Methods for the preparation of 1,3-benzodioxole heterocyclic compounds

1. A method for the preparation of a compound of formula (I)

wherein R 1 is selected from CHF 2 and CF 3 , and Q is selected from chloro, bromo and fluoro, the method comprising each of the following steps:

(1) reacting a compound of formula (II)

wherein R 2 is selected from C 1-6 -alkyl, and arylalkyl, and R 21 is C(O)CH 3 with a compound of formula (III)

wherein “ ” represents a single bond, a double bond, or two single bonds, and when “ ” represents a double bond or two single bonds, “══” is a single bond, and when “ ” represents a single bond, “══” is a double bond; R 3 represents oxygen when “ ” represents a double bond and R 3 represents O—C 1-6 -alkyl when “ ” represents a single bond or two single bonds; in the presence of an acid catalyst to form a compound of formula (IV)

wherein R 2 and R 21 are as defined above;

(2a) reacting the resulting compound of formula (IV) with an aromatic or aliphatic thiol to form a compound of formula (VI)

wherein R 21 is as defined above;

(2b) reacting the resulting compound of formula (VI) with aqueous N(Bu) 4 + OH − to form a compound of formula (VII)

wherein R 21 is as defined above;

(3) alkylating the resulting compound of formula (VII) with a hydrochlorofluorocarbon reagent,

R 1 —Cl  (VIII)

wherein R 1 is as defined above, to form a compound of formula (IX)

wherein R 1 and R 21 are as defined above;

(4) reacting the resulting compound of formula (IX) with a pyridine compound of formula (X)

wherein Q is as defined above and Q x is selected from chloro, bromo, fluoro, and iodo to form a compound of formula (XI);

wherein R 1 and Q are as defined above; and

(5) oxidating the resulting compound of formula (XI) to prepare the compound of formula (I)

wherein R 1 and Q are as defined above.

2. The method according to claim 1 wherein the reaction in step (2a) is conducted in a solvent selected from NMP, DMSO, DMF, methanol, ethanol, and mixtures thereof, and in the presence of a base.

3. The method according to claim 1 wherein the reaction in step (3) is conducted using a hydrochlorofluorocarbon in the presence of a polar solvent.

4. The method according to claim 1 wherein the reaction in step (4) is conducted in a polar solvent, and in the presence of abase.

5. The method according to claim 1 wherein R 1 is CHF 2 .

6. The method according to claim 1 wherein each Q and each Q x are chloro.

7. The method according to claim 1 , wherein the method produces a compound of formula (I)

wherein R 1 is selected from CHF 2 and CF 3 , and Q is selected from chloro, bromo, and fluoro.

8. The method according to claim 1 , wherein the acid catalyst of reaction in step (1) is a silicate mineral selected from Montmorillonite K10, Montmorillonite K30, Montmorillonite KSF, Zeolite HSZ-341NHA, Zeolite HSZ-331NHA, Zeolite HSZ-350HUA, and Zeolite HSZ-360HUA.

9. The method according to claim 1 , wherein the reaction in step (3) is conducted using chlorodifluoromethane in an aprotic polar solvent selected from DMF (N,N-dimethylformamide), NMP (N-methylpyrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile), and THF (tetrahydrofuran), and mixtures thereof.

10. The method according to claim 1 , wherein the oxidation reaction in step (5) is conducted with a reagent selected from PAA (peracetic acid) in AcOH (acetic acid), and aqueous H 2 O 2 in formic acid or acetic acid.

11. A method for preparing a compound of formula (I)

wherein R 1 is selected from CHF 2 and CF 3 , and Q is selected from chloro, bromo, and fluoro, comprising each of steps (2a), (2b), (3), and (4) as defined in claim 1 , and subsequently oxidizing the resulting compound.

12. A method for preparing a compound of formula (I)

wherein R 1 is selected from CHF 2 and CF 3 , and Q is selected from chloro, bromo, and fluoro, comprising each of the following steps:

(2a) reacting a compound of formula (IV)

with an aromatic or aliphatic thiol to form a compound of formula (VI)

wherein R 21 is C(O)CH 3

(2b+3) reacting the compound of formula (VI) with a difluorocarbene source in a polar solvent in the presence of a base, to form a compound of formula (IX)

wherein R 1 and R 21 are as defined above; and

(4) reacting the compound of formula (IX) with a pyridine compound of formula (X)

wherein Q is as defined above and Q x is selected from chloro, bromo, fluoro, and iodo to form a compound of formula (XI);

wherein R 1 and Q are as defined above;

subsequently oxidizing the resulting compound.

13. The method according to claim 12 , wherein the reaction in step (2b+3) is conducted in a solvent selected from NMP (N methylpyrolidone), DMI (1,3-dimethyl-2-imidazolidinone), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), MeCN (acetonitrile), THF (tetrahydrofuran), ethanol, methanol, water, and mixtures thereof, and in the presence of a base, selected from K 2 CO 3 , Na 2 CO 3 , KHCO 3 , NaHCO 3 , Cs 2 CO 3 , TEA (triethylamine), tert-BuOLi (lithium tert butoxide), sodium methoxide, sodium ethoxide, DIPEA (N,N-diisopropylethylamine), KOH, NaOH, and LiOH.

14. The method according to claim 12 , wherein the difluorocarbene source of reaction in step (2b+3) is selected from sodium chloro-difluoroacetate, diethyl bromodifluoromethylphosphonate, chlorodifluoromethyl phenylsulfone, and 2-chloro-2,2-difluoroacetophenone.

15. An intermediate compound of formula (VII),

wherein R 21 is C(O)CH 3 .

16. An intermediate compound of formula (IX),

wherein R 1 is selected from CHF 2 and CF 3 , and R 21 is C(O)CH 3 .