WO1997014694A1 - Procede ameliore de production d'heptastigmine et nouveau compose intermediaire utile dans ce procede - Google Patents

Procede ameliore de production d'heptastigmine et nouveau compose intermediaire utile dans ce procede Download PDF

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Publication number
WO1997014694A1
WO1997014694A1 PCT/EP1996/004296 EP9604296W WO9714694A1 WO 1997014694 A1 WO1997014694 A1 WO 1997014694A1 EP 9604296 W EP9604296 W EP 9604296W WO 9714694 A1 WO9714694 A1 WO 9714694A1
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WO
WIPO (PCT)
Prior art keywords
process according
eseroline
carried
heptastigmine
previous
Prior art date
Application number
PCT/EP1996/004296
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English (en)
Inventor
Mario Pinza
Nicola Cazzolla
Maria Alessandra Alisi
Original Assignee
Mediolanum Farmaceutici S.P.A.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Mediolanum Farmaceutici S.P.A. filed Critical Mediolanum Farmaceutici S.P.A.
Priority to AU72841/96A priority Critical patent/AU7284196A/en
Publication of WO1997014694A1 publication Critical patent/WO1997014694A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an improved process for producing heptastigmine and a new intermediate compound useful in said process.
  • heptastigmine is used to mean 1 ,3a,8-trimethyl-1 ,2,3,3a,8a- hexahydropyrrole[2,3-b]indol-5(3aS,8aR)-heptylcarbamate of formula:
  • Heptasigmine and the acid addition salts thereof with organic acids inhibit acetylcholine esterase and are particularly useful for treating Alzheimer disease.
  • EP-A-O 154 864 discloses the preparation of heptastigmine by hydrolyzing physostigmine (also known as eserine) with a salt of an alkaline alkoxylate compound under vacuum. The thus obtained eseroline alkaline salts are then reacted, still under vacuum, with heptyl isocyanate in the presence of a polar hydrocarbon solvent medium, preferably benzene. The total yield ranges from 40 to 70%.
  • EP-A-O 298 202 mainly refers to heptastigmine acid addition salts with organic acids. However, it also aims to overcome some drawbacks of the process disclosed by EP-A-O 154 864 (need of performing all the synthesis under vacuum and low yields). To this purpose, EP-A-0 298
  • EP-A-0 499 179 suggests to perform the reaction of eseroline with heptyl isocyanate, optionally prepared in situ from 1- bromoheptane and potassium cyanate, into a polar aprotic solvent, preferably acetonitrile or ethyl acetate, and in the presence of a catalytic amount of a quaternary ammonium salt as well as of a metal cyanate or alcoholate. This reaction is also carried out under nitrogen for 8 hours when heptyl isocyanate is used or 19 hours, under reflux, when the latter is prepared in situ.
  • step (1) when desired, forming an acid addition salts of heptastigmine with an organic acid, wherein the improvement is that the step (1) is carried on a) by reacting physostigmine with a suitable silylating agent to afford a compound of formula
  • R,, R 2 and R 3 are a lower alkyl, a lower alkylene or an aryl, and b) then by replacing into the thus obtained compound of formula (II) the group SiR ⁇ with a hydrogen atom.
  • R 1 ? R 2 and R 3 are methyl, ethyl, propyl, butyl, vinyl and phenyl. Most preferably, R,, R 2 and R 3 are methyl.
  • suitable silylating agents are disilazane such as, for example, 1 ,3-dimethyl-1 , 1 ,3,3-tetraphenyldisilazane, 1 ,3-diphenyl- 1 ,1 ,3,3-tetramethyldisilazane, 1 ,3-divinyl-1 ,1 ,3,3-tetramethyldisilazane, and 1,1,1 ,3,3,3-hexamethyldisilazane (HDMS).
  • HDMS 1,1,1 ,3,3,3-hexamethyldisilazane
  • the preferred silylating agent is HDMS (1 ,1 ,1 ,3,3,3-hexadimethylsilazane).
  • step 1a is preferably carried on by using, as a diluent, an excess of the silylating agent itself.
  • the reaction can also be carried on in the presence of a suitable organic diluent or a suitable mixture of organic diluents, which can be easily preselected by a person skilled in the art, case by case, depending on the silylating agent which is used and by simple experimental routine trials.
  • Reaction temperature and time of the step 1a will vary depending on the silylating agent and the possible diluents which are used, by parameters which are well known to the person skilled in the art.
  • the reaction can be carried on without adding any diluent at a temperature of from 100°C to 125°C, preferably at about 125°C, for 4 to 8 hours, preferably for about 6 hours.
  • the reaction is carried out in the presence of a diluent selected from aromatic hydrocarbons such as, for example, toluene, xylene and tetrahydronaphthalene, at the reflux temperature of the reaction mixture.
  • a diluent selected from aromatic hydrocarbons such as, for example, toluene, xylene and tetrahydronaphthalene
  • An example of a preferred diluent is toluene.
  • the molar ratio of physostigmine to HMDS is preferably of from 1 : 2 to 1 : 10. More preferably it is of 1 : 2.5.
  • Step 1a affords compound (II), which is a distillable oil, in an almost quantitative yield, together with N-methyl urea.
  • the compound of formula (II) is a new stable and protected derivative of eseroline. Therefore, it is a further object of the present invention to provide an intermediate compound of formula (II).
  • Step 1 b is preferably carried on by methanolysis at room temperature for 1 hour. After removal of volatile products, the thus obtained crude eseroline can be transformed into heptastigmine (step 2) according to known techniques such as, for example, those described by EP-A-O 499 179.
  • step 2 when the addition reaction of heptyl isocyanate to eseroline (step 2) is carried out in the presence of a base and of a polar aprotic diluent the reaction time is substantially reduced compared to that required when the same reaction is carried on in a polar aprotic diluent but in the presence of a system formed by (i) catalytic amounts of a quaternary ammonium salt and a metal cyanate or by (ii) catalytic amounts of a quaternary ammonium salt and a metal alcoholate.
  • Suitable polar aprotic diluents are: acetonitrile, tetrahydrofuran and ethers of glycols such as 1 ,2-dimethoxyethane,
  • Diglime is the preferred diluent.
  • suitable bases are: sodium hydride, sodium carbonate, potassium carbonate, sodium methoxide, triethylamine.
  • the preferred base is potassium carbonate.
  • crude eseroline is taken up with diglime and added, in the presence of potassium carbonate and under nitrogen flushing, with heptyl isocyanate in a molar ratio of from 1 : 0.1 to 1 : 1 ; preferably 1 :
  • the reaction may be carried on at a temperature of from 0° to 220°C, preferably of from 20° to 25°C.
  • reaction mixture is worked up to afford heptastigmine that can be transformed, when desired , into an acid addition salt thereof (step 3), such as tartrate, according to known techniques.
  • a third relevant feature of the present invention is the short time required, even at room temperature, when crude eseroline is reacted with heptyl isocyanate in the presence of a base and of a polar aprotic diluent.
  • Example 4 Preparation of heptastigmine tartrate. 80 mg of heptastigmine tartrate were obtained by working in the same way as described in Example 3, starting from 0.5 g of trimethyl- 1 ,3a,8-hexahydro-1 ,2,3,3a,8,8a-pyrrole(2,3-b)indol-5-(3aS, 8aR) t ⁇ ' methylsilylether and using sodium hydride (molar ratio 1 : 1 to eseroline formed during the reaction) instead of potassium carbonate.
  • Example 5 Preparation of heptastigmine tartrate A solution of trimethyl-1 ,3a,8-hexahydro-1 ,2,3,3a,8,8a-pyrrole(2,3- b)indol-5-(3aS, 8aR)trimethylsilylether (II) (0.6 g; 2.05 mmol) in methanol (6 ml) was kept under stirring at room temperature and under a nitrogen stream for 1 hour. After evaporating of methanol under vacuum, the thus obtained crude eseroline (0.45 g) was dissolved in 5 ml of acetonitrile.
  • II trimethyl-1 ,3a,8-hexahydro-1 ,2,3,3a,8,8a-pyrrole(2,3- b)indol-5-(3aS, 8aR)trimethylsilylether

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

On décrit un procédé amélioré de production d'heptastigmine et de sels d'addition d'acide de celle-ci avec des acides organiques, l'amélioration consistant à préparer cette heptastigmine à partir de physostigmine par mise en réaction de l'heptastigmine avec un agent de silylation approprié, puis par remplacement du composé silyle ainsi obtenu par un atome d'hydrogène. De manière avantageuse, on ajoute ultérieurement à l'éséroline un isocyanate d'heptyle, et ce en présence d'une base et d'un diluant aprotique polaire.
PCT/EP1996/004296 1995-10-13 1996-10-02 Procede ameliore de production d'heptastigmine et nouveau compose intermediaire utile dans ce procede WO1997014694A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72841/96A AU7284196A (en) 1995-10-13 1996-10-02 An improved process for producing heptastigmine and a new intermediate compound useful in this process

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI95A002097 1995-10-13
IT95MI002097A IT1276928B1 (it) 1995-10-13 1995-10-13 Processo migliorato per produrre eptastigmina e nuovo intermedio utile allo scopo

Publications (1)

Publication Number Publication Date
WO1997014694A1 true WO1997014694A1 (fr) 1997-04-24

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Application Number Title Priority Date Filing Date
PCT/EP1996/004296 WO1997014694A1 (fr) 1995-10-13 1996-10-02 Procede ameliore de production d'heptastigmine et nouveau compose intermediaire utile dans ce procede

Country Status (5)

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AR (1) AR003831A1 (fr)
AU (1) AU7284196A (fr)
IT (1) IT1276928B1 (fr)
WO (1) WO1997014694A1 (fr)
ZA (1) ZA968284B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7795307B2 (en) 2003-10-21 2010-09-14 Colucid Pharmaceuticals, Inc. Carbamoyl esters that inhibit cholinesterase and release pharmacologically active agents
US8101782B2 (en) 2007-02-02 2012-01-24 Colucid Pharmaceuticals, Inc. Compounds that inhibit cholinesterase

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154864A1 (fr) * 1984-03-01 1985-09-18 Consiglio Nazionale Delle Ricerche Dérivés de la physostigmine, ayant des propriétés inhibitrices d'acétylcholinestérase, et procédé de préparation correspondant
EP0298202A1 (fr) * 1987-04-03 1989-01-11 Mediolanum Farmaceutici S.P.A. Sels organiques de dérivés de la physostigmine
EP0499179A1 (fr) * 1991-02-14 1992-08-19 LABORATORIO CHIMICO INTERNAZIONALE S.p.A. Un procédé pour la préparation de 1,3a,8-triméthyl-1,2,3,3a,8,8a-hexahydropyrrole[2,3-b]indole[3aS,8aR)-heptylcarbamate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0154864A1 (fr) * 1984-03-01 1985-09-18 Consiglio Nazionale Delle Ricerche Dérivés de la physostigmine, ayant des propriétés inhibitrices d'acétylcholinestérase, et procédé de préparation correspondant
EP0298202A1 (fr) * 1987-04-03 1989-01-11 Mediolanum Farmaceutici S.P.A. Sels organiques de dérivés de la physostigmine
EP0499179A1 (fr) * 1991-02-14 1992-08-19 LABORATORIO CHIMICO INTERNAZIONALE S.p.A. Un procédé pour la préparation de 1,3a,8-triméthyl-1,2,3,3a,8,8a-hexahydropyrrole[2,3-b]indole[3aS,8aR)-heptylcarbamate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7795307B2 (en) 2003-10-21 2010-09-14 Colucid Pharmaceuticals, Inc. Carbamoyl esters that inhibit cholinesterase and release pharmacologically active agents
US7897639B2 (en) 2003-10-21 2011-03-01 Colucid Pharmaceuticals, Inc. Carbamoyl esters that inhibit cholinesterase and release pharmacologically active agents
EP2314571A2 (fr) 2003-10-21 2011-04-27 CoLucid Pharmaceuticals, Inc. Esters de carbamoyle inhibant la cholinesterase et liberant des agents pharmacologiquement actifs
US8101782B2 (en) 2007-02-02 2012-01-24 Colucid Pharmaceuticals, Inc. Compounds that inhibit cholinesterase

Also Published As

Publication number Publication date
ITMI952097A1 (it) 1997-04-13
IT1276928B1 (it) 1997-11-03
AR003831A1 (es) 1998-09-09
ZA968284B (en) 1997-05-02
ITMI952097A0 (fr) 1995-10-13
AU7284196A (en) 1997-05-07

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