CONVERSION OF STEROIDAL 17-CYANOHYDRINS TO CORTICOIDS

Abstract: The invention involves a two-step chemical transformation of a steroidal 17-cyanohydrin of formula (II) to a 17 alpha -hydroxy-21-halo-20-keto steroid of formula (IV) intermediate which can readily be converted to pharmaceutically useful corticoids.

Description: CONVERSION OF STEROIDAL 17-CYANOHYDRINS TO CORTICOIDS BACKGROUND OF THE INVENTION 1. Field of the Invention The invention involves the chemical transformation of a steroi- dal 17-cyanohydrin to a 17 -hydroxy-21-halo-20- eto steroid inter¬ mediate which can readily be converted to pharmaceutically useful corticoids. 2. Description of the Related Art 17α-Hydroxy-17j9-cyanosteroids (I) are known to those skilled in the art. The transformation of the 17α-hydroxy-17jS-cyanosteroids (I) to 17α-hydroxyprotected-17?-cyanosteroids (II) is also known to those skilled in the art. The reduction of nitriles to imines followed by hydrolysis to give aldehydes is well known in organic chemistry. US Patent 4,424,159. discloses the transformation of a C^y-cyano steroid to the corresponding steroidal C j Ly-carboxaldehyde using diisobutylaluminum hydride. However, because the other substituent at C^y was -H, that reaction was much simpler and did not in any way indicate that the reduction of a compound of the formula STEROID-17α- [-0-protec.ted] - 173- [CN] would be operable. The transformation of ketone-derived, protected cyanohydrins to the corresponding protected aldehydes with sodium bis(2-methoxyethoxy)aluminum hydride in 57-70% yields is reported in Helv. Chim. Acta 61, 1903 (1978), see p 1905. J.A.C.S. 102, 1742 (1980) reports the reduction of a tri e hylsilyl protected cyanohydrin to the corresponding aldehyde in only 75% yield using 4 equivalents of diisobutylaluminum hydride in toluene at 0" . The transformation of protected steroidal cyanohydrins (II) to the corresponding protected steroidal aldehydes (III) has not been reported. The reduction of the 17α-hydroxy protected-17,0-cyano- steroids (II) of the present invention surprisingly gives the protec¬ ted aldehyde (III) in > 90% yield. Protected steroid aldehydes (III) are not known. Unprotected' steroidal 17 -hydroxy-179-carboxaldehydes are known, see French patents 1,369,325 (Δ 9 n ) and 1,369,314 (11-keto) , Dutch patent 89,348 (11-keto) and Endocrinol. Japan 4, 214 (1957) (11^-hydroxy) . The conversion of a ketone to α-chloroketones via the addition of Cl2CHLi followed by treatment with butyllithium was reported in J. Organometal. Chem., 40, Cl (1972). The yield was only about 60% and the product was contaminated with 8-15% of α-chloroaldehydes formed in a competing rearrangement. The same reaction was reported, Tetrahedron Letters 4117 (1972) , using lithium piperidide in place of butyllithium giving yields of 56, 70 and 87% using simple monofunc- tional ketones, not aldehydes. The authors did not take into account the yield for the formation of their substrate from aldehydes and ketones. The conversion of a simple monofunctional aldehyde to an α-bromoketone in 62% yield using B^CHLi was reported in Bull. Soc. Chim. France 1797 (1975). The same authors then reported, J. Organometal. Chem., 97, 325 (1975), the conversion of a few more simple carbonyls to a-haloketones using CH2X2 and lithium piperidide. Yields of the reaction of the carbonyl with X2CHLi ranged from 50-87% (typically 60-65%) for production of the halohydrin and conversion of these adducts to α-haloketones in 60-90% yield (typically 70-80%) which gives a typical overall yield of about 40-60%. Many of these products contained 8-65% α-haloaldehyde, although some reactions provided the α-haloketone selectively. All of these references disclose reactions which involved the generation of X2CHLi where X is a bromine or chlorine atom by treating X2CH2 with either a lithium amide base or butyllithium at < -70° . Solutions of these reagents are unstable at temperatures above -70° . The process of the present invention avoids the need to work with such unstable solutions at such low temperatures.. J. Am. Chem. Soc, 96, 3010 (1974) and Bull. Chem. Soc. Japan 50, 1588 (1977) report a simple procedure for the reaction of methylene bromide with aldehydes and ketones to give the same halohydrin intermediates as described in the above re erences. Their procedure required the use of a large excess (2-24 equivalents) of C 2H2 and the yield with the aldehyde substrates was only 73-79%. The process of the present invention uses < 3 equivalents of base, preferably about 2.8 equivalents, to transform he protected steroid¬ al aldehyde (II-I) all the way to the desired protected 21-halo-17α- hydroxy-20-keto steroid (IV) , not just to the halohydrin intermediate as with the above references. The conversion of protected 21-halo-17 -hydroxy-20-ke o steroids to the corresponding protected 21-acyloxy-17α-hydroxy-20-keto steroids and then to corticoids is well known to those skilled in the art. SUMMARY OF INVENTION Disclosed is a process for the preparation of a protected aldehyde of formula (III) STER0ID-17α- [ -ORJ . ] -17 β- [-CHO] (III) where Rχy.χ is -Si-(S-i7-2 2( R 17-3^ where -2 and R 17-3 are c l" c 4 alkyl or φ , which comprises (1) contacting a protected cyanohydrin of formula (II) STEROID-17α-[-OR 17 . 1 ]-17^-[-CN] (II) where χ7-χ is as defined above with at least one hydride equivalent of a reducing agent in.the presence of an ether and (2) hydrolyzing the reaction mixture of step (1) . Also disclosed is a process for the preparation of a protected 21-halo steroid of formula (IV) STER0ID-17α-[-0R 17 . 1 ]-17 J 8-[-C0-CH 2 -R2l.l] (IV) where Rχy.χ is -Si-(R y_2)2( R 17-3) where Rχy-2 and R 17-3 are c l" c 4 alkyl or φ and 21-I i -Cl or -Br, which comprises (1) contacting a protected aldehyde of formula (III) STER0ID-17α- [ -aEi 17 _ 1 ] --17β- [-CHO] (III) where Rχy.χ is as defined above, with a strong base in the presence of a compound of the formula CH2 R2i-χ)2 where 2I-I i as defined above. Further disclosed is a protected aldehyde of formula (III) STEROID -17a- [ -0R 17 _ λ ] - 17 β- { -CHO] (III) where Rχy.χ is -Si-(Rιy-2^2 R 17-3) where χ .2 and 17-3 are c l" c 4 alkyl or φ . Additionally disclosed is a process for the preparation of a protected 21-halo steroid of formula (IV) STER0ID-17α-[-0R 1 y. 1 ]-17^-[-C0-CH 2 -R2i.ι] (IV) where Rχy_χ is -Si-(Rχy_2>2( R 17-3) where Rχy_2 and R 17-3 are c l" c 4 alkyl or φ and 2I-I is -Cl or -Br, which comprises (1) contacting a protected cyanohydrin of formula (II) . - STER0ID-17α-[-0R 1 y. 1 ]-17^-[-CN] ' (II) where Rχy.χ is as defined above with at least one hydride equivalent of a reducing agent in the presence of an ether to produce a protec- ted aldehyde of formula (III) STEROID-17α-[-OR 17 . 1 ]-17^-[-CHO] (III) where Rχy.χ is as defined above and (2) contacting the protected aldehyde of formula (III) with a strong base in the presence of a compound of the formula CH2 2l-l)2 w ^ ere R 21-l - s as de f ned above. DETAILED DESCRIPTION OF THE INVENTION The steroidal cyanohydrins (I) are known to those skilled in the art or can be readily be prepared by methods known to those skilled in the art from known steroid starting materials. The steroid A- , B- and C- rings are known to those skilled in the art include the usual steroidal nucleus. More particularly, they include the A-, B- and C- rings set forth in CHART B. First, the A-ring C3 ketone of the cyanohydrins (I) is protected as is known to those skilled in the art, for example, as the alkyl Δ 3 ' 5 -dienolether, Δ 5 -3-ketal or enamine. Next, the 17α-hydroxy group of the cyanohydrin is protected as is known to those skilled in the art. Suitable protecting groups include silyl ethers, acetals, or readily " removed ethers. The silyl ether is the preferred protecting group but any group which remains on and protects the 17α-hydroxyl group during the reaction and is readily removable at the end of the process is acceptable. Preferred is the tri ethylsilyl ether. The protected cyanohydrin (II) is transformed to the correspond- ing protected aldehyde (III) by reaction with at least one hydride equivalent' of a reducing agent. Suitable reducing agents are aluminum hydrides. These include diisobutylaluminum hydride, lithium aluminum hydride, sodium bis-(2-methoxyethoxy)aluminum hydride and lithium tri-tertbutoxyaluminum hydride. Preferred is diisobutyl- aluminum hydride. At least 1 hydride equivalent of reducing agent is necessary. Preferred is 1.2 - 2.0 equivalents, more preferred is 1.4 -1.5 equivalents. The term "hydride equivalent" is used since one molar equivalent of some of the above reducing agents contain more than one hydride equivalent. The reaction is performed in any organic solvent compatible with the reducing agent, however some ether must be present. The quantity of ether may range from about 0.1% to 100%. Ethers include THF, ether and methyl t-butyl ether and mixtures thereof. Suitable co-solvents include the above ethers and toluene, me hylene chloride and mixtures thereof. It is preferred that at least 0.1 % ether be present, more preferably at least 0.5 %, still more preferably at least 5 % ether. The amount of ether depends on the particular ether, the particular reducing agent, the particular protected cyanohydrin (II) etc. Preferred is methyl t- butyl ether containing about 10% THF (v/v) . Temperature is not critical and the process can be performed from about -80 to about 80°, preferably about -30" to about 0°. Any order of addition is operable, the reducing agent can be added to the steroid or the steroid to the reducing agent. Following contacting the protected cyanohydrin (II) with at least one hydride equivalent of the reducing agent in the presence of an ether, the reaction mixture is hydrolyz- ed. It is preferred to perform the hydrolysis with aqueous acid. It is preferred that the acid be a carboxylic acid, it is preferred that the carboxylic acid be acetic acid. The protected aldehyde (III) can be isolated by means known to those skilled in the art or can be carried on through to the next step without isolation; it is preferred that the protected aldehyde (III) be carried on without isolation. For the protected aldehyde (III) it is preferred that Rχ 7 _χ is trime hy1silyl. It is preferred that the protected aldehyde (III) A-ring have (A-I) R 5 is R 5 _ 1 :R 5 _2. R 6 is R 6-l :R 6-2- R 10 is «-Rl0-l : 0- R 10-2 where one of Rg_χ and Rg_2 is -H and the other taken together with one of R5.X and 5.2 forms a second bond between C5 and Cg, Rχo-2 ^- s -CH3, Rχo-X and the other of R5- and 5.2 taken together are -CH2- CH 2 -C(R3_χ)-CH- where* R3. is Cχ-C alkyloxy, -O-φ where φ is optionally substituted with 1 C _C alkyl; (A-II) R5 is R5.3^5. , R6 is g_3:R _4 and Rχ 0 is α-Rχ 0 _ 3 : - Rχθ.4, where one of Rg.3 and Rg.4 is -H and the other taken together with one of R5.3 and R5.4 forms a second bond between C5 and Cg, Rχo- 4 is -CH3, Rχo-3 and the other of R5.3 and R5.4 taken together are -CH2-CH2-C(α:-R3_3)( / 8- 3_4)-CH2- , where R3.3 and 3_4 taken together are -0-CH 2 -C(CH3) 2 -CH2-0- or -0-(CH 2 ) n χ-0- where is 2 or 3. It is preferred that the protected aldehyde (III) C-ring have R is R ll-l :R H-2 or α " R ll-3 : " R ll-3 where Rχχ.3 and Rχχ.4 are both -H. It is preferred that the protected aldehyde (III) D-ring have Rχg.χ and Rχg_2 are both -H. The preferred protected aldehydes (III) are selected from the group consisting of 3,17α-dihydroxyandrosta-3,5,9(11) -triene-17/3-carboxaldehyde 3- methyl 17-trimethylsilyloxy die her, 3,3,17α-trihydroxyandrost-5-ene-17/3-carboxaldehyde 3,3-ethylene ketal 17-trimethylsilyloxy ether, 3,3,17α-trihydroxyandrosta-5,9(11)-diene-17 / 3-carboxaldehyde 3,3- ethylene ketal 17-trimethylsilyloxy ether. The protected aldehyde (III) is transformed to the corresponding protected 21-halo steroid (IV) by contacting with a strong base in the presence of CH 2 2χ.χ)2 here 21-1 is " Br or " cl - Strong bases are amide bases of the formula Metal-N-(R ) where Metal is lithium, sodium, potassium and magnesium and is -H, Cχ-Cg alkyl, where R2 is Cχ.Cg alkyl. It is preferred that the amide is selected from the group consisting of lithium diisopropylamide, lithium dieth lamide, lithium piperidide and lithium dicyclohexylamide. The preferred base is lithium diisopropylamide. It is preferred that the halogenated agent be methylene bromide. About 2.5 to 3, preferably 2.8, equivalents of strong base are utilized. One equivalent per equivalent of CH2R21 i needed plus 1.8 equivalents for the transfor¬ mation of the halohydrin intermediate to the 21-halo ketone. Slightly greater than 1 equivalent of halogenated agent is required, preferably 1.05 equivalents. The reaction is performed in an etheral solvent with or without a hydrocarbon co-solvent. Preferred is about 50 % hydrocarbon with about 50 % ether; preferably hexane/THF (1/1). Temperature is not critical, about -100 to about 0* is operable, preferred is about -40 to about -30° . The order of addition of reactants is not critical so long as the base is added last. The protected 21-halo steroid (IV) Is then transformed to the corresponding protected 21-ester (V) by means known to those skilled in the art, see Organic Reactions in Steroid Chemistry, Vol II, Fried and Edwards, Van Nostrand editor, Reinhold Co, N.Y. , 1972, p 217-227. The protected 21-ester (V) Is transformed to the corresponding corticoid (VI) by means known to those skilled in the art. The protection of the steroid A-ring is necessary during the transformation of the protected cyanohydrin (II) to the protected aldehyde (III) and then for the protected aldehyde (III) to the 21- halo steroid (IV) . While it is not necessary, in a number of cases it is desirable to leave the C3 protecting group on after the protected 21-halo steroid (IV) is obtained. When desired the protecting groups are removed by means known to those skilled In the art. Hence, the nature of the steroid nucleus does not change during the reaction. In the present Invention all process chemistry changes take place in the side chain attached to Cχ 7 . Therefore, for simplicity the traditional 4 ring steroid nucleus in the present process has been defined in CHART B and identified as "STEROID". DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and 5 the claims. I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES The chemical formulas representing various compounds or molecu¬ lar fragments In the specification and claims may contain variable substituents in addition to expressly defined structural features. 10 These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, "Zχ π or "Rχ M where "i" is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group ∑χ would repres- 15 ent a bivalent variable if attached to the formula CH3-C(=Zχ)H. Groups R j _ and R would represent monovalent variable substituents if attached to the formula C^-C^-C^) (R H2. When chemical formulas • are drawn in a linear fashion, such as those above, variable sub¬ stituents contained in parentheses are bonded to the atom immediately 20 to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left which is not enclosed in parentheses. Thus, in the formula above, both R^ and Ri are 25 bonded to the preceding carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as C^, where "i" is the integer cor¬ responding to the carbon atom number. For example, Cg represents the 6 position or carbon atom number in the steroid nucleus as tradition¬ 30 ally designated by those skilled in the art of steroid chemistry. Likewise the term "Rg" represents a variable substituent (either monovalent or bivalent) at the Cg position. Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol "-" in general 3.5 represents a bond between two atoms in the chain. Thus CH3-O-CH2- CH(R i )-CH3 represents a 2-substituted-l-methoxypropane compound. In a similar fashion, the symbol "=-" represents a double bond, e.g., and the symbol "~≡" represents a triple bond, e.g., HC»C-CH R i )-CH2-CH3. Carbonyl groups are represented in either one of two ways: -CO- or -C(-O)-, with the former being preferred for simplicity. Chemical formulas of cyclic (ring) compounds or molecular fragments can be represented in a linear fashion. Thus, the compound 4-chloro-2-me hylpyridine can be represented in linear fashion by N*-C(CH3)-CH-CC1-CH-C*H with the convention that the atoms marked with an asterisk (*) are bonded to each other resulting in the formation of a ring. Likewise, the cyclic molecular fragment, 4- (ethyl)-1-piperazinyl can be represented by -N*- 012 2-^ ^2 )-CH 2 - C*H 2 . A cyclic (ring) structure for any compound herein defines an orientation with respect to the plane of the ring for substituents attached to each carbon atom of the cyclic compound. In formulas depicting such compounds, a substituent attached to a carbon atom below the plane of the ring is identified as being in the alpha (α) configuration and is indicated by a broken, dashed or dotted line attachment to the carbon atom, i.e., by the symbol "- - -" or "....". The corresponding substituent attached above the plane of the ring Is identified as being in the beta β) configuration. When a variable substituent is' bivalent, the valences may be taken together or separately or both in the definition of the variable. For example, a variable R^ attached to a carbon atom as -C(— ^)- might be bivalent and be defined as oxo or keto (thus forming a carbonyl group (-CO-) or as two separately attached monovalent variable substituents α-R j i and When a bivalent variable, ^, is defined to consist of two monovalent variable substituents, the convention used to define the bivalent variable is of the form "α-Rχ r :^-R^_^.n or some variant thereof. In such a case both α-R^.j and β- ^.y^ are attached to the carbon atom to yield -C(α-R^_j) 3-Rχ.j ς )-. For example, when the bivalent variable R , -C(—Rg)-is defined to consist of two monovalent variable substituen¬ ts, two monovalent variable substituents are α-Rg_χ:,S-Rg_2 α-Rg_ 9 : -Rg_ 10 , etc, yielding -C(α-Rg_χ) (,3-Rg_ 2 )- -C( -R .g) ( -Rg_χg)-, etc. Likewise, for the bivalent variable Rχχ > -C(-Rχχ)-, two monovalent variable substituents are <*-Rχχ.χ: -Rχχ_2- For a ring substituent for which separate α and β orientations do not exist (e.g. due to the presence of a carbon carbon double bond in the ring) , and for a substituent bonded to a carbon atom which is not part of a ring the above convention is still used, but the and β designations are omitted. Just as a bivalent variable may be defined as two separate monovalent variable substituents, two separate monovalent variable substituents may be defined to be taken together to form a bivalent variable. For example, in the formula -Cχ(Rχ)H-C 2 (Rj)H- (0χ and C 2 define arbitrarily a first and second carbon atom, respectively) R^ and R.; may be defined to be taken together to form (1) a second bond between 0χ and C2 or (2) a bivalent group such as oxa (-0-) and the formula thereby describes an epoxide. When R^ and Rj are taken together to form a more complex entity, such as the group -X-Y- , then the orientation of the entity is such that 0χ in the above formula is bonded to X and C2 is bonded to Y. Thus, by convention the designa- tion "... Rx and Rj are taken together to form -CH 2 -CH 2 -0-C0- ..." means a lactone in which the carbonyl is bonded to C . However, when designated "... R^ and R^ are taken together to form -CH2-CH2-O-CO- the convention means a lactone in which the carbonyl is bonded to Cχ> The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as "Cχ-C4", where both "1".- and "4" are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, "Cχ-C4 alkyl" represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given) . Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C alkoxycarbonyl describes a group CH3-(CH2) n -0- C0- where n is zero, one or 2. By the second method the carbon atom content of only each portion of the definition is indicated separate¬ ly by enclosing the "Ci-Cj" designation in parentheses and placing it immediately (no intervening space) before the portion of the defini¬ tion being defined. By this optional convention (C -C3)alkoxy¬ carbonyl has the same meaning as C2-C alkoxycarbonyl because the "C -C3" refers only to the carbon atom content of the alkoxy group. Similarly while both C 2 -Cg alkoxyalkyl and (0χ-C3) lkox (CX-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms. When the claims contain a fairly complex (cyclic) substituent, at the end of the phrase naming/designating that particular sub¬ stituent will be a notation in (parentheses) which will correspond to the same name/designation in one of the CHARTS which will also set forth the chemical structural formula of that particular substituent. II. DEFINITIONS STEROID refers to the steroid nucleus as set forth in CHARTS A, B and C. All temperatures are in degrees Centigrade. TLC refers to thin-layer chromatography. HPLC refers to high pressure liquid chromatography. THF refers to tetrahydrofuran. LDA refers to lithium diisopropylamide. Saline refers to an aqueous saturated sodium chloride solution. NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (£) downfield from tetramethyl- silane. φ refers to phenyl (CgH5 . Ether refers to diethyl ether. When solvent pairs are used, the ratios of solvents used are volume/volume (v/v) . Androstenedione refers to androst-4-ene-3,17-dione. EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to Its fullest extent. The following detailed examples describe how to prepare- the various " compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. EXAMPLE 1 3,17α-Dihydroxyandrosta-3,5,9(ll)-triene-17^-carbox aldehyde 3-methyl 17-trimethylsilyloxy diether (III) 170-Cyano-3,17α-dihydroxyandrosta-3,5,9(ll)-triene 3-methyl 17- trimethylsilyloxy diether (II, 17.46 g) is dissolved in methyl t-bu- tyl ether (50 ml) and THF (5.7 ml). The resulting solution is cooled to -28°. Diisobutylaluminum hydride (12.6 ml) is dissolved in methyl t-butyl ether (26.6 ml) and this solution is cooled to -30° before being added dropwise to the steroid mixture. The addition is done over 35 min and the • reaction temperature is maintained between -25 and -30°. Following the addition, the mixture is allowed to warm to 0° slowly over 2.5 hr at which time the reaction is complete as measured by TLC. Methanol (5.5 ml) is added dropwise while maintaining the temperature between 0 and 10°. After stirring, the resulting cloudy mixture for 10 min a solution of aqueous acetic acid (50%, 66 ml) is slowly added while maintaining the temperature below 25°. After stirring the resulting two-phase mixture at 25° for 0.5 hr, toluene (70 ml) is added and the mixture " is distilled under vacuum at 30° until 50 ml of distillate are collected. The two phases are separa¬ ted and the aqueous fraction is extracted with toluene (2 x 15 ml) . The combined organic phases are washed twice with water (20 ml) , then with saturated sodium bicarbonate (20 ml) , then with water again (20 ml) , and then finally with saline (20 ml) . After drying over an¬ hydrous magnesium sulfate (1 g) and silica gel (5 g) , the mixture is filtered and the solvent is removed under reduced pressure to give an oily residue. TLC and HPLC indicate .that the product is >95% pure. The product is crystallized by dissolving it In a minimum of ethyl acetate and adding methanol until it becomes cloudy. After gentle heating and then cooling to 25° seed crystals are added and the mixture is then left at -15° for 15 hr. Filtration gives a solid which is crystallized to give the title compound, mp - 90-92°. A second crop can be obtained following silica gel chromatograp- hy of the mother liquor eluting with hexane/acetone (98/2), NMR (dDCl 3 ) 0.1, 0.65, 1.15, 3.6, 5.2, 5.3, 5.5 and 9.65 S . EXAMPLE 2 21-Bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione 17-trimethylsilyloxy ether (IV) 3,17α-Dihydroxyandrosta-3,5,9(ll)-triene-17/3-carboxaldehyde 3- methyl 17-trimethylsilyloxy diether (III, EXAMPLE 1, 1.18 g) is dissolved in THF (1.2 ml) and hexane (2.3 ml) is added. After degassing with nitrogen, the solution is cooled to -35° and ethylene bromide (0.22 ml) is added. A solution of lithium diisopropylamide in THF/hexane (IM, -2:1) is then added dropwise over 10 min maintain¬ ing the temperature between -30 and -35°. The resulting mixture is then stirred for 1/2 hr during which time the temperature is allowed to climb to -10°. The mixture is then transferred to a flask containing hydrochloric acid (3N, 7 ml) and methylene chloride (3 ml) which is previously cooled to -20°. A 10° exotherm Is observed during this addition. The resulting mixture is then allowed to warm up to 20-25°. After a total hydrolysis time of 1.5 hr methylene chloride (30 ml) is added and the two layers are separated. The aqueous phase is extracted with methylene chloride (5 ml) and the combined organic fractions are washed successively with water (10 ml), sodium bicarbonate (10%, 10 ml) and saline (10 ml). After drying over anhydrous magnesium sulfate (-1 g) and filtering through a short column of silica gel (—5 g, eluting with about 10 ml methyl- ene chloride) , the solvent is removed to give the title compound, mp - 155-156°; NMR (CDCI3) 0.15, 0.55, 1.35, 4.1, 4.3, 5.6 and 5.75 S . EXAMPLE 3 3 ,3,17α-Trihydroxyandrost-5-ene-17/3-carboxaldehyde „ 3,3-ethylene ketal 17-trimethylsilyloxy ether (III) Following the general procedure of EXAMPLE 1 and making non- critical variations but starting with 17yS-cyano-3,3,17a-trihydroxy- androst-5-ene 3,3-ethylene ketal 17-trimethylsilyloxy ether ( ' II) the title compound is obtained, mp — 128-134° . EXAMPLE 4 21-Bromo-17α-hydroxypregn-4-ene-3,20-dione 17-tri methylsilyloxy ether (IV) Following the general procedure of EXAMPLE 2 and making non- critical variations but starting with 3,3,17α-trihydroxyandrost-5- ene-173-carboxaldehyde 3,3-ethylene ketal 17-trimethylsilyloxy ether (III, EXAMPLE 3) the title compound is obtained, NMR (CDCI3) 0.15, 0.6, 1.15, 4.1, 4.3 and 5.75 5; TLC (methylene chloride/methanol, 98/2) R f - 0.64; TLC (methylene chloride/acetone, 95/5) R f - 0.68. EXAMPLE 5 3 , 3, 17α-Trihydroxyandrosta-5,9(11)-diene ..70-carbox- aldehyde 3,3-ethylene ketal 17-trimethylsilyloxy ether (III) Following the general procedure of EXAMPLE 1 and making non- critical variations but starting, with 17β-cyano-3,3,17ct-trihydroxy- androsta-5,9(11)-diene 3,3-ethylene ketal 17-trimethylsilyloxy ether (II) the title compound is obtained, mp = 131-134° . EXAMPLE 6 21-Bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione 17-trimethylsilyloxy ether (IV) Following the general procedure of EXAMPLE 2 and making non- critical variations but starting with 3,3,17α-trihydroxyandrosta- 5,9(ll)-diene-17 -carboxaldehyde 3,3-ethylene ketal 17-trimethyl- silyloxy ether (III, EXAMPLE 5) the title compound is obtained. CHART A 15 CN 25 35 CHART A - Continued 35 CHART B where : (A-I) R 5 is R5.χ:Rs-2' R 6 is R 6-l :R 6-2> R 10 is tt - R 10-l : - R 10-2 where one of Rg.χ and Rg_ 2 is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.X and R5.2 forms a second bond between C5 and Cg, Rχo-2 ~^- s -CH3, Rχo-1 and the other of R5.X and R5_2 taken together are -CH 2 -CH2-C R3_ -CH- or -CH=CH-C(R3„χ)-CH- where R 3 .χ is Cχ-Cg alkyloxy, -Q-φ where φ is optionally substituted with 1 C _C4 alkyl or -N(R 3 . 2 )( 3-6> where R 3 _ 2 is Cχ-C 3 alkyl, R 3 .g is C . 3 alkyl or φ , where the R3.2 and R3_ may be cycllzed to form a he erocyclic ring selected from the group consisting of pyrollidine, piperidine, morphollne, piperazine; (A-II) R5 Is ^5-3^5=4, <$ is 8. -3:8-6-4 and R 10 is α " R 10-3 : ^~ lθ-4 > where one of Rg.3 and Rg.4 Is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.3 and R5.4 forms a second bond between C5 and Cg, Rχo-4 is -CH3, Rχø-3 and the other of Rs_3 and R$_ 4 taken together are -CH2-CH2-C(α-R3_3)GS-R3_4)-CH2- , where one of R3_3 and R3_4 is -H and the other of R3.3 and R3.4 is -OH or -OR3.5 where R3.5 is Cχ-Cg alkyl, -CH 2 -^ or -Si-(R3_ ) 2 R3.8) where R 3 .y and 3-8 are ^1-4 and > and where R3_3 and R3.4 taken together are -0- CH2-C(CH 3 ) 2 -CH2-0- or -0-(CH 2 ) n ι-0- where n x is 2 " or 3; (C-I) R x is Rχχ.χ:Rχι_2 where one of Rχχ.χ and Rχχ_ 2 taken together with R9 to form a second bond between C9 and 0 and the other of Rχχ_χ and Rχχ_ 2 is " H ; (C-II) R is α-H: -0-, where β-0- is taken together with R 9 to form a 3-epoxide between C9 and Oχ ; CHART B - Continued (C-III) Rg is -H and Rχ χ is -0-CH2-C(CH 3 )2-CH 2 -0- or -0-(CH 2 ) n2 - 0- where n2 is 2 or 3, <*-Rχχ-3:9- χχ-4 where one of Rχχ.3 and Rχχ.4 is -H and the other of Rχχ.3 and Rχχ.4 is -H, -OH or -ORχχ.5 where Rχχ.5 is Cχ-Cg alkyl, -C -φ or -Si-(Rχχ-g)2( R χχ-7) where Rχχ-g and ll"7 are ^1-4 and Φ - CHART C The six partial structural formulas of CHART A can be represent¬ ed by where R g is <*-Rχg-χ:S-Rχ6-2 where one of Rχ6.χ and Rχg_2 -H and the other of Rχg.χ and Rχg. 2 is " H > _CH 3 or " 0H ; where for the cyanohydrin (I) R is α-0H: -CN, for the protected cyanohydrin (II) Rχ is α-0Rχy„χ:j8-CN, for the protected aldehyde (III) Rχ is α-0Rχ _χ:j3-CH0, for the protected 21-halo steroid (IV) Rχ 7 Is α-0Rχ 7 _χ: -C0- for the protected 21-ester (V) Rχ 7 is α-0Rχ 7 .χ:^-C0-CH 2 -0-C0- 21-2 an for the corticoid (VI) Rχ 7 is α-0H:^-C0-CH 2 -0-C0-R 2 χ_2. CHART D STER0ID-17α-[-OH] - 11 β- [ -CN] (I) STEROID-17α- [-0Rχ 7 .χ]-170- [-CN] (ID STER0ID-17α- [-OR 17 .χ] -175- [-CHO] (III) STEROID-17α- [-ORχ 7 .χ] -173- [ -CO-CH 2 -R 2 χ.χ] (IV) STEROID-17α-[-0Rχ 7 .χ] -173- [-0C-CH 2 -0-C0-R 2 χ_2] (V) STER0ID-17«-[-0H]-17 -[-C0-CH 2 -0-C0-R 21 _ 2 ] (VI) STEROID refers to the steroid nucleus as set forth in CHARTS A, B and C.

Claims: CLAIMS 1. A process for the preparation of a protected aldehyde of formula (III) where R g is <*-Rχ6-l : -Rχg. 2 where one of Rχg.χ and Rχg. 2 "H and the other of Rχg.χ and Rχg_ 2 is _H > " CH 3 ° r _0H ' Rχ 7 .χ is -Si-( χ 7 _2)2( R 17-3 wh re Rχ 7 _2 and Rχ 7 _3 are C -C4 alkyl or φ , and which comprises (1) contacting a protected cyanohydrin of formula (II) where R g and Rχ 7 .χ are as defined above with at least one hydride equivalent of a reducing agent in the presence of an ether and (2) hydrolyzing the reaction mixture of step (1) . 2. A process according to claim 1 where the reducing agent is an aluminum hydride. 3. A process according to claim 1 where the reducing agent is selected from the group consisting of diisobutylaluminum hydride, ■ lithium aluminum hydride, sodium bis-(2-methoxyethoxy)aluminum hydride and lithium tri-tertbutoxyaluminum hydride. 4. A process according to claim 1 where the reducing agent is diisobutylaluminum hydride. 5. A process^ according to claim 1 where about 1.2 to about 2.0 equivalents of reducing agent are used. 6. A process according to claim 1 where the ether is selected from the group consisting of THF, ether and methyl t-butyl ether and mixtures thereof. 7. A process according to claim 1 where hydrolysis is performed with aqueous acid. 8. A process according to claim 7 where the acid is a carboxylic acid. 9. A process according to claim 1 where the steroid A-B-C rings are where: (A-I) R 5 is R 5 _ :R 5 _ 2 , Rg is g. :R6-2. X0 is α - 10-l : - R 10-2 where one of Rg.χ and Rg_ is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.X and Rs_ forms a second bond between C5 and Cg, Rχo-2 i s "CH3, Rχo-1 and the other of 5.X and 5.2 taken together are -CH 2 -CH 2 -C(R 3 .χ)-CH- or -CH=CH-C(R 3 _χ)«CH- where R 3 .χ is Cχ-Cg alkyloxy, -0-^ where φ is optionally substituted with 1 Cχ.C4 alkyl or -N(R 3 _2)(R3_g) where R 3 . 2 is Cχ-C 3 alkyl, R- .ς, is Cχ. 3 alkyl or φ , where the R3_ 2 and 3.g may be cyclized to form a heterocycllc ring selected from the group consisting of pyrollidine, piperidine, morpholine, piperazln ; (A-II) R 5 is 5.3^5.4, &6 is R 6-3 :R 6-4 and R 10 is α - R 10-3 : ^ _ R 10-4 » where one of Rg.3 and Rg.4 is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.3 and s_4 forms a second bond between C5 and Cg, Rχo-4 is " CH 3> R 10-3 and the other of R5.3 and R5. 4 taken together are -CH -CH 2 -C(α- 3„3 (/3- 3„4)-CH 2 - , where one of R3.3 and R3.4 is -H and the other of R3.3 and R3.4 is -OH or -OR3.5 where R3_5 is Cχ-Cg alkyl, -CH 2 -^ or -Si-(R3_ 7 )2(R3-8 where R3_ 7 and R3.8 are C _4 and φ , and where R3.3 and R3.4 taken together are -0- CH 2 -C(CH 3 )2-CH2-0- or -0-(CH 2 ) n χ-0- where n L is 2 or 3; (C-I) Rx is β -iχ.χ: β -χχ-2 where one of Rχχ.χ and χ.2 taken together with R9 to form a second bond between C9 and 0χχ and the other of Rχχ_χ and Rχχ.2 "H; (G-II) is x_t-E:β-0- , where β-0- is taken together with R9 to form a ?-epoxide between C and Oχχ; (C-III) R 9 is -H and R χl is -0-CH 2 -C(CH 3 ) 2 -CH2-0- or -0-(CH 2 ) n 2- 0- where n2 is 2 or 3, α-Rχ -3^- χχ_ where one of Rχχ.3 and Rχχ-4 is -H and the other of Rχχ.3 and Rχχ.4 is -H, -OH or -0Rχχ_5 where Rχχ.5 is Cχ-Cg alkyl, -C^-^ or -Si-(Rχχ-g)2(Rχχ- 7 ) where Rχχ-g and ll"7 are ^1-4 an Φ - 10. A process according to claim 1 where the protected cyanohydrin (II) Is selected from the group consisting of 17/3-cyano-3,17α-dlhydroxyandrosta-3,5,9(ll)-triene 3-methyl 17- trimethylsilyloxy diether, 17 -cyano-3,3,17<x-trihydroxyandrost-5-ene 3,3-ethylene ketal 17- trimethylsilyloxy ether, 17 -cyano-3,3,17α-trihydroxyandrosta-5,9(11)-diene 3,3-ethylene ketal 17-trimethylsilyloxy ether. 11. A process for the preparation of a protected 21-halo steroid of formula (IV) where Rxg is <*-Rχ6-l : ^" 16-2 where one of Rχg.χ and Rχg.2 i ~H and the other of Rχg.χ and Rχg.2 -H, -CH3 or -OH; R 17-l i -Si-(Ri7-2)2( R 17-3) where Rχ 7 .2 and Rχ 7 _3 are Cχ-C alkyl or φ and R χ_χ is -Cl or -Br, which comprises (1) contacting a protected aldehyde of formula (III) CHO where Rxg and Rχ 7 .χ are as defined above, with a strong base in the presence of a compound of the formula CH 2 (R2i_ι)2 where 21-I is as defined above. 12. A process for the preparation of a protected 21-halo steroid according to claim 11 where the strong base is selected from the group consisting of amides of the formula Metal-N-(Rχ)2 where Metal is lithium, sodium, potassium and magnesium and R is -H, Cχ-Cg alkyl, -Si(R 2 )3 where R 2 is Cχ.Cg alkyl. 13. A process for the preparation of a protected 21-halo steroid according to claim 11 where the amide is selected from the group consisting of lithium diisopropylamide, lithium diethylamide, lithium piperidide and lithium dicyclohexylamide. 14. A process for the preparation of a protected 21-halo steroid according to claim 11 where the strong base is lithium diisopropyl¬ amide. 15. A process for the preparation of a protected 21-halo steroid according to claim 11 where < 3 equivalents of the strong base are used. 16. A process for the preparation of a protected 21-halo steroid according to claim 11 where R2χ.χ is -Br. 17. A process for the preparation of a protected 21-halo steroid according to claim 11 where the steroid A-B-C rings are where: (A-I) R 5 is R 5 .χ:R 5 .2, 6 is R 6-l :R 6-2> R 10 is Q! - R 10-l : 3 - R 10-2 where one of Rg.χ and Rg_ 2 is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of 5. and R5.2 ' forms a second bond between C5 and Cg, Rχo-2 is -^3, Rχo-1 and the other of 5. and 5. taken together are -CH2-CH 2 -C(R 3 _χ)-CH- or -CH=CH-C(R 3 .χ)=CH- where R 3 . is Cχ-Cg alkyloxy, -0-φ where φ is optionally substituted with 1 C .C4 alkyl or -N(R 3 . 2 ) ( 3-δ) where R 3 . 2 is Cχ-C 3 alkyl, R 3 .g is Cχ_ 3 alkyl or φ , where the R3.2 and R3_ may be cyclized to form a heterocyclic ring selected from the group consisting of pyrollidine, piperidine, morpholine, piperazine; (A-II) R 5 is R5. 3 :R5.4, Rg is Rg.3-.Rg.4 and R 10 is α-Rχ 0 _ 3 :3- χθ-4 > where one of Rg.3 and Rg.4 is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.3 and R5.4 forms a second bond between C5 and Cg, Rχo-4 is -CH3, Rχo-3 and the other of R5.3 and R5. 4 taken together are -CH2-CH2-C(α-R3_3)(/3-R3.4)-CH2- , where one of R3.3 and R3.4 is -H and the other of R3.3 and R3.4 is -OH or -OR3.5 where R3.5 is Cχ-Cg alkyl, -C^- or -Si-(£3.7)2( 3-8) where R 3 . 7 and R3.8 are Cχ.4 and φ , and where R3.3 and R3.4 taken together are -0- CH2-C(CH3 2-CH2-0- or -0- CH2) n -0- where n^ is 2 or 3; (C-I) R x is Rχχ.χ:Rχχ.2 where one of Rχχ.χ and Rχχ_2 taken together with R9 to form a second bond between C9 and Oχχ and the other of Rχχ.χ and Rχχ.2 is -H; (C-II) Rxx is a-R :β-0- , where β-0- is taken together with R 9 to form a yS-epoxide between Cg and 0χχ; (C-III) Rg is -H and R χl is -0-CH2-C(CH 3 )2-CH 2 -0- or -0-(CH 2 ) n 2- 0- where nj is 2 or 3, α " R ll-3 : ^-Rii-4 where one of Rχχ.3 and Rχχ.4 is -H and the other of Rχχ_3 and Rχχ.4 is -H, -OH or -ORχχ.5 where Rχχ.5 is Cχ-Cg alkyl, -CR2 -Φ or -Si-(Rχχ-g)2(Rχχ- ) where Rχχ-g and Rχχ- 7 are Cχ.4 and φ . 18. A process for the preparation of a protected 21-halo steroid according to claim 11 where the protected aldehyde (III) is selected from the group consisting of 3,17α-dihydroxyandrosta-3,5,9(11)-triene-17/3-carboxaldehyde 3- methyl 17-trimethylsilyloxy diether, 3,3,17α-trihydroxyandrost-5-ene-173-carboxaldehyde 3,3-ethylene ketal 17-trimethylsilyloxy ether, 3,3,17α-trihydroxyandrosta-5,9(11)-diene-17,5-carboxaldehyde 3,3- ethylene ketal 17-trimethylsilyloxy ether. 19. A protected aldehyde of formula (III) where (A-I) R 5 is R 5 .χ: 5-2> R 6 is R 6-l :R 6-2> R 10 is <*- R 10-l : ^- R 10-2 where one of Rg.χ and Rg. 2 i -H, -F, -Cl, -Br, -CH 3 and the other taken together with one of 5.X and R5.2 forms a second bond between C5 and Cg, Rχo-2 ^- s " CiI 3> R 10-l and t * ιe other of 5. and R5-2 taken together are -CH 2 -CH 2 -C(R3_χ)«CH- or -CH-CH-C(R 3 «,χ)-CH- where R 3 .χ is Cχ-Cg alkyloxy, -0-^ where φ is optionally substituted with 1 C _C4 alkyl or -N(R 3 . 2 )( R 3-δ) where R 3 . 2 is Cχ-C 3 alkyl, R 3 .g is Cχ_ 3 alkyl or φ . where the R3_2 a ^d 3.6 ma oe cyclized to form a heterocyclic ring selected from the group consisting of pyrollidlne, piperidine, morpholine, plperazine; (A-II) 5 is R5-3 * . 5-4. &6 ^ s R 6-3 : 6-4 and 10 ^ s a- iQ- '.β- 10-4» where one of Rg.3 and Rg.4 is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.3 and R5.4 forms a second bond between C5 and Cg, Rχo-4 is -CH3, Rχo-3 and the other of R5.3 and R5. 4 taken together are -CH -CH 2 -C(α-R3_3)(0-R3.4 -CH2-, where one of R3.3 and 3_4 is -H and the other of R3.3 and R3.4 is -OH or -OR3.5 where R3.5 is Cχ-Cg alkyl, -CH -^ or -Si-(R3_ 7 2( 3-8 where R3_ 7 and 3-8 are c l-4 and Φ - atl where R3.3 and Rs_4 taken together are -0- CH2-C(CH 3 ) 2 -CH 2 -0- or -0-(CH 2 ) n χ-0- where m is 2 or 3; (C-I) Rxx is Rχχ.χ-'Rχχ-2 where one of Rχχ.χ and Rχχ_ taken together with Rg to form a second bond between Cg and 0 χ and the other of Rχχ.χ and Rχχ_ 2 -H; (C-II) Rxx is α-H:/3-0-, where β-0- is taken together with Rg to form a 0-epoxide between Cg and Cχχ,- (C-III) Rg is -H and R lχ is -0-CH 2 -C(CH 3 ) 2 -CH 2 -0- or -0-(CH 2 ) n2 - 0- where n is 2 or 3, <*-Rχχ_3:/3-R χ.4 where one of Rχχ.3 and Rχχ.4 is -H and the other of Rχχ.3 and x .4 is -H, -OH or -0Rχχ. 5 where Rχχ_ 5 is Cχ-Cg alkyl, -CR 2 -Φ or -Si-(Rχχ-g) 2 (Rχχ-y) where Rχχ-6 and Rχχ-y are Cχ.4 and φ ; Rxg is <*-Ri6-l : " R 16-2 here one of Rχ6-χ and Rχg. is -H and the other of Rχg.χ and Rχ6-2 is -H, -CH3 or -OH; R 17-l is " si "( R 17-2)2( R 17-3) where Rχ 7 . 2 and Rχ 7 .3 are C -C4 alkyl or φ . 20. A protected aldehyde (III) according to claim 19 where Rχy.χ is trimethylsilyl. 21. A protected aldehyde (III) according to claim 19 where (A-I) R 5 is R5.χ:R 5 . 2 , Rg is Rg_χ:Rg_ 2 , Rχ 0 is <*-Rχo-i:S-Rχo-2 where one of Rg.χ and Rg_ 2 is -H and the other taken together with one of 5.X and s_ forms a second bond between C5 and Cg, Rχo-2 ' s -CH3, Rχo-l and the other of R5.X and R5. ; taken together are -CH 2 - CH 2 -C(R3_χ)-CH- where 3.X is Cχ-Cg .alkyloxy, -Q-φ where φ is " optionally substituted with 1 Cχ.C4 alkyl; (A-II) R 5 is R 5 . 3 :R 5 . 4 , Rg is Rg. 3 :Rg_4 and R 1Q - is α-Rχ 0 . 3 :/S- R 10-4 > where one of Rg.3 and Rg.4 is -H and the other taken together with one of R5.3 and R5.4 forms a second bond between C5 and C , Rχo- 4 is -CH3, Rχo-3 and the other of R5.3 and R5.4 taken together are -CH 2 -CH 2 -C( -R3.3) ( / 3-R3.4)-CH 2 -, where R3.3 and R3.4 taken together are -0-CH 2 -C(CH 3 ) 2 -CH 2 -0- or -0-(CH 2 ) n χ-0- where ^ is 2 or 3. 22. A protected aldehyde (III) according to claim 19 where Rxx is R ll-l :R ll-2 or α " ll-3 : " R ll-3 where Rχχ.3 and Rχχ_4 are both -H. 23. A protected aldehyde (III) according to claim 19 where Rχg.χ and R 16-2 are b°th -H. 24. A protected aldehyde (III) according to claim 19 which is selected from the group consisting of 3,17α-dihydroxyandrosta-3,5,9(11)-triene-17/3-carboxaldehyde 3- methyl 17-trimethylsilyloxy diether, 3,3,17α-trihydroxyandrost-5-ene-17/3-carboxaldehyde 3,3-ethylene ketal 17-trimethylsilyloxy ether, 3,3,17α-trihydroxyandrosta-5, (11)-diene-170-carboxaldehyde 3,3- ethylene ketal 17-trimethylsilyloxy ether. 25. A process for the preparation of a protected 21-halo steroid of formula (IV) where g Is ce- χ6-l : 0" R χ6-2 where one of Rχg.χ and Rχg_ 2 is -H and the other of Rχg.χ and Rχg_ is -H, -CH3 or -OH; Rχ 7 _χ is -SI-(Rχy.2 8-17-3) where R y.2 and R 17-3 are c l" c 4 alkyl or φ ; R2χ. is -Cl or -Br which comprises (1) contacting a protected cyanohydrin of formula (II) where R g and Rχy.χ are as defined above with at least one hydride equivalent of a reducing agent in the presence of an ether to produce a protected aldehyde of formula (III) where Rxg and Rχ 7 .χ are as defined above and (2) contacting the protected aldehyde of formula (III) with a strong base ' in the presence of a compound of the formula CH2(R2l-i)2 where 21-I is as defined above. 26. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where the reducing agent is an aluminum hydride.- 27. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where about 1.2 to about 2.0 equivalents of reducing agent are used. 28. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where, the ether is selected from the group consisting of THF, ether and methyl t-butyl ether and mixtures thereof. 29. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where the hydrolysis is performed with aqueous acid. 30. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where the strong base is selected from the group consisting of amides of the formula Metal-N- (Rχ)2 where Metal is lithium, sodium, potassium and magnesium and R is -H, Cχ-C 6 alkyl, -Si(R 2 ) 3 where R 2 is Cχ.Cg alkyl. 31. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where < 3 equivalents of the strong base are used. 32. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) where the steroid A-B-C rings are where: (A-I) R 5 is R 5 .χ:R 5 _2. R 6 is R 6-l :R 6-2> R 10 is α£ - R 10-l : J 9 - R 10-2 where one of Rg.χ and g.2 i -H, -F, -Cl, -Br, -CH3 and the other taken together with one of s„ and 5„2 fo ms a second bond between C5 and Cg, Rχo-2 is -CH3, 8.χg.χ and the other of R5. and R5.2 taken together are -C^-C^-C^.^-CH- or -CH«CH-C(R3„ )«CH- where R 3 _χ is Cχ-Cg alkyloxy, -0-φ where φ is optionally substituted with 1 C .C4 alkyl or -N(R 3 . 2 )(R3-6 where R 3 . 2 is Cχ-C 3 alkyl, R 3 .g is Cχ.3 alkyl or φ , where the R3.2 and R3_ may be cyclized to form a heterocyclic ring selected from the group consisting of pyrollidine, piperidiή ' e " , '" morpholine, piperazine; (A-II) R 5 is R5.3^5.4, Rg is R6-3: 6-4 and R 10 is α " R 10-3 : ~ Rχθ-41 where one of Rg.3 and Rg.4 is -H, -F, -Cl, -Br, -CH3 and the other taken together with one of R5.3 and R5.4 forms a second bond between C5 and Cg, Rχø-4 is -CH3, Rχo-3 and the other of R 5 _ 3 and R5. 4 taken together are -CH 2 -CH 2 -C(α-R3_3)( / 8-R 3 _4)-CH 2 - , where one of R3_3 and R3.4 is -H and the other of R3.3 and R3.4 is -OH or -OR3.5 where R3.5 is Cχ-Cg alkyl, -CH 2 -< or -Si-(R3_ 7 ) 2 (R 3 _ g ) where R 3 . 7 and R3.8 are Cχ.4 and φ , and where R3.3 and R3.4 taken together are -0- CH 2 -C(CH3)2-CH 2 -0- or -0-(CH 2 ) n χ-0- where ^ is 2 or 3; (C-I) Rxx is Rχχ-χ:8χχ. 2 where one of Rχχ.χ and Rχχ_ 2 taken together with Rg to form a second bond between Cg and 0χ and the other of Rχχ.χ and 8.χχ. 2 is -H; (C-II) Rx is α-H: / 9-0-, where β-0- is taken together with Rg to form a ^-epoxide between Cg and 0χχ; (C-III) Rg is -H and R χl is -0-CH 2 -C(CH 3 ) 2 -CH 2 -0- or -0-(CH 2 ) n2 - 0- where 112 is 2 or 3, α " R ll-3 : ^" R ll-4 where one of Rχχ.3 and Rχχ.4 is -H and the other of Rχχ.3 and Rχχ.4 is -H, -OH or -0Rχχ_ 5 where R ll-5 is c l" c 6 alkyl, -CH2-Ψ or -Si-(Rχχ-g)2(8.χχ- 7 ) where Rχχ-g and R ll"7 are ^1-4 and Φ - 33. A process according to claim 25 for the preparation of a protected 21-halo steroid of formula (IV) which is selected from the group consisting of 3,17α-dihydroxyandrosta-3,5,9(11)-triene-17 / 3-carboxaldehyde 3- ethyl 17-trimethylsilyloxy diether, 3,3,17o-trihydroxyandrost-5-ene-17 / 3-carboxaldehyde 3,3-ethylene ketal 17-trimethylsilyloxy ether, 3,3,17α-trihydroxyandrosta-5,9(11)-diene-17 -carboxaldehyde 3,3- ethylene ketal 17-trimethylsilyloxy ether.

Inventors: REID JOHN G, REID, JOHN, G.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1988
Main classification: C07J51
IPC codes: C07J3, C07J5, C07J7, C07J51