture is washed once with 10 ml of water, dried over magnesium sulphate and evaporated. The solid residue was triturated with ethyl acetate, the mixture was filtered and the filtrate was subjected to silica gel column chromatography (60 to 200 mesh) using ethyl acetate as eluent. Removal of impurities of high R @ 2 yields 740 mg of 9alpha-hydroxy-1alpha,

15alpha-bis- (2-tetrahydropyranyloxy) -17- (2-thienyl) -cis-5-trans-13-omega-trinoroprostadienoic acid.

Similarly, analogs of 16- (p-biphenylyl) - (iCs 1,705, 970 cm @ -1), 16- (beta-naphthyl) - (IR: 1,710, 970 cm @ -1) and 16- (alpha) may be prepared analogously. (naphthyl) derivatives (IR: 1 705, 970 cm -1). Example 5

9alpha-hydroxy-1alpha, 15alpha-bis- (2-tetrahydropyranyloxy) -17- (2-furyl) -cis-5-trans-13-omega-trinorprostadienoic acid

To a solution of 3.36 g (7.6 mmol) of (4-carboxybutyl) triphenylphosphonium bromide in 15.0 mL of dry dimethylsulfoxide was added, under a dry nitrogen atmosphere, 7.0 mL (14.0 mmol) of 2.0 mL of sodium methylsulfinylmethylide solution. dimethylsulfoxide. A solution of 1.3 g (2.81 mmol) of gamma-hemiacetal 2- [5alpha-hydroxy-3alpha- (2-tetrahydropyranyloxy) -2beta- (3alpha- (2-tetrahydropyranyloxy)] was added dropwise to the resulting red ylide solution over 20 minutes. -5- (2-furyl) -trans-1-penten-1-yl) -1α-cyclopentyl] acetaldehyde in 5.0 mL of dry dimethylsulfoxide. After stirring for another 2 hours at room temperature, the reaction mixture was poured into ice-water, the basic aqueous solution was washed twice with 20 ml of ethyl acetate and acidified to about pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted three times with 20 ml of ethyl acetate. the extracts were washed once with 10 ml of water, dried over magnesium sulphate and evaporated to a solid which was triturated with ethyl acetate. The mixture was filtered and the filtrate was subjected to silica gel column chromatography (60 to 200 mesh) using ethyl acetate as eluent. After removal of high Rj impurities. 1.53 g of 9α-hydroxy-11α, 15α-bis- (2-tetrahydropyranyloxy) -17- (2-furyl) -ois-5-trans-13-omega-trinoroprostadienoic acid are obtained.

Other compounds of the invention prepared by the above-described procedures are summarized in the following summary:

T R

THPO

Ar n _z x) T R preparation according to example number Ifi (cm-1) p-biphenyl 1 D α-OTHP H 1 1, 705, 970 p-biphenyl 1 D P-OTHP H 3 1, 705, 970 o-tolyl 1 D α-OTHP H 1 1712, 975 o-tolyl 1 D P-OTHP H 3 1712, 975 P-naphthyl 1 D α-OTHP H 1 1710, 970 α-naphthyl 1 D P-OTHP H 3 1710, 970 α-naphthyl 1 D α-OTHP H 1 1, 705, 970

7 201029 Ar n 2 ^) T R preparation according to IR (cm ^-1 ) example number α-naphthyl · - 1 D β-ΟΤΗΡ H 3 1, 705, 970 phenyl 1 WITH and —OTHP H 1 1 710 phenyl 1 WITH β-ΟΤΗΡ H 3 1 710 phenyl 0 with (xx) -OTHP H 1 1 710

Legend: x) D = trans-double bond, S = single bond (xx) = epimer mixture THP = 2-tetrahydropyranyl

Claims (1)

SUBJECT MATTER FROM U A process for the preparation of bis (tetrahydropyranyl) ethers of prostenoic acid derivatives of the general formula I (I) in which: Ar is alpha-furyl or beta-furyl, alpha-thienyl or beta-thienyl, alpha-naphthyl or beta-naphthyl, 3,4-dimethoxyphenyl or phenyl optionally monosubstituted by phenyl, methyl or methoxy, n is an integer of 0 to 5, wherein when Ar is a phenyl group optionally substituted by the above method or a naphthyl group, n is 0 or 1, R represents a hydrogen atom or a methyl group, THP represents a 2-tetrahydropyranyl group, W represents a single bond or a cis-double bond and Z represents a single bond or a trans-double bond, characterized in that the compound of formula (II) is present OH (II) THPO (CH _{2) n} -Ar OTHP in which Ar, n, R, Z and THP are as defined above, is reacted with an ylide of formula (C ₆ H _{5) 3} P = CH-CH ₂ -CH ₂ -CH ₂ -COO ^<_) to give a compound of formula I in which Ar, n, R, THP and Z are as defined above and W represents a cis-double bond, and the resulting product is optionally converted by hydrogenation to a compound of formula I in which Ar, n, R, THP and Z are as above and W represents a single bond.