Method for preparation of 6-methylene derivatives of androst-1,4-diene-3,17-dione

专利摘要:
The invention relates to a new process for the preparation of known aromatase inhibitors of the following formula (I) whereineach of R₁ and R₃, independently, is hydrogen or C₁-C₆ alkyl;R₂ is hydrogen, halogen or C₁-C₆ alkyl; andR₄ is hydrogen or fluorine;the process comprising submitting to Mannich reaction a com­pound of formula (II) whereinR₁, R₂, R₃ and R₄ are as defined above and R is a lower alkyl group, and then dehydrogenating the respective 6-methylene-3-oxo-Δ⁴-steroid derivative thus obtained.
公开号:SU1757470A3
申请号:SU894613294
申请日:1989-01-25
公开日:1992-08-23
发明作者:Лонго Антонио；Ломбарди Паоло
申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
IPC主号:

专利说明:

The invention relates to a new method for producing 6-methylene derivatives of androsta-1,4-diene-3,17-dione of the general formula
where each Ri and Pz is independently hydrogen or Ci-Cd alkyl;
R ₂ is hydrogen, halogen or Ci-Cd alkyl;
R4 is hydrogen or fluorine, known aromatose inhibitors.
The purpose of the invention is to simplify the process by eliminating the column stage
where each Ri and R3 is independently H or C1-C4 alkyl; R2-H, halogen or Ci-Cd alkyl; R4 is H or F, which are aromatose inhibitors. The goal is to simplify the process. S are obtained from the corresponding Δ ^5,6 -dezmetilenproizvodnogo and 30-40% aqueous formaldehyde solution and an amine hydrochloride _{NH (R a) (Rb)} , wherein R _a lower alkyl: Rb - phenyl, in an organic solvent at 30-50 ° C followed by dehydrogenation by bromination. The resulting compound is debrominated to give a compound that is subjected to dehydrobromination.
chromatographic separation and exclusion of a reagent such as dichlorodicyanobenzoquinone (DDC).
The specified goal is achieved by the fact that according to the method, namely, that the compound of the formula
SU „1757470 AZ where Ri - Vd have the indicated meanings: R - lower alkyl, is reacted with a 30-40% solution of formic aldehyde. A synthetic solution of formaldehyde and amine hydrochloride of the formula where R _a is lower alkyl: Rb ~ phenyl,.
in an organic solvent, at 30 to give a compound of the formula
ABOUT
50 ° C
about
H ₂ ^sn where Ri - R "have the indicated meanings, which are then dehydrogenated by bromination to give a compound of general formula ^L
Br
ABOUT
at
IN"
Bg where Ri - R4 are indicated which are then debrominated to give 35 compounds of the general formula,
Br *
ABOUT*
About sn ₂ where Ri - R4 have the indicated meanings, and its dehydrobromination to obtain the target compound.
/ -Example). 6-Methyleneandrost-4-ene3,17-diode (IV, Ri = R ₂ = R3 = R4 = H).
A 1000 ml 4-necked round-bottomed flask equipped with a condenser, thermometer and dropper and a mechanical stirrer is charged with 20 g of androst-4-en-3,17-diode, 130 ml of anhydrous tetrahydrofuran, 20 ml of ethanol. 20 ml of triethylorthoformate and 260 mg of p-toluenesulfonic acid and heated at 40 ° C.
After 1 h, a second aliquot and 260 mg of p-tobenesulfonic acid were added to this stirred mixture, and after 1 h after additional stirring, 7.8 ml of N-methylaniline and 7-10 ml of 40% water15 were added after 2 hours of additional stirring at 40 ° C. chilled (20 ° C) reaction. the mixture is treated with 50 ml of concentrated hydrochloric acid, which is added dropwise. After 1 h of further stirring, the reaction mixture was cooled to 0-5 ° C, treated with 350 ml of cold water, which was added dropwise (5 ° C), and stirred for 1 h.
The resulting precipitate was filtered with a filter, washed with water and dried under vacuum at 40 ° C. 14.8 g (73% yield) of the title compound are obtained, mp 160-163 ° C.
Example 2. 2,6-Dibromo-b-bromomethylandrost-4-en-3,17-dione (V, Ri - R ₂ = R ₃ = R 4 -Η).
A 500 mm 3-liter 3-neck round-bottom flask equipped with a condenser, thermometer, dropper (dropping funnel) and magnetic stirrer is charged
4.98 g of 6-methyleneandrost-4-en-3,17-dione, 140 ml of diethyl ether and are cooled to 2-3 ° C with an external cooling bath.
5 drops of a 33% solution of HBg in acetic acid, 1.73 ml of HBg dissolved in 17 ml of glacial acetic acid were added in order of 5 drops in order of 10 minutes, and after 5 minutes of additional stirring, a mixture of 25 ml of ethanol and 25 ml of water was added. .
The diethyl ether was evaporated in vacuo and the reaction mixture was treated with 100 ml of water and stirred for 1 h. The resulting precipitate was filtered off with a filter, washed with water and dried in vacuo at 30-35 ⁶ С. 7.6 g (14.15 40 mmol) were obtained. yield 84%) of the title compound as white crystals.
Example 3.2 “5rom-6-methyleneandrost-
4-en-3,17-dione (Vi. Ri - R2 = · = R3 = Rα = H).
2.68 g of 2,6-dibromo-6-bromomethylanilrost-4-en-3,17-diode, 100 ml of acetone are charged into a 250-milliliter 3-necked round-bottom flask equipped with a condenser, thermometer and magnetic stirrer.
5.99 g of sodium iodide. The resulting suspension was refluxed for 15 minutes, cooled to room temperature, filtered and evaporated in vacuo. The residue was collected with 50 ml of chloroform, washed twice with a saturated aqueous solution of sodium thiosulfate, twice with water and dried over anhydrous calcium chloride. After evaporation of the solvent in vacuo, 1.86 g of the crude title compound are obtained, which are directly used in the next step. /
1757470 6
Example 4. b-Methyleneandrosta-1,4 diene-3, 17-dione (I, Ri = R2 = R3 = R4 = H)
1.86 g of crude 2-bromo-methyleneandrost4-en-3,17-dione, 50 ml of anhydrous DMF, 1.84 g of carbonate are charged into a 100 ml 3-necked round-bottom flask equipped with a condenser, thermometer and magnetic stirrer. lithium and 2.11 g of lithium chloride. The reaction mixture is stirred and heated at 120 ° C. for 2.5 hours, cooled-1 is allowed to reach room temperature, and it is poured dropwise into a 4-fold volume of stirred water. The resulting precipitate was collected by suction, washed with water and dried under vacuum at 40 ° C. 700 mg (2.36 mmol, 47% yield based on the compound of formula V) of the title compound are obtained, mp: 192-195 ° C.
Found. %: C 81.01: H 8.16. /.· <: „. · С2ОН24О2!
Calculated,%: C 81.04: H 8.05. UV (EtOH, m μ): 247 (ε = 13750). NMR (CDCI3, <5): 0.94 (ZN, s.); 1.17 (ЗН. С.): 5.04 (2Н.m.); 6.18 (1H, broad s): 6.25 (1H, dd): 7.09 (1H, d).
Using the same procedure and starting from a suitable compound of formula (VI), the following final products can be obtained.
4-Methyl-6-methyleneandrosta-1,4-diene3,17-dyon,
Found,%: C 81.15: H 8.32.
C21H26O2 ^: Calculated,%: C 81.25; H, 8.44.
4-Chloro-6-methyleneandrosta-1,4-diene-3, 17-dione, mp 148-150 ° C.
Found,%: C 72.40: H 6.91: CI 10.53. S2N23SYU2
Calculated,%: C 72.61; H 7.01; C110.72. NMR (SDC1z, δ): 0.84 (ZN, s); 1.24 (ZN, s); 5.13 (1Ή. S); 6.37 (1H, d): 7.08 (1H, / 0;
M (m / z): 330. 4-Bromo-6-methyleneandrosta-1,4-diene-Z,. 17-dione.
Found,%: C 63.90; H, 6.03: Wh, 21.15. С20Н23ВГО2 · * 'Calculated,%: C 64.00, H 6.18: Vg 21.29.
4-Fluoro-6-methyleneandrosta-1,4-diene-3, 17-dione.
Found,%: C 76.35; H 7.34; F 6.01. C2OH23FO2.
Calculated,%: C 76, 41: H 7.37; F 6.04.
a-Methyl-6-methyleneandrosta-1,4-diene-3,17-dione.
NMR δ, ppm: 0.91 (S, d): 0.94 (S, s); 1.16 (3H, s): 4.97 (2H. M): 6.14 (1H, d); 6.27 (1 Nd); 7.08 (1H, d).
Ms (m / z): 310.
PRI me R 5. 1 a-Methyl-6-methyleneandrosta-4-en-3,17-dione (IV, Ri “-CH3; R2 = R3 = R4 = H4).
Using the procedure described in example 1.3 g of 1 a-methyl androst-4-en3,17-dione, 3 ml of diethyl orthoformate, 80 mg of p-toluenesulfonic acid, 1.1 ml of N-methylaniline and 1.2 ml of 40% an aqueous solution of formic aldehyde gives 2.34 g (yield I0 75%) of the title compound.
NMR (SDS1.s. Δ): 0.90 (3Η, s); 0.95 (ZN, d); 1.20 (3H, s): 4.95 (2H, d): 5.98 (1H, s).
An example. 1a-Methyl-2,6-dibromo-6b rommethyl l anrost-4-ene-3,17-dione (V, Ri I5-CH3; R2 = R3 - R 4 - Η).
When using the methodology described in example 2.1.79 g of 1 a-methyl-6-methyleneandrost-4-en-ZL7-dione and 0.7 ml of Vgg. dissolved in glacial acetic acid; ! 0 give 2.5 g (81% yield) of the title compound as white crystals.
PRI me R 7. 1 a-Methyl-2-bromo-6-methyleneandrost-4-en-3,17-dione (VI, Ri ”CH3; R2 = R3 = R4 = H).
using the procedure described in example 3, 2.5 g of Nmethyl-2,6-dibromo-6-bromomethyl-androst-4-en-3,17-dione and 5.5 g of sodium iodide in acetone give 1.6 g of crude in the name of the compound that is directly used in the next step.
PRI me R 8. 1 a-Methyl-6-methyleneandrosta-1,4-diene-ZL7-diene-3,17-dione (I, Ri = CH3: R2 = R3 · R4 = H),
Using a procedure similar to that described in Example 4.1.6 g of crude 1.-methyl-2-bromo-6-methyleneane drost-4-en-3.17-dione, 1.6 g of lithium carbonate and 2 g of lithium chloride in DMF give 625 g of the title compound, mp. 158-161 ° C.
Found. %: C 80.23: H 8.34.
S21N26O2
Calculated,%: C 81.25: H 8.44.
NMR (CDC1S, δ): 0.93 (ZN, s); 1.27 (ZN, 45 s): 2.13 (ZN.d); 4.97 (2H, m); 6.10 (1H, d); 6.20 (1H, m).
Using the same procedure and starting from a suitable compound of formula (VI), the following final products can be obtained.
1-Ethyl-6-methyleneandrosta-1,4-diene-3, 17-dione.
Found. %: C 81.32, H 8.62.
S22N28O2
Calculated,%: C 81.44, H 8.70.
-Metyl-4-fluoro-6-methyleneandrosta-
1,4-diene-Z, 17-dione.
Found. %: C 76.75; K 7.62; F 5.71.
C21H25FO2
Calculated,%: C 76.80; H, 7.67; F 5.79.
Similarly, the following 7- and / or 16-substituted derivatives can be prepared as epimers or mixtures thereof.
1,7-Dimethyl-16-fluoro-6-methyleneandro sta-1,4-diene-3,17-dione.
Found,%: C 77.05; H 7.80; F 5.45.
C22H27FO2
Calculated,%: C 77.16; H 7.95; F 5.55.
Thus, the method allows to obtain the target products, excluding the stage of column chromatographic separation and Using DDH.

权利要求:
Claims (1)
[1]
The claims where R _{a is} lower alkyl; Rb is phenyl,
10 in an organic solvent at 30-50 ° C. to obtain a compound of the general formula
The method of obtaining 6-methylene derivatives of 15 derivatives and ndrosta-1,4-diene-3,17-dione of the General formula
Bi
R „.
R <
ABOUT
R ₂ ch ₂ where each Ri and R3 independently is hydrogen 25 or a Ci-Ci alkyl;
R2 is hydrogen, halogen or C1-C4 alkyl;
Ri is hydrogen or fluorine, characterized in that, in order to simplify the process, ‘interact the compounds of General formula (P);
CH ₂ where Ri - Ri have the indicated meanings, which are then dehydrogenated by bromination to give a compound of the general formula
Ri
Vg
ABOUT
-Br
R ₂ H ^ag i QF ^1.
where Ri - R4 have the indicated meanings, which are then debromized to give a compound of general formula
About where Ri - Ri have the indicated meanings;
R is lower alkyl, with a 30-40% aqueous formaldehyde solution and amine hydrochloride of the general formula
CH ₂ <. <
where Ri - R4 have the indicated meanings, and its dehydrobromination to obtain the target compound.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB888801697A|GB8801697D0|1988-01-26|1988-01-26|Improvements in synthesis of 6-methylene derivatives of androsta-1 4-diene-3 17-dione|

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