CS200167B2 - Method of producing 11,15-bis/tetrahydropyranyl/-ether of prostaglandin-carboxamide - Google Patents

Description

The invention relates to a process for the preparation of compounds which are suitable as starting materials for the preparation of novel analogues of naturally occurring prostaglandins. In particular, the invention relates to the production of substances suitable for the production of novel N-substituted prostaglandin N-substituted carboxamides.

The present invention relates to a process for the preparation of the 11,15-bis (tetrahydropyronyl) ether of the prostaglandine carboxyamide of formula V

R is C 2 -C 8 alkanoyl or C 4 -C 8 cycloalkanoyl, aroyl or substituted aroyl of 7 to 11 carbon atoms in which the substituent is methyl, halogen or methoxy, alkylsulfonyl of 1 to 7 carbon atoms, thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl,

R1 is hydrogen or (C1-C3) -alkyl,

R 2 is C 5 -C 11 alkyl,

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

Z denotes a single bond or a trans-double bond,

M is oxo,

4 ^ or \ _OH and

THP stands for 2-tetrahydropyranyl, characterized in that the hemiacetal of formula VI is reacted

(Know where

R1, R2, THP and Z are as defined above, with an ylide of formula VII

O (C 6 H 5) 3 P = CH - CH 2 - CH 2 - CH 2 - C - NHR (VII) where

R is as defined above to form a compound of formula V wherein W is a cis-double bond and R, R1, R2, Z, M and THP are as defined above and is then optionally hydrogenated to a compound of formula V wherein R, R 1, R 2 M, THP and Z are as defined above and W represents a single bond.

To prepare the above compounds suitable as starting compounds for prostaglandin analogs, the corresponding hemiacetal precursor is reacted with the disodium salt of the novel substituted carboxamide, butyltriphenylphosphonium bromide, in a molar ratio of about 1: 2 to 1:10. Such precursors are, for example:

2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- (tetrahydropyran-2-yloxy-trans-1-octenyl) -cyclopent-1a-yl) acetaldehyde, χ- hemiacetal for PGFi _and PGEi PGAi,

PGA 2, PGE 2, PGA ₂ , 13,14-dihydro-PGF _1α , PGE 2 and PGA 1,

2- [5α-Hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3β-lower alkyl-3α (tetrahydropyran-2-yloxy) -trans-1-octen-yl) -cyclopent-1α -yl] acetaldehyde, yhemiacetal for the 15-lower alkyl derivatives of these prostaglandins,

2- [5α-Hydroxy-3 '- (tetrahydropyran-2-yloxy) -2 ₍ 3'-methyl-3a-2-yloxy) oct-1-yl) cyclopent-1-yl] acetaldehyde, phemiacetal for 13 14 dihydro PGF2a _and, PGE ₂ and PGA.

2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3/3-lower alkyl-3α- (tetrahydro-pyrrolidin-2-yloxy-octyl)) -cyclopent-1 α-yl] acetaldehyde, χ-hemiacetal for the 15-lower aclyl derivatives of 13,14-dihydro-PGF ₁ K, PGE 2 and PGA ₁ ; and

2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α- (tetrahydropyran-2-yloxy) -cis-5-trans-1-octadien-1-yl) -cyclopent- 1a-yl] acetaldehyde, χ-hemiacetal for PGF _3a and PGF ₃ .

The reaction is preferably carried out at 25 to 65 ° C in an inert solvent such as dimethylsulfoxide and under an inert atmosphere for up to 4 hours or until the reaction is substantially complete.

Products containing substituted carboxamides can be converted to substituted carboxamide analogs of prostaglandin as described by Coreya et al. in J. Am. Chem. Soc. 93, 1490 (1971). The procedure is described in detail in the appended examples.

For the preparation of 15-epimeric, 15-lower alkyl derivatives or 15-emimer-15-lower alkyl derivatives of all the aforementioned prostaglandin carboxamides, only the hemiacetal of the general formula VHIb and XV to XIX is used and proceeded as above to produce the desired compound.

(XV /

(XVI) p

β then ethyl acetate as eluents. Removal of high Rf impurities yielded 1.15 g (67.8% yield) of N-acetyl-9α-hydroxy-11a, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide, as a viscous colorless oil.

The IR spectrum (CHCl 3) of the product shows a strong absorption of 5.80 µ (carboniles).

NMR Spectrum (CDCl3)

x / x;

The following examples illustrate and do not limit the scope of the appended claims. All temperatures are in degrees Celsius and boiling points are uncorrected.

Example 1

To a solution of 5.82 g (12.0 mmol) of [4- (acetylaminocarbonyl) butyl] triphenylphosphonium bromide in 6.0 mL of dry dimethylsulfoxide was added dropwise 9.8 mL (23.5 mmol) of a 2.4 M solution of sodium methylsulfonylmethide in dimethylsulfoxide. solution of 1.32 g (3.0 moles) of χ-hemiacetal 2- [5'-hydroxy-3'- (tetrahydropyran-2-yloxy) -2β- (3α- (tetrahydropyran-2-yloxy) -trans) dropwise 1-octen-1-yl) cyclopent-1-yl] -acetaldehyde in 3.0 mL of dry dimethyl sulfoxide over 0.5 hour After stirring at room temperature for 20 hours, the reaction mixture is poured onto ice with water. ether and intensively stirred mixture was acidified to pH 3 by addition of 10% aqueous hydrochloric acid, the acidic aqueous layer was further extracted twice with ether, the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a semi-solid of 4.0 g The semi-solid is purified by column chromatography on silica gel using chloroform and multiplet at 5.27-5.68 <5 for olefinic protons, wide singlet at 4.60-4.80 8 for OH, and

NH, multiplets at 3.25-4.30 8 for —CHO and —CH2O—, singlet at 2.37 8 for —COCH3, and multiplets at 0.68 - 2.37 5 for remaining protons.

The above product can be subjected to cautiously catalytic reduction to afford N-acetyl-9α-hydroxy-11a, 15α-bis (tetrahydropyran-2-yloxy) -trans-13-prostanamide, which can be converged by known reactions [EJ Corey et al. J. Am. Chem. Soc. 92, 2586 (1970)] to N-acetylprostaglandin F 1 _and -carboxamide and N-acetyl-15-methylprostaglandin E 1 -carboxamide, which can be converted to N-acetylprostaglandin A 1 -carboxamide, or reduced to N-acetylprostaglandin F ₁ -carboxamide.

The above product can be subjected to catalytic reduction to prepare N-acetyl-9α-hydroxy-11a, 15α-bis (tetrahydro-pyran-2-yloxy) -prostanamide, hereinafter referred to as Compound A. Compound A can be hydrolyzed to give N acetyl-13,14-dihydroprostaglandin F-, carboxainide Compound A can be oxidized and then hydrolyzed to prepare N-acetyl-13,14-dihydroprostaglandin E-carboxamide, hereinafter referred to as Compound B. Compound B can be dehydrated and prepare N-acetyl-13,14-dihydroprostaglandin N-carboxamide, or reduce to N-acetyl-13,14-dihydroprostaglandin Fip-carboxamide.

Example 1 a d 2

To a solution of 2.03 g (4.00 mmol) of (4-propionylaminocarbonylbutyl) triphenylphosphonium bromide (vacuum dried overnight at 110 ° C in 5 mL of dimethylsulfoxide) was added 8.97 mL (17.0 mmol) of 1.89 M sodium methylsulfonylmethide solution. To the resulting red ylide solution was added dropwise a solution of 876 mg (2.00 mmol) of the known χ-hemiacetal 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2 / 3- / 3 of- ( tetrahydropyran-2-yloxy) -1-trans-octen-1-yl / cyclopent-1-yl] acetaldehyde in 2.0 mL dimethylsulfoxide The mixture was stirred under nitrogen for 2.5 hours and then poured onto a stirred ice mixture The aqueous layer was acidified to approximately pH 3 with 10% hydrochloric acid and the acidified aqueous layer was extracted twice with ether.The combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude oil The oil was purified by column chromatography on silica gel using benzene, chloroform and then ethyl After removal of the less polar impurities, a colorless oily N-propionoyl-4α-hydroxy-11a, 15ce-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide of 507 mg (43 g) was obtained. 6% yield).

The NMR spectrum of the oily product shows a multlplet of 5.66 to 5.27 δ for olefinic protons, a wide singlet at 4.70 δ for - O — CH — O—, multiplets at 4.26 to 3.22 δ for - CHO a

CH2 - O, broad singlet at 9.10 5 for NH, quartet center at 2.63 <5 for

NHCCHz

II o

triplet center at 1.20 δ for CH3 and multiplets at 2.83 to 0.67 δ for remaining protons.

Example 1 a d 3

To a solution of 1.53 g (3.00 mmol) of [4- (cyclopropyranbonylaminocarbonyl) butyl] triphenylphosphopium bromide (vacuum dried at 110 ° C overnight) in 4.0 mL of dimethylsulfoxide S was added 3.38 mL (6.93) 2.05 M of methylsulfinyl methide in dlmethylsulfoxide, a solution of 438 mg (1.00 mmol) of the known 2- (5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2-yloxy) -2- (tetrahydropyran-2-yloxy) -2- solution is added dropwise to the resulting red ylide solution. 3- [3- [(tetrahydro-pyran-2-yloxy) -1-trans-octen-1-yl] -cyclopeut-1-yl] -acetaldehyde in 2.0 mL of dimethylsulfoxide, stirred overnight under nitrogen and then poured into stirring The aqueous layer was acidified to approximately pH 3 with 10% hydrochloric acid solution and the acidified aqueous layer was extracted twice with ether, the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude oil. column chromatography on silica gel using 10% benzene in chloroform as eluent removal of less polar impurities yielded a colorless oily N-cyclopropanecarbonyl-4af-hydroxy-11f, 15'-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide weighing 289 mg (49.0% yield) .

The IR spectrum (CHCl 3) of the oily product shows a strong absorption at 1670 and 1720 cm ^-1 attributed to carbonyl groups and at 970 cm ^-1 attributed to a trans-double bond. The NMR spectrum (CDCl 3) of the oily product shows a multplet at 5.66-5.275 for olefinic protons, a broad singlet at 4.70 δ for —O — CH — O—, multiplets at 4.26-3.22 δ for —CHO, and

CH2 - O, broad singlet at 9.10 δ for NH and multiplets at 2.83 to 0.63 δ for remaining protons.

Example 4

To a solution of 1.22 g (2.32 mmol) of (4-trimethylacetylaiminocarbonylbutyl) triphenylphosphonium bromide in 4.0 mL of dry dimethylsulfoxide was added 2.22 mL (4.54 mmol) of a 2.05 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. a solution of 0.219 grams (0.5 mmol) of 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2 H- [3- (tetrahydro-pyran-2-ylxoy) -trans-1] -tetrahydrate] is added dropwise. -octen-1-yl / cyclopent-1-yl] acetaldehyde in 1.0 mL of dry dimethylsulfoxide After stirring for 20 hours at room temperature under nitrogen, the reaction mixture was poured onto ice and water. The aqueous mixture was extracted three times with ether, the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a viscous oil. The crude product was purified by column chromatography on silica gel using chloroform. The resulting semi-solid was triturated with ether and hexane to give an oily N-trimethylacetyl-1 H -hydroxy-11,15a-bisphthetrahydropyrah-2-yioxy) -cis-5-trans-13-prostadienamide weighing 401 mg.

The NMR spectrum (CDCl 3) shows a singlet at 1.20 5 for C (CH 3) s, a broad singlet at 4.48-4.73 δ for OCHO and a multiplet at 5.15-5.60 5 for olefinic protons as different absorption .

Example 5

To a solution of 10.4 g (20.0 mmol) of (4-methanesulfonylaminocarbonyl) butyl] triphenylphosphonium bromide in 12.0 mL of dry dimethylsulfoxide was added dropwise 21.8 mL (39.0 mmol) of a 1.8 M solution of sodium methylsulfinylmethide in The resulting red ylide solution was stirred under nitrogen for 5 minutes, and then a solution of 2.19 g (5.0 mmol) of the known 2- [5α-hydroxy-3α- (tetrahydropyran-2-yl) -hylacetamide] was added dropwise over 30 minutes. -oxy) -2,3- (3-tert-tetrahydropyran-2-yloxy) -trans-1-octen-1-yl] -cyclopent-1 H -yl] acetaldehyde in 5.0 mL dry dimethylsulfoxide The solution was stirred overnight then The mixture was acidified to about pH 3 with 10% aqueous hydrochloric acid, the acidified aqueous layer was extracted with ether, and the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude yellow oil. The oil was purified by column chromatography on silica gel eluting with Use of a mixture of benzene and chloroform as eluents After removal of the less polar impurities, a colorless oily N-methanesulfonyl-9α-hydroxy-11β, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide is obtained. weight 2.59 g (86.4% yield).

The NMR spectrum (CDCl 3) of the product shows a multiplet at 5.70 to 5.13 δ attributed to olefinic protons, a broad singlet at 4.80 to 4.52 δ attributed to OCHO, multiplets at 4.20 to 3.00 δ attributed

CH — O and CH2O, singlet at 3.22 δ attributed to SO2CH3 and multiplets at 2.75 to 0.68 δ for the remaining protons.

Example 6

To a solution of 2.68 g (5.1 mmol) of [(4-methanesulfonylaminocarbonyl) butyl] triphenylphosphonium bromide (dried overnight at 144 ° C), in 5 mL of dry dimethyl sulfoxide, was added dropwise 6.22 mL (9.7 mmol). 1.56 M of sodium methylsulfinyl methide in dry di-dimethylsulphoxide. The resulting red ylide solution was stirred under nitrogen for 15 min. and then a solution of 770 mg (1.50 mmol) of 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3/3-methyl-3'-) tetr ahydropyran- 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2β- (3α-methyl-) 2-yloxy] -trans-1-octem-1-yl) cyclopent-1i-yl] acetaldehyde and χ-hemiacetal 3 H- (tetrahydropyran-2-yloxy) - tr, ans-1-octen-1-yl) cyclopent-1-yl] acetaldehyde in 2 mL of dry dimethylsulfoxide. The mixture was stirred under nitrogen overnight and then poured onto a mixture of ice-water and ether. The aqueous layer was acidified with a 10% aqueous hydrochloric acid solution and then extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude yellow oil which was purified on silica gel by column chromatography using chloroform / ethyl acetate mixtures as eluents. For eluting less polar impurities, oily products, N-methanesulfonyl-9α-hydroxy-11a, 15α-bis (tetrahydropyran-2-yloxy) -15 H -methyl-cis-5-trans-13-prostadienamide and N-methanesulfonyl are obtained. -9α-hydroxy-11a, 15 ₁ 3-bis (tetrahydropyran-2-yloxy) -15α-methyl-cis-5-trans-13-tprostadienamide weighing 300 mg.

The NMR spectrum (CDCl3) of the chromatographic product shows a multiplet at 5.60 to 5.09 δ for olefinic protons, a broad singlet at 4.74 to 4.44 δ for OCHO, multiplets at 4.21 to 3.92 δ for CH2O and CHO , singlet at 3.24 δ for SO2CH3, two singlets at 1.30 and 1.11 δ for C — CH3, and multiplets at 2.67 to 0.56 δ for the remaining protons.

Example 7

To a solution of 835 mg (1.61 mmol) of phosphonium bromide as used in Examples 5 and 6, 1.42 mL (2.72 mmol) of 1.91 M solution was added dropwise in 2.0 mL of dry dimethylsulfoxide. methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 250 mg (0.54 mmol) of 2- [5α-hydroxy-3 - (tetrahydropyran-2-yloxy) -2β- / 3α- (tetrahydropyran-2-yloxy) χ-hemiacetal]. -4,4-dimethyl-trans-1-octan-1-yl / cyclopent-1-yl] acetaldehyde in 1.0 mL dry dimethylsulfoxide over 5 minutes. After stirring at room temperature for 20 hours, the reaction mixture was poured on ice with water. The aqueous solution was overlaid with ethyl acetate and the vigorously stirred mixture was acidified to pH 3 by addition of a 10% aqueous hydrochloric acid solution. The acidified aqueous layer was further extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude oil. The oil was purified by silica gel column chromatography using chloroform / ethyl acetate mixtures as eluents. After removal of the less polar impurities, the desired N-methanesulfonyl-9α-hydroxy-11a, 15α-bis (tetrahydro-propyran-2-yloxy) -16,16-dimethyl-cis-5-trans-13-prostadienamide is obtained, such as colorless oil 249 mg (75.5% yield).

The NMR spectrum (CDCl3) of the chromatographed product shows a multiplet at 5.70 to 5.13 δ for vinyl protons, a multiplet at 4.80 to 4.46 δ for OCHO, a singlet at 3.24 δ for SO2CH3, multiplets at 4.26 up to 3,05 δ for CH 2 O and

CHO, singlet at 0.80 δ for attached dimethyl groups and multiplets at 2.71 to 0.50 δ for remaining protons.

Example 8

To a solution of 2.60 g (5.36 mmol) of phosphonium bromide as used in Example 1, in 20 milliliters of dry dimethyl sulfoxide, was added dropwise 5.45 ml (10.22 mmol) of a 1.88 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution is added dropwise a solution of 250 mg (0.54 mmol) of 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2,3- / 3α- (tetrahydropyran-2-yloxy) ε-hemiacetal. (-4,4-Dimethyl-trans-1-octan-1-yl) -cyclopent-1a-yl] acetaldehyde in 1.0 mL of dry dimethyl sulfoxide over 5 min. After stirring at room temperature for 20 hours, the reaction mixture was poured on ice with water. The aqueous solution was overlaid with ethyl acetate and the vigorously stirred mixture was acidified to pH 3 by addition of a 10% aqueous hydrochloric acid solution. The acidified aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give the crude product. The crude product was purified by silica gel column chromatography using mixtures of benzene and chloroform as eluents. Removal of the less polar impurities gave the desired N-acetyl-9α-hydroxy-11a, 15or-bs (tetrahydropyran-2-yloxy) -16,16-dimethyl-cis-5-trans-13-prostadienamide as a viscous colorless oil. 250 mg (78.5% yield).

The NMR spectrum (CDCl3) of the chromatographed product shows a singlet at 9.3 δ for NH, a multiplet at 5.65 and 5.22 δ for olefinic protons, a broad singlet at 4.65 δ for OCHO, multiplets at 4.20-3, 20 δ for CHO and

CH2O, singlet at 2.32 <5 for COCH3, singlet at 0.80 δ for attached dimethyl groups and multiplets at 2.69 to 0.61 δ for remaining protons.

Example 9

To a solution of 2.42 g (5.00 mmol) of [4- (acetylaminocarbonyl) butyl] triphenylphosphonium bromide in 5.0 mL of dry dimethylsulfoxide was added dropwise 10.5 mL (10.0 mmol) of a 0.95 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. . To this red ylide solution was added dropwise a solution of 450 milligrams (1.00 mmol) of 2- [5α-hydroxy-3 H- (tetrahydropyran-2-yloxy) -2β- / 3β-tetraphenyl-3α- (tetrahydropyran-2-yloxy) β-hemiacetal. 2'-trans-1-octen-1-yl / cyclopent-1'-yl] acetaldehyde and χ-hemiacetal 2- [5'-hydroxy-3'-tetrahydro-pyran-2-yloxy) -2 / 3- (3a-methyl) -3 H- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl / cyclopent-1-yl] acetaldehyde in 2.0 mL of dry dimethylsulfoxide over 0.5 hour After stirring at room temperature for 20 hours The reaction mixture was poured onto ice-water, the aqueous solution was overlaid with ethyl acetate, and the vigorously stirred mixture was acidified to pH 3 by the addition of 10% aqueous hydrochloric acid, the acidified aqueous layer was further extracted twice with ethyl acetate. The crude product is purified by column chromatography to give the desired N-acetyl-9. N -hydroxy-11a, 15α-bis (tetrahydropyran-2-yloxy) -15S-methyl-cis-5-trans-13-propadiene amide and N-acetyl-hydroxy-11a-1H-bis (tetrahydropyran) -2-yloxy) -1Sa-methyl-cis-5-trans-13-prostadienamide.

Example 10

To a solution of 2.53 g (4.36 mmol) of [4-benzenesulfonylaminocarbonylbutyltriphenylphosphonium bromide in 3.0 mL of dry dimethylsulfoxide was added dropwise 5.05 mL (8.72 mmol) of a 1.73 M solution of sodium methylsulfinylmethide in dry dimethylsulfoxide. . The resulting red ylide solution was stirred under nitrogen for 5 minutes, and then a solution of 0.476 g (1.09 mmol) of the known 2- [5α-hydroxy-3α- (tetrahydropyran-2-yloxy) -2 H-] - was added dropwise. 3α- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl / cyclopent-1'-yl] acetaldehyde in 2.0 mL of dry dimethylsulfoxide. The solution was stirred for 2.75 hours and then poured onto a mixture of ethyl acetate and ice with water. The vigorously stirred solution is acidified to approximately pH 3 with a 10% aqueous hydrochloric acid solution. The acidified layer was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude yellow oil. The oil was purified by silica gel column chromatography using chloroform / ethyl acetate mixtures as eluents. Removal of the less polar impurities afforded the desired N-benzenesulfonyl-9α-hydroxy-11α, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadienamide as a colorless oil weighing 294 mg (40, 8% yield).

The NMR spectrum (CDCl 3) of the chromatographed product shows multiplets at 8.19 to 7.92 δ and 7.72 to 7.37 δ for aromatic protons, multiiplet at 5.70 to 5.12 δ for vinyl protons, multiplet at 4, 83 to 4.60 δ for OCHO, multiplets at 4.29 to 3.20 δ for CHaO and

CHO and multiplets at 2.49 to 0.70 δ for the remaining protons.

Example 11

To a solution of 2.68 g (4.50 mmol) of [4- (p-toluenesulfonylaminocarbonyl-1-butyl) triphenylphosphonium bromide (dried overnight at 144 ° C) in 2.0 mL of dry dimethyl sulfoxide was added dropwise 4.65 mL (9 mL). 1.00 M solution of sodium methylsulfinyl methide in dry dimethylsulfoxide The resulting red ylide solution was stirred under nitrogen for 15 minutes, and then 653 mg (1.50 mmol) of the known 2- [5α-hydroxy-3α-] - hemiacetal was added. (tetrahydropyran-2-yloxy) -2,3- [3- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl / cyclopent-1-yl] acetaldehyde in 20 mL of dry dimethylsulfoxide. The mixture was stirred under nitrogen for 5 hours and then poured onto ice / water / ether, the aqueous layer was acidified with 10% aqueous hydrochloric acid solution and then extracted three times with ether and the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude. A yellow oil which was purified on silica gel by column chromatography The mixture of chloroform and benzene was eluted with ethyl acetate to give a colorless oily Np-toluenesulfonyl-9α-hydroxy-11a, 15α-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-prostadiene amide, 383 mg (37, 9% yield).

The NMR spectrum (CDCl3) of the oily product shows two doublets at 7.89 and 7.23 δ (J = 8 cps) for aromatic protons, multiplet at 5.64 to 5.00 δ for olefinic protons, wide singlet at 4.63 δ for O — CH — O, multiplets at 4.28 to 3.20 δ for —CHO— a

- CH2, singlet at 2.42 δ for —CH3 and multiplets at 2.68 to 0.48 δ for remaining protons.

The IR spectrum (CDCl 3) shows strong absorption at 1710 cm ^-1 attributed to carbonyl absorption and at 970 cm ^-1 attributed to the trans-double bond.

Example 12

To a solution of 2.34 g (4.0 mmol) of [4- (2-thiophenesulfonyl) aminocarbonylbutyl] triphenylphosphonium bromide in 2.0 mL of dry dimethyl sulfoxide was added dropwise 3.59 mL (7.5 mmol) of a 2.09 M methylsulfinylmethide solution. sodium in dry dimethylsulfoxide. The resulting red ylide solution was stirred under nitrogen for 5 minutes, and then a solution of 0.438 g (1.0 mmol) of the known 2- [5α-hydroxy-3 '- (tetrahydro-propyran-2-yloxy) -2,3-tetrahydroetal] was added dropwise over 10 minutes. 3 '- (tetrahydropyran-2-yloxy) -trans-1-octen-1-yl / cyclopent-1-yl] acetaldehyde in 2.0 mL of dry dimethylsulfoxide The solution was stirred overnight and then poured onto ethyl acetate. The aqueous solution was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give a crude yellow oil. After removal of the less polar substances and 2% diethylamine in diethyl acetate, colorless oily N- (2-thiophenesulfonyl) -α-hydroxy-11β-bis (tetrahydropyran-2-yloxy) -1-cis-5 is obtained by oleolysis with ethyl acetate. -trans-13-prostadiene amide weighing 113 mg.

The NMR spectrum (CDCl 3) of the chromatographic product shows multiplets at 7.86 to 7.48 δ and 7.23 to 6.90 <5 for thiophene protons, multiplet at 5.60 to 5.06 δ for vinyl protons, multiplet at 4 , 72 to 4.43 δ for OCHO, multiplets at 4.20 to 3.14 δ for CH2O and

CHO and multiplets at 2.63 to 0.52 5 for the remaining protons.

Example 13

To a solution of 2.73 g (5.0 mmol) of (4-benzoylaminocarbonylbutyl) triphenylphosphonium bromide in 10 mL of dry dimethyl sulfoxide was added 2.22 mL (4.54 mmol) of a 2.05 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. A solution of 0.219 g (0.5 mmol) of 2- [5α-hydroxy-3 '- (tetrahydropyran-2-yloxy) -2β- (3''-tetrahydropyran-2-yloxy) β-hemiacetal is added dropwise to the red ylide solution. tris-1-octen-1-yl / cyclopent-1a-yl] actalddehyde in 1.0 mL of dry dimethylsulfoxide. After stirring for 20 hours at room temperature under nitrogen, the reaction mixture was poured on ice with water. The aqueous solution was overlaid with ether and acidified to approximately pH 3 by the addition of a 10% hydrochloric acid solution. The aqueous mixture was further extracted three times with ether, the combined ether extracts were dried over anhydrous magnesium sulfate and evaporated to give a viscous oil. Purification of the crude product is carried out on silica gel chromatography to give N-benzoyl-9α-hydroxy-11a, 15α-bis (tetrahydro-propyran-2-yloxy) -cis-5-trans-13-prostadienamide.

SUBJECT

Claims (1)

SUBJECT VYNALEZU A process for the preparation of the 11,15-bis (tetrahydropyranyl) ether of the prostaglandin carboxamide of formula (V) R is C 2 -C 8 alkanoyl or C 4 -C 8 cycloalkanoyl, aroyl or substituted C 7 -C 11 aroyl wherein the substituent is methyl, halogen or methoxy, C 1 -C 7 alkylsulfonyl, thiophenesulfonyl, benzenesulfonyl or toluenesulfonyl. R1 is hydrogen or alkyl of 1 to 3 carbon atoms, R 2 is C 5 -C 11 alkyl, W represents a single bond or a cis-double bond, Z denotes a single bond or a trans-double bond, M is oxo, OH or THP stands for 2-tetrahydropyranyl, characterized in that the hemiacetal of formula VI is reacted R1, R2, THP and Z are as defined above, with an ylide of formula VII O (C 6 H 5) 3 P = CH - CH 2 - CH 2 - CH 2 - C - NHR (VII) where R is as defined above to form a compound of formula V wherein W is a cis double bond and R, R 1, R 2, Z, M and THP are as defined above and is then optionally hydrogenated to a compound of formula V wherein R, R 1, R 2, M, THP and Z are as defined above and W represents a single bond. Severography, n., Plant 7, Moet