Method for the production of 1,4-benzothiepin-1,1-dioxide derivatives

1. A method for the production of the compound of the formula I

in which

R2, R2′, R3, R3′, R4, R4′, R5, R5′, independently of one another, are H, Cl, Br, I, OH, —(CH 2 )—OH, CF 3 , NO 2 , N 3 , CN, S(O) p —R6, O—S(O) p —R6, (C 1 -C 6 )-alkylene-S(O) p —R6, (C 1 -C 6 )-alkylene-O—S(O) p —R6, COOH, COO(C 1 -C 6 )alkyl, CONH 2 , CONH(C 1 -C 6 )alkyl, CON[(C 1 -C 6 )alkyl] 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 6 )-alkyl, where, in the alkyl radicals, one, more, or all hydrogen(s) can be replaced by fluorine;

phenyl, —(CH 2 )-phenyl, —(CH 2 ) n -phenyl, O-phenyl, O—(CH 2 ) m -phenyl, —(CH 2 )—O—(CH 2 ) m -phenyl, where the phenyl ring may be mono- to trisubstituted with F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CONH 2 ;

where always at least one of the radicals R2, R2′, R3, R3′, R4, R4′, R5, R5′ has the meaning —O—(CH 2 ) m -phenyl or —(CH 2 )—O—(CH 2 ) m -phenyl, where the phenyl ring may be mono- to trisubstituted with F, Cl, Br, I, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 , SO 2 —CH 3 , COOH, COO—(C 1 -C 6 )-alkyl, CONH 2 ;

R6 is H, OH, (C 1 -C 6 )-alkyl, NH 2 , NH(C 1 -C 6 )-alkyl, N((C 1 -C 6 )-alkyl) 2 ;

n is 2, 3, 4, 5, 6;

m is 1, 2, 3, 4, 5, 6;

p is 0, 1, 2;

which comprises

G) reacting the compound of the formula 5

with a compound of the formula 8

to give the compound of the formula 10

and then in a further process step

H) reacting the compound of the formula 10 in the presence of BF 3 and Et 3 SiH to give a compound of the formula 11

and then in a further process step

I) reacting the compound of the formula 11 in the presence of H 2 O 2 to give compound 12

and then in a further process step

J) reacting the compound of the formula 12 in the presence of TEMPO (2,2,6,6-tetramethylpiperidinyloxyl) to give compound 13

and then in a further process step

K) reacting the compound of the formula 13 in the presence of tBuOK in THF to give compound 15/15A

and then in a further process step

L) isolating the compound of the formula 15

and then in a further process step

M) reacting the compound of the formula 15 with the help of H 2 /Pd—C to give a compound of the formula 16

and then in a further process step

N) reacting the compound of the formula 16 in the presence of HNMe 2 to give a compound of the formula 17/17A

and then in a further process step

O) isolating the compound of the formula 17

and then in a further process step

P) reacting the compound 17 with the compound 18, in which the radicals have the meanings given above

to give a compound of the formula 19

and then optionally in a further process step

Q) reacting the compound of the formula of the formula 19, in which the radicals have the meanings given above, to give a compound of the formula 20, in which the radicals have the meanings given above,

where any protective groups present are cleaved off, and then in then optionally in a further process step

R) reacting the compound of the formula 20, in which the radicals have the meanings given above, to give a compound of the formula Ia, in which the radicals have the meanings given above,

as a result of which the substituents R2, R2′, R3, R3′, R4, R4′, R5, R5′ from formula 20 can be exchanged.

2. A method for the production of the compound of the formula 10

in which R in the compounds of the formulae 35 and 30 has the meaning (C 1 -C 6 )-alkyl, which comprises, in a first step,

reacting the compound of the formula 8 with the compound of the formula 35 in the presence of an aqueous base and then, in a second step,

completely converting the resulting mixture consisting of the compound of the formula 30 and the compound of the formula 10 to the compound of the formula 10 by alkaline hydrolysis.

3. The method for the production of the compound of the formula 10 as claimed in claim 2 , wherein the aqueous base used is sodium carbonate, potassium carbonate or cesium carbonate.

4. A method for the production of the compound of the formula 11

which comprises reacting the compound of the formula 10 with a suitable reducing agent to give the compound of the formula 11.

5. The method for the production of the compound of the formula 11 as claimed in claim 4 , wherein hydrophosphorous acid/iodine, sodium borohydride/aluminum(III) chloride, triethylsilane/trifluoroacetic acid, isobutylaluminum dichloride, butylsilane/boron trifluoride, polyhydroxymethylsilane (PHMS) or triethylsilane/boron trifluoride is used as a suitable reducing agent.

6. A method for the production of the compound of the formula 12

which comprises reacting the compound of the formula 11 with a suitable oxidizing agent to give the compound of the formula 12.

7. The method for the production of the compound of the formula 12 as claimed in claim 6 , wherein sodium perborate, hydrogen peroxide/sodium tungstate, hydrogen peroxide/molybdenum(IV) oxide dichloride, ozones or hydrogen peroxide/acetonitrile/ethanol is used as suitable oxidizing agent.

8. A method for the production of the compound of the formula 13

which comprises reacting the compound of the formula 12 with a suitable oxidizing agent to give the compound of the formula 12.

9. The method for the production of the compound of the formula 13 as claimed in claim 8 , wherein oxalyl chloride/DMSO, sulfur trioxide-pyridine complex/DMSO, pyridinium dichromate, periodane or sodium hypochloride/TEMPO is used as suitable oxidizing agent.

10. The method for the production of the compound of the formula I as claimed in claim 1 , wherein

R2, R2′ R3, R3′, R4, R4′, R5, R5′, independently of one another, are H, OH, —(CH 2 )—OH, (C 1 -C 6 )-alkylene-S(O) p —R6, (C 1 -C 6 )-alkylene-O—S(O) p —R6, —O—(CH 2 ) m -phenyl, —(CH 2 )—O—(CH 2 ) m -phenyl, where always at least one of the radicals R2, R2′, R3, R3′, R4, R4′, R5, R5′ has the meaning —O—(CH 2 ) m -phenyl or —(CH 2 )—O—(CH 2 ) m -phenyl;

R6 is H, OH;

n is 2, 3, 4, 5, 6;

m is 1, 2, 3, 4, 5, 6;

P is 0, 1, 2.

11. The method for the production of the compound of the formula I as claimed in claim 1 or 10 , wherein

R2 is H;

R2′ is OH;

R3 is —O—CH 2 -phenyl;

R3′ is H;

R4 is H;

R5 is —SO 3 H, —SO 3 − NH 4 + ;

R5′ is H.

12. A method for the production of the compound of the formula I as claimed in claim 11 , wherein the compound of the formula I has the structure 53