AU605007B2 - Steroidal compounds and process for lengthening the side-chain of certain steroids - Google Patents

Description

Signa- (3) ture. of Applicant (8) or Beal of Company and Signatures of its Officers as prescribed by its Articles of Assoclation.

by D. B. Mischlewski Form COMMONWEALTH r0- AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPEC IFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: b05007 Complete Specification Lodged: Accepted: Published: Prority: ,Related Art: o c Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: WISCONSIN ALUMNI RESEARCH FOUNDATION 614 North Walnut Street, Madison, Wisconsin 53705, United States of America HECTOR F. DeLUCA, NOBUO IKEKAWA and YOKO TANAKA EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: STEROIDAL COMPOUNDS AND PROCESS FOR LENGTHENING THE SIDE- CHAIN OF CERTAIN STEROIDS The following statement is a full description of this invention, including the best method of performing it known to us i i -L Sipiun of dedr ant(s) (s o anntatson qumred) Note: b.Atw II sIteratio Edward Waters Son, S- O. u001pn, f trpi P M& P I rne .30.f ir- Vni i N7 1 STEROIDAL COMPOUNDS AND PROCESS FOR LENGTHENING THE SIDE-CHAIN OF CERTAIN STEROIDS This invention relates to novel steroidal compounds useful for preparing vitamin D derivatives, especially 24-homovitamin D derivatives, as well as a process fo- lengthening the side chain of certain steroids.

Vitamin D is known to regulate calcium and phosphorus metabolism in animals and humans and it has now been firmly established that the biological efficiency of vitamin D depends upon its metabolic conversion, in vivo, to hydroxylated derivatives. Thus vitamin D 3 is hvdroxylated in vivo to 25-hydroxyvitamin D 3 in the liver which in turn is converted into lo',25-dihydroxyvitamin D 3 in the kidneys. It is the latter compound which is now recognised as being the circulating hormonal form of Sfit Vitamin D.

Because of their biological activity in promoting calcium and phosphorus transport in the intestine and the mobilization and mineralization of bone these forms of vitamin D are important pharmaceutical products which are eminently suitable for use in the treatment of various bone disorders.

New derivatives of vitamin D 3 have now been found which express excellent vitamin D-like activity and which, therefore, could readily serve as a substitute for vitamin

D

3 in known applications, such as the treatment of various disease states manifesting calcium and phosphorus imbalance such as bypoparathyroidism, osteodystrophy, osteomalacia and osteoporosis.

These derivatives are 24-homovitamins, particularly 1p,25-dihydroxy-22E(orZ)-dehydro-24homovitamin D 3 and l,25-dihydroxy-24-homovitamin D 3 These derivatives are described and claimed in our Application No. 47761/85.

I I 4i I 2 These compounds can be represented by the formula: S

OR

3

(RR

R,

where R 1

R

2 and R 3 are each independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R 4 and R each represent hydrogen atoms or taken together form a carbon to carbon bond.

SThe compounds can be prepared in accordance with the following schematic and detailed description where like numbers identify like compounds.

The intermediates of formulae 7 to 10 and 13 are novel and form the subject of the present invention.

Accordingly the present invention provides compounds having the formulae: i wherein each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl, and Rg 1 wherein R 1

R

2 and R 3 are each independently hydrogen, acl having from 1 to 4 carbon atoms or benzoyl and R 4 and R 5 represent hydrogen atoms or taken together form a carbon to carbon bond

K

OOH

0- Nor* 2. R=THP 3 k:1m 0004 0 C 0 1, 00 4 0 0 o oo 00 0 0004 00 O 0 o 400 00 0 0 00 0 04 00 0 4 00 0 04 0 0 0 0 00 00 0 0 00 0 04 o 0" 0 ,k4 0 0 0440 0 q 0 00 0 00 0 0 0 0 0 40 f1 DA4 7R=A;~ ~1

I

4 4 In accordance with the prces's' ei t-s inventiel.

Bisnorcholenic acid acetate was reduced with lithium aluinum hydride and subsequently oxidized with dichlorodicyanobenzcclinone to afford the 1,4 ,6-triene-3-one in 47% yield. 22-7T--ether of b was treated with alkaline hydrogen peroxide to give the lcx,2a-epoxide in 41% yield.

Reduction of with lithiumi and a-mnrriurn chloride in licuid aflroru-a-tetrahydrofuran at and subseqient treatrPnt with chlorarethyl rethyl ether provided the direthyoxymethyl ether (MOW) in 38% yield. Removal of the fliP group, fol1ou-- by Sw r-n oxidation gave the a-ldehyd3e in 81% yield. This was reacted with vinylxagnesium braride to provi--de the allylalcohol in 94% yield. This alcohol was heated in refluxed j xylene with triethyl ortho acetate and a catalytic amrount of 215 prcpionic acid, to afford the ester in 93% yield. Then, the ester w;as reacted with rrethyii-iagnesin braaide to pro~vide the alcohol in 93% yield. Rez-ovaa of 101~ group, follomad byacylation, e.g. acetylation gave (22E)-1-9,38-diaoetoxy- 25-hydroxy-24-.hcm-cholesta-5,22-cliene in 73% yield.

Allylic bra-,inatin of with 14rr~sciirie I It folloqed by treat-,ent with tetra-n-butyla.7miurn brom~ide and than with tetra-n-butylarrmonium, fluoride gave the 5,7,22triene (10) as a r-ain product in 24% yield. The 5,7-diene was irradiated with a rrediurn pressure mrercury la~ in bnerzene-ethanl for 5 min, subsequently refluxed for 1 hr, and then hydrolyzed to afford (22E) -la, 25-d:iydroxy-22-dehydro-24hc-,ovitam'in D(11) in 22% yield by analogous methods well 'k:awn in the art other acylates or benzoates can be prepared which would be equally useful in the succeeding prcess steps.

a 4 44 1 44 9 4 t44 4 tIIt4 4I a The 5, 22-d-iene was selectively hydrogenated, e.g. using tetra n-b.atylamxoniun fluoride, to provide the 5--ene (12) in 92% yield. This caTpound was converted to 1, z5-dihydroxy-24-hcovitanin D(14) via the 5,7-diene (13) as described above in 12% ovecr--.ll 5 yield.

In the following detailed description melting points were deterT-dned with a hot-stage mnicroscope and were -ancorrected.

1 H-NR spectra were taken

I

with a Hitachi R-24A (60 M-1z) in CX1I with Me 4Si as an intern'al standard, unless otherwise noted. Mass spectra were obtained with a Shirradzu OP-iCCO mass spectrcn-eter at 70 eVI.

UV spectra were obtained in ethanol solution with a Shiinadzu UV-200 double beam spectrophotcreter. Column Chromatcgraphy was effected using silica gel Merck, Kieselgel 60, 70-230 mresh). Preparative thin laye~r chromatography was carried out on precoated plates of silica gel Merck, Kieselgel F 2 54 0.25 mmr thickness). The usual. work-up 1refers to dilution with water, extraction with an organic solvent indicated in parenthesis, washing the extract to neutrality, drying over anhydrous iragnesium sulphate, filtration, and 40*4,removal of the solvent under reduced pressure. The follair:, abbreviations are used; THP tetrahydropyranyl; THF tetrahydrofuran; ether diethyl ether, MjeCH methanol, I4CM trethoxyirethyl. Teroperatures are in centigrade.

22-Hydroxy-23 ,24-dinorchola-l, 4, 6-triene-3-one (b) To a solution of 3 A-acetoxydinorcholenic r' 0 g, 18.04 nmmle) in THF (20 mL,) lithium aluminum hydride (3.0 g, a 20 78.95 nmole) was added. This mixture was stirred at 60"C for 14 h. To this reaction inixiaire water and ethyl acetate were go 0 64carefully added. Filtration and removal of the solvent gave 4 the residue (5.2 g) This in dioxane (140 o.L) was treated 4 with dich" Llocdicyanobenzoquinone (11.7 g, 51.54 niwole) under 0 t 25 reflux for 14 i'h. After cooling to room terrperature the react-ion mix.-ture was filtered and -the filtrate was evaporated to leave the residue, which was applied to a column of alumina (200 g) Elution with dichloroirethane provided the trienone (2.8 g, 47%) rip 156-l57* (ether) UVtj~OH rn 299 (13u0), 252 (9200) 224 (12000) 1 H-NM (CDCI 3 0.80 (3H, s, 18-H 3 1.04 (3H, d, !16 Hiz, 21-H 3 1.21 (3H, s, 19-H 3 3.10-3.80 (311, ri, 22-H 2and OH), 5.90-6.40 (4H, m, 2-H, 4-H,6-H, and 7.05 (111, d, J=10 Hz, 1-H)U, I-IS mhz: 326 311, 308, 293, 267, 112.

lt, 2a-Epoky-22-tetrahvdro2pvranyloxy-23 ,24-dinorchola-4, 6-dirn- 1 4 t 4 04 t 4 1 4 449 4o 4 4 4 4 4 4444 3-one (1) The alcohol (2.7 g, 8.28 rmole) in dichlororrmethane miL) was treated with dihydropyrane (1.5 nmL, 16.42 nrrmole) and ptoluenesulfonic acid (50 mg) at roam terperature for 1 h. The usual work-up (ethyl acetate for etraction) gave a crude product. To a solution of this product in MeOH (70 rrmL), H 202 (4.8 miL) and 10% NaOH/MeH (0.74 it) were added and this mixture 9as stirred at rocmn temperature for 14 h. The usual work-up (ethyl acetate for extraction) gave a crude product, which was applied to a column of silica gel (50 g).

Elution with benzene-ethyl acetate (1CO 1) provided the EtOH eoxide (1.45 g, 41%):'mp 113-115 (hexane) UVX m rmax 290 (22000), 'H-NMR (C1 3 8: 0.80 (3H, 5, 18-H 3 1.07 (3H, d, J=6 Hz, 21-H3), L.18 (3H, s, 19-H 3 3.38 dd, J=4 and 15 1.5 Hz, 3.55 (1H, d, J=4 Hz, 3.30-4.10 (4H, m, 22-H 2 and THP), 4.!0 m, THP), 5.58 (1H, d, J=1.5 Hz, 6.02 (2H, s, 6-H and MS m/z: 342 (M -DHP), 324 (M THPOH), 309, 283, 1la,3 -Dimethox-vmethoxy-23, .24-dinorchol-5-en-22-tetra- 20 hydropyranyl ether (2) Lithium C00 g) was added in small portion to liquid arronia (2CO ml) at -780 under argon atrcsphere during 30 min.

After stirring for 1 hr at -780, la, 2a-epoxy-22-tetrapyranyloxy-23,24-dinorchola-4,6-diene-3-ne (2.00 g, 4.69 m rol) in dry THF (150 ml) was added dropwise at -780 during 30 min, and this mixture was stirred for 1 hr at To this reaction mixture, anhydrous NH 4 C1 (60 g) was added in small portion at -780 during 1 hr. After 1.5 hr the cooling bath was rerroved and monst of the anronia was rexoved by bubbling argon. The usual twork-up (ether was used as a solvent) gave a crude product. This was treated with chloro-rethyl mrethyl ether (2.0 ml, 26.34 i nol) and N,N-diethylcyclohexylamine (4.6 ml, 24.93 mn mol) in dioxane (20 ml) at 450 for *24 hr.

The usual work-up (ethyl acetate) gave a crude product, which was applied to a 'column of silica gel (40 Elution with hexane-ethyl acetate (5 1) provided the dimethoxymethyl ether (922 img, 38%) as an oil. 'H-NMR 8 0.70 (3H, s, 18-H 3 1.02 (3H, s, 19-H 3 1.04 (3H, d, J=6 Hz, 21-H 3 3.34 (3H, s, -O-CH 3 3.37(3H, s, -O-CH 3 ),4.63 (2H, ABq, J=7 Hz, LAB=ll Hz, cl-O-CH 2 4.64 (2H, s, 3-0O-CH 2 and 5.50 (1H, m, 6-H).

la, 3 -Dimethoxyrrthoxy-23,24-dinorchol-5-en-22-ol (3) The TEP ether (922 mg, 1.77 rmol) in T~F (8 ml) ard (8 ml) was treated with 2M HC1 (1 ml) at room temperature for 2 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a column of silica gel (40 g).

SElution with hexane-ethyl acetate (2 1) gave the alcohol (3) (678 mg, 88%) as an amorphous solid. 1 H-NMR 6 0.70 (3H, s, 18-H 3 1.02(3H,s,19-H 3 1.04 (3H, d, J=6 Hz, 21-H 3 3.34 (3H, s, -0-CH 3 3.38 (3H, s, -0-CH 3 4.65 (2H, ABq, J=7 Hz, L d AB 11 Hz, la-O-CH 2 4.66 (2H,s,3A-O-CH 2 5.53 S(lH,m,6-H).

la, 3 B-Dimethoxymethoxy-23,24-dinorchol-5-en-22-al (4) To a solution of oxalyl chloride (0.27 ml, 3.09 rnml) in dichloromethane (8 ml) dimethyl sulphoxide (0.44 ml, 6.21 rmtl) was added at -78 0 C under argon. The mixture was stirred at -78 0 C for 10 min. To the solutioh the alcohol (660 mg, 1.51 mnl) in dichloramethane (5 ml) was added at -78 0

C.

After stirring for 15 min, triethylamine (1.89 ml, 13.6 rmol) was added. The mixture was stirred at -78 0 C under argon for min, and warmed up to room temperature. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 Elution with hexane-ethyl acetate (4 1) gave the aldehyde (607 g, 92%) as a crystal. mp 71-72 0

C

(hexane;, H-NN*R 8 0.74 (3H, s, 18-H 3 1.04 (3H, s, 19-H 3 1.12 (3H, d, J=6 Hz, 21-H 3 3.35 (3H, s, -O-CH 3 3.39 (3H, s, -0-CH 3 3.7 (IH, m, 10-H), 4.65 (2H, ABq, J=7 Hz, AB 11, Hz, loa-O-CH 2 4.66 (2H, s, 3A-0-CH-O-), 5.52 (1H, m, 6-H), and 9.61 (1H, d, J=3 H2, -CHO), Anal. Calcd for C 26

H

42 0 5

C,

71:85; H, 9.74. Found: C, 71.71; H, 9.68.

8 23-dien-22-ol To magnesium (70 mg, 2.92 rrml) in 'IF (3 ml) solution of vinyl brcnide in THF (0.42 ml, 2.98 mrol) was added. The mixture was stirred at room temperature under argon for 30 min. To the resulting Grignard reagent the aldehyde (595 mg, 1.37 Txmol) in THF (6 ml) was added at roan temperature. The mixture was stirred at roam temperature for 1 h. The usual work-up (ether) gave a crude product, which was applied to a column of silica gel (30 Elution with hexane-ethyl acetate (3 1) gave the allylic alcohol (595 mg, 94%) as an amorphous solid. B-NMR 6: 0.70 (3H, s, 18-H 3 1.02 (3H, s, 19-H 3 3.35 (3H, s, -0-CH 3 3.38 (3H, s, CH 3 3.69 (1H, m, 1A-H), 4.20 (1H, m, 22-H), 4.64 (2H, SABq, J=7 Hz, AAB 11 Hz, la-O-CH2 4.65 (2H, s, 3-0-CH 5.52 m, 4.90-6.0 (3H, m, 23-H and 24-H (22E) 3B-Dirmthoxyrrethoxy-27-norcholesta-5 22-dien-26oic acid ethyl ester (6) A solution of the allylic alcohol (590 mg, 1.28 rmol), triethyl orthoacetate (1.0 ml, 5.46 mtol) propionic acid (4 drops), and xylene (8 ml) was refluxed under argon for 2 h. Removal of the solvent under reduced pressure gave the residue, which was applied to a column of silica gel (30 g).

Elution with hexane-ethyl acetate (4 1) gave the ester (6) (630 mg, 93%) as an oil. 1 H-NR 8: 0.68 (3H, s, 18-H3), 0.97 (3H, d, J=6 Hz, 21-H 3 1.03 (3H, s, 19-H3). 1.24 (311, t, J=7 Hz, -CO2 CH23) 3.35 (3H, s, -O-CH3 3.39 (3H, 7, -O-CH3), 3.70 (1H, m, 1B-H), 4.11 (2H, q, J=7 Hz, -COH 2 C 3 4.64 (2H, ABq, J=7 Hz, LAB 11 Hz, la-0-CH 2 4.65 (2H, s, 3 -0-CH 2 5.29 mn, 22-H and 23-H), 5.52 (1H, m, 6-H).

If desired the 22E stereo isaer, carompound can bs readily converted to the 22Z stereo isomrer by treatment with iodine. Thus, treatment of compound in ether with a catalytic amount of iodine of the amount of while under diffuse daylight for 1 hr. results in a trans to cis i isw.reri'zation which, after HPLC purification, (Zorba-A-Sil coluri, 4.6 3, 25 cm, 6% 2-propanol/hex- ane) yielded the 22Z stereo isomer.

(22E) -lc4,3 0-Diietho yrretoxy-2 4-hc.-cholesta-5,22-diene-25-ol (7) To a solution of the ester (605 iwg, 1. 14 itxrl) in THF (6 ml) IM solution of nrethylwagnesiui bromide in THF (4.5 ml, nxto1) was added at roan. temp~erature. The mixture was stirred at roa, teirlperature for 1 h. 'The usual work-=n (ether) gave a crude product. which was applied to a column of silica gel (30 g) Elution- with hexane-ethvl acetate (3 :1) gave the alcohol ()(548 rtg, 93%) as an oil. 1 -H-NM b: 0.68 (311, s, 18-H 3 0.97 (3H1, d, J=6 Hz, 21-H 3 1.01 (3H1, s, 19-H 3 1. 21 (6H1, s, 26-H3 and 27-H 3 3.33 (3H1, s, -0-CU 3 715 3.38 (3Hi, s, -0-CH) 3.70 (1H, m, lp-H), 4.64 (2H1, ABq, 7 in2-H and 23-) ,a taed w5 ih 6Hl(l) at 0 product, which was applied to a colturm of silicz gel (20 g) 11t 04 Elution with hexazne-ethyl acetate (1 1) gave the triol (8) (428 mg, 95%) as a crystal. mp9 164-1661C (hexane-et-hyl acetate), 3 11-M 5: 0.68 (3H1, s, 18-H3), 0.95 (3H1, s, J=6 Hz, 21-H 3 1.00 (3H1, s, 19-H 3 1. 20 (6H1, s, 26-H and 27H 3.80 m, 2. 3.92 (1H1, m, cc--H) 5.30 (211, mn, 22-H and 23-H) and 5.53 (1H1, m, 6-H).

(22t) -laL, 3 P-DiacetSxL 2-hdoy24hncolsa572-in (9) A solution of the triol (395 mg, 0.919 frol) in pyridine (2 ml) was treated with acetic anhydride (1 ml) at rocm temperature for 16 h. The usual work-up (ethyl acetate) gave a crude product, which was applied to a colmn of silica gel (20 Elution -with hexane-ethyl acetate (2 gave the diacetate (361 rrg 77%) as an oil. 1 H-NM 8: 0.67 (3H, s, 18-H 3 0. 97 (3H, d, J=6 Hz, 1. 07 (3H, s, 19-H), 1. 21 (6H, s, 26-H,3 and 27-H 3 2.01 O3H, s, acetyl), 2.04 (3H, s, acetyl) 4.98 (1H, m, 3(X-H) 5.05 m, lp-H) 5. 31 (2H1, m, 22-H and 23-H) and 5.52 (1H, m, 6-H) (22E) -la, 3 g-Diacetoxy-25-hydox-24-hanocholesta-5, 7, 22-triene A solution of the 5-ene (51 mg, 0,0992 inrol) and N-brnr-succinimide (21 mng, 0.118 nml) in carbontetrachioride (3 ml) was ref luxed under argon for 20 min. After the mixture had been cooled to 0 0 C, -the cesulting precipitate was filtered off. The filtrate was concentrated below 40 0 C to leave the residue. This in THF (5 ml) wias treated with a catalytic amtunt of tetra-n-butyla~niun brcmide at room temrperature 15 for 50 min. Then, the mixture was treated with a solution of 04 0 4 tetra-n-butyammni.m fluoride in ThE' (3.5 ml, 3.5 mrol) at room tem.perature for 30 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chrcxTatography (hexane-ethyl acetate, 4 1, developed five time~s) The band of RE value 0.48 was scraped cff and eluted with ethyl acetate. Renoval of the solvent provided the 5,7-diene (10) 12.5 mgz, UXEC Max: 293, 282, and 271.

104* ia, ?9-D.ydox-22E-dehydro-24-hcrrovitamin D 3 (11I) A solution of the 5,7-diene (10) (7.3 nrq, 0.0143 'mml) in 4tbenzene (90 ml) and ethanol (40 mrl) was irradiated with with a mredium pressure n'ercury lamp through a Vycol filter at 0 0

C

under argon for 5 m The reaction mixture was refluxed under argon for 1 h. Removal of the solvent under reduced pressure gave a crude product, which was submitted to preparative thin layer chrocatography (hexane-ethyl acetate,4 1, developed five tinres). The band of Rf value 0.38 was srraped off and el.uted with ethyl acetate. Peroval of the solvent gave the vitamiun D 3 diacetate 1.8 irq, ,The band /2 11 of Rf value 0.43 was scraped off and eluted with ethyl acetate. Removal of the solvent recovered the 5,7-diene (2.1 mg, 29%).

The vitamin D diacetate (1.8 mg, 2.15 Imol) in THF (4 ml) was treated with 5% KOH/MeOH (1 ml) at room tenperature for 20 min. The usual work-up (ethyl acetate) gave a crude product, which was submitted to preparative thin layer chromatography (hexane-ethyl acetate, 1 2, developed three times). The band of Rf value 0.43 was scraped off and eluted with ethyl acetate. Renoval of the solvent gave the vitamin D3 analogue (11) mg, The purity of the product (11) was determined as 100% by high performance liquid chrcaTatography (a Shimadzu C-3A; column, Zorbax ZI normal phase, 4.6 rm I.i. x 15 cm; solvent, MeOH-CHI 2 C12, 1 49; floi rate, 3 -7l/min; retention time, 11.5 min). The vitamin D 3 EtOH analogue (11) had the following spectral data; UVX 265 EH- May.

nm, l-tO 228 nm, MS m/z: 428 (N 410, 392 (base peak), 374, 287, 269, 251, 152, 134, 123, 59, H-Rd (360 MHz) 6: 0.55 (3H, s, 18-H 3 1.02 (3H, d, J=6.6 Hz, 21-H 3 1.22 (6H, s, 26-H 3 and 27-H 2.32 (1H, dd, J=13.2 and 6.7 Hz), 2.60 (1H, dd, J=13.0 and, 3.0 Hz), 2.83 (1H, dd, J=12.0 and 3.0 Hz), 4.23 n, 4 Hz, 3a-H), 4.43 (1H, m, 16.9 Hz, l-H) 5.00 bs, W/2 3.2 Hz, 19-H) 5.30 (1L, ad, 1/2 J=15.0 and 7.1 Hz, 22-H or 23-H), 5.33 (1H, bs, W1 3.2 Hz, 19-H), 5.37 (11r, dd, J=15.0 and 5.8 Hz, 22-H or 23-H), 6.01 (1H, d, J=11.0 Hz, 6.32 (1II, d, J=11.0 Az, 6-H).

la, 3 -Diaetoxv-24-hoocholest-5-en-25-ol (12) A mixture of the 5,22-diene (40 mg, 0.0778 nmrol) and Pd-C (4 mg) in etlyl acetate (2 ml) was stirred at room tenmerature under hydrogen for 3 h. The Pd catalyst was filtered off and the filtrate was concentrated to leave the residue, which was applied to a column of silica gel (5 g).

Elttion with hexane-ethyl acetate (4 1) gave th -L sne (12) (37 N, 92%) as an oil. 1 H-NMR 8: 0.66 (3H, s, lI 'A 3 1.08 (3H, s, 19-H 3 1.20 (6H, s, 26-H 3 and 27-H 3 2.02 (ZH, s, L -12acetyl), 2.05 (3H, s, acetyl) 4.97 (II, mn, 3a-H) 5.07 (1Hi, mn, 10-H), 5.53 (LE, m, 6-H) lot, 35- )aeo~y-4h ~oet-, 7-dien-25-ol (13) The 5-e (12) (19 mg, 0.037 rniL-.l) was converted, as described for (10) to the 5, 7-diene (:132I 8 mg, 31%).

EtCH 293, 282, 271 rim.

la, 25-Dihydrcxy-24-hcn-ovitarnin D 3 (14) The 5,7-diene 413) (5.8 rng, 0.0113 =mrl) was converted, as described for (21) to the vita=i D 3 analogue (14) (890 The retention tirm of. (14) under t.7-, ahcve-described EPLC corditi"Lon w-as 11.0 mnin. UVXEtOH 265 X 228 rim. M~S m/z 430 412, 394 (base r-eak, mnun 376, 287, 269, 251, 152, 134, 59.

4If desired, the compounds of this inventLjn can be readilyobtained in crystalline form by crsalzto frcrni atsuitable solvents, eg. hexane, ehr, alcoholis, or mixtures thereof as will be apparent to those skilled in the art.

The present invent.ion thus also provides a process for converting a al OR side chain of a steroid nucleus to a

OH

s.'.de chain which comprises reacting trie starting matercial with triethyl orthoacetate to provide the ester side chain and reacting the ester with a methyl magnesium halide.

L

Claims (13)

1. A compound having the formula Ro wherein each R is independently hydrogen, acyl having from 1 to 4 carbon atoms, benzoyl or methoxymethyl. 5

2. A compound according to claim 1 wherein each R is methoxymethyl.

3. A compound according to claim 1 wherein each R is hydrogen.

4. A compound according to claim 1 wherein each R is acetyl. A compound having the formula 0 4 4 I0 I wherein R 1 R 2 and R 3 are eac independently hydrogen, acyl having from 1 to 4 carbon atoms or benzoyl and R4 and R 5 represent hydrogen atoms or taken together form a carbon to carbon bond. L3 i i i; II i.

L-~ i li'._il 14

6. A compound according to claim 5 wherein R I and R 2 are each independently acyl having from 1 to 4 carbon atoms or benzoyl.

7. A compound according to claim 5 wherein R 1 and R 2 are both acetyl and R 3 is hydrogen.

8. A compound according to any one of claims to 7 wherein R4 and R 5 together form a carbon to carbon bond.

9. A compound according to any one of claims to 7 wherein R 4 and R 5 represent hydrogen atoms.

Process for converting a 1 OH side chain of a steroid nucleus to a A a 4 4 OH j4 dii side chain which comprises reacting the starting material with triethyl orthoacetate to provide the ester side chain WCO 2 t E and reacting the ester with a methyl magnesium halide.,

11. Process according to claim 10 wheerein the I. 1 I 0 15 halide is methylmagnesium bromid'e.

12. Process according to claim 10 or 11 wherein the reaction with triethyl orthoacetate is carried out in the presence of propionic acid, as catalyst.

13. Process according to claim 10 substantially as hereinbefore described. DATED this 29th day of December 1988. WISCONSIN ALUMNI RESEARCH FOUNDATION EDWD. WATERS SONS PATENT ATTORNEYS QUEEN STREET MELBOURNE. VIC. 3000. L