GB2094798A - Ergot alkaloids - Google Patents
Ergot alkaloids Download PDFInfo
- Publication number
- GB2094798A GB2094798A GB8206892A GB8206892A GB2094798A GB 2094798 A GB2094798 A GB 2094798A GB 8206892 A GB8206892 A GB 8206892A GB 8206892 A GB8206892 A GB 8206892A GB 2094798 A GB2094798 A GB 2094798A
- Authority
- GB
- United Kingdom
- Prior art keywords
- process according
- group
- formula
- buta
- ergot alkaloid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960003133 ergot alkaloid Drugs 0.000 title claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 39
- 125000006239 protecting group Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 239000005864 Sulphur Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 229930013930 alkaloid Natural products 0.000 abstract 1
- 150000003797 alkaloid derivatives Chemical class 0.000 abstract 1
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- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
- C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 8
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract
A process for the production of an argot alkaloid comprising intramolecularly cyclising a 3-iminoethyl- 4-trans-buta-1',3'-dienyl-indole to produce an 8-ergolene and as necessary converting the resultant ergolene into the desired ergot alkaloid.
Description
SPECIFICATION
Process for the production of ergot alkaloids.
This invention relates to a process for the production of ergot alkaloids, in particular derivatives of lysergic acid. The inventon relates to ergot alkaloids produced in accordance with the process of the invention, as well as to novel intermediates employed in the process of the invention.
Ergot alkaloids are well known compounds with a tetracyclic nucleus of formula
A double bond may be present in the ring D in the ergolene sub-class e.g. in the 8, 9 or 9, 10 position. The rings A, B, C and D may bear substituants e.g. as known in ergot chemistry, e.g., as described in "Ergot Alkaloids and related compounds" Ed. B. Berde and H. O. Schild,
Springer-Verlag, 1 978.
The ergolenes have two asymmetric centres giving rise to stereoisomerism in positions 5 and 10 (e.g. for 8-ergolenes) or 5 and 8 (for 9-ergolenes). Each of these ergolenes may therefore exist in racemic or optically active form.
One of the most important ergolenes is lysergic acid, which is a valuable intermediate for a wide variety of drugs useful in human therapy. The acid in optically active form may be obtained, for example, from ergot peptide alkaloids, occuring naturally or produced by fermentation, by alkaline hydrolysis.
Various total synthesis of lysergic acid and other ergot alkaloids have been described in the literature. These synthesis all suffer from various shortcomings, e.g. costly starting materials, low overall yields and many steps, e.g. because rings C and D are built up separately-with the result that none are completely satisfactory for commercial production.
The present invention provides a new synthesis of ergot alkaloids which is characterized by the simultaneous formation of rings C and D, the use of a few elegant steps to produce ergot alkaloids from known indole compounds, and satisfactory overall yields. Moreover, the synthesis may be employed for the preparation of a wide variety of ergot alkaloids bearing substituents, e.g. halogen atoms, or alkyl, alkoxy, hydroxy or optionally substituted amino groups. Substituents can be, for example, in the ring A and in the position 2.
Examples of such substituted compounds are 1 2-hydroxylysergic acid diethylamide, 13bromo-dihydrolysergic acid, 2,1 3-dibromo-dihydrolysergic acid glycinamide, 2-chloro-6-methyl 8ss-cyano-methylergoline, I-methyl-dihydrolysergol, 1 -formyl-dihydro-homolysergic acid nitrile, 1 2-hydroxy-dihydroergometrine 2-methyl-a-ergo-cryptine,2-methyl-lysergic acid and 1 2-methoxymethergine, which are all known compounds.
An overview of the process of the present invention is presented in the following basic steps:i) producing a 3-iminoethyl-4-trans-buta.1 ',3'-dienylindole having the buta-1 ',3'-dienyl moiety in protected form and optionally having a protecting group on the iminoethyl moiety, ii) deprotecting the trans buta-1 ',3'-dienyl moiety, iii) intramolecularly cyclising the resultant 3-iminoethyl-4-trans-buta-1 ',3'-dienylindole to produce an 8-ergolene, which may then have the protecting group on the 6 position, and iv) converting the resultant 8-ergolene as necessary into the desired ergot alkaloid.
The individual steps of the present process will be described in more detail below and illustrated with respect to a certain class of ergot alkaloids, it being appreciated that similar conditions may be employed for the production of other ergot alkaloids.
The steps may be visualized as follows:- i) producing a compound of formula I
wherein the dotted line indicates that the trans-buta-1 ',3'-dienyl moiety is protected form,
X1 is an inert group,
R is a protecting group, and
R' is a hydrogen or an imino-protecting group.
ii) deprotecting the trans-buta-1 ',3'-dienyl-moiety in a compound of formula I to produce a compound of formula II
iii) intramolecularly cyclising the resultant compound of formula II to produce a compound of formula Ill
iv) converting the resultant 8-ergolene as necessary into the desired ergot alkaloid.
The group X1 may be chosen to be inert in basic steps ii) and iii). In basic step iv) it may be converted, if desired, into a pharmacologically acceptable group or a group convertable into a pharmacologically accetable group, e.g. COOH. Protecting group R or R' may be chosen such that they are inert in any one of basic steps ii) to iii). Such groups may then be converted into a pharmacologically acceptable group, or a group convertable into a pharmacologically acceptable group, in basic step iv). Alternatively the protecting group may be chosen such that it is a pharmacologically acceptable group in which case it remains unchanged throughout the whole synthesis.
Suitable pharmacologically accetable groups will be apparent to one skilled in the art.
The group X1 may be any group known as a substituent in the 8 position of an ergot alkaloid, for example cyano, carbamoyl, carbamoyl mono-substituted e.g. by alkyl(C1 -4), carbamoyl disubstituted e.g. by alkyl (C,~4) or an or an alkylidene (C35) chain, or hydroxymethyl CH2OH), if desired witfl the hydroxy group in protected from. Preferably the group X, is alkoxy(C, 4)carbonyl, e.g. methoxycarbonyl.
R may be a group such that i-NH2 is capable of forming an imino derivative with 3indolylacetaldehyde, which is stable to high temperature, but which can be split off when desired under appropriate conditions.
R may be for example alkoxy (C1 -4), acyloxy or optionally substituted benzyloxy.
Alternatively the imino derivative may be a hydrazone derivative, and R is e.g. amino, or amino substituted by (C1 4)alkyl, acyl, or a sulphonyl group such as alkyl(C1 4)sulphonyl.
When R contains an acyl moiety, this is, for example, aliphatic acyl of 1 to 20, e.g. up to 5, carbon atoms. The acyl group may be optionally substituted, e.g. by one, two, or three substituents. Alternatively the acyl may be aromatic acyl, e.g. containing phenyl or phenylalkyl (C,~4) wherein the phenyl ring of either of the last two radicals may be optionally substituted.
Where R contains substituted alkyl or phenyl moities, suitable substituents include for example halogen, e.g. chlorine or fluorine, and (C1 4)alkoxy.
R is preferably alkoxy.
R' may be an alkyl(C, 4). Alternatively R' may be e.g. a carbonyl group e.g. an alkyl(C14)car.
bonyl group or a carboxylate group such as alkoxy(C1 4)carbonyl, or a sulphonyl group e.g. a tosyl group.
It will be appreciated that the exact choice of protecting group will depend on the reacton conditions through which the group has to survive, and the reaction conditions used for splitting the group off. For the production of lysergic acid it is preferred to have X, = COOAlk(C, 4); R = OCH3 and R1 = H.
In the last basic step iv) of the process the starting material is an 8-ergolene.
The ergolene may contain a protecting group such as the group R as specified above in the 6 position. Moreover the ergolene maybe protected in the 1 position, e.g. by a group R' as specified above. Additionally the starting material may be a mixture of protected and unprotected forms when the basic step iii) results in a mixture. Additionally the 8-ergolene may be mixed with the corresponding 9-ergolene when spontaneous isomerization has occurred during the basic step iii).
Any protecting group may be split off, and converted into pharmacologically acceptable groups in conventional manner. The double bond may be hydrogenated, or isomerized, e.g.
under basic conditions, to form a 9-ergolene and other interconversions, such as basic hydrolysis of any appropriate group X, to form a carboxylic acid group, effected to form ergot alkaloids useful as intermediates or pharmacologically active agents. Naturally these interconversions may be effected in any order.
The resultant compounds may be peptide or non-peptide ergot alkaloids, e.g. those described in "Ergot Alkaloids and Related Compounds" Ed. B. Berde and H. O. Schild, Springer Verlag, 1978.
If desired the ergot alkaloid in racemic form may be separated into individual optical isomer forms according to known procedures, e.g. fractional crystallization of diastereoisomeric salts. In the case of lysergic acid it is known to use the hydrazide derivative and fractionally crystallize the norephedride salt.
The ergot alkaloids having a protecting group, e.g. in the 6-position are particularly useful intermediates for the preparation of pharmcologically active ergot alkaloids. The provision of these ergot alkaloids is a particularly notable feature of the present invention.
In another aspect the present invention provides a process for the production of an ergot alkaloid which comprises deprotecting an ergot alkaloid bearing an imino protecting group in the 6-position to produce an ergot alkaloid uprotected in the 6-position and as necessary converting the resultant ergot alkaloid into the desired ergot alkaloid. The ergot alkaloid bearing a protecting group in the 6-position may have the formula IV:
wherein X1, R and R' are as defined above, and the dotted line signifies a double bond may be present in the 8,9 or 9,10 position.
Conveniently any protecting group in the 6-position is alkoxy.
In a further aspect of the present invention provides a process for the production of an ergot alkaloid which comprises replacing an imino protecting group in th 6-position of a protected ergot alkaloid by a pharmacologically accepatable group.
The above-mentioned deprotecting and/or replacement steps may be effected in conventional manner. The exact reaction conditions will of course depend on the protecting group present.
For example, when it is desired to produce alkylated derivatives, conventional alkylation agents may be used, if desired effecting the alkylation after splitting off the protecting group.
In a particularly elegant varitation of the basic step iv), and 8-ergolene is converted into a quaternary derivative of an ergot alkaloid which has attached to the nitrogen atom in the 6position a pharmacologically accetable group and a protecting group, which then split off.
The present invention also provides a process comprising deprotecting a quaternary derivative of an ergot alkaloid which has attached to the nitrogen atom in the 6-position a pharmacologically acceptable group and a protecting group.
The ergot alkaloid quaternary derivative may have the formula V
wherein X1, R' are as defined above,
R" is a pharmacologically acceptable group, and
R"'is a protecting group
Where the pharmocologically accetable group (tri) is alkyl and the protecting group (R"') is methoxy, it is convenient to use mild reducing conditions, e.g. amalgamated aluminium foil.
Suitable temperatures are from about - 5" C to about 50"C. Preferably an aqueous solution, e.g. with an aprotic solvent, is employed.
The alkylation may be effected for example by using an alkyl fluorosulphate, or trimethyloxonium tetrafluoroborate salt. The reaction is conveniently effected at from about 0 C to about 50"C. Preferably the reaction is effected in a organic solvent such as nitroethane or dichloromethane.
In the case of lysergic acid it is preferred to start from methyl 6-methoxy-8-ergolene-8carboxylate, methylate this to form the 6-methyl quaternary salt, reduce the resultant compound with aluminum to give 6-methyl-8-ergolene-8-carboxylic acid, and treat the compound with alkali to produce lysergic acid.
It is to be appreciated that basic step iv) need not be necessary in certain instances, when the product of basic step iii) is the desired product, e.g. when X1, R and R' are all pharmacologically acceptable groups.
Basic step iii) concerns the simultaneous formation of rings C and D. This step is an important feature of the present invention. Accordingly in yet a further aspect the invention provides a process for the production of an ergot alkaloid which comprises intramolecularly cyclizing a 3iminoethyl-4-trans-buta-1 ',3'-dienyl indole to produce an 8-ergolene, and as necessary converting the resultant ergolene into the desired ergot alkaloid.
The 3-iminoethyl-4-trans-buta-1',3'-dienyl indole may bear at least one protecting group and other substituents as necessary. The compound may have the formula II
and the product will be of formula IV above wherein the double bond is in the 8,9 position, unless some isomerization to the 9,10 position has occurred.
The intramolecular cyclization may be effected in conventional manner for a Diels-Alder reaction using analogous starting materials. Naturally, the conditions should be chosen to minimize formation of dimers. It is preferred to keep the concentration of the compound of formula Il as low as possible.
Preferably a high temperature is used, e.g. 1 50 C to 800"C.
Preferably an inert gas atmosphere e.g. argon, is present. The reaction may be effected in a solvent e.g. at about 1 80 to 250"C, preferably 200"C. Suitable solvents include phthalate esters, e.g. diethyl or dimethylphtalate, and substituted benzenes, e.g. 1,2,4-triisopropylbenzene, 1,2,4-trimethoxybenzene and particularly 1,2,4-trichlorobenzene.
Alternatively the reaction may be effected in the gas phase e.g. at 600"C to 800"C.
As indicated above under these conditions some isomerization of the 8,9 double bond into the 9,10 position may occur.
The 3-iminoethyl-4-trans-buta-1 ',3'-dienyl indole may not be readily isolatable, so it is preferred to generate this compound in situ as a transient intermediate from a 3-iminoethyl-4trans-buta-1 ',3'-dienyl indole having the trans-buta-1 ,3-dienyl moiety in protected form. This is accomplished in basic step ii). In an elegant variation the butadienyl moiety is protected by a group which may be split off under the same reaction conditions used for basic step iii). The deprotection accomplished in basic step ii) is preferably effected under the same reaction conditions as basic step iii).
For example the trans-buta-1 ,3-dienyl moiety may be protected in the form of a moiety
or in the form of a moiety (b)
Preferably only the vinyl moiety of the trans-buta-1 ,3-dienyl moiety is protected and the compound of formula Il obtained by removing the protecting group of compounds of formula VI
wherein X1, R and R' are as defined above and A is a protecting group capable of being split off under the conditions of the intramolecular cyclization.
The protecting group A may be a moitey -S-. Alternatively it may be a moiety of formula c)
wherein X2 is oxygen, sulphur or methylene optionally substituted by alkylidene with 1 to 4 carbon atoms, the ring being optionally substituted by one or two alkyl groups each containing 1 to 4 carbon atoms. It is to be appreciated that such compounds of formula VI may exist as endo and exo isomers and, if desired, be used as a mixture of such isomers.
In the case of when the protecting group A is moiety (c), the protecting group A, together with the two carbon atoms to which it is bound, suitably is of formula (d)
wherein R, and R2 are both hydrogen or both methyl and R3 and R4 are both hydrogen or form together a group = C(CH3)2. Preferably, R1, R2, R3 and R4 are hydrogen.
A alternatively may be a moiety (e)
wherein R5 is an inert group, e.g. hydrogen or alkyl(CI 4) (see H. Wohlweber, Diels Alder
Reaktion, Thieme Verlag, 1962, p. 160).
If desired, the two step reaction, basic steps ii) and iii), may be carried out by very slow addition of a dilute solution of the compound of formula VI in an inert solvent, into the same solvent preheated to about 180-250 , preferably 200 under an inert gas atmosphere, e.g.
argon.
The two-step reaction alternatively may be effected in the gas phase. For example, a compound of formula VI in an inert solvent may be slowly dropped into a vertically mounted quartz tube, filled with chips, e.g. of quartz, preheated to e.g. 600 to 800"C.
A gas stream may be used to sweep the vapours into a cooled zone where the product is collected.
The concentration of the compound of formula VI in the reaction mixture suitably does not exceed 5%. A 1% solution is preferred. Suitable solvents include the phthalate esters and substituted benzenes mentioned above.
Basic step i) involves the production of 3-iminoethyl-4-trans-buta-1 ',3'-dienyl indole having the buta-1 ',3'-dienyl moiety in protected form. This may be accomplished in any of a wide variety of ways.
For example the starting material of formula VI may be prepared from a 4-hydroxymethyl indole according to the following scheme, e.g. as described in example 1, a) to g), hereinafter (Ts = tosyl):-
Following this scheme, the compounds of formula IX may be obtained by reacting the compound of formula VIII with a compound of formula XII
wherein A and X, as defined above.
The compounds of formula XII wherein A is a moiety c as defined above, wherein X2 is CH2 and X1 is COOCH3 may be obtained as a mixture of exo- and endoisomers by formylation of the corresponding methyl bicyclo[2.2.1]hept-5-enyl-2-carboxylates. The formylation may be carried out by successive treatment with LDA and methylformate followed by chromatography (SiO2). In this case, the product is believed to be the exo-formyl-ester of formula XII along with a side product arising from a SiO2-promoted retro-Claisen rearrangement of the minor endo-formyl isomer which does not interfere with the subsequent Wittig reaction.
Wittig reaction of this mixture with the phosphorane derived from the compound of formula
VIII may yield sterioselectively the (E)-vinylindoles of formula IX, e.g. in an aprotic polar solvent such as DMSO at a slightly elevated temperature such as 50-100"C.
The nitroethylindols of formula Xl may be obtained from the compounds of formula X by a
Michael addition to nitroethylene. More efficiently, they may be obtained from the compounds of formula X in two steps, by a Mannich reaction followed by treatment of the crude Mannich product with nitromethane and dimethyl acetylenedicarboxylate according to the method of H.
Plieninger and col., Liebigs Ann. Chem. 743, 95 (1971).
Transformation of the nitro compounds of formula Xl to the oxime-ethers of formula VI may be achieved in one operation by reduction of the sodium nitronate derived from the compounds of formula XI with an excess of aq TiCl3/NH4OAc in MeOH/H2O (3:1) in the presence of N-Rhydroxylamine (R being alkyl). The stable oxime ether of formula VI may be obtained as a mixture of syn- and antiisomers and reacted further as such.
Insofar as the production of any particular starting material is not particularly described, this compound may be obtained in conventional manner, or in a manner analogous to that described herein.
In the following example, all temperatures are in degrees Centigrade and are uncorrected.
The heading compound of step c) hereinafter may of course exist in two isomeric forms, namely the endo and exo forms. The product obtained according to e.g. NMR spectroscopy is isomerically pure. As the formation of the side product in step c) may be rationalised easily on the basis of a Claisen rearrangement of the endo isomer it is believed that the heading compound has the exo configuration. This configuration will of course be maintained in the steps d) to g) hereinafter.
Carbomethoxy = COOCH3
Example: (f)-Lysergic acid a) 4-Bromomethyl- 1-tosylindole (VII)
1.74 g (6.6 mmol) triphenylphosphine are added under nitrogen to a stirred solution of 1.0 g (3.33 mmol) 4-hydroxymethyl-1-tosylindole and 2.2 g (6.6 mmol) CBr4 in 15 ml dry dimethylformamide. Stirring of the mixture at room temperature for 30 min, evaporation of the solvent at 0.05 Torr, filtration of the residue in CH2CI2 through SiO2 (50 g) and trituration of the evaporated filtrate with nhexane yields the crystalline bromide; m.p.:133-134.5 .
b) 4-(Tributylphosphonio)methyl- 1 -tosylindole bromide (VIII) A solution of 10.0 g (27.5 mmol) of the bromide obtained under a) and 7.8 g (38.5 mmol) tri-nbutylphosphine in 1 50 ml dry benzene is heated at reflux under nitrogen for 2 hours. The resultant precipitate is filtered off, washed with ether and dried in vacuo to give the phophonium salt; m.p.: 99-105".
c) Methyl 2-formyl-bicyclo[2.2. 1]hept-5-enyl-2-carboxylate (XII) 55 ml (0.11 mol of 2.0 N nbutyllithium in hexane are added over 10 minutes to a stirred solution of 1 7 ml (0.12 mol) of diisopropylamine in 60 ml dry tetrahydrofuran under argon at - 75". The mixture is stirred at - 75" for 30 minutes, 15.2 g (0.1 mol) methyl bicyclo[2.2.1]hept-5-enyl-2-carboxylate in 15 ml tetrahydrofuran at - 75" is added and the mixture stirred at - 75" for 1 hour. 1 5 ml (0.24 mol) methyl formate in 1 5 ml tetrahydrofuran is added slowly at - 75'.The mixture is stirred at - 75" for 2 hours and treated with 50 ml saturated aq. NH4CI at - 75'. Slow warming to room temperature, acidification to pH 5 with 1 N HCI, extraction with ether, evaporation of the washed (sat. aq. NH4CI) and dried (on sodium sulphate) ether-phase and flash-chromotography (hexane/ethyl acetate 30:1 < 19:1 affords the formylester as an oil, containing about 18% of methyl cis-4,4a,5,7a-tetrahydrocyclopenta(b] pyranyl-3carboxylate. The crude heading compound is subjected to the Wittig reaction, described below, without further purification.
d) 4-(2-Carbomethoxy-bicyclo[2. 2. 1] hept-5-enyl-2-(E)-vinylene)- 1 -tosylindole (IX)
A mixture of 135 mg (5.6 mmol) NaH and 2 ml dry DMSO is heated with stirring under aragon at 75 for 45 minutes. 2.8 g (5 mmol) of the phosphonium bromide obtained under b) in 5 ml DMSO at 10 is rapidly added, the resulting red solution is stirred for 3 minutes, and 1.2 g (5.2 mmol) of the crude aldehyde obtained under c) are added slowly. The reaction mixture is stirred at room temperature for 1 6 hours, and evaporated in vacuo.Shaking of the residue with water/ether, evaporation of the dried (Na2SO4) ether phase and trituration of the residue gives the trans-vinylindole as a solid residue which can be used as described below without further purification; m.p.:148-150 after recrystallization from diisopropylether.
e) 4-(2-Carbomethoxy-bicyclo[2 .2.1] hept-5-enyl-2-(E)-vinylene)-indole (X)
A solution of 1.6 9 (3.58 mmol) of the N-tosylindole obtained under d) in 32 ml 2 N NaOH in methanol is heated at reflux under argon for 1.5 hours. Concentration of the reaction mixture in vacuo, shaking of the residue with water/ether, evaporation of the dried (Na2SO4) ether phase and flash chromatography (hexane/CH2Cl2/ethyl acetate (20:2:1) yields the heading compound as an oil.
f) 3-(2-Nitroethyl)-4-(2-carbomethoxy-bicyclo[2.2. 1] hept-5-enyl-2-(E)-vinylene)-indole (Xl)
Procedure a.A mixture of 3 ml acetic acid, 2.5 ml 40 % aq. dimethylamine and 1.2 ml 36% aq. fromaldehyde is added to a solution of 41 5 mg (1.42 mmol) of the vinyl-indole obtained under e) in 0.4 ml ether. The reaction mixture is stirred at room temperature for 2 hours, then adjusted to pH 39 with 20% aq. NaOH and extracted with ethyl acetate. Evaporation of the dried (Na2SO4) extracts and crystallization of the residue yields crystalline 3-(2-N,N-dimethylami noethyl)-4-(2-caromethoxy-bicyclo[2 .2.1 ]hept-5nyl-2-(E)-vinylene)-indole: m.p.:11 9 - 1 22.
After successive addition of 245 mg (4 mmol) nitromethane and 60 mg (0.42 mmol) dimethyl acetylene-dicarboxylate to a solution of 1 35 mg (0.386 mmol) of 3-(2-N,N-dimethyl)-4 (exo-2-carbomethoxy-bicyclo[2.2. 1 ]hept-5-enyl-2-(E)-vinylene)-indole in 3 ml dry tetrahydrofuran under argon, the mixture is stirred at room temperature for 5 hours. Evaporation and chromatography (toluene/ethylacetate 94:6) yields the heading nitroethylindole as an oil.
Procedure b.-1.6 ml (1.84 mmol) of 1.15 M nitroethylene in toluene are added to a solution of 270 mg (0.92 mmol) of the indole obtained under e) in 5 ml toluene. Stirring of the mixture at room temperature for 66 hours, followed by evaporation and chromatography (toluene/ethylacetate 95:5) yields the heading nitroethylindole.
g) 3-N-Methoxyiminomethyl-4-(2-carbomethoxy-bicyclof2. 2. l hept-5-enyl-2-(E)-vinylene)4ndole (VI) [Completion of basic step i)] 1 58 mg (1.89 mmol) O-Methylhydroxylamine hydrochloride in 9.2 ml (1.89 mmol) 0.205 N
NaOMe in methanol are added to a solution of 230 mg (0.63 mmol) of the nitroethyl indole obtained under f) in 3.7 ml (0.76 mmol) 0.205 N NeOMe in methanol. A solution of 7.7 g ammonium acetate and 13.9 ml 15% aq. TiC3 in 24 ml degassed water under argon at 10 is added rapidly to the reaction mixture which is then stirred for 2 hours at 20 and extracted with ether (3 x). Washing (aq.NaHCO3, sat. aq. Nacl), drying (Na2S(:)4) and evaporation of the ether phase and chromatography of the oily residue in methylene chloride yields a 1:1 mixture of the syn- and antiisomers of the heading compound.
h) Methyl 6-meThoxy-8-ergolene-8-carbo;ylate (IV) [Basic steps ii) and iii)]
A solution of 73 mg (0.2 mmol) of the compound obtained under g) in 7.3 ml 1,2,4trichlorobenzene is added dropwise by means of a syringe drive over 5 hours through a water cooled reflux condenser into 146 ml 1,2,4-trictlliorobenzene, stirred at 200 under argon.
Evaporation at 0.1 Torr and chromatography of the residue (methylene chloride/ethyl acetat 39:1 yields the heading compound as an oily 2:3-mixture of diastereoisomers of ergolene I and
II respectively.
i) ( )-Lysergic acid [Basic step iv)]
8.1 iLl (0.672 mmol) methyl fluorosulfonate are added to a solution of 10 mg (0.0336 mmol) of the compound obtained under h) in 0.5 ml dichloromethane (distilled from CaH2). The mixture is stirred at room temperature for 1 8 hour and then evaporated to yield a solid residue.
This is stirred with 30 ml amalgamated aluminium foil [in tetrahydrofuran/water (2:1 at O to + 5" for 18 hours]. Evaporation of the filtered reaction mixture and subsequent preparative thin-layer chromatography (it2, ethyl acetate/melthanol 39:1) yields a mixture of 6-methylergolenes which was heated at reflux in 0.5 N KOH in ethanol/H20 1:1 (0.7 ml) under nitrogen for 1 hour. Concentration of the solution, followed by acidification with 1 N HCI to pH 5.5 leads to the precipitation of crystalline ( + )-lysergic acid showing identical 'N-NMR and Mass spectradata as authentic racemic lysergic acid.
The resultant lysergic acid may be resolved into optically active lysergic acid by the method described in A. Stoll et al. Hopp-Seylers, Z. Physiol. Chem. 250, 7, (1937).
In analogous manner the following compounds may be produced: 1 2-methoxymethergine 1 2-hydrozylysergic acid diethylamide
1 3-brorno-dihydroiysergic acid using as necessary appropriate hydrogenation reactions to produce any dihydro moiety.
Claims (16)
1. A process for the production of an ergot alkaloid which comprises intramolecularly cyclising a 3-iminoethyl-4-trans-buta-1 1,3'-dienyl-indole to produce an 8-ergolene and as necessary converting the resultant ergolene into the desired ergot alkaloid.
2. A process according to claim 1 wherein the imino group is protected by acyloxy, alkoxy or acyl.
3. A process according to claim 2 wherein the protecting group is methoxy.
4. A process according to claim 2 or 3 wherein the 4-trans-buta-1 ',3'-dienyl group is generated in situ from a protected form thereof.
5. A process according to claim 4 wherein the protected form of the 4-trans-buta-1 ',3'- dienyl group is of formula
wherein X1 is an inert group, or of formula
wherein X, is as defined above and A is -S- or of formula
wherein X2 is oxygen, sulphur or methylene optionally substituted by alkylidene with 1 to 4 carbon atoms, the ring being optionally substituted by dne or two alkyl groups each containing 1 to 4 carbon atoms, or of formula
wherein R5 is an inert group.
6. A process according to claim 5 wherein X1 is alkoxy(C1 4)carbonyl
7. A process according to any preceding claim wherein the cyclisation is effected at from 180 to 250"C.
8. A process according to any preceding claim wherein the cyclised ergot is substituted in ring A or in position 2.
9. A process according to claim 1 substantially hereinbefore described with reference to the example step h).
10. A process for the production of an ergot alkaloid which comprises splitting off an imino protecting group from an ergot alkaloid bearing an imino-protecting group in the 6-position and as necessary converting the resultant ergolene into the desired ergot alkaloid.
11. A process according to claim 10 wherein the imino protecting group is split off from an ergot alkaloid in the form of a quaternary derivative which bears a pharmacologically acceptable group in the 6-position.
1 2. A process according to claim 10 or 11 wherein the ergot alkaloid bearing an imino protecting group is produced according to the process as claimed in any one of claims 1 to 9.
1 3. A process according to claim 10 substantially as hereinbefore described with reference to the Example step h) and i).
14. An ergot alkaloid whenever produced by a process according to any one of claims 1 to 13.
1 5. A 3-iminoethyl-4-trans-buta-1 ',3'-dienylindole having the buta-1 ',3'-dienyl-moiety in protected form or in unprotected form.
16. A compound of formula I, 11, Ill, IV, VII, VIII, IX, X, Xl or XII as defined herein.
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GB8206892A GB2094798B (en) | 1981-03-13 | 1982-03-09 | Ergot alkaloids |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4491664A (en) * | 1981-03-13 | 1985-01-01 | Sandoz Ltd. | Process for the production of ergot alkaloids |
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1982
- 1982-03-09 GB GB8206892A patent/GB2094798B/en not_active Expired
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US4491664A (en) * | 1981-03-13 | 1985-01-01 | Sandoz Ltd. | Process for the production of ergot alkaloids |
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