PL162542B1 - Method of obtaining novel analogs of 24-dehydro-1,25-dihydroxychole calciferol and 24-dehydro-1,25-dihydroxergocalciferol - Google Patents

Abstract

1-793 Warszawa, R. S people producing new analogs of 24-dehydro-1,25-dihydroxycholecalciferol and 24-dehydro-1,25-di-hydroxyergocalciferol of formula 1, in which R is hydrogen or methyl, consisting in obtaining the ester first (5Z, 7E) - (1S, 3R) -1-hydroxy-3-acetoxy-9,10-seco-5,7,10 (19) -cholatriene-24-oic acid of formula 2, characterized by this compound is reacted with t-butyldimethylsilyl chloride and the obtained ether derivative is reduced, and the obtained compound of formula 3 is oxidized by Swem's method to the corresponding aldehyde of formula 4, and this is coupled with a sulfonone of formula 5, wherein R is as defined above, and the resulting 24-hydroxy-24'-phenylsulfone derivatives of formula 6, wherein R is as defined above, is firstly dehydroxydesulfonylated to give compounds of formula 7, wherein R has the meaning given above and then the silyl groups are removed. W ZÓR 1 PL

Description

The subject of the invention is a process for the preparation of new analogs of 24-dehydro-1,25-dihydroxycholecalciferol and 24-dehydro-1,25-dihydroxyergocalciferol, namely: (24E) -24dehydro-24,24-dihomo-1,25-dihydroxycholecalciferol of formula 1, where R is hydrogen, and (24S) - and (24R) -20,20-dihomo-1,25-dihydroxyergocalciferols of formula I wherein R is methyl.

1, ^^^ iDi ^ ydroksycholecalciferol and its analogs with a modified side-chain structure are used in the treatment of some forms of skin diseases, especially certain types of psoriasis (Morimoto, Arch. Dermatol. 1989, 125, 231; Staberg er al., Acta Derm. Venereol. 69, 147, 1989). Moreover, these compounds stimulate the transformation of human neoplastic cells into healthy cells, which may find application in the treatment of leukemia (Ostrem et al., J. Biol. Chem., 1987, 29, 14164; Eguchi et al., Chem. Pharm. Bull. ., 1988, 36, 2303).

There is a known method of obtaining (22E} -22-dehydro-1,25-dihydroxycholecalciferol analogs with an extended side chain, which consists in the conversion of 22,23 dinorcholanic acid into 22,23-bisnor-9,10-seco-cholatrien-22-al, which by coupling with an alkyl sulfone gives the analogs of (22E) -22-dehydro-1,25-dihydroxycholecalciferol (Kutner et al., J. Org. Chem., 1988, 53, 3450; Perlman et al., Biochemistry, 1990, 29,190; DeLuca et al., US 4,847,012 1989).

The essence of the invention is the method of obtaining new analogs of 24-dehydro-1,25-dihydroxycholecalciferol and 24-dehydro-1,25-dihydroxyergocalciferol with an extensive side chain structure. In the course of a multi-stage synthesis that runs through intermediates, also not described in the literature, known reactions and those used in steroid chemistry are performed.

The new analogs have a different location of the double bond in the side chain, ie at C-24, not at C-22, from the one found in the vitamin D series. It is predicted that these compounds will have a beneficial effect in reducing the activity of calcium metabolism in the body.

The method according to the invention consists in obtaining the (5Z, 7E) - (1S, 3R) -1-hydroxy-3-acetoxy-9.10-seco-5.7, -0 (-9) -cholatriene acid methyl ester by the known method. Of the formula II, which gives an ether derivative by reaction with t-butyldimethylsilyl chloride and after reduction with the corresponding derivative of formula 3. This compound is oxidized by the Swern method to the aldehyde of formula IV, which is coupled with the appropriate sulfone derivative 5, wherein R is as defined above. The obtained 24-hydroxy-24'-phenylsulfonic derivatives of formula 6, in which R is as defined above, are first subjected to dehydroxydesulfonylation, yielding compounds of formula 7, in which R is as defined above, and then the groups are removed. silyl.

The sulfone derivatives of formula 5, where R is hydrogen or methyl, are prepared from 3-bromopropionic acid methyl ester, which is converted by Grignard reaction to 4-bromo-2-methylbutanol-2, which is treated with thiophenol to give 4 -phenylthio-2-methyl-butanol-2. This compound is oxidized to 4-phenylsulfonyl-2-methyl-2-butanol-2, in which the hydroxyl group is protected as triethylsilyl ether.

The following examples illustrate the invention without limiting its scope.

Example 1 (5Z, 7Ej- (1S, 3R) -1-hydroxy-3-acetoxy-9.10-seco-5,7,10 (19) -cholatriene-24-oic acid methyl ester (2).

The mixture of the isomers (5Z, 7E) and (5E, 7E) of the compound of formula 2 (1.5 g) in 11 g of benzene and in the presence of 4.5 g of anthracene was irradiated with radiation with a wavelength above 300 nm at ca. 20 ° C under nitrogen. After removal of the solvents under reduced pressure, the anthracene was separated and the isomet (5E, 7E) was removed with maleic anhydride. After chromatography on alumina of activity III in benzene and crystallization from a benzene-acetone mixture, 400 mg of the ester of formula 2 were obtained. HPLC R _v 11.2 ml; UV (10% 2-propanol in hexane) λ -c 264 nm, λ mn 227 nm; NMR (CD3COCD3) <5 0.58 (3H, s, 18-CH3), 0.96 (3H, d, 21-CH3), 1.97 (3H, s, 3-COCH3), 3.58 (3H , s, 22-CO ₂ CH 3), 4.29 (1H, m, 1-H), 5.11 (1H, m, 19Z-H), 5.31 (1H, m, 19E-H), 6.00 (1H, d, 7-H); MS m / z 444 (M + 12), 426 (8), 384 (100), 366 (42), 251 (18), 134 (91).

Example II. (5Z, 7E) - (1S, 3R) -1,3-Bis [(t-butyldimethylsilyl) -oxyI-9,10-seco-5,7,10 (19) -cholatriene-24-ol (3).

To a solution of 100 mg (0.23 mmol) of the ester of formula 2 in 10 ml of anhydrous THF was added 10 ml of 0.1N methanolic KOH solution with stirring. The solution was stirred at room temperature for 80 min. The product was extracted with ethyl acetate and removal of the solvent afforded 84.5 mg (93%) of the product as a light yellow oil. This product was dissolved in 5 ml of DMF, 250 mg (3.6 mol) of imidazole were added, and a stirred solution of 250 mg (1.6 mmol) of t-butyldimethylsilyl chloride in 2 ml of DMF was added. The solution was stirred for 15 min. at 55 ° C under nitrogen. The product was extracted with hexane. The hexane layer was washed with saturated aqueous NaCl solution and dried over anhydrous MgSO. The solution was filtered through Sep-Pak and solvent evaporation gave 135 mg (97 %%) of the product as a light yellow oil. A solution of 135 mg (0.21 mmol) of this product in 5 ml of anhydrous THF was cooled to 0 ° C under argon and added with vigorous stirring. 25 mg (0.65 mmol) LiA1H ₄ . Stirring was continued for 15 min at 0 ° C under argon. Was then added dropwise 1 ml of a 10% solution of water in THF and _c ałość stirred for another 15 min. The product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO _4, and filtered through Sep-Pak. After removal of the solvents gave 85 mg (67%) of the alcohol of formula 3 in the form of a colorless _oil. HPLC R ₂ 16 ml; IR (KB _r ) 3331, 1453, 1388, 1269 oti '! UV (10% 2-pro _p anol in hexane)] _max 264 nm, R _min * 22 7 _{n m;} NMR (CD ₃ COCD ₃ ) δ 0.00 (12H, s, Si-CH ₃ ), 0.11 [18H, s, Si C (CH ₃ ) ₃ J, 0. m5 (3H, _s , 18-CH ₃ ), n, 95 (3H, d, 21-CH ₃ ), 43.25 (1H, m, 3-H), 4.45 (1H, m, 1-H), 4.84 (1H, m, 19Z-H), 5.25 (1H, m, 19E-H), 6.08 (1H, C, 7-H), 6.31 (UH, d, 6-H) _; MS m1z 602 (M ⁺ , 11), 587 (2), 470 (55), 248 (100).

Example III. (5Z, 7E) - (1S, 3R) - 1,3-Bis [(t -botyldimethylsilyl) -oxyI-9,10-seco-5,7,10 (19) -cholatrien-24-al (4).

To a solution of 100 µl (1.4 mmol) DMSO in 3 ml of CH 2 Cl 2 cooled to -60 ° C, 60 µl (0.68 mmol) of oxalyl chloride in 1 ml of CH 2 ° 12 was added dropwise. The mixture was stirred for 10 min at -60 ° C, then a solution of 60 mg (0.1 mmol) of alcohol 3 in 1 ml of CH ₂ Cl _{2 was} slowly added dropwise. Stirring was continued for 30 min at -60 ° C under argon. Then 0.2 ml of triethylamine was added and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried over anh. MgSO ₄ and filtered through Sep-Pak. 38 mg (63%) of the aldehyde of formula 4 was obtained in the form of a light yellow oxide. HPLC R _v 18.2ml; IR (KB ^ an36, 1278, 3388, 1269, 1090 ^ ^- ^ Uw (10% 2-propanol in hexane) ^L max 264 nm, λ _min 228 nm; NM R (CD ^ OCDa) δ 0.00 (12H , s, SiCH; j), 0.12 [18H, s, SiC (CH ₃ ) ₃ ], m, 69 βΗ ^{- -} , 18-CH ₃ ), n, 9 d, d-CHaC, 4.26 ( 1H, m, 3-H), 4. S6 (1H, m, 2 H1, H.85

162 542 (1H, m, 19Z-H), 5.25 (1H, m, 19E-H), 6.07 (1H, d, 7-H), 6.31 (1H, d, 6-H) , 9.74 (1H, m, 24-H); MS m / z 600 (M + 12), 468 (54), 411 (7), 248 (100).

Example IV. 2-Methyl-4- (phenylsulfonyl) -2 - [(triethylsilyl) oxy] butane (formula 5, R = H).

A solution of 13.48 g (88.1 mmol) of 3-bromopropionic acid in 30 g (980 mmol) of methanol containing 0.5 ml of concentrated H 2 SO 4 was heated under reflux for 5 h. The product was isolated by standard method to give 10.3 g (70%) of the corresponding ester. To a solution of 7.3 g of this ester in 100 ml of anhydrous THF, 50 ml of a 3-molar solution of methylmagnesium bromide in diethyl ether were introduced in several portions under nitrogen. The mixture was stirred for 48 hours at room temperature. The mixture was then acidified to pH 1 with 2N HCl saturated with NaCl. The organic layer was separated and the aqueous layer was extracted with benzene. 6.5 g (64%) of the product was isolated from the combined organic layers. This compound was reacted with 5.5 g of triophenol and 6 g of potassium t-butoxide in dry DMF with stirring for 24 h under argon. 20 ml of water was then added to the reaction mixture. Extraction with benzene and column chromatography gave 5.2 g (68%) of the corresponding sulfide. This compound was oxidized with 3.6 g of m-chloroperbenzoic acid in 30 ml of anhydr. CH 2 O 2 to give 5.0 g (84%) of the corresponding sulfone. The obtained sulfone (1 g) was silylated with 1.4 g of triethylchlorosilane and 1.0 g of imidazole in 5 ml of anhydrous. DMF. Column chromatography gave 1.8 g of the protected sulfone (formula 5, R = H). HPLC Rv 39 ml; UV (10% 2-propanol in hexane) λmax 270.4, 263.4 257.8 nm, λ min 235.8 260.2 267.8 nm; IR (KBr) 2964, 2914, 2884, 1458, 1309, 1160, 1125, 1050 cm -1; MS m / z 342 (M ⁺ , 6), 313 (100), 227 (8); NMR (CDCl) 6 0.58 (6H, m, SiCH 2 CH 3), 0.86 (9H, m, SiCH 2 CH 3), 1.18 (6H, s, 1-CHa, 2-CHa), 7.6 and 7.9 (5H, m, Ar).

ExampleV. (24E) -24-Dehydro-24,24-dihoino-1,25-dihydroxycholecalciferol (formula 1, R = H).

Up to 85μ! (0.123 mmol) of a 1.5M solution of n-BuLi in hexane, cooled under argon to -75 ° C, was added dropwise, in the presence of a solution of 1,10-phenanthroline in 100 µl THF, 40 µl (0.28 mmol) of diisopropylamine. After 20 min of vigorous stirring at -75 ° C, a solution of 50 mg (0.16 mmol) of sulfone (formula 5, R = H) in 200 µl anh. THF. Stirring was continued for 30 min and a solution of 20 mg (0.033 mmol) of aldehyde 4 in 200 μl anhydrous was added. THF. The solution was stirred at -70 ° C for 1.5 h under argon. Then 1 ml of saturated aqueous NH ₄ Cl solution was added. The products were extracted with ethyl acetate. The organic layer was washed with brine and dried over anh. MgSO ₄ . The unreacted aldehyde 4 (3 mg, R _v 12 ml) and the sulfone (formula 5, R = H, 22 mg, R _v 64 ml) and the product of formula 6 (R = H, 6.2 mg, were isolated by preparative HPLC). 20%, R _v 56 ml) as a colorless oil, to 0.5 ml of a saturated methanolic solution of Na ₂ HPO ₄ was added, under argon, 80 mg anh. Na ₂ HPO ₄ and cooled to 0 ° C. Then a solution of 3 mg of the vitamin sulfone of formula 6 (R = H, 3.2 mmol) in 0.5 ml anhydrous was added with stirring. THF. After stirring for 5 min, approx. 200 mg of 5% sodium amalgam was added and the mixture was stirred for 3 h at 5 ° C under argon. Then 2 ml of hexane was added, the solution was decanted and the solid was washed with hexane. The combined organic layers were washed with brine, dried over anh. MgSO ₄ and filtered through Sep-Pak. After removal of the solvent, the protected triol of formula 7 (R = H) was obtained as a colorless oil. To a solution of this compound in 0.5 ml of anhydr. THF was added 20 μl of a 1M solution of tetrabutylammonium fluoride in THF and stirred vigorously under argon at 55 ° C for 2 h. An identical aliquot of fluoride was then added again and stirred until no starting material and intermediates were present. After extraction with ethyl acetate and preparative HPLC chromatography, 645 μg of the triol of formula 1 (R = H, 46% from vitamin sulfone of formula 6, R = H) was obtained as a colorless oil: UV (10% 2-propanol in hexane) λ ™ 26 263.63 nm, λ _min 237.6 nm; MS m / z 442 (M ⁺ , 5), 424 (12), 285 (12), 267 (6), 251 (4), 152 (24), 134 (62), 59 (100); NMR (CD ₃ COCD ₃₎ <0.57 (3H, _s, 18-CH3), 0 ^ 6 (3H, d, 21-CH _3), 4.17 (lH, _m, 3H), 4, 39 (lH, _m , 1-H), 4.86 (1H, s, 19Z-H), 5.31 (1H, _s , 19E-H), 5.48 (- _m , 29 ° C, 43 ° C) , 6.09 (1H, d, 7H), 6H (1H, d, 6-H) ¹

Example VI. 124R) -2 ^-) 20lDihorr, o- ^1l 25 dihydroksyergo2alciferol (Formula 1, R = CH _3).

The analog of formula 1 (R = CH ₃ ) was prepared according to the method described in Example 5 from 30 mg (0.096 cco) of the sulfone of formula 5 {) 8 = CH ₃ , [? D = 7-23.4 (c 0, 71 5% propanol-2 in hexa0 and m)} and 8.5 mg (0.014 mmol) of the aldehyde 4. The unreacted aldehyde 4 (1 mg, Rv 12 ml) and the sulfone of formula 5 (R = CH ₃ ) were isolated by oreparatypine HPLC chromatography , 10 mg R _v 64 ml) and

Product of Formula 6 (R = CH3, 3.0mg 19%, Rv 55ml) as a colorless oil. The vitamin sulfone of formula 6 (R = CH3, 3mg, 3.1mmol) was converted to the protected triol of formula 7 (R = CH3) and then to the analog of formula 1 (R = CH3) by the method described in Example 5 After preparation of HPLC chromatography, Rv 27 ml, 420pg of triol of formula 1 (R = CH3, 30% from sulfone of formula 6, R = CH3) was obtained as a colorless oil: UV (10% 2-propanol in hexane). λ 263.2 nm, λ _{m and} "229.0 nm; MS m / z 438 (M + - H ₂ O), 420 (31), 405 (8), 195 (11), 152 (6), 93 (24), 59 (88); NMR (CD3COCD3) δ 0.57 (3H, s, 18-CH3), 0.96 (3H, d, 21-CH3), 0.99 (3H, d, 28-CHa), 4.17 (1H, m, 3-H), 4.39 (1H, m, 1-H), 4.87 (1H, s, 19Z-H), 5.31 (1H, m, 19E-H), 5.47 ( 2H, m, 22-H, 23-H), 6.09 (1H, d, 7-H), 6.28 (1H, d, 6-H).

Example VII. (24S> -2O.2 (ODihomo-1,25-dihydroxyergocalctferol (formula 1, R = CH ₃ ). The analog of formula 1 (R = CH ₃ ) was prepared according to the method described in example 5 from 35 mg (0.112 mmol) of the sulfone of formula 5 {R = CH ₃ , [α] ²⁰ !) = - 23.6 (c 0.70 5% 2-propanol in hexane)} and 15 mg (0.112 mmol) of aldehyde 4. By preparative HPLC chromatography, the unreacted aldehyde 4 (2 mg, Rv 12 ml) and sulfone of formula 5 (R = CH3.12 mg, Rv 65 ml) and the product of formula 6 (R = CH3.6.1 mg, 21%, Rv 54 ml) in This product was converted to the protected triol of formula 7 (R = CH3) and then to the analog of formula 1 (R = CH3) by the method described in Example V. Preparative HPLC gave 810 pg of the triol of formula 1 (R = CH3, 31% from sulfone of formula 6, R = CH3) as a colorless oil: UV (10% 2- ⁱⁿ ropanol in hexane) ΛΟ3χ 265.2 nm, Λ _Ο ι "228.0 nm; NMR (cD ₃ COCD ₃ ) δ 0.57 (3H, s, 18-Ch ₃ ), 0.96 (3H, d, 21 _- CH ₃ ), 1.00 (3H, d, 28- ^), 4.16 ( 1H, _m , 3-H), 4.38 (1H, m, 1H), 4.86 (1H, s, 19Z-H), 5.31 (1H, _s , 19EOH), 5.47 (2H, m, 22-H and 23aH), 6.09 (1H, d , 7-H). 6.28 (1H, d, 6-H).

MODEL 7

OSiEt ₃

-BuMeoSiO

OSiEl ·

MODEL 6

MODEL 3

PATTERN 4

Publishing Department of the UP RP. Circulation of 90 copies. Price: PLN 10,000

Claims (1)

Patent claim A method for the preparation of new analogs of 24-dehydro-1,25-dihydroxycholecalciferol and 24-dehydro-1,25-dihydroxyergocalciferol of the formula 1, in which R is hydrogen or methyl, by first preparing the acid methyl ester (5Z, 7E) - (1S, 3R ) -1-hydroxy-3-acetoxy-9,10-seco-5,7,10 (-9) -cholatriene-24-a of the formula 2, characterized in that this compound is reacted with t-butyldimethylsilyl chloride and the obtained derivative the ether is reduced and the resulting compound of formula 3 is oxidized by Swern to the corresponding aldehyde of formula 4, which is coupled to the sulfonone of formula 5, wherein R is as defined above, and the resulting 24-hydroxy-24 'derivatives - phenylsulfonates of formula 6 in which R is as defined above are first dehydroxydesulfonylated to give compounds of formula 7 in which R is as defined above, followed by removal of the silyl groups.