Патент USA US3062852код для вставки
f, ‘i 3,652,846 p Patented Nov. 6, 1962 2 dihydroxylated steroids, such as 3,062,846 16a,17a-dihydroxyprogesterone, (LOWER ALKOXYWIETHYL ETHER DERIVATIVES 1 111,2l-dihydroxyprogesterone, 1 1a,17a-dihydroxyprogesterone, 0F STEROIDS AND PROCESS THEREFOR Josef Fried, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation 5 corticosterone, 9a-halocorticosterone (e.g., 9a-?uorocorticosterone), of Virginia cortisone, No Drawing. Filed Apr. 28, 1961, Ser. No. 106,178 9a-halocortisone, 12 Ciaims. (Cl. 260-3914) prednisone, This invention relates to the synthesis of steroids, and 10 9a-haloprednisone (e.g., 9a-?uoroprednisone), has for its object the provision of a new class of steroids 6u-halo-16a,17a-dihydroxyprogesterone (e.g., 6a-?uoro and the provision of a new process by which they are 16a,17a-dihydroxyprogesterone), made. It has been found that when a steroid having an un— 12u-halocortisone, hindered primary or secondary hydroxyl group is reacted 15 with a lower alkyl acetal of formaldehyde and formalde trihydroxylated and tetrahydroxylated steroids, such as hyde (or a source of formaldehyde) in the presence of hydrocortisone, a strong acid catalyst, a (lower alkoxy)methyl ether 9a-halohydrocortisones (e.g., 9a-?uorohydrocortisone derivative is formed. By a steroid having an unhindered and 9a-chlorohydrocortisone)prednisolone, hydroxyl group is meant a steroid containing a hydroxyl 20 9oa-haloprednisolones (e.g., 9u-?uoroprednisolone and group at one or more of the following positions: la, 9a-chloroprednisolone), 15, 2a, 2,8, 3a, 35, 40a, 4,8, 60:, 6,8, 70:, 75, 110:, 12a, 12a, 150a, 15,8, 1604, 16/3, 18 or 19. In addition, such steroids include ‘those of the androstane series containing a 1700 or 175 hydroxyl group and those of the pregnane series 25 containing a 20a, 20;? or 21 hydroxyl group. ‘If more than one unhindered hydroxyl group is pres ent in the steroid reactant and a poly-alkoxyrnethyl ether M-pregnene-l lor,17a,21-t1'lOl-3,20-d101'16, 9u-halo-16a-methylprednisolones (e.g., dexamethasone), 12a—halohydrocortisones (e.g., 12a-?uorohydrocortisone and 12a-chlorohydrocortisone), 12a-haloprednisolone (e.g., 12a-?uoroprednisolone, ‘ -6oc,12u-prednisolone), 16a-hydroxyhydrocortisone, 16a-hydroxycortisone, 16a-hydr0xyprednisolone, l6ot-hydroxyprednisone, 9a-halo-16a-hydroxyhydrocortisones (i.e., 9a-?uoro-16a hydroxyhydrocortisone, 9a-chloro-l6a-hydroxyhydro is formed, and assuming the hydroxyl groups involved display a difference in reactivity, the compound may be selectively hydrolyzed by treatment with an acid, such as a dilute mineral acid (e.g., aqueous sulfuric acid), or an organic acid (e.g., oxalic acid) to yield a less etheri ?ed product. Although the process of this invention may be utilized with any steroid containing an unhindered hydroxyl cortisone, 9u-bromo~16u-hydroxyhydrocortisone and 9a-iod0-16a-hydroxyhydrocortisone) , 9a-halo-16a-hydroxycortisones, 9a-halo-l6a-hydroxyprednisolone (e.g., triarncinolone), 9u-halo-16a-hydroxyprednisones, 12ot-halo-16a-hydroxyhydrocortisones (e.g., 12oz-?1101‘0~ 16a-hydroxyhydrocortisone), group, the preferred steroid reactants are those of the pregnane series, particularly those of the general formula 12a-halo-16a-hydroxycortisones (e.g., 12oc-Ch101‘O-16uc hydroxycortisone) , 12a-halo-16a~hydroxyprednisolones (e.g., 12a-?uoro 16a-hydroxyprednisolone), 12a-halo~l6ot-hydroxyprednisones, 6u-methyl-16a-hydroxycortisone, 6a-methyl-16a-hydroxyprednisolone, 6m-methyl-l6u-hydroxyprednisone, Zea-methyl-16a-hydroxyhydrocortisone, Za-methyl-16a-hydroxycortis0ne, Z-methyl-16a-hydroxyprednisolone, wherein the 1,2; 4,5; 5,6; and 6,7 positions are saturated or double-bonded; R is hydrogen, R’ is a-hydroxy, a-acyloxy, ?-hydroxy, or ?-aeyloxy or together R and R’ is keto; R" is hydrogen, R'” is u-hydroxy, a-acyloxy or 18~hydroxy, or together R" and R’” is keto; the X’s are the same or different and represent hydrogen, halogen, or lower alkyl, at least one X being hydrogen; Y is hy drogen, hydroxy or acyloxy; Y’ is hydrogen or methyl; Y" is hydrogen, halogon or methyl; Z is hydrogen or hydroxy; and Z’ is hydrogen, halogen, hydroxy, acyloxy, or methyl. Examples of such steroids of the pregnane series in clude: monohydroxylated steroids, such as Z-metyl- 1 6u-hydroxyprednisone, 2a,6<x-dimethyl-16a-hydroxyhydrocortisone, 2a,6a-dimethyl-16u-hydroxycortisone, 9a-halo-2-rnethy1-16a-hydroxy prednisolones (e.g., 60 Z-methyltriamcinolone), 9u-halo-6a-methyl-16a-hydroxyhydrocortisones (e.g., 9a-?uoro-6a-rnethyl-16u-hydroxyhydrocortisone), 9u-halo-6u-methyl-16a-hydroxyprednisolones (e.g., 6a-methyl triamcinolone) , 16a-hydroxy-6-dehydrocortisone, 16a-hydroxy-6-dehydrohydrocortisone, 16u-hydroxy-6-dehydroprednisolone, 9a-halo-16a-hydroxy-6-dehydroprednisolones, 1 la-hydroxyprogesterone, 1 15, 16a, I7a-trihydroxyprogesterone, pregnenolone, ZI-hydroxyprogesterone, 12a-hydroxyprogesterone, 15 a-hydroxyprogesterone A4-pregnene-20?-ol-3-one, 1 l-keto-l 6a,17a-dihydroxyprogesterone, 60a and G?-hydroxyprogesterone and l9-hydroxy progesterone; 1113,16a,17a-trihydroxy-l-dehydroprogesterone, 1 l-keto-l 6oz, 17¢x-dihydroxy-1-dehydroprogesterone, 9a-halo-1 13,16rx,17a-trihydroxyprogesterones (e.g., 9a-chloro-1118,16a,17a-trihydroxyprogesterone and 9OL-?L1OIO-1 118, 16a,17a-trihydroxyprogesterone) , 3,062,846 4 3 In addition the process of this invention is applicable 9a-halo-16a,17a-dihydroxy-l l-keto-progesterones (e. g., in treating steroids of the androstane series, particularly 9d'?uOl'O-16BC,17d-dlhydI'OXy-1 l-keto-progesterone) , those of the general formula 9a-halo-l 15,16a,l7a-trihydroxy-l~dehydroprogesterones (e.g., 9a-?l10rO-l 1 5, 1 611,17 a-trihydroxy-l-dehydro progesterone), 12a-halo-115,16a,17a-trihydroxyprogesterones (e. g., X A II B I I 12a-?uoro-ll5,16a,l7a-trihydroxyprogesterone), 12a-halo-l 15,16a, l7a-trihydroxy-l-dehydroprogesterones ( e. g., llu-?uoro-l15,l6n,l7ot-trihydroxy-l-dehydro progesterone), 10 21-halo-115,16a,17a-trihydroxyprogesterones (e. g., Zl-?uoro-l15,160‘,17a-trihydroxyprogesterone), 2l-halo-l 15,16a,l7a~trihydroxy-l-dehydroprogesterones, 9a,21-dihal0-115,1605,l7u-trihydroxyprogesterones (e.g., 90:,21-di?l101'0-1 15, l 6a,17a-trihydroxyprogesterone) , 15 9m,21-dihalo-6a-methy1-115,16u,l7a-trihydroxy-1 dehydroprogesterones, are as hereinbefore de?ned, and A is hydrogen or lower alkyl, B is hydroxyl or acyloxy, or together A and B 16a-hydroxy-l2a-(lower alkyl) -hydrocortisones (e.g., l6a-hydroxy-12a-methyl-hydrocortisone) , 16a-hydroxy-12a-(lower alkyl) -cortisones (e.g., 20 is keto. Examples of such steroids of the androstane series include: monohydroxylated steroids, such as testos terone 9a-?uoro-ll-ketotestosterone l2ot-?uoro-1l-keto 16a-hydroxy-12a-methylcortisone) , 16a-hydroxy-9u-(lower alkyl)-hydrocortisones (e.g., testosterone, l6ot-?uorotestosterone, lla-hydroxyandros 16whydroxy-9u-methylhydrocortisone ) , l6m-hYdl'OXY-90t-(1OWCI‘ alkyl)cortisones (e.g., 16u-hydroxy-9a-methyl-cortisone) , tenedione, etiocholanolone, androsterone and l9-nor 25 testosterone; dihydroxylated steroids, such as 9a-?uoro 115 - hydroxy - testosterone - 16a - hydroxy - testosterone, 16a-hYCl1'OXY-12ot-(IOWCI' alkyl ) prednisolone ( e. g., 15u-hydroxy - testosterone - lloc - hydroxy - 17a _ methyl 16a-hydroxy-l Za-methylprednisolone) , testosterone, and 19-hydroxy-testosterone; and trihydrox ylated steroids. 16a-hydroxy-[ l2oc-( lower alkyl) prednisones, 16a-hydroxy-9a-(lower alkyl) prednisolones (e.g., '16u-hydroxy-9a-methylprednisolone) , 30 16a-hydroxy] -9 a-( lower alkyl ) predniscnes, 12a-( lower alkyl)-115,1611,l7a-trihydroxyprogesterones (e.g., 12a-methyl-115,16a,17a-trihydroxyprogesterone), 9a-(l0wer alkyl)-115,16u,l7a-trihydroxyprogesterones (e.g., 9u-methyl-115,16a,17a[trihydroxyprogesterone), 12m-(1OW€1‘ alkyl)-11-keto-16a,17a]-dihydroxy of formaldehyde which may be used can be mentioned 35 methylal, ethylal, and the butylalcetal of formaldehyde. The reaction is conducted in the presence of a strong acid catalyst. Suitable acids include perchloric acid and progesterones, 12a-(lower alkyl)-A4l6-pregnadiene-115,16a,17a-trio1 p-toluenesulfonic acid. The alkoxymethyl ethers formed, which represent new 40 compounds of this invention, are useful as intermediates in the synthesis of steroids. Thus, the process of this 3,20-diones, 9a-( lower alkyl)-A4,6-pregnadiene-115,16a,17a-triol invention affords a method for protecting otherwise re active alcoholic groups during future chemical opera tions on other parts of the molecule utilizing either neu tral or alkaline reagents. As such, the products of this invention represent useful intermediates in steroidal syn— 3,20-diones, 12a-(lower alkyl)-A1'4-pregnadiene-1l5,16a,17a-triol 3,20-diones, 9a~( lower alkyl)-A1'4-pregnadiene-115,16a,17a-triol 3,20-di0nes, 12a-( lower alkyl) -A1-4-pregnadiene-16a, l7a-diol 3,11,20-triones, 9oc-( lower alkyl)-A1,4-pregnadiene-16a,l7a-diol-3,11,20 theses. In addition, those compounds which are alkoxy methyl ether derivatives of physiologically active steroids, contrary to what would be expected, retain their activity 50 triones, 3,20-diones, 12vt-(lower alkyl)-A1-416-pregnatriene-115,16a,17a-triol~ The following examples illustrate the invention (all temperatures being in eentigrade): 3,20-diones, IZa-(lower alkyl)-A4-pregnene-1la,l6a,17a,21-tetrol 3 ,20-diones (e.g., 12a-methyl-A4-pregnene-11a,16a, EXAMPLE 1 17a,21-tetrol-3,ZO-dione) , 17a,21-tetrol-3,20-dione) , 12ot-(lower a1ky1)-A1'4-pregnadiene-1 1a,16a, 1711,21 tetrol-3,20-diones, Qua-(lower alkyl)-A1'4-pregnadiene-11a,16a,17a,21-tetr01 3,20-diones, 12a-(lower alkyl)-A4-pregnene-11a,16a,l7¢z-triol-3 ,20 diones, 9ot-(lower alkyl)-A4-pregnene-11u,16a,17a-triol-3,20 diones, 12ot-(lower alkyl) -A114-pregnadiene—1 1m,16OL,17tZ-t1‘l0l— -3,20-diones, 9a-(l0wer alky1)-A1-4-pregnadiene-l 1oz,16a,17:x-tri01 3,20-diones and hence can be used for the same purpose as the parent compound. Thus, alkoxymethyl other derivatives of glucocorticoids, such as triamcinolone and hydro cortisone, possess glucocorticoid activity and ‘may be used in the treatment of rheumatoid arthritis. 9a-(lower alkyl)-A1-4-6-pregnatriene-1l5,16a,17a-diol 9oz-( lower alkyl)-A4-pregnene-l1m,16a,17o:,2l-tetrol 3,20-diones (e.g., 9u-rnethyl-A4-pregnene-1 111,1611, The formaldehyde used in the reaction can be sup plied as such (e.g., as gaseous formaldehyde) or pre pared in situ from a polymerized form of formaldehyde, such as trioxane. Among the suitable lower alkyl acetals 9a-(lower alkyl)-1 1-k8t0-16ot,l70t-dll'1yd1'OXy progesterones, wherein the 1,2; 4,5; and 6,7-positions are saturated or double-bonded, and R, R’, R”, R'”, X, Y’, Y”, and Z’ ‘ 3-Meth0xymethyIene-A5-Pregnene-35-Ol-20-Orze (it) To a suspension of 1 g. of pregnenolone in 50 ml. of methylal and 20 g. of trioxane is added with stirring .5 ml. of 70% perchloric acid. The suspension clears within 1/2 minute and the reaction is allowed to proceed for 20 minutes. Six ml. of 1 N sodium hydroxide is then added " and after dilution with water the methylal and trioxane are removed in vacuo. The residual suspension is ex tracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue (about 1.18 g.) upon re 70 crystallization from a small amount of acetone and mostly hexane furnishes the pure methoxymethylene de~ rivative of pregnenolone possessing the following prop erties: MP. about 102-104“; [a]D +19° (c., 1.32 chlf.); and Ila-esters thereof, particularly esters with hydro A1322‘ No OH band, 5.87, 6.02 (weak) I115 carbon carboxylic acids having less than ten carbon atoms, 75 3,062,846 5 6 Analysis.—Calcd. for Casi-13603 (360.52): C, 76.62; H, 10.07; OCH3, 8.65. Found: C, 76.54; H, 9.97; OCH3, 8.95. EXAMPLE 7 I6a,21-Bis-(Methoxymethylene) and 16a-M0n0-(Meth oxymethylene) Derivatives of Triamcinolone EXAMPLE 2 1 1 -Meth0xymethylene-1 1 a-Hydroxyprogesterone To a solution of 600 mg. of triamcinolone in 30 ml. of methylal and 24 g. of trioxane is added with stirring .3 ml. of 70% perchloric acid. The reaction is allowed to proceed at room temperature for 22 hours, after which To a suspension of 1 g. of llu-hydroxyprogesterone in 50 ml. of methylal and 20 g. of trioxane is added with stirring at room temperature .5 ml. of 70% perchloric time it is neutralized rapidly by the addition of sodium acid. The solution clears within 3 minutes and the re 10 bicarbonate solution. Water is added, the mixture ?ltered action is allowed to proceed for a total of 30 minutes. and the methylal and trioxane removed in vacuo. The Eight ml. of 1 N sodium hydroxide is added and the solution diluted with water. Evaporation in vacuo to resulting crystalline precipitate about (400 mg.) is ?ltered and after recrystallization from 95% alcohol furnishes the pure bis-(methoxymethylene) derivative of triarn remove methylal and trioxane leaves an aqueous suspen sion, which is extracted with chloroform, the chloroform 15 cinolone possessing the following properties: M.P. about washed with water, dried over sodium sulfate and evapo rated to dryness in vacuo. The residual material is taken up in 5 ml. of benzene and 5 ml. of hexane and chromat ographed on 20 g. of acid-washed alumina. Benzene 2l8—219°; [81D +34“ (0., 1.1chlf.); ANuiol mm 2.92, 5.81, 6.0, 6.14 and 622p, Analysis.—Ca-lcd. for C25H35OSF (482.53): C, 62.22; hexane 1:1 (1000 ml.) and benzene (500 m1.) elutes 20 H, 7.31; F, 4.02; OCH3, 12.87. Found: C, 62.05; H, 7.58; F, 4.14; OCH3, 14.67. crystalline material, which after one recrystallization Chromatography of 100 mg. of this material on 2 g. from acetone-hexane melts sharply at about 138-139“. of silicagel from a solution containing 4 ml. of chloro The material has the following properties: ]; +169° form and 16 m1. of benzene furnishes on elution with (c., 1.37 chlf.); chloroform-benzene (1:4) pure material-melting at about M153, 241 mu (e=16,000); A231?‘ N0 OH band, 5.91, 6.02, 224—225°. and 622p. . Analysis.-—Calcd. for Cal-13404 (374.50): C, 73.76; H, 9.15; OCH3, 8.28. Found: C, 73.50; H, 9.40; OCH3, over sodium sulfate and evaporation of the solvent in vacuo about 370 mg. of material which after crystalliza tion from 95% ethanol melts at about 188—200°. To 10.29. EXAMPLE 3 achieve complete puri?cation this material is dissolved 1 7-Meth oxymethylene-Testosterone Following the procedure of Example 2 but substituting in 4 ml. of chloroform and 8 ml. of benzene and chromat ographed on 7 g. of silicagel. Elution with mixtures of 1 g. of testosterone for the 1lot-hydrox'yprogesterone, 17 methoxymethylene-testosterone is obtained. ' Extraction of the aqueous mother liquors With chloro form furnishes after drying of the chloroform extract chloroform, benzene and 100% cholroform eluted about 43 mg. of material, which is discarded. This is followed by the 16-mono-methoxymethylene derivative of triam cinolone when the elution is continued with chloroform 1 EXAMPLE 4 21 -Meth0xymethylen e-Qa-Fluorocortisol containing 5% of acetone. The 16-mono-rnethoxymeth To a suspension of 200 mg. of 9a-?uorocortisol in 10 40 ylene derivative of triamcinolone obtained from 900‘ ml. ml. of methylal and 8 g. of trioxane is added with stirring of this eluant after three crystallizations from acetone .1 ml. of 70% perchloric acid. The reaction is allowed hexane has the following properties: M.P. about 220 to proceed at room temperature for 22 hours after which time dilute sodium bicarbonate and water is added. The methylal and trioxane are removed in vacuo and the resi due extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residue is taken up in 4 ml. of chloroform and 2 ml. of benzene and chromatographed on 4.2 g. of acid-washed alumina. 223°; [111323 +42“ (c., .52 chlf.); am“ 2.95, 5.88, 6.02, 6.18, and 6.23,. Analysis.—Calcd. for C23H31O7F (438.48): C, 63.00; max. H, 7.13. Found: C, 63.40; H, 7.39. EXAMPLE 8 l6a-Mono-Methoxymethylene Derivative of Triamcinolone Elution with chloroform-benzene 2:1 (250 ml.) elutes about 96 mg. of crystalline material, which on recrystal 30 mg. of 16,21-bis-(methoxymethylene) triamcinolone lization ?rst from acetone-hexane and then from 95% in 10 m1. of methanol and .34 ml. of 14% aqueous sul ethanol furnishes pure 21-methoxymethylene-9a-?uoro furic acid is heated at re?ux for 2 hours, the mixtures cortisol possessing ‘the following properties: M.P. about 55 neutralized with dilute sodium bicarbonate, the methanol 288-294"; [@1323 +43° (c., .65 chlf.); A113; 238 (e=15,700); A222‘ 2.91, 5.82, 6.0 and (811.) 6.15.11. Analysis.—Calcd. for C23H33O6F (424.49): C, 65.06; H, 7.83. Found: C, 64.92; H, 7.50. _ removed in vacuo and the residual suspension extracted with chloroform. The residue (about 20 mg.) after crystallization from acetone-hexane melts at about 219 222° ‘and possesses an infrared spectrum identical with 60 that of 16-methoxymethylenetriamcinolone obtained in Example 7. EXAMPLE 5 EXAMPLE 9 21~Méth0xymethylene-Cortisol 2] ~A'cetate of 16~Meth0xymethylenetriamciizolone Following the procedure of Example 4 but substituting 65 A solution of 33 mg. of 16-methoxymethylenetriam 200 mg. of cortisol for the 90t-?LlOI‘OCOI'tiSOl, 21-methoxy cinolone in 1 ml. of pyridine and .5 ml. of acetic anhy methylene-cortisol is obtained. dride is allowed to stand at room temperature for 18 EXAMPLE 6 hours. After removal of the reagents in vacuo the residual material is crystallized from ‘acetone-hexane. 21 -Methoxymethylene-M-Pregnene-I 7a,21 70 After two crystallizations the material has the following Diol-3,20-Dione properties: M.P. about 178—180°; [(111323 +32° (c., 1.02 Following the procedure of Example 4 but substituting 200 mg. of A‘t-pregnene-17og21-diol-3,20-dione for the 9m chlf.); ?uorocortisol, 21-methoxymethylene-M-pregnene-170:,21 A313; 239 mu (e=16,500); A231?‘ 2.92, 5.71, 5.79, 6.01, 6.18, diol-3,20-dione is obtained. . 75 and 6.23/1. ' 3,062,846 - o O 7 ample 11 and following the Procedure of the example, Analysis.-—Calcd. for C25H33O8F (480.51): C, 62.48; the corresponding 16,2l-bis-butoxymethylene) derivative H, 6.92. Found: C, 61.66; H, 7.34. is obtained. EXAMPLE 10 This invention may be variously otherwise embodied 16,21-Bis-(Methoxymethylene) 9a-Flu0r0-16a-Hydroxy within the scope of the appended claims. Prednisone What is claimed is: 1. (Lower alkoxy)methyl ether of a steroid of the A solution of 50 mg. of 16,21-bis-(methoxymethylene) triamcinolone in 1 ml. of pyridine is added to a suspen sion of 50 mg. of chromium trioxide in 1 ml. of pyridine. The resulting mixture is allowed to remain at room tem general formula 10 perature for 20 hours, after which time water and chloro form is added. The chloroform solution is Washed With water to remove excess pyridine, dried over sodium sul fate and evaporated to dryness in vacuo. The amorphous residue is dissolved in 15 ml. of benzene and chroma tographed on a column of 900 mg. of acid-Washed alu~ mina. Elution with 10% chloroform in benzene fur nishes material, which after recrystallization from ace tone-hexane melts at about 139-140"; 20 A331?‘ 3.03, 5.80, 6.01, 6.17 and 6.23;; wherein the 1,2; 4,5; 5,6; and 6,7 positions are saturated or double-bonded; R is hydrogen, R’ is ,B-hydroxy and together R and R’ is keto; R" is hydrogen, R’” is selected from the group consisting of a-hydroxy, wacyloxy and B-hydroxy, and together R" and R’ is keto; the X’s are each selected from the group consisting of hydrogen, halo gen and lower alkyl, at least one X being hydrogen; Y is selected from the group consisting of hydrogen, hy droxy and acyloxy; Y’ is selected from the group con sisting ‘of hydrogen and methyl; Y" is selected from the group consisting of hydrogen, halogen and methyl; Z is selected from the group consisting of hydrogen and hydroxy; and Z’ is selected ‘from the group consisting of Analysis.—-Ca1cd. for C25H33O8F (480.51); C, 62.48; H, 6.92. Found: C, 62.44; H, 6.98. EXAMPLE 11 16,21-Bis-(Methoxymethylene)-16a-Hydr0xy-9a F luorocortisol To a stirred suspension of 200 mg. of 16u-hydroxy-9a ?uorocortisol in 10 ml. of methylal and 8 g. of trioxane is added at room temperature .1 ml. of 70% perchloric acid. After 20 hours at room temperature all material has dissolved ‘and the reaction mixture is neutralized by the addition of sodium bicarbonate solution. Water is added and the methylal and trioxane removed in vacuo. The resulting crystals are ?ltered, the aqueous mother liquor is extracted with chloroform and the chloroform extract taken to dryness in vacuo. The combined crystals and material ‘from the chloroform extract (about 293 mg.) is dissolved in 2 ml. of chloroform and 8 ml. of benzene and chromatographed on 6 g. of si‘ricagel hydrogen, hydroxy, and methyl. 2. A process for preparing a (lower alkoxy)methyl ether of a steroid of the androstane and pregnane series having an unhindered hydroxyl group, which comprises reacting said steroid with a lower alkyl acetal of form aldehyde and formaldehyde in the presence of a strong acid catalyst selected from the group consisting of per chloric acid and p-toluenesulfonic acid. 3. The process of claim 2 wherein the formaldehyde is prepared in situ by the reaction of a polymer of form aldehyde with said strong acid. 4. A process for preparing a methoxymethyl ether of Chloroform-benzene 1:4 (‘200 ml.) elutes approximately 25 mg. of material which is discarded. The bulk of the material is eluted with chloroform-benzene 4:1 (800 ml.) and with chloroform (150 ml.). Recrystallization of this material from acetone furnishes the pure bis-(meth a steroid of the androstane and pregnane series having oxymethylene)-l6u-hydroxy-9a - ?uorocortisol possessing the following properties: M.P. about 213°; [@1323 +7l0° (0., .43 chlf.); an unhindered hydroxyl group, which comprises reacting said steroid with methylal and trioxane in the presence X113 239 mg (er-15,500), in,“ 2.92, 5.84, 5.99 and 6.15# ing of perchloric acid and p-toluenesulfonic acid. of a strong acid catalyst selected from the group consist 5. A process for preparing a 16,21-di-(lower alkoxy) methyl ether of a steroid of the pregnane series having hydroxyl groups in at least the 1611-, 17w and 2l-positions, which comprises reacting said steroid with a lower alkyl acetal of formaldehyde and formaldehyde in the presence of a strong acid catalyst selected from the group consist Analysis.-—C~alcd. for (1251-1370813 (484.54): C, 61.96; H, 7.69. Found: C, 61.82; H, 7.18. Similarly, by following the procedure of Example 11, but substituting an equivalent amount of the following steroids for the 16whydroxy-9tx-fluorocortisol, the indi cated product is formed: Steroid Reaetant ?a-Fluorotriamcinolone __________ .._ Product: l?éa‘l-lliis?nethoxy e v ?a-lt‘luorotriamcinolone. ing of perchloric acid and p-toluenesulfonic acid. 6. The process of claim 5 wherein the formaldehyde is prepared in situ by the reaction of a polymer of formal 60 dehyde with said strong acid. 7. The process of claim 5 wherein the di(lower alkoxy) l?a-?ydroxycortisol _____________ __ 16a-Hydroxyprednis010ne. (id-Methyl-1?a-hydroxycortisoL.___ ?a-Methyl-ltiwhydroxyeortisol. 16wllyrlroxyprednisolone ________ __ EXAMPLE 12 16,2] -Bis-(Etlioxymethylene)-16ot-Hydr0xy-9a Fluorocortisol Following the procedure of Example 11 but substitut 70 mg an equivalent amount of ethylal for the methylal, 16,21 - bis - (ethoxymethylene) - 16a - hydroxy - 9a ?uorocortisol is obtained. Similarly, by substituting an equivalent amount of the dibutylacetal of formaldehyde for the methylal in Ex 75 methyl ether is then hydrolyzed to a mono-ether com pound by treatment with a mineral acid. 8. A compound. of the formula CHzO CH2OCHs 0:0 3,062,846 9 1Q 9. A compound of the formula. 11. A compound of the formula CH3 <E=o --—0H nofl: Tocmoom 5 10 0113001120 ] O: 12. A compound of the formula 10. A compound of the formula CHRO CHQOCHB 15 OHQOCMQ ‘ 2o 47:0 I——-0H HOW/\Q / F No references cited.