N-Boc-endo-3-aminotropane

White Solid

Compound 3b (7.0 g, 22.2 mmol), ammonium formate (7.0 g, 111 mmol), and 20percent palladium hydroxide/carbon (0.7 g of) was dispersed in ethanol (200 ml) and reacted for 2 hours at 50° C. After cooled, the reaction solution was filtered by suction. Then the filtrate was subjected to rotary evaporation and column chromatography separation to give compound 3c (4.7 g, 94percent).The endo compound (3.6 g, 11.3 mmol) from Example 65 was dissolved in CHtert-butyl (1R, 5S)-3-amino-8-azabicyclo[3.2.1]octane-8-carboxylateTo a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, ~50percent wet with water; Degussa type E101NE/W) under a stream of Nc. c. To a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, 50percent wet with water; Degussa type E101NE/W) under a stream of NTo a solution of the product of the previous step (75.4 g, 0.335 mol) in methanol (1 L) was added ammonium formate (422.5 g, 6.7 mol), water (115 mL) and 65 g of palladium on activated carbon (10percent on dry basis, 50percent wet with water; Degussa type E101NE/W) under a stream of NTo a solution of compound ii-35a (5.00 g, 22.19 mmol) in methanol (100 mL) and water (10 mL) were added ammonium formate (13.99 g, 222 mmol) and 10percent-palladium/carbon (2.362 g) in turn. The resultant was stirred at room temperature for 2 days. Celite was used to filtrate the reaction liquid, and then the filtrate was diluted with chloroform, washed with an aqueous sodium hydroxide solution and a saturated salt solution, and dried over magnesium sulfate. Magnesium sulfate was filtrated off, and then the liquid was concentrated under reduced pressure to yield compound ii-35b (5.60 g). Compound ii-35b yielded was used as it was, without being purified, in the next reaction.The total amount of compound ii-35b yielded was dissolved in methanol (50 mL) and acetic acid (5 mL). Thereto were then added a 36percent aqueous formalin solution (8.49 mL, 111 mmol) and hydrogenated sodium triacetoxyborate (9.41 g, 44.4 mmol) in turn. The resultant was stirred at room temperature for 1 hour. To the reaction liquid was added an 8 N aqueous sodium hydroxide solution to set the pH thereof to 10. Thereafter, this liquid system was subjected to extraction with chloroform. To the organic phase was added a 0.5 N aqueous hydrochloric acid solution, and then the liquid-system was separated to two phases. Thereafter, the water phase was made into basicity, and then subjected to extraction with chloroform. The organic phase was washed with a saturated salt solution, and dried over magnesium sulfate. Magnesium sulfate was filtrated off, and then the organic phase was concentrated under reduced pressure to yield compound ii-35c (2.43 g, 43percent).Add to 50mL reaction bottle in turn4- (4-chloro-6, 7-dihydro-8H-pyrimido [5, 4-b] [1, 4] oxazin-8-yl) -3-fluorophenylacetonitrile (0.2g, 0.7mmol) , endo-N-Boc Tropinamine (0.23g, 1.0mmol), Pd2 (dba) 3 (0.14 mmol), X-Phos (0.14 mmol), CS2CO3 (1.75 mmol) and anhydrous dioxane (8 mL).The reaction solution was protected under nitrogen and reacted at reflux overnight. After the reaction is over, The reaction solution was extracted twice with ethyl acetate and washed twice with saturated sodium chloride.Dry over anhydrous sodium sulfate and evaporate to obtain the crude product.Purification by silica gel column chromatography (PE: EA = 1: 1) gave 0.17 g of a yellow solid with a yield of 52%.General procedure: To the solution of compound 8 (0.23g, 1.2mmol) in THF (5mL) was added DIPEA (1.8mmol) and bicyclic amine or piperidin amine (1.44mmol). The reaction was stirred at r.t. for overnight. Then the mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography to give the product. 4.1.4 40 tert-butyl 4-((2-chloro-6, 7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (9) (0018) Yellow solid, 87% yield. 1H NMR (600MHz, CDCl3) delta (pmm): 4.35 (d, J=7.6Hz, 1H), 4.27-4.01 (m, 3H), 3.02-2.83 (m, 4H), 2.60 (t, J=7.4Hz, 2H), 2.20-2.09 (m, 2H), 2.08-1.98 (m, 2H), 1.46 (s, 9H), 1.33(m, 2H). MS-ESI: [M-H]-:351.2.General procedure: To the solution of compounds 22 (0.3 g, 1.5 mmol) in DMF wereadded K2CO3 (1.95 mmol) and 4-amino-1-Boc-piperidine (2.7 mmol). The reaction was stirred at 80 C for 8 h. Then the mixture was extractedwith ethyl acetate, washed with brine, dried over MgSO4, andevaporated. The residue was purified by column chromatography togive the product (0.5 g, 92% yield).General procedure: To the solution of compound 8 (0.23g, 1.2mmol) in THF (5mL) was added DIPEA (1.8mmol) and bicyclic amine or piperidin amine (1.44mmol). The reaction was stirred at r.t. for overnight. Then the mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography to give the product. 4.1.4 40 tert-butyl 4-((2-chloro-6, 7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)piperidine-1-carboxylate (9)

Molecular Weight:226.32
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:226.168127949
Monoisotopic Mass:226.168127949
Topological Polar Surface Area:55.6
Heavy Atom Count:16
Complexity:271
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes