IE41476B1 - Improvements in or relating to elymoclavine - Google Patents

Description

This invention relates to novel intermediates, their preparation and a process for their conversion into the natural product elymoclavine. This application is a divisional of Patent Specification No.

The invention relates to ergolene compounds of the formulae wherein R is formyl and alk is C^-Cg alkyl.

The compounds of formula (II) can be prepared by reacting a compound of formula 4147« ίο wherein alk is C^-C.^ alkyl, with an oxidising agent.

The formyl compounds are novel intermediates useful in the synthesis of the natural product elymoclavine.

The synthesis of elymoclavine, having the formula ch2oh N-CH. can be achieved by reduction of a compound of formula (II). This process provides elymoclavine in excellent yield.

The conversion of the primary alcohol to the corresponding aldehyde can be carried out by a variety of oxidative procedures. For example, sodium dichromate in a mixture of pyridine hydrochloride and pyridine, chromic oxide-pyridine complex in methylene dichloride, potassium dichromate in aqueous sulfuric acid, t,-butyl chromate in benzene, nickel peroxide in benzene, silver carbonate in benzene or silver oxide in phosphoric and acetic acids, manganese dioxide in a variety of known solvents, lead tetraacetate in pyridine, sulfur trioxide-pyridine complex in a mixture of dimethyl sulfoxide and triethylamine, tetrachloro-1,2-benzoquinone (TCBQ) and similar oxidation systems can all be employed [See Compendium of Organic Synthetic Methods, Harrison and Harrison, (John Wiley and Sons, Inc., New York, 1971) Section 48 at page 137-143].

We prefer to employ manganese dioxide in chloroform or other suitable inert solvents as the oxidising agent to prepare the aldehyde from the primary alcohol. An alternate oxidising procedure which gives similarly excellent yields consists of using dicyclohexylcarbodiimide in a solvent consisting of a mixture of dimethylsulfoxide, pyridine and trifluoroacetic acid. D-6-methyl-8-formyl10a-methoxy-8-ergolene, can also be prepared by contacting D-6-methyl-8-hydroxymethyl-10a-methoxy-8-ergolene in dimethylsulfoxide solution with a mixture of pyridine and trifluoroacetic acid. Dicyclohexylcarbodiimide is then added and the primary alcohol group oxidised to an aldehyde according to the procedure of Moffatt, J, Am. Chem. Soc., 89.2697 (1967). D-6-methyl-8-formyl-10a-methoxy-8ergolene prepared by this procedure was purified by chromatography and crystallised.

The reduction of the 8-formyl-10a-alkoxy-8-ergolene, formula (II), with the cocommitant elimination of the 10aalkoxy group can be accomplished by a variety of reagents. We prefer to employ an active metal in an acidic medium as for example, zinc in acetic acid. Iron in dilute hydrochloric acid can also be employed as can the metal hydride reducing agents as exemplified by lithium aluminum hydride and lithium aluminum (tri-t-butyloxy) hydride.

The term active metal used above in conjunction with an acid medium and a reduction system, of course, refers to those metals which are capable of displacing hydrogen in acidic medium; the hydrogen being the reducing substance. Reference to any] table of standard oxidation-reduction potentials will indicate a large number of metals which have a potential greater than the hydrogen-hydrogen ion couple taken as zero. Included among these metals are: iron, cadmium, cpbalt, nickel, tin, zinc, aluminum and sodium.

This invention is further illustrated by the following examples in which some of the terms are defined as follows: Van Urk test - reagent is composed of: 18 mg. of ferric chloride; 0.5 g. of p.-dimethylaminobenzaldehyde; in 250 ml. of concentrated sulfuric acid and 140 ml. of water. Equal volumes of reagent and test solution are prepared; colour formed is blue or green when an ergolene having no substituent in the 2-position is present. nmr - nuclear magnetic resonance, measured in parts per million (δ).

UV - ultraviolet, measured in millimicrons (mp,.) and ε is molar absorptivity.

Example 1 A solution containing 515 mg. of D-6-methyl-8-hydroxymethyl-10a-methoxy-8-ergolene in 150 ml. of chloroform was prepared. Four g. of manganese dioxide were added and the reaction mixture stoppered and stirred at room temperature for one-half hour. The reaction mixture was filtered, and the filter cake washed with chloroform. Evaporation of the filtrate to dryness yielded a residue of D-6-methyl8-formyl-10a-methoxy-8-ergolene. The residue was chromatographed over 30 g. of florisil (Trade Mark) using chloroform containing 1 to 2 percent methanol as the eluant. Fractions shown to contain the 8-formyl compound by thin layer chromatography were combined and the solvent evaporated therefrom. Recrystallisation of the resulting residue yielded purified D-6-methyl-8-formyl-ΙΟα-methoxy8-ergolene melting at 196-7°C. with decomposition.

Yield of 65%.

Analysis on ci7HigN2°2 (percent) calc.: C, 72.32; H, 6.43; N, 9.92; Found: C, 72.07; H, 6.20; N, 9.65. nmr (CDCl^): 2.57 (s,J^N—CH3) δ 3.15 (a, —OCH3) H δ 7.70 (s, ^C=C^ ) δ 8.77 (b, indole NH) δ 9.72 (s,—C—H) Example 2 A solution containing 505 mg. of D-6-methyl-8hydroxymethyl-10a-methoxy-8-ergolene in 25 ml. of dimethyl sulfoxide with a mixture of 0.15 ml. of pyridine and 0.22 ml. of trifluoroacetic acid was prepared. 1.2 g. of dioyclohexylcarbodiimide was then added to the solution. The solution was stirred for 1 1/4 hours at room temperature under nitrogen, then poured into aqueous tartaric acid and filtered. The filtrate was extracted with chloroform. The organic layer was discarded. The aqueous layer was made basic with ammonium hydroxide and extracted with ethyl acetate until the extract gave a negative Van Urk test. The organic solution was washed with water, then saturated sodium chloride and dried over sodium sulfate. The resulting residue was comprised of D-6-methyl-8-formyl-10a-methoxy-8-ergolene. Yield of 89% ' 41476 This product was identical with that obtained in Example 1 Example 3 A solution was prepared containing 300 mg. of D-6methyl-8-formyl-10a-methoxy-8-ergolene in 25 ml. of acetic acid. Two g. of zinc dust were added and the reaction mixture stirred at room temperature for 45 minutes. The reaction mixture was filtered and the filtrate poured over ice. The aqueous layer was made strongly basic with 10 percent aqueous ammonium hydroxide, and the alkali10 insoluble organic material extracted with chloroform.

The chloroform extractions were continued until a chloroform extract showed a negative Van Urk test. The chloroform extracts were combined and washed with saturated aqueous sodium chloride. Evaporation of the organic solvent yielded elymoclavine. Yield of 50% UV in ethanol my,. 292 282 277 225 ε ,320 6,170 6,000 ,090; and Mass spectrum was identical to known elymoclavine from Norich Chemical Company Example 4 A solution was prepared containing 865 mg. of D-6methyl-8-formyl-10a-methoxy-8-ergolene in 150 ml. of tetrahydrofuran (THE). One g. of lithium aluminum hydride was added thereto in portions. After the addition had been completed, the reaction mixture was stirred at room temperature under a nitrogen atmosphere for one hour.

Next, a solution of 1 g. of aluminum chloride in 50 ml. of THF was added in dropwise fashion. Again, after the addition had been completed, the reaction mixture was diluted with water, and the aqueous layer extracted with chloroform until a chloroform extract showed a negative Van Urk test. The chloroform extracts were combined, washed with saturated sodium chloride and dried, and the solvent evaporated. Recrystallization of the resulting residue from methanol yielded a 50s 50 mixture of elymoclavine and lysergol, separable by chromatography. The analysis of the mixture was (percent) Calc. : C, 75.56; H, 7.13; N, 11.01; Found : C, 75.37; H, 7.35; H, 10.72.

Claims (8)

1. CLAIMS :1. An ergolene of the formula: wherein R is formyl and alk is C^-C^ alkyl. 5

2. D-6-methyl-8-formyl-10a-methoxy~8-ergolene.

3. A process for the preparation of a compound of formula (II) as claimed in Claim 1 or 2 which comprises oxidising a compound of the formula 10 wherein alk is as defined in Claim 1.

4. A process according to Claim 3 substantially as hereinbefore described with reference to Example 1 or 2.

5. A compound of formula II whenever prepared by a process as claimed in Claim 3 or 4. 15

6. A process of preparing elymoclavine having the formula: 414*76 ίο - which comprises reducing a compound of formula (II) as claimed in Claim 1, 2 or 5.

7. A process according to Claim 6 substantially 5 as hereinbefore described with reference to Example 3 or 4.

8. Elymoclavine whnever prepared by a process according to Claim 6 or 7.