US2655520A - Process of preparing amino-compounds of the steroid series - Google Patents

Process of preparing amino-compounds of the steroid series Download PDF

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Publication number
US2655520A
US2655520A US278132A US27813252A US2655520A US 2655520 A US2655520 A US 2655520A US 278132 A US278132 A US 278132A US 27813252 A US27813252 A US 27813252A US 2655520 A US2655520 A US 2655520A
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Prior art keywords
compounds
water
androstene
amino
solution
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Expired - Lifetime
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US278132A
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English (en)
Inventor
Schmidt-Thome Josef
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Hoechst AG
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • the present invention relates to the manufacture of compounds having the character 01' the male sexual hormones-.-
  • the present invention is based on the observation that 1-7-acetylamino-compounds of the 0y.- clopentano-polyhydrophenanthrene series, which contain a hydroxyl or acetylatedhydroxyl group as a substituent in the 3-position, can be hydrolysed very readily with inorganic, alkaline substances at a temperature above 95 C.
  • the free l'l-amines are obtained from the 1'7-acetylami'nes in a yield exceeding per cent.
  • the hydrolysis of the l'I-acet'ylainines with inorganic alkalinesubstances may be carriedv out either in solvents boiling above 0., advantageously monoliydric or, polyhydric alcohols, such as n-butyl alcohol, amyl alcohol, isoamyl alcohol, ethylene glycol, propylene glycol, glycerin or the ike, or organic bases, such as ethanolamine, quinoline or the like.
  • the hydrolysis may be carried out in an autoclave with the addition of a monohydric or polyhydri'c alcohol, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl or isoamyl alcohol, ethylene.
  • glycol, propylene glycol or glycerin, or an organic base such asethanolamine, pyridine, quinoline or the like as a solvent.
  • Suitable inorganic alkaline substances are alkaline earth hydroxides, alkali carbonates and above all alkali hydroxides. They are advantageously used in a concentration of 15 to 20 per cent.- If, for example, an. alcoholic solution of sodium hydroxide of 20 per cent. strength is used in a closed vessel at a temperature of 160 C.-"C., and the duration of the heating is 3 hours, the free 17-amine is obtained from 17-acetylamine in a yield exceeding 90 per cent. The same yield is obtained by boilingfor 2 hours in a solution of 15 per cent. strength of potassium hydroxide in ethylene glycol.
  • the free 17-amines may be prepared as such and isolated. As, however, they are sometimes obtained in an oily form, it is of advantage to isolate them in the form of their salts. This may be carried out, for example, by adding an ethereal solution of an acid to an ethereal solution'of the amine. The amine salt then precipitates.
  • Organic or inorganic acids may be used for the precipitation, for example, acetic acid, oxalic acid, 'succinic acid, benzoic acid, phthalic acid, sulfuric acid, hydrochloric acid, perchloric acid or the like.
  • the free amines can easily be recovered from the salts by mixing the latter in an alcoholic solution with alkali and pouring the mixture into water.
  • the amine, which separates, can then be isolated by filtration and washed with water or extracted with ether.
  • the compounds of the invention are useful as medicaments or as intermediate products for the preparation of medicaments.
  • Example 1 700 milligrams of 3 S-acetoxy-17-acetylamino- A -androstene are suspended in 20 cc. of alcohol, a solution of 3 grams of sodium hydroxide in 10 cc. of water is added, and the mixture is heated for 4 hours at 180 C. in a closed copper tube or in a V2-steel tube. The reaction solution is poured into water, the product is extracted with ether, and the ethereal solution is washed with water, dried and concentrated by evaporation. When a small portion of glacial acetic acid is added, the acetate of Be-hydroxy-l'l-amino- A -androstene precipitates. The yield amounts to 620 milligrams (95 per cent.
  • the product may be recrystallized from a mixture of alcohol and ethyl acetate, and is then obtained in the form of fine needles.
  • sodium hydroxide the corresponding quantity of potassium hydroxide may be used equally well.
  • ethyl alcohol there may be used methyl, propyl or isopropyl alcohol or a polyhydric alcohol, such as ethylene glycol or glycerin.
  • An organic base such as pyridine, ethanolamine or the like, may also be used as solvent, in which case the reaction temperature and the period of reaction must, if required, be increased.
  • the free hydroxy-amine base can be obtained from the salt or directly from the hydrolysis solution as follows:
  • the free amine may be isolated directly in the hydrolysis, as follows:
  • the crude compound may be purified as follows:
  • the benzal compound may be split again as follows:
  • Example 2 1 gram of 3e-hydroxy-I'I-acetylamino-A -androstene is heated in a mixture of cc. of alcohol and 3 grams of sodium hydroxide (dissolved in 5 cc. of water) in a closed tube for 4 hours at 160-180 C. The reaction solution is then poured into water, extracted with ether and the ethereal solution is washed with water, dried and concentrated to about 100 cc. On adding a small quantity of a solution of oxalic acid in ether, the oxalate of 3,8 hydroxy 1'7 amino A androstene precipitates.
  • Example 3 250 milligrams of 3,3-acetoxy-l'l-acetylaminoandrostane in a mixture of 10 cc. of alcohol and 1.25 g. of sodium hydroxide (dissolved in 2.5 cc. of water) are heated for 2 hours in a closed copper tube at 180 C. The reaction solution is poured into water and the white precipitate which separates is filtered off with suction, washed with water and dried. 180 milligrams of lie-hydroxyl'I-amino-androstane are obtained melting at 150 C. The yield amounts to per cent. of the theoretical yield.
  • the product recrystallizes sparingly from methanol, it is dissolved in ether, and the ethereal solution, after being dried, is concentrated by evaporation and mixed with a few drops of glacial acetic acid.
  • the acetic acid salt which precipitates at once melts at 217 C. (uncorrected).
  • the pure acetate of 3fi-hydroxy-l'l-aminoandrostane is obtained in the form of lamellar crystals which melt at 228 C. (uncorrected).
  • Example 4 1.8 grams of 3fl-acetoxy-l'l-acetylamino-A androstene are heated at the boil for 3 hours under reflux in cc. of glycol together with 15 grams of potassium hydroxide. The solution is then poured into water and extracted with ether. The ethereal solution is washed with water, dried with sodium sulfate, concentrated to about 100 cc. and gradually mixed with acetic acid. 1.5 grams of the acetate of 3,8-hydroxy-17-amino-A androstene precipitate. It melts at 227 C. (uncorrected). Instead of the potassium hydroxide there may be used the corresponding quantity of sodium hydroxide.
  • Example 5 500 milligrams of 3;3hydroxy-17-acetylamino- A -androstene are heated at the boil for 2 hours in a reflux apparatus in a solution of 5 grams of potassium hydroxide in 30 cc. of ethylene glycol. A small content of water is not detrimental, but the boiling point of the solvent mixture must be higher than 180 C.
  • the reaction mixture is poured into water, the precipitate, which separates in the form of flocks, is filtered oil and washed with water. After recrystallization from methanol, 370 milligrams (85 per cent. of the theoretical yield) of Sp-hydroxy-l'l-amino-A androstene are obtained; the product melts at 160 C. (uncorrected). It is not essential to carry out the hydrolysis at the boiling temperature. Thus, the hydrolysis may be conducted at a temperature below the boiling point, but then the period of the reaction is correspondingly increased. Thus, for example, heating for 4 hours at 180 C. is necessary.
  • the acetylamine may also be hydrolyzed with sodium hydroxide or potassium hydroxide in butanol, but in this case the period required for the reaction is substantially increased.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)
US278132A 1951-03-30 1952-03-22 Process of preparing amino-compounds of the steroid series Expired - Lifetime US2655520A (en)

Applications Claiming Priority (1)

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DE748215X 1951-03-30

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US2655520A true US2655520A (en) 1953-10-13

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US (1) US2655520A (en:Method)
GB (1) GB748215A (en:Method)
NL (1) NL79353C (en:Method)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3101358A (en) * 1960-10-11 1963-08-20 Ormonoterapia Richter Spa 17beta-acetamino-steroids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3101358A (en) * 1960-10-11 1963-08-20 Ormonoterapia Richter Spa 17beta-acetamino-steroids

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Publication number Publication date
GB748215A (en) 1956-04-25
NL79353C (en:Method)

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