DE2021706C2 - Process for the production of peptide-like ergot alkaloids - Google Patents

Description

H-NH-A

OD

wherein -NH-A has the above meaning, their salts in the form in a solvent inert under the reaction conditions, organic solvent or solvent mixture in the presence of tertiary organic bases, at -20 ° to - to react 10 ° Cumsetztunddas reaction mixture for a short time at temperatures of below 0 ⁰ C. leaves.

2. The method according to claim 1, characterized in that that 1.3 to 2 mol of the mixed anhydrides of trifluoroacetic acid with compounds of the general formula III, wherein R, hydrogen, a lower alkyl group, the allyl or the Benzyl group means and fjfj for "iie grouping

CH-CH = C

/ C = CH-CH

CH-CH ₂ -CH

stands, with 1 mol of compounds of the general formula II in which -NH-A is a cyclic one Polypeptide residue of the type in the structure of the ergot peptide alkaloids involved polypeptide residues means, converts in the form of their salts.

3. The method according to claim 1, characterized in that the starting material used is any mixture of acids of the general formula III, wherein z ~ x ~ y has the meaning given above.

The invention relates to a process for the preparation of compounds of the general formula I.

O A

Il /

C-NH

where χ y for the grouping

_CH ₂ -CH or -CH =

and R ₁ denotes a hydrogen atom, a lower allyl group, the allyl or benzyl group and -NH-A denotes a cyclic polypeptide residue of the type of polypeptide residues involved in the structure of the mother corapeptide alkaloids and is defined by the claims above.

The type of compound of the general formula I includes, for example, those in Examples 1-10 listed compounds, as well as 9,10-dihydroergostine, 9,10-dihydroergovaline, 9,10 dihydroergonine and Ergoptin.

A preferred embodiment of the process according to the invention consists in using a mixture of 1-Ri-lysergic acids, 1-Ri-isolysergic acids and 1R, -6-methyl- ⁸ 5-ergolen-8-carboxylic acids as the compound of the general formula UI used

In the preparation according to the invention of the mixed anhydrides of compounds of the general Formula III with trifluoroacetic acid becomes the ratio of the output products chosen so that based on

1 Mon! of compounds of the formula III as a monohydrate 2-2.4 moles of trifluoroacetic anhydride, or based on 1 mole of the dry compounds of the general Formula III I -1.4MoI trifluoroacetic anhydride and

2 moles of trifluoroacetic acid are used. In the case of one that deviates from the monohydrate or the dry form The water content of the compounds of general formula III is the amount of trifluoroacetic anhydride used and the trifluoroacetic acid varies accordingly in. In this reaction, therefore, are in each case on 1 mol of the mixed anhydride of the compounds of the general formula III with trifluoroacetic acid about 3 moles of trifluoroacetic acid formed.

If one proceeds from the connections of the general J5 formula III, where zlTy for the grouping

CH-CH = C
/ \

and R _{1 has the} above meaning, these are advantageously used as hydrates, as a result of which considerable substance losses can be avoided when these decomposable carboxylic acids are dried.

Compounds of the general formula III, in which z ~ x ~ y represents the grouping

CH-CH ₂ -CH
\

C = CH-CH

stands and R | has the above meaning, can be prepared by heating to max. 150 ⁰ C in vacuum to dry easily, and also, surprisingly, mixtures of 1-R, -Lysergsäuren, 1-R, 1-R -Isoiysergsäuren and _r 6-methyl ^ '■ ⁹ -ergolen-8-carboxylic acids. These compounds or mixtures are therefore preferably used in dry form. b5

As an inert organic under the reaction conditions Solvent or solvent mixture can, for. B. acetonitrile, dimethylformamide. Dimethylacetamide, Propionitrile, N-methylpyrrolidone, methylene chloride or mixtures thereof are used. The order of addition of reagents for preparation the mixed anhydride is interchangeable. For example, the connections of the general Formula III suspended in anhydrous form in one of the organic solvents mentioned above and brought into solution by adding 1 to 5 mol, preferably about 2 mol of trifluoroacetic acid, whereupon 1 mole of trifluoroacetic anhydride enters, or both reagents are simultaneously in a suspension of the compounds of general Formula III was added dropwise in an inert solvent. It is also possible to change the order of the Trifluoroacetic acid and Ti ifluoroacetic anhydride to exchange.

Since the 'mixed anhydrides thus obtained of the compounds of the general formula III with trifluoroacetic acid are very decomposable, they become instantaneous reuse as a solution. In this solution of the mixed anhydrides, a compound is now immediately established of the general formula II in the form of its salt, e.g. B. as Hydrochloride, registered, with a ratio of 1 mol of a to achieve optimal yields Salt of a compound of the general formula II to 13 to 2 mol of the mixed anhydride of trifluoroacetic acid with the compounds of general formula III recommends. By adding a large excess a tertiary organic base at -20 ° C to -10 ° C is now the base of the general formula II in freedom set that spontaneously with the mixed anhydride of trifluoroacetic acid with the compounds of general Formula III reacts. Optionally, the order of addition of the base and the compounds of general formula II are interchanged in the form of their salts. The reaction mixture is left for a short time React time at temperatures below 0 ° C, advantageously 15 to 100 minutes in one Temperature range from -15 ° C to 0 ° C.

The compounds of the general formula I are thus obtained in a practically quantitative yield and so on high purity that a chromatographic purification of the process end products is mostly unnecessary.

The use of compounds of the general formula III in the form has proven to be particularly advantageous a mixture of lysergic acid, isolysergic acid and e-methyl-Zl ^ -ergolencarboxylic acid as the starting material. This mixture can be obtained directly by saprophytic cultivation of the fungal strain NRRL 3080 of the species Claviceps paspali Stevens et Hall are obtained (see DE-OS 14 42 294).

From Chem. Ber. 87, 248-256 (1954) it is known that certain aliphatic carboxylic acids (glycine and Alanine) with trifluoroacetic anhydride to form mixed anhydrides and these are mixed with aniline to the allow the corresponding carboxylic acid anilides to react.

In US-PS 27 36 728 is the preparation of the mixed anhydride from trifluoroacetic acid and Lysergic acid and in US Pat. No. 2,997,470 the production of individual simple lysergic acid amides by reaction of mixed anhydride. The yields obtained by these processes are not very high. In addition, this process cannot easily be applied to the production of ergot peptide alkaloids of the kind described herein.

From HeIv. Chim. Acta 46 (1963), p. 2306 ff., Especially

S. 2316, 2317 and 2327, it is known that the primary amine components of the peptide-like ergot alkaloids, the so-called aminocycloles, only in the form of their salts, e.g. B. the hydrochloride, are resistant. The attempt to produce the free bases from the salts fails. Even under mild alkaline reaction conditions (sodium hydrogen carbonate), an irreversible and almost quantitative rearrangement into the N-cyclol takes place. This rearrangement takes place in absolute pyridine at - 10 ⁰ C. The thus-formed N-Cyclol is provided as tertiary amine "> in the absence of a hydrogen atom an inappropriate for a condensation, non-reactive component.

Therefore, it was not foreseeable that the activation of lysergic acid in the form would the mixed anhydride with trifluoroacetic as described in the present "one-pot" process enough to avoid this rearrangement and at low reaction temperatures (-20 ° to - 10 ⁰ C ) to achieve a smooth reaction of ^2I) lysergic acid with aminocyclole hydrochloride, which proceeds in high yields.

Numerous synthetic possibilities for producing the peptide bond are known from the literature; See, for example, DE-PS 10 51 861, AT-PS 2 16 679 and J. Org. Chem. 24,368 ff. (1959) and generally also Chimia 16:403 (1962). When applied to the production of lysergic acid amides, it was found that these methods can be used for reaction with simple, low molecular weight amines. The received Yields are around 65 to 85%. When using this method using However, the yields of peptides are only 5 to 25%.

If the mixed anhydride of lysergic acid is used according to US Pat. No. 2,736,728 and 29 97,470 Trifluoroacetic acid with 5 moles of amine, on the other hand, could be used in the reaction with simple amines im Within a one-pot reaction at temperatures from -15 ° to the reaction temperature, only moderate yields achieve from about 20% amides.

In analogy to the above-mentioned substantial deterioration in the yields in the case of the known Manufacturing processes with a transition from simple amines to peptides, one would have, in particular taking into account the low reaction temperatures, also with a substantial decrease in yield have to calculate what should have led to a hopeless reaction sequence. So it was astonishing that in the case as claimed here, one proceeds excellent yields peptide-like ergot alkaloids.

It was therefore surprising according to the invention that the known rearrangement of the salt of aminocyclole (primary amine) in the non-reactive N-Cyclol (tertiary amine) did not take place. Likewise, it was not too o expect that compared to a similar process in which simple amines are reacted with the Peptides no reduction in yield, but on the contrary an increase in yield takes place. Also the The fact that the activation of sergic acid at so w> low reaction temperatures is sufficient and such a smooth reaction with yields of 70 and 85% could not be achieved to be expected.

Another aspect is that one can work with favorable <>'< molar ratios of the starting compounds (preferably only 1 mol of valuable aminocycH as salt to 13-2 mol of lysergic acid), compared to the large excess of about 5 mol of amine component that would otherwise be used.

Another advance is that the claimed process is in the form of a one-pot process it is carried out that the mixed anhydrides are not isolated.

The advantage of the method according to the invention over that for ergot peptide alkaloids so far known methods, for example via the lysergic acid chloride hydrochloride to be isolated, is that the new synthesis has been reduced by an essential step. It was also surprising that the Implementation of the mixed anhydride from trifluoroacetic acid and a mixture of the corresponding lysergic acid, Isolysergic acid and ö-methyl - ^^ - ergolen-S-carboxylic acid with the corresponding aminocyclole in the form of the salts in a single stage is possible Mixture of lysergic acid, isolysergic acid and e-MethyM ^ -ergolen-e-carboxylic acid used as starting material can be easily obtained by saprophytic breeding. A condensation of these mixtures with the amine component according to known processes does not succeed or at most m "-t very poor Exploit. After the production of the functional, reactive derivatives, a separation into the make individual components, which would cause considerable difficulties.

The yields are based on the aminocyclole hydrochloride used.

example 1
Ergotamine and Ergotamine

3.72 g (13 mmol) of d-lysergic acid monohydrate are dissolved in 20 ml of abs. Suspended acetonitrile and cooled ^{to -20 0 C with stirring.} Then a solution of 5.46 g (26 mmol) of trifluoroacetic anhydride in 20 ml of abs. Acetonitrile is added dropwise such that the temperature does not exceed -20 ⁰ C. After stirring for 10 minutes at -20 ° C, 3.68 g (10 mmol) (2RpS ₁ ICAlObS) -2-amino-5-benzyl-3,6-dioxo-1 Ob-hydroxy-2-methyl-

octahydro-SH-oxazoIofS ^ -a ^ yrroloss.l-cJpyrazine hydrochloride added to the clear solution and immediately add 20 ml of abs. Pyridine was added dropwise so that the temperature does not rise above -10 ⁰ C. After lstündigem stirring at - 10 ⁰ C to 0 ⁰ C, the reaction mixture in 500 ml of methylene chloride is cast, layered with 100 ml 2 N sodium carbonate solution and shaken. The aqueous phase is separated off, extracted four times with 100 ml of methylene chloride each time, and the combined organic phases are washed with 50 ml of 2N sodium carbonate solution and dried over 20 g of sodium sulfate and 2 g of activated charcoal with stirring. After the solvent has been distilled off at a pressure of 20 mbar, the last residue of pyridine is removed by adding 2 200 ml of toluene and subsequent distillation. The resulting ocher-colored powder as a healing residue is crystallized from 50 ml of methanol, and so pure kristaliines ergotaminine of melting point 236-237 ⁰ C (dec.) Was obtained, [α]? = + 375 ° (c = 0.5 in chloroform).

The mother liquor is concentrated to dryness and the ergotamine is absorbed as a sparingly soluble sulfate in a mixture of 40 ml of methanol and 7 ml of glacial acetic acid with the addition of vr η 0.25 g of sulfuric acid in a little Methanol crystallizes. After standing in the refrigerator for 2 hours, a precipitate of brown,

shiny crystals with a melting point of 201-203 "C, which is extracted between 5% aqueous ammonia and chloroform and after drying over sodium sulfate and activated carbon. Add the theoretical amount of d-tartaric acid in methanol and then Directly constrict an almost pure white ergotamine tarrate without further purification results.

The mother liquor from ergotamine sulfaic crystallization is concentrated in vacuo and - as described above - worked up. By chromatography on the 3C times the amount of aluminum oxide. Activity I. become even more pure with methylene chloride as the elution medium Ergotamine and with methylene chloride, which contains 0.5% methanol, further ergotamine was obtained. The ergotamine can be obtained by dissolving it in twice the amount of glacial acetic acid and adding the theoretical amount Amount of sulfuric acid in ten times the amount of methanol by simply allowing it to stand at room temperature be rearranged in ergotamine sulphate, which increases the yield of pure hrgotamine tartrate increased accordingly. Overall yield 80%.

Example 2
Ergotamine and Ergotamine

10.7 g (4OmMoI) of an anhydrous mixture of 40% ö-MethyM ^ -ergolen-S-carboxylic acid, 40% lysergic acid and 20% isolysergic acid are abs in 40 ml. Suspended dimethylformamide and brought into solution by adding 9.12 g (8OmMoI) trifluoroacetic acid with stirring. This solution is cooled to -20 ⁰ C. 10.08 g (48 mmol) of trifluoroacetic anhydride in 40 ml of abs. Acetonitrile was added dropwise so that the temperature ^{does not exceed -15 =} C and then stirred for 10 minutes at this temperature. Then 736 g (20 mmol) (2R.5S.I0aS.10bS) -2-amino-5-ber.zyi-3. & - dioxo-! 0b hydroxy-2-methy! Cc! 2hydro-8H-oxazolo [ 3.2-a] pyrrolo [2.1-c] pyrazine hydrochloride is shown: and quickly 40 ml abs. Pyridine was added dropwise so that the temperature does not exceed -10 ° C. After ¹ i /. H stirring between - 10 ⁰ C and 0 ~ C, the reaction is completed. The reaction mixture is poured into 1 1 of methylene chloride, extracted with 200 ml of 2N soda solution and worked up as in Example 1. In this way, whitish ergotamine with a melting point of 234 ° (decomp.) And light brown, shiny ergotamine sulphate with a melting point of 203 ° (decomp.) Are obtained. The ergotamine is converted into ergotamine sulphate as in Example 1. Overall yield 85%.

Example 3

Ergostin

Ergostin is prepared according to the procedure described in Example 2, using

10.7 g (4OmMoI) of an anhydrous mixture of

40% e-MethyM ^ -ergolen-e-carboxylic acid, 40% lysergic acid and 20% isolysergic acid,
9.12 g (80 mmol) trifluoroacetic acid,

10.08 g (48 mmol) of trifluoroacetic anhydride and
11.12 g (20 mmol) (2R, 5S.10aS, 10bS) -2-amino-

2-ethyl-5-benzyl-3,6-dioxo-1 Ob-hydroxyociahydro-oH-oxazoiofB ^ -ajpyiTolo- [2,1-cipyraziii -hydrochlorid ■ 2 Dioxane
obtain. Yield about 70%.

Example 4 Ergocristine

Ergocristine is by the process described in Example 2 ■ · methods using 10.7 g (4OmMoI) of an anhydrous mixture of 40% 6-MethyM ^8ll -ergolen-8-carbonsäiire. 40% lysergic acid and 20% isolysergic acid, 9.12 g (80 mmol) trifluoroacetic acid and i ') 10.08 g (48 mmol) trifluoroacetic anhydride and 9.4 g (20 mmol) (2R.5S.10aS, 10bS) -2-amino -5-benzyl-S.ö-dioxo-lOb-hydroxy ^ -isopropyloctahydro-8H-oxazolo [3,2-a] pyrrolo {2.1-c] pyrazine hydrochloride · dimethylformamide ''' .

B e i s ρ i e 15

Ergovalin

^: "'Ergovaiin will ικαίΐ uciü in Example 2 using the method described

10.7 g (4OmMoI) of an anhydrous mixture of

40% 6-MeihyM ⁸¹⁾ -ergolen-8-carboxylic acid, 40% lysergic acid and 20% isolysergic acid, - '"■ 9.12 g (80 mmol) trifluoroacetic acid.

10.08 g (48 mmol) trifluoroacetic anhydride and 6.4 g (20 mmol) (2R, 5S, 10aS, IObS) -2-amino-2-me-

ethyl-5-isopropyl-10b-hydroxy-3,6-dioxoö <iiihydro-8H-oxazolo [3.2-a] pyrrolo [2, l-c] J "pyrazine hydrochloride

obtain.

According to the method described in Examples 2 to 5, ergocornine can be prepared in an analogous manner. Manufacture ergocryptine and ergonine.

Example 6-9, iÖ-dihydroergotamine

4Π 2.05 g (7.5 mmol) of 9,10-dihydrolysergic acid with a water content of 0.2 molar equivalents are abs in 20 ml. Dimethylformamide suspended by the addition of 1.72 g (15 mmol) of trifluoroacetic acid in solution, and with stirring at - 10 ⁰ C cooled. 2.10 g are added dropwise

^: '(10 mmol) of trifluoroacetic anhydride, then contributes 23 ml of abs. Pyridine and the reaction mixture stirred for a further 15 minutes at - 10 ⁰ C. To this is again to - 15 ⁰ C cooled, 1.84 g (5 mmol) of (2R3S, 10aS, 10bS) -2-amino-5-benzyl-3 , 6-dioxo-1 Ob-hydroxy-2-methyloctahydro-8H-oxazolo- [3 ^ -a] pyrrolo [2, lc] pyrazine hydrochloride added, and immediately add 10 ml of abs. Pyridine were added dropwise for 1 hour between -10 ⁰ C 0 ⁰ C and allowed to react. The reaction mixture is cooled in ice, 5% aqueous

'' Poured ammonia and extracted with 3 χ 500 ml of methylene chloride. After the combined organic phases have been dried over sodium sulfate with the addition of activated charcoal, the solvent is gently distilled off in vacuo and the light yellow crude base, which is obtained in the form of a foam, is taken up in 15 ml of aqueous acetone, whereupon the 9,10-dihydroergotamine immediately as hydrous acetone crystals fails in light yellow, shiny prisms drying in high vacuum at 80 ⁰ C, the crystal solvent is removed, and is obtained by thin layer chromatography pure 9,10-Dihydroergotaiiiin of melting point 235 C (dec.), [α]? = -63 ° (c = 0J5 in pyridine). From the mother liquor can be chromatographed on the

50 times the amount of aluminum oxide, activity I, with methylene chloride containing 0.5% methanol elute additional 9,10-dihydroergotamine. Overall yield 72%.

Example 7 Ergostin

tvJ. 75 g (37.5 mmol) of d-lysergic acid monohydrate in 500 ml abs. Suspended acetonitrile and cooled to −20 ° C. with stirring. Then 15.8 g (75 mmol) of trifluoroacetic anhydride were quickly added dropwise, the resulting clear solution for a further 5 minutes -20 ° C stirred and 13.9 g (25 mmol) (2R.5S, l0aS.I0bS) -2-amino-2-ethyl-5-benzyl-3,6-dioxo-10b-hydroxy-octahydro-8H- oxazolo [3 ^ -a] pyrrolo [2, lc] pyrazine hydrochloride, which contains 2 mol of Kxistalldioxan, at -15 ° C added. Then 50 ml of abs. Pyridine was added dropwise so that the temperature does not exceed -10 ° C and Leave the resulting clear solution at between -10 ° C. and 0 ° C. for 1 hour. For work-up, the reaction mixture is poured into 1 1 of methylene chloride with 300 ml of 2N Sodium carbonate solution layered, shaken and re-extracted with 3 × 500 ml of methylene chloride.

The combined organic phases are dried over sodium sulfate with the addition of activated charcoal and gently freed from the solvent in vacuo. This gives a yellow-brown foam which is 15 times the amount of aluminum oxide, activity I, chromatography. With methylene chloride as the eluent, a mixture of ergostin and ergostinin is obtained, which is dissolved in ethanol with the addition of a little glacial acetic acid and mixed with a little more than the theoretical amount of maleic acid. After 3tägigem standing at room temperature, concentrating the reaction mixture in vacuo and filtration, a whitish crystalline Ergostinbimaleinat a melting point of 74- 75 ⁰ C (dec.) [E] = + 87 ° (c \, H;!? Q : Ethanol = 1: 1). After evaporation to dryness, partitioning between methylene chloride and 2N sodium carbonate solution and chromatography of the crude base obtained after drying and distilling off the organic phase on 30 times the amount of aluminum oxide, activity I, with methylene chloride as the eluent, additional ergostin in the form of a yellowish foam can be obtained from the filtrate after evaporation to dryness which is converted into the bimaleate in an analogous manner. Overall yield about 70%.

Example 8 9,10-dihydroergocristine

A suspension of 8.2 g (30 mmol) of 9,10-dihydrolysergic acid with a water content of 03 mol 03 molar equivalents in 200 ml of anhydrous acetonitrile is cooled to -15 ° and 8.4 g (40 mmol) of trifluoroacetic anhydride are added dropwise, with stirring The suspension changes into a homogeneous solution. 9.4 g (20 mmol) of (2R ^ S, 10aS, l 0bS) -2-amino-5-benzyl-3,6-dioxo-1 Ob-hydroxy ^ -isopropyloctahydro-SH are then added -oxazoIoss ^ -aJpyrrolo [2, lc] pyrazine hydrochloride was added, the mixture was stirred at -15 ° C. until a complete solution was formed and 30 ml of anhydrous pyridine was then added. The reaction mixture was continued for 1 hour at -10 ° C. to 0 ^{° C. 0} C stirred, 10 ml of water added and brought to dryness under reduced pressure. The residue is dissolved in a mixture of 200 ml of methylene chloride / methanol (8: 2) and 50 nil IN hydrochloric acid, the phases are separated, the organic phase with

Washed 2 × 50 ml IN hydrochloric acid, the combined aqueous phases with 4 χ 50 ml methylene chloride / metha-

, nol (8: 2) extracted, the combined organic phases washed with 100 ml of 4N sodium carbonate solution, dried over sodium sulfate and brought to dryness. The residue is dissolved in 50 ml of hot acetone; then allowed to crystallize at 0 ° C. After filtration and drying, 9,10-dihydroergocristine with a melting point of 182 ° C. (decomp.), [«] *> = -53 ° (c = \ in pyridine) is obtained. Total bulge 70%.

Example 9 '' 9,10-Dihydroergocryptine

To a suspension of 4.1 g (15 mmol) of 9,10-dihydrolysergic acid (with 0.3 molar equivalents of water content) in 120 ml of anhydrous acetonitrile are under

per stirring at ^{-15 =} C. 4.2 g (20 mfvioi) of trmuoroacetic anhydride are added dropwise, the mixture is stirred for 1 hour at -15 ° C. and 4.2 g (10 mmol) of (2R, 5S, 10aS.10bS) -2 -Amino-3,6-dioxo-10b-hydroxy-2-isopropyl-5- (2-methylpropyl-1) octahydro-8H-oxazolo [3,2-a] pyrrolo-

j'i [2.1-c] pyrazine hydrochloride added. After full Dissolution are 15 ml abs. Pyridine was added and the mixture was then stirred at -10.degree. C. to 0.degree. C. for 1 hour. After adding 10 ml of 4N sodium carbonate solution, the reaction mixture becomes under reduced pressure

in brought to dryness at 30 ° C, the residue in a mixture of 100 ml of methylene chloride / methanol (8: 2) and 20 ml of 4N sodium carbonate solution and dissolved the phases separated. The organic phase is with

3 × 20 ml of 4 N sodium carbonate solution and washed ) -. the combined aqueous phases with 4 × 50 ml of methylene chloride / methanol (8: 2) extracted. The combined organic phases are over sodium sulfate and Animal charcoal dried and evaporated to dryness. The residue is dissolved in 20 ml of hot ethanol,

jo one adds ether until a cloudiness arises and lets it crystallize. The 9,10-dihydric oergocryptin thus obtained melts at 236 ° C. (decomp.) Γ «!" = -41 ° (c = 1 in pyridine). Yield 72%.

■ r, example 10

9,10-dihydroergocornine

To a suspension of 4.1 g (15 mmol) of 9,10-dihydrolysergic acid (Water content 03 molar equivalents) in

-, n 120 ml of anhydrous acetonitrile are added dropwise with stirring at -15 ° C. 4.2 g (20 mmol) of trifluoroacetic anhydride, the reaction mixture is then stirred for 1 hour at -15 ° C. and 4.0 g (10 mmol) of (2R4S. 1 OaS ₁ I ObS) -2-amino-3,6-dioxo-1 Ob-hydroxy-2,5-di-isopropyloctahydro-eH-oxazoIop ^ -aJpyrrolo- [2, lc] pyrazine hydrochloride. After a clear solution has formed, 15 ml of abs. Of pyridine was added, stirred for 1 hour at -10 ⁰ C to 0 ⁰ C, 10 ml

4 N sodium carbonate solution was added and the mixture was evaporated to dryness at 30 ° C. under reduced pressure The residue is dissolved in a mixture of 100 ml of methylene chloride / methanol (8: 2) and 20 ml of 4N sodium carbonate solution dissolved the phases separately, the organic phase with 4 × 20 ml of 4 N sodium carbonate solution washed, the combined aqueous phases extracted with 4 × 50 ml of methylene chloride / methanol (8: 2) and the combined organic phases are dried over sodium sulfate and animal charcoal and dried to dryness

Il

steamed. The residue is dissolved in 20 ml of hot ethanol, ether is added until the onset of cloudiness and left to crystallize. The 9,10-dihydroergocornine obtained in this way melts at 185 ° C. (Zcrs.). [λ] '47 ° (c = 1 in pyridine).

Claims (1)

Patent claims: 1. Process for the preparation of compounds of the general formula I. IO 15th 20th where x ~ y for the grouping -CH ₂ -CH or -CH = C and R, a hydrogen atom, a lower alkyl group, the allyl or the benzyl group and -NH-A is a cyclically structured polypeptide residue of the type in the structure of the parent compeptide alkalo loid polypeptide residues involved means, characterized in that one compound of the general formula HI COOH Ν —CHj J5 (ffl) -10 45 wherein R _{1 has the} above meaning and ; χ y for the grouping CH-CH = C C = CH-CH CH-CH ₂ -CH ■
/ \ is, with Triflüöfessigsäüfciiöhydrid in the presence of trifluoroacetic acid in an inert organic solvent or solvent mixture under the reaction conditions at -20 ⁰ C to ι - 10 C and the resulting mixed anhydrides of trifluoroacetic acid with a compound of the general formula III, wherein R, and £ ~ x ~ v have the above meaning without isolation of the reaction mixture with compounds of the general formula II