CS221421B1 - Process for producing 2-acyl derivatives of ergoline - Google Patents

Abstract

The invention relates to a method for the production of 2-acyl derivatives of ergoline, preferred intermediates in the synthesis of pharmacodynamically active substances, by reacting an unsubstituted precursor with an aliphatic acyl anhydride in the presence of a Lewis acid, in particular boron trifluoroetherate, as a catalyst, at a temperature of 15 to 25 °C, after which the obtained products are converted into the corresponding addition salts by neutralization with inorganic or organic acids.

Description

The present invention relates to a process for the preparation of ergoline 2-acyl derivatives, preferred intermediates for the synthesis of pharmacodynamically active compounds, by reacting an unsubstituted precursor with an aliphatic acylanhydride in the presence of a Lewis acid, in particular boron trifluoride etherate catalyst, at 15-25 ° C. inorganic or organic acids in the respective addition salts.

The present invention relates to a process for the preparation of 2-acyl ergoline derivatives of general formula (I)

where it means:

R ¹ is hydrogen, methyl, 2-cyanoethyl or .acetylskupinu,

R ² aliphatic acyl group having 2 to 5 carbon atoms,

R ³ alkyl of 1 to 3 carbon atoms,

R ^{4 is} methoxycarbonyl, cyianmethyl, carbamoylmethyl or diethylureido, and their acid addition salts.

The compounds of formula I are valuable intermediates for the preparation of pharmacodynamically active substances.

According to the invention, the compounds of the formula I are prepared by the preparation of a compound of the formula II

in which

R ^1, R ³ and R ⁴ have the same meaning · as in formula I, is reacted with the formula III lacylanhydridem

R_CO-O-CO-R 1 (III), wherein

R @ ¹ and R @ ¹ , identical or different, denote alkyl having 1 to 4 carbon atoms, in the presence of a Lewis acid, preferably boron trifluoroieitherate, in an acyl anhydride of the formula III or in an inert organic solvent such as nitromethane or chloroform. up to 90 ° C, preferably at 15 to 25 ° C, after which the obtained products are converted into an addition salt by neutralization with an inorganic or organic acid.

The process according to the invention is described in more detail in the following non-limiting examples.

Example 1

2-Acetyl-8/3-methoxycarbonyl-6-methylergoline-I

To a stirred mixture of 10 g (0.0352 mol) of dihydrolysergic acid-I ester and 80 g (0.784 mol) of acetic anhydride is added a solution of 14.9 ml (0.118 mol) of boron trifluoride etherate in 15 ml of acetic anhydride at 10 ° C over 10 minutes. The mixture was stirred for 15 minutes at room temperature and poured into a stirred mixture of 100 g of ice, 50 ml conc. ammonium hydroxide and 200 ml dichloromethane. The basicity of the mixture is adjusted by adding conc. The organic layer is separated, the solvent is evaporated off under reduced pressure and the residue is chromatographed on a silica gel column with 2% methanol in chloroform. The homogeneous fractions were combined, evaporated and the residue crystallized from 90% aqueous ethanol. A crystalline product is obtained at mp 220-222 ° C, (α) _D ²⁰ = -172.85 ° (c, 0.2; pyridine).

As in Example 1, the following were prepared:

2-acetyl-8β-cyanomethyl, 1-6-methyl, lergolin-1, mp 271-273 ° C (?) _N 20 = -158.0 ° (c 0.2; pyridine)

2-acetyl-1S-methoxycarbonyl-1,6-diimethylergoline-1, it. mp 190-191 ° C; i (a) _D ²⁰ = -164.14 ° (c 0.2; pyridine)

2-acetyl-l-cyanoethyl-8 ₁ 3-cyanomethyl-O-methyl-ergoline-I, mp 260-261 ° C, f, a) _D 20 = -138.89 ° (c 0.2, pyridine)

1. .. 2-dialethyl-8, .alpha.-methoxycarbonyl-6-methylergoline-I, mp 175 DEG-176 DEG C., [ ^.alpha .] D @ ²⁰ = -66.62 DEG (c 0.2; pyridine)

2-acetyl-8H-3-carbamoylmethyl-6-meithylergoline-1, m.p. greater than 350 ° C, (a) _D ²⁰ = -106.6 ° (c 0.2, pyridine)

2-acetyl-8- [beta] -carbamoyl, methyl-6-propylorgolin-1, i. mp 275-279 ° C, (α) _D ²⁰ = -89.41 ° (c 0.2, pyridine)

1. 2-diacetyl-8? - (Ν, Ν-diethylureido) -6-methylergoline-I, non-crystalline oil: (a) _D ²⁰ = 30.99 ° (c 0.2; pyridine) 1,2- idiacetyl-8a- (Ν, Ν-diethylureido) -6-methylergoline-II, non-crystallising oil, (α) D ²⁰ = 98.82 ° (c 0.2; pyridine)

Example ¹

2-acetyl-8,3-imethoxycarbonyl-6-methylergolin-1

To a stirred mixture of 2.84 g (0.01 mol) of 8β-methoxycarbonyl-6-methylenegin-I and 30 g

6 (0.34 mol) of OH5COOCHO was added at 15% 5 g (01.036 mol) of boron trifluoride etherate and then stirred for a further 20 minutes at room temperature. The reaction mixture was worked up as in Example 1. The title product was obtained, mp 219-221 ° C, (α) _D ²⁰ = -173.0 ° (c 0.2, pyridine).

Example 3

8β-Imethoxycarbonyl-6-methyl-2-propionylergoline-I

To a stirred mixture of 2.84 g (0.01 mole of 8i / 3-methoxycarbonyl-O-methylergoHnu-Ι) and 40 g (0.31 mole) of propionic anhydride was added 5 g (0.036 mol) of boron trifluoride etherate at 10 ° C and stirred to · additional 30 ¹ minute at room temperature. the reaction mixture was poured onto · excess cold saturated solution of ^Na HCO 3 and extracted repeatedly with dichloromethane. the organic extracts were combined, dichloromethane was evaporated under · vacuo and the residue chromatographed on silica gel, 2% The homogeneous fractions were combined, evaporated to dryness under reduced pressure, and the residue was crystallized from methanol to give the title product, mp 209-211 ° C, (α) _D ²⁰ = -165.9 ° , (c 0.2, pyridine).

In a similar manner, N, N -cyanmaithyl-6-methyl-2-propionylergoline-1, mp 225-227 ° C, was prepared. (?) _D ²⁰ = -147.45 ° (c 0.2, pyridine) .

Example 1 a d 4

2-tert-butyryl-8S-imethoxycarbonyl-6-methylergoline-I

To a stirred suspension of 2.84 g (0.01 mol). 8-Methoxycarbonyl-6-methylergoline-I and 32 grams (0.2 mol) of tert-butyrylanhydride are added at room temperature to 5 g (0.036 mol) of boron trifluoride etherate and the mixture is stirred at this temperature for 16 hours. It is then added to 300 ml of a 2% aqueous tartaric acid solution and shaken repeatedly with dichloroethane. The aqueous phase was separated, basified with ammonium hydroxide to pH = 8 and shaken repeatedly with dichloromethane. The organic extracts were combined, evaporated and the residue chromatographed on a silica gel column with 2% methanol in chloroform. 196 DEG-200 DEG C., ( _.alpha. ) _D @ ²⁰ = -148 DEG (c 0.2, pyridine).

Analogously 2-terc.butyryl 8jl-cyanomethyl-6-methyl-I, mp 206 to 209% ( «) _n ²⁰ = -134.0 DEG (c 0.2, pyridine). Example 5

Acid imaleinate 2-acetyl-8/3-methoxycarbonyl-O-methylergoline-I

To a boiling solution of 326 mg (1 mmol) of 2-acetyl-β-methoxycarbonyl-6-methylergoline-I in 5 mL of methanol was added a solution of 140 mg (1.2 mmol) of maleic acid in a minimum amount of hot methanol. After cooling, the title product crystallizes, mp 228-234% (α) _D ²⁰ = -120.7.4 ° (c 0.2, pyridine).

SUBJECT

Process for the preparation of ergoline 2-acyl derivatives of the general formula I

R ( ¹⁾ is hydrogen, methyl, 2-cyanethyl or acetyl,

R ² aliphatic acyl group having 2 to 5 carbon atoms,

R ³ alkyl of 1 to 3 carbon atoms,

^R4 methoxycarbonyl, kyanroethylskuplnu, carbamoylmethyl group ^ι · u. Or di-

Claims (1)

OF THE INVENTION ethylureido group, and acid addition salts thereof, characterized in that a compound of formula II wherein R ¹ , R ³ and R ⁴ have the same meaning as in formula I is reacted with an acyl anhydride of formula III R - CO - O - CO - R '(III) wherein R and R', the same or different, denote alkyl having 1 'to 4 carbon atoms, in the presence of a Lewis acid, preferably boron trifluoride etherate, in an acyl anhydride of formula III; in an inert organic solvent such as nitromethane or chloroform at a temperature of from 0 to 50 ° C, preferably at 15 to 25 ° C, whereupon the products obtained are optionally converted by neutralization with an inorganic or organic acid into an addition salt.