2-CHLOROTHIAZOLE-5-CARBONITRILE

3.4 g (27 mmol) 2-Amino-5-cyanothiazole and 5.1 g (30 mmol) dihydrated cupric chloride were dispersed in 100 ml acetonitrile. 3.4 g (27 mmol) 2-Amino-5-cyanothiazole (Example 43) and 5.1 g (30 mmol) dihydrated cupric chloride were dispersed in 100 ml acetonitrile. 2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile (3-1) 4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (2-5, 5.94 g, 24.9 mmol) was dissolved in 50 mL anhydrous tetrahydrofuran (THF) under N2. NaH (60% suspension, 2.99 g, 74.8 mmol, 3 equiv) was added (vigorous bubbling occurred) and the resulting mixture was stirred for 15 minutes. 2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile (3-1) 4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (2-5, 5.94 g, 24.9 mmol) was dissolved in 50 mL anhydrous tetrahydrofuran (THF) under N2. NaH (60% suspension, 2.99 g, 74.8 mmol, 3 equiv) was added (vigorous bubbling occurred) and the resulting mixture was stirred for 15 minutes. 2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamino]-thiazole-5-carbonitrile (3-1) 4-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridin-2-ylamine (2-5, 5.94 g, 24.9 mmol) was dissolved in 50 mL anhydrous tetrahydrofuran (THF) under N2. NaH (60% suspension, 2.99 g, 74.8 mmol, 3 equiv) was added (vigorous bubbling occurred) and the resulting mixture was stirred for 15 minutes. 3.4 g (27 mmol) 2-Amino-5-cyanothiazole (Example 43) and 5.1 g (30 mmol) dihydrated cupric chloride were dispersed in 100 ml acetonitrile. To the mixture, with vigorous stirring, 5.7 ml solution of isoamyl nitrite in acetonitrile was added rapidly dropwise over 30 min, followed by continuing the reaction for 10 hr. The reaction mixture was concentrated, dissolved in ethyl acetate, and filtered to remove insoluble matters. The organic phase was concentrated, and separated by a column chromatography to obtain 2.6 g of a liquid (yield 67%), which was placed aside to precipitate a needle crystal with mp 54-57C, 13C NMR (CDCl3, ppm) 108.16, 110.41, 150.59, 157.36; MS(EI)144.1(M+).3.4 g (27 mmol) 2-Amino-5-cyanothiazole (Example 43) and 5.1 g (30 mmol) dihydrated cupric chloride were dispersed in 100 ml acetonitrile. To the mixture, with vigorous stirring, 5.7 ml solution of isoamyl nitrite in acetonitrile was added rapidly dropwise over 30 min, followed by continuing the reaction for 10 hr. The reaction mixture was concentrated, dissolved in ethyl acetate, and filtered to remove insoluble matters. The organic phase was concentrated, and separated by a column chromatography to obtain 2.6 g of a liquid (yield 67%), which was placed aside to precipitate a needle crystal with mp 54-57 C., 13C NMR (CDCl3, ppm) 108.16, 110.41, 150.59, 157.36; MS (EI) 144.1 (M+). (1-2) A flame dried round bottom flask under N2 was charged with 150 mL anhydrous MeCN. CuCl2 (12.9 g, 95.9 mmol, 1.2 equiv) was added and the reaction was maintained in a room temperature bath tert-Butylnitrite (14.3 mL, 120 mmol, 1.5 equiv) was added gradually over 10 minutes. After 10 minutes, 2-amino-thiazole-5-carbonitrile (1-1, 10.0 g, 79.9 mmol) was added as a solid gradually. The reaction was stirred at room temperature for 4 hours. The reaction was poured into 400 mL 0.5M HCl (aq). The mixture was extracted 3* with EtOAc. The organic phases were dried over Na2SO4, filtered and concentrated to afford pure desired product. 1H NMR (CDCl3) delta 8.04 (s).A flame dried round bottom flask under N2 was charged with 150 mL anhydrous MeCN. CuCl2 (12.9 g, 95.9 mmol, 1.2 equiv) was added and the reaction was maintained in a room temperature bath. tert-Butylnitrite (14.3 mL, 120 mmol, 1.5 equiv) was added gradually over 10 minutes. After 10 minutes, 2-amino-thiazole-5-carbonitrile (1-1, 10.0 g, 79.9 mmol) was added as a solid gradually. The reaction was stirred at room temperature for 4 hours. The reaction was poured into 400 mL 0.5M HCl (aq). The mixture was extracted 3 times with EtOAc. The organic phases were dried over Na2SO4, filtered and concentrated to afford pure desired product. (1-2) A flame dried round bottom flask under N2 was charged with 150 mL anhydrous MeCN. CuCl2 (12.9 g, 95.9 mmol, 1.2 equiv) was added and the reaction was maintained in a room temperature bath. tert-Butylnitrite (14.3 mL, 120 mmol, 1.5 equiv) was added gradually over 10 minutes. After 10 minutes, 2-amino-thiazole-5-carbonitrile (1-1, 10.0 g, 79.9 mmol) was added as a solid gradually. The reaction was stirred at room temperature for 4 hours. The reaction was poured into 400 mL 0.5M HCl (aq). The mixture was extracted 3* with EtOAc. The organic phases were dried over Na2SO4, filtered and concentrated to afford pure desired product. 1H NMR (CDCl3) delta8.04 (s).A dried flask under nitrogen was charged with acetonitrile (7.990 rnL), and copper(II) chloride (645 mg, 4.79 mmol) was added. The reaction mixture was maintained in a 25C bath, and tert-Butyl nitrite (0.712 mL, 5.99 mmol) was added over 10 minutes. After an additional 10 minutes, 2-aminothiazole-5-carbonitrile (500 mg, 4.00 mmol) was added gradually and the reaction mixture was stirred at 25C for 5 hours. 0.5M HCl (2OmL) was added to the reaction mixture and the organics were extracted with EtOAc, washed with brine, and dried over Na2SO4. Concentration in vacuo gave a rust colored oil that slowly began to crystalize in the flask. This material was purified by ISCO (100% DCM isocratic). Concentration of the fractions in vacuo provided the title product as a yellow crystalline solid (372 mg).1U NMR (300 MHz, CHLOROFORM-J) delta ppm 8.07 (s, 1 H).2-(Pyridin-2-ylamino)-thiazole-5-carbonitrile (9-3) A flame dried round-bottom flask under Ar was charged with NaH (60% dispersionm 0.037 g, 0.91 mmol). Anhydrous THF, 2 mL, was added followed by the addition of 2-aminopyridine (0.032 g, 0.033 mmol). To terf-butyl azetidin-3-ylcarbamate hydrochloride (300 mg, 1 .44 mmol) in acetonitrile (10 mL), To an NMP (1 mL) solution of (fraiis)-/V-(azetidin-3-yl)-3-(5-fluoro-2- methoxyphenoxy)cyclobutanecarboxamide, trifluoroacetic acid salt (Intermediate 71 ) (27 mg, 0.066 mmol) and To an NMP (1 mL) solution of (trans)- 3-(5-fluoro-2-methoxyphenoxy)-/V-(pyrrolidin-3- yl)cyclobutanecarboxamide hydrochloride (Intermediate 70) (38 mg, 0.1 1 mmol) and 2- chlorothiazole-5-carbonitrile (16 mg, 0.1 1 mmol) in a microwave reaction vial was added N, N- diisopropylethylamine (0.08 mL, 0.4 mmol). The reaction was heated in a microwave (135 C) for 3.5 h, concentrated and loaded onto a semi-prep HPLC (NH4OH as modifier) for purification to afford the title compound as a tan solid (31 mg, 62%). 1H NMR (400 MHz, CDCI3) delta 2.09 (dd, J = 13, 7 Hz, 1 H), 2.42 (dd, J = 13, 6 Hz, 1 H), 2.46-2.58 (m, 2 H), 2.74 (ddd, J = 14, 7, 4 Hz, 2 H), 2.95-3.04 (m, 1 H), 3.40 (dd, J = 1 1 , 4 Hz, 1 H), 3.57-3.69 (m, 2 H), 3.81 -3.89 (m, 1 H), 3.84 (s, 3 H), 4.64-4.74 (m, 1 H), 4.94 (t, J = 7 Hz, 1 H), 5.59-5.72 (m, 1 H), 6.47 (dd, J = 10, 3 Hz, 1 H), 6.59 (td, J = 8, 3 Hz, 1 H), 6.78 (dd, J = 9, 5 Hz, 1 H), 7.71 (s, 1 H); LC-MS (LC- ES) M+H = 417.General procedure: [00874] fe/ -Butyl ((2-(naphthalen-2-ylthio)thiazol-5-yl)methyl)carbamate was synthesised according to general procedures GP3 - from i)

Molecular Weight:144.58
XLogP3:2
Hydrogen Bond Acceptor Count:3
Exact Mass:143.9548969
Monoisotopic Mass:143.9548969
Topological Polar Surface Area:64.9
Heavy Atom Count:8
Complexity:129
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes