Process for synthesizing heterocyclic compounds
View Patent ↗The invention provides the process illustrated in scheme 1 for synthesizing heterocyclic compounds of formula I. In the process, an isothiocyanate of formula II is initially reacted with a primary amine or formula III to give a thiourea of formula IV. Subsequently, the thiourea of formula IV is converted to the corresponding heterocycle of formula I using a base and a sulfonyl chloride.
1. A process for preparing heterocycles of formula Ia,
wherein:
X is sulfur, oxygen or NR5,
where R5 is hydrogen or (C1-C4)alkyl;
n is zero, 1, 2 or 3;
Ar is phenyl, naphthyl or heteroaryl, each of which may be optionally substituted by 1, 2, 3, 4 or 5 R11 radicals
where R11 is in each case independently selected from the group consisting of (C1-C4)alkyl, F, Cl, Br, I, CN, NO 2 , OH, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;
R1, R2, R3 and R4
are each independently hydrogen, F or (C1-C4)alkyl
where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;
or
R1 and R3 together are a bond,
and
R2 and R4, together with the two carbon atoms to which they are attached, form an aromatic six-membered carbocycle in which one or two carbon atoms may be replaced by nitrogen and the aromatic six-membered ring may be substituted by 1, 2, 3 or 4 R7 radicals,
where R7 is in each case independently selected from the group consisting of (C1-C4)alkyl, F, Cl, Br, I, CN, NO 2 , OH, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms,
where n=0;
or
R1 and R3 are each independently hydrogen or (C1-C4)alkyl
and
R2 and R4, together with the two carbon atoms to which they are attached, form a saturated 5-, 6-, 7- or 8-membered carbocycle in which one or two carbon atoms may be replaced by O, S, NH and N(C1-C4)alkyl and which carbocycle may be substituted by 1, 2, 3, 4, 5 or 6 R8 radicals where R8 is in each case independently selected from the group consisting of (C1-C4)alkyl, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms,
where n=0;
excluding compounds in which Ar is unsubstituted phenyl, X is oxygen or sulfur, R1 and R2 are each independently hydrogen, (C1-C4)alkyl or benzyl, R3 and R4 are each hydrogen and n is zero,
and their tautomers and their salts,
which process comprises, as shown in scheme 2
a) reacting an aromatic isothiocyanate of formula IIa with a primary amine of formula IIIa to give a thiourea of formula IVa, and
b) converting the thiourea of formula Iva, using a sulfonyl chloride R6SO 2 Cl in the presence of a base, to the corresponding compound of formula Ia,
where, in the compounds of formulae IIa, IIIa and IVa,
Ar, X, n and R1 to R4 are each as defined in formula Ia and
R6 is phenyl which is unsubstituted or substituted by methyl, trifluoromethyl, F, Cl or Br.
2. A process for preparing heterocycles of formula Ia,
wherein:
X is NR5,
where R5 is hydrogen or (C1-C4)alkyl;
n is zero, 1, 2 or 3;
Ar is phenyl, naphthyl or heteroaryl, each of which may be optionally substituted by 1, 2, 3, 4 or 5 R11 radicals
where R11 is in each case independently selected from the group consisting of (C1-C4)alkyl, F, Cl, Br, I, CN, NO 2 , OH, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;
R1, R2, R3 and R4
are each independently hydrogen, F or (C1-C4)alkyl
where some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms;
or
R1 and R3 together are a bond,
and
R2 and R4, together with the two carbon atoms to which they are attached, form an aromatic six-membered carbocycle in which one or two carbon atoms may be replaced by nitrogen and the aromatic six-membered ring may be substituted by 1, 2, 3 or 4 R7 radicals,
where R7 is in each case independently selected from the group consisting of (C1-C4)alkyl, F, Cl, Br, I, CN, NO 2 , OH, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms,
where n=0;
or
R1 and R3 are each independently hydrogen or (C1-C4)alkyl
and
R2 and R4, together with the two carbon atoms to which they are attached, form a saturated 5-, 6-, 7- or 8-membered carbocycle in which one or two carbon atoms may be replaced by O, S, NH and N(C1-C4)alkyl and which carbocycle may be substituted by 1, 2, 3, 4, 5 or 6 R8 radicals where R8 is in each case independently selected from the group consisting of (C1-C4)alkyl, O(C1-C4)alkyl, and COO(C1-C4)alkyl, and some or all of the hydrogen atoms of the alkyl radicals may be replaced by fluorine atoms,
where n=0;
excluding compounds in which Ar is unsubstituted phenyl, X is oxygen or sulfur, R1 and R2 are each independently hydrogen, (C1-C4)alkyl or benzyl, R3 and R4 are each hydrogen and n is zero,
and their tautomers and their salts,
comprising converting a thiourea of formula Iva, using a sulfonyl chloride, R6SO 2 Cl, in the presence of a base, to a compound of formula Ia
wherein in the compounds of formula Iva,
Ar, X, n, R1 to R4 and R6 are each as defined in formula Ia, and
R6 is phenyl which is unsubstituted or substituted by methyl trifluoromethyl, F, Cl or Br.
3. The process of claim 1 , in which the reaction is carried out as a one-pot reaction.
4. The process of claim 1 , wherein steps a) and b) are each independently conducted continuously or batchwise.
5. The process of claim 1 , wherein Ar is phenyl, thienyl or isoxazolyl, each of which is optionally substituted by 1, 2, 3, 4 or 5 R11 radicals.
6. The process of claim 1 , wherein R6 is phenyl or p-methylphenyl.
7. The process of claim 1 , wherein the base used in step b) is sodium hydroxide or potassium hydroxide.
8. The process according to claim 1 wherein Ar is selected from the group consisting of
each of which may be optionally substituted by 1, 2, 3, 4 or 5 R11 radicals.
9. The process according to claim 8 wherein Ar is selected from thienyl and isoxazolyl each of which may be optionally substituted by 1, 2, 3 or 4 R11 radicals.
10. The process according to claim 2 wherein Ar is selected from the group consisting of
each of which may be optionally substituted by 1, 2, 3, 4 or 5 R11 radicals.
11. The process according to claim 10 wherein Ar is selected from thiophene and isoxazolyl each of which may be optionally substituted by 1, 2, 3, 4 or 5 R11 radicals.