DE1468900B - Process for debromination of 9 alpha-bromo-1 lbeta-hydroxy- or -1 lbetafluor-steroids or 5alpha-bromo-6-beta-hydroxy-steroids - Google Patents

Description

In the chemical synthesis of organic compounds it is often necessary to remove halogen from an organic halide without undesired attack elsewhere in the molecule. For example, in previous attempts at the reductive dehalogenation of halohydrins found that the hydroxyl group was removed to form an unsaturated product. This Problem occurs particularly often in the synthesis of complicated carbocyclic structures, such as at steroids and alkaloids, where usually a number of other groupings, such as keto, acetyloxy, hydroxy, alkoxy or carboxy groups and the like are present and an attack on these groups is undesirable.

A process for the debromination of 9a-bromo-11j8-hydroxy- or -11 / J-fluoro-steroids has now been established or 5a-bromo-6 /? - hydroxy steroids using low-valent metal salts as reducing agents found, which is characterized in that one with a Cr (II) -, Fe (II) -, Ti (III) -, Tl (I) - or Sn (II) salt reduced in the presence of a hydrogen donor in an inert polar solvent.

The process according to the invention generally gives relatively good yields and selectivity is good.

The reducing agent is preferably a chromium (II) salt of an organic carboxylic acid, preferably a lower (C ₁ _ ₆₎ alkanoic acid such as butyric acid, propionic acid, or preferably acetic acid, however, can have substituents such. B. Halogen atoms. Chromium (II) acetate is particularly suitable.

Debromination of bromohydrins according to the invention is of particular interest in the art of steroid synthesis, as the reaction proceeds easily without eliminating the neighboring hydroxy group. In a corresponding manner, an adjacent fluorine atom also remains unaffected.

A particularly interesting class of steroids which can advantageously be subjected to the process according to the invention are the 1 lβ-hydroxy-J ⁴ -3-ketosteroids, which have a bromine atom in the ^ / position. l ⁴ -3-ketosteroids with an oxygen function in the 11-position are common among the physiologically active steroids, e.g. B. cortisone, hydrocortisone, prednisone, prednisolone, 16-methylprednisolone, 16 / f-hydroxyprogesterone. In the synthesis of these compounds it is often economically advantageous to start from more readily available steroids which are unsubstituted in the 11-position and then to introduce the desired oxygen function. Many of the methods heretofore proposed for introducing an 11-oxygen function into the steroid molecule are particularly troublesome and require a large number of steps.
It has been found that it is difficult to employ reactions which occur selectively at the 11-position, and other functions in the molecule have usually had to be protected beforehand and the protecting groups removed afterwards. In particular, it has

ίο so far proven difficult to introduce an 11-hydroxy substituent in the ^ -configuration, and methods of converting the more accessible IIIa-hydroxy steroids are also cumbersome. The inventive method allows easy conversion of the 9 "bromo-ll / i-hydroxy-l ⁴ -3-keto steroids in their analogs having hydrogen at the 9a-position without appreciable elimination of LLSs-hydroxy group.

The process according to the invention also permits the production of those which are unsubstituted in the 5'-position 6 / i-Hydroxy steroids from the easily accessible 5 «, 6 /? - bromohydrins. Such 6 / ^ - hydroxy compounds are for example as intermediates in the,. Manufacture of 19-nor- or 19-hydroxysteroids valuable.

Debromination of the above 9 ″ -Bromo-llp'-hydroxy steroids it has been found to provide other compounds to a relatively small extent. For example, in addition to the desired product, the corresponding 9 (1 l) -Dehydro-steroid is performed Elimination of both bromine and hydroxyl as well as another llß-hydroxy compound, the one 5,9-cyclo compound is formed. These products can be represented by the following sub-formulas will:

1 ljS-Hydroxy-J ⁴ -3-ketosteroid

9 (1 L) -Dehydro-zl ⁴ -3-ketosteroid
HO

ll /? - Hydroxy-5,9-cyclo-3-ketosteroid

It has been found that different reaction conditions have different proportions supply these products, and it is not difficult to choose conditions that allow the formation of the desired Favor the product at the expense of the other two substances.

3 4

The reaction according to the invention is also carried out using solvents. The main consideration at Valuable as it is the manufacture of llp'-fluoro and the choice of a solvent is the solubility of the 6 / i-fluoro compounds with hydrogen on the 9u steroid parent compound. This allows solution and 5a positions. Such steroids are new agents, for example an alcohol, ketone, cyclic compounds, and generally show improved bio-ether or a substituted amide or sulfonic activity compared to their non-fluorosolvent, methanol, ethanol, acetone, methyl-containing analogues. The invention therefore also relates to ethyl ketone, dioxane, tetrahydrofuran, and dimethyl form, the production of amide, dimethylacetamide, and dimethyl sulfoxide which are unsubstituted in the 9u position. Pro-11 / i-fluoro steroids and solvents which are unsubstituted in the 5 <z position, such as dimethylacetamide, diten 6/3 fluoro steroids. io methylformamide and dimethyl sulfoxide are preferred

As mentioned above, the hydrogen atom that is attached. : ■

replaced the bromine atom, supplied by a substance, the reaction temperature does not seem to be critical

which is present in the reaction mixture and free water and can be between the freezing point and the

material radicals available. Although no fixed boiling point of the reaction medium, for example

interpretation to be made to any theory, it is 15, between about -50 and 100 ⁰ C. Appropriate

but assumed that the reaction is caused by a but the reaction temperature is about room temperature

introductory transfer takes place at which the temperature.

Eliminates halogen and reduces the valency of the- If the reducing agent is a chromium (II) salt

the metal or metal ion is increased by that of a carboxylic acid, this can expediently by

to deliver the necessary electron, and a free radical 20 reaction of chromium (II) chloride with a salt

at the originally flttrch the eliminated halogen of such an acid, z. B. an alkali acetate,

atom occupied position is generated. Then preferably in an inert atmosphere to avoid

Hydrogen by converting a hydrogen into oxidation and preferably into water

atoms are prepared from a suitable solvent in the reaction mixture or ethanol,

existing substance delivered. Such water- 25 The chromium (II) salt of the organic acid falls normally

Material donors are H ₃ PO ₂ , hydrides, such as triaryl, and can then be from the reaction

silanes or triaryl tin hydrides, 1,4-dihydroaroma mixture, separated off and preferably dried

table compounds such as 1,4-dihydrobenzene and are.

l-Benzyl-l, 4-dihydronicotinamide and especially chromium (II) chloride is expediently by reducing

Thiols of the general formula R - SH. 30 tion of chromium (III) chloride with amalgamated zinc

For example, the group R in the thiol can be dust-produced.

an aliphatic, araliphatic or aromatic The melting points, which are on a Koflerbank group the substituents, if desired, as was correct, are uncorrected. If nothing else Hydroxy, ether, thioether, keto, carboxyl, are indicated, the ultraviolet spectra are in methaester May have carboxyl groups and the like. 35 nol and the optical rotations in chloroform are unsubstituted Hydrocarbon groups are true however. The infrared spectra were preferred using For example, lower alkyl groups or an Infracord Model 137 spectrophotometer unsubstituted aryl groups such as phenyl groups. definitely.

It has been found that in Example 1 according to the invention

reductive dehalogenation reaction thiols derive from 40 chromium chloride
prey on desired dehalogenated analogs

greatly improve, largely being converted into di-amalgamated zinc dust by 10minusulfide, RSSR. This latter term mixing of 30 g of zinc dust, 1.2 g of mercury determination suggests the assumption of the postulated silver (II) chloride, 30 ml of water and 6 nil concentration mechanism of free radicals, since the transferred hydrochloric acid and Decanting of the supernatant transfer of R - SH into the disulfide normalizing liquid. A solution of 25 g requires wise oxidizing conditions. Chromium (III) chloride hexahydrate in 100 ml fresh from the steroid series can have the starting compound boiled deionized water and 6 ml concen-trated substituents, for example in 3-, 16-, 17-positional hydrochloric acid, with stirring to the above position or be unsaturated, for example 50 amalgamated zinc dust under carbon dioxide at the C-1 (2) position. Added to substituents, the pre-sphere. The reduction (which can take about 2.5 hours, includes, for example, hydroxy, which takes) was allowed to proceed in this inert atmosphere from keto, methylenedioxy, acyl, alkyl, alkynyl groups,
and fluorine atoms, and in particular the group can chromium (II) acetate
pation at C-17 be one of the groupings 55

result in physiological activity, for example a light blue colored solution of chromium (II) chloride

Keto, acetyl, 8-acetyl-a-hydroxy group. Reactive was stirred into a solution of 50 g of Na-

Groups, such as keto groups, can contain desired trium acetate crystals in 100 ml of deaerated and deionized

protected if necessary, for example by over- watered water kept under carbon dioxide

guided tour in ketal groups. The 16 positions can be added to 60, whereupon quickly red chromium (II) -

advantageous alkyl groups, such as methyl groups, precipitated in the acetate. Care must be taken that

have α or / S configuration. There is no air admission at this stage. To the Filtra

The reducing agent is preferably in the ion, the following apparatus has proven to be very useful

at least stoichiometric amounts, based on the proven: The slurry of chromium (II) acetate

Steroid, and advantageously in excess. It can be quickly transferred to a sintered glass filter,

nen for example 1 to 10 moles of reducing agent, which is provided with an airtight rubber stopper

preferably about 5 moles can be used. would. The plug was with inlet and outlet

The reaction takes place in an inert polar discharge tube for carbon dioxide and a dropping funnel

fitted. During the transfer, the filtration and washing and drying the chromium (II) acetate, dry carbon dioxide was released from the Filter passed. By carefully adjusting the carbon dioxide rate, weak suction can be achieved applied to the filter. The product was deaerated several times with small portions and deionized water until the wash waters were free of chloride ion, which was achieved by silver nitrate solution has been checked. Drying was accomplished by washing with a little absolute ethanol (preferably distilled in a nitrogen atmosphere) and then carried out with ether, the last traces of ether being carried by the stream of dry Carbon dioxide (3 hours) were removed.

The brick-red chromium (II) acetate powder must be completely dry in order to be sufficiently stable Deliver the product before it is exposed to air, as it is very quickly oxidized when wet. The (titrimetrically determined) purity of the freshly prepared Materials varies from 75 to 85%. The yield was 12.5 g or 75.5% of theory, based on chromium (III) chloride hexahydrate. The content drops in a few days, even if the product is kept in a desiccator previously filled with carbon dioxide.

9a-Bromo-11/5-hydroxysteroids were in dimethyl sulfoxide debrominated by treatment with chromium (II) acetate and n-butyl mercapten. The yield of entbrominated Connection varies from 75 to 80%. A typical experiment is shown below:

Reductive dehalogenation of
9 "-Bromo-1β-hydroxyprogesterone

To a solution of 0.5 g of 9a-bromo-lß-hydroxyprogesterone and 1 ml (about 7.5 mol equivalents) of n-butyl mercaptan in 40 ml of dimethyl sulfoxide (Matheson, Coleman and Bell, not further purified) 1.35 g (74%, 5 molar equivalents) Chromium (II) acetate was added at room temperature with stirring and under carbon dioxide. The stirring continued overnight. Carbon dioxide was introduced for about 10 hours. The reaction mixture was then poured into ice water and extracted with methylene chloride. The extract was made with Washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvent in vacuo gave crude crystalline 11/3 hydroxyprogesterone, when treated with a small volume of ethyl acetate prisms (0.3 g, 75%) from

Mp = 182-185 ⁰ C gave (Lit. mp = 186-188 ° C). Chromatography of the concentrated mother liquors on 3.5 g of aluminum oxide washed with acid and eluting with methylene chloride containing 0.4% methanol gave a further 24 mg of the compound with a melting point of 165 to 180 ^° C. The total yield was 0.324 g (80.4%).

Example 2

Example 1 was repeated using different solvents. The results are in the Table I below:

Table I.

solvent n-butyl mercaptan ^ "" »- Progesterone 11 / S-hydroxyprogesterone 5,9-cyclo-
connection Tetrahydrofuran (70 ml)
(anhydrous)
the same
Benzene (anhydrous) 100 ml
Benzene (anhydrous) 100 ml
DMS (not distilled) 40 ml 5 moles
5 moles
5MoI
10 moles no reaction
no reaction 72
72.5
no reaction
no reaction
69 -

In a blind experiment, 1 lß-hydroxyprogesterone was treated under identical conditions, the recovery of the starting material was about 85%.

Example 3

Example 2 was using 10 moles of thiophenol instead of n-butyl mercaptan and 940 ml of DMS repeated as a solvent. 11/3 hydroxyprogesterone was obtained in 75% yield, and diphenyl disulfide was also isolated (chromatographic).

The experiment was carried out using tetrahydrofuran as the solvent in both light and also repeated in the dark, the results are given in Table II below:

Dry THF steroid Table II yield
Diphenyl disulfide 1 ί, S-hydroxy
progesterone attempt 70 ml
70 ml 500 mg
500 mg Thiophenol 230 mg (88%, based on
the steroid)
113 mg (43%, based on
the steroid) 73%
20% 1 (light)
2 (dark) 875 g
875 g

Example 4

Example 1 was repeated using various thiols as hydrogen donors. The results are shown in Table III below.

Table III

DMS Mercaptan Yield (%) attempt an lljS-hydroxy- 40 ml Butyl mercaptan progesterone 1 (7.5 molar equivalent) 80 30 ml Ethyl mercaptan 2 (5 molar equivalents) 67 40 ml Methyl mercaptan 3 (about 30 molar equi 81 valentine)

B e rs-p i e 1 5

Example 1 was made using 9 "-Bromocortisol Acetate and 7.5 molar equivalents of n-butyl mercaptan repeated, with a yield of 77% Cortisol was obtained.

Examples

Example 5 was made using 9 "-Bromocortisol bismethylene dioxide repeated to give a yield of 80% cortisol bismethylene dioxide.

B e i s ρ i e 1 7

Reduction of 9RA-bromo-ll ^/: hydroxyprogesterone in dimethyl sulfoxide with chromium (II) acetate

To a solution of 500 mg of bromohydrin in 40 ml of DMS containing 1.3 g (10 molar equivalents) of thiophenol, 1.3 g (5 molar equivalents) of 80% chromium (II) acetate were added at room temperature under carbon dioxide. Stirring was continued overnight. Carbon dioxide was introduced for 9 hours. The reaction mixture was poured into water and extracted with methylene dichloride. The extract was shaken with 100 ml of dilute sodium hydroxide solution (10%) for 15 minutes, washed with water and dried. Chromatography of the product (about 1.4 g) on 35 g of aluminum oxide in methylene chloride, which contained increasing amounts of methanol, gave firstly 1 g of bisphenyl disulfide with a melting point of 59 to 61 ° C. and secondly 11 / I-hydroxyprogesterone. After recrystallization from ethyl acetate, this compound formed prisms with a temperature of 180 to 188 ° C, [a] S ⁵ = + 215.4 ° (c = 0.76 in acetone), l _max = 242 πΐμ (ε 16000), ν ™ = 3500 (st), 1700 (st), 1655 (s.st), 1625 (m) cm " ^1. The yield was 300 mg (74%). The product was identical to an authentic sample (mixed melting point, IR spectrum ); F. = 186 to 188 ° C [α] ff = + 217 ° (acetone), X _max = 242 πΐμ (log e = 4.26).

Examples
17,20,20,21 -Bismethylenedioxycortisol

Under the conditions described for the reduction of 9'-bromo-lß-hydroxyprogesterone in Example 1, 571 mg of 17,20,20,21-bismethylenedioxy 9a-bromocortisol in 60 ml of DMS containing 1.05 ml (7.5 Mole equivalent) of n-butyl mercaptan was treated with 1.26 g (about 5 mole equivalents) of 79% chromium (II) acetate to give a crude product which, after treatment with ethyl acetate, contained 318 mg of 17,20,20,21-bismethylenedioxycortisol as prisms from F. = 229 to 237 ⁰ C, [«] ?? = + 27.5 ° (c = 0.87), ?. _max = 242 ma (f = 15,600), ι · ** = 3600 (a), 1675 (s.st.), 1625 (m) cm " ^1. The product was identical to a sample (mixed melting point, IR- Spectrum), m.p. = 217 to 222 ° C., [a] _D = +26. The mother liquor, when concentrated and chromatographed on aluminum oxide, gave a further yield of 69 mg with a m.p. = 215 to 230 ° C. The total yield was 387 mg (81%).

'5 B e i s ρ i e 1 9

Cortisol-21-acetate

602 mg of 9a-bromocortisol-21-acetate in 35 ml of DMS containing 1 ml of n-butyl mercaptan were treated as in the previous example with 1.4 g (about 5 molar equivalents) of 74% chromium (II) acetate. Recrystallization of the crude product from methanol gave 387 mg (77%) of cortisol-21-acetate with a temperature of 205 to 210 ° C., ["]" = + 157.7 ° (c = 0.66), l _max = 241 πΐμ (, · ■ 16 000), r KBr = 3500 (st.), 3400 (st), 1750 (st), 1725 (st.), 1630 (s.st), 1235 (st.) Cm " ¹ , das was identical to an authentic sample (mixed melting point and IR spectrum), 216 to 218.5 ° C, [«] §" = + 156 ° (c = 0.36), / 5, 'ix = 241 ηΐμ (ε 16 700). Chromatography of the concentrated mother liquor on aluminum oxide and elution with methylene dichloride containing 0.5% methanol gave 6 mg of a second crop of mp = 202-205 ° C. The total yield was 393 mg (78%).

Example 10

Debromination of 9a-bromoprednisolone-21-acetate 40

(a) 10 g of prednisolone 21 acetate were ^{heated for 1} _1/2 hours on a steam bath with 80 ml of freshly distilled dimethylformamide, 10 ml of dry pyridine and 6.6 ml of methanesulfonyl chloride. The cooled reaction mixture was poured into dilute sodium bicarbonate solution and the product (7 g) was filtered off. Chromatography of this product on 210 g of silica gel in methylene dichloride and eluting with methylene dichloride in increasing amounts

Methanol contained, gave 4.37 g (46%) ^ - ^ "- Pregnatrien-17a, 21-diol-3,20-dione-21-acetate from M. = 210 to 221 ° C, [α] f = +50, 7 ° (c = 1.3), A _max = 238 πΐμ (ε 15 100), λ j *** = 3500 (m), 1750 (st.), 1725 (st.), 1660 (s.st) , 1620 (st), 1605 (st.), 1240 (st.) Cm " ¹ .

2 g of the above compound in 200 ml of purified dioxane, the 20 ml of aqueous 0.5N perchloric acid and Containing 10 ml of water were treated with 1 g of N-bromoacetamide. After stirring for 1 hour treated with dilute aqueous sodium sulfite solution and extracted thoroughly with methylene dichloride. The extract was washed with dilute sodium bicarbonate solution and with water, dried and evaporated in vacuo. Recrystallization from acetone gave 1.6 g of the 9,11-bromohydrin with a melting point of 183 - 65 to 189 ° C (decomposition) in the form of prisms.

[α] »= + 142 ° (c = 1.06 in dioxane), l _max = 242 ηΐμ (ε = 13 830), / Lt '= 3510 (m), 3400 (m), 1740 (m), 1720 (st), 1665 (s.st), 1620 (m), 1605 (s.).

209528/589

(b) Prednisolone 21-acetate

600 mg of the above bromohydrin in 35 ml of DMS containing 1 ml (about 7.5 molar equivalents) of 1-butyl mercaptan were mixed with 1.4 g (about 5 molar equivalents) of 74% chromium (II) acetate according to the general procedure described treated. Recrystallization of the product from methylene dichloride-hexane gave 350 mg of prednisolone-21-acetate, mp = 210 to 220 ⁰ C, [a] f = + 111 ° (c = 0.72 in dioxane), A = 242 _MFLX ΐημ _(f = 14 550) ,, · Lt ¹ = 3500 and 3400 (not resolved), 1755 (st.), 1725 (st.), 1650 (s.st.), 1590 (S-St) Cm " ¹ , the with an authentic sample was identical [mp = 237-239 ⁰ C (decomposition) [a] S ⁵ = 116 ° (dioxane) _λ ηαχ = 242 m.mu. (e = 15,000)]. a second crop of 20 mg of F . = 217 to 222 ° C. was obtained from the mother liquor. The net yield was 74%.

A corresponding reduction using methyl (3 ml, about 43 molar equivalents) afforded 380 mg (76%) of the prednisolone acetate mp = 212-220 ⁰ C [ «] ?? ^. + 111 ° (c = 0.66 in dioxane).

Example 11

Reduction of 9 "-Brom-II / ^ - hydroxyprogesteron with Chromium (II) acetate in DMS, the following compounds

contained
(a) 1,4-cyclohexadiene

500 mg of the bromohydrin in 30 ml DMS, which contained 2 g (about 20 molar equivalents) 1,4-cyclohexadiene, were treated with 1.4 g (about 5 molar equivalents) of 70% chromium (II) acetate according to the general procedure treated. Chromatography of the reduction product on 20 g of aluminum oxide and elution with methylene dichloride containing increasing amounts of methanol (0.40%) gave 268 mg (66%) 11 / i-Hydroxyprogesterone from M. = 180 to 185 ° C, the (F. and IR spectrum) was identical to an authentic sample.

(b) triphenylsilane

500 mg of the bromohydrin in 35 ml of DMS containing 1.5 g (about 5 molar equivalents) of triphenylsilane were treated with 1.4 g of 70% chromium (II) acetate as above. The chromatography of the crude product (about 1.7 g) of 40 g of aluminum oxide and eluting with methylene dichloride, the increasing amounts Containing methanol gave the following fractions:

1. predominantly triphenylsilane, 1.14 g, m.p. = 44 to 45 ° C, > ■ S ⁰¹ = 2140 (s. St.), 1590 (s.), 1425 (s. St.), ¹

2.1 l /? - hydroxyprogesterone (163 mg, 40%) F. = 165 to 18O ⁰ C.

3. ll /? - Hydroxy-5,9-cyclopregnan-3,20-dione (97 mg, 24%) F. = 130 to 143 ° C.

(c) triphenyltin hydride

Triphenyltin hydride was made by reducing triphenyltin chloride with lithium aluminum hydride manufactured.

500 mg of the bromohydrin in 35 ml of DMS containing 3.2 g (7.5 molar equivalents) of triphenyltin hydride was treated with 1.4 g of 70% chromium (II) acetate. The crude product was allowed to stand with about 10 ml of methylene dichloride. About 1 g of hexaphenyl tin with a ^{temperature of 237 to 240 °} C. was filtered off. Chromatography of the filtrate on 35 g of aluminum oxide yielded the following main fractions:

1. A mixture of hexaphenyl tin and probably triphenyl tin bromide (1.45 g) dated

M.p. = 95 to 215 ° C;

2. a mixture of 11 / i-hydroxyprogesterone and Trace organotin compound (eluted with 0.5% methanol), about 300 mg.

The latter gave on repeated chromatography and crystallization from ethyl acetate 261 mg (65%) Π / Ϊ-Hydroxyprogesterone from M. = 182 to 188 ° C.

B e i s ρ i e 1 12 3 / ^ - acetoxy-6 / miydroxyandrostan-17-one

A solution of 522 mg of S 6 /? - hydroxyandrostan-17-one in 35 ml of DMS and 1.5 ml (11 molar equivalents) of n-butyl mercaptan was supplemented with 1.4 g (5 molar equivalents) of 73% chromium (II) acetate the general procedure. Chromatography of the crude product on 20 g of acid-washed alumina _t in methylene dichloride yielded 277 mg (65%) of the entbromierten steroid in the form of prisms, mp = 165-182 ° C. For the analysis, it was recrystallized from ethyl acetate. The result was hexagonal prisms from F. = 183 to 184 ° C IaYo ⁵ = + 40.9 ° (c = 1.07),,. ^ = 3600 (st), 3000 (st), 2900 (st), 1750bis 1725 (s.st), 124 ¹

Analysis: C ₂₁ H ₃₂ O ₄ .

Calculated ... C 72.36, H 9.29, 0 18.37%; found .... C 72.72, H 9.17, O 18.33%.

Example 13

11 / i-Fluor-J ⁴ -pregnen-17 ", 21-diol-3,20-dione-21-acetate

600 mg of 9 ″ -Bromo-II / i-fluoro-J ⁴ -pregnen-17a, 21-diol-3,20-dione-21-acetate in 50 ml of DMS, which is 2 ml (14.8 molar equivalents) of n-butyl mercaptan were treated with 1.4 g of 70% chromium (II) acetate according to the general procedure. After the usual work-up, about 500 mg of a crystalline residue with a melting point of 185 to 193 ° C. were obtained. This contained no bromine (Beilstein). A thin-layer chromatogram (19: 1 methylene dichloride-methanol as the mobile phase) showed essentially one component (R _f = 0.57). Recrystallization from ethyl acetate gave 474 mg (94%) of prisms, mp = 196-204 ⁰ C. The analytical sample had a melting point 204-206 ° C (Vp ₀ ⁴ = + 142.8 ° (c = 0.57) , X _max = 240 ΐημ (ε = 15 360), ν ™ = 3300 (wide), 1750 (st), 1725 (st), 1665 (st), 1620, 1240 (st) cm " ¹ .

Analysis: C ₂₃ H ₃₁ O ₅ F.

Calculated ... C 67.95, H 7.69, F 4.68%;

found .... C 67.09, H 7.56, F 4.95%. 6o

Chromatography of the concentrated mother liquor on 4 g of aluminum oxide in methylene dichloride, which contained 0.6% methanol, and recrystallization from ethyl acetate-hexane gave 10 mg of prisms with a temperature of 190 to 197 ° C, ΐ'ίίϊί " ¹ = 3510 (m) , 1730 (m), 1705 (st), 1675 (st), 1620 (s.) Cm " ¹ .

The infrared spectrum was different from that of the main product.

containing 50 ml of unpurified tetrahydrofuran, distilled. 2300 g (5.3 mmoles) of 16a-methylpregna-1,4, 9 (11) -triene -17a, 21-diol-3.20-dione-21-carbethoxylate and 835 g (6.0 mmoles) of N-bromoacetamide in separate tetrahydrofuran solutions were carefully poured into the reaction flask. The solution was magnetically stirred for 1 hour in the dry ice bath and 2 hours in an ice water bath. Then it was slowly and carefully poured into 21 ice-cold 10% sodium carbonate solution with stirring. The mixture was extracted with methylene chloride. The organic solution was washed with water, filtered and evaporated under reduced pressure. The residue was crystallized from acetone / cyclohexane. The yield was 2.325 g (83%) with a melting point of 195 to 199 ° C. (decomposition). Recrystallization of a small portion to a constant melting point (205 to 206 ° C [decomposition]) provided a pure sample (solvated). It was heated to constant weight at 100 ° C under vacuum. [u] o ^s = + 104 °, * £ * = 1610, 1625, 1665, 1730, 1750, 3000, 3700cm- ¹ , / ^ _x ⁰ "= 240 ΐημ (B 000).

Analysis: C ₂₅ H ₃₂ O ₆ BrF.

Calculated ... C 56.92, H 6.07, Br 15.19, F 3.61%; found .... C 57.00, H 5.99, Br 14.88, F 3.59%.

(b) Reductive debromination of

9a-bromine-l l / J-fiuor-loa-methylpregna-l ^ dien-

17a, 21-diol-3,20-dione-21 -carbethoxylate

1.910 g of 9a- bromine-1 3-fluorine- 16 ”-methylpregna-1,4-diene-17 <z.21-diol-3.20-dione-21-carbethoxylate were dissolved in 35 ml of dimethyl sulfoxide, and the solution became freed of oxygen by bubbling through a vigorous stream of carbon dioxide with magnetic stirring. After one hour, 5.0 ml of n-butyl mercaptan and 4.6 g of chromium (II) acetate were added. The carbon dioxide inlet tube was removed and the flask was sealed and stirred overnight. The purple solution was poured into 500 ml of dilute (0.1 saturated) aqueous sodium chloride solution. The steroid was extracted with methylene chloride and washed well (five times) with water. The residue obtained after evaporation of the organic solvent was chromatographed on 50 g of acid-washed aluminum oxide. Benzene, methylene chloride, then 0.4% methanol in methylene chloride were used as eluents. The latter eluent eluted 1.4 g of steroid in three fractions which, when examined by thin layer chromatography, appeared to be only slightly contaminated. Crystallization from methanol gave 750 mg (46%) of material with a melting point of 178 to 181 ° C. The use of acetone / cyclohexane resulted in less material and of poor quality. It was recrystallized from methanol to constant melting point 176-178 ⁰ C. [>] ?? = + 80 °, /. JJf _x ⁰ "= 242 πΐμ (14700), λ ** = 1600, 1620, 1660, 1730, 1765, 3000, 3500 cm

-1

Analysis: C ₂₅ H ₃₃ O ₆ F.

Calculated ... C 66.96, H 7.37, F4.24%; found .... C 66.76, H 7.32, F 3.97%.

, Example 18

Use of 1.-BenzyJTl, 4-dihydronicotinamide as a hydrogen donor in the reductive

Standard debromination

10 mg of a deoxygenated dimethyl sulfoxide solution of 250 mg of 9a-bromo-llß-hydroxyprogesterone were with 340 mg dihydronicotinamide (prepared according to D. Mauzerall and F. H. W e s theimer, J. Am. Chem. Soc, 77, 2261 [1955]) and 750 mg of chromium (II) acetate and treated overnight stirred under a carbon dioxide atmosphere. After standing for an additional 24 hours, it was diluted into 250 ml (0.1 saturated) aqueous sodium chloride solution poured. The organic material was washed with methylene chloride extracted, which in turn was washed with water, 1 η-hydrochloric acid and three times with water would. The solvents were removed under reduced pressure. The residue (225 mg) showed one major component and one minor component when tested by thin layer chromatography with the correct polarity (Rf = 0.3 with 3% methanol in methylene chloride). Chromatography on 11 g Alumina washed with acid gave 165 mg of a polar fraction (with 0.5% methanol in Methylene chloride eluted), which was crystallized from ethyl acetate, yielding 135 mg (67%) of pure IIβ-hydroxyprogesterone from m.p. = 188 to 192 ° C. The infrared spectrum (KBr) was identical to that of one authentic sample.

Example 19

Reductive debromination of 5a-bromocholestane-3 / ?, 6 /? - diol-3-acetate

25 ml of dimethyl sulfoxide were freed of oxygen by bubbling carbon dioxide through them for 1 hour. 0.78 g of chromium (II) acetate, 1.0 ml of butyl mercaptan and 275 mg of 5a-bromocholestane-3 / ?, 6 // - diol-3-acetate were admitted. The flask was sealed and stirred for 3 hours.

The usual work-up was followed by chromatography on aluminum oxide washed with acid and recrystallization from cyclohexane, yielding 155 mg (67%) 6/3-hydroxycholesteryl acetate of m.p. = 162 to 165 ° C, whose infrared spectrum (KBr) was identical to that of an authentic sample.

Claims (1)

Claim: Process for the debromination of 9a-bromo-11 /? -Hydroxy- or -11 / 3-fluoro-steroids or 5h-bromo- 6ß- hydroxy-steroids using low-valent metal salts as reducing agents, characterized in that one with a Cr (II) -, Fe (II) -, Ti (III) -, Tl (I) - or Sn (II) salt reduced in the presence of a hydrogen donor in an inert polar solvent.