PROCESS FOR THE PREPARATION OF HALO-SUBSTITUTED BENZENES

Abstract

The invention relates to a process for the preparation of compound of formula (I) wherein R.sub.1 is halogen and R.sub.2 is halogen or hydrogen; comprising a) reacting the compound of formula (II) in an aprotic organic solvent in the presence of an aprotic polar co-solvent with a magnesium amide base followed by a halogenating agent, to the compound of formula I wherein R.sub.1 is halogen and R.sub.2 is hydrogen, and b) reacting the compound of formula (I), wherein R.sub.1 is chloro and R.sub.2 is hydrogen, in an aprotic organic solvent in the presence of an aprotic polar co-solvent with a magnesium amide base followed by a halogenating agent to a compound of formula I, wherein R.sub.1 is chloro and R.sub.2 is halogen.

##STR00001##

Claims

1. A process for the preparation of a compound of formula I ##STR00022## wherein R.sub.1 is halogen and R.sub.2 is hydrogen or R.sub.1 is chloro and R.sub.2 is halogen; comprising a) for the preparation of a compound of formula I, wherein R.sub.1 is halogen and R.sub.2 is hydrogen, reacting the compound of formula II ##STR00023## in an aprotic organic solvent in the presence of an aprotic polar co-solvent with a magnesium amide base followed by a halogenating agent, to the compound of formula I ##STR00024## wherein R.sub.1 is halogen and R.sub.2 is hydrogen; and b) for the preparation of a compound of formula I, wherein R.sub.1 is chloro and R.sub.2 is halogen, reacting the compound of formula I, wherein R.sub.1 is chloro and R.sub.2 is hydrogen, in an aprotic organic solvent in the presence of an aprotic polar co-solvent with a magnesium amide base followed by a halogenating agent to a compound of formula I, wherein R.sub.1 is chloro and R.sub.2 is halogen.

2. A process according to claim 1, characterized in that in step a) the magnesium amide base is a compound of formula IV ##STR00025## complexed with lithium chloride; wherein R.sub.3 and R.sub.4 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl; or and X is halogen.

3. A process according to claim 1, characterized in that in step b) the magnesium amide base is a compound of formula IV ##STR00026## complexed with lithium chloride; wherein R.sub.3 and R.sub.4 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl; or and X is halogen.

4. A process according to claim 1, characterized in that the magnesium amide base of reaction steps a) and b) is identical.

5. A process according to claim 1, characterized in that the aprotic polar co-solvent in reaction step a) is selected from the group consisting of the compounds of formula V ##STR00027## wherein R.sub.5, R.sub.6 and R.sub.7 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl; or R.sub.5, R.sub.6 or R.sub.7 together form a C.sub.4-C.sub.7carbocycle; the compounds of formula VI ##STR00028## wherein R.sub.8 and R.sub.9 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl and both R.sub.10 together represent a —CH.sub.2—CH.sub.2— or —CH.sub.2—CH.sub.2—CH.sub.2— chain; and the compounds of formula VII ##STR00029## wherein R.sub.11 and R.sub.12 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl; or both R.sub.11 or both R.sub.12 together represent a —CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2— or —CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2— chain;

6. A process according to claim 1, characterized in that the aprotic polar co-solvent in reaction step b) is selected from the group consisting of the compounds of formula V ##STR00030## wherein R.sub.5, R.sub.6 and R.sub.7 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl; or R.sub.5, R.sub.6 or R.sub.7 together form a C.sub.4-C.sub.7carbocycle; the compounds of formula VI ##STR00031## wherein R.sub.8 and R.sub.9 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl and both R.sub.10 together represent a —CH.sub.2—CH.sub.2— or —CH.sub.2—CH.sub.2—CH.sub.2— chain; and the compounds of formula VII ##STR00032## wherein R.sub.11 and R.sub.12 are, independently from each other, C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.7cycloalkyl or C.sub.1-C.sub.6alkoxylalkyl; or both R.sub.11 or both R.sub.12 together represent a —CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2— or —CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2—CH.sub.2— chain.

7. A process according to claim 1, characterized in that the halogenating agent in step a) is selected from chlorine, bromine, iodine, N-halogen amides, sulfonyl chlorides, polyhalogenated hydrocarbons, sulfuryl chloride and hexachloroacetone

8. A process according to claim 1, characterized in that the halogenating agent in step b) is selected from chlorine, bromine, iodine, N-halogen amides, sulfonyl chlorides, polyhalogenated hydrocarbons, sulfuryl chloride and hexachloroacetone.

9. A process according to claim 1, characterized in that the aprotic organic solvent and the aprotic polar co-solvent are identical for steps a) and b).

10. A process according to claim 1, comprising a) reacting the compound of formula II ##STR00033## in an aprotic organic solvent selected from organic ethers in the presence of an aprotic polar co-solvent selected from the compounds of formulae Va and VIa ##STR00034## with a magnesium amide base selected from the compounds of formulae IVa and IVb, ##STR00035## followed by a halogenating agent selected from chlorine, bromine, iodine, N-halogen amides, sulfonyl chlorides, polyhalogenated hydrocarbons, sulfuryl chloride and hexachloroacetone; to the compound of formula I, wherein R.sub.1 is halogen and R.sub.2 is hydrogen ##STR00036## and b) reacting the compound of formula I wherein R.sub.1 is chloro and R.sub.2 is hydrogen in an aprotic organic solvent selected from organic ethers in the presence of an aprotic polar co-solvent selected from the compounds of formulae Va and VIa ##STR00037## with a magnesium amide base selected from the compounds of formulae IVa and IVb, ##STR00038## followed by a halogenating agent selected from chlorine, bromine, iodine, N-halogen amides, sulfonyl chlorides, polyhalogenated hydrocarbons, sulfuryl chloride and hexachloroacetone; to a compound of formula I, wherein R.sub.1 is chloro and R.sub.2 is halogen.

Description

PREPARATORY EXAMPLES

Example 1: Preparation of 5-bromo-1,3-dichloro-2-fluoro-benzene

[0032] ##STR00020##

[0033] A dry, argon-flushed Schlenk-flask equipped with a magnetic stirrer and a septum was charged with 20 mL freshly titrated iPrMgCl.LiCl (1.24 M in THF, 1.0 equiv.) to which 3.8 mL of diisopropylamine (1.1 equiv.) was added dropwise at 25° C. The reaction mixture was stirred at this temperature until gas evolution was completed (ca. 48 h). The formed precipitate was dissolved with additional dry THF. The fresh solution of iPr.sub.2NMgCl.LiCl in THF was titrated at 25° C. with benzoic acid and 4-(phenylazo)diphenylamine as an indicator. A concentration of 0.59 M was obtained.

[0034] To a solution of 4-bromo-2-chloro-1-fluoro-benzene (0.209 g, 1.00 mmol) in THF (1 mL) was added iPr.sub.2NMgCl.LiCl (0.59 M, 3.39 ml, 2.00 mmol) at 25° C. and the resulting mixture was stirred for 15 min at 25° C. Hexachloro-2-propanone (0.397 g, 1.50 mmol) was added at 0° C. and the mixture was stirred for 15 min. The resulting mixture was then quenched with sat. aq. NH.sub.4Cl, extracted with ethyl acetate and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the solvent was removed in vacuo. Quantitative GC measurement showed that the ratio between 5-bromo-1,3-dichloro-2-fluoro-benzene and regioisomer is about 12:1. Purification by flash column chromatography (SiO.sub.2, i-hexane) furnished 5-bromo-1,3-dichloro-2-fluoro-benzene (0.190 g) as a colorless oil.

[0035] Diisopropylamine (3.1 ml, 21 mmol) was added dropwise to 1.3 M iPrMgCl.LiCl in THF (15.0 ml, 19.5 mmol) and the resulting suspension was stirred at ambient temperature for 20 h. DMPU (1.5 ml, 12 mmol) was added resulting in a clear solution. The fresh solution of iPr.sub.2NMgCl.LiCl in THF with DMPU as an additive was titrated at 25° C. with benzoic acid and 4-(phenylazo)diphenylamine as an indicator. A concentration of 1.10 M was obtained.

[0036] To a solution of 4-bromo-2-chloro-1-fluoro-benzene (0.993 g, 4.74 mmol) in THF (4.7 mL) was added the solution of iPr.sub.2NMgCl.LiCl (1.10 M, 4.70 ml, 5.21 mmol) prepared above at ambient temperature and the resulting mixture was stirred for 20 min. This reaction mixture was added dropwise to a solution of hexachloroacetone (1.90 g, 7.11 mmol) in THF (2 ml) and stirring was continued for 15 min. Quantitative LC/MS analysis using decafluorobiphenyl as an internal standard indicated that the reaction mixture contains 5-bromo-1,3-dichloro-2-fluoro-benzene (0.957 g) and 4-bromo-2-chloro-1-fluoro-benzene (0.150 g). No regioisomeric product was observed under these conditions.

[0037] It is clear from the experiments above that the addition of a polar aprotic additive provides an advantage in doing the reaction using only an easily available magnesium base since it provides an improved regioselectivity and avoids the use of large excess of base (1.1 eq vs 2.0 eq without additive). In addition higher concentration of the reaction media was achieved which is beneficial for production on a large scale.

Preparation of 5-bromo-1,3-dichloro-2-fluoro-benzene under flow conditions

[0038] The flow system (FlowSyn, Uniqsis) was dried by flushing it with dry THF (flow rate of all pumps: 1.00 mL/min; run-time: 30 min). Injection loop A was loaded with 4-bromo-2-chloro-1-fluorobenzene (0.425 g, 2.03 mmol, 1.00 M in dry THF+10 vol % DMPU; 3.0 mL) and injection loop B was loaded with (Magnesium Diisopropyl Amide).LiCl (1.10 M in dry THF+10 vol % DMPU; 2.23 mmol, 3.0 mL). The solutions were simultaneously injected into separate THF streams (pump A and B; flow rates: 0.25 mL/min each) and mixed in a T-shaped tube connector. The combined streams passed a coiled and a tube reactor (2.5 mL; residence time: 5 min; 25° C.) and were collected in a dry, argon-flushed flask equipped with a magnetic stirrer and a septum containing hexachloroacetone (2.03 M in dry THF, 1.10 mL; 2.23 mmol). After collecting the magnesiated intermediate, the pumps were turned off and the reaction mixture was stirred for additional 1.5 h. The reaction was quenched with sat. aq. NH.sub.4Cl (30 mL) and the aq. layer was extracted with EtOAc (3×40 mL). The combined organic fractions were dried over anhydrous Na.sub.2SO.sub.4, filtrated and the solvent was removed in vacuo. Purification by flash column chromatography (SiO.sub.2, i-hexane) furnished a colorless oil (0.440 g) containing 5-bromo-1,3-dichloro-2-fluoro-benzene as well as approx. 10% of 4-bromo-2-chloro-1-fluorobenzene. No regioisomeric product was observed under these conditions.

Example 2: Preparation of 5-bromo-1-chloro-2-fluoro-3-iodo-benzene

[0039] ##STR00021##

[0040] To a solution of 2,2,6,6-tetramethylpiperidine (0.266 g, 1.86 mmol) in THF (4.3 ml) was added dropwise at −20° C. n-butyllithium in hexanes (2.5M, 0.69 ml, 1.72 mmol). The reaction media was stirred at −20° C. for 15 min before being cooled down to −78° C. 4-bromo-2-chloro-1-fluoro-benzene (0.300 g, 1.43 mmol) was added dropwise and stirring was continued for 2 h. Then a solution of iodine (0.40 g, 1.58 mmol) in THF (1.4 ml) was added dropwise. After stirring for another 10 min the reaction was quenched with aq NaHCO.sub.3 and the aqueous layer was extracted with cyclohexane (3×). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. Analysis of the crude mixture by quantitative 1H NMR using trimethoxy benzene as an internal standard gave 53% of 5-bromo-1-chloro-2-fluoro-3-iodo-benzene, 32% of regioisomer containing one iodine, 11.5% of starting material and 3.6% of byproduct containing two iodines.

[0041] This preparatory example demonstrates that a use of strong lithium bases such as lithium tetramethylpiperidine (LiTMP) is not suitable for obtaining compounds of formula I when R.sub.2 is chloro in high yield and regioselectivity.