CH215816A - Process for the preparation of dihydrotestosterone. - Google Patents
Process for the preparation of dihydrotestosterone.Info
- Publication number
- CH215816A CH215816A CH215816DA CH215816A CH 215816 A CH215816 A CH 215816A CH 215816D A CH215816D A CH 215816DA CH 215816 A CH215816 A CH 215816A
- Authority
- CH
- Switzerland
- Prior art keywords
- agent
- alcohols
- acetalizing
- acetal
- process according
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 12
- 229960003473 androstanolone Drugs 0.000 title claims description 8
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- RAJWOBJTTGJROA-RNQTWYFASA-N androstane-3,17-dione Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC21 RAJWOBJTTGJROA-RNQTWYFASA-N 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 150000001241 acetals Chemical class 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- -1 testosterone acetals Chemical class 0.000 claims description 2
- ZETHHMPKDUSZQQ-UHFFFAOYSA-N Betulafolienepentol Natural products C1C=C(C)CCC(C(C)CCC=C(C)C)C2C(OC)OC(OC)C2=C1 ZETHHMPKDUSZQQ-UHFFFAOYSA-N 0.000 claims 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims 1
- PCSMJKASWLYICJ-UHFFFAOYSA-N Succinic aldehyde Chemical compound O=CCCC=O PCSMJKASWLYICJ-UHFFFAOYSA-N 0.000 claims 1
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testosterone Natural products O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims 1
- 150000007513 acids Chemical class 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- HEOKFDGOFROELJ-UHFFFAOYSA-N diacetal Natural products COc1ccc(C=C/c2cc(O)cc(OC3OC(COC(=O)c4cc(O)c(O)c(O)c4)C(O)C(O)C3O)c2)cc1O HEOKFDGOFROELJ-UHFFFAOYSA-N 0.000 claims 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 229960003604 testosterone Drugs 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000001476 alcoholic effect Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- FGQLGYBGTRHODR-UHFFFAOYSA-N 2,2-diethoxypropane Chemical compound CCOC(C)(C)OCC FGQLGYBGTRHODR-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- NLTQZUCBHQFOIO-UHFFFAOYSA-N acetohydrazide;trimethylazanium;chloride Chemical compound [Cl-].C[NH+](C)C.CC(=O)NN NLTQZUCBHQFOIO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000003420 transacetalization reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- 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)
Description
Verfahren zur Herstellung von Dihydrotestosteron. Gegenstand des vorliegenden Patentes ist ein Verfahren zur Herstellung des als Arznei mittel oder als Zwischenprodukt für die Her stellung von Arzneimitteln zu verwendenden Dihydrotestosterons, das dadurch gekennzeich net ist, dass man Androstandion durch Be handlung mit einem acetalisierenden Mittel in das 3-Monoacetal überführt,
in diesem die freigebliebene Ketogruppe durch Einwirkung eines Reduktionsmittels in die OH-Gruppe umwandelt und aus dem so erhaltenen Di- hydrotestosteronacetal das bekannte Dihydro- testosteron durch Hydrolyse freisetzt.
Als acetalisierendes Mittel hat sich ins besondere o-Ameisensäureester bewährt. Man kann aber auch andere Acetale, wie Aceton- diäthylacetal auf das Androstandion einwirken lassen, wobei, besonders in Gegenwart von Katalysatoren, eine Umacetalisierung statt findet.
Die Reduktion der freien Ketogruppe zur Ry- droxylgruppe kann z. B. mit Natrium in Alkohol erfolgen, doch können auch andere an sich bekannte Verfahren, zum Beispiel die Reduk tion nach Meerwein und Ponndorf mit Al koholen in Gegenwart von Aluminium- oder Magnesium-Alkoholaten angewandt werden.
Die hydrolytische Freisetzung des Dihydro- testosterons aus dem Reduktionsprodukt kann vorzugsweise ohne weitere Reinigung erfolgen. Man bedient sich dazu mit Vorteil einer Säure, wie z. B. Schwefelsäure, Salzsäure usw., am besten in alkoholischer Lösung.
Falls erforderlich, kann das Hydrierungs- produkt in bekannter Weise gereinigt werden, zum Beispiel durch Umkristallisieren, Destil lieren im Hochvakuum oder durch Behand lung mit besondern Ketonreagenzien, insbe sondere dem sogen. Girard-Reagens (Tri- methylammonium - Essigsäurehydrazid - hydro- chlorid) usw.
<I>Beispiel 1:</I> 1,44 g Androstandion (Schmp. 132 , (a)D -,- <B>113,6"</B> in Chloroform) werden in 10 em3 Benzol gelöst und mit 2 g Ortlio- Ameisensäureäthylester, 1,4 g absolutem Al kohol und 10 Tropfen einer 8,4 "/oigen abso lut alkoholischen Salzsäure zersetzt. Die Lösung wird eine Stunde auf 75" erhitzt.
Das Reaktionsprodukt wird darin mit niethyl- alkoholischer Natronlauge alkalisch gemacht, in Wasser gegossen und mit Äther extrahiert. Die ätherische Lösung wird mit Wasser ge waschen, getrocknet und verdampft.
Der kristallinische Rückstand wird aus pyridin- haltigem Alkohol umkristallisiert und liefert das in der 3-Stellung acetalisierte Andro- standion vom Schmp. 123 und der Drehung (a)D -f- 82 (Chloroform).
1 g des Acetals wird in reinem n-Prop3-1- alkohol gelöst und auf 100" erhitzt. Wälirend des Erhitzens werden 2 g Natrium eingetragen. Das Erhitzen wird fortgesetzt, bis alles Na trium gelöst ist. Nach dem Abkühlen wird das Reduktionsprodukt in Wasser gegossen und in Äther aufgenommen. Die Ätherlösung wird mit Wasser gewaschen und verdampft, der Rückstand wird mit wässrig-alkoholischer Salzsäure 15 Dlinuten auf dem Wasserbad erhitzt.
Durch Eingiessen in Wasser, Extrak tion mit Äther, Waschen, Trocknen und Ver dampfen des Äthers erhält man als kristal linischen Rückstand das Dihydrotestosteron, das durch Kristallisation aus Essigester ge reinigt wird und einen Schmp. von<B>177'</B> und eine Drehung von (a)D -f- 32" (in Alkohol) besitzt.
<I>Beispiel 2:</I> 1,44 g Androstandion-3,17 werden in 10 cm' Benzol gelöst und 0,85 g Ortho- ameiseiisä,ureäthylester, 0,7 g absoluten Al kohol und 5 Tropfen 8 "/oige alkoholische Salzsäure hinzugefügt. Nach einstündigem Er hitzen auf<B>75"</B> wird aufgearbeitet und als Rohprodukt ein Kristallisat erhalten.
Dureh weitere Reinigung aus pyridinhaltigem Alko hol wird Alidrostandion-3,17-diäthyl-acetal-3 erhalten, Schmp. 121-1230, (a)' D'-+ 7ä,6" (Dioxan).
In eine auf 100 " erhitzte Lösung von 100 mg Androstalidion-3,17-Diätliylacetal-3 in 5 cm3 n-Propylalkohol werden 200 mg Natrium eingetragen. Nach der Auflösung des Natriums wird mit Wasser versetzt und mit Ätlier aufgenommen. Die ätherisehe Lö sung wird neutral. gewaschen, getrocknet und verdampft.
Der Rückstand wird in Alkohol z -itif, --eiioiiinieiittilddie.ilkoliot"scheLiisungiiach <B>1</B> Zusatz von etwas verdünnter Salzsäure 15 Minuten auf dem Wasserbad erhitzt. Danach wird wieder finit Wasser versetzt, mit Äther aufgenommen und die ätherische Lösung ge waschen, getrocknet und verdampft.
Der Rückstand lieferte bei der Kristallisation aus Essrester 1)iliydrotestosteron vom Sclimp. <B>176 -177</B> " und der Drehung (a)C = + 32 " ( AllLuhul).
Process for the preparation of dihydrotestosterone. The subject matter of the present patent is a process for the production of the dihydrotestosterone to be used as a medicament or as an intermediate for the manufacture of medicaments, which is characterized in that androstandion is converted into 3-monoacetal by treatment with an acetalizing agent
in this the remaining free keto group is converted into the OH group by the action of a reducing agent and the known dihydro testosterone is released by hydrolysis from the dihydrotestosterone acetal thus obtained.
In particular, o-formic acid esters have proven to be useful as acetalizing agents. However, other acetals, such as acetone diethylacetal, can also be allowed to act on the androstandion, with transacetalization taking place, especially in the presence of catalysts.
The reduction of the free keto group to the ry- droxylgruppe can z. B. done with sodium in alcohol, but other methods known per se, for example the reduction according to Meerwein and Ponndorf with alcohols in the presence of aluminum or magnesium alcoholates can be applied.
The hydrolytic release of the dihydro testosterone from the reduction product can preferably take place without further purification. It is advantageous to use an acid such as B. sulfuric acid, hydrochloric acid, etc., preferably in an alcoholic solution.
If necessary, the hydrogenation product can be purified in a known manner, for example by recrystallization, distillation in a high vacuum or by treatment with special ketone reagents, in particular the so-called special. Girard reagent (trimethylammonium - acetic acid hydrazide - hydrochloride) etc.
<I> Example 1: </I> 1.44 g of androstandion (mp. 132, (a) D -, - <B> 113.6 "</B> in chloroform) are dissolved in 10 cubic meters of benzene and mixed with 2 g of ethyl Ortlio formate, 1.4 g of absolute alcohol and 10 drops of 8.4 "/ oigen absolute alcoholic hydrochloric acid decomposed. The solution is heated to 75 "for one hour.
The reaction product is then made alkaline with ethyl alcoholic sodium hydroxide solution, poured into water and extracted with ether. The ethereal solution is washed with water, dried and evaporated.
The crystalline residue is recrystallized from pyridine-containing alcohol and provides the androstandion, acetalized in the 3-position, of melting point 123 and the rotation (a) D -f- 82 (chloroform).
1 g of the acetal is dissolved in pure n-prop3-1 alcohol and heated to 100 ". During the heating, 2 g of sodium are added. Heating is continued until all of the sodium is dissolved. After cooling, the reduction product is dissolved in water Poured and taken up in ether. The ethereal solution is washed with water and evaporated, the residue is heated with aqueous-alcoholic hydrochloric acid for 15 minutes on a water bath.
By pouring into water, extracting with ether, washing, drying and evaporating the ether, dihydrotestosterone is obtained as a crystalline residue, which is purified by crystallization from ethyl acetate and has a melting point of 177 'and has a rotation of (a) D -f- 32 "(in alcohol).
<I> Example 2: </I> 1.44 g of androstandion-3.17 are dissolved in 10 cm 'benzene and 0.85 g of ortho-ameiseiisä, ureäthylester, 0.7 g of absolute alcohol and 5 drops of 8 "/ The above alcoholic hydrochloric acid is added. After heating to <B> 75 "for one hour, the product is worked up and crystals are obtained as the crude product.
Through further purification from alcohol containing pyridine, alidrostandion-3,17-diethyl-acetal-3 is obtained, melting point 121-1230, (a) 'D' - + 7ä, 6 "(dioxane).
200 mg of sodium are added to a solution, heated to 100 ", of 100 mg of androstalidione-3,17-diethyl acetal-3 in 5 cm3 of n-propyl alcohol. After the sodium has dissolved, water is added and the ether is taken up. The ethereal solution is added neutral. washed, dried and evaporated.
The residue is heated on a water bath for 15 minutes in alcohol, for example, with a little bit of dilute hydrochloric acid. Then finite water is added again, and ether is added, and the ethereal solution is added ge wash, dry and evaporate.
When crystallized from ethyl ester 1), the residue yielded iliydrotestosterone vom Sclimp. <B> 176 -177 </B> "and the rotation (a) C = + 32" (AllLuhul).
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE215816X | 1938-06-28 | ||
| CH210427T | 1938-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH215816A true CH215816A (en) | 1941-07-15 |
Family
ID=25724868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH215816D CH215816A (en) | 1938-06-28 | 1938-09-29 | Process for the preparation of dihydrotestosterone. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH215816A (en) |
-
1938
- 1938-09-29 CH CH215816D patent/CH215816A/en unknown
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