Process for the synthesis of 1-aryl-1-trifluoromethylcyclopropanes

Abstract

The present invention relates to a process for the manufacturing of 1-aryl-1-trifluoromethylcyclopropanes, which serve as intermediates for the manufacturing of calcium T channel blockers of the general formula (A) ##STR00001##
which are described in WO 2015/186056.

Claims

1. A process, comprising: the reaction of a compound of formula (II) ##STR00020## with SF.sub.4 and HF, to give a compound of formula (III) ##STR00021## wherein R.sup.1 is H or Br.

2. The process according to claim 1, wherein R.sup.1 is H.

3. The process according to claim 1, wherein R.sup.1 is Br.

4. The process according to claim 1, wherein dichloromethane is used as a solvent.

5. The process according to claim 1, wherein SF.sub.4 is added in an amount of 2 to 10 equivalents.

6. The process according to claim 1, wherein R.sup.1 is H and the amount of HF is from 0.4 to 2.5 equivalents.

7. The process according to claim 1, wherein R.sup.1 is Br and the amount of HF is from 1.5 to 2.5 equivalents.

8. The process according to claim 1, said process further comprising the reaction of a compound of formula (III) ##STR00022## wherein R.sup.1 is Br, with a solvent, K.sub.3PO.sub.4, Pd(OAc).sub.2, (2-biphenyl)-di-tert-butylphosphine, and ##STR00023## to give a compound of formula (V) ##STR00024## wherein R.sup.2 is methyl, ethyl, isopropyl, n-butyl, or benzyl.

9. The process according to claim 8, wherein R.sup.2 is methyl.

10. The process according to claim 1, further comprising converting a compound of formula ##STR00025## to a compound of formula ##STR00026##

11. The process according to claim 8, further comprising one of the following steps: a) treatment of the compound of formula (V), wherein R.sup.2 is methyl, ethyl, isopropyl, n-butyl, or benzyl, with NaOH solution, followed by decarboxylation with HCl at 75-100 C.; or b) treatment of the compound of formula (V), wherein R.sup.2 is methyl, ethyl, isopropyl, n-butyl, or benzyl, with NaOH solution, followed by treatment with HCl at 15-30 C. to obtain an intermediate product of formula (VII) ##STR00027## followed by decarboxylation of formula (VII) with HCl at 75-100 C. to obtain the product of formula (I); wherein either step a or b results in the manufacture of the compound of formula (I) ##STR00028##

12. A process for the manufacturing of the compound of formula (III) ##STR00029## said process comprising the reaction of a compound of formula (II) ##STR00030## wherein R.sup.1 is H or Br, with SF.sub.4 and HF.

13. The process according to claim 12, wherein dichloromethane is used as a solvent.

14. The process according to claim 12, wherein SF.sub.4 is added in an amount of 2.7 to 10 equivalents.

15. The process according to claim 12, wherein R.sup.1 is H, and the amount of HF is from 0.4 to 2.5 equivalents.

16. The process according to claim 12, wherein R.sup.1 is Br, and the amount of HF is from 1.5 to 2.5 equivalents.

17. A compound of formula (Va) ##STR00031## wherein each R.sup.2 is methyl, ethyl, isopropyl, n-butyl, benzyl or H, or a salt of said compound.

Description

ABBREVIATIONS AND TERMS USED IN THIS TEXT

Abbreviations

(1) The following abbreviations are used throughout the specification and the examples:

(2) Ac acetyl

(3) aq aqueous

(4) bp boiling point

(5) DCM dichloromethane

(6) eq. equivalent(s)

(7) ET external temperature

(8) GC gas chromatography

(9) h hour(s)

(10) IPC in process control

(11) IT internal temperature

(12) JohnPhos (2-biphenyl)di-tert-butylphosphine

(13) LC-MS liquid chromatographymass spectroscopy

(14) min minute(s)

(15) MS mass spectroscopy

(16) MTBE tert.-butyl-methylether

(17) NMR nuclear magnetic resonance

(18) org. organic

(19) rpm rounds per minute

(20) rt room temperature

(21) % a/a percent determined by area ratio

(22) TFA trifluoroacetic acid

(23) vol 1 vol means 1 L solvent per 1 kg reference starting material

(24) wt 1 wt means 1 kg of reagent per 1 kg of reference starting material

(25) LC-MS method

(26) Column: Waters XBridge C18, 4.630 mm, 2.5 m

(27) Wavelength: 210 nm

(28) Make up eluent: acetonitrile/water 7:3, 0.240 mL/min

(29) Injection volume: 1.00 L

(30) Flow: 4.5 mL/min

(31) Eluent A: water 0.04% TFA

(32) Eluent B: acetonitrile

(33) Gradient: 0.00-0.01 min: 5% B, 1.00-1.45 min: 95% B, 1.55-1.60 min: 5% B

EXPERIMENTAL PART

1. 1-(trifluoromethyl)cyclopropyl)benzene IIIa

(34) 1-Phenyl-1-cyclopropane carboxylic acid (1.0 eq.) (commercially available, Acros, No. 17068) was loaded into a 15 L stainless steel autoclave. A mixture of dichloromethane (1 vol) and anhydrous hydrogen fluoride (1 eq.) was prepared in a 5 L polypropylene bottle and transferred to the autoclave. SF.sub.4 (3.0 eq.) was pressurized into the vessel and heated to 75 C. for 16 h. When cooled, the volatiles were vented through a concentrated potassium hydroxide scrubber and the contents transferred into a 20 L vessel of ice. The vessel was washed out with pressurized dichloromethane (0.5 vol). The solution was then carefully basified with a solution of 50% potassium hydroxide (5 vol) maintaining temperature below 25 C. The mixture was separated and the aqueous layer extracted with dichloromethane (21 vol). The combined organic layers were dried (MgSO.sub.4) filtered, and concentrated at 50 C. under atmospheric pressure to give crude material as a brown liquid containing 36% dichloromethane (by 1H NMR spectra). The product was purified by distillation at bp 78-80 C. at 30 mmHg to give the desired product in 78% yield. .sup.1H NMR (300 MHz, CDCl.sub.3) : 0.01-1.15 (m, 2H), 1.33-1.56 (m, 2H), 7.28-7.79 (m, 5H); .sup.19F NMR (300 MHz) : 3.05.

2. 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene IIIb

(35) 1-(4-Bromo-phenyl)cyclopropane carboxylic acid (1 eq.) (commercially available, Matrix Scientific, No. 82869) was placed in an autoclave. A mixture of anhydrous HF (2 eq.) and dichloromethane (2 vol) was added, followed by SF.sub.4 (3 eq.). The vessel was then heated to 100 C. for 35 h. The reaction was cooled to rt, the volatiles were allowed to vest through a hydroxide scrubber and the vessel contents were transferred to a 5 L vessel of ice (1 vol) and washed with dichloromethane (0.5 vol). The solution was carefully basified with a solution of potassium hydrogen carbonate. Once the solution reached pH 8, the mixture was separated and the aqueous layer extracted with dichloromethane (21 vol). The combined organic layers were dried (MgSO.sub.4) filtered and concentrated at atmospheric pressure. The crude product was purified by distillation at 85 C. at 1 mmHg to give the desired product (58%, >95% assay by 1H NMR and GC) as a pale yellow liquid. Analytical data correspond to those published (ACS Medicinal Chemistry Letters, 2013, 4, 514-516). .sup.1H NMR (500 MHz, CDCl.sub.3) : 1.01-1.05 (m, 2H), 1.36-1.41 (m, 2H), 7.33-7.39 (m, 2H), 7.48-7.51 (m, 2H)

3. 1-methyl-4-(1-(trifluoromethyl)cyclopropyl)benzene XI

(36) 1-(p-tolyl)cyclopropane carboxylic acid (1 eq.) (commercially available, Acros, No. 17070) was placed in an autoclave. A mixture of anhydrous HF (2 eq.) and dichloromethane (2 vol) was added, followed by SF.sub.4 (3 eq.). The vessel was then heated to 100 C. for 72 h. The reaction was cooled to rt, the volatiles were allowed to vest through a hydroxide scrubber and the vessel contents were transferred to a 5 L vessel of ice (1 vol) and washed with dichloromethane (0.5 vol). Significant quantity of black tar was observed. The mixture was carefully basified with a solution of potassium hydrogen carbonate. Once the solution reached pH 8 the mixture was separated and the aqueous layer extracted with dichloromethane (21 vol). The combined organic layers were dried (MgSO.sub.4), filtered and distilled at atmospheric pressure. 1H and 19F NMR showed no desired product, mainly decomposition products.

4. 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetonitrile IX

(37) 1-(4-(cyanomethyl)phenyl)cyclopropane-1-carboxylic acid (VIII) was prepared from 1-(p-tolyl)cyclopropane carboxylic acid by methods known to those skilled in the art.

(38) A solution of 1-(4-(cyanomethyl)phenyl)cyclopropane-1-carboxylic acid (VIII) (20 g, 1 eq.) and dichloromethane (1 vol) was stirred and anhydrous HF (2 eq.) was added. The 250 ml autoclave was evacuated and the solution was transferred to the autoclave under vacuum. SF.sub.4 (3 eq.) was added under nitrogen pressure and the reaction was heated to 75 C. for 16 h. The reaction was cooled to rt, transferred to a 5 L vessel of ice (1 vol) and washed with dichloromethane (0.5 vol). The mixture was carefully basified with a solution of potassium hydrogen carbonate. Once the solution reached pH 8 the mixture was separated and the aqueous layer extracted with dichloromethane (21 vol). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated at atmospheric pressure to give a tarry material. .sup.1H and .sup.19F NMR showed no desired product, mainly acid fluoride.

5. 1-bromo-3-(1-(trifluoromethyl)cyclopropyl)benzene IIIc

5.1 1-(3-bromo-phenyl)cyclopropane-1-carbonitrile

(39) 3-Bromophenylacetonitrile (1 eq.), 1-bromo-2-chloroethane (1.5 eq.) and benzyl triethylammonium chloride (0.08 eq.) were placed into a 5 L 3-neck round bottom flask and stirred for 15 min. A solution of 50% aq sodium hydroxide (6 eq.) was added over 30 min. The reaction was heated at 60 C. for 16 h. IPC showed 100% completion. The reaction was cooled to rt and water (3.3 vol) and CH.sub.2Cl.sub.2 (3.3 vol) were added and layers separated. The aqueous layer was further extracted with CH.sub.2Cl.sub.2 (3.3 vol) and combined organics washed with water (3.3 vol), 1M HCl (3.3 vol) and brine (3.3 vol). The organic layer was dried (MgSO.sub.4), filtered and concentrated under reduced pressure. The crude product was purified by distillation to give clean product (95-97%). .sup.1H NMR (300 MHz, CDCl.sub.3) : 1.36-1.51 (m, 2H), 1.70-1.85 (m, 2H), 7.22-7.29 (m, 2H), 7.41-7.48 (m, 2H).

5.2 1-(3-Bromo-phenyl)cyclopropane-1-carboxylic Acid

(40) 1-(3-bromo-phenyl)cyclopropane-1-carbonitrile (1 eq.), lithium hydroxide (2 eq.) and water (6.0 vol) was placed into a 5 L 3-neck round bottom flask. The reaction was heated at reflux (110 C.) for 16 h. The reaction was cooled to rt and diluted with water (5 vol). The aqueous was washed with CH.sub.2Cl.sub.2 (23 vol) and then the aqueous was acidified to pH 3 using concentrated HCl (1 vol). This was then extracted with MTBE (23 vol), dried (MgSO.sub.4), filtered and concentrated under reduced pressure to give a white crystalline powder (92%). .sup.1H NMR (300 MHz, CDCl.sub.3) : 1.21-1.35 (m, 2H), 1.62-1.76 (m, 2H), 7.17-7.22 (m, 1H), 7.28-7.31 (m, 1H), 7.40-7.47 (m, 1H), 7.51-7.52 (m, 1H).

5.3 1-bromo-3-(1-(trifluoromethyl)cyclopropyl)benzene IIIc

(41) 1-(3-Bromo-phenyl)cyclopropane-1-carboxylic acid (1 eq.) was placed in an autoclave. To this was added dichloromethane (2 vol), anhydrous HF (2 eq.) followed by SF.sub.4 (3 eq.). The vessel was then heated to 100 C. for 36 h. The reaction was cooled to rt, transferred to a 5 L vessel of ice (1 vol) and washed with dichloromethane (0.5 vol). The solution was carefully basified with a solution of potassium hydrogen carbonate. Once the solution reached pH 8, the mixture was separated and the aqueous layer was extracted with dichloromethane (21 vol). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated at atmospheric pressure to yield a mixture of acid fluoride and decomposition products.

6. 1-bromo-2-(1-(trifluoromethyl)cyclopropyl)benzene IIId

(42) 1-(2-Bromo-phenyl)cyclopropane carboxylic acid acid (1 eq.) (commercially available, Combi-Blocks) was placed in an autoclave and to this was added dichloromethane (2 vol), anhydrous HF (2 eq.), followed by SF.sub.4 (3 eq.). The vessel was then heated to 100 C. for 36 h. The reaction was cooled to rt, transferred to a 5 L vessel of ice (1 vol) and washed with dichloromethane (0.5 vol). The solution was carefully basified with a solution of potassium hydrogen carbonate. Once the solution reached pH 8 the mixture was separated and the aqueous layer extracted with dichloromethane (21 vol). The combined organic layers were dried (MgSO.sub.4), filtered and concentrated at atmospheric pressure to yield the acid fluoride.

7. 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene IIIb

(43) The preparation has been performed in analogy to US2013/0196964 A1 [1340-1342].

7.1 Preparation of the Catalyst

(44) To a 5 L 3-neck flask was charged a solution of zinc bromide (0.05 eq.) in anhydrous methanol (0.85 vol), K10 montmorillonite (0.24 vol) was added with stirring at rt under an atmosphere of nitrogen. The mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and the flask was connected to a distillation set up. Residual methanol was removed by heating to 200 C. under gentle vacuum (450 mmHg) overnight to give a pink/beige fine solid (ca. 205 g). The catalyst was stored in a glass jar for use as required.

7.2 Bromination

(45) To a 20 L flange flask was charged 1-phenyl-1-(trifluoromethyl)cyclopropane (1.0 eq.), pentane (6 vol) and the activated zinc bromide catalyst (prepared above, 0.3 vol). The flask was then completely covered to reduce incidence of light and bromine (2.0 eq.) was added dropwise over 15 min at rt. The mixture was left stirring at rt for 16 hours. GC and .sup.19F NMR analysis indicated that the reaction was complete. The foil was removed and the reaction mixture was cooled to 15 C. Sodium metabisulfite solution (0.62 eq.) in water (2.35 vol) was added and the biphasic mixture was stirred until the colour of bromine was removed over 30 min. This was filtered to remove precipitated salts and solid slurried in pentane (23 vol) and filtered. The combined biphasic mixture was separated and the aqueous layer extracted with pentane (4.4 vol). The combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the crude product as a pale yellow oil (Average 93%). The product was purified by distillation at bp 82-88 C. at 1 mmHg to give the desired product (yield 78%). .sup.1H NMR (500 MHz, CDCl.sub.3) : 1.01-1.05 (m, 2H), 1.36-1.41 (m, 2H), 7.33-7.39 (m, 2H), 7.48-7.51 (m, 2H).

8. Dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate V and 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic Acid I

(46) 8.1 K.sub.3PO.sub.4 (3 eq) and toluene (10 vol) were charged in a reactor. After three nitrogen-vacuum cycles, solvent (4.7 vol) was removed by distillation at 110 C. jacket temperature and 250-280 mbar. Note: residual volume in reactor approximately 5 vol. 1-Bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (1.0 eq.) was added to the reactor at 20 C. Separately, in a round bottom flask, Pd(OAc).sub.2 (0.03 eq), JohnPhos (0.06 eq), and toluene (0.2 vol) was vacuum degassed with nitrogen (applied vacuum to 80-100 mbar until bubbling occurred, followed by pressurization with nitrogen to atmospheric pressure). This suspension was introduced into the reactor with nitrogen pressure. Dimethyl malonate (1.05 eq) was added at 20 C., followed by a rinse of the lines with toluene (0.4 vol). The reactor was vacuum degassed with nitrogen as described above. The mixture was stirred (270 rpm) at reflux at 125-130 C. jacket temperature for 2 h 20 min. In-process control (IPC, approx. 10 mL of reaction mixture withdrawn at 95-100 C.; 20-30 L thereof was mixed with 1 mL acetonitrile/water 1:1 and filtered) by GC-MS showed >99% conversion. After cooling to 20-30 C., the suspension was filtered over a nutsche equipped with a Teflon cloth. The cake was washed with toluene (2 vol) by application of vacuum. The filtrate (approximately 8 vol) was concentrated at 110 C. jacket temperature and 300 mbar to a residual volume of 1.2-1.6 vol to afford dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate (V, R.sup.2=methyl) as a black solution in toluene that was used as such in the following step. An aliquot was stripped to dryness: 52% w/w solution, the residue solidified to a shiny brown solid. Yield: 96% as a solution in toluene. .sup.1H NMR (500 MHz, CDCl.sub.3) : 1.02-1.07 (m, 2H), 1.35-1.39 (m, 2H), 3.77-3.82 (m, 6H), 4.66-4.69 (m, 1H), 7.38-7.41 (m, 2H), 7.46-7.50 (m, 2H).

8.2 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic Acid I

(47) Hydrolysis-decarboxylation

(48) To the solution of dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate (V, R.sup.2=methyl) in toluene (for yield calculation, a 100% yield of the preceding step is assumed) was added water (3.4 vol) and 32% NaOH (1.2 vol). The mixture was heated at reflux at ET 100-105 C. (IT 86 C.) for 2.5 h. IPC (LC-MS) showed complete conversion to the sodium 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate (VI). After cooling to 25 C., toluene (0.4 vol) was added and the phase separated. The aqueous phase was circulated through a 3M charcoal cartridge at rt for 30 min. The color changed from a brown-orange to a yellow solution. Water (1 vol) was used for rinse and added to the filtered aqueous phase to the reactor. Toluene (2 vol) was added and solvent (organic: 2 vol, aqueous: 0.4 vol) was removed by distillation at 80-100 C. jacket temperature (IT 80-86 C.) and under reduced pressure (800-900 mbar). Toluene (2 vol) was added and solvent (organic: 2 vol, aqueous: 0.4 vol) was removed by distillation at 80-100 C. jacket temperature and under reduced pressure (800-900 mbar). Toluene (1.2 vol) was added and solvent (organic: 1.2 vol, aqueous: 0.2 vol) was removed by distillation at 80-100 C. jacket temperature and under reduced pressure (600-900 mbar). After cooling to 25 C., the content of the reactor (4.7 vol) was transferred into a feed tank and added to 32% HCl (5.0 eq.) at 80-90 C. during 50 min. The mixture was stirred at 95-100 C. for 2 h 15 min. IPC (LC-MS) showed full conversion. Toluene (2.4 vol) was added to the beige emulsion, cooled to 25 C. for phase separation. The organic phase was washed with water (2.4 vol), filtered through a Whatman Polycap polish filter (approximately 70 m), and stripped to dryness in a rotavap at 55 C. and reduced pressure (100-8 mbar) to afford the desired product as a light-yellow powder. Yield: 68% over the two steps. 100% a/a by LC-MS. .sup.1H NMR assay: 96% w/w. Mp 99.5-100.1 C. .sup.1H NMR (500 MHz, CDCl.sub.3) : 0.99-1.09 (m, 2H), 1.33-1.40 (m, 2H), 3.64-3.71 (m, 2H), 7.27-7.31 (m, 2H), 7.42-7.47 (m, 2H).

9. 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonic Acid (VII) and 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic Acid I

9.1 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonic Acid VII

(49) In a 5-L double-jacketed flask, a mixture of dimethyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonate (V) (1 eq.), toluene (1 vol), water (3 vol), and 32% NaOH (3.5 eq.) was heated to reflux, 105-100 C. bath temperature. After 70 min at reflux (98% conversion by LC-MS), the mixture was cooled to rt, filtered over a pad of Celite (0.7 wt), and the filter washed with water (20.5 vol). The layers were separated. The aqueous phase (pH 14) was washed with toluene (1 vol). In the cleaned reactor, the aqueous phase was set to pH 1-2 by addition of 32% HCl (3.5 eq.) at 20-30 C. The thick, white suspension was cooled to 10 C. and filtered. The cake was washed with water (31 vol) and dried at air overnight to afford the desired product as off-white fine water-wet solid. Yield uncorrected for water (106%). 1H NMR (500 MHz, DMSO) : 1.09-1.16 (m, 2H), 1.30-1.36 (m, 2H), 4.66-4.73 (m, 1H), 7.26-7.48 (m, 4H), 12.40-13.46 (m, 2H).

9.2 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic Acid I

(50) 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonic acid VII (water-wet) was suspended in water (1 vol) and 32% NaOH (0.85 eq.) was added to achieve a clear orange solution after stirring at 25 C. for 15 min. This aqueous phase was washed with toluene (1 vol). The viscous aqueous phase was filtered over a pad of Celite (0.08 wt)/charcoal (0.12 wt)/Celite (0.08 wt), and the cake was washed with water (0.2 vol). The reactor was washed with water and acetone (black-grey precipitation, not soluble in toluene). 24.5% HCl (10 eq.) was heated at reflux (jacket 120 C.) for 40 min to reach the azeotropic steady state of approx. 20% HCl. The basic solution of the sodium salt of 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)malonic acid (filtrate above, 4 vol) was added to the refluxing HCl (120 C. oil bath temperature) over 50 min. IPC indicated 67% conversion. The white suspension turned into an emulsion. After stirring at reflux for additional 60 min, a precipitation formed. IPC indicated 99% conversion. The mixture was cooled to 0 C. over 20 min, filtered, the cake was washed with water (61 vol), and dried in air for 16 h to afford the desired product as white granular solid. Yield (67%). 100% a/a by LC-MS. >99.5% w/w NMR assay. .sup.1H NMR (500 MHz, CDCl.sub.3) : 0.99-1.09 (m, 2H), 1.33-1.40 (m, 2H), 3.64-3.71 (m, 2H), 7.27-7.31 (m, 2H), 7.42-7.47 (m, 2H).