183170-69-6|tert-Butyl 4-(1-hydroxyethyl)piperidine-1-carboxylate| Ambeed

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Quality Control of [ 183170-69-6 ] Purity: 96% SDS Specification

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Product Details of [ 183170-69-6 ]

CAS No. :	183170-69-6
Formula :	C₁₂H₂₃NO₃
M.W :	229.32
SMILES Code :	O=C(N1CCC(C(O)C)CC1)OC(C)(C)C
MDL No. :	MFCD15474944
InChI Key :	SQOMPUDOUGDJPH-UHFFFAOYSA-N
Pubchem ID :	21989903

Safety of [ 183170-69-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P280-P301+P312-P302+P352-P305+P351+P338

Application In Synthesis of [ 183170-69-6 ]

* 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.

Downstream synthetic route of [ 183170-69-6 ]

[ 183170-69-6 ] Synthesis Path-Downstream 1~35

1
[ 175213-46-4 ]
[ 183170-69-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; LiAlH4; In tetrahydrofuran; water;	Step 3. 1-t-Butoxycarbonyl-4-(hydroxyethyl)piperidine To a solution of 5 g (696.6 mmol) of LiAlH4 in 800 mL of THF at rt was carefully added 30 g (232.2 mmol) of 1-t-butoxycarbonyl-4-(methoxycarbonyl methyl)piperidine and the reaction mixture was stirred at rt for 24 h. To the reaction mixture was slowly added 30 mL of H2O over a period of 2 h, followed by 30 mL of a 15% NaOH solution and 30 mL of H2O. The mixture was diluted with ether, filtered, and the solids were triturated several times with ethyl acetate. The combined organic fractions were concentrated to give the title compound.

References: [1]Patent: US2002/13348,2002,A1 .

2
[ 183170-69-6 ]
1-t-Butoxycarbonyl-4-(methoxyethyl)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In water; N,N-dimethyl-formamide; mineral oil;	Step 4. 1-t-Butoxycarbonyl-4-(methoxyethyl)piperidine To a solution of 825 mg (3.6 mmol) of 1-t-butoxycarbonyl-4-hydroxyethylpiperidine in 2.5 mL of DMF was added 0.21 g (7.2 mmol) of NaH (80% dispersion in mineral oil) in 3 portions over a period of 30 min. After 16 h 10 mL of H2O was added to the reaction mixture and it was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=4:1) to give the title compound.

References: [1]Patent: US2002/13348,2002,A1 .

3
[ 6457-48-3 ]
[ 24424-99-5 ]
[ 183170-69-6 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine; In 1,2-dichloro-ethane; at 20℃;Reflux;	(+/-)-1-(4-Piperidinyl)ethanol (see reference: WO 9725992A, 12.44 g, 65.7 mmol) in 1,2-dichloroethane (500 mL) was stirred at room temperature and BOC2O (14.36 g, 65.8 mmol) was added followed by Et3N (19 mL, 136 mmol). The stirred mixture was heated at gentle reflux for 15 min and then allowed to cool to room temperature and stirred overnight. The solution was washed twice with 10% citric acid, once with 10% Na2CO3, dried over MgSO4, filtered and concentrated to afford (+/-)-1,1-dimethylethyl 4-(1-hydroxyethyl)-1-piperidinecarboxylate (14 g, 93% yield) as a light amber oil. 1H NMR (400 MHz, DMSO-d6): δ 4.35 (d, 1H, J=4.8 Hz), 3.92 (m, 2H), 3.32 (m, 1H), 2.59 (m, 2H), 1.68 (m, 1H), 1.47 (m, 1H), 1.34 (s, 9H), 1.25 (m, 1H), 1.08-0.88 (m, 2H), 0.97 (d, 3H, J=6.4 Hz).
	With sodium hydroxide; In tetrahydrofuran;	EXAMPLE 18 1-t-Butyloxycarbonyl-4-hydroxyethylpiperidine A solution of di-t-butyl dicarbonate (10.15 g, 47 mmol) in tetrahydrofuran (15 mL) was added slowly to a 0 C. solution of 4-hydroxyethylpiperidine (5.0 g, 39 mmol) and sodium hydroxide (1.86 g, 47 mmol) in THF. After stirring for 24 hours at room temperature, the mixture was poured into water (200 mL) and extracted with ethyl acetate (3*200 mL). The solution was dried (MgSO4), filtered, and concentrated under vacuum to yield a colorless oil (9.0 g, quant.). 1 H NMR (300 MHz, CDCl3 /TMS, δ): 4.1(m,2H), 3.7(q,2H,J=5Hz), 2.7(br t,2H), 1.7(m,2H), 1.43(s,9H), 1.12-1.00(m,3H) MSCI: 230(MH+, base).
	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0 - 20℃; for 18h;Inert atmosphere;	Di-tert-butyl dicarbonate (1.858 g, 8.51 mmol) was added dropwise to a solution of sodium bicarbonate (0.715 g, 8.51 mmol) and l-(piperidin-4-yl)ethan-l-ol (1 g, 7.74 mmol) in Water (10 mL) and 1,4-Dioxane (10 mL) at 0 C under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL). The aqueous layer was extracted with further DCM (3 x 50mL) and the combined organic extracts were dried by passing through a hydrohpbic frit. The solvent was removed under reduced pressure to afford the crude title compound (1.87 g). The material was used directly in the next step.

References: [1]Patent: US2010/29650,2010,A1 .Location in patent: Page/Page column 77.
[2]Patent: US5252586,1993,A .
[3]Patent: WO2018/192864,2018,A1 .Location in patent: Page/Page column 170; 171.

4
[ 183170-69-6 ]
[ 1032825-55-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane;	EXAMPLE 20 1-t-Butyloxycarbonyl-4-methanesulfonyloxyethylpiperidine Methanesulfonyl mL, was chloride (4.0 mL, 52 mmol) was added slowly to a 0 C. solution of <strong>[183170-69-6]1-t-butyloxycarbonyl-4-hydroxyethylpiperidine</strong> (10.0 g, 43.7 mmol) and diisopropylethylamine (7.3 mL, 52 mmol) in dichloromethane (100 mL) with stirring under a nitrogen atmosphere. After 24 hours at room temperature, the mixture was extracted with water (4*100 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield a clear oil which crystallized upon standing. Mp:60-63 C. MSCI:252(MH+, base) 1 H NMR(300 MHz, CDCl3 /TMS, δ): 4.3(br t,2H), 4.1(br d,2H), 3.0(S,3H), 2.7(br t,2H), 1.7-1.1(m,16H).

References: [1]Patent: US5252586,1993,A .

5
[ 183170-69-6 ]
[ 3355-31-5 ]
1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine [ No CAS ]
[ 152903-08-7 ]

Yield	Reaction Conditions	Operation in experiment
16%	In ethyl acetate; N,N-dimethyl-formamide;	EXAMPLE 39 1-Phenethyl-4-[(3-phenyl-2-propynyloxy)-ethyl] piperidine, hydrochloride salt Sodium hydride (0.912 g, 23 mmol, 60% oil disp.) which had been rinsed with hexanes (310 mL), and dry N,N-dimethylformamide (50 mL) were cooled to 0 C. with stirring under a nitrogen atmosphere. A solution of <strong>[183170-69-6]1-t-butyloxycarbonyl-4-hydroxyethylpiperidine</strong> (4.3 g, 19 mmol) in dry DMF (15 mL) was added, and the mixture stirred for 1 hour. 3-Phenylpropargyl chloride (2.8 g, 19 mmol) was added, and the mixture was heated to reflux for 24 hours. After cooling, the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and extracted with water (3100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluding with 5% ethyl acetate in hexanes, and concentrated under reduced pressure to yield 1-t-butyloxycarbonyl-4-[(3-phenyl-2-propynyloxy)ethyl]piperidine (1.02 g, 16%) as a dark oil. 1 H NMR (300 MHz, CDCl3 /TMS, δ): 7.5(m,2H), 7.3(m,3H), 4.4(s,2H), 4.1(m,2H), 3.6(t,2H), 2.7(br t,2H), 1.8-1.1(m,16H). MSCI: 344 (MH+, base).

References: [1]Patent: US5252586,1993,A .

6
[ 135716-09-5 ]
[ 183170-69-6 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium borohydride; In methanol; diethyl ether; water;	REFERENCE EXAMPLE 50 N-t-Butoxycarbonyl-4-(1-hydroxyethyl)piperidine In diethyl ether (20 ml) was dissolved ethyl N-tert-butoxycarbonyl-4-piperidineacetate (1.18 g) followed by addition of methanol (0.19 ml). Then, lithium borohydride (123 mg) was added under ice-cooling. The mixture was stirred at room temperature for 15 hours, after which time water was added under ice-cooling. The mixture was diluted with ethyl acetate, washed with aqueous NaCl solution, dried over MgSO4, and concentrated to provide the title compound as colorless oil (0.96 g). 1 H-NMR (CDCl3) δ: 1.0-1.4(4H,m), 1.45(9H,s), 1.5-1.8(4H,m), 2.69(2H,t,J=13.3Hz), 3.6-3.8(2H,brm), 4.0-4.2(2H,brm). IR (Neat): 3350, 2927, 1697, 1672, 1429, 1169 cm-1.

References: [1]Patent: US5753664,1998,A .

7
[ 183170-69-6 ]
[ 124-63-0 ]
[ 1032825-55-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 0.5h;	Step 4: tert-butyl 4-{l-[(methylsulfonyl)oxy]ethyl}piperidine-l-carboxylateTo a 250 ml round bottom flask was added tert-butyl 4-{ 1-[(methylsulfonyl)oxy] ethyl }piperidine-l-carboxylate from the previous step, triethylamine (27.4 ml, 196 mmol) and 100 ml methylene chloride. Methanesulfonyl chloride was added via a syringe at 0 0C. The resulting reaction mixture was stirred at 0 0C for 30 minutes. It was diluted with 300 ml ether, washed sequentially with 150 ml IN HCl, 100 ml saturated aqueous Na2CO3 and 100 ml brine. The organic layers were dried over sodium sulfate, filtered and concentrated to give 29 g light yellow sticky material.
	With triethylamine; In dichloromethane; at 0 - 20℃; for 16h;	2: 4-(1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid tert-butyl esterTo a solution of <strong>[183170-69-6]4-(1-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester</strong> (18.24 g, 79.54 mmol) in dichloromethane (400 mL) and triethylamine (12.20 mL, 87.49 mmol) at 0 C. is added methanesulfonyl chloride (9.23 mL, 119.30 mmol). The reaction is allowed to warm to room temperature over 16 h. The mixture is washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate, water, and brine. The material is dried over magnesium sulfate, filtered, and concentrated to dryness. The crude material is purified by flash chromatography over silica gel to afford 22.65 g of the title compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 1.19-1.30 (m, 2H), 1.39 (d, 3H), 1.44 (s, 9H), 1.6-1.8 (m, 3H), 2.66 (m, 2H), 2.99 (s, 3H), 4.16 (m, 2H), 4.62 (t, 1H).
815 g	With triethylamine; In dichloromethane; at 0℃; for 0.5h;	Compound 7 (655 g, 2.86 mol) was dissolved in dichloromethane (3.93 L)Triethylamine (598 mL, 4.29 mol) at room temperature,After the reaction system was cooled to 0 C,Methanesulfonyl chloride (392.6 g, 3.43 mol) was added dropwise,After completion of the dropwise addition,And the mixture was stirred at 0 C for 0.5 hour.The reaction solution was treated with HCl (1 N, 1.5 L)Water (2.0 L)And sodium carbonate (2 L)And brine (3 L)The organic phase was dried over anhydrous sodium sulfate,Filtered and concentrated to give compound 8 (815 g) as a yellow oil,Without further purification,Directly for the next reaction.

	With triethylamine; In dichloromethane; at 0℃; for 2h;	Intermediate 141, tert-butyl 4-(1 -hydroxyethyl)piperidine-1 -carboxylate (2.0 g, 8.73 mmol) andEt3N (3.64 mL, 26.3 mmol) were dissolved in dichloromethane (20.0 mL) and cooled to 0 C.Intermediate 142, methanesulfonyl chloride (0.82 mL, 10.4 mmol) was added dropwise andthe reaction mixture was allowed to stir at 0 C for 2 h. The reaction mixture was diluted withwater (100 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give crude tert-butyl 4-{1-[(methylsulfonyl)oxy]ethyl}piperidine-1-carboxylate (2.0 g, 75 %) as an oil. The crude product was used in the next step without further purification.LCMS (Method I): mlz 252 (M+H-56) (ES), at 4.51 mi UV active.
	With triethylamine; In dichloromethane; at 0℃; for 4h;Inert atmosphere;	To a solution of tert-butyl 4-(l-hydroxyethyl)piperidine-l-carboxylate (805 mg, 3.51 mmol) and triethylamine (0.979 mL, 3.86 mmol) in DCM (10 mL) was added mesyl-CI (0.301 mL, 3.86 mmol) at 0 C under an atmosphere of nitrogen. The reaction mixture was left to stir for 4 h. The reaction mixture was diluted with ether (30 mL) and washed sequentially with 1M aqueous HCI solution (20 mL), saturated aqueous NaHCC solution (20 mL) and brine (10 mL). The organic phase was passed through a hydrophobic frit and the solvent removed under reduced pressure to afford the crude title compound (980 mg). The material was used directly in the next step.

References: [1]Journal of Medicinal Chemistry,2021,vol. 64,p. 11014 - 11044.
[2]Patent: WO2009/45382,2009,A1 .Location in patent: Page/Page column 34.
[3]Patent: US2011/15199,2011,A1 .Location in patent: Page/Page column 6.
[4]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 1064 - 1068.
[5]Patent: CN105669647,2016,A .Location in patent: Paragraph 0045; 0046; 0047; 0048.
[6]Patent: WO2017/21730,2017,A1 .Location in patent: Page/Page column 66.
[7]Patent: WO2018/192864,2018,A1 .Location in patent: Page/Page column 171.

8
[ 206989-61-9 ]
[ 183170-69-6 ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With sodium tetrahydroborate; In ethanol; at 20℃; for 1h;	To a solution of 0.400 g (1.76 mmol) of 4-acetyl-piperidine-l-carboxylic acid ie/ -butyl ester in ethanol (3 mL) is added 0.134 g (3.52 mmol) of sodium borohydride. The mixture is stirred at room temperature for 1 hour then a saturated aqueous solution of ammonium chloride is added to consume excess reactants. The mixture is washed with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.390 g (96.6%) of 4-(l-hydroxy-ethyl)- piperidine-l-carboxylic acid ieri-butyl ester as a colorless oil.
		Step 3: tert-butyl 4-(l-hydroxyethyl)piperidine-l-carboxylate <n="35"/>tert-Butyl 4-acetylpiperidine-l-carboxylate from the previous step was dissolved in 50 ml methanol. NaBH4 (2.01g, 53 mmol) was added in batches at 0 0C. The resulting reaction mixture was stirred at 0 0C for 30 minutes. The volatiles were removed under vacuum. The residue was partitioned between 150 ml 10% KOH solution and 200 ml ether. The organic layers were washed with 100 ml brine, dried over sodium sulfate and concentrated to give 22.5 g colorless oil, which was azotropically dried by addition of 50 ml toluene and reconcentration under vacuum. This material was used for next step without further purification.1H-NMR (CDCl3): 54.17 (b, 2H), 3.62 (m, IH), 2.69 (b, 2H), 1.85 (m, IH), 1.6 (m, IH), 1.48 (s, 9H), 1.46 (m, IH), 1.24 (m, HH), 1.22 (d, J = 6.2 Hz, 3H).
655 g	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 0.5h;	Compound 6 (652 g, 2.87 mol) was dissolved in methanol (1.5 L)Sodium borohydride (108.6 g, 2.87 mol) was added portionwise under ice-cooling and the reaction system temperature was maintained at 0-5 C,And the mixture was stirred at room temperature for 0.5 hour.After the reaction system was concentrated,Water (3 L)And methyl tert-butyl ether (3 L)The aqueous phase was treated with methyl t-butyl ether (1.5 L x 3)The organic phases were combined,Brine washing,Dried over sodium sulfate,And concentrated by filtration to obtain Compound 7 (655 g) as a colorless oil,Without further purification,Directly for the next reaction.

380 mg

With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1.66667h;

To a stirred solution of tert-butyl 4-acetylpiperidine-l-carboxylate (390 mg, 1.715mmol, 1.0 equiv.) in MeOH (7 mL) was added NaBEL (97 mg, 2.57 mmol, 1.5 equiv.) portion wise at 0 C and stirred for 10 minutes. The reaction mixture was allowed to stir for 1 hour 30 min at RT. Product formation was confirmed by TLC and LCMS. After completion of reaction, reaction mixture was quenched with water and extracted with ethyl acetate (3 x 50 mL). Combined organic extracts were washed with water (2 x 50 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure to obtain tert-butyl 4-(l -hydroxy ethyl) piperidine-l-carboxylate as colorless liquid (380 mg).

References: [1]Patent: WO2011/84985,2011,A1 .Location in patent: Page/Page column 85.
[2]Patent: WO2009/45382,2009,A1 .Location in patent: Page/Page column 33-34.
[3]Patent: CN105669647,2016,A .Location in patent: Paragraph 0041; 0042; 0043; 0044.
[4]Patent: WO2021/69721,2021,A1 .Location in patent: Paragraph 281.

9
[ 75-16-1 ]
[ 137076-22-3 ]
[ 183170-69-6 ]

Yield	Reaction Conditions	Operation in experiment
97.7%	In tetrahydrofuran; at 0 - 20℃; for 1h;	To a stirred solution of t-butyl 4-formylpiperidine-1-carboxylate (0.5 g, 2.34 mmol) in THF (10 mL) was added MeMgBr (1.5M in THF) (3 mL, 4.68 mmol at 0 C. and reaction allowed to stir at room temperature for 1 h. Reaction was monitored by TLC. Reaction was quenched with aq. NH4Cl, extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to give 525 mg (97.7%) of t-butyl 4-(1-hydroxyethyl)piperidine-1-carboxylate. MS: 230.2[M++1]
		Preparation 4; 4-(1-Methanesulfonyloxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester1: 4-(1-Hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl esterTo a solution of N-tert-butoxycarbonyl-4-piperidinecarboxaldehyde (32.20 g, 151.45 mmol) in tetrahydrofuran at -78 C. is added methyl magnesium bromide (2 M in diethyl ether, 100.96 mL, 302.89 mmol). The reaction is stirred at -78 C. for 4.5 h, and then warmed to -50 C. for 30 min. The reaction is quenched with water at -50 C. and allowed to warm to room temperature for 16 h. The solvents are removed and the material is partitioned between diethyl ether and 0.1 M hydrochloric acid. The mixture is extracted with diethyl ether. The combined organic layers are washed with 0.1 M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude is purified by flash chromatography over silica gel to afford 16.90 g of the title compound as a colourless oil. MS (m/z) 229 (M+1).

References: [1]Patent: US2017/291910,2017,A1 .Location in patent: Paragraph 0308; 0309.
[2]Patent: US2011/15199,2011,A1 .Location in patent: Page/Page column 6.

10
[ 183170-69-6 ]
[ 6457-48-3 ]

Yield	Reaction Conditions	Operation in experiment
88.7%		To 0.390 g (1.70 mmol) of the above ester is added 5.0 mL (5.0 mmol) of hydrogen chloride as a 1.0 M solution in diethyl ether followed by several drops of methanol to generate a homogeneous mixture. To resulting mixture is stirred at room temperature for 2 hours then an excess of sodium hydroxide is added to make the pH alkaline. The mixture is extracted with ethyl acetate and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.200 g (88.7%) of l-piperidin-4-yl-ethanol as a light yellow oil

References: [1]Patent: WO2011/84985,2011,A1 .Location in patent: Page/Page column 85.

11
[ 183170-69-6 ]
[ 1314528-14-7 ]

References: [1]Patent: WO2011/84985,2011,A1 .

12
[ 183170-69-6 ]
[ 1314530-70-5 ]

References: [1]Patent: WO2011/84985,2011,A1 .

13
[ 183170-69-6 ]
[ 1314530-71-6 ]

References: [1]Patent: WO2011/84985,2011,A1 .

14
[ 183170-69-6 ]
[ 1138327-90-8 ]