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PF-06747775 (Pfizer) Third generation covalent EGFR inhibitors

March 23, 2016 11:46 am / Leave a comment

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PF-06747775 ≥98% (HPLC)

PF-06747775 (Pfizer)

PF06747775; PF06747775; PF 06747775; PF6747775; PF 6747775; PF6747775. PFE-X775

N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

CAS 1776112-90-3
Chemical Formula: C18H22FN9O2
Exact Mass: 415.188

Recruiting, Phase I/II (NTC02349633)

Epidermal growth factor receptor antagonists

Antineoplastics

Non-small cell lung cancer

Dose escalation study to evaluate safety, PK, PD and efficacy in advanced EGFRm+ NSCLC

02 May 2015Phase-I clinical trials in Non-small cell lung cancer (Metastatic disease, Second-line therapy or greater) in USA (PO) (NCT02349633)
05 Feb 2015Pfizer plans a phase I trial for Non-small cell lung cancer (Second-line therapy or greater) in USA (NCT02349633)
05 Jan 2015Preclinical trials in Non-small cell lung cancer in USA (PO)

PF-06747775 is an orally available inhibitor of the epidermal growth factor receptor (EGFR) mutant form T790M, with potential antineoplastic activity. EGFR T790M inhibitor PF-06747775 specifically binds to and inhibits EGFR T790M, a secondarily acquired resistance mutation, which prevents EGFR-mediated signaling and leads to cell death in EGFR T790M-expressing tumor cells. Compared to some other EGFR inhibitors, PF-06747775 may have therapeutic benefits in tumors with T790M-mediated drug resistance.

for the oral treatment of patients with locally advanced or metastatic EGFR mutant (del19 or L858R) non-small cell lung cancer

Kinetic mechanism for two-step covalent inhibition of EGFR

PATENT

US 20150141402

Example 7

(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin -6-amine

(MOL) (CDX)

A suspension of 6-chloro-2-fluoro-9H-purine (5.49 g, 31.8 mmol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60 g, 40.34 mmol, 1.26 eq), and N,N-diisopropylethylamine (16.6 mL, 95.5 mmol, 3.00 eq) in DMSO (31.8 mL) was stirred at ambient temperature for 19 hr. The reaction mixture was then concentrated in vacuo at 50° C., poured into water (250 mL), and stirred vigorously at 0° C. for 1 hr. The resulting solids were filtered off, washed with ice cold water (20 mL), and dried for 16 hr at 50° C. to give the title compound (7.26 g, 87% yield, 96% purity) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3H). m/z (APCI+) for C₁₀H₁₁FN₇O 264.2 (M+H)⁺.

Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl -9H-purin-6-amine

(MOL) (CDX)

To a vigorously stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (7.25 g, 27.5 mmol, 1.00 eq) and potassium carbonate (7.61 g, 55.1 mmol, 2.00 eq) in 1,4-dioxane (92.0 mL), was added dimethyl sulfate (2.90 mL, 30.3 mmol, 1.10 eq) in a dropwise manner over 3 min. After 4 hr, additional portions of 1,4-dioxane (50.0 mL), potassium carbonate (3.80 g, 27.5 mmol, 1.00 eq), and dimethyl sulfate (1.00 mL, 10.4 mmol, 0.30 eq) were added to the reaction mixture. After a further 16 hr, the reaction mixture was concentrated in vacuo, diluted with water (120 mL), and stirred at ambient temperature for 1 hr. The resulting solids were filtered, washed with water (20 mL), and dried for 16 hr at 60° C. to give the title compound (6.42 g, 84% yield, >95% purity) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H) 3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C₁₁H₁₃FN₇O 278.2 (M+H)⁺.

Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol -4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

To a stirred suspension of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (554 mg, 2.00 mmol, 1.00 eq) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (500 mg, 2.10 mmol, 1.05 eq) in DMSO (4.2 mL) was added N,N-diisopropylethylamine (0.83 mL, 5.00 mmol, 2.50 eq). The reaction mixture was then heated at 100° C. for 16 hr, cooled to ambient temperature, diluted with THF (4 mL), and treated with potassium tert-butoxide (4.00 mL, 1 M in THF, 2.00 eq). After 1 hr, an additional portion of potassium tert-butoxide (0.50 mL, 1 M in THF, 0.25 eq) was added to the reaction mixture. After a further 1 hr, the reaction mixture was poured into phosphate buffer (50 mL, pH=7) and water (50 mL), and extracted with ethyl acetate (5×40 mL). The combined organic layers were combined, dried (Na₂SO₄), and concentrated under reduced pressure. This crude product was then dissolved in ethyl acetate (40 mL) at 60° C. and then treated with heptanes (20 mL), at which point the solution became cloudy and was allowed to cool to ambient temperature and then to 0° C. After 16 hr at 0° C., the resulting solids were filtered and dried at ambient temperature to give the title compound (620.5 mg, 75% yield) as a white powder. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C₁₈H₂₃FN₉O₂416.3 (M+H)⁺.

Example 7A

(Scheme F): Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

Preparation Step 1A: Preparation of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione

(MOL) (CDX)

A mixture of xylene, (1.2 L), benzylamine (120 g, 1.10 mol, 1.0 eq) and L-(+)-tartaric acid (173 g, 1.15 mol, 1.05 eq) were heated at 135° C. for 12 hr (flask jacket temperature). Upon reaction completion, the mixture was cooled to 65° C. and MeOH (120 mL, 1 vol) was added. The resulting mixture was stirred for 1 hr and the resulting suspension was cooled to 20° C. followed by the addition of EtOAc (480 mL). Stirring was continued at 10° C. for 2 hr. The crude product was isolated by filtration and washed with EtOAc (120 mL) and dried on the filter. The crude product was then taken up in MeOH (480 mL) and heated at a gentle reflux for 1 hr, then cooled to 20° C. and granulated for 1 hr. The suspension was filtered and the precipitate washed with MeOH (240 mL) and dried to give the title compound (191 g, 864 mmol, 79%) as a white granular solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.38-7.30 (m, 2H) 7.30-7.22 (m, 3 H) 6.32 (br. s., 1 H) 4.59 (d, J=14.8 Hz, 1 H) 4.53 (d, J=14.8 Hz, 1 H) 4.40 (br. D., J=4.3 Hz, 2 H). m/z (EI+) for C₁₁H₁₁NO₄221.0 (M)⁺.

Preparation Step 2A: Preparation of (3S,4S)-1-benzylpyrrolidine-3,4-diol

(MOL) (CDX)

To a mixture of (3R,4R)-1-benzyl-3,4-dihydroxypyrrolidine-2,5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt %, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt %. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70%). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12%). ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.26 (m, 4 H) 7.25-7.20 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.57 (d, J=13.0 Hz, 1 H) 3.46 (d, J=13.0 Hz, 1 H) 2.74 (dd, J=9.4, 5.9 Hz, 2 H) 2.30 (dd, J=9.4, 4.4 Hz, 2 H). m/z (EI+) for C₁₁H₁₅NO₂194.2 (M+H)⁺.

Preparation Step 3A: Preparation of (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ⁶-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester

(MOL) (CDX)

To a 5 L jacketed reactor (Reactor 1) was added 1,4-dioxane (1.8 L), (3S,4S)-1-benzylpyrrolidine-3,4-diol (180 g, 0.932 mol, 1.0 eq) and TEA (792 mL, 5.68 mol, 6.1 eq) and the resulting mixture stirred at 10° C.

To a 2 L jacketed reactor (Reactor 2) was added 1,4-dioxane (1.6 L) and chlorosulfonyl isocyanate (596 g, 2.80 mol, 3.0 eq) and the resulting solution was cooled to 10° C. A solution of tert-butanol (211 g, 2.85 mol, 3.05 eq) in 1,4-dioxane (180 mL) was added over 45 min while maintaining the temperature between 10° C. and 20° C., and the resulting solution was then stirred for 15 min at 10° C.

The solution in Reactor 2 was transferred to Reactor 1 over 50 min while controlling the internal temperature of Reactor 1 from 10° C. to 20° C. Once the addition was complete, the jacket temperature was warmed at 20° C. and the resulting mixture was stirred for 16 hr. When UPLC analysis confirmed that the bis-alkylated intermediate was fully formed (target <3% mono-alkylated intermediate), the entire batch was filtered and the filtrate was sent into a clean reactor. The residual TEA-HCl cake was washed with dioxane (300 mL) and the wash was combined with the filtrate. The resulting dioxane solution was then heated to 80° C. and held for 3 hr. After sampling for reaction completion (<1% intermediate remaining), the batch was distilled (pot temp=80° C.) under partial vacuum (400 mbar) to less than half volume. The reaction mixture was diluted with EtOAc (2 L) and washed twice with water (2×2 L). The mixture was then washed with 0.5 N sodium bicarbonate (2 L) and then dried over sodium sulfate (360 g, 2 wt eq) and filtered into a clean dry reactor. The EtOAc solution was concentrated under partial vacuum to about 400 mL total volume resulting in the formation of a thick slurry. The mixture was cooled to 0° C. and stirred for 1 hr and then filtered and washed with cold EtOAc (200 mL) and then dried in a vacuum oven at 40° C. to give 173 g of the title compound. A second crop of product was isolated by concentrating the filtrate and then cooling, granulating and filtering to give an additional 28.4 g of the desired product. In total, the title compound was isolated in 61% yield (201 g, 568 mmol). ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 5.36 (dd, J=7.3, 3.8 Hz, 1 H) 4.79-4.73 (m, 1 H) 4.48 (d, J=4.8 Hz, 2 H) 3.38-3.31 (m, 2 H), 3.70 (d, J=13.4 Hz, 1 H) 3.62 (d, J=13.4 Hz, 1 H) 3.13-2.99 (m, 2 H) 2.48-2.40 (m, 2 H) 1.46 (s, 9 H). m/z (EI+) for C₁₆H₂₂N₂O₅S 355.2 (M+H)⁺.

Preparation Step 4A: Preparation of (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate

(MOL) (CDX)

A solution of 1M tetrabutylammonium fluoride in THF (1.27 L, 1.27 mol, 2.5 eq) and (3aR,6aS)-5-benzyl-2,2-dioxo-tetrahydro-1-oxa-2λ⁶-thia-3-5-diaza-pentalene-3-carboxylic acid t-butyl ester (180 g, 0.508 mol, 1.0 eq) were heated at 60° C. (jacket temperature) for 2 hr. Upon reaction completion, the mixture was partially distilled under vacuum to remove the THF. After concentration to a low stir volume, THF was displaced with EtOAc (2×500 mL). After again reducing to a low stir volume, EtOAc (3.6 L) and p-toluenesulfonic acid monohydrate (396 g, 2.10 mol, 4.1 eq) were charged and heated at 80° C. for 2 hr. The mixture was cooled to 10° C. over 1.5 hr and then granulated at 10° C. for 2 hr. The solid product was filtered and washed with EtOAc (2×900 mL) and dried at 50° C. in a vacuum oven for 12 hr. The title compound was isolated as an air stable crystalline solid in 83% yield (231 g, 419 mmol). ¹H NMR (400 MHz, D₂O) δ ppm 7.69-7.61 (m, 4 H) 7.56-7.42 (m, 5 H) 7.36-7.29 (m, 4 H) 5.65-5.49 (m, 1 H) 4.47 (br. s., 2H) 4.37-4.23 (m, H) 4.15 (ddd, J=12.8, 8.2, 1.4 Hz, 1 H) 3.88 (dd, J=19.1, 1.2 Hz, 1 H), 3.74 (ddd, J=33.2, 14.0, 5.5 Hz, 1 H) 3.44 (dd, J=12.8, 8.2 Hz, 1 H) 2.34 (s, 6 H). m/z (EI+) for C₁₁H₁₅FN₂194.8 (M+H)⁺.

Preparation Step 5A: N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

(MOL) (CDX)

A suspension of 1,1′-carbonyldiimidazole (73.0 g, 441 mmol, 1.1 eq) in acetonitrile (3.3 L) was stirred at 20° C. until a clear solution was obtained. 3-(methylsulfonyl)propanoic acid (67.0 g, 440 mmol, 1.1 eq) was then added and the mixture was stirred at 25° C. for 3 hr. (3R,4R)-1-benzyl-4-fluoropyrrolidin-3-amine bis-tosylate (220 g, 400 mmol, 1.0 eq) was added and the mixture was stirred at 25° C. for 16 hr resulting in a fine white slurry. The solids were filtered off and the byproduct cake washed with acetonitrile (600 mL). The acetonitrile solution was then concentrated to a low stir volume and then taken up in EtOAc (2.0 L) and washed with 1 N aqueous sodium bicarbonate (1.3 L). The aqueous layer was back extracted with EtOAc (500 mL) and the combined EtOAc layers were washed with water (1.0 L). The resulting EtOAc solution was distilled to remove about 2.0 L of distillate and then displaced with 2-propanol under atmospheric conditions until the internal temperature rose to 78° C. while maintaining a total volume of 2 L. The batch was then cooled to 20° C. and granulated at 20° C. for 12 hr resulting in product crystallization. The desired product was isolated by filtration and the cake washed with 2-propanol (600 mL), then dried in an oven at 40° C. under reduced pressure for 12 hr. The title compound (108 g, 308 mmol) was isolated in 77% yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.36 (br. d., J=7.0 Hz, 1 H) 7.37-7.29 (m, 4 H) 7.29-7.23 (m, 1 H) 4.90 (ddt, J=53.4, 5.3, 2×1.7 Hz, 1 H) 4.25 (dddd, J=26.4, 13.9, 7.0, 1.4 Hz, 1 H) 3.61 (d, J=13.2 Hz, 1 H) 3.57 (d, J=13.2 Hz, 1 H) 3.36-3.28 (m, 2 H) 3.03 (dd, J=9.3, 7.5 Hz, 1 H) 2.97 (s, 3 H) 2.80 (dd, J=24.0, 11.6 Hz, 1 H) 2.66 (ddd, J=30.6, 11.6, 5.3 Hz, 1 H) 2.57 (td, 2×7.7, 1.4 Hz, 2 H) 2.18 (dd, J=9.4, 6.7 Hz, 1 H). m/z (EI+) for C₁₅H₂₁FN₂O₃S 329.7 (M+H)⁺.

Preparation Step 6A: N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide

(MOL) (CDX)

To a Parr reactor was added N-((3R,4R)-1-benzyl-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (86.5 g, 263 mmol, 1.0 eq), palladium hydroxide (20% on carbon, 2.59 g, 3.69 mmol, 3 wt/wt %) and MeOH (430 mL). The reactor was purged three times with nitrogen (50 psi) and then purged three times with hydrogen (20 psi). The reactor was heated at 50° C. and then pressurized to 50 psi while stirring at 1200 rpm. The material was hydrogenated for 7 hr and then cooled to 20° C. and purged with nitrogen. The mixture was filtered to remove the catalyst and the cake was washed with MeOH (173 mL). The combined filtrate and wash were concentrated to about 200 mL followed by addition of MTBE (200 mL) and then concentrated to a low stir volume. Additional MTBE (200 mL) was added and the resulting slurry granulated at 20° C. for 16 hr. The desired product was isolated by filtration, washed with MTBE (300 mL) and then dried in an oven at 40° C. for 12 hr. The title compound was isolated in 90% yield (53.3 g, 224 mmol) as a white crystalline solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (br. d., J=6.8 Hz, 1 H) 4.96-4.78 (m, 1 H) 4.14-4.01 (m, 1 H) 3.32 (dd, J=8.0, 7.3 Hz, 2 H) 3.13 (dd, J=11.8, 6.8 Hz, 1 H) 3.01-2.93 (m, 1 H) 2.98 (s, 3 H) 2.88 (d, J=3.0 Hz, 1 H) 2.60 (br. s., 1 H) 2.5 7-2.52 (m, 3 H). m/z (EI+) for C₈H₁₅FN₂O₃S 239.1 (M+H)⁺.

Step 1: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

(MOL) (CDX)

A suspension of 6-chloro-2-fluoro-9H-purine (88% potency, 5.90 kg, 30.20 mol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (98% potency, 5.55 kg, 33.22 mol, 1.10 eq), and sodium bicarbonate (10.1 kg, 120.81 mol, 4.00 eq) in EtOAc (106 L) was stirred at 50° C. for 12 hr. The reaction mixture was then cooled to 20° C., granulated for 1 hr, filtered, and the solids were washed with EtOAc (18 L) and dried on the filter. The crude product was charged back into the reactor and suspended in water (106 L) and stirred at 35° C. for 2 hr. The resulting slurry was cooled to 20° C. and the desired product was isolated by filtration and the cake was washed with water (30 L) and then with EtOAc (30 L) and dried for 16 hr at 50° C. to give the title compound (6.26 kg, 23.8 mol, 79% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3 H). m/z (APCI+) for C₁₀H₁₁FN₇O 264.2 (M+H)⁺.

Step 2: Preparation of 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine

(MOL) (CDX)

To a 100 L reactor fitted with a caustic scrubber was added 2-methyltetrahydrofuran (44.0 L), 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (2.20 kg, 8.36 mol, 1.00 eq) and potassium phosphate tribasic (7.10 kg, 33.43 mol mmol, 4.00 eq). The resulting mixture was stirred at 5° C. and dimethyl sulfate (1.42 kg, 11.28 mol, 1.35 eq) was added and the resulting mixture was stirred at 5° C. for 1 hr. The reaction was warmed from 5° C. to 15° C. over 2 hr and then held at 15° C. for 20 hr. The reaction mixture was cooled to 5° C. and quenched with water (44.0 L) while maintaining the internal temperature below 10° C. The mixture was then heated at 50° C. for 2 hr and then cooled to 10° C. and granulated for 2 hr. The product was isolated by filtration and washed with water (11.0 L) and then with 2-methyltetrahydrofuran (11.0 L). The cake was dried under vacuum at 40° C. for 8 hr to give the title compound (1.99 kg, 7.18 mol, 86% yield) as an off white solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (br. s., 1 H) 8.13 (br. s., 1 H) 7.67 (s, 1 H) 3.78 (s, 3 H)3.70 (s, 3 H) 3.69 (br. s., 3 H). m/z (APCI+) for C₁₁H₁₃FN₇O 278.2 (M+H)+.

Step 3: Preparation of N-((3R,4R)-4-fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

(MOL) (CDX)

To a 200 L Hastelloy reactor heated to 40° C. was added sulfolane (22.4 L) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (4.03 kg, 16.9 mol, 1.05 eq) and stirred the resulting mixture until all solids were dissolved. To this solution was added 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (4.47 kg, 16.1 mol, 1.00 eq) and N,N-diisopropylethylamine (8.50 L, 48.7 mol, 3.0 eq) and the mixture heated at 115° C. for 16 hr. The reaction mixture was cooled to 30° C., and a solution of potassium hydroxide (2.26 kg, 40.3 mol, 2.5 eq) in water (44.7 L) was added. After stirring for 4 hr, the reaction mixture was cooled to 20° C., water (44.7 L) was added and the resulting mixture granulated for 12 hr. The crude product was isolated on a Nutsche filter and washed with water (27 L) and then dried under nitrogen on the filter. The reactor was cleaned and then charged with water (35.8 L) and acetone (53.6 L). The crude product cake was charged back into the reactor and heated to 60° C. until all of the solids had dissolved. The batch was then cooled to 40° C. and then transferred into a speck free 100 L reactor via an in-line 10 μm filter. The 200 L reactor, line and filter were rinsed with acetone (5 L) and sent into the 100 L reactor. The batch was concentrated with the jacket temperature set at 70° C. under partial vacuum until the acetone content reduced to 5 wt %, as determined by gas chromatography head space. The batch was then cooled to 20° C. and granulated for 4 hr. The product was filtered, washed with water (18 L) and dried in a vacuum oven at 55° C. for 8 hr. The title compound (3.942 kg, 9.49 mol, 59%) was isolated as a white crystalline solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C₁₈H₂₃FN₉O₂416.3 (M+H)⁺.

Summary of 1st generation and 2nd generation EGFR inhibitors

REFERENCES

Planken, S.; Murray, B. W.; Lafontaine, J.; Weinrich, S.; Hemkens, M.; Kath, J. C.; Nair, S. K.; Johnson, T. O.; Cheng, H.; Sutton, S. C.; Zientek, M.; Yin, M. -J.; Solowiej, J.; Nagata, A.; Gajiwala, K. Abstracts of Papers, 249th ACS National Meeting & Exposition, Denver, CO, United States, March 22–26, 2015; MEDI-248

//////Third generation, covalent EGFR inhibitors, PF-06747775, Pfizer, PFE-X775

Compound name AND SMILES string
Rociletinib COC(C=C(N1CCN(C(C)=O)CC1)C=C2)=C2NC3=NC=C(C(F)(F)F)C(NC4=CC=CC(NC(C=C)=O)=C4)=N3
Osimertinib CN(CCN(C)C)C(C(NC(C=C)=O)=C1)=CC(OC)=C1NC2=NC=CC(C3=CN(C)C4=C3C=CC=C4)=N2
EGF816 ClC1=C2C(N=C(NC(C3=CC(C)=NC=C3)=O)N2[C@H]4CN(C(/C=C/CN(C)C)=O)CCCC4)=CC=C1
PF-06747775 CN1C2=NC(N3C[C@@H](NC(C=C)=O)[C@H](F)C3)=NC(NC4=CN(C)N=C4OC)=C2N=C1
PF-06459988 CN(N=C1)C=C1NC2=NC3=C(C(Cl)=CN3)C(OC[C@H]4CN(C(C=C)=O)C[C@@H]4OC)=N2
WZ4002 ClC1=CN=C(NC2=C(OC)C=C(N3CCN(C)CC3)C=C2)N=C1OC4=CC=CC(NC(C=C)=O)=C4

Fosfluconazole

February 20, 2016 9:19 am / Leave a comment

Fosfluconazole

Fosfluconazole; 194798-83-9; UNII-3JIJ299EWH; 3JIJ299EWH; NCGC00182029-01;

2-(2,4-difluorophenyl)-1,3-di(1h-1,2,4-triazol-1-yl)propan-2-yl dihydrogen phosphate;

2,4-difluoro-α,α-bis(1H-1,2,4-triazol-1-ylmethyl) benzyl alcohol, dihydrogen phosphate

Molecular Formula:	C₁₃H₁₃F₂N₆O₄P
Molecular Weight:	386.250688 g/mol

Agouron Pharmaceuticals, Inc.

Research Code：UK-292663, UK 292663, F-FLCZ, F FLCZ

Trade Name：Prodif^{® PFIZER}

MOA：Azole antifungal

Indication：Cryptococcus neoformans; Candidiasis

Status：Approved, Japan PMDA OCT 16 2003

Company：Pfizer (Originator)

Candidiasis,Cryptococcus neoformans, Injection, Solution, Eq. 100 mg/200 mg/400 mg fluconazole per vial

Fosfluconazole (INN) is a water-soluble phosphate prodrug of fluconazole – a triazole antifungal drug used in the treatment and prevention of superficial and systemic fungal infections. The phosphate ester bond is hydrolysed by the action of a phosphatase – an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group (see dephosphorylation).

Fosfluconazole was approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on Oct 16, 2003. It was developed and marketed as Prodif^® by Pfizer in Japan.

Fosfluconazole is a water-soluble phosphate prodrug of fluconazole – a triazole antifungal drug. It is indicated for the treatment of candida and cryptococcus infections.

Prodif^® is available as solution for intravenous use, containing 100, 200 or 400 mg of free Fosfluconazole per vial. The recommended dose is 50 to 100 mg administered intravenously once daily for candidiasis. Another dose is 50 to 200 mg fluconazole once daily for cryptococcosis.

Route 1

Reference：1. WO9728169A1 / US6977302B2.

2. Org. Process Res. Dev.2002, 6, 109-112.

http://pubs.acs.org/doi/pdf/10.1021/op010064%2B

2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)- 2-propyl dihydrogen phosphate (2). A slurry of dibenzyl 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazole-1-yl)-2-propyl phosphate (30.1 kg, 53.13 mol), 5% palladium-on-carbon catalyst (50% wet, type 5R39, 1.5 kg), and sodium hydroxide (4.36 kg, 108.9 mol) in low-endotoxin water (75.7 L) was hydrogenated at ambient temperature and 414 kPa (60 psi) for 12 h. The slurry was filtered, and the catalyst was washed with low-endotoxin water (9.8 L). After separating the toluene by-product, the aqueous phase was slurried with carbon (3.1 kg) for 30 min. After the carbon was removed by filtration, the aqueous phase was acidified to pH 1.45 by that addition of sulfuric acid (6.69 kg) in low-endotoxin water (25 L) over 2 h. The resulting slurry was granulated at ambient temperature for 1 h and then filtered. The product was sequentially washed with filtered low-endotoxin water (103 L) and filtered acetone (103 L). The product was dried under vacuum at 50 °C for 12 h to give the title compound (18.1 kg, 88%) a white powder: mp 223-224 °C.

1H NMR (DMSO) δ 5.07 (2H, d), 5.24 (2H, d), 6.77-6.83 (1H, m), 7.00-7.18 (2H, m), 7.75 (2H, s), 8.53 (2H, s).

Found: C, 40.28; H, 3.39; N, 21.63;

[MH]+ 387.0786. C13H13F2N6O4P requires: C, 40.43; H, 3.39; N, 21.78; [MH]+ 387.0782.

US6977302

https://www.google.com/patents/US6977302

EXAMPLE 1 1-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl dihydrogen phosphate

(a) Dibenzyl 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl phosphate

Method A

A solution of 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (also known as fluconazole, 10.0 g, 32.6 mmol), 1H-tetrazole (6.85 g, 97.8 mmol), dibenzyl diisopropyl phosphoramidite (22.55 g, 65.2 mmol) in methylene chloride (100 ml) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The mixture was then cooled to 0° C., and a solution of 3-chloroperoxybenzoic acid (13.5 g, 50-55% w/w, 39.1 mmol) in methylene chloride (50 ml) was added maintaining the temperature at 0° C. The resulting mixture was allowed to warm to room temperature for 1 hour before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO₄) the solvent was removed and replaced with methyl isobutyl ketone (37 ml) and tert-butyl methyl ether (74 ml). After granulating at −10° C. for 1 hour the product was filtered and washed with ice cold methyl isobutyl ketone and tert-butyl methyl ether (1:3, 15 ml) and dried at 50° C. under vacuum for 18 hours to give the subtitle compound (16.05 g, 87%), m.p. 93° C.

Found: C, 57.12; H, 4.46; N, 14.85. C₂₇H₂₅F₂N₆O₄P requires C, 57.24; H, 4.46; N, 14.84%. m/z 567 (MH⁺) ¹H NMR (300 MHz, CDCl₃) δ=4.90 (d, 2H), 4.95 (d, 2H), 5.05 (d, 2H), 5.19 (d, 2H), 6.58-6.73 (m, 2H), 6.88-6.95 (m, 1H), 7.20-7.30 (m, 4H) 7.32-7.38 (m; 6H), 7.80 (s, 2H), 8.36 (s, 2H).

Method B

To stirred ethyl acetate (1530 ml) was added 2-(2,4-difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)propan-2-ol (also known as fluconazole, 306 g, 1.00 mol) and pyridine (237.3 g, 3.00 mol) before cooling to 0° C. Phosphorus trichloride (137.4 g, 1.00 mol) was added dropwise to the reaction mixture maintaining the temperature between 0-5° C. before allowing the reaction mixture to warm to 15° C. over 30 minutes. Benzyl alcohol (216 g, 2.00 mol) was then added over 30 minutes at 15-20° C. After a further 30 minutes hydrogen peroxide (27.5% w/w in water, 373 g) was added maintaining the temperature at 15-20° C. After 30 minutes the aqueous phase was removed and the organic phase washed with aqueous sodium metabisulphite, dilute hydrochloric acid and water. The solvent was removed at reduced pressure and replaced with methyl isobutyl ketone (850 ml) and tert-butyl methyl ether (1132 ml). After granulating at 20° C. for 1 hour and at 0° C. for 1 hour, the product was filtered and washed with ice cold tert-butyl methyl ether (2×220 ml) and dried at 50° C. under vacuum for 18 hours to give the subtitle compound (358 g, 63%). The melting point and spectroscopic data was identical to that stated in method A.
(b) 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl dihydrogen phosphate

A slurry of the compound of step (a) (9.80 g, 17.3 mmol), 5% palladium on carbon catalyst (50% wet, 1.0 g) and sodium hydroxide (1.38 g, 34.6 mmol) in water (26 ml) was hydrogenated at room temperature and 414 kPa (60 p.s.i.) for 20 hours. The solution was filtered through a pad of celite (trade mark) and washed with water (5 ml). The toluene was separated and the aqueous phase cooled to 0° C. whereupon sulphuric acid (1.70 g, 17.3 mmol) was added. The resulting slurry was granulated at 0° C. for 1 hour and then filtered, washed with water (2×5 ml) and dried under vacuum at 50° C. to give the title compound (5.80 g, 87%). m.p. 223-224° C.

Found: C, 40.28; H, 3.39; N, 21.63. C₁₃H₁₃F₂N₆O₄P requires C, 40.43; H, 3.39; N, 21.76%. ¹H NMR (300 MHz, DMSO) δ=5.07 (d, 2H) 5.24 (d, 2H), 6.77-6.83 (m, 1H), 7.00-7.18 (m, 2H), 7.75 (s, 2H), 8.53 (s, 2H).

EXAMPLE 2 2-(2,4-Difluorophenyl)-1,3-bis(1H-1,2,4-triazol-1-yl)-2-propyl disodium phosphate

A solution of the compound of Example 1(a) (10.0 g, 17.7 mmol) and sodium acetate (2.90 g, 35.3 mmol) in ethanol (160 ml) and water (20 ml) was hydrogenated over Pearlman’s catalyst (1.00 g) at room temperature and at 345 kPa (50 p.s.i.) for 16 hours. The solution was filtered through a pad of celite (trade mark) and the solvents removed at reduced pressure to leave a thick syrup. This was dissolved in ethanol (100 ml) with the aid of sonication and warmed to reflux. The resulting solution was allowed to cool slowly and granulate for 1 hour at room temperature. The product was filtered, washed with ethanol (10 ml) and dried under vacuum at 50° C. to give the title compound (4.48 g, 59%). m.p. 160-162° C.

¹H NMR (300 MHz, D₂O) δ=5.01 (d, 2H), 5.40 (d, 2H), 6.60 (m, 1H), 6.79 (m, 1H), 7.11 (m, 1H), 7.63 (s, 2H), 8.68 (s, 2H).

Route 2

Reference：1. CN103864844A.

http://www.google.com/patents/CN103864844A?cl=en

TRANSLATED BY MACHINE…….TEXT MAY VARY

forskolin fluconazole (fosf Iuconazole, Formula I) is fluconazole (Formula IV) of monophosphate prodrugs, fluconazole in the tertiary alcohol into a phosphate ester, not only did not introduce a chiral center, also increased water solubility, because a long time to overcome the low water solubility of fluconazole resulting larger infusion volume defects. After intravenous administration in the role of phosphatases in vivo hydrolysis into fluconazole, pharmacological effect. Blessing from the Central Institute of the United States Secretary of fluconazole Fai end developed, launched in Japan in 2004 I May 15, for the treatment of candidiasis and cryptococcal infections caused deep as true bacteremia, respiratory fungal disease, fungal peritoneum

Inflammation, gastrointestinal fungal disease, fungal urinary tract infections, fungal meningitis.

Synthesis gas itraconazole on forskolin in W09728169, Organic Process Research & Development (200 2), 6 (2), 109-112, CN1789270, Art of Drug Synthesis (2007), 71-82, etc. have been reported in the literature . Which Organic Process Research & Development (2002) described in detail in the first blessing Secretary fluconazole and improved synthetic route for the route problems to adapt to industrial mass production of synthetic routes.

Document Organic Process Research & Development (2002), 6,109-112 discloses the following two synthetic routes.

Route One:

Route two:

The final step is a route to the removal of benzyl group in a methanol solvent by palladium on carbon catalyzed hydrogenation reaction yield was 65%. Since forskolin fluconazole final product insoluble in methanol, and therefore there is a route following shortcomings: a catalyst poisoning, the final product is easy to form methanol solvate, removing the catalyst in the loss of product, the final product are difficult to separate, low yield not suitable for industrial production.

Two routes still using palladium on carbon hydrogenation debenzylation, except that the solvent was changed to sodium hydroxide solution, the product of soluble and stable in aqueous sodium hydroxide solution, after filtering off the catalyst, forskolin fluoro itraconazole by acidification of sodium sulfate can be easily obtained blessing Secretary of fluconazole, the reaction yield of 85-90%.

In the prior art, the removal of benzyl preparation blessing Secretary of fluconazole, the use of a pressure hydrogenation, relatively harsh reaction conditions; and blessing Secretary of fluconazole in water and slightly soluble in methanol, for blessing Secretary fluconazole further refined and purified more difficult. The present invention aims to provide a new and suitable for industrial production methods blessing Secretary fluconazole.

Example 1

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- two P sat 1-yl) -2-propyl-di-benzyl-pity Cool ( Preparation blessing Secretary fluconazole dibenzyl ester)

Step The method according to CN1210540A in Example 1 A or Method B of (a), was prepared to give the title compound, having 1H-NMR shown in Figure 1 (SOi) MHz, DMS0-D6) spectrum.

Example 2

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas

Itraconazole ammonium salt) Preparation

Formula III blessing Secretary fluconazole two benzyl ester (566g, lmol), 120g of dry Pd / C (containing 5% palladium) and ammonium formate (315g, 5mol) in methanol (6L), and stirred under reflux for 5h , TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (566ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 415g, yield 98.8%.

] lH-Mffi (500MHz, DMS0-D6) δ: 4.87-4.90, 5.58-5.61,6.56-6.60, 6.94-7.03,7.52-7.61,8.96, having 1H-NMR shown in Figure 2 (500MHz, DMS0 -D6) spectrum.

Example 3

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- two 1-yl) -2-propyl-pity acid dioxide Cool (forskolin

Fluconazole) Preparation of

[0052] Formula II forskolin fluconazole salt (420g, Imol), in water (IL) while stirring, filtered, 2mol / L sulfuric acid aqueous solution (500ml), 5 ° C under stirring for lh, filtered, cold water ( 200ml) wash, 50 ° C under dry blessed Division fluconazole 379g, yield 98%.

1H-Mffi (SOOMHz) DMSO-De) δ:. 5.09-5.12,5.25-5.28,6.80-6.84,7.05-7.16,7.77,8.55,10.32 [0054] Example 4

2_ (2,4_ two gas-phenyl) -1, double 3_ (1Η-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 84g of dry Pd / C (5% containing button) and ammonium formate (189g, 3mol) in anhydrous methanol (5L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 410g, yield 97.5%.

Example 5

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 30g of dry Pd / C (containing 10% palladium) and ammonium formate (315g, 5mol) in anhydrous methanol (5L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 405g, yield 96.4%.

Example 6

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 30g of dry Pd / C (containing 10% palladium) and ammonium formate (315g, 5mol) in ethanol (12L) and stirred was refluxed for 5h, TLC monitoring completion of the reaction, was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 395g, 94% yield.

Example 7

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

forskolin fluconazole dibenzyl ester (566g, lmol), 170g of dry Pd / C (containing 5% of palladium) and ammonium formate (315g, 5mol) in ethanol (16L) was stirred under reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g, yield 94.7%.

Example 8

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (566g, lmol), 120g of dry Pd / C (containing 5% palladium) and ammonium formate (315g, 5mol) in isopropanol (12L) in the mixture was stirred at reflux for 5h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 402g, a yield of 95.7%.

Example 9

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

[0071] under nitrogen blessing Secretary fluconazole dibenzyl ester (566g, lmol), 60g of dry Pd / C (containing 5% palladium) and ammonium formate (504g, 8mol) in methanol (8L) in, 50 ° C under stirring reaction 40h, TLC monitoring completion of the reaction, was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added ^ OOml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g, yield 94.8%.

Example 10

2_ (2,4_ two gas-phenyl) -1, double 3_ (1H-1, 2,4_ two 1-yl) propyl pity _2_ di press (forskolin gas itraconazole salt) Preparation

Under nitrogen, forskolin fluconazole dibenzyl ester (5668,111101), 8 (^ dry? (1 / (:( containing palladium 5%) and ammonium formate (315g, 5mol) for n-propyl alcohol (12L) in, 60 ° C the reaction was stirred 20h, TLC monitoring completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, ethanol was added (300ml), stirred for beating, and filtered to give a solid forskolin fluconazole salt 398g 95% yield.

Example 11

2- (2,4-gas-phenyl) -1,3-bis (1H-1, 2,4- sit two P-1-yl) -2-propyl-pity acid dioxide Cool (forskolin fluconazole) Preparation of [0077] under nitrogen blessing Secretary fluconazole dibenzyl ester 566 g (Imol) adding 56g of dry Pd / C (containing 5% palladium), methanol 6L, 315 g of ammonium formate, stirring boil under reflux for 5h, TLC after completion of the reaction was filtered, 50 ° C the solvent was distilled off under reduced pressure, addition of IL of water and dissolved with stirring, filtered, 2mol / L sulfuric acid 500mL, 5 ° C with stirring to precipitate lh, filtered, 200mL cold water, 50 ° C drying 365 g, 95% yield.

Example 12 forskolin fluconazole salt and HPLC detection methods blessing Secretary fluconazole:

High performance liquid chromatography (Chinese Pharmacopoeia 2010 edition two Appendix VD): octadecylsilane bonded silica as a filler, Column: Thermo BDS C18 (4.6 X 150mm, 3.5 μ m); methanol as mobile phase A, phosphate buffer (take potassium dihydrogen phosphate 0.68g, set 1000ml water, triethylamine 6ml, adjusted to pH 5.0 with phosphoric acid) as the mobile phase B, a flow rate of 1.0ml / min; column temperature 35 ° C; detection wavelength was 210nm, linear gradient.

After the examination, according to the peak area calculation, purity prepared in Example 2-11 was the implementation of the target product of 99.5%.

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