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[ CAS No. 84477-85-0 ] {[proInfo.proName]}

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Chemical Structure| 84477-85-0
Chemical Structure| 84477-85-0
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Product Details of [ 84477-85-0 ]

CAS No. :84477-85-0 MDL No. :MFCD07367776
Formula : C13H18N2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :JRPIQMPFKMFAOX-UHFFFAOYSA-N
M.W : 234.29 Pubchem ID :10421542
Synonyms :

Calculated chemistry of [ 84477-85-0 ]

Physicochemical Properties

Num. heavy atoms : 17
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.46
Num. rotatable bonds : 4
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 73.34
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) : -6.74 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.78
Log Po/w (XLOGP3) : 1.4
Log Po/w (WLOGP) : 0.7
Log Po/w (MLOGP) : 1.41
Log Po/w (SILICOS-IT) : 1.42
Consensus Log Po/w : 1.54

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.17
Solubility : 1.58 mg/ml ; 0.00673 mol/l
Class : Soluble
Log S (Ali) : -1.88
Solubility : 3.11 mg/ml ; 0.0133 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.15
Solubility : 0.165 mg/ml ; 0.000705 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.71

Safety of [ 84477-85-0 ]

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

Application In Synthesis of [ 84477-85-0 ]

* 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 [ 84477-85-0 ]
  • Downstream synthetic route of [ 84477-85-0 ]

[ 84477-85-0 ] Synthesis Path-Upstream   1~8

  • 1
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YieldReaction ConditionsOperation in experiment
85.1% at 0 - 8℃; for 2 h; Example 1
In a 100 ml four-neck flask, 5.00 g (= 0.0499 mole) of racemic 2-methylpiperazine was placed, and 44 g of 1-butanol (water content 0.05 wtpercent) was added for dissolution.
The solution was cooled to 0°C, and 8.47 g of benzyl chlorocarbonate (= 0.0489 mole, purity by HPLC determination analysis 98.5 wtpercent, 0.98 molar time) was added dropwise in a liquid temperature range from 0 to 8°C.
Then, stirring was carried out at 0 to 5°C for 2 hours, and the reaction solution was partially sampled and determined by the internal standard method (internal standard: anisole).
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 83.9percent (based on the amount of 2-methylpiperazine).
The reaction solution was further stirred at room temperature for 12 hours and analyzed.
As a result, the reaction yield was 85.1percent.
Example 3 A reaction was performed as described for Example 1, except that the amount of benzyl chlorocarbonate used was changed from 8.47 g to 10.1 g (= 0.0597 mole, 1.17 molar times). As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 93.8percent (based on the amount of 2-methylpiperazine) after lapse of 2 hours at 0 to 5°C. Stirring was carried out at room temperature for further 12 hours, being followed by analysis. As a result, the reaction yield was 95.1percent.
83.4% at 0℃; for 2 h; Example 6
A reaction was carried out as described for Example 1, except that the solvent was changed from 44 g of 1-butanol to 44 g of ethanol (water content 0.06 wtpercent).
After stirring at 0°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 83.4percent (based on the amount of 2-methylpiperazine).
82.5% With pyridine In water; butan-1-ol at 0 - 10℃; for 2 h; Example 8
In a 100 ml four-neck flask, 5.04 g (= 0.0503 mole) of racemic 2-methylpiperazine was placed, and 5.37 g of water and 45.13 g of 1-butanol were added for dissolution (water content 10.6 wtpercent).
Furthermore, 3.99 g (= 0.0504 mole) of pyridine was added, being followed by stirring and subsequent cooling down to 0°C, and 8.67 g of benzyl chlorocarbonate (= 0.0494 mole, purity by HPLC determination analysis 97.1 wtpercent, 0.98 molar time) was added dropwise with the liquid temperature kept in a range from 5 to 10°C.
Then, stirring was carried out at 0°C for 2 hours.
The reaction solution was analyzed, and as a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 82.5percent.
47% With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3 h; Step 1: CbzCl (17 g, 0.1 mol) was added into a solution of compound 219-1 (30 g, 0.3 mol) and DIPEA (40 g, 0.3 mol) in DCM (200 mL) at 0°C, then the mixture was stirred at room temperature for 3h and the solvent was removed, the crude product was purified by column chromatography to deliver compound 2 (11 g, yield 47percent) as yellow oil. MS ESI calcd for C13H18N2O2 [M+H]+ 235, found 235.
37.7% at 0℃; for 2 h; Comparative example 6 A reaction was carried out as described for Example 6, except that the solvent was changed from 44 g of ethanol to a mixed solvent consisting of 22 g of water and 22 g of ethanol (water content 50.0 wtpercent). As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 37.7percent (based on the amount of 2-methylpiperazine).
33.6% at 0 - 5℃; for 2 h; Example 5
A reaction was carried out as described for Example 1, except that the solvent was changed from 44.7 g of 1-butanol to a mixed solvent consisting of 5.3 g of water and 40 g of 1-butanol (water content 10.6 wtpercent).
After stirring at 0 to 5°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 82.1percent (based on the amount of 2-methylpiperazine).
Comparative Example 1
A reaction was carried out as described for Example 1, except that the solvent was changed from 44 g of 1-butanol to a mixed solvent consisting of 9 g of water and 35 g of 1-butanol (water content 20.5 wtpercent).
After stirring at 0 to 5°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 59.6percent (based on the amount of 2-methylpiperazine).
Comparative Example 2
A reaction was carried out as described for Example 4, except that the solvent was changed from 44 g of 1-butanol to a mixed solvent consisting of 18 g of water and 27 g of 1-butanol (water content 40.0 wtpercent).
After stirring at 0°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 51.6percent (based on the amount of 2-methylpiperazine).
Comparative Example 3
A reaction was carried out as described for Example 1, except that the solvent was changed from 44 g of 1-butanol to a mixed solvent consisting of 22 g of water and 22 g of 1-butanol (water content 50 wtpercent).
After stirring at 0°C for 2 hours, the reaction solution was analyzed.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 33.6percent (based on the amount of 2-methylpiperazine).

Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 16; 17
[2] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18
[3] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
[4] Synthetic Communications, 2007, vol. 37, # 20, p. 3623 - 3634
[5] Patent: EP3124482, 2017, A1, . Location in patent: Paragraph 0476; 0477
[6] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18
[7] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 17; 18
[8] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 3, p. 770 - 773
[9] Patent: EP1122242, 2001, A1,
[10] Patent: US6673799, 2004, B1, . Location in patent: Page column 14
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YieldReaction ConditionsOperation in experiment
94.5%
Stage #1: at 0 - 20℃; for 14 h;
Stage #2: With sodium hydroxide In water; toluene
Example 2
A reaction was performed as described for Example 1, except that the amount of benzyl chlorocarbonate used was changed from 8.45 g to 9.25 g (= 0.0533 mole, 1.07 molar times).
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 91.7percent (based on the amount of 2-methylpiperazine) after lapse of 2 hours at 0 to 5°C.
Furthermore, the reaction solution was stirred at room temperature for further 12 hours and analyzed.
As a result, the reaction yield was 94.5percent.
From the obtained reaction solution, 1-butanol was distilled away, and 30 g of water was added to the concentrate.
The pH was adjusted to 11.2 using 48percent sodium hydroxide.
To the solution, 40 g of toluene was added, and the lower layer was removed.
Subsequently, the upper layer was concentrated under reduced pressure to distill away toluene, for obtaining 11.1 g of a recovered solution.
The obtained recovered solution was analyzed, and as a result, the intended 1-bunzyloxycarbonyl-3-methylpiperazine occupied 87.2 area percent, and as for impurities, benzyl alcohol occupied 0.52 area percent, 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.01 area percent, 1-benzyl-2-methylpiperazine, 0.10 area percent, and 1,4-dibenzyloxycarbonyl-2-methylpiperazine, 11.9 area percent (solvent toluene, 1.9 area percent).
Therefore, the total of impurities was 6 liquid chromatography area percent.
Example 12 The reaction solution obtained by the same operation as in Example 2 was concentrated and 31 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 30 g of water. Subsequently 35percent hydrochloric acid water was used for adjusting the pH to 0.8. Then, 22 g of toluene was added, and stirring was carried out for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated for carrying out washing operation. Subsequently 48percent sodium hydroxide aqueous solution was used to keep the pH of the reaction solution at 11.5. In this case, white turbidity occurred due to liberated 1-benzyloxycarbonyl-3-methylpiperazine. To the white turbid solution, 40 g of toluene was added, and stirring was carried out for 30 minutes. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70°C in temperature. Then, toluene was distilled away to obtain 10.13 g of 1-benzyloxycarbonyl-3-methylpiperazine. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 98.0 liquid chromatography area percent. The impurities showed 0.40 liquid chromatography area percent for benzyl alcohol, 0.04 liquid chromatography area percent for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.10 liquid chromatography area percent for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (1.46 liquid chromatography area percent for solvent toluene). Therefore, the total of impurities was 0.55 liquid chromatography area percent.Example 13 The reaction solution obtained by the same operation as in Example 2 was concentrated and 28 g of 1-butanol was distilled away under reduced pressure, being followed by addition of 30 g of water. Subsequently 35percent hydrochloric acid water was used for adjusting the pH to 0.7. Then, 22 g of toluene was added, and stirring was carried out for 30 minutes. The upper layer was then removed, and the same amount of toluene was added again. The same operation was repeated for carrying out washing operation. Subsequently 48percent sodium hydroxide aqueous solution was used to keep the pH of the reaction solution at 11.8. In this case, white turbidity occurred due to liberated 1-benzyloxycarbonyl-3-methylpiperazine. To the white turbid solution, 40 g of toluene was added, and stirring was carried out for 30 minutes. The lower layer was then removed, and the upper layer was concentrated under reduced pressure at 60 to 70°C in temperature. Then, toluene was distilled away. Ten point three two grams of the obtained 1-benzyloxycarbonyl-3-methylpiperazine was placed in a 10 ml heart flask and distilled in vacuum. When the oil bath reached 145°C, the removal by distillation started, and the temperature was raised finally up to 170°C. The internal pressure ranged from 40 to 53 Pa, and the temperature at the column top ranged from 131 to 140°C. The obtained compound was analyzed. As a result, the intended 1-benzyloxycarbonyl-3-methylpiperazine accounted for 99.7 liquid chromatography area percent. The impurities showed 0.03 liquid chromatography area percent for benzyl alcohol, 0.18 liquid chromatography area percent for 1-benzyl-4-benzyloxycarbonyl-2-methylpiperazine, 0.04 liquid chromatography area percent for 1-benzyl-2-methylpiperazine and no detection for 1,4-dibenzyloxycarbonyl-2-methylpiperazine (for solvent toluene either). Therefore, the total of impurities was 0.25 liquid chromatography area percent.
Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 16; 20-21
  • 3
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YieldReaction ConditionsOperation in experiment
85.9% at 0 - 25℃; for 14 h; Example 7
A reaction was carried out as described for Example 1, except that 12.5 g of (S)-2-methylpiperazine D-tartaric acid salt (5.0 g = 0.0499 mole as 2-methylpiperazine) was used instead of 5.0 g (= 0.0499 mole) of 2-methylpiperazine) and that the amount of benzyl chlorocarbonate used was changed from 8.47 g to 8.90 g (= 0.0514 mole).
However, after reaction at 0°C for 2 hours, aging was carried out at 25°C for 12 hours.
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 85.9percent (based on the amount of 2-methylpiperazine).
51.6% at 0 - 25℃; for 14 h; Comparative Example 7
A reaction was carried out as described for Example 7, except that the solvent was changed from 44 g of 1-butanol to 26 g of 1-butanol and 18 g of water (water content 40.9 wtpercent).
As a result, the reaction yield of 1-benzyloxycarbonyl-3-methylpiperazine was 51.6percent (based on the amount of 2-methylpiperazine).
Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 18-19
[2] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 19
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Reference: [1] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 18, p. 2973 - 2974
[2] Tetrahedron, 2000, vol. 56, # 32, p. 5843 - 5856
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Reference: [1] Tetrahedron, 2000, vol. 56, # 32, p. 5843 - 5856
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Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 21
[2] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 21-22
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Reference: [1] Patent: EP1548010, 2005, A1, . Location in patent: Page/Page column 22-23
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Reference: [1] Tetrahedron, 2000, vol. 56, # 32, p. 5843 - 5856
[2] Tetrahedron, 2000, vol. 56, # 32, p. 5843 - 5856
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