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Chemical Structure| 120737-59-9
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Product Details of [ 120737-59-9 ]

CAS No. :120737-59-9 MDL No. :MFCD03001706
Formula : C10H20N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :FMLPQHJYUZTHQS-UHFFFAOYSA-N
M.W : 200.28 Pubchem ID :2756810
Synonyms :

Calculated chemistry of [ 120737-59-9 ]

Physicochemical Properties

Num. heavy atoms : 14
Num. arom. heavy atoms : 0
Fraction Csp3 : 0.9
Num. rotatable bonds : 3
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 63.31
TPSA : 41.57 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.89 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.67
Log Po/w (XLOGP3) : 0.89
Log Po/w (WLOGP) : 0.45
Log Po/w (MLOGP) : 0.86
Log Po/w (SILICOS-IT) : 0.6
Consensus Log Po/w : 1.09

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.44
Solubility : 7.2 mg/ml ; 0.0359 mol/l
Class : Very soluble
Log S (Ali) : -1.35
Solubility : 8.99 mg/ml ; 0.0449 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.44
Solubility : 7.29 mg/ml ; 0.0364 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.72

Safety of [ 120737-59-9 ]

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

Application In Synthesis of [ 120737-59-9 ]

* 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 [ 120737-59-9 ]
  • Downstream synthetic route of [ 120737-59-9 ]

[ 120737-59-9 ] Synthesis Path-Upstream   1~10

  • 1
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  • [ 25057-77-6 ]
Reference: [1] Patent: WO2011/130661, 2011, A1,
[2] Patent: WO2017/147700, 2017, A1,
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  • [ 24424-99-5 ]
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YieldReaction ConditionsOperation in experiment
96.5% at 20℃; for 24 h; 1)
3-Methylpiperazine-1-carboxylic acid tert-butyl ester
Di-tert-butyl dicarbonate (21.7 g) was added at room temperature to 2-methylpiperazine (10.0 g) in methanol (200 mL), followed by stirring for 24 hours.
The reaction solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform - methanol), to thereby give 3-methylpiperazine-1-carboxylic acid tert-butyl ester as an oily product (19.3 g, 96.5percent).
1H-NMR (300MHz, CDCl3) δ: 1.04 (3H, d, J=6.24Hz), 1.46(9H,s), 2.39(1H,br s), 2.70-2.77(3H,m), 2.94(1H,br s), 3.93(2H,br s).
MS(FAB)m/z:201(M+H)+.
83% With triethylamine In dichloromethane at 0 - 20℃; for 16 h; Inert atmosphere To a stirring solution of 2-methylpiperazine 7 (3 g, 30.00 mmol) in CH2C12 (100 mL) under argon atmosphere were added triethylamine (9 mL, 90.00 mmol) and Boc-anhydride (7.2 mL, 33.00 mmol) at 0 °C; warmed to RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the volatiles were removed in vacuo. The crude was washed with -pentane (2 x 20 mL) and dried in vacuo to afford compound 9 (5 g, 83percent) as off- white solid. TLC: 5percent MeOH/ CH2C12 (R/. 0.4); 1H-NMR (OMSO-d6, 400 MHz): δ 3.80- 3.62 (m, 2H), 3.27-3.09 (m, 2H), 2.83-2.71 (m, 2H), 2.37-2.17 (m, 1H), 1.39 (s, 9H), 0.92 (d, J= 6.3 Hz, 3H).
81.5% at 0 - 15℃; for 2 h; Example 9 In a 100 ml four-neck flask, 5.06 g (= 0.0505 mole) of racemic 2-methylpiperazine was placed, and 50.00 g of 1-butanol (water content 0.05 wtpercent) was added for dissolution. After cooling down to 0°C, 10.91 g (= 0.0500 mole, 0.99 molar time) of di-tert-butyl dicarbonate was added dropwise with the liquid temperature kept in a range from 5 to 15°C. Then, stirring was carried out at 5 to 10°C for 2 hours. The reaction solution was analyzed, and as a result, the conversion of 2-methylpiperazine was 94.7percent, while the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 89.3percent (reaction yield 84.6percent).Example 10 An experiment was carried out as described for Example 9, except that the amount of di-tert-butyl dicarbonate used was changed to 11.97 g (= 0.0548 mole, 1.10 molar times). As a result, the conversion of 2-methylpiperazine was 100.0percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 81.5percent (reaction yield 81.5percent).
75% With pyridine In dichloromethane at 0 - 20℃; General Procedure 1. Chemoselective N-acylation reaction of 2-substitued piperazines (6-9, 43-45). 2-Substituted piperazine (6.0 mmol) was dissolved in dry dichloromethane (80 mL) and cooled to 0 oC. A solution of the appropriate acylating agent in dichloromethane (6.0 mmol, 20 mL) was added dropwise in 30 minutes, and then pyridine (9 mmol). The reaction mixture was kept into an ice-water bath with stirring 12 hours and left at room temperature until TLC showed that all the starting material had reacted. The reaction mixture was evaporated to dryness to obtain the corresponding monoacylderivative. Column chromatography gave the pure compounds in high yields. l-tert-Butoxycarbonyl-3-methylpiperazine (6).37 The product was obtained as a syrup and purified by column chromatography using dichloromethane-methanol (15:1) as eluent (0.90 g, 75percent yield). MS (CI): m/z 201 (20percent) [M+H]+. 1H NMR (500 MHz, DMSO-d6) 0 3.75-3.7 1 (m, 2H), 2.85-2.82 (m, 1H), 2.75-2.69 (m, 1H), 2.60-2.54 (m, 3H), 2.39-2.34 (m, 1H), 1.41 (s, 9H), 0.96 (d, J = 6.3 Hz, 3H). 13C RMN (125 MHz, DMSO-d6) δ 154.5, 79.3, 51.2, 50.5, 45.5, 44.4, 28.6, 19,3. HRMS (m/z): calcd. for C10H20N2O2 200.1528 [M]+.; found 200.1525.
65.9%
Stage #1: at 0 - 15℃; for 2 h;
Stage #2: With sodium hydroxide In water at 0 - 26℃; for 2.5 h;
Comparative Example 10 A 200 ml four-neck flask with a pH meter and dropping funnel was charged with 10.08 g (= 0.101 mole) of racemic 2-methylpiperazine, and 50.0 g of 1-butanol was added for dissolution, being followed by addition of 50.3 g of water (water content 50.1 wtpercent). With vigorous stirring, benzyl chlorocarbonate was added dropwise. In this case, 48 wtpercent sodium hydroxide aqueous solution was added dropwise to keep the pH value of the system at 10 to 11, and as required, the system was cooled with ice to keep the internal temperature at 23 to 26°C (final water content 53.2 wtpercent). After completion of dropwise addition, with vigorous stirring, aging was carried out for 2.5 hours. The reaction solution was sampled and analyzed, and as a result, the conversion of 2-methylpiperazine was 85.5percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 77.2percent (reaction yield 66.0percent).Comparative Example 11 A 200 ml four-neck flask with a pH meter and dropping funnel was charged with 10.22 g (= 0.102 mole) of racemic 2-methylpiperazine, and 80.5 g of 1-butanol was added for dissolution, being followed by addition of 27.5 g of water (water content 25.4 wtpercent). With vigorous stirring, benzyl chlorocarbonate was added dropwise. In this case, 48 wtpercent sodium hydroxide aqueous solution was added dropwise to keep the pH value of the system at 8 to 9.5, and as required, the system was cooled with ice to keep the internal temperature at 23 to 26 (final water content 26.9 wtpercent). After completion of dropwise addition, with vigorous stirring, aging was carried out for 2.5 hours. The reaction solution was sampled and analyzed, and as a result, the conversion of 2-methylpiperazine was 89.6percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 73.5percent (reaction yield 65.9percent).
42% With triethylamine In dichloromethane at 0 - 20℃; To a solution of 2-methyl-piperazine (2.0 g, 0.02 mol) and triethylamine (6 mL) in methylene chloride (15 mL) at 0° C. was added (Boc)2O (4.14 g, 0.019 mol) dropwise. The mixture was stirred at room temperature for 1 hour, and then the solvent was removed by rotary evaporation. The residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate and brine, dried over Na2SO4, and purified by column chromatography on silica gel (DCM:MeOH:Et3N=75:1:0.2) to give an white solid (1.65 g, 42percent). LC-MS (ESI) m/z: 201 (M+1)+.
42% With triethylamine In dichloromethane at 0 - 20℃; for 1 h; Example 126Atert-Butyl 3-methylpiperazine- 1 -carboxylate[00770] To a solution of 2-methyl-piperazine (2.0 g, 0.02 mol) and triethylamine (6 mL) in methylene chloride (15 mL) at 0 °C was added (Boc O (4.14 g, 0.019 mol) dropwise. The mixture was stirred at room temperature for 1 hour, and then the solvent was removed by rotary evaporation. The residue was dissolved in methylene chloride, washed with saturated sodium bicarbonate and brine, dried over Na2S04, and purified by column chromatography on silica gel (DCM: MeOH:Et3N = 75 : 1 : 0.2) to give an white solid (1.65 g, 42percent). LC-MS (ESI) m/z: 201 (M+l)+.
33.9% at 0 - 15℃; for 2 h; Example 11 An experiment was carried out as described for Example 9, except that 45.55 g of 1-butanol and 4.61 g of water (water content 9.2 wtpercent) were used instead of 50.00 g of 1-butanol. As a result, the conversion of 2-methylpiperazine was 94.3percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 85.8percent (reaction yield 80.9percent).Comparative Example 8 An experiment was carried out as described for Example 9, except that 37.56 g of 1-butanol and 12.67 g of water (water content 25.2 wtpercent) were used instead of 50.00 g of 1-butanol. As a result, the conversion of 2-methylpiperazine was 81.6percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 70.9percent (reaction yield 57.9percent).Comparative Example 9 An experiment was carried out as described for Example 9, except that 25.00 g of 1-butanol and 25.00 g of water (water content 50.0 wtpercent) were used instead of 50.00 g of 1-butanol. As a result, the conversion of 2-methylpiperazine was 81.2percent, and the selectivity of 1-tert-butoxycarbonyl-3-methylpiperazine was 41.8percent (reaction yield 33.9percent).

Reference: [1] Patent: US2003/153556, 2003, A1,
[2] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 33
[3] Patent: WO2016/168619, 2016, A1, . Location in patent: Paragraph 00286
[4] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
[5] Journal of Medicinal Chemistry, 2016, vol. 59, # 11, p. 5432 - 5448
[6] Patent: WO2017/144624, 2017, A1, . Location in patent: Page/Page column 21
[7] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 20
[8] Patent: US5300506, 1994, A,
[9] Patent: US2009/281114, 2009, A1,
[10] Patent: US5434154, 1995, A,
[11] Patent: US2010/35883, 2010, A1, . Location in patent: Page/Page column 92
[12] Patent: WO2011/130661, 2011, A1, . Location in patent: Page/Page column 180
[13] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
[14] Patent: US6825200, 2004, B1, . Location in patent: Page column 28
[15] Patent: US6673799, 2004, B1, . Location in patent: Page column 12
[16] Journal of Polymer Science, Part A: Polymer Chemistry, 2012, vol. 50, # 23, p. 4947 - 4957
[17] Patent: WO2017/147700, 2017, A1, . Location in patent: Paragraph 00481
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YieldReaction ConditionsOperation in experiment
89% at 0℃; for 2 h; [Referential Example 82]; 3-Methylpiperazine-1-carboxylic acid tert-butyl ester; [] 2-Methylpiperazine (3.19 g) was added to 2-(tert-butylcarbonyloxyimino)-2-phenylacetonitrile (7.87 g) in tetrahydrofuran (100 mL) at 0°C, followed by stirring for 2 hours. The residue obtained by removal through evaporation of the reaction solvent under reduced pressure was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol mixture), to thereby give the title compound as an oily product (5.70 g, 89percent).1H-NMR(400MHz,CDCl3)δ: 1.05(3H,d,J=6.4Hz), 1.46(9H,s), 2.40(1H,br), 2.65-2.84(3H,m), 2.90-3.00(1H,br), 3.94(2H,br). MS(ESI)m/z: 201(M+H)+.
Reference: [1] Patent: EP1591443, 2005, A1, . Location in patent: Page/Page column 61
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YieldReaction ConditionsOperation in experiment
89% at 0℃; for 2 h; 2-Methylpiperazine (3.19 g) was added at 0°C to 2-(tert-butylcarbonyloxyimino)-2-phenylacetonitrile (7.87 g) in tetrahydrofuran (100 mL), and the mixture was stirred for 2 hours. The reaction solvent was removed under reduced pressure, and the residue was purified through silica gel column chromatography (chloroform - 7N ammonia/methanol), to thereby give the title compound as an oil (5.70 g, 89percent). 1H-NMR(400MHz,CDCl3)δ:1.05(3H,d,J=6.4Hz), 1.46(9H,s), 2.40 (1H,br), 2.65-2.84(3H,m), 2.90-3.00 (1H,br), 3.94(2H,br). MS(ESI)m/z:201(M+H)+.
Reference: [1] Patent: EP1621537, 2006, A1, . Location in patent: Page/Page column 39-40
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Reference: [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 6, p. 690 - 698
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Reference: [1] Patent: WO2004/18419, 2004, A2, . Location in patent: Page 339
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Reference: [1] Patent: US4880808, 1989, A,
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Reference: [1] Patent: EP1122242, 2001, A1,
  • 9
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Reference: [1] Asian Journal of Chemistry, 2014, vol. 26, # 1, p. 209 - 215
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Reference: [1] Chemical Communications, 2012, vol. 48, # 71, p. 8892 - 8894
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