1-Boc-3-[(Dimethylamino)methylene]-4-oxopiperidine

A mixture of N, N-dimethylformamide dimethyl acetal (18 g, 20 mL, 151 mmol) and l-(tert-butoxycarbonyl)piperidin-4-one (30 g, 151 mmol) in DMF (240 mL) was stirred at 80 °C for 24 h. The mixture was concentrated in vacuo to give the title compound as a yellow solid (38.4 g, 100percent). MS (ESI, pos. ion) m/z: 255 [M + H]N, N-dimethylformamide dimethyl acetal (18 g, 20 mL, 151 mmol) and1- (tert-butoxycarbonyl) piperidin-4-one (30 g, 151 mmol)N, N-dimethylformamide (240 mL)The mixture was heated and stirred at 80 ° C for 24 hours.The reaction was complete and concentrated under reduced pressure to give the title compound as a yellow solid (38.4 g, 100percent).S1. Add N- t-butoxycarbonyl-4-piperidone (1) (12g, 60mmol) in 250ml flask, 150ml DMF-DMA, reaction at 95 1.5h, TLC showed the reaction was complete, concentrated to give 3 - ((N, N- dimethylamino) - methylene) -N- tert-butoxycarbonyl-4-piperidone (2) (white solid, 14.4g), yield 94.4percent.Preparation 21 Preparation 21 Step 1DMF dimethyl acetal (5.82 mL, 0.044 mol) was added to a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (8.73 g, 0.044 mol) in DMF (80 mL) and the reaction mixture was heated to 80 °C under NN-tert-butoxycarbonyl-4-piperidone (58, 5.8 g, 31.4 mmol) wasdissolved in N, N-dimethylformamide dimethyl acetal (45.0 mL), and the solution was heated under reflux for 1.5 h and concentrated.The residue was triturated with hexane, filtered, andwashed with hexane to give 59 as a yellow powder (5.1 g, 63.8percent):mp 135e136 C; To a solution of 59 (5.0 g, 20.8 mmol) in EtOH(200.0 mL) were added guanidine carbonate (15.0 g, 84.0 mmol)and sodium acetate (13.7 g, 167.0 mmol), and the solution washeated under reflux for 48 h. The reaction mixturewas filtered, andthe insoluble material was extracted with CHCl3 and washed withwater. The organic layer was dried over anhydrous MgSO4 andevaporated. The resultant solid was triturated with 2-propanol, filtered, and washed with 2-propanol and Et2O to give a colorlesspowder. It was dissolved in TFA (50.0 mL) at 0 C, and the solutionwas stirred at room temperature for 1 h and concentrated. Theresidue was dissolved in 2-propanol and treated with concentrated HCl (4.0 mL). The precipitated solidwas filtered andwashed with 2-propanol and Et2O to give 60a (4.2 g, 81.6percent) as a colorless powder: Mp 258e260 C; Compound 57g was obtained from 60a in thesame way as 57f.A solution of N-t-Butoxycarbonyl-4-piperidone (10.0 g, 50.19 mmol) and N, N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in 1, 4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8percent MeOH in EtOAc) to obtain the title compound as an orange oil which crystallized on standing (7.64 g, 60percent).Stage 1: tert-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylateTert-Butyl 4-oxo-1-piperidinecarboxylate (39.8 g; 0.2 mol; 1 eq) was dissolved in DMF (300 ml) after which N, N-dimethylfomamide dimethyl acetal (26.2 g; 0.22mol; 1.1 eq) was added under stirring. The mixture was heated for 8h at 90°C and subsequently stirred at RT overnight. The mixture was then evaporated and the resulting yellow oil was extracted with ethanol acetate and saturated NaC1 solution. The organic phase was washed with further saturated NaC1 solution, dried over MgSO4 and evaporated. Tert-butyl 3- ((dimethylamino)methylene) -4- oxopiperidine-1-carboxylate was obtained with a yield of 50.6 g (0.199 mol; 99percent). Under stirring and under cooling and argon atmosphere, a 60percent solution of sodium hydride (16.8 g; 420 mmol; 2.1 eq) was added to 800 ml ethanol. 4-hydroxybenzamidine hydrochloride (34.5 g; 200 mmol; 1 eq) was added as well as a solution of 50.9 g tert-butyl 3- ((dimethylamino)methylene) -4- oxopiperidine- 1- carboxylate (200 mmol; 1 eq) in 200 ml ethanol, which was added slowly. The mixture was heated under reflux for 5h and incubated overnight. The resulting mixture was evaporated, stirred with water and neutralized with 400m1 iN AcOHto pH 6-7. The resulting gum-like product was crystallized with a glass stirring rodwhile stirring for several hours, filtered, washed with water and evaporated overP205 at 40°C giving compound XXIIIb with a yield of 62.5 g (191 mmol; 95percent).Compound XXIVb was prepared in accordance with the second step of scheme 7.Compound XXIIIb (62.5 g; 191 mmol; 1 eq) was dissolved in DMF (800 ml). Cesiumcarbonate (71.5 g; 220 mmol; 1.15 eq) and 4-chlorobenzylbromide (43.2 g; 210mmol; 1.1 eq) were added under stirring and the mixture was stirred for 2h at RT.The mixture was evaporated and the residue was extracted with DCM and water.The organic phase was washed twice with water, evaporated and dried overMgSO4. The yellow residue(93 g) was recrystallized in 900 ml ethylacetate withactivated charcoal, cooled and the precipitated crystals were obtained, washed withcold ethylacetate and n-pentane and dried under vacuum at 40°C. Compound XXIVb was obtained with a yield of 57 g (126 mmol; 66.1percent).S1.A 250 ml flask was charged with N-tert-butoxycarbonyl-4-piperidone (1) (12 g, 60 mmol) and 150 ml of DMF-DMA, The reaction at 95 1.5h, TLC showed the reaction was complete, Concentration gave 3 - ((N, N-dimethylamino) -methylene) -N-tert- butoxycarbonyl-4piperidone (2) (white solid, 14.4 g)Yield 94.4percent.With reference to the procedure of Example 1, 2, 6-dichloro-3, 5-dimethoxyaniline, N-BOC-4-piperidinone, N-ethylpiperazine and 3-hydroxy-4-fluoronitrobenzene were used as starting materials to synthesize and produce Compound Ih-10. According to scheme II, with reference to the process described in the patent application , Compound Ij-10 was synthesized and produced. Compound Ij-10 (1.0 mmol) and Compound Ih-10 (1.2 mmol) were dissolved in 10ml ethanol, and potassium carbonate (1.05 mmol) was added. The mixture was stirred under flux for 2 days to produce Compound Ik-10 (0.67 mmol). Compound Ik-10 (0.25 mmol) was dissolved in 15ml dichloromethane, and a HCl gas was introduced for 30min. The mixture was concentrated to produce Compound Im-10 (0.25mmol). Compound Im-10 (0.25mmol) and Compound Ib-1 (0.26 mmol) were suspended in 10ml dioxane, and cesium carbonate (1.1 mmol) was added. The mixture was stirred evenly, and Pd2(dba)3 (0.025 mmol) and BINAP (0.03 mmol) were added. The mixture was reacted under the nitrogen protection at 100C for 48 hours, cooled to room temperature, and filtered. The filtrate was concentrated to an oily substance, and an appropriate amount of methanol was added. A solid separated out. The mixture was filtered to remove the solid (BINAP), and the filtrate was separated by thin layer chromatography to produce Compound I-10 (0.028 mmol) in a yield of 11%.ESI(+)m/z: 573S2. A 100 ml flask was charged with 3 - ((N, N-dimethylamino) -methylene) -N-tert-butoxycarbonyl-4-piperidine(2.54 g, 10 mmol), 2-amidinopyridine hydrochloride (3) (1.73 g, 11 mmol), tert-butanol 50 ml, triethylamine(4.2 mL, 30 mmol) and the reaction was stirred at 85 C for 12 h. TLC showed the reaction was complete. Concentrated to give the crude product, and then separated by column chromatography, The conditions were petroleum ether: ethyl acetate = 1: 1 to give the compound 2- (2-pyridyl) -N-tert-butoxycarbonyl-5, 7, 8-trihydropyrido[4, 3-d] pyrimidine (4) (light yellow solid, 1.56 g) in 50% yield.A mixture of S1.A 250 ml flask was charged with N-tert-butoxycarbonyl-4-piperidone (1) (12 g, 60 mmol) and 150 ml of DMF-DMA, The reaction at 95 1.5h, TLC showed the reaction was complete, Concentration gave 3 - ((N, N-dimethylamino) -methylene) -N-tert- butoxycarbonyl-4piperidone (2) (white solid, 14.4 g)Yield 94.4%.A solution of 1- (tert-butoxycarbonyl) -3 - ((dimethylamino) methylene) piperidin-4-one (5.3 g, 20.8 mmol)Guanidine carbonate (4 g, 22.2 mmol) andSodium acetate (4 g, 48.8 mmol)In ethanol (10 mL) was reacted in a microwave for 115 1 hour.reactionFinished, cooled to room temperature, filtered. The filter cake was washed with ethanol (20 mL). The filtrate was collected and concentrated under reduced pressure. The residue was chromatographed on silica gel (stoneOil ether / ethyl acetate (v / v) = 4/1) to give the title compound as a white solid (2.9 g, 55%).Tert-Butyl 4-oxo-1-piperidinecarboxylate (39.8 g; 0.2 mol; 1 eq) was dissolved in DMF (300 ml) after which N, N-dimethylfomamide dimethyl acetal (26.2 g; 0.22mol; 1.1 eq) was added under stirring. The mixture was heated for 8h at 90C and subsequently stirred at RT overnight. The mixture was then evaporated and the resulting yellow oil was extracted with ethanol acetate and saturated NaC1 solution. The organic phase was washed with further saturated NaC1 solution, dried over MgSO4 and evaporated. Tert-butyl 3- ((dimethylamino)methylene) -4- oxopiperidine-1-carboxylate was obtained with a yield of 50.6 g (0.199 mol; 99%). Under stirring and under cooling and argon atmosphere, a 60% solution of sodium hydride (16.8 g; 420 mmol; 2.1 eq) was added to 800 ml ethanol. 4-hydroxybenzamidine hydrochloride (34.5 g; 200 mmol; 1 eq) was added as well as a solution of 50.9 g tert-butyl 3- ((dimethylamino)methylene) -4- oxopiperidine- 1- carboxylate (200 mmol; 1 eq) in 200 ml ethanol, which was added slowly. The mixture was heated under reflux for 5h and incubated overnight. The resulting mixture was evaporated, stirred with water and neutralized with 400m1 iN AcOHto pH 6-7. The resulting gum-like product was crystallized with a glass stirring rodwhile stirring for several hours, filtered, washed with water and evaporated overP205 at 40C giving compound XXIIIb with a yield of 62.5 g (191 mmol; 95%).Compound XXIVb was prepared in accordance with the second step of scheme 7.Compound XXIIIb (62.5 g; 191 mmol; 1 eq) was dissolved in DMF (800 ml). Cesiumcarbonate (71.5 g; 220 mmol; 1.15 eq) and 4-chlorobenzylbromide (43.2 g; 210mmol; 1.1 eq) were added under stirring and the mixture was stirred for 2h at RT.The mixture was evaporated and the residue was extracted with DCM and water.The organic phase was washed twice with water, evaporated and dried overMgSO4. The yellow residue(93 g) was recrystallized in 900 ml ethylacetate withactivated charcoal, cooled and the precipitated crystals were obtained, washed withcold ethylacetate and n-pentane and dried under vacuum at 40C. Compound XXIVb was obtained with a yield of 57 g (126 mmol; 66.1%).

Molecular Weight:254.33
XLogP3:0.8
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:254.16304257
Monoisotopic Mass:254.16304257
Topological Polar Surface Area:49.8
Heavy Atom Count:18
Complexity:367
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes