[ CAS No. 191739-40-9 ]

Name: 191739-40-9|4-N-Cbz-(2-Hydroxymethyl)piperazine|97%
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COA NMR CNMR HPLC LC-MS

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Product Details of [ 191739-40-9 ]

CAS No. :	191739-40-9	MDL No. :	MFCD03001722
Formula :	C₁₃H₁₈N₂O₃	Boiling Point :	147.1°C at 760 mmHg
Linear Structure Formula :	-	InChI Key :	-
M.W :	250.29 g/mol	Pubchem ID :	2757383
Synonyms :

Calculated chemistry of of [ 191739-40-9 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.46
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	74.5
TPSA :	61.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.38
Log Po/w (XLOGP3) :	0.35
Log Po/w (WLOGP) :	-0.32
Log Po/w (MLOGP) :	0.58
Log Po/w (SILICOS-IT) :	0.8
Consensus Log Po/w :	0.76

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.53
Solubility :	7.4 mg/ml ; 0.0296 mol/l
Class :	Very soluble
Log S (Ali) :	-1.21
Solubility :	15.4 mg/ml ; 0.0613 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.59
Solubility :	0.639 mg/ml ; 0.00255 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.86

Safety of [ 191739-40-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 191739-40-9 ]

* 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 [ 191739-40-9 ]
Downstream synthetic route of [ 191739-40-9 ]

[ 191739-40-9 ] Synthesis Path-Upstream 1~1

1
[ 501-53-1 ]
[ 191739-40-9 ]

Reference： [1] Patent: WO2013/188856, 2013, A1,

[ 191739-40-9 ] Synthesis Path-Downstream 1~20

1
[ 191739-40-9 ]
[ 369-34-6 ]
(+/-)-4-(2-fluoro-4-nitrophen-1-yl)-3-hydroxymethylpiperazine-1-carboxylic acid phenylmethylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dipotassium hydrogenphosphate; In dimethyl sulfoxide; at 90℃; for 24h;	To a flame dried flask under an inert atmosphere containing <strong>[191739-40-9](+/-)-<strong>[191739-40-9]3-hydroxymethylpiperazine-1-carboxylic acid phenylmethylester</strong></strong> (Step 4, 6.00 g, 23.97 mmol) in DMSO (150 mL) and K2HPO4 (16.70 g, 95.88 mmol) is added 3,4-difluoronitrobenzene (5.31 mL, 47.94 mmol) and heated to 90C for 24 hours. The reaction is cooled to ambient temperature, concentrated in vacuo, and diluted with methylene chloride (200 mL) and water (150 mL). The layers are separated and the aqueous phase is extracted with methylene chloride (4 X 100 mL). The organic extracts are combined, washed with saline, dried over Na2SO4, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 500 mL), eluting with chloroform/methanol (99.5/0.5). The appropriate fractions are combined (Rf= 0.05, TLC, hexane/ethyl acetate, 75/25) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.82, 7.73, 7.30-7.25, 6.87, 5.09, 4.16-4.07, 3.92, 3.65, 3.32-3.24.

Reference： [1]Patent: EP874852,2004,B1 .Location in patent: Page 11

2
(+/-)-tetrahydro-3-oxo-3 H-oxazolo(3,4-a)pyrazin-7(1 H)-carboxylic acid phenylmethylester [ No CAS ]
[ 191739-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In water;	Step 4: Preparation of (+/-)-3-Hydroxymethylpiperazine-1-carboxylic acid phenylmethylester. To a flame dried flask under an inert atmosphere containing potassium tert-butoxide (12.18 g, 108.58 mmol) and water (900 mg, 50.00 mmol) at 0 C. is added (+/-)-tetrahydro-3-oxo-3 H-oxazolo(3,4-a)pyrazin-7(1 H)-carboxylic acid phenylmethylester (Step 3, 10.00 g, 36.19 mmol). The reaction is warmed to ambient temperature, stirred for 2 hours, cooled to 0 C., acidified to pH=2 with conc. HCl, adjusted to pH=9 with 1N NaOH, and extracted with methylene chloride (2*100 mL). The organic extracts are combined, dried over Na2 SO4, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 250 mL), eluding with chloroform/methanol (95/5). The appropriate fractions are combined (Rf =0.13, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.34-7.25, 5.09, 3.95, 3.55-3.53, 3.41, 3.34, 2.92, 2.72-2.70.
		To a flame dried flask under an inert atmosphere containing potassium tert-butoxide (12.18 g, 108.58 mmol) and water (900 mg, 50.00 mmol) at 0C is added (+/- )-tetrahydro-3-oxo-3H-oxazolo(3,4-a)pyrazin-7(1H)-carboxylic acid phenylmethylester (Step 3, 10.00 g, 36.19 mmol). The reaction is warmed to ambient temperature, stirred for 2 hours, cooled to 0C, acidified to pH=2 with conc. HCl, adjusted to pH=9 with 1N NaOH, and extracted with methylene chloride (2 X 100 mL). The organic extracts are combined, dried over Na2SO4, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 250 mL), eluting with chloroform/methanol (95/5). The appropriate fractions are combined (Rf= 0.13, TLC, chloroform/methanol, 90/10) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.34-7.25, 5.09, 3.95, 3.55-3.53, 3.41, 3.34, 2.92, 2.72-2.70.

Reference： [1]Patent: US5922707,1999,A
[2]Patent: EP874852,2004,B1 .Location in patent: Page 11

3
dipotassium hydrogenphosphate [ No CAS ]
[ 191739-40-9 ]
[ 369-34-6 ]
(+/-)-4-(2-fluoro-4-nitrophen-1-yl)-3-hydroxymethylpiperazine-1-carboxylic acid phenylmethylester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide;	Step 5: Preparation of (+/-)-4-(2-Fluoro-4-nitrophen-1-yl)-<strong>[191739-40-9]3-hydroxymethylpiperazine-1-carboxylic acid phenylmethylester</strong>. To a flame dried flask under an inert atmosphere containing <strong>[191739-40-9](+/-)-<strong>[191739-40-9]3-hydroxymethylpiperazine-1-carboxylic acid phenylmethylester</strong></strong> (Step 4, 6.00 g, 23.97 mmol) in DMSO (150 mL) and K2 HPO4 (16.70 g, 95.88 mmol) is added 3,4-difluoronitrobenzene (5.31 mL, 47.94 mmol) and heated to 90 C. for 24 hours. The reaction is cooled to ambient temperature, concentrated in vacuo, and diluted with methylene chloride (200 mL) and water (150 mL). The layers are separated and the aqueous phase is extracted with methylene chloride (4*100 mL). The organic extracts are combined, washed with saline, dried over Na2 SO4, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 500 mL), eluding with chloroform/methanol (99.5/0.5). The appropriate fractions are combined (Rf =0.05, TLC, hexane/ethyl acetate, 75/25) and concentrated in vacuo to give the title compound, NMR (CDCl3) 7.82, 7.73, 7.30-7.25, 6.87, 5.09, 4.16-4.07, 3.92, 3.65, 3.32-3.24.

Reference： [1]Patent: US5922707,1999,A

4
[ 191739-40-9 ]
[ 757982-39-1 ]
[ 879271-24-6 ]

Yield	Reaction Conditions	Operation in experiment
65%		To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in 3.0 mLof CH2CI2 was added 3-hydroxymethyl-piperazine-l-carboxylic acid benzyl ester (226 mg, 0.58mmol) and triethylamine (190 uL, 1.37 mmol). The reaction mixture was stirred for 12 hours atroom temperature, and additional 3-hydroxymethyl-piperazine-l-carboxylic acid benzyl ester(100 mg, 0.4 mmol) and triethylamine (200 uL, 1.4 mmol) was added, and the reaction mixturewas heated at 40 C for 6 h. The reaction mixture was cooled, and diluted with 5 mL of CH2CI2and 5 mL of water, and the organic layer was separated and dried over NaoSCU- The solventwas removed under reduced pressure, and the residue was purified by silica gel chromatographyeluting with 20-85% EtOAc/hexanes to give 3-hydroxymethyl-4-[2-(2-hydroxy-phenyi)-7-methyl-quinazolin-4-yl]-piperazine-l-carboxylic acid benzyl ester(216 mg, 65 %). LCMS: m/z485 (M+H)+ at 3.03 min (10%-99% CH3CN/H20)
64%	With triethylamine; In dichloromethane; at 40℃; for 6h;	To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in 3.0 mLof CH2CI2 was added sequentially 3-hydroxymethyl-piperazine-l-carboxylic acid benzyl ester(336.3 mg, 1.34 mmol) and triethylamine (190 mL, 1.37 mmol), and the reaction mixture washeated at 40 C for 6 h. The reaction mixture was cooled and extracted with water (2x10 mL)and the organic layer was separated and dried over Na2SC>4. The solvent was removed underreduced pressure to give an oil. The residue was purified by normal phase LC (20-85% EtOAc-hexanes) to give 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (216 mg, 64% yield). LC/MS: m/z 485.4 (M+H)+ at3.02 min (10%-99% CH3CN (0.035% TFA)/H20 (0.05% TFA)).

Reference： [1]Patent: WO2006/28904,2006,A1 .Location in patent: Page/Page column 144-145
[2]Patent: WO2006/28904,2006,A1 .Location in patent: Page/Page column 201-202

5
[ 191739-40-9 ]
[ 1202237-10-2 ]
[ 1202237-12-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 80℃; for 18h;	Part B:To a solution of compound 81 (396 mg, 1.0 mmol) and DfEA (0.523 L1 3.0 mmol) In THF (10 rnL) was added 4-I?/-benzyioxycarbonyl-2-hydroxymethyfpiperazine (300 mg, 1.2 mmol) and the reaction mixture heated at 800C for 18 hours. The reaction was quenched with the addition of 1 N HCI and extracted with EtOAc. Drying over magnesium sulfate and concentration afforded compound 82 which was subjected to flash silica chromatography, gradient elution (0 to 100 %) hexane / ethyl acetate (345 rng, 68 %). HPLC-MS tR = 1.99 min (UV2S4 ^n); mass calculated for formula C26H4IN3O7 507.3, observed LCMS m/z 508.3 (M+H).

Reference： [1]Patent: WO2009/158369,2009,A1 .Location in patent: Page/Page column 65

6
(R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate [ No CAS ]
[ 191739-40-9 ]