DE1126386B - Process for the preparation of steroid 21-amino acid esters - Google Patents

Description

It is already known that z. B. 21-Aminoacetates of 21-hydroxypregnan-3,20-dione, hydrocortisone, prednisolone and 9 -fluorohydrocortisone obtained when the corresponding 21-Hydroxypregnan- or 21-Hydroxypregnen-Derivate with Treated chloroacetic anhydride and the 21-chloroacetates obtained are reacted with secondary amines (cf. German patent specification 1 037 451).

It has now been found that steroid 21-amino acid esters the general formula

CH ₂ -O-CO- (CH ₂ ) -CR

C = O

HO-

OH

Method of manufacture
of steroid 21-amino acid esters

Applicant:

Farbwerke Hoechst Aktiengesellschaft

formerly Master Lucius & Brüning,

Frankfurt / M., Brüningstr. 45

Dr. Werner Fritsch, Neuenhain (Taunus),
has been named as the inventor

CH ₃

wherein X stands for a chlorine atom or the mesyl radical, in Presence of dialkylformamides with an alkali salt of an amino acid of the general formula

where η is the numbers 0 to 2, R is hydrogen or a low molecular weight alkyl radical, R _{1 is} hydrogen or a low molecular weight alkyl radical and R _{2 is} hydrogen, a low molecular weight alkyl radical or an aralkyl radical optionally substituted in the phenyl nucleus, or in which R ₁ and R ₂ together with the Nitrogen atom denotes the radical of a saturated five- or six-membered ring, optionally interrupted by a second heteroatom, and in which one of the two radicals R can also stand for phenyl, is obtained when a steroid of the general formula is obtained

CH ₂ -X

CO

HO

OH

CH ₃

HOOC- (CHs) ₈ -CR

in which n, R, R ₁ and R _{2 have} the abovementioned meaning, treated and, if appropriate, the compounds obtained are converted into corresponding salts with inorganic or organic acids in a manner known per se.

As starting materials, for example, 21-chlorooc-methyl-zl ^ -pregnadiene-II / I, 17a-diol-3,20-dione or 21-mesyl-6 "-methyl- / l ¹ ' ⁴ -pregnadiene-II / S, 17 "-diol-3,20-dione, hereinafter referred to as 21-chloro-6" -methylprednisolone and 21-mesyl-6 <x -methyl-prednisolone for short. The 21 ~ mesyl-6'-methyl-prednisolone is advantageously obtained by reacting 6'-methyl-prednisolone with mesyl chloride in pyridine, preferably in the presence of an inert solvent. The manufacture succeeds in particularly good yield

209 557/454

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position, if you like the reaction at O ⁰ C and in and can after drying for cleaning the presence of acetone as a diluent from suitable organic solvents, eg. B. from leads, since the desired 21-mesyl derivative after ethyl acetate, are recrystallized,
this embodiment in practically analytically pure form, if desired, the 21-ami form obtained in this way can be obtained. The 21-chloro-6'-methyl prednisolone 5 nosäureester by treatment with inorganic is advantageously converted by reaction of 6'-methyl or organic acids in the corresponding acid prednisolone with organic sulfochlorides, preferential addition salts. As an inorganic way with mesyl chloride, in the presence of pyridine and acids, for. B. hydrohalic acids, such as inert solvents or diluents at he-hydrochloric or hydrobromic acids, sulfuric acid at elevated temperature. io or phosphoric acid in question, while as organic

As reaction components of the aforementioned Ausnische acids, for example formic acid, acetic acid, the alkali salts, preferably acid, propionic acid, fumaric acid, maleic acid, sodium and potassium salts, any amino stinic acid, tartaric acid, malic acid, citric acid or acid included in the given general formula ethylenediaminetetraacetic acid are suitable,
falls into consideration. The products of the process represent new compound amino groups, mono- or disubstituted amines and, with good water solubility, are suitable for valuable acids. Examples include: Diethyl- full therapeutic properties. For example, beaminoacetic acid, pyrrolidinoacetic acid, piperidino- the new compounds have a stronger glucoacetic acid, morpholinoacetic acid, | 8-amino - /? - methyl corticoid activity and a higher inflammatory butyric acid, γ-aminobutyric acid, α-amino propionic-20 inhibiting effect than the known 21-hemisucic acid. "-Methylamino-propionic acid," -Diethylamino-cinate des 6 "-Methyl-prednisolons.
propionic acid, Ä-n-butylamino-propionic acid, y-Me-

ethyl- "v> aminobutyric acid, y-methyl - ^ - methylamino- Example 1

butyric acid, ₇ -methyl- «- diethylamino-butyric acid, ÖÄ-methyl-prednisolone ^ l-diethylammoacetate

Λ-piperidino-propionic acid, p-phenyl-p-aminobutter- 25

acid, N- [2- (m-methoxyphenyl) -2-ethyl-biityl] -amino- 5.23 g of 21-chloro-6 «-methyl-zl ¹ > ⁴ -pregnadiene-II / 3,

acetic acid. 17 «-diol-3,20-dione are in a suspension of

The reaction is introduced according to the process according to 7 g of sodium diethylaminoacetate in 25 ecm of dimethyl of the invention, expediently in the presence of dialkyl formamide, and the reaction mixture is formamides, e.g. B. of dimethylformamide, as Lö- 30 is stirred for 2 hours at a bath temperature of 65 ° C solution or diluent at temperatures. After cooling, 15 cc of methanol between 20 and 100 ⁰ C, preferably between 65 and added, the mixture is treated with 2N hydrochloric acid is 70 ⁰ C, made. The reaction time is acidified and 150 ecm of water are added. Little generally between 1 and 20 hours. If flakes are used, ether is removed by extraction with 21-mesyl-6 * -methyl-prednisolone as an extract. The aqueous phase is adjusted with sodium starting material, the most favorable reaction time is about bicarbonate solution, which is 16 to 18 hours, while the 21-chloro-6'-methyl-α-methyl-prednisolone ^ l-diethylaminoacetate crystal prednisolone generally shorter reaction times lin fails. After filtering and washing the needed. An advantageous embodiment of the filter residue with water is obtained by the 21-chloro- or 40 6'-methyl-prednisolone-21-diethylaminoacetate in Va-21-mesyl-6 * -methyl-prednisolone in dimethyl form - uum dried at 50 ⁰ C. The yield is amide dissolved or suspended, the mixture is moderately 5.35 g, the melting point is from 172 to 206 to 208 ^° C. elevated temperatures, for example up to 60 bis (Kofler melt bank). After recrystallization at 70 ^° C., heated, either equivalent or excessively from glacial acetic acid, the substance melts at 174 to 209 ^° C. Schüssige amounts of the corresponding amino acid in 45. B. how the shape of the sodium or potassium salt can be represented in the following way: 2.84 g of ow-methyl-predniso-distributed form are added and the temperature of the reac-ion diethylaminoacetate are suspended in 20 ecm of methanol with mechanical stirring and some with cooling and keep stirring at 60 to 70 ^° C. for hours. 58.2 ecm of 1.0 η hydrochloric acid were added. After leaving

If in the reaction the alkali salts of such 50 evaporate the methanol under reduced pressure

Amino acids are used, the isoelectric of which shows the clear aqueous distillation residue a Ph

Point strongly towards the alkaline range from 4.3 to 4.4. After freeze drying, the

(e.g. in the case of | 3-amino- / S-methyl-butter- oa-methyl-prednisolone ^ l-diethylaminoacetate-hydro-

acid), it has proven to be advantageous to obtain the reactive chloride in practically quantitative yield,

tion component in the form of a free amino 55

acid and the alkali salt of the amino acid consisting of Example 2

Use buffer mixture ÖÄ-Methyl-prednisolon ^ l-diethylaminoacetat

For working up, the reaction mixture is expediently treated with dilute acids, e.g. B. 2 η-hydrochloric acid, acidified in a stirred suspension of 8.4 g of sodium and then diluted with water. Un- 60 diethylaminoacetate in 30 ecm of dimethylformamide are dissolved by filtration or by 5.98 g of 21-mesyl-6 "-methyI-Zl ¹ > * - pregnadiene extraction of the reaction mixture with a water II / ?, 17" - diol-3,20-dione entered. The reaction immiscible solvent, e.g. B. diethyl ether mixture is 8 hours with thorough stirring on or methylene chloride, separated. The 70 ⁰ C in the reaction heated. After cooling, the 21-amino acid ester of 6'-methyl-65 mixture obtained is acidified with 2η-hydrochloric acid and diluted with 500 ecm of prednisolone by neutralizing the acidic, cold water. A slight cloudiness is removed from the aqueous phase with the aid of bases, such as sodium hydroxide solution, by extraction with ether. The aqueous sodium carbonate or sodium bicarbonate solution, off-phase is adjusted to pH 8 with 2N sodium carbonate solution

Claims (1)

5 6 set, whereby the OÄ-methyl-prednisolon ^ l-di- (S-methyl) -butyrate from melting point 160 to 165 ⁰ C äthylaminoacetat precipitates. Obtained after filtering off (with decomposition, Kofler melting bank). Washing with water and drying in vacuo carries the yield of 6 * -methyl-prednisolone-21-di- Example 6 ethylaminoacetate 6.22 g, the melting point is 5 6Ä-methyl-prednisolone-21-N- [2- (m-methoxyphenyl) - 209 ° C (Kofler melting bench). 2-ethyl-butyl] aminoacetate . 10 g of the sodium salt of the N- [2- (m-methoxy- Example 3 phenyl) -2-ethyl-butyl] -aminoacetic acid and 5.88 g 6a-methyl-prednisolone-21-piperidino-acetate 21 - mesyl - 6 "- methyl - A M - pregnadiene-1 , 17a-diol- A well triturated mixture of 3.1 g sodium io 3,20-dione is, as described in Example 3, reacted in piperidino acetate and 2.38 g 21-mesyl-6 <x-methyl- 30 ecm dimethylformamide and dissolved. JM-pregnadien-ll / UTÄ-diol-S ^ O-dione is working in 12 ecm. After recrystallization from dimethylformamide Essigester 16 hours with stirring to be 5.9 g of 6 "-methyl-prednisolone-21-N- [2- (m-meth-70 ⁰ C heated. Further work-up is carried out as in oxyphenyl) -2-ethyl-butyl] -aminoacetate from melting example 2 indicated. 2.78 g of 6'-methyl- 15 point 169 ° C. (Kofler melt bank) are obtained.
prednisolone-21-piperidino-acetate of melting point 208 ⁰ C (Kofler melting bank) obtained. The example / Vehicle product can, as described in Example 1, 6 * -methyl-prednisolone-21-y-aminobutyrate be converted into the corresponding hydrochloride. 5 g of the sodium salt of γ-amino butyric acid . 20 and 2.95 g of 21-mesyl-6a-methyl-zJ ¹ ' ⁴ -pregnadiene-ll / ?, ^Beispie14 17x-diol-3,20-dione are, as in Example 3 6 * -Methyl-prednisolone-21-morpholino-acetate wrote, converted into 17 ecm dimethylformamide 6.2 g of sodium morpholino acetate and 4.8 g and worked up. There are added 0.5 g of 6 "-methyl-predni-21-mesyl-6% -. Methyl-zl ^1-4 -Pregnadien-ll / ?, 17A-diolsolon-21-y-aminobutyrate of melting point 175 ° C 3, 20-dione are obtained in 25 ecm of dimethylformamide. in accordance with the rule given in example 3, for example 8 set and processed. 5.41 g of 6x-methyl- ^ ,,,, 1 ■, -. <, Η · η λ ιχ prednisolone-21-morpholino-acetate with a melting point of 6 "-Methyl-predmsolone-21 - (/? - anuno - /? - phenyl) - 162 to 214 ° C (Kofler melting bench) obtained. butyrate 30 5.85 g of 21-mesyl-6a-methyl-zl ¹ ' ⁴ -pregnadiene-ll _j 8, ^Beis P ^{iel b} 17 _Ä -diol-3,20-dione and 4.5 g of the sodium salt of 6Ä-methyl-prednisolone-21- (0-amino - /? - methyl) - ^ -amino-zS-phenyl-butyric acid are dissolved in 40 ecm di- butyrate methylformamide 5 hours under mechanical Heating a mixture of 4.9 g of sodium .beta.-amino-.beta.-methyl stirring at 7O ⁰ C. The further work-up of butyrate and 0.5 g of ß-amino-ß-methyl-butyric acid is carried out as indicated in Example 2. There are 2.6 g along with 2.5 g of 21-mesyl-6 "-methyl-zl ^1-4 -pregna- 6%-methyl-prednisolone-21 - (/ 3-amino - /? - phenyl) butyrate dien-1 Eat, 17 (X-diol-3,20-dione in 20 cc Dimethylform- a melting point of 223 ⁰ C (Kofler melting Bank) eramid 18 hours under stirring at 70 ⁰ C heated. stopped. the process product may after in After cooling, the mixture is acidified into the corresponding acid using the 2 η salt- Example 1 given instructions and converted from the little precipitated flakes 40 hydrochloride,
sucked off. The filtrate is then adjusted to a ρπ value of 8.5 to 9 with 2N sodium carbonate solution discontinued, the resulting 6 «-Methyl-prednisolon- PATENT CLAIM: 21- (j8-amino - /? - methyi) butyrate filtered off, with water and dried in vacuo at 5O ⁰ C. There 45 methods of making steroid 21-amino 1.49 g of 6'-methyl-prednisolone-21- (ß-amino acid esters of the general formula CH ₂ - O - CO - (CH ₂ ) ,, - CR ■■ C = O ^Rl CH ₃ where η stands for the numbers 0 to 2, R hydrogen or a low molecular weight alkyl radical and or a low molecular weight alkyl radical or R _{2 is} hydrogen, a low molecular weight alkyl one of the two radicals R is the phenyl radical, R _{1 is the} water radical or optionally one in the phenyl nucleus substituted aralkyl radical, where R ₁ and R ₂ together with the nitrogen atom can also represent the radical of a saturated five- or six-membered ring, optionally interrupted by a second heteroatom, characterized in that a steroid of the general formula wherein X stands for a chlorine atom or the mesyl radical, in the presence of dialkylformamides with an alkali salt of an amino acid of the general formula HOOC- (CH ₂₎ "- C-R in which n, R, R ₁ and R ₂ are as defined above, treated and, if appropriate, the compounds obtained are reacted with inorganic or organic acids in a manner known per se. Considered publications:
German interpretative document No. 1 016 708. © 209 557/454 3.62