1-(CYCLOPROPYLMETHYL)PIPERAZINE97

S3: A 10 L four-necked flask with mechanical stirring and a thermometer was charged with N-Boc-4-(cyclopropylmethyl)piperazine (2.00 kg, 8.32 mol).5 kg of isopropanol, heated to 40 ° C, slowly added concentrated hydrochloric acid (2.04 kg, 20.80 mol), temperature control 40 ° C -50 ° C.After the dropwise addition is completed, the reaction is carried out at 40 ° C to 50 ° C for 4 h.The reaction solution was concentrated to remove most of the isopropanol, and the residue was adjusted to pH = 10-11 with a 5 mol/L aqueous sodium hydroxide solution.Extract with dichloromethane (5L*3), combine the dichloromethane phase, and wash once with 5kg saturated sodium chloride solution.Diluted with dichloromethane to give a pale yellow liquid1-cyclopropylmethylpiperazine 1.11 kg yield 94percent.The nuclear magnetic warp alignment is consistent with the standard map.To a solution of tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate (275, 30 g, 124 mmol) in DCM (100 mL) was added TFA (50 mL). After stirring at room temperatureovernight, the reaction mixture was neutralized with saturated sodium bicarbonate solution(500 mL) and extracted with DCM (200 mL x 2). The combined organic phases were driedover Mg504, filtered and concentrated in vacuo to provide 1-(cyclopropylmethyl)piperazine(276, 13 g, 92 mmol), which was used carried forward in the next step without furtherpurification. MS (ESI +): m/z 141 [M + HjtS3: A 10 L four-necked flask with mechanical stirring and a thermometer was charged with N-Boc-4-(cyclopropylmethyl)piperazine (2.00 kg, 8.32 mol).5 kg of isopropanol, heated to 40 C, slowly added concentrated hydrochloric acid (2.04 kg, 20.80 mol), temperature control 40 C -50 C.After the dropwise addition is completed, the reaction is carried out at 40 C to 50 C for 4 h.The reaction solution was concentrated to remove most of the isopropanol, and the residue was adjusted to pH = 10-11 with a 5 mol/L aqueous sodium hydroxide solution.Extract with dichloromethane (5L*3), combine the dichloromethane phase, and wash once with 5kg saturated sodium chloride solution.Diluted with dichloromethane to give a pale yellow liquid1-cyclopropylmethylpiperazine 1.11 kg yield 94%.The nuclear magnetic warp alignment is consistent with the standard map.Step 2 1-(Cyclopropylmethyl)-4-[[(2R)-oxiran-2-yl]methyl]piperazine; Tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate 31a (2 g, 8.30 mmol) was dissolved in 40 mL of dichloromethane followed by the addition of 20 mL of a 4 M solution of hydrogen chloride in dioxane. The reaction solution was stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure followed by the addition of 40 mL of dichloromethane and dropwise with 20 mL of triethylamine to adjust pH to 10 to 11. The resulting solution was concentrated under reduced pressure. The residue was added with 50 mL of ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, added with 50 mL of ethyl acetate and 20 mL of water, then added with (R)-2-chloromethyl-oxirane (0.92 g, 9.96 mmol) and sodium hydroxide (0.66 g, 16.60 mmol). The reaction solution was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, added with 50 mL of water and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-(cyclopropylmethyl)-4-[[(2R)-oxiran-2-yl]methyl]piperazine 31b (0.91 g, yield: 57.0%) as a yellow oil. MS m/z (ESI): 197.3 [M+1]To a solution of tert-butyl 4-(cyclopropylmethyl)piperazine-1-carboxylate (275, 30 g, 124 mmol) in DCM (100 mL) was added TFA (50 mL). After stirring at room temperatureovernight, the reaction mixture was neutralized with saturated sodium bicarbonate solution(500 mL) and extracted with DCM (200 mL x 2). The combined organic phases were driedover Mg504, filtered and concentrated in vacuo to provide 1-(cyclopropylmethyl)piperazine(276, 13 g, 92 mmol), which was used carried forward in the next step without furtherpurification. MS (ESI +): m/z 141 [M + HjtInto a 250-mL round-bottom flask, was placed 1, 4- dioxaspiro [4.5] decan-8- one (2.75 g, 0.018 mmol, 1.20 equiv), l-(cyclopropylmethyl)piperazine (2.06 g, 14.690 mmol, 1 equiv), HO Ac (0.88 g, 0.015 mmol, 1.00 equiv), DCM (100 mL). This was followed by the addition of NaBH(OAc)3 (3.74 g, 0.018 mmol, 1.20 equiv) at 0 degrees C. The resulting solution was stirred for overnight at room temperature. The pH value of the solution was adjusted to 8 with NaHC03 (2mol/L). The resulting solution was extracted with 3x100 mL of dichloromethane concentrated. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated. This resulted in 2.9 g (70.40%) of l-(cyclopropylmethyl)-4-[l, 4- dioxaspiro [4.5] decan-8- yl] piperazine as colorless oil. LC-MS (ES, m/z ): 28l[M+l] +

Molecular Weight:140.23
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:140.131348519
Monoisotopic Mass:140.131348519
Topological Polar Surface Area:15.3
Heavy Atom Count:10
Complexity:104
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes