[ CAS No. 888952-55-4 ] {[proInfo.proName]}

Name: 888952-55-4|Methyl 1-Boc-3-methylpiperidine-3-carboxylate|97%
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SKU: A450772
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Quality Control of [ 888952-55-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 888952-55-4 ]

CAS No. :	888952-55-4	MDL No. :	MFCD11977502
Formula :	C₁₃H₂₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QCXGMLPZKNFRRV-UHFFFAOYSA-N
M.W :	257.33	Pubchem ID :	46911995
Synonyms :

Calculated chemistry of [ 888952-55-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.85
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	72.04
TPSA :	55.84 Å²

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) :	-6.58 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.16
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	1.82
Log Po/w (MLOGP) :	1.58
Log Po/w (SILICOS-IT) :	1.53
Consensus Log Po/w :	1.98

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.25
Solubility :	1.44 mg/ml ; 0.0056 mol/l
Class :	Soluble
Log S (Ali) :	-2.61
Solubility :	0.628 mg/ml ; 0.00244 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.96
Solubility :	2.82 mg/ml ; 0.0109 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	2.97

Safety of [ 888952-55-4 ]

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

Application In Synthesis of [ 888952-55-4 ]

* 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 [ 888952-55-4 ]
Downstream synthetic route of [ 888952-55-4 ]

[ 888952-55-4 ] Synthesis Path-Upstream 1~1

1
[ 888952-55-4 ]
[ 534602-47-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With lithium hydroxide monohydrate In tetrahydrofuran; water at 70℃; for 6 h;	Step 2. 1-tert-Butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (15.86 g, 0.062 mol) in THF (100 ml) and H₂O (10 ml) was added LiOH.H₂O (7.76 g, 0.186 mol) at room temperature. The mixture was refluxed at 70° C. for 6 h. After TLC (Petroleum ether/EtOAc, 4:1, stained by iodine) showed the starting material to be consumed, the mixture was concentrated to dryness. The residue was diluted with H₂O (300 mL) and then extracted with MTBE (100 mL×2). The organic layers were discarded. The resulting aqueous layer was acidified to pH 1 with 1M HCl (aq.) and then extracted with MTBE twice. The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to dryness to give 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (13.97 g, 93percent) as a white solid.

Reference： [1] Patent: US2015/158864, 2015, A1, . Location in patent: Paragraph 0487
[2] Patent: US2007/82900, 2007, A1, . Location in patent: Page/Page column 158

[ 888952-55-4 ] Synthesis Path-Downstream 1~34

1
[ 888952-55-4 ]
[ 534602-47-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With lithium hydroxide monohydrate; In tetrahydrofuran; water; at 70℃; for 6h;	Step 2. 1-tert-Butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (15.86 g, 0.062 mol) in THF (100 ml) and H2O (10 ml) was added LiOH.H2O (7.76 g, 0.186 mol) at room temperature. The mixture was refluxed at 70 C. for 6 h. After TLC (Petroleum ether/EtOAc, 4:1, stained by iodine) showed the starting material to be consumed, the mixture was concentrated to dryness. The residue was diluted with H2O (300 mL) and then extracted with MTBE (100 mL×2). The organic layers were discarded. The resulting aqueous layer was acidified to pH 1 with 1M HCl (aq.) and then extracted with MTBE twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (13.97 g, 93%) as a white solid.
	With sodium hydroxide; ethanol; at 25 - 70℃; for 3h;	A solution of ester from Preparative Example X-910-C (1.08 g, 4.20 mmol) in EtOH (16.8 mL) at 25 C. was treated with NaOH (0.050 g, 3 equiv.). The solution was heated at 70 C. for 3 h. The solution was cooled to 25 C. and concentrated under reduced pressure. The residue was dissolved in H2O (50 mL). The aqueous layer was washed with Et2O (2×30 mL). The aqueous layer was acidified to pH=1 with 1 M HCl. The aqueous layer was extracted with Et2O (2×30 mL) and the organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was used directly in the next reaction.

Reference： [1]Patent: US2015/158864,2015,A1 .Location in patent: Paragraph 0487
[2]Patent: US2007/82900,2007,A1 .Location in patent: Page/Page column 158

2
[ 74-88-4 ]
[ 888952-55-4 ]

Yield	Reaction Conditions	Operation in experiment
95.8%		To a -78 C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) in dry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M in THF, 10.03 mmol) dropwise. The reaction was stirred at this temperature for 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was cooled and then quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted three times with 20 ml of EtOAc and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexanes/EtOAc (0>15%) to yield 2.25 g (95.8%) of 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Intermediate 54). 1H NMR (400 MHz, CDCl3) delta ppm 1.0 (s, 3 H), 1.3 (s, 9 H), 1.4 (m, 2 H), 1.9 (m, 2 H), 3.0 (d, J=13.2 Hz, 1 H), 3.1 (m, 1 H), 3.3 (m, 1 H), 3.5 (s, 3 H), 3.7 (d, J=13.4 Hz, 1H).

Reference： [1]Patent: US2006/116376,2006,A1 .Location in patent: Page/Page column 16

3
[ 888952-55-4 ]
[ 406212-48-4 ]

Yield	Reaction Conditions	Operation in experiment
42.1%		To a 0 C. stirred solution of Intermediate 54 (1.17 g, 4.56 mmol) in dry THF (20 ml) was added LiAlH4 (1.0 M in THF, 9.11 ml, 9.11 mmol) dropwise and the reaction was allowed to warm to room temperature. Upon completion as indicated by TLC, the reaction was carefully quenched with saturated NH4Cl and EtOAc was added. The layers were separated, the aqueous layer was extracted with EtOAc (3×15 ml) and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 0.844 g (42.1%) of 3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 55). 1H NMR (400 MHz, CDCl3) delta ppm 0.9 (s, 3 H), 1.3 (m, 2 H), 1.5 (s, 9 H), 1.5 (m, 3 H), 2.9 (s, 1 H), 3.1 (s, 1 H), 3.5 (d, J=11.5 Hz, 1 H), 3.8 (m, 2 H).

Reference： [1]Patent: US2006/116376,2006,A1 .Location in patent: Page/Page column 16-17

4
[ 148763-41-1 ]
[ 74-88-4 ]
[ 888952-55-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step 1. 1-tert-Butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate. To a solution of <strong>[148763-41-1]1-tert-butyl 3-methyl piperidine-1,3-dicarboxylate</strong> (15 g, 0.062 mol) in THF (250 ml) was added LHMDS (74.4 ml, 0.074 mol) dropwise at -65 C. under N2 protection. The reaction mixture was stirred at -65 C. for 1 h. MeI (10.5 g, 0.074 mol) was added dropwise. The resulting solution was stirred at -65 C. for 2 h and at room temperature for 1 h. The resulting solution was quenched with sat.NH4Cl (aq) (200 ml). The organic layer was separated and the aqueous layer was extracted with MTBE (200 ml×2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give 1-tert-butyl 3-methyl 3-methylpiperidine-1,3-dicarboxylate (15.86 g, 100%) as yellow oil. 1H NMR (400 MHz, DMSO-d6) delta 1.08 (s, 3H) 1.32-1.47 (m, 12H) 1.94 (br s, 1H) 3.05 (d, J=12.30 Hz, 2H) 3.42 (br s, 1H) 3.61 (br s, 3H) 3.82 (br s, 1H).
96%		LiHMDS (450 mL, 0.45 mol, 1 M) was added dropwise to a solution of intermediate 31 (54.75 g, 0.22 mmol) in THF (1 L) at -78 C and under an atmosphere of N2. The solution was stirred at -78 C for 1 hour and then methyl iodide (63.9 g, 0.45 mmol) was added dropwise at this temperature. After the addition was completed, the reaction mixture was allowed to warm to RT. The RM was then treated with a saturated aqueous NH4CI solution. The aqueous layer was extracted with Et20. The combined OL were dried over MgSC^, filtered and evaporated. The resulting residue was purified via flash column chromatography, using as eluent a 20% solution of EtOAc in heptane, to provide intermediate 32 (55.5 g, 96%> yield).
83%	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 25℃; for 4h;	A solution of ester (1.23 g, 5.05 mmol) in THF (20 mL) at -78 C. was treated with LIHMDS (6.1 mL of a 1.0M solution in THF, 1.2 equiv.) dropwise. The solution was stirred at -78 C. for 1 h and treated with CH3I (0.38 mL, 1.2 equiv.) dropwise. The solution was stirred at -78 C. for 2 h. and at 25 C. for 1 h. The solution was quenched by the addition of saturated NH4Cl (100 mL). The aqueous layer was extracted with Et2O (3×25 mL). The combined organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by an Analogix purification system using a RediSep 40 g column (25% ethyl acetate-hexanes) to provide (1.08 g, 83%) a white solid.

60.5%		Example 1 - Preparation of Intermediate 1 The synthesis of Intermediate 1 followed General Procedure 1 following. Intermediate 1 To a solution of diisopropylamine (6.55 g, 64.7 mmol, 2.1 eq) in cold THF (-780C, 80 mL) was added n-butyllithium (4.04 g, 63.1 mmol, 2.05 eq), and then stirred for 1 hour at 00C. The reaction mixture was then cooled to -780C and to it was then added <strong>[148763-41-1]1-(tert-butyl)-3-methylpiperidine-1,3-dicarboxylate</strong> (7.5 g, 30.8 mmol, 1 eq). The mixture was stirred for 1 hour, and to it was added methyl iodide (13.12 g, 97.4 mmol, 3.0 eq). The reaction mixture was warmed to room temperature overnight. It was monitored by TLC and LC-MS. After completion, the reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate (2 x 150 mL). The combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography using silica gel (60-120 mesh size), eluting with 5-10% ethyl acetate in n-hexane to give product (Intermediate 1, 4.8 g, yield: 60.5%) m/z 202 [M- 56]+ 1H NMR (400 MHz, CDCl3) delta 3.87 (d, J = 13.3 Hz, 1H), 3.70 (s, 3H), 3.46 (s, 1H), 3.27 (d, J = 5.9 Hz, 1H), 3.15 (d, J = 13.3 Hz, 1H), 2.04 (dd, J = 12.7, 6.2 Hz, 1H), 1.58 (s, 1H), 1.49 (m, 11H), 1.18 (s, 3H) ppm.
		A solution of 1-tert-butyl 3-methyl piperidine-1, 3-dicarboxylate (5g, 20.57 mmol) in THF (100 mL) was added LiHMDS (30.8 mL, 1 M in THF) at -78 under nitrogen, then the mixture was stirred at -78 for 1 hour. MeI (5.52 g, 28.79 mmol) was added to the solution at -78 via cylinder, the mixture was stirred at 25 for 16 hours. Staturated NH4Cl (20 mL) was added to the solution at 0, the solution extracted by EA (100 mL) . The organic layer was washed with H2O (30 mL) and brine (30 mL) , dried over any hydrous Na2SO4, concentrated to afford the crude product which was purified on silica gel chromatography to give 1-tert-butyl 3-methyl 3-methylpiperidine-1, 3-dicarboxylate.1H NMR (400MHz, CD3Cl) delta3.82 (d, J13.3 Hz, 1H) , 3.65 (s, 3H) , 3.47-3.38 (m, 1H) , 3.25-3.17 (m, 1H) , 3.09 (d, J13.3 Hz, 1H) , 2.04-1.96 (m, 2H) , 1.60-1.51 (m, 2H) , 1.42 (s, 9H) , 1.22 (t, J7.0 Hz, 1H) , 1.13 (s, 3H) ppm.
560 mg	With lithium hexamethyldisilazane; In tetrahydrofuran; at -78℃; for 0.333333h;	To a solution of <strong>[148763-41-1]1-(tert-butyl) 3-methyl piperidine-1,3-dicarboxylate</strong> (530 mg, 2.18 mmol, 1 eq) in anhydrous THF (10 mL) at -78 C was added LiHMDS 1M in THF (4.36 mL, 4.36 mmol, 2 eq) then iodomethane (271 muL, 4.36 mmol, 2 eq). The reaction was stirred at -78 C for 20 min then was quenched with a solution of ammonium chloride. The product was extracted with ethyl acetate and the solvent was removed under reduced pressure to afford 560 mg as a yellow oil. [MH]+ 258

Reference： [1]Patent: US2015/158864,2015,A1 .Location in patent: Paragraph 0486
[2]Patent: WO2018/83098,2018,A1 .Location in patent: Page/Page column 56
[3]Patent: US2007/82900,2007,A1 .Location in patent: Page/Page column 157-158
[4]Patent: WO2016/138532,2016,A1 .Location in patent: Paragraph 0236
[5]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 66; 67
[6]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1848 - 1853

5
[ 888952-55-4 ]
[ 29874-83-7 ]
[ 851012-93-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of LDA (lithium diisopropylamide) (prepared by mixing 0.64 mL of i-Pr2NH and 2.7 mL of a 1.6 M solution of n-BuLi in hexanes in 4 mL of anhydrous THF) at -78 C. under N2 was added a solution of <strong>[888952-55-4]1-(1,1-dimethylethyl) 3-methyl 1,3-piperidinedicarboxylate</strong> (prepared as in U.S. Pat. No. 5,190,953, 1.009 g, 4.15 mmol) in 6 mL of anhydrous THF. The reaction mixture was stirred at -78 C. for 30 min. A solution of 2-Chloro-4-phenylquinazoline (1.002 g, 4.16 mmol) in 8 mL of anhydrous THF was then added dropwise into the reaction mixture at -78 C. The reaction mixture was stirred at -78 C. for 20 min. and then slowly warmed to room temperature in 3 hours. The mixture was cooled back to 0 C. Saturated NH4Cl solution was added to quench the reaction. The mixture was extracted with EtOAc (2*50 mL). The combined organic extracts was dried with MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with 10% ethyl acetate in hexanes to remove the unreacted 2-Chloro-4-phenylquinazoline. The column was then eluted with 20% ethyl acetate in hexanes to give 1.803 g of product as a white foam. APCI MS m/z 348, 392, 448 (M++1, 100%).

Reference： [1]Patent: US2005/96327,2005,A1 .Location in patent: Page/Page column 23

6
[ 888952-55-4 ]
[ 534602-48-7 ]

Reference： [1]Patent: US2015/158864,2015,A1

7
[ 888952-55-4 ]
[ 1158759-06-8 ]

Reference： [1]Patent: US2015/158864,2015,A1

8
[ 888952-55-4 ]
tert-butyl 3-methyl-3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2015/158864,2015,A1

9
[ 888952-55-4 ]
N-(3-methylpiperidin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine [ No CAS ]

Reference： [1]Patent: US2015/158864,2015,A1

10
[ 888952-55-4 ]
1-(3-methyl-3-((7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ No CAS ]

Reference： [1]Patent: US2015/158864,2015,A1

11
[ 888952-55-4 ]
1-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one [ No CAS ]

Reference： [1]Patent: US2015/158864,2015,A1

12
[ 888952-55-4 ]
(S)-1-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one [ No CAS ]
(R)-1-(3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one [ No CAS ]

Reference： [1]Patent: US2015/158864,2015,A1

13
[ 888952-55-4 ]
methyl 3-methylpiperidine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In methanol; at 20℃; for 16h;	A solution of HCl in MeOH (20 mL, 4M) was added 1-tert-butyl 3-methyl 3-methylpiperidine-1, 3-dicarboxylate (2 g, 7.7 mmol) , and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated to give methyl 3-methylpiperidine-3-carboxylate which is used to next step without further purification.
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 0.0833333h;	HCl in dioxane 4M (11 mL, 43.5 mmol, 20 eq) was added to <strong>[888952-55-4]1-(tert-butyl) 3-methyl 3-methylpiperidine-1,3-dicarboxylate</strong> (560 mg, 2.18 mmol, 1 eq). The mixture was stirred at room temperature for 3 days.3 The solvent was removed to afford methyl 3-methylpiperidine-3-carboxylate as a yellow solid. [MH]+ 158

Reference： [1]Patent: WO2016/106623,2016,A1 .Location in patent: Page/Page column 67
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1848 - 1853

14
[ 888952-55-4 ]
methyl 1-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-3-methylpiperidine-3-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/106623,2016,A1

15
[ 888952-55-4 ]
methyl 3-methyl-1-((4-((2-methylquinolin-4-yl)methoxy)phenyl)sulfonyl)piperidine-3-carboxylate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1848 - 1853

16
[ 888952-55-4 ]
3-methyl-1-((4-((2-methylquinolin-4-yl)methoxy)phenyl)sulfonyl)piperidine-3-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1848 - 1853

17
[ 888952-55-4 ]
3-methyl-1-((4-((2-methylquinolin-4-yl)methoxy)phenyl)sulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-3-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1848 - 1853

18
[ 888952-55-4 ]
N-hydroxy-3-methyl-1-((4-((2-methylquinolin-4-yl)methoxy)phenyl) sulfonyl)piperidine-3-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1848 - 1853

19
[ 888952-55-4 ]
tert-butyl 3-(5-(((5-chlorothiophen-2-yl)methyl)amino)-1H-pyrazol-3-yl)-3-methylpiperidine-1-carboxylate [ No CAS ]