Process for preparing antihelmintic 4-amino-quinoline-3-carboxamide derivatives

1. A process for preparing a compound of formula (II) from a compound of formula (I):

wherein

Y is halogen or Q;

X is C═O, C—OH, or C—NR 3 R 3′ ;

indicates an aromatic ring system or in the case that X is C═O valid double bonds in the ring system;

R 1 is absent in the case that X is C—OH or C—NR 3 R 3′ , or is a hydrogen atom in the case that X is C═O;

R 2 is C 1 -C 3 -alkyl;

R 3 and R 3′ independently of each other are hydrogen or C 1 -C 3 -alkyl, or

R 3 and R 3′ together with the nitrogen to which they are bonded form a morpholinyl-ring;

R 4 is hydrogen or halogen;

Q is phenyl, substituted with 1 to 5 substituents Z 1 to Z 5 , wherein

Z 1 to Z 5 are independently from each other selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, and C 1 -C 4 -halogenoalkyl having 1-5 halogen atoms; and

A is a group selected from the group consisting of

wherein in the process the groups Q, NR 3 R 3′ and NH-A in formula (II) are obtained by reaction of the groups R 2 , X and Y in formula (I) by the steps B-a, B-b, B-c and B-d, which are carried out in the following order:

Step B-a:

wherein R 2 is C 1 -C 3 -alkyl and R 3 , R 3′ and R 4 have the meaning as defined above, and wherein X is C═O and R 1 is hydrogen or X is C—OH and R 1 is absent, corresponding to the formulae (a-I-c) and (a-I-d):

and wherein said process Step B-a is carried out using thionyl chloride (SOCl 2 ); followed by

Step B-b:

wherein G represents a boron compound of formula

(Q) n B(OH) 3-n

wherein

n is 1,2, or 3

or

G represents a boron compound of formula

(Q) 4 B − M +

wherein

M is lithium, sodium, or potassium,

or

G represents a boron compound of formula

QBF 3 − M +

wherein

M is lithium, sodium, or potassium,

or

G represents a boron compound of formula

and wherein

Q is phenyl, substituted with 1 to 5 substituents Z 1 to Z 5 , wherein

Z 1 to Z 5 are independently from each other selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, and C 1 -C 4 -halogenoalkyl having 1-5 halogen atoms; followed by

Step B-c:

wherein R 2 is C 1 -C 3 -alkyl;

wherein base is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, or an alkaline earth metal carbonate;

wherein acid is a mineral acid; followed by

Step B-d:

wherein A has the meaning as defined above; and

wherein said process Step B-d is carried out by using DMT-MM as the coupling agent;

and wherein in the reaction steps B-a to B-d the remaining substituents have the meaning as defined above.

2. The process according to claim 1 , which further comprises the previous Step A for preparing the compound according to the formula (I):

wherein P 2 O 5 is present in the reaction batch in an absolute amount of >1 eq P 2 O 5 and in an amount of 7.0 to 23.0 wt.-% relative to methane sulfonic acid (MSA).

3. The process according to claim 1 , which is represented by the following formulae:

Step B-a:

wherein said process Step B-a is carried out using thionyl chloride (SOCl 2 ); followed by

Step B-b:

wherein G represents a boron compound of formula

(Q) n B(OH) 3-n

wherein

n is 1,2, or 3

or

G represents a boron compound of formula

(Q) 4 B − M +

wherein

M is lithium, sodium, or potassium,

or

G represents a boron compound of formula

QBF 3 − M +

wherein

M is lithium, sodium, or potassium,

or

G represents a boron compound of formula

and wherein

Q is phenyl, substituted with 1 to 5 substituents Z 1 to Z 5 , wherein

Z 1 to Z 5 are independently from each other selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, and C 1 -C 4 -halogenoalkyl having 1-5 halogen atoms; followed by

Step B-c:

wherein R 2 is C 1 -C 3 -alkyl; wherein base is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, or an alkaline earth metal carbonate;

wherein acid is a mineral acid; followed by

Step B-d:

wherein A is a group selected from the group consisting of

and

wherein said process Step B-d is carried out by using DMT-MM as the coupling agent.

4. The process according to claim 3 , wherein

R 4 is selected from hydrogen and fluorine;

Z 1 , Z 3 and Z 5 are hydrogen

Z 2 and Z 4 are chlorine and

A is a group

5. The process according to claim 1 , wherein the group A is selected from the group consisting of

thereby providing the compound (II) or (III) in the enantiomeric form

respectively.

6. The process according to claim 1 , wherein one or more the process steps B-a, B-b, B-c and B-d is further characterized by one or more of the following process conditions:

in Step B-a stoichiometric amounts of thionyl chloride are used;

in Step B-a the amount of thionyl chloride is between 1.15 to 2.30 equivalents;

in Step B-a a pH of 8 to 10 is adjusted;

in Step B-a a solvent is used which is selected from the group consisting of toluene, chlorobenzene or xylene;

in Step B-a catalyst selected from the group consisting of DMF, DEF, DBF or DIF;

in Step B-a a catalyst is used in amounts between 0.8 to 5.0 mol %;

in Step B-a the amine compound is dimethylamine;

in Step B-a the amine compound is added in an amount of ≥1.35 equivalents;

in Step B-b the palladium-catalyst is used in an amount of ≥0.3 mol;

in Step B-b the amount of residual palladium is reduced to ≤200 ppm;

in Step B-b the palladium-catalyst is selected from the group consisting of, Pd(OAc) 2 , Pd(acac) 2 and PdCl 2 (L) 2 , without or in combination with a phosphine ligand L;

in Step B-b, when present, the phosphine ligand L is a monodentate phosphine ligand P(Ar) n (Alkyl) 3-n with n=0, 1, 2 or 3;

in Step B-c the palladium content of the ester compound is ≤200 ppm;

in Step B-c the saponification of the ester compound is carried out by using NaOH;

in Step B-c the HCl salt of the resulting product is prepared;

in Step B-d the starting compound is used in the form of the HCl salt;

in Step B-d a solvent is used which is selected from the group consisting of toluene or chlorobenzene;

in Step B-d the coupling agent DMT-MM is used as the isolated DMT-MM compound or is generated in situ from NMM and CDMT;

in Step B-d the starting compound is used in an amount between 1.05 to 1.4 equivalents;

in Step B-d an amount of 5.0 to 15.0 equivalents;

in Step B-d and amount of 1.25 to 2.00 equivalents;

in Step A the prepared intermediate cyclization precursor is used in the subsequent reaction diluted in an inert solvent;

in Step A an absolute amount between 1.5 and 3.5 equivalents;

in Step A the amount of P 2 O 5 relative to the amount of MSA is 7.0 to 23.0 wt. %; and

in Step A the total amount of the phosphorous pentoxide is added batchwise in two or more portions.

7. The process according to claim 1 , wherein the compound of formula (II) is a compound of formula (IV), (IV′), (V) and/or (V′):

8. The process for preparing the intermediate compounds according to the formula (a-II-1) as defined in claim 1 and the intermediate compounds

by carrying out the process Step B-a, followed by isolation and optionally purification of the resulting compounds.

9. The process for preparing the intermediate compounds according to the formula (b-III) as defined in claim 3 and the intermediate compounds

wherein Z 1 to Z 5 are as defined in claim 1 ,

by carrying out the process Step B-b, followed by isolation and optionally purification of the resulting compounds.

10. The process for preparing the intermediate compounds according to the formula (c-II-1) as defined in claim 1 and the intermediate compounds

by carrying out the process Step B-c

followed by isolation and optionally purification of the resulting compounds.

11. The process for preparing the intermediate compounds according to the formula (a-IV) as defined in claim 3 and the intermediate compounds

by carrying out the process Step B-a, followed by isolation and optionally purification of the resulting compounds.

12. The process for preparing the intermediate compounds according to the formula (c-III) as defined in claim 3 and the intermediate compounds

by carrying out the process Step B-c

followed by isolation and optionally purification of the resulting compounds.