# US 5,705,704 A · Tricyclic compounds

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- Number: US 5,705,704 A
- Document ID: US5705704A
- Status: Granted
- Kind: A
- Application number: 08/609,679
- Filed: 1996-03-01
- Granted: 1998-01-06
- Earliest claimed: 1995-03-03
- Assignees: Roussel Uclaf
- Inventors: Francis Brion; Bernadette Chappert; Christian Diolez; Christian Marie; Alain Mazurie; Michel Middendorp; Didier Pronine; Edmond Toromanoff
- Web page: https://patentgrep.com/patent/US5705704A

## CPC

- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07C 45/56: from heterocyclic compounds (C07C45/55 takes precedence)
- C07C 45/63: by introduction of halogen; by substitution of halogen atoms by other halogen atoms
- C07C 49/747: containing six-membered aromatic rings
- C07C 49/755: a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
- C07C 309/73: to carbon atoms of non-condensed six-membered aromatic rings
- C07C 2603/30: containing seven-membered rings
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Novel tricyclic compounds of formula I as defined in the specification, a process for their preparation and their use for the preparation of optically active or racemic colchicine and thiocolchicine derivatives.

## Claims

### Claim 1

A compound of the formula ##STR81## wherein a) R.sub.1 and R.sub.2 are alkyl of 1 to 6 carbon atoms and R.sub.3 is hydrogen or A--SO.sub.2 -- or b) R.sub.2 and R.sub.3 are hydrogen and R.sub.1 is A--SO.sub.2 -- or c) R.sub.1, R.sub.2 and R.sub.3 are all hydrogen or all alkyl of 1 to 6 carbon atoms or d) R.sub.1 is A--SO.sub.2 -- or hydrogen and R.sub.2 and R.sub.3 together with the oxygens to which they are attached form --O--X--O--, X is selected from the group consisting of B(OR.sub.4)--, C(O)-- and --CR.sub.5 R.sub.6 --, R.sub.4 is hydrogen or alkyl of 1 to 6 carbon atoms, R.sub.5 and R.sub.6 are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms and phenyl optionally substituted with 1 to 3 members of the group consisting of --OH and alkyl and alkoxy of 1 to 6 carbon atoms or R.sub.5 and R.sub.6 together with the carbon atom to which they are attached form a carbocyclic of 5 to 6 carbon atoms or e) R.sub.3 is A--SO.sub.2 -- and R.sub.1 and R.sub.2 together with the oxygens to which they are attached form --O--X--O-- or f) R.sub.1 is hydrogen and R.sub.2 and R.sub.3 are both alkyl of 1 to 6 carbon atoms or together with the oxygens to which they are attached form --O--X--O-- and A is selected from the group consisting of alkyl of 1 to 6 carbon atoms, phenyl optionally substituted with 1 to 3 alkyls of 1 to 6 carbon atoms and naphthyl optionally substituted with 1 to 5 alkyls of 1 to 6 carbon atoms.

### Claim 2 (depends on 1)

A compound of claim 1 wherein all of R.sub.1, R.sub.2 and R.sub.3 are hydrogen or alkyl of 1 to 6 carbon atoms.

### Claim 3 (depends on 2)

A compound of claim 2 wherein all of R.sub.1, R.sub.2 and R.sub.3 are hydrogen or methyl.

### Claim 4 (depends on 1)

A compound of claim 1 wherein R.sub.1 is A--SO.sub.2 -- and R.sub.2 and R.sub.3 are both hydrogen or both alkyl of 1 to 6 carbon atoms.

### Claim 5 (depends on 4)

A compound of claim 4 wherein R.sub.1 is tosyl and R.sub.2 and R.sub.3 are both hydrogen or both methyl.

### Claim 6 (depends on 1)

A compound of claim 1 wherein R.sub.3 is A--SO.sub.2 -- and R.sub.1 and R.sub.2 are both alkyl of 1 to 6 carbon atoms.

### Claim 7 (depends on 6)

A compound of claim 6 wherein R.sub.3 is tosyl and R.sub.1 and R.sub.2 are methyl.

### Claim 8 (depends on 1)

A compound of claim 1 wherein R.sub.3 is hydrogen and R.sub.1 and R.sub.2 are both alkyl of 1 to 6 carbon atoms.

### Claim 9 (depends on 8)

A compound of claim 8 wherein R.sub.1 and R.sub.2 are methyl.

### Claim 10 (depends on 1)

A compound of claim 1 wherein R.sub.1 is hydrogen and R.sub.2 and R.sub.3 are methyl.

### Claim 11 (depends on 1)

A process for the preparation of a compound comprising i) reacting a compound of the formula ##STR82## wherein R'.sub.1, R'.sub.2 and R'.sub.3 respectively have the meaning as R.sub.1, R.sub.2 and R.sub.3 as defined in claim 1, with the exception of hydrogen and for R'.sub.3 --A--SO.sub.2 --, with a halogenation agent to obtain the corresponding acyl halide, ii) reacting the latter with a reagent of the formula ##STR83## wherein Ra and Rb individually are alkyl of 1 to 6 carbon atoms, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocycle of 5 or 6 members optionally containing another heteroatom selected from 0 and N to obtain a compound of the formula ##STR84## iii) reacting the latter with a halogenation agent to obtain a compound of the formula ##STR85## wherein Hal.sub.1 is halogen iv) reacting the latter with a Lewis acid to obtain a compound of the formula: ##STR86## corresponding to the compounds of formula I (a) as defined in claim 1, in which R.sub.3 is A--SO.sub.2 --, to the compounds of formula I (c) as defined in claim 1, in which all three of R.sub.1, R.sub.2 and R.sub.3 are alkyl and to the compounds of formula I (e), as defined in claim 1 and optionally reacting the compound of formula (e), (v)-- either if R'.sub.1 is A--SO.sub.2 -- and R'.sub.2 and R'.sub.3 do not together represent --X--, with a hydrolysis agent to obtain a compound of the formula ##STR87## in which R".sub.2 and R".sub.3 both are alkyl corresponding to the compounds of formula I (a) as defined in claim 1 in which R.sub.3 is hydrogen, optionally reacting the latter with an alkylation agent to obtain a compound of the formula ##STR88## corresponding to the compounds of formula I (c) as defined claim 1, in which R.sub.1, R.sub.2 and R.sub.3 are alkyl, optionally subjecting the latter to a hydrolysis of all alkoxys to obtain the compound of the formula ##STR89## corresponding to the compound of formula I (c) as defined in claim 1, in which R.sub.1, R.sub.2 and R.sub.3 are hydrogen, (viii) or subjecting a compound of formula (e) in which all three of R'.sub.1, R'.sub.2 and R'.sub.3 are alkyl, to a hydrolysis of all alkoxys to obtain the compound of formula (h) defined above, ix) optionally reacting the latter with a protection reagent of diols chosen from compounds of the formulae:
B(OR.sub.4).sub.3, C(O)R.sub.5 R.sub.6, C(O)Y.sub.2 and CR.sub.5 R.sub.6 (Y).sub.2,
wherein R.sub.4, R.sub.5 and R.sub.6 are as defined in claim 1 and Y is halogen or Ar--O-- in which Ar is phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino and nitro; or with a reagent of the formula CH.sub.2 (Y).sub.2, Y being defined as above, in the presence of a reagent of the formula P(Hal).sub.5, in which Hal is halogen, followed by a hydrolysis to obtain a compound of the formula ##STR90## corresponding to the compounds of formula I (d) as defined in claim 1, in which R.sub.1 is hydrogen, which is treated with an agent of the formula A--SO.sub.2 Y, in which A is defined as in claim 1 and Y is defined as above to obtain a compound of the formula ##STR91## corresponding to the compounds of formula I (d) as defined in claim 1, in which R.sub.1 is A--SO.sub.2 --, x) optionally reacting the latter with a deprotection reagent of the diol to obtain a compound of the formula ##STR92## corresponding to the compounds of formula I as defined in claim 1, in which R.sub.2 and R.sub.3 are hydrogen, optionally (xi) reacting the latter with an alkylation agent to obtain a compound of the formula ##STR93## corresponding to the compounds of formula I (b) as defined in claim 1 in which alkyl are defined in claim 1, optionally reacting a compound of formula (j) (xii) or (1) with a hydrolysis agent of A--SO.sub.2 -- to obtain a compound of the formula ##STR94## respectively, corresponding to the compounds of formula I (f) as defined in claim 1.

### Claim 12 (depends on 11)

The process of claim 11 wherein
the halogenation agent used is thionyl chloride;
the reagent of formula (b) is 1-(N-morpholinyl)cyclopentene;
the halogenation agent used is oxalyl chloride--(COCl).sub.2 ;
the Lewis acid used is ferric chloride or tin tetrachloride;
the protection reagent of the diols is trimethyl or triethyl borate;
the ASO.sub.2 Y reagent wherein A is alkyl or phenyl substituted by 1 to 3 alkyls.