[ CAS No. 1137868-52-0 ]

Name: 1137868-52-0|4-((9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide|98+%
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SKU: A621588
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{[proInfo.proName]} (Synonyms:TAK-960) ,{[proInfo.pro_purity]}

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Quality Control of [ 1137868-52-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1137868-52-0 ]

CAS No. :	1137868-52-0	MDL No. :	MFCD22420821
Formula :	C₂₇H₃₄F₃N₇O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GWRSATNRNFYMDI-UHFFFAOYSA-N
M.W :	561.60	Pubchem ID :	53357478
Synonyms :	TAK-960

Safety of [ 1137868-52-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1137868-52-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 1137868-52-0 ]
Downstream synthetic route of [ 1137868-52-0 ]

[ 1137868-52-0 ] Synthesis Path-Upstream 1~10

1
[ 41838-46-4 ]
[ 1137867-66-3 ]
[ 1137868-52-0 ]

Reference： [1] Patent: WO2009/42711, 2009, A1, . Location in patent: Page/Page column 359; 388
[2] Patent: US2009/318408, 2009, A1, . Location in patent: Page/Page column 70
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250
[4] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 12, p. 3662 - 3666

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[ 1001345-78-3 ]
[ 1062246-03-0 ]
[ 1137868-52-0 ]

Reference： [1] Patent: WO2009/42711, 2009, A1, . Location in patent: Page/Page column 414-415

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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250

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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250

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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250

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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250

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[ 126541-66-0 ]
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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250

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[ 1003-03-8 ]
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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1247 - 1250

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[ 924868-81-5 ]
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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 12, p. 3662 - 3666

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[ 1001345-80-7 ]
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Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 12, p. 3662 - 3666

[ 1137868-52-0 ] Synthesis Path-Downstream 1~11

1
[ 41838-46-4 ]
[ 1137867-66-3 ]
[ 1137868-52-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Product distribution / selectivity;	Compound 116: 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(l- methylpiperidin-4-yl)benzamide; The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo- 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5- <n="360"/>methoxybenzoic acid and l-methylpiperidin-4-amine as described in the general procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1U NMR (400 MHz, DMSO-J6) delta ppm 1.60-1.73 (m, 11 H), 1.88 - 2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J=13.8 Hz, 2 H) 4.81 (d, J=8.1 Hz, 1 H) 7.18 (d, J=6.6 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J=13.4 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.; The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5- methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][l,4]diazepin-2-ylamino)-2-fluoro-5- methoxybenzoic acid (obtained above, 12 mg) as described in the general procedure for amide bond synthesis using HATU and l-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base (8 mg, 55percent). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.60-1.73 (m, 11 H), 1.88 - 2.21 (m, 8 H) 2.78 (br. s., 2 H) 3.73 (br. s., 1 H) 3.91 (s, 3 H) 4.08 (t, J= 14 Hz, 2 H) 4.81 (d, J= 8 Hz, 1 H) 7.18 (d, J= 7 Hz, 1 H) 7.91 (br. s., 1 H) 8.04 (s, 1 H) 8.24 (d, J= 13 Hz, 1 H) 8.30 (s, 1 H). [M+H] calc'd for C27H34F3N7O3, 562; found 562.
		(I-176) To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-benzoic acid (I-169), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 g (0.32 mmole) of 4-amino-1-methylpiperidine was added. The mixture was stirred at room temperature for 18 hours, then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with 1M sodium hydroxide solution then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluding with methanol-dichloromethane (gradient, 0:100-20:80) to give 0.038 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-176).

Reference： [1]Patent: WO2009/42711,2009,A1 .Location in patent: Page/Page column 359; 388
[2]Patent: US2009/318408,2009,A1 .Location in patent: Page/Page column 70
[3]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1247 - 1250
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 3662 - 3666

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[ 1001345-78-3 ]
[ 1062246-03-0 ]
[ 1137868-52-0 ]

Yield	Reaction Conditions	Operation in experiment
		4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H- pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(l-methylpiperidin-4- yl)benzamide: A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro- 5H-pyrimido[4,5-b][l,4]diazepin-6(7H)-one (25 g, 79.1 mmol), 4-amino-2-fluoro-5- methoxy-N-(l-methylpiperidin-4-yl)benzamide (23.3 g, 83 mmol), isopropanol (197 ml), and concentrated hydrochloric acid (8 mL) was stirred in an oil bath of 1000C (temp, inside the flask was 83 0C) for 3 days (lots of precipitate appeared after first day of stirring). The reaction mixture was cooled down and the white solid was filtered and washed with more iPrOH, finally dired to give 40 g tan solid as HCl salt. Above obtained HCl salt (40 g) was dissolved in 1 L of MeOH with an effective stirring bar. It was cooled to 0 0C, sodium bicarbonate solid (28.1 g, 0.33 mol) was added slowly. <n="416"/>The reaction mixture was then stirred at r.t for 4 h. After which, it was filtered through a pad of celite. The filtrate concentrated in vacuo to 500 mL in volume, and 500 mL of water was charged into the flask. The mixture was then kept on rotavaping at 20 0C. Lots of pinkish precipitate appeared. Until around 100 mL of MeOH left, 500 mL more of water was added to the flask. The whole was filtered, solid washed with more water (500 mL) and dried to give 35 g of product as light pinkish solid (>99 percent pure by LC). To a 500 mL round bottom flask, was added 60 g of the free base and EtOH (200 ml). It was heated at 85 0C for 0.5 h. It was then cooled down, solid filtered and washed with more EtOH (200 mL). When dried, around 48 g of off- white solid was obtained (filtrate contained color and some impurities). The solid was then completely dissolved in 4L of MeOH, filtered on the paper. The filtrate was concentrated to a solid. It was then dissolved in 200 mL of EtOH. The suspension was then heated at 60 0C with effective stirring for 24 h. The slurry was then cooled down gradually to room temperature, filtered. The solid was washed with more EtOH (200 mL), dried in a vacuum oven (60 0C) for 3 days. Finally, 44 g of product as white solid was obtained (73percent recovery). The combined filtrate (contained mostly product) was concentrated and set aside for further purification by prep-HPLC. 1H NMR (400 MHz, DMSO-J6) delta ppm 1.47 - 1.82 (m, 10 H) 1.90 - 2.04 (m, 4 H) 2.16 (s, 3 H) 2.74 (d, J= 11.6 Hz, 2 H) 3.63 - 3.77 (m, 1 H) 3.92 (s, 3 H) 4.09 (t, J= 13.9 Hz, 2 H) 4.82 (m, 1 H) 7.19 (d, J= 6.8 Hz, 1 H) 7.91 (dd, J= 7.7, 3.4 Hz, 1 H) 8.04 (d, J= 1.3 Hz, 1 H) 8.25 (d, J= 13.4 Hz, 1 H) 8.31 (s, 1 H). Melting point 194.5-195.5 0C. [M+H] calc'd for C27H34F3N7O3, 562; found 562.

Reference： [1]Patent: WO2009/42711,2009,A1 .Location in patent: Page/Page column 414-415

3
[ 1137868-52-0 ]
[ 1137868-76-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium hydroxide; water; In N,N-dimethyl-formamide; at 20℃; for 1h;	Compound 140: 3-(cyclopentyl(2-(5-fluoro-2-methoxy-4-(l-methylpiperidin-4- ylcarbamoyl)phenylamino)-5-(methylamino)pyrimidin-4-yl)amino)-2,2-difluoropropanoic acid; To a mixture of compound 116 (300 mg, 0.53 mmol) in 2 ml of DMF, was added IN NaOH (1 ml) dropwise. The reaction mixture was stirred at rt. for 1 h and then subjected to reverse phase HPLC purification using basic column (Gemini 5mu Cl 8 column, mobile phase A: H2O; B: 20percent H2O in CH3CN which contains 10 muM NH4HCO3). The final compound was directly lyophilized and then dried in the vacuum oven at 6O0C for 3 days to give 234 mg white solid (76percent). 1H NMR (400 MHz, DMSO-J6) delta ppm 1.48-1.98 (m, 12 H) 2.60 - 2.81 (m, 6 H) 3.03 (m, 2 H) 3.79 - 4.08 (sm, 6 H) 4.16 (m, 1 H) 7.14 (d, J=6.8 Hz, 1 H) 7.52 (s, 1 H) 7.71 (s, 1 H) 8.03 (br. s., 1 H) 8.34 - 8.38 (d, J=16 Hz, 1 H) 9.81 (br. s., 1 H). [M+H] calc'd for C27H36F3N7O4, 580; found 580.

Reference： [1]Patent: WO2009/42711,2009,A1 .Location in patent: Page/Page column 384

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[ 1137868-52-0 ]