Process for the preparation of efavirenz and devices suitable therefore

Abstract

The invention relates to a process for the preparation of Efavirenz via an efficient transition metal catalyzed cyclization, to a device suitable to perform such process as well as to novel intermediates.

Claims

1. A process for the preparation of 6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one comprising reacting 4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol with at least one cyanate in the presence of at least one transition metal compound; wherein the at least one cyanate is selected from the group consisting of alkali cyanates and alkaline earth cyanates; and wherein the at least one transition metal compound is selected from the group consisting of copper, nickel, palladium, rhodium and platinum compounds.

2. The process according to claim 1, wherein the at least one cyanate comprises sodium cyanate.

3. The process according to claim 1, wherein the at least one transition metal compound is selected from formulae (Ia), (Ib), (IIa), (IIb) and (III),
M(Y.sup.1).sub.2(Ia)
and
M(Y.sup.2)(Ib), wherein M is independently nickel, palladium or copper(II) for formula (Ia) and formula (Ib); Y.sup.1 is chloride, bromide, acetate, nitrate, methanesulphonate, trifluoromethane-sulphonate, trifluoroacetate or acetylacetonate; and Y.sup.2 is sulphate;
MY.sup.3(IIa)
and
[M(B).sub.4](Y.sup.3)(IIb), wherein M is copper(I) for formula (IIa) and formula (IIb); Y.sup.3 is chloride, bromide, iodide, acetate, methanesulphonate, trifluoromethanesulphonate, tetrafluoroborate, trifluoroacetate hexafluorophosphate, perchlorate, hexafluoroantimonate, tetra(3,5-bistrifluoromethylphenyl)borate or tetraphenylborate; and B is a nitrile; and
[M(D).sub.2](III), wherein M is palladium or nickel for formula (III); and D is a (C.sub.4-C.sub.12)-diene.

4. The process according to claim 1, wherein the at least one transition metal compound is selected from the group of copper(I) iodide, copper(II) triflate, copper(II) nitrate trihydrate, copper sulphate, and copper(I) tetraacetonitrile tetrafluoroborate.

5. The process according to claim 1, wherein the at least one transition metal compound is used in combination with at least one ligand capable of coordinating to the transition metal of the at least one transition metal compound, wherein the transition metal is copper, nickel or palladium.

6. The process according to claim 5, wherein the at least one ligand is selected from the group consisting of diamines, carbenes, phosphines, phosphites phenanthrolines, hydroxyquinolines, bis imines, bipyridines, salicylamides, pyrrolidines, glycine, proline, sparteine, and mixtures thereof.

7. The process according to claim 5, wherein the at least one ligand is selected from the group consisting of phenanthroline, N,N-dimethyl-1,2-diaminoethan (DMEDA) and N,N-dimethyl-1,2-diaminocyclohexane (CyDMEDA).

8. The process according to claim 5, wherein the at least one ligand is employed in an amount of from 0.5 to 10 mol per mol of the transition metal compound employed and calculated on the transition metal content present in the transition metal compound.

9. The process according to claim 1, wherein the process is carried out in absence of phase transfer catalysts.

10. The process according to claim 1, wherein copper (II) compounds are employed and additionally copper(0).

11. The process according to claim 3, wherein copper (II) compounds are employed and additionally copper(0).

12. The process according to claim 1, wherein the process is carried out batchwise or continuously.

13. The process according to claim 1, wherein (4S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol is employed with an enantiomeric excess (ee) of at least 80%.

14. The process of claim 10, wherein the copper(0) is in form of finely divided elemental copper.

15. The process of claim 11, wherein the copper(0) is in form of finely divided elemental copper.

16. The process of claim 13, wherein (4S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol is employed with an enantiomeric excess (ee) of at least 90%.

17. The process of claim 13, wherein (4S)-4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol is employed with an enantiomeric excess (ee) of at least 95%.

18. The process of claim 3, wherein the nitrile is acetonitrile, benzonitrile or benzyl nitrile.

19. The process of claim 3, wherein the (C.sub.4-C.sub.12)-diene is norbornadiene or 1,5-cyclooctadiene.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows an exemplary, simplified flow diagram of a process according to the invention using a flow-through reactor 10.

(2) FIG. 2 shows an exemplary, simplified flow diagram of steps A) and B) in the process according to the invention using a flow-through reactor 30 having three reaction zones.

(3) FIG. 3 shows an exemplary, simplified flow diagram of steps C) and D) in the process according to the invention using a flow-through reactor 60 having two reaction zones and a quenching zone.

EXAMPLES

(4) The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

(5) Further modifications and alternative embodiments of various aspects of the invention will be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description of the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims.

Experimental

(6) General Information

(7) All experiments were carried out under an atmosphere of argon. Flash column chromatography was performed over SiliCycle silica gel 230-400 mesh. .sup.1H NMR, .sup.19F NMR and .sup.13C NMR spectra were acquired by Varian Mercury-400 MHz. The proton signal of residual non-deuterated solvent ( 7.26 ppm for CHCl.sub.3) was used as an internal reference for .sup.1H spectra. NMR chemical shifts () are reported in ppm and coupling constants (J) are reported in Hz. NMR split patterns are abbreviated as follows: s (singlet), d (doublet), t (triplet), dd (doublet of doublets) and m (multiplet). High resolution mass spectra were obtained using an Agilent 6210 ESI-TOF mass spectrometer.

(8) Commercially obtained chemicals were used without further purification and all reactions were set up using anhydrous solvent from a dry solvent system (JC Meyer Solvent System) then degassed under argon. Copper powder was obtained for Sigma Aldrich: 99%, spherical and 10 m in diameter. n-Butyl lithium solutions were diluted to the required concentration with HPLC grade hexanes. Quench columns were made using SiliCycle silica gel 230-400 mesh that was further dried by heating it to 135-140 C. under vacuum for 3-5 days. N-trifluoroacetylmorpholine was synthesized according to literature procedure and all corresponding characterization was comparable to the literature. Characterization of all compounds previously reported also corresponds to their literature i.e. WO2012097510, WO 9814436 A1 and A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517-3521.

Examples 1 to 6

(9) General Procedure and Equipment Used for Trifluoroacylation in Flow

(10) A Vapourtec E-Series System was utilized in for pumping of reagents with the compatible pump tube: i.e. n-butyl lithium in hexanes, 1,4-dichlorobenzene in THF, and N-trifluoroacetylmorpholine in THF. All solvents and reagent stock solutions were kept under an atmosphere of dry argon. The flow reactor was built using 1.6 mm ( 1/16) O.D.0.3 mm (0.012) I.D. PTFE tubing and connected by ETFE T-mixers. Quench columns were made using FEP tubing ( 5/16) O.D.(0.025) I.D., and connected in-line using 5/16 inch ETFE flangeless ferrules, 5/16 inch -20 Peek flangeless nuts and female 5/16-24 to male 1/14-28 KEL-F (PCTFE) adapters. All tubing, connectors and adapters were purchased from IDEX Health and Science. Quench columns were prepared with the required amount of dry silica and the ends of the column were packed with short plugs of glass wool to prevent leaching of silica and clogging of the tubing.

(11) A general setup was chosen as shown in FIG. 2.

(12) Standard Flow Conditions:

(13) Dichlorobenzene (PDCB) was dissolved in anhydrous, degassed THF (D1) to a concentration of 1.75 M. nBuLi (1.6 M in hexanes from Sigma Aldrich) was diluted to a concentration of 1.5 M in dry degassed hexanes and the limiting reagent, trifluoroacetyl morpholide (TFAM), was dissolved to a concentration of 1 M in dry degassed THF (D2). All reagent solutions were prepared and kept under argon. The E-Series and reactor loops were set up as described above. The temperature of the chiller 50, an ethanol cold bath was maintained at 45 C. using a HUBER TC50E chiller. The temperature in the chiller 51, also being an ethanol cold bath was maintained at 10 C. using liquid nitrogen and dry ice. The whole reactor was first flushed with anhydrous, degassed solvent, the reaction was performed on a 0.5 mmol scale with respect to trifluoroacetyl morpholide (4 minute pumping at a flow rate of 0.125 mL/min). To ensure complete quenching and capture of morpholine, a quench column of 2.0 or 2.5 grams of dry silica was used per 0.5 mmol reagent. Flow rates were adjusted to 0.125 ml/min via pumps 32, 34 and 38a. The volumes of the reaction zones were 1 ml for reaction zone 1 (36), 5 ml for reaction zone 2 (40) and 0.5 ml for the further reaction zone (42).

(14) For optimization: Quench columns were made using 2.0 grams of dry silica (per 0.5 mmol of limiting reagent). The yellow solution containing the product 2 was collected and the solvent removed under vacuum. Mesitylene was then added as an internal standard for yield determination.

(15) For determination of a two-step isolated yield: The scavenging column (43) was made using 2.5 grams of dry silica (per 0.5 mmol of limiting reagent). The crude yellow solution was collected at the end of the scavenging column (43) and kept refrigerated (20 C.) until use for the second step.

(16) Table 1 shows the results of the trifluoroacylation using varying reaction parameters

(17) TABLE-US-00001 TABLE 1 Example Deviation from standard flow conditions Yield (%)* 1 None 87 2 55 C. 61 3 35 C. 70 4 Reaction zone 2: Volume 3 mL (8 min 78 residence time) 5 Reaction zone 2: Volume 7 mL (18.67 min 74 residence time time) 6 1.2M concentration of TFAM 73 *NMR yields based on mesitylene internal standard.

Examples 7 to 11

(18) General Procedure and Equipment Used for Alkynylation in Flow

(19) A Vapourtec E-Series System was utilized for pumping of reagents with the compatible pump tube: i.e. n-Butyl lithium in hexanes, cyclopropylacetylene in THF, and 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanone of formula (IV) (IP) obtained by example 1 in a mixture of hexanes and THF. All solvents and reagent stock solutions were kept under an atmosphere of dry argon. The flow reactor was built using 1.6 mm ( 1/16) O.D.0.3 mm (0.012) I.D. PTFE tubing and connected by ETFE T-mixers. All tubing, connectors and adapters were purchased from IDEX Health and Science. All reagent solutions were prepared and kept under argon. The E-Series and reactor zones were set up as described in FIG. 3 and the corresponding description above. The temperature the chiller (70) was maintained at 20 C. using a HUBER TC50E chiller.

(20) General Flow Conditions:

(21) 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanone of formula (IV) (IP) obtained by example 1 at a concentration of 0.33 M was used. nBuLi (1.6 M in hexanes from Sigma Aldrich) was diluted to a concentration of 0.43 M with anhydrous, degassed hexanes. Cyclopropylacetylene (C) was dissolved to a concentration of 0.5 M in anhydrous degassed THF (D3). The E-Series and reactor zones were set up as described above. The reaction was done on a 0.5 mmol scale of IP (1 minute pumping at a flow rate of 0.5 mL/min). The reactor was first flushed with anhydrous, degassed solvent.

(22) The volumes of the reaction zones were 1 ml for reaction zone 3 (66) and 3 ml for reaction zone 4 (81).

(23) For optimization: 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanone of formula (IV) (IP) obtained by example 1 (kept in the freezer at 20 C.) was re-dissolved in 2:1 THF:Hexanes mixture to a concentration of 0.33 M. The dark yellow solution containing product POH was quenched in cold brine (ice bath) and extracted with ethyl acetate (320 mL). The solvent was removed under vacuum, NMR conversions were determined based on fluorine NMR.

(24) For determination of a two-step isolated yield: 1-(2,5-dichlorophenyl)-2,2,2-trifluoroethanone of formula (IV) (IP) obtained by example 1 was used directly after collection from example 1. The reaction was performed assuming full conversion on a 0.5 mmol scale of limiting reagent (TFAM). The dark yellow solution was quenched in cold brine (ice bath) and extracted with ethyl acetate (320 mL). The solvent was then removed under vacuum. Product alcohol 2 was isolated from the brown oil by flash column chromatography using 10:1 Hexanes:EtOAc as a pale yellow oil. (112.4 mg-73% yield over steps A) to D)).

(25) Table 2 shows the results of the alkynylation using varying reaction parameters

(26) TABLE-US-00002 TABLE 2 Residence Time Rate Reaction zone 3 (s)/ Example (mL/min) T ( C.) Reaction zone 4 (s) Conversion (%) 7 1.0 20 30 /60 90 8 0.5 20 60 /120 93 9 0.25 20 120 /240 92 10 0.5 5 60 /120 67 11 0.5 20 60 /120 92 (73)* *isolated yield over steps A) to D)

Examples 12 to 21

(27) General Procedure for Copper Catalyzed Cyclization in Batch

(28) Pure 4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol (0.1 mmol, 31 mg), NaOCN (0.2 mmol, 13 mg) and CuI (0.02 mmol, 3.8 mg) were placed in a 2-5 mL sealable borosilicate tube with magnetic stir bar and aluminium crimp cap. The tube was evacuated and backfilled with argon, then 0.5 mL anhydrous, degassed toluene was added and the tube was flushed again with argon. Trans-N,N-dimethyl-1,2-cyclohexanediamine (0.08 mmol, 13 L) was then added, followed by another 0.5 mL toluene. The tube was flushed with argon again, sealed, and placed in an oil bath at 120 C. for 16 hours. The heterogeneous mixture was allowed to cool and was then filtered with ethyl acetate (3-5 mL) through a short column of silica gel and concentrated under vacuum. NMR yields were obtained using mesitylene as an internal standard.

(29) Table 3 shows the results of the copper catalysed cyclization in batch

(30) TABLE-US-00003 TABLE 3 Example [Cu] (mol %) Ligand (Cu:L ratio) Yield (%) 12* CuI (20) DMEDA(1:2) Trace 13* CuI (20) Phen (1:2) 0 14* CuI (20) CyDMEDA (1:2) 12 15 CuI (20) CyDMEDA (1:4) 42 16** CuI (20) CyDMEDA (1:4) n.d 17 (CuOTf).sub.2benzene CyDMEDA (1:4) 36 18 Cu(MeCN).sub.4BF.sub.4 CyDMEDA (1:4) 48 19 CuSO.sub.4 (20) CyDMEDA (1:4) 62 20 Cu(NO.sub.3).sub.23H.sub.2O CyDMEDA (1:4) 60 21*** CuI (20) CyDMEDA (1:4) 9 *Performed in 1 mL dioxane **10 mol % tetrabutylammonium chloride added. ***Performed under air. CyDMEDA: (trans-N,N-dimethyl-1,2-cyclohexane-diamine), DMEDA: (N,N-dimethyl-1,2-ethylene diamine), Phen: (phenanthroline), n.d.: none detected.

Examples 22 to 27

(31) General Procedure for Copper Catalyzed Cyclization in Flow

(32) Standard Procedure for Flow Optimization:

(33) Design for packed bed: A reactor according to FIG. 1 was used. The reaction zone (16) was built using OMNIFIT HiT glass columns (6.6 mm internal diameter, 100 mm height, 40 m PTFE frit filters, adjustable end caps). NaOCN (20 equiv., 130 mg) and Celite (750 mg) was thoroughly mixed and packed tightly into the reaction zone. After packing the reaction zone had an internal volume of approximately 2.0 mL. The reactor was assembled as shown in FIG. 1 using the Vapourtec E-series fitted with a standard column heated reactor and a manual injection loop as feeding zone (11). The injection loop (2 mL) was built using (1.6 mm O.D.0.3 mm I.D.) PTFE tubing connected to the main stream using two switchable 3-way (HEX) valves obtained from OMNIFIT.

(34) Injection loop: Pure 4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol (0.1 mmol, 31 mg, IP), and copper nitrate tri-hydrate (0.02 mmol, 3.8 mgs) were placed in a pear shaped flask and the flask was evacuated and backfilled three times with argon. Anhydrous, degassed acetonitrile (1 mL) was added and the flask was flushed again with argon. Trans-N,N-dimethyl-1,2-cyclohexanediamine (0.08 mmol, 12.6 L) was injected, followed by 1 mL anhydrous, degassed toluene. The solution was sonicated to ensure homogeneity and transferred to the manual injection loop under argon.

(35) Flow conditions: The reactor was first flushed with anhydrous toluene and then heated under 0.7 MPa until the column temperature was recorded at 120 C. for a flow rate of 33 l/min (corresponding to a residence time of 60 minutes). The manual valves were then switched to allow injection of the reagent stream into the column reactor. The resulting mixture was collected and filtered with ethyl acetate (approx. 10 mL) through a short column of silica gel and concentrated under vacuum. Conversions of the crude mixture were determined based on fluorine NMR.

(36) Table 4 shows the results of the copper catalysed cyclization in flow-through reactor

(37) TABLE-US-00004 TABLE 4 Conversion** [Cu] Cu]/L Cu Conc. of IP to POH Example (mol %) (mol %) (equiv IP [M] (%) (%) 22 Cu(NO.sub.3).sub.2 5/10 1 0.05 90 44 3H.sub.2O 23 Cu(NO.sub.3).sub.2 5/20 1 0.05 93 41 3H.sub.2O 24 Cu(NO.sub.3).sub.2 5/20 2 0.05 97 35 3H.sub.2O 25* 0/10 1 0.05 100 n.d 26 Cu(OTf).sub.2 5/10 0.5 0.15 91 63 *for comparison only, not according to the invention **Conversions based on .sup.19F NMR.

Example 27

(38) Pure 4-cyclopropyl-2-(2,5-dichloro-phenyl)-1,1,1-trifluoro-but-3-yn-2-ol (0.4 mmol, 124 mg), and copper (II) triflate (0.02 mmol, 7.2 mg) were placed in a pear shaped flask and the flask was evacuated and backfilled three times with argon. Anhydrous, degassed acetonitrile (0.5 mL) was added and the tube was flushed again with argon. Trans-N,N-dimethyl-1,2-cyclohexanediamine (0.04 mmol, 6.3 L) was injected, followed by 1.5 mL anhydrous, degassed toluene. The solution was sonicated to ensure homogeneity and transferred to the manual injection loop under argon. The packed bed column was built using OMNIFIT HiT glass columns (6.6 mm internal diameter, 100 mm height, 40 m PTFE frit filters, adjustable end caps). NaOCN (20 equiv., 520 mg), Celite (700 mg), and copper powder (0.2 mmol, 13 mg) were thoroughly mixed and packed into the column. After packing the column had an internal volume of approximately 2.0 mL. The reaction was performed at a flow rate of 33 l/min; corresponding to a residence time of 60 mins. The collected crude mixture was diluted with ethyl acetate (approx. 10 mL) and filtered through a short column of silica, followed by a plug of neutral alumina to remove the copper salts. Solvent was removed under vacuum to obtain a pale yellow solid. The purified compound, rac-Efavirenz, was obtained as an off-white solid by crystallization with hexanes:dichloromethane 78.0 mg, 62% yield).

(39) Main other product in examples 12 to 27 was 2-(3-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol.

(40) NMR Data:

(41) ##STR00005##

(42) .sup.1H NMR (400 MHz, CDCl.sub.3, ppm) 7.71 (s, 1H), 7.60 (d, J=7.6 Hz, 1H), 7.39-7.31 (m, 2H), 3.03 (s, 1H), 1H), 1.40-1.34 (m, 1H); 0.92-0.79 (m, 4H);

(43) .sup.13C NMR (100 MHz, CDCl.sub.3, ppm) 137.6, 134.1, 129.5, 129.3, 127.5, 125.4, 123.1 (q, J.sub.C-F=284 Hz), 93.1, 72.3 (q, J.sub.C-F=32 Hz), 70.5, 8.5, 0.7;

(44) .sup.19F NMR (376 MHz, CDCl.sub.3, ppm) 80.57.

(45) HRMS (ESI) m/z (M-H).sup.+ calculated: 273.0300, found: 273.0325.

(46) LRMS (ES) m/z (M).sup.+ calculated: 274.0372, found: 274.0361.