Dihydroergocristine Question.

wyndowlicker · Member of the Month

HEy now,

Can anyone give me a workable formula for dihydroergocristine?As detailed as possible or a good link.

W.L Razz

mk-1 · Sat Apr 09, 2005 11:50 pm

should be a patent about those.
Il try and find it later on.... see edit later

meme · Sun Apr 10, 2005 1:34 am

Monograph Number: 3685
Title: Ergoloid Mesylates
CAS Registry Number: 8067-24-1
CAS Name: Dihydroergotoxine monomethanesulfonate (salt)
Additional Names: co-dergocrine mesylate
Manufacturers' Codes: CCK-179
Trademarks: Circanol (3M); Coristin (San Carlo); Dacoren (Nattermann); DCCK (Rentschler); Decril (Mediolanum); Dulcion (Dulcis); Ergodesit (Graf); Ergohydrin (Streuli); Ergoplus (Formosan); Hydergine (Sandoz); Lysergin (Toa Eiyo); Novofluen (Engelhard KG); Orphol (Sanofi); Pérénan (Sanofi Winthrop); Progeril (Midy); Redergin (Lek); Sponsin (Farmasan); Trigot (Bristol-Myers Squibb)
Literature References: Hydrogenated ergot alkaloids, specifically an equiproportional mixture of dihydroergocornine methanesulfonate, dihydroergocristine methanesulfonate and a- and b-dihydroergocryptine methanesulfonate in the ratio of 1.5-2.5:1. Neuropharmacological investigations: D. M. Loew et al., Postgrad. Med. J. 52, Suppl. 1, 40 (1976).

Derivative Type: Dihydroergocristine methanesulfonate
CAS Registry Number: 24730-10-7
Trademarks: Decme (Spitzner); Defluina (Simes); Enirant (Desitin); Insibrin (Byk-Liprandi); Nehydrin (TAD); Simactil (Rorer); Unergol (Poli)
Molecular Formula: C36H45N5O8S
Molecular Weight: 707.85.
Percent Composition: C 61.09%, H 6.41%, N 9.89%, O 18.08%, S 4.53%

Therap-Cat: a-Adrenergic blocker (treatment of impaired mental function in the elderly).

wyndowlicker · Member of the Month

Hey now,

Thanks MK-1 that would be great I do need that.MeMe thanks for the basic imput info for the posts sake.Im looking for an actual procedure more than just the patent.Can anyone help here?

W.L Razz

java · Consumer

I found this article , unfortunately it's only the abstract, put it in the wanted journal articles if you feel it will help in your quest......java
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ABSOLUTE CRYSTAL STRUCTURE DETERMINATION OF ERGOT ALKALOID - DIHYDROERGOCRISTINE METHANESULFONATE MONOHYDRATE

Jan CEJKAa, Jan ONDRACEKa, Michal HUSAKa, Bohumil KRATOCHVILa, Alexandr JEGOROVb,*, and Josef STUCHLIKc
Collection of Czechoslovak Chemical Communications 1995, vol.60, no.8, 1333-1342
doi: 10.1135/cccc19951333

Abstract
Dihydroergocristine methanesulfonate monohydrate crystallizes in orthorhorhombic space group P21212 (No. 1 Cool

with Z = 4, a = 12.736(2) A, b = 39.089(5) A, c = 7.130(1) A, V = 3549.6(9) A3. The indole moiety is nearly planar, both the ergoline ring C and the tripeptide ring F addopt an envelope E6 conformation. The ergoline ring D and the tripeptide ring E have a chair 1C4 conformation. The conformation of the ring G is between E1 and 5T1. The benzene ring H is planar. The structure was solved by direct methods and refined anisotropically to the final R value of 0.078 for 4219 statistically significant observed reflections [I o 1.96s(I)]. The absolute chirality was determined based on anomalous dispersion as: C4 (R), C8 (R), C6 (R), C17 (R), C25 (S), C24 (S), C19 (S).

IndoleAmine · Dreamreader Deluxe

Hm - I guess you mean hydrolysis of said compound, to get rid of the peptide garbage?

Not that I would know anything about it, just wanted to clarify for other bees willing to help (before anyone starts digging out a complete dihydroergocristine synthesis) Mr. Green

i_a

wyndowlicker · Member of the Month

HEy now,

Im looking for the patent number and/or the workable procedure for making dihydroergocristine from ergocristine.

W.L Razz

meme · Sun Apr 10, 2005 8:30 am

From Ergot Alkaloids Kobel and Sanglier 1986:

"Of all the naturally occuring ergot alkaloids, only two are used in therepy: ergotamine and ergometrine. The rest of the therapeutically imortant ergot compounds underwent some chemical changes. One such operation is the elimination of the 9,10-double bond by catalytic hydrogenation, transforming ergotamine into dihydroergotamine and the corresponding ergotoxines into dihydroergocristine, dihydroergocornine, dihydro-alpha-ergocryptine and dihydro-beta-ergocryptine."

"For more details about the structure and chemistry we recommend the following papers: HOFMANN (1964), GROGER (1972), RUTSCHMANN and STADLER (1978), and STADLER and GIGER (1984)."

Maybe one of the papers ref'd have a procedure?

wyndowlicker · Member of the Month

Hey now,

Do you have the exact references or can someone drop something to link these papers to here.Thanks meme.

W.L Razz

mk-1 · Sun Apr 10, 2005 11:56 pm

PROCESS FOR PREPARING SUBSTITUTED AMIDES OF D-LYSERGIC AND D-DIHYDROLYSERGIC ACIDS AND DERIVATIVES THEREOF[/url]

wyndowlicker · Member of the Month

Hey now,

Thanks bees Ive found something.Its just a straight hydrogenation.Can any Russian bees help on the translation?

W.L

PROCESS FOR PREPARING ERGOT ALKALOIDS
The hydrogenated ergot alkaloids mentioned above, the production of which is described in Helv chim Acta 26 2070 ( 1943), are char:

Russian Patents RU2192253 & RU 2063968
Ergocristine is hydrogenated over Raney Nickel Catalyst without addition of external hydrogen to reaction mixture. Catalyst is prepared by heating at 45-50 C. for 1 hour, followed by washing with water for 7-10 minutes up to pH 7 or 8.

method involves hydrogenation of ergocristine over freshly prepared Raney-Ni in ethanol. Then catalyst is separated and dihydroergocristine is isolated as salt with methanesulfonic acid. EFFECT: simplified process.

The surprising observation has now been made that ergotamine, ergotoxine, ergocristine, ergotinine, ergosine and sensibamine, and addition products and salts thereof can successfully be hydrogenated to form their dihydro compounds if the hydrogenation is carried out in the presence of finely divided platinum or rhodium deposited on a carrier, at atmospheric pressure or at a higher pressure not exceeding 10 atmospheres, the hydrogenation being carried out initially at room temperature and completed at an elevated temperature not exceeding 1000 C This process allows the hydrogenation to be carried out, at ordinary pressure or only slightly higher pressure, with the production of crystalline dihydro derivatives.

The platinum or rhodium catalyst can for example be deposited in finely divided form on the carrier by precipitation.

As already mentioned, the hydrogenation can be conducted at atmospheric pressure or at a higher pressure not exceeding 10 atmospheres A pressure of 4 to 5 atm is advantageous for obtaining a good hydrogenation velocity; it has been found that an additional increase in pressure beyond this range does not result in any improvement in the capacity of the process for isolating crystallised dihydro compounds.

The use of the carrier in the process of the invention results in uniform products and good yields; examples of suitable carriers are carbon, aluminium oxide, Ba SO,, Sr SO 1, Ba CO,, Ca CO, and silica gel.

It has been found that it is not necessary, as was formerly assumed to be the case, for the reduction to take place in an inert solvent, but that it is also possible to operate in solvents containing hydroxyl groups without there being any danger of rearrangement to a substantial degree The hydrogenation carried out under the novel conditions according to the invention proceeds so gently that any risk of the rearrangement of the amide of lysergic acid or isolysergic acid is practically excluded.

Instead of the free amides, it is also possible to use their salts or their addition products with for example hydrocarbons or ketones, for hydrogenation purposes, for example the tartrates, succinates, alkyl sulphates or ethionates The free bases can if desired be converted into their salts after the hydrogenation.

The following examples further illustrate the invention: EXAMPLE 1.

1.0 g of ergotamine is shaken with hydrogen at a pressure of 4 atn in 20 cc of dioxane and in the presence of 2 g of rhodium-carbon catalyst ( 5 %), the rhodium being deposited in finely divided form on the carbon carrier, so that the temperature rises within 7 hours from room temperature to 80 C., the shaking being continued until the mixture has cooled After separation of the catalyst, an amorphous white substance is precipitated on adding petroleum ether; this substance is recrystallised from 75 % acetone.

Yield: 0 98 g Characteristics of the starting product (ergotamine).

Melting point: 210-213 C (with decomposition); lol D= 157 ' ( 200 C c= 0 8 in chloroform); Fluorescence: intensive bluish; Solution of 10 mg in 100 ml of 1 % aqueous tartaric acid solution; 1 vol + 2 vol of pdimethyl aminobenzaldehyde reagent (Brit.

Ph.) gives a blue solution, the extinction of which, measured in a Zeiss-Pulfrich photometer, is 0 94 per cm of optical path with an "S.61 " filter and 0 92 with an " S 57 " filter.

Characteristics of the final product (dihydroergotamine acetone water compound):Melting point: 236-239 C (with decomposition); lal D=-62 ( 20 C c= 0 5 in pyridine); Fluorescence: scarcely perceptible; Solution of 15 mg in 100 ml of 1 O/,, aqueous tartaric acid solution: 1 vol + 2 vol.

of the above reagent gives a blue solution, the extinction of which, determined as above, is 0.76 when using an "S 61 " filter and 0 93 when using an " S 57 " filter.

EXAMPLE 2.

2 g of dry ergotamine are shaken with hydrogen at atmospheric pressure in 75 cc of absolute dioxane with 5 g of 5 %/O finely divided platinum coated on carbon The temperature is initially left for one hour in the region of 20 C after which it is raised to 60-70 C this temperature being maintained for 4 hours The catalyst is then filtered off with suction, whereupon the filtrate is washed with dioxane and then gently concentrated by evaporation to 40-50 cc It is now mixed with 100-150 cc of petroleum ether, the dihydroergotamine being crystallised out as minute crystals 2 g of crude product are obtained This product is dissolved in 20 parts of chloroform which contains 10 % of methanol and then filtered The solvent is evaporated off and the residue recrystallised in 10 parts of acetone, which contains 10 % of water 1.8 g of crystalline dihydroergotamineacetone substance are obtained, the melting point of which is 237 C with decomposition.

The determination of the optical rotation shows lal D 2 U=-60 o (c=l in pyridine).

In a manner similar to that described above, ergotoxine, ergocritine and ergosine, and also their addition products with, for example, hydrocarbons or ketones, or their salts, can be reduced to the corresponding dihydro compounds.

Description of GB1298277

PATENT SPECIFICATION

( 11) 1298277 NO DRAWINGS Application No 15306/70 ( 22) Filed 31 March 1970 Convention Application No 5895 ( 32) Filed 18 April 1969 Convention Application No 13262 ( 32) Filed 2 Sept 1969 in Switzerland (CH)

Complete Specification published 29 Nov 1972

International Classification C 07 D 99/02 Index at acceptance C 2 C 182-198-281 191-194-196 213 214 220 226 22 Y 247 250 252 255 25 Y 28 X 29 X 29 Y 303 30 Y 342 34 Y 351 352 360 363 36 Y 604 62 X 672 790 KR ( 72) Inventors PAUL STADLER and ALBERT HOFMANN ( 54) PREPARATION OF ERGOT PEPTIDE ALKALOIDS ( 71) We, SANDOZ LTD, of 35 Lichtstrasse, 4000 Basle, Switzerland, a Swiss Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:The present invention relates to a new process for the production of a compound of formula I, i N A It / c NHX R 1 signifies hydrogen, a lower alkyl radical of from 1 to 4 carbon atoms, the allyl or the benzyl radical, and -NH-A signifies a polypeptide radical with cyclic structure of the type known in ergot peptide alkaloids.

The specific polypeptide radical is described in respect of some ergot alkaloids in the Examples below However, it is to be understood that other peptide groups are also contemplated, in particular the polypeptide group contained in ergotamine, ergostine, ergocristine, ergovaline, ergocryptine, ergocornine and ergonine.

The new process is characterized in that a salt of a compound of formula II, H-NH-A II 35 in which -NH-A has the above significance, is reacted with a lysergic pound of formula III, acid type comin which x y signifies the group -CH/-CH CH 2 CH or / -CH=C, and Pl ( 21) ( 31) ( 31) ( 31) ( 45) ( 51) ( 52) I lPrice 25 pl in which 1,298,277 e-z_,z x y signifies the group \ / CH-CH=C, / \ \ / C= CH-CH or or / CH-CH CH, /\ and R, has the above significance, in an inert organic solvent and in the presence of an N di(lower'alkyl substituted acid amide of an aliphatic monocarboxylic acid having 1 to 3 carbon atoms, the N (lower)alkyl substituents being same or different, and each N (lower)alkyl substituent having from 1 to 4 carbon atoms, a chlorinating agent and an acid-binding agent.

One preferred method of carrying out the process of the invention consists in that a mixture, composed of 1 R, lysergic acids, 1 R, isolysergic acids and 1 R 6 methyl 5 ergolene 8 carboxylic acids, is used as compound of general formula III For example, a mixture of lysergic acid, isolysergic acid and 6 methyl ' ergolene S carboxylic acid, obtained by saprophytic cultivation of the fungus strain NRRL 3080 of the species Claviceps paspali Stevens et Hall, may be used as compound of general formula III The compound of general formula II is employed in the form of a salt, since such compounds are normally unstable in free base form Hydrochloric acid is preferably used as salt-forming acid, although other mineral acids may likewise be used.

The reaction in accordance with the invention forms as intermediary an amido halide by the action of the chlorinating agent on the N di(lower)alkyl substituted acid amide of an aliphatic monocarboxvlic acid; this amido halide is capable of activating the compounds of general formula III by the formation of an adduct This activation reaction is independent of the sequence of the addition of the reagents, since the intermediary formation of the amido halide and the reactive adduct takes place even if the compounds of general formula III are added in a mixture of an N di(lowerzalkyl substituted acid amide of an aliphatic monocarboxvlic acid having 1 to 3 carbon atoms and an inert solvent, and the halogenating agent is subsenuently added.

Examples of suitable halogenating agents are thionyl chloride, phosgene, phosphorus oxychloride, phosphorus oxybromide or oxalyl chloride.

The acid-binding agent, which causes the liberation of the base of general formula II from its salts, may likewise be added to the reaction mixture before or after the addition of a salt of a compound of general formula II.

Examples of suitable inert organic solvents for the reaction of the invention are acetonitrile, chloroform, methylene chloride and an excess of dimethyl formamide, and suitable acid'-binding agents are tertiary 65 amines, e g pyridine The reaction may be effected at a temperature between -10 and + 200 C; the reaction period ranges between 1/2 and 24 hours After the reaction is complete, the final product is isolated from the 70 reaction solution and purified in manner known per se.

A suitable ratio of the starting materials, i.e of the compounds of general formula II and the compounds of general formula III, is 75 1.5 to 2 mols of the compound of general formula III calculated on one mol of the compound of general formula II, in the form of its salts.

After the reaction is complete, the reac 80 tion mixture is worked up in manner known per se.

An advantage of the process of the invention, as compared with the known reaction of an acid chloride hydrochloride of the lysergic 85 acid series with a salt of the basic peptide portion of ergot alkaloids, in an inert organic solvent and in the presence of an ac-id-binding agent, consists in that the production and isolation of the chloride hydrochloride of the 90 lysergic acid series are here avoided.

In the case of the production of the acid chloride hydrochlorides of the lysergic acid series it is necessary to use a large excess of pure phosphorus trichloride and phosphorus 95 pentachloride The destruction of this excess after completion of the reaction is a problem.

Furthermore the acid chloride hydrochlorides of the lysergic acid series can only be handled on a technical scale with difficulty, due to 100 their extreme hygroscopicity and liability to decomposition In accordance with the process of the present invention such disadvantages are eliminated; furthermore the synthesis of ergot peptide alkaloids is shortened by one 105 stage.

The use of compounds of general formula III in the form of a mixture of lysergic acid, isolysergic acid and 6 methyl A 8 ' ergolene 8 carboxylic acid as starting material, 110 has been found to be specially advantageous.

This mixture may be obtained directly by saprophytic cultivation of the fungus strain NRRL 3080 of the species Clazviceps paspali Stevens et Hall The facts indicated above show 115 that the process of the invention permits a' 1,298,277 the production of the pharmacologically highly effective compounds of general formula I, e g.

the alkaloids of the ergotamine and the ergotoxin group, using technically readily obtainable and considerably less expensive starting materials than those hitherto used This results in a considerable lowering of production costs for the products of the process in accordance with the present invention.

Compounds I are known, and many specific members thereof are of known therapeutic value In general compounds I can be described as vaso-active and also have activity on the central nervous system Particulars on the activity and use of compounds of known therapeutic value are available in the literature.

In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are corrected.

Example 1

Ergotamine and ergotaminine.

A solution of 3 18 g ( 25 millimols) of oxalyl chloride in 20 cc of absolute acetonitrile is added dropwise during the course of 5 minutes while stirring vigorously to 40 cc of absolute dimethyl formamide cooled to -10 , and the resulting crystal mass is stirred at the indicated temperature for 10 minutes 5 36 g ( 20 millimols) of an anhydrous mixture of 40 % 6 methyl A', _ ergolene 8 carboxylic acid, 40 %' lysergic acid and 20 '% isolysergic acid are subsequently added, and the resulting dark brown suspension is stirred at about -10 for a further 5 minutes 40 cc of absolute pyridine are then allowed to flow into the mixture while cooling well, at such a rate that the temperature does not exceed -10 .

A suspension of 3 68 g ( 10 millimols) of 2 R, S,1 Oa S,l Ob S)2 amino 5 benzyl 3,6dioxo 10 hydroxy 2 methyloctahydro8 H oxazolol 3,2 alpyrrolol 2,1 clpyrazinehydrochllloride in 40 cc of absolute dimethyl formamide is then added, and the reaction mixture is stirred for 2 hours at a temperature between -10 and 00 Working up is effected by diluting with 500 cc of methylene chloride and shaking thoroughly with 200 cc of a 2 N sodium carbonate solution The aqueous phase is extracted thrice with 300 cc of methylene chloride After drying the combined organic solutions over sodium sulphate and removing the solvent by distillation in a vacuum, the remaining pyridine is removed by the addition of two 200 cc portions of toluene and subsequent distillation The residue obtained as light ochrecoloured powder is crystallized from 50 cc of methanol, whereby pure crystalline ergotaminine, having a M P of 236-237 (decomp), lalD 2 =+ 375 (c= 0 5 in chloroform), is obtained.

The mother liquor is evaporated to dryness, and ergotamine is crystallized as difficultly soluble sulphate by taking up in a mixture of 40 cc of methanol and 7 cc of glacial acetic acid with the addition of 0 25 g of sulphuric acid in a small amount of rnethanol After allowing to stand in a refrigerator for 2 hours, a precipitate of brown, lustrous crystals, having a M P of 201-203 , is obtained; this precipitate is shaken out between 5 % aqueous ammonia and chloroform, and after drying over sodium sulphate and active charcoal, adding the theoretical amount of d tartaric acid in methanol and subsequently concentrating by evaporation, directly yields an almost pure white ergotamine tartrate without further purification.

The mother liquor of the ergotamine sulphate crystallization is concentrated by evaporation in a vacuum and worked up to a base as described above Chromatography on a 30-fold quantity of aluminium oxide, activity I, using methylene chloride as eluant, yields a further amount of pure ergotamine, and elution with methylene chloride containing 0 5 %, of methanol yields a further amount of ergotamine Ergotamine may be rearranged to ergotamine sulphate by dissolving in a twofold quantity of glacial acetic acid and adding the theoretic amount of sulphuric acid in a tenfold quantity of methanol, by simply allowing to stand at room temperature, whereby the yield of pure ergotamine tartrate is correspondingly increased.

Example 2

Ergostine.

Ergostine is obtained in accordance with the process described in Example 1, using 3.18 g ( 25 millimols) of oxalyl chloride, 5 36 g ( 20 millimols) of an anhydrous mixture of % 6 methyl AX,' ergolene 8 carboxylic acid, 40 % lysergic acid and 20 % isolysergic acid and 5 56 g ( 10 millimols) of ( 2 R,5 S,l Oa S,l Ob S) 2 amino 2 ethylbenzyl 3,6 dioxo 10 b hydroxyoctahydro 8 H oxazolol 3,2 alpyrrolol 2,1 clpyrazine hydrochloride 2 dioxane.

Example 3

Ergocristine.

Ergocristine is obtained in accordance with the process described in Example 1, using 3.18 g ( 25 millimols) of oxalyl chloride, 5.36 g ( 20 millimols) of an anhydrous mixture of 40 % 6 methyl A',' ergolene -8carboxylic acid, 40 %,' lysergic acid and 20 % isolysergic acid and 4 7 g ( 10 millimols) of ( 2 R,S Sl Oa S,10 b S) 2 amino 5 benzyl3,6 dioxo 10 b hydroxy 2 isopropyloctahydro 8 H oxazolol 3,2 alpyrrolol 2,1 clpyrazine hydrochloride dimethyl formamide.

Example 4

Ergovaline.

Ergovaline is obtained in accordance with 4 1,298,277 A the process described in Example 1, usin 3.18 g ( 25 millimols) of oxalyl chloride, 5 36 ( 20 millimols) of an anhydrous mixture c %, 6 methyl A 8 ergolene 8 car boxylic acid, 40, lysergic acid and 20 '/' isolysergic acid and 3 2 g ( 10 millimols) o 2 amino 2 methyl 5 isopropyl b hydroxy 3,6 dioxo octahydro oxazolel 3,2 ajpyrrolol 2,1 clpyrazin hydrochloride.

Ergocornine, ergocryptine and ergonine ma) be produced in a manner analogous to th( processes described in Examples 1 to 4.

Example 5

Ergotamine and ergotaminine.

A mixture of 10 cc of absolute dimethyl formamide and 30 cc of absolute methylene chloride is cooled to -10 ', and a solution of 2 14 g of thionyl chloride in 10 cc of methylene chloride is added dropwise.

4.02 g of high vacuum dried d lysergic acid are subsequently added at -10 ', and the mixture is stirred at -10 for 5 minutes.

3.68 g of 2 amino 2 methyl 5 benzyl 10 b hydroxy 3,6 dioxo octahydro oxazolol 3,2 clpyrrolol 2,1 clpyrazine hydrochloride are subsequently added, and immediately thereafter 10 cc of absolute pyridine are added dropwise at -10 during the course of 15 minutes while stirring The reaction mixture is then stirred in the dark, first at 0 for half an hour and subsequently at room temperature for 1 1/2 hours Working up is effected by diluting with 500 cc of methylene chloride and extracting this solution with 250 cc of a 4 N aqueous potash solution The aqueous phase is extracted thrice with 500 cc amounts of methylene chloride, the methylene chloride solution is washed with a dilute common salt solution, dried with sodium sulphate, and the solvent is removed, whereby a brown crude mixture of bases is obtained, which upon crystallization from 40 cc of methanol yields crude ergotamine having a M P of 225-227 (decomp) Further crystallization of this crude crystalline product from methylene chloride/ methanol yields pure ergotaminine having a M P of 231 (decomp), laln'O=+ 375 (c= 0 5 in chloroform).

The mother liquor of the crystallization of the ergotaminine crude crystalline product is filtered with suction until dry, is dissolved in a small amount of aqueous acetone, and seeding is effected, whereby ergotamine crystallizes in the form of characteristic crystals.

M.P 172-175 (decomp), lalD 2 = 1 7 7 (c=l in pyridine).

Example 6

1 Methyl ergotamine and 1 methylergotaminine.

5.95 g of thionyl chloride are added dropgwise while stirring during the course of 5 g minutes to a solution cooled to -10 of f 50 cc of absolute dimethyl formamnide in cc of absolute methylene chloride, and the mixture is stirred for a further 5 minutes.

f 14 1 g of 1 methyl d lysergic acid are subsequently added at -10 ', and the mixture is stirred for a further 5 minutes.

e 30 cc of absolute pyridine are then added dropwise at -10 with stirring during the y course of 5 minutes to the brown-coloured e solution, immediately followed by 9 2 g of 2 amino 2 methyl 5 benzyl 10 bhydroxy 3,6 dioxo octahydro oxazolol 3,2 alpyrrolol 2,1 clpyrazine hydrochloride The reaction mixture is stirred for 1 a further half hour at O and then at room temperature for 3 hours Working up is effected by diluting with 700 cc of ethyl acetate and extracting with 500 cc of a 20 % potash solution After extracting the potash solution thrice with 700 cc amounts of ethyl acetate, the ethyl acetate solutions are washed with a common salt solution, dried with sodium sulphate, and the solvent is removed in a vacuum The residue is chromatographed on 500 g of aluminium oxide, activity I.

1 Methyl ergotamine is eluted with methylene chloride containing 0 1 % of methanol, and after crystallization from methylene chloride/methanol the compound is obtained in pure form M P 219-220 (decomp), l-l,D =+ 390 (c= 0 5 in pyridine) 1Methyl ergotamine is washed from the column with methylene chloride and 0 2 % of methanol and is purified by crystallization from methylene chloride/methanol M P.

167-170 (decomp), ll,2 = -163 (c= 0 5 in chloroform).

Example 7

9,10 Dihydro ergotamine.

10.8 g ( 40 millimtols) of 9,10 dihydro I lysergic acid are suspended in 100 cc of absolute dimethyl formamide, and the suspension is cooled to -10 4 72 g ( 40 millimols) of thionyl chloride are then added dropwise during the course of 5 minutes and 1 the reaction mixture is stirred at a temperature between -5 and O for 30 minutes.

After the addition of 40 cc of absolute pyridine at -15 while stirring vigorously, 7 36 g ( 20 millimols) of 2 amino 2 methyl 5 1 benzyl 10 b hydroxy 3,6 dioxo octahydro oxazolol 3,2 alpyrrolol 2,1 clpyrazine hydrochloride are added, and the resulting brick-red coloured slurry is stirred at -5 to O for a further 100 minutes, 1:

whereby the reaction mixture turns honeyyellow coloured.

Working up is effected by diluting with 500 cc of chloroform, shaking with 300 cc of a 2 N ammonia solution and extracting the 1 aqueous phase thrice with 200 cc of chloroform containing 5 % of methanol After wash1,298,277 1,298,277 r ing the combined organic phases with water, drying over sodium sulphate and removing the solvent in a vacuum, a yellow foam is obtained, which after drying in a high vacuum at 100 for 2 hours yields pure, crystalline 9,10 dihydroergotamine from 60 cc of 90 % aqueous acetone; after drying at 100 in a high vacuum for 2 hours the compound has a M P of 235-239 (decomp).

lalD 2 =-64 (c= 1 in pyridine).

Example 8

9,10 Dihydro ergocryptine.

10.8 g ( 40 millimols) of 9,10 dihydrolysergic acid are suspended in 100 cc of absolute dimethyl formamide, and the suspension is cooled to -10 ' 4 72 g ( 40 millimols) of thionyl chloride are then added dropwise during the course of 5 minutes, and the reaction mixture is stirred at a temperature between -5 and O for a further minutes After the addition of 40 cc of absolute pyridine at -15 while stirring vigorously, 7 24 g ( 20 millimols) of 2 amino2 isopropyl 5 isobutyl 10 b hydroxy3,6 dioxo octahydro oxazolol 3,2 alpyrrolol 2,1 clpyrazine hydrochloride are added, and the resulting brick-red coloured slurry is stirred at -5 to O for a further minutes, whereby the reaction mixture turns honey-yellow coloured.

Working up is effected by diluting with 500 cc of chloroform, shaking with 300 cc of a 2 N ammonia solution and extracting the aqueous phase thrice with 200 cc of chloroform containing 5 ' % of methanol After washing the combined organic phases with water, drying over sodium sulphate and removing the solvent in a vacuum, a yellow foam is obtained, which after drying in a high vacuum at 100 for 2 hours yields pure, crystalline 9,10 dihydro ergocryptine from 60 cc of ethyl alcohol; after drying at 100 in a high vacuum for 2 hours the compound has a M.P of 230-235 (decomp) lal 2 o=-41 (c= 1 in pyridine).

Example 9

9,10 Dihydro ergocristine.

10.8 g ( 40 millimols) of 9,10 dihydrolysergic acid are suspended in 100 cc of absolute dimethyl formamide, and the suspension is cooled to -10 4 72 g ( 40 millimols) of thionyl chloride are then added dropwise during the course of 5 minutes, and the reaction mixture is stirred at a temperature between -5 and O for a further 30 minutes After the addition of 40 cc of absolute pyridine at -15 while stirring vigorously, 7 96 g ( 20 millimols) of 2 -amino2 isopropyl 5 benzyl 10 b hydroxy3,6 dioxo octahydro oxazolol 3,2 alpyrrolol 2,1 clpyrazine hydrochloride are added, and the resulting brick-red coloured slurry is stirred at -5 to O for a further minutes, whereby the reaction mixture turns honey-yellow coloured.

Working up is effected by diluting with 500 cc of chloroform, shaking with 300 cc of a 2 N ammonia solution and extracting the aqueous phase thrice with 200 cc of chloroform containing 5 % of methanol After washing the combined organic phases with water, drying over sodium sulphate and removing the solvent in a vacuum, a yellow foam is obtained, which after drying in a high vacuum at 100 for 2 hours yields pure, crystalline 9,10 dihydro ergocristine from 60 cc of acetone, after drying in a high vacuum at for 2 hours the compound has a M P.

of 178-180 (decomp) lcalD 20 =-64 (c= 1 in pyridine).
________________________________________

W.L Razz