DE2226067C3 - Process for the preparation of 16beta-methyl-17alpha-hydroxy-1,4,9 (11) pregnatriene-3,20-dione (1) - Google Patents

Description

As the 16 / y-MethyI-9a-fluorprednisolon, in general Called betamethasone, and its derivatives pharmacologically the most effective corticosteroids are, from a medical point of view, they are considered to be the most important connections in their group.

Various publications relate to their production (see, for example, German Offenlegungsschrift 20 59 050). For the process of U.S. Pat. No. 3104,246, 16 / i-methyl-17a-hydroxy-1.4,9 (11 ) -pregnatriene-3,20-dione of the formula

45

(D

55

used as an intermediate in the manufacture of betamethasone. The manufacture of this intermediate product is also described in this patent.

The present invention is based on the object of producing 16 / i-methyl-17 »j-hydroxy-1,4,9 (11) -pregnatriene-3,20-dione by eliminating some previously required for the production of this intermediate product To simplify procedural steps. Compared to the procedures of the USA patent specification 3104 246, the process of the present invention also eliminates the need for reacetylation. The inventive The process is based on chemical reactions known per se, but on new compounds to be applied in a new order via intermediates, most of which new and described for the first time below. These connections are also used to manufacture other steroids than betamethasone are valuable, so that the present invention can be used widely the steroid synthesis opened. In other words, the present invention describes a new and independent one Process for the production of steroids or betamethasone and its 21-acylates.

The object on which the present invention is based results from the claim. The sequence of reactions adopted according to the invention enables the desired 16 / f-methyl.17u-hydroxy-1,4,9 (II) -pregnatriene in comparison to all known processes -3,20-dione not only on the shortest route so far, but also in a larger yield from the starting product generally used for the manufacture, namely derr 3-acetoxy-16-pregnen-3,20-dione, as it is made from diesel Compound the starting product for the process of the present invention, namely the 16rc-17 "-Epoxy 5 / i-pregnan-3, l 1,20-trione, can be produced in two process steps. As far as the inventive level of this process is concerned, it should first be noted that, as is known from the literature, the yields of the ethylene ketal protection depend to a large extent on the various substances present in the steroid molecule and that the difficulties To achieve hollow yields, even greater, if at the same time protection for the keto group at C-. and C-20 is desired (R. Raussc r, J Org. Chem. Vol. 31, p. 27 [1966], 2nd column, 3rd paragraph A. B ο wcrs et al., .1. Am. Chem Soc, Vol. 80, p. 309

[1958], 1. Spake. 3rd and 4th paragraph; W. S. A11 e η J. Am. Chem. Soc, Vol. 76, p. 6116 [1954], 2nd column; D Taub et al., J. Am. Chem. Soc, Vol. 82, p. 4017 and 4018 [1960].

Yields are at the 21 deoxy-pregnane steroid series of about 40% for the 3.20 bis-ketalization by R. A η t ο η u c c i et al (Journ. Org. Chem Vol. 17, p. 1369 [1952]) for the 11-non-oxygenated r ^ -Pregnene published; W. S. Allen et al (J. Am. Chem. Soc, Vol. 76, p. 6116 [1954]) report yields in the 11 u-hydroxylated pregnancy series from 63 to 76% and in the 11 non-oxygenated series from 79%.

The inventive merit is based on the discovery that the 3- and 20-keto groups of 16α, 16 / ί-epoxy - 5ß - pregnane - 3,11,20 - trione - a 11 - oxygenated Piegnanderivat - simultaneously and selectively with a yield of over 84% can be ketalized, while for example the lo-PregnenOJl ^ O-trione, when subjected to the same process of ketalization, gives an oily product which cannot be crystallized and from a mixture of mono-, diketalized and unconverted connections exist.

The manufacture of betamethasone is described by R. Rausser in US Pat. No. 3,164,618, by D. Taub in US Pat. No. 3,485,854, and by J. A m i a r d in US Pat. No. 3,140,4246. There are 23 or 17 process steps required to obtain from the same starting compound 3a-acetoxy-16-pregnen-11,20-dione Get betamethasone while according to the present invention in combination with the method the German Offenlegungsschrift 20 59050 the production of betamethasone from the same Starting material is possible in 15 process steps. As a result, the overall yield also increases by the method of the present invention is very remarkable over the known prior art elevated.

Another advantage of the present method over that of A m i a r d is that the introduction the 16-methyl group into the 3,20-bis-ketal derivative without side reactions is possible, while a corresponding methylation of the 3'-acetoxy protected Compound according to the method of Am i a r d leads to the formation of secondary products, the cannot be removed in a satisfactory manner.

The method of the invention is based on the 16a, 17 «- Epoxy-5 / <- pregnan-3, l 1,20-trione of the formula

11-one of the formula

(II)

(IH)

The reduction of compound 11 by sodium or potassium borohydride leads to the new compound loa.na-Epoxy-S ^ O-bis-äthylendioxy-II / i-hydroxy-5 / i-pregnan the formula

CH ₃

J5 (IV)

Subsequent dehydration of compound IV by methanesulfonyl chloride, which contains a catalytic amount of SO ₃ or thionyl chloride, leads to the new compound 16a, 17a-epoxy-3,20-b "
dioxy-5 ^ -pregn-9 (ll) -en of the formula

CH ₃

40

45

(V)

If the compound V is then reacted with a large excess of halomethyl magnesium, the new compound 16 / i-methyl-17a-hydroxy-3,20-bis-ethylenedioxy-5 /? - pregn-9 (l) -ene of the formula q ^

55

60

OH

from, first published by E. E rco 1 i and P. de Ruggicri, Gazz.Chim. Hai., 85, pp. 1304-1315 (1955). Dikctalisicrung at C-3 and C-20 leads to the new connection 16u, l 7a - epoxy - 3.20- bis - äthylendioxy - 5 // - pregnan-

(VI)

receive.

Decelalization of the compound VI in an acidic medium gives the 16 / i-methyl-17 «-hydroxy-5 / f-pregn-9 (II) -en-3,20-dione the formula

O = *

(VI)

> 5

the compound described in US Pat. No. 3104,246 in terms of its parameters is.

Compound I, which is the end product of the process of the present invention, can be obtained as follows be prepared: by dibromination at C-I and C-4 with a subsequent desbromination by do you prefer the dibrominated counter-clockwise? Establishes connection, that is the 16 / i-methyl-2 ", 4 / <dibromo-17" -hydroxy-5 / * - pregn-9 (II) -en-3,20-dione the formula

CH ₃

C = O

OH

(VIII)

35

40

and then desbrominated; but one can also establish the connection by directly treated compound VII with 2,3-dihalo-5,6-dicyano-1,4-benzoquinone (DDQ). This step leads directly from compound VII to compound I, i.e. H. in just one process step.

The diketalization takes place by means of excess ethylene glycol and p-toluenesulfoiic acid as a catalyst; the preferred medium is anhydrous benzene, which allows the removal of water by a preferred Dean-Stark trap filled with sodium sulphate. Implementation is after 15 to 28 hours Heat to reflux completely. The reaction mixture is then washed with a sodium bicarbonate solution washed to remove excess ethylene glycol and the p-toluenesulfonic acid from the reaction mixture separate. The benzene phase is dried using anhydrous sodium sulphate and then in vacuo evaporates. The compound III crystallizes from the residue obtained in this way using hot, 1% pyridine containing methanol. The reduction of the kelon function at C-11 is achieved at reflux temperature using sodium or potassium borohydride, wherein the medium is tetrahydrofuran, methanol and water. The implementation is after 3 to 4 hours Completely. The compound IV crystallizes after removal of the organic solvents under reduced Pressure off.

The U / f-hydroxy group thus formed is by means of Melhansulfonylchlorid removed and so formed a double bond in the 9 (11) position. That used The solvent is preferably dimethylformamide to which excess pyridine has been added, to keep the reaction mixture alkaline and thus prevent decetalization. To get a full To achieve conversion is the presence of a catalytic amount of sulfur trioxide or Thionyl chloride required.

Methanesulfonyl chloride is preferably added at a temperature between -15 and -5'C and then stir the reaction mixture for 3 to 4 hours to slowly warm it up. The raw product crystallizes after precipitation from a mixture of water containing 0.1% pyridine and ice cream.

Simultaneous introduction of the methyl group in the steric position β at C-16 and the hydroxyl group in the steric position at C-17 is carried out in such a way that a halomethylmagnesium, preferably methylmagnesium bromide, is introduced. in an inert medium such as tetrahydrofuran and diethyl ether, the final reaction of the Grignard reagent is 3 to 3.3 χ normal and then the mixture is refluxed at a temperature between +85 and +95 C for 15 to 20 hours. When the reaction is complete, the mixture is diluted with tetrahydrofuran and then cooled and the excess reagent is destroyed by the slow addition of water, whereby the new compound VI is obtained. Optionally, the excess can be effected by adding the reaction mixture to a mixture containing water, ice and hydrochloric acid, whereby the compound VII is obtained directly. This compound can also be obtained from compound VI in such a way that its tetrahydrofuran solution is treated at room temperature of 10% hydrochloric acid or with 60 to 70% acetic acid at a temperature of +85 to +95 C for half an hour for one hour.

According to the invention, the two double bonds at C-2 and C-4 are introduced as desired in two different ways. The dibromination is carried out in such a way that the 2u, 4 / fast-turning Dibromo derivative receives. The other way is through DDQ in a manner known per se.

Examples for carrying out the process according to the invention are given below.

example 1
Phase 1

There were 67.5 g of 16 ", 17" -epoxy-pregnan-3, 1 1,20-trione (E. E r c ο 1 i and P. de R u g g i e r i, Gazz. Chim. Ital., 85, 1304 [1955]) with a melting point of 194 to 201 "C with stirring in 3600 ml of benzene, the 472.5 ml Containing ethylene glycol and 3.15 g of p-toluenesulfonic acid, heated under reflux. The capacitor was fitted with a Dean-Stark trap; the collector contained anhydrous sodium sulphate; after heating during 19 hours under reflux the reaction was complete, as evidenced by an aliquot can be determined. After the reaction mixture had cooled down, it was mixed with 675 ml of 2N sodium carbonate, diluted with 2700 m. water, washed.

After the benzene phase had been separated off, this was dried with anhydrous sodium sulphate and concentrated in vacuo until an oil was received. After adding methanol containing 1% pyridine, the new compound crystallized 16u, 17 «- epoxy - 3.20 - bis - ethylenedioxy - 5 // - pregnan-1 l-one (III) off; F. = 153 to 155 C, specific Rotation: [«]„ +90 (<· = I in chloroform). Howling 56 g. The Mutlerlaugen were taken up and a second fraction in an amount of 13.8 g. which contained a satisfactorily pure product.

Analysis for C ₂₅ H ₁₁₁ O ,, (molecular weight: 432.6):
For indoor heating:

Calculated ... C 69.42, 118.39, O 22.19%;
found .... C 69.8. H 8.2. O 22.3%.

Phase 2

With stirring and under a nitrogen atmosphere, 89 g of potassium borohydride were added to 450 ml of water, 180 g 16 (1.17 «- epoxy - 3.20 - bis - ethylenedioxy - 5 // - pregnan-1 1-one combined in 2250 ml of tetrahydrofuran and 9 (K) ml of methanol. After heating 3600 ml of water and the organic solvents were added over 3 hours under reflux removed by distillation under reduced pressure, whereupon the l6u, l7 <i-epoxy-3-20-bis-ethylenedioxy-l Ι / ί-hydroxy-5 / i-pregnane (IV) crystallized. Bulge 158.8 g. The infrared absorption spectrum showed none Maximum in the area of 5.5 to 6.5 u.

Analysis for C ₂₅ H ₃₈ O ,, (molecular weight: 434.6):
Composition:

Calculated

C 69.1, H 8.81, 0 22.09%;

Found ... C 68.9, H 8.7, O 22.2%.

Phase 3

70 ml of methanesulfonyl chloride with traces of SO _{3 were added} dropwise at a temperature of -10 ° C. 150 g of the product obtained in phase 2 in 750 ml of dimethylformamide and 200 ml of pyridine. When the addition was complete, the reaction mixture was stirred for 5 hours and then allowed to warm slowly. The reaction mixture was then poured into 6500 ml of water and ice, containing 0.65 ml of pyridine, whereupon a sticky mass erred and which slowly crystallized on stirring. Yield 147g . After Umkristalli sation from 1% pyridine enthallendem methanol of pure product were obtained 136.6 g. The infrared absorption spectrum showed no maximum in the area from 2 \ 5 to 3.2 µ.

Analysis: C ₂₅ H ₃₆ O ₅ (molecular weight: 416.6): Composition:

Calculated ... C 72.8, H 8.71, O 19.2%; found .... C 71.7, H 8.6, O 19.3%. Grignard Reactions were between 3 and 3.3 normal and then the mixture was refluxed for 18 hours. The reaction mixture was then cooled to 40 ° C. and 1200 ml of tetrahydrofuran were added, and when the temperature was 20 to 25 ° C., water was added in such a way that this temperature of the reaction mixture was maintained. After the excess Grignard reagent had been destroyed, 2000 ml of water were added and at least half the amount of tetrahydrofuran was removed under reduced pressure. The 16 // - methyl-17 "-hydroxy-3,20-bis-ethyl-dioxy-5 / <- pregn-9 (11) -ene crystallized. Yield 99.4g.

Analysis: C ₂₁₁ H ₄₀ O ₅ (molecular weight: 432.6): Composition:

Calculated ... C 72.19, H 9.32, O 18.49%; found .... C 72.01, H 9.18, O 18.61%.

The product obtained was dissolved in 100 ml of 70% acetic acid and dissolved over half an hour 90 ° C., whereupon precipitation took place by adding 500 ml of water and then 16 // - methyl-17u-hydroxy-5 / f-pregn-9 (II) -en-3,20-dione crystallized. A lump of 77.1 g was obtained after washing with isopropyl ether.

B. The reaction mixture was optionally cooled and, after refluxing, diluted and poured into a mixture of water and ice containing 12% concentrated hydrochloric acid, whereupon 1000 ml of ethyl ether were added. After stirring and returning the phases thus formed for 2 hours, the organic solvents were removed under reduced pressure, the crystals formed filtered place. It was washed with water and then with isopropyl ether. The product obtained in this way in a yield of 81.2% with a melting point of 187 ° C. is pure 16 /; - methyl-17 «-hydroxy-50-pregn-9 (11) -en-3,20-dione.

40 phase 5

Phase 4

A. TOOg of the product obtained in phase 3 were added to 550 ml of methylmagneshimbromide 2 to 2 ^ -N in tetrahydrofuran under a nitrogen atmosphere. The reaction mixture was concentrated to such an extent that the concentration of 51.6 ml of elemental bromine in 2630 ml of acetic acid, 172 g of the product obtained in phase 4 B in 200 ml of dioxane and 2000 ml of acetic acid, which contained 1 g of anhydrous hydrogen bromide, were obtained with stirring, added at + 5 'C for 25 minutes. The mixture was stirred for 3 hours and then the reaction mixture was poured into a mixture of water and ice and in this way 16 / i-methyl-2 ", 4 / i-di-bromo-17n-hydroxy-5p-; pregn -9 ( 1 l) en-3,20-dione precipitated. The product thus obtained crystallized from isopropyl ether; Yield 21.20 g of the levorotatory 2,4-dibrominated product.

Analysis: C ₂₂ H ₃₀ O ₃ Br ₂ (molecular weight: 502.3): Composition :

Calculated ... C 52.6, Br 31.82%; found .... 52.4.3Zl%.

Phase 6

50 g of the dibrominated product obtained according to phase 5 in 500 ml of dimethylformamide containing 100 g of anhydrous lithium carbonate and 50 g of anhydrous lithium bromide were desbrominated by heating to 125 to 130 ° C. for 25 minutes. The reaction mixture was cooled and slowly poured into 3 liters containing 200 ml of acetic acid

609639/202

55

to

Poured water and ice. It was filtered, washed and dried. After recrystallization from ethyl acetate and isopropyl alcohol, 32 g of 16 // - McIh) I-17 «-hydroxy-1,4,9 (11) ■ pregnalricn-3.20-dione were obtained. The product has a melting point of 170 to 172 C. L ^; . | ^ "4 Br (<■ = 1 in ethanol); Otherwise it corresponds to the compound obtained by the process of US Pat. No. 3,04,246.

Example 2

There were KK) g of the compound VII obtained according to phase 4 B of Example I in 2 liters of dioxane for 24 hours. containing 2 (X) g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, heated under reflux. The solution was cooled and the crystals thus formed were taken up. After treatment with active charcoal, the filtrate was concentrated in vacuo. Recrystallization of the residue thus obtained from ethyl acetate and isopropyl ether immediately gave 61 g of 16 // methyl-1,4,9 (11) -pregnantriene-3.20-dione. E | ^ _m 436 at 240 ιτίμ (in ethanol). Bclamethasone and its 21-acylates can be prepared from this intermediate by the methods of German Offenlegungsschrift 20 59 050 or the examples in US Pat. No. 3,10,4246.

Further possible embodiments of the process of the invention with regard to reaction media, temperatures, Duration etc. are tabulated below.

Reaction media

Process step a);

Benzene;

Procedure b):

a mixture of tetrahydrofuran. Methanol and water;

Traversing speed c):

lower dialkylformamide:

Process step d):

Tetrahydrofuran, lower dialkyl alcohol;

Process step e):

Methanol, tetrahydrofuran, aqueous acetic acid: Procedure step I):

Dioxane, ethyl acetate:

Process step g):

lower dialkylformamide.

Conversion temperatures

Procedure step a):
Pvreflux temperature;

Procedure b): Reflux cmpcrati!;: Process step c): - 15 to 4 45 C; Process step d) reflux temperature;

Concentration of the Cirig-

naid reagent 3 to 3.3 N;

Procedure step e): κ. f 15 to + 25 C. if 10% hydrochloric acid is present:

b / w. f 85 to ι 95 C. if acetic acid is present:

Procedure step I):

less than +8 C.

Procedure step g): + 130 to + 138 C.

Reaction time

Procedure a): 15 to 28 hours;

Procedure step b):. 3 to 4 hours; Process step c): 4 to 5 hours; Procedure step d):

15 to 20 hours; Process step c): V ₂ to 1 hour; Process step f) · '1 to 3 hours; Process step g): 2 to 3 hours.

For process step c) pyridine can be used as the tertiary amine and for process step d) methylmagnesium bromide can be used as haloalkyl magnesium.

For process step c) 10 to 15% hydrochloric acid can be used as aqueous acid and methanol and tetrahydrofuran as solvents or 75% aqueous Acetic acid can be used without an additional solvent.

Further examples are given that the desbromination is carried out with lithium bromide and lithium carbonate, and that the compound VIl with an excess of Z ^ -dichloro-S ^ -dicyan-l ^ -benzocbinone for the direct preparation of the compound 1 from the compound VII or reacted with the equivalent 2,3-dibromo derivative in dioxane and refluxed for 16 to 28 hours.

Claims (1)

Claim: Process for the preparation of 16 / i-methyl-17 «-hydroxy-1,4,9 (1 l) -pregnatriene-3,20-dione (I), characterized in that one according to methods known per se a) 16u, 17 «-Epoxy-5fJ-pregnan-3, l 1,20-trione (II) with excess ethylene glycol in the presence of a solvent to form an azeotropic Reacts mixture with water and in the presence of p-toluenesulfonic acid, b) the 16a, l: 7a-epoxy-3,20-bis-ethylenedioxy-5 / f-pregnan-II-one obtained (III) with sodium or potassium borohydride in an aqueous organisehen Medium implements, c) the obtained 16o, 17 ″ -epoxy-3,20-bis-äthylendioxy-n /? - hydroxy-5 /? - pregnane (IV) with methanesulfonyl chloride, which contains a catalytic amount of SO ₃ or thionyl chloride, in an anhydrous reacts inert medium in the presence of a tertiary amine, d) Yes received dioxy-5 / * - pregn-9 (ll) -en (V) with a large Reacts excess of a methyl magnesium halide in the presence of an inert medium, e) the 16/1 methyl-17 "-hydroxy-3,20-bis obtained - äthylendioxy - 5 / i - pregn - 9 (11) - en (Vl) where appropriate reacts with an aqueous acid solution in the presence of an organic solvent, f) the 16 / i-methyl-17a-hydroxy-5 / <pregn-9 (II) -en-3,20-dione obtained (VII) with elemental bromine in a solvent or in a mixture of inert solvents, which the formation favor the levorotatory 1,4-dibromo derivative in the presence of a catalytic amount converts anhydrous hydrogen bromide into acetic acid and g) the levorotatory 16 / <- methyl- 2nAß -dibromo-Hu- hydroxy -5 // - pregn -9 (11) -en-3,20-dione (VIII) obtained is reacted with a desbrominating agent in an organic medium.