194726-40-4|(R)-1-tert-Butyl 3-ethyl piperidine-1,3-dicarboxylate| Ambeed

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Quality Control of [ 194726-40-4 ] Purity: 95% SDS Specification

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Product Details of [ 194726-40-4 ]

CAS No. :	194726-40-4
Formula :	C₁₃H₂₃NO₄
M.W :	257.33
SMILES Code :	O=C(N1C[C@H](C(OCC)=O)CCC1)OC(C)(C)C
MDL No. :	MFCD07374389
InChI Key :	YCXCRFGBFZTUSU-SNVBAGLBSA-N
Pubchem ID :	1514446

Safety of [ 194726-40-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 194726-40-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	0
Fraction Csp3	0.85
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	72.3
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.84 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.35
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.82
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.58
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.42
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.0

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.19
Solubility	1.68 mg/ml ; 0.00652 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.61
Solubility	0.628 mg/ml ; 0.00244 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.76
Solubility	4.48 mg/ml ; 0.0174 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.58 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.06

Application In Synthesis of [ 194726-40-4 ]

* 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.

Downstream synthetic route of [ 194726-40-4 ]

[ 194726-40-4 ] Synthesis Path-Downstream 1~39

1
[ 24424-99-5 ]
(R)-3-piperidinecarboxylic acid ethyl ester (+)-tartrate [ No CAS ]
[ 194726-40-4 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

2
[ 194726-40-4 ]
[ 194726-46-0 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

3
[ 24424-99-5 ]
[ 25137-01-3 ]
[ 194726-40-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 610 - 625.
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2829 - 2834.
[4]Patent: US6335324,2002,B1 .Location in patent: Page column 253.

4
[ 194726-40-4 ]
[ 116574-71-1 ]

Yield	Reaction Conditions	Operation in experiment
87.1%	With sodium tetrahydroborate; ethanol; at 50℃;	compound IV 5.42 g (0.025 mol) in step S3, 95% ethanol 23 mL, and sodium borohydride 2.87 g (0.075 mol) was added to the reaction flask, stirred and the reaction temperature was controlled at 50 C.The progress of the reaction was monitored by thin layer chromatography until the compound IV was completely reacted and the reaction was completed;Add hydrochloric acid solution to adjust the pH to 7, and then concentrate under reduced pressure, and extract the organic phase with ethyl acetate.The extract is sequentially passed through saturated sodium bicarbonate,Washed with purified water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate for 24h.After suction filtration, the filtrate was obtained, and the filtrate was evaporated under reduced pressure to give a solvent.The crystals were naturally cooled, suction filtered to obtain a cake, and the cake was recrystallized from n-hexane and dried under reduced pressure at 40 C.(R)-N-tert-butoxycarbonyl-3-hydroxymethylpiperidine (Compound V) product 3.72g,The yield of this step was 87.1% (based on compound IV), and the purity was 98.8% (detected by high performance liquid chromatography).

References: [1]Patent: CN109988098,2019,A .Location in patent: Paragraph 0022; 0023; 0027-0030; 0034-0037; 0041-0044.
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.
[3]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 2829 - 2834.
[4]Patent: US6335324,2002,B1 .Location in patent: Page column 253.

5
[ 24424-99-5 ]
(R)-piperidine-3-carboxylic acid ethyl ester*l-tartaric acid [ No CAS ]
[ 194726-40-4 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium carbonate; In tetrahydrofuran; water; at 0 - 20℃; for 20h;pH 10.0;	Adding Compound III in step S2 and 25 mL of purified water to a reaction flask, stirring to dissolve Compound III to obtain an aqueous solution of Compound III;Sodium carbonate was added to the reaction flask to adjust the pH to 10, and 25 mL of tetrahydrofuran was added to the reaction vessel.And controlling the temperature to 0 C, a solution of Boc anhydride tetrahydrofuran (4.0 g of Boc anhydride + 7 ml of tetrahydrofuran) having a temperature of 0 to 5 C was added dropwise to the reaction vessel under stirring.The reaction was carried out for 20 h at room temperature, and the progress of the reaction was monitored by thin layer chromatography until the compound III was completely reacted, and the reaction was completed;After cooling to room temperature, the aqueous phase and the organic phase are separated, and the organic phase is sequentially neutralized with dilute hydrochloric acid.Wash with water and a saturated aqueous solution of sodium chloride, dry over anhydrous sodium sulfate for 2 to 4 h, and then suction filtered to give filtrate, and the filtrate is concentrated under reduced pressure at 40 C.The reaction product oil concentrate is obtained; the temperature of the reaction product concentrate is controlled to be -2 to 2 C, and 1 mL of n-hexane is added to the reaction product concentrate, and then placed in a refrigerator at -10 to 0 C for 4 hours to freeze and crystallize.Filtering to obtain a filter cake, and rinsing the filter cake with a small amount of n-hexane,Drying under reduced pressure at 40 C gave compound IV 5.42 g, the yield of this step was 92% (based on compound III);

References: [1]Patent: CN109988098,2019,A .Location in patent: Paragraph 0022; 0026; 0029; 0033; 0036; 0040; 0043; 0044.
[2]Organic letters,2000,vol. 2,p. 4037 - 4040.

6
[ 2627-86-3 ]
[ 194726-40-4 ]
1-N-(t-butoxycarbonyl)-(3R)-piperidine-N-((1S)-phenyl-1-ethyl)carboxamide [ No CAS ]
(S)-3-((S)-1-Phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Organic letters,2000,vol. 2,p. 4037 - 4040.

7
[ 917112-58-4 ]
[ 194726-40-4 ]

References: [1]European Journal of Organic Chemistry,2006,p. 4343 - 4347.

8
sodium hydroxidein water [ No CAS ]
[ 24424-99-5 ]
[ 194726-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sodium monohydrogen sulfate; In tetrahydrofuran; n-heptane; ethyl acetate;	(R)-Ethyl nipetcotate tartrate (10.0 g, 32.5 mmol) were suspended in tetrahydrofuran (90 ml). An 1 N solution of sodium hydroxidein water (98 ml, 98 mmol) was added. A solution of di-tert-butyl dicarbonate (7.10 g, 32.5 mmol) in tetrahydrofuran (90 ml) was added. The reaction mixture was stirred for 16 h at room temperature. Ethyl acetate (400 ml) was added. The reaction mixture was washed with a 10% aqueous solution of sodium hydrogen sulfate (400 ml). The aqueous solution was extracted with ethyl acetate (2*200 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane 1:4 as eluent, to give 4.13.g of (3R)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. 1H-NMR (CDCl3): delta 1.27 (t, 3H); 1.48 (s, 9H); 1.54 (m, 1H); 1.62 (m, 1H); 1.73 (m, 2H); 2.05 (m, 1H); 2.45 (m, 1H); 2.81 (m, 1H); 2.98 (br, 1H); 3.93 (m, 1H); 4.14 (q, 1H).

References: [1]Patent: US6919315,2005,B1 .

9
[ 194726-40-4 ]
[ 194726-46-0 ]
[ 254905-64-1 ]

Yield	Reaction Conditions	Operation in experiment
	With diisobutylaluminium hydride; In diethyl ether; water; toluene;	A 1.2 M solution of diisobutylaluminum hydride in toluene (30.8 ml, 36.9 mmol) was added at -78 C. to a solution of <strong>[194726-40-4](3R)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester</strong> (4.13 g, 16.1 mmol) in diethyl ether (30 ml). The reaction mixture was stirred for 2.5 h at -78 C. Water (9.6 ml) was added dropwise. The reaction mixture was warmed to room temperature. The precipitation was removed by filtration through a plug of celite. The celite was washed with tert-butyl methyl ether (3*100 ml). The liquids were combined and dried over magnesium sulfate. The solvent was removed in vacuo, to give 1.94 g of crude (3R)-3-formylpiperidine-1-carboxylic acid tert-butyl ester, which was used for the next step without further purification. 1H-NMR (CDCl3): delta 1.45 (s, 9H); 1.67 (m, 2H); 1.95 (m, 1H); 2.43 (m, 1H); 3.10 (m, 1H); 3.32 (dd, 1H); 3.52 (d, 1H); 3.66 (m, 1H); 3.95 (m, 1H); 9.69 (s, 1H). (3S)-3-(Dimethylaminomethyl)piperidine-1-carboxylic acid tert-butyl ester

References: [1]Patent: US6919315,2005,B1 .

10
[ 75-16-1 ]
[ 194726-40-4 ]
[ 1003560-61-9 ]

Yield	Reaction Conditions	Operation in experiment
		Methyl magnesium bromide (2 mL, 3M in diethyl ether, 6 mmol) was added dropwise to a solution of the <strong>[194726-40-4]1-tert-butyl 3-ethyl (3R)-piperidine-1,3-dicarboxylate</strong> (514 mg, 2 mmol) in diethyl ether (20 mL) and THF (20 mL) during 10 min. The mixture was stirred for 30 min and thereafter slowly quenched with NH3Cl solution (10 mL, 3M). The phases were separated and the organic phase was evaporated to yield an oil. The oil was dissolved in EtOAc (50 mL) and HCl was bubbled through the solution in a gentle stream for 10 minutes and then left at room temperature on. The solvent was evaporated and the residue dissolved in EtOAc (100 mL) and stirring for 3 h at room temperature gave a solid that was filtered off and dried in vacuum to yield the title compound as white crystals.

References: [1]Patent: US2008/21022,2008,A1 .Location in patent: Page/Page column 97.

11
[ 614-18-6 ]
[ 194726-40-4 ]

References: [1]European Journal of Organic Chemistry,2006,p. 4343 - 4347.

12
[ 3335-05-5 ]
[ 194726-40-4 ]

References: [1]European Journal of Organic Chemistry,2006,p. 4343 - 4347.

13
[ 194726-40-4 ]
[ 384830-08-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

14
[ 194726-40-4 ]
(2S,3R)-4-Oxo-3-(S)-1-piperidin-3-ylmethyl-azetidine-2-carboxylic acid benzyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

15
[ 194726-40-4 ]
(S)-3-((2S,3R)-2-Carboxy-4-oxo-azetidin-3-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

16
[ 194726-40-4 ]
[ 384830-09-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

17
[ 194726-40-4 ]
3-[1-(<i>tert</i>-butyl-dimethyl-silanyl)-2-carboxy-4-oxo-azetidin-3-ylmethyl]-piperidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

18
[ 194726-40-4 ]
[ 384830-10-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

19
[ 194726-40-4 ]
BMS-363130 [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

20
[ 194726-40-4 ]
[ 384830-11-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3235 - 3238.

21
[ 194726-40-4 ]
[ 254905-64-1 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

22
[ 194726-40-4 ]
[ 254905-67-4 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

23
[ 194726-40-4 ]
N,N-dimethyl-N-(((3R)-piperidin-3-yl)methyl)amine dihydrochloride [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

24
[ 194726-40-4 ]
[ 254905-66-3 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

25
[ 194726-40-4 ]
[ 254905-69-6 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

26
[ 194726-40-4 ]
[ 254905-68-5 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

27
[ 194726-40-4 ]
(2E)-5-amino-5-methylhex-2-enoic acid N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

28
[ 194726-40-4 ]
(2E)-4-(1-aminocyclobutyl)but-2-enoic acid N-((1R)-1-{N-[(1R)-1-benzyl-2-((3S)-3-(dimethylaminomethyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylamide [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

29
[ 194726-40-4 ]
[ 254905-70-9 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

30
[ 194726-40-4 ]
[ 254905-71-0 ]

References: [1]European Journal of Medicinal Chemistry,2002,vol. 37,p. 487 - 501.

31
ethyl N-Boc-(R)-nipecotate-L-tartrate [ No CAS ]
[ 24424-99-5 ]
[ 194726-40-4 ]
[ 163438-09-3 ]

Yield	Reaction Conditions	Operation in experiment
6.25 g (92%)	With hydrogenchloride; LiOH; triethylamine; In 1,4-dioxane; methanol; water; ethyl acetate;	EXAMPLE 23 Synthesis of N-Boc-(R)-Nipecotic Acid (25) A solution of ethyl N-Boc-(R)-nipecotate-L-tartrate (24) (10.00 g, 32.5 mol) in 50 mL of dioxane and 50 mL of H2O was cooled in ice-water bath and NEt3 (9 mL) was added with stirring. Stirring and cooling were continued while di-tert-butyl dicarbonate (7.44 g, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred for 4 h. 100 mL of Ethyl acetate and 20 mL of H2O were added to mixture. The aqueous layer was extracted with ethyl acetate (2100 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 250 mL), aqueous HCl (5%, 250 mL), brine (50 mL), and dried over anhydrous sodium sulfate, filtered and evaporated to give ethyl N-Boc-(R)-nipecotate as a colorless oil 8.37 g (100%). To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H2O dropwise at 4 C. The reaction mixture was stirred overnight at 4 C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10% w/w). The aqueous layer was extracted with ethyl acetate (3100 mL). The extracts were combined and washed with aqueous NH4Cl (sat., 2*50 mL), brine (50 mL), and dried over anhydrous Na2SO4, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).
6.25 g (92%)	With hydrogenchloride; LiOH; triethylamine; In 1,4-dioxane; methanol; water; ethyl acetate;	EXAMPLE 23 Synthesis of N-Boc-(R)-nipecotic acid (25) A solution of ethyl N-Boc-(R)-nipecotate-L-tartrate (24) (10.00 g, 32.5 mol) in 50 mL of dioxane and 50 mL of H2O was cooled in ice-water bath and NEt3 (9 mL) was added with stirring. Stirring and cooling were continued while di-tert-butyl dicarbonate (7.44 g, 1.05 eq.) was introduced. The mixture was warmed to room temperature and stirred for 4 h. 100 mL of Ethyl acetate and 20 mL of H2O were added to mixture. The aqueous layer was extracted with ethyl acetate (2100 mL). The extracts were combined and washed with aqueous potassium carbonate (sat., 250 mL), aqueous HCl (5%, 250 mL), brine (50 mL), and dried over anhydrous sodium sulfate, filtered and evaporated to give ethyl N-Boc-(R)-nipecotate as a colorless oil 8.37 g (100%). To a solution of ethyl N-Boc-(R)-nipecotate (7.61 g, 29.6 mmol) in 25 mL of methanol was added LiOH (2.48 g, 2 eq.) in 25 mL of H2O dropwise at 4 C. The reaction mixture was stirred overnight at 4 C. The pH of the mixture was adjusted to ca. 1 by adding aqueous HCl (10% w/w). The aqueous layer was extracted with ethyl acetate (3100 mL). The extracts were combined and washed with aqueous NH4Cl (sat., 2*50 mL), brine (50 mL), and dried over anhydrous NaSO4, filtered and evaporated to give N-Boc-(R)-nipecotic acid 25 as a white solid 6.25 g (92%).

References: [1]Patent: US6645980,2003,B1 .
[2]Patent: US2002/16337,2002,A1 .

32
[ 194726-40-4 ]
[ 163438-09-3 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 610 - 625.

33
[ 194726-40-4 ]
[ 1002359-83-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With hydrazine hydrate; at 120 - 125℃; for 5h;	(R)-N-Boc-ethyl-piperidine-3-carboxylate (1.1 kg, 4.28 mol) was liquefied by warming and transferred to a round bottom flask (10 L), to this was charged hydrazine hydrate (0.470 kg, 9.41 mol) and stirring was started. The reaction mixture was stirred at about 120C to 125C for 5 hours. As the TLC showed (Chloroform: methanol 9:1) completion of reaction, the reaction mixture was cooled to room temperature and diluted with water (5.5 L) followed by dichloromethane (11 L) and was stirred for 20 minutes. The layerswere separated and aqueous layer was extracted with additional dichloro methane (5.5 L). Combined organic layer was washed with water (2.75 L). The organic layer was dried over sodium sulfate and evaporated under vacuum to provide a thick gel which upon stirring and seeding in the presence of cyclohexane (5.5 L) provided white solid. The suspension was filtered and wet cake was washed with fresh cyclohexane (0.5 L). The cake was dried at 35C under vacuum to provide (R)-N-Boc-piperidine-3-carboxylic acid hydrazide as a white solid in 0.90 kg quantity in 87% yield. Analysis NMR: (CDC13): 7.42 (br s, 1H), 3.92 (d, 1H), 3.88 (s, 2H), 3.54-3.65 (br s, 1H), 3.17 (br t, 1H), 2.98 (br s, 1H), 2.22-2.32 (br s, 1H), 1.82-1.90 (br m, 2H), 1.76 (s, 1H), 1.60-1.70 (m, 1H), 1.45 (s, 9H). Mass (M+l): 244.1 for C11H21N303. Specific rotation: [ ]25D = -53.5 (c 0.5, Methanol). HPLC purity: 99%
87%	With hydrazine hydrate; at 120 - 125℃; for 5h;Large scale;	(R)-N-Boc-ethyl-piperidine-3-carboxylate (1.1 kg, 4.28 mol) was liquefied by warming and transferred to a round bottom flask (10 L), to this was charged hydrazine hydrate (0.470 kg, 9.41 mol) and stirring was started. The reaction mixture was stirred at about 120 C. to 125 C. for 5 hours. As the TLC showed (Chloroform:methanol 9:1) completion of reaction, the reaction mixture was cooled to room temperature and diluted with water (5.5 L) followed by dichloromethane (11 L) and was stirred for 20 minutes. The layers were separated and aqueous layer was extracted with additional dichloromethane (5.5 L). Combined organic layer was washed with water (2.75 L). The organic layer was dried over sodium sulfate and evaporated under vacuum to provide a thick gel which upon stirring and seeding in the presence of cyclohexane (5.5 L) provided white solid. The suspension was filtered and wet cake was washed with fresh cyclohexane (0.5 L). The cake was dried at 35 C. under vacuum to provide (R)-N-Boc-piperidine-3-carboxylic acid hydrazide as a white solid in 0.90 kg quantity in 87% yield. ;Analysis NMR: (CDCl3): 7.42 (br s, 1H), 3.92 (d, 1H), 3.88 (s, 2H), 3.54-3.65 (br s, 1H), 3.17 (br t, 1H), 2.98 (br s, 1H), 2.22-2.32 (br s, 1H), 1.82-1.90 (br m, 2H), 1.76 (s, 1H), 1.60-1.70 (m, 1H), 1.45 (s, 9H). Mass (M+1): 244.1 for C11H21N3O3
	With hydrazine; In methanol; at 100℃; for 3h;Microwave irradiation;	Stirred a solution of (R)-l-tert-butyl 3-ethyl piperidine-l,3-dicarboxylate (5 g,19.4 mmol), hydrazine (anhydrous; 2 ml) in MeOH (5 ml) in a microwave oven at 100C for 3 hours. Cooled and solvent was evaporated. Chromatographed residue on silica gel eluting with 3% MeOH: DCM to yield (R)-tert-butyl 3 -(hydrazinecarbonyl)piperidine-l -carboxylate as colorless oil (5.1 g).

References: [1]Patent: WO2014/135931,2014,A1 .Location in patent: Page/Page column 10; 11.
[2]Patent: US9657021,2017,B2 .Location in patent: Page/Page column 9.
[3]Patent: WO2012/58127,2012,A2 .Location in patent: Page/Page column 74-75.
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 4067 - 4086.

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[ 1374353-10-2 ]

References: [1]Patent: WO2012/58127,2012,A2 .

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[ 1374353-12-4 ]

References: [1]Patent: WO2012/58127,2012,A2 .

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[ 1374353-11-3 ]

References: [1]Patent: WO2012/58127,2012,A2 .

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[ 1374353-13-5 ]

References: [1]Patent: WO2012/58127,2012,A2 .

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[ 194726-40-4 ]
(R)-5-(5-(piperidin-3-yI)-1H-1,2,4-triazol-3-yl)-3-(pyridin-4-yl)-1H-indazole trifluoroacetate [ No CAS ]

References: [1]Patent: WO2012/58127,2012,A2 .

39
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[ 1374351-11-7 ]

References: [1]Patent: WO2012/58127,2012,A2 .

Historical Records

Technical Information

• Acyl Group Substitution • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • Ester Cleavage • Hydride Reductions • Lawesson's Reagent • Preparation of Amines • Reactions of Amines • Reactions with Organometallic Reagents • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Specialized Acylation Reagents-Ketenes

Related Functional Groups of
[ 194726-40-4 ]

Amides

A207234 [130250-54-3]

Ethyl 1-Boc-3-piperidinecarboxylate

Similarity: 1.00

A154626 [148763-41-1]

Methyl N-Boc-piperidine-3-carboxylate

Similarity: 0.98

A705857 [932035-01-3]

1-tert-Butyl 3-ethyl 4-aminopiperidine-1,3-dicarboxylate

Similarity: 0.97

A113602 [1357354-49-4]

2-tert-Butyl 9-ethyl 2,7-diazaspiro[4.4]nonane-2,9-dicarboxylate

Similarity: 0.95

A171976 [534602-47-6]

1-(tert-Butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid

Similarity: 0.95

Esters

A207234 [130250-54-3]

Ethyl 1-Boc-3-piperidinecarboxylate

Similarity: 1.00

A154626 [148763-41-1]

Methyl N-Boc-piperidine-3-carboxylate

Similarity: 0.98

A705857 [932035-01-3]

1-tert-Butyl 3-ethyl 4-aminopiperidine-1,3-dicarboxylate

Similarity: 0.97

A113602 [1357354-49-4]

2-tert-Butyl 9-ethyl 2,7-diazaspiro[4.4]nonane-2,9-dicarboxylate

Similarity: 0.95

A119165 [142851-03-4]

Ethyl N-Boc-piperidine-4-carboxylate

Similarity: 0.95

Related Parent Nucleus of
[ 194726-40-4 ]

Piperidines

A207234 [130250-54-3]

Ethyl 1-Boc-3-piperidinecarboxylate

Similarity: 1.00

A154626 [148763-41-1]

Methyl N-Boc-piperidine-3-carboxylate

Similarity: 0.98

A705857 [932035-01-3]

1-tert-Butyl 3-ethyl 4-aminopiperidine-1,3-dicarboxylate

Similarity: 0.97

A171976 [534602-47-6]

1-(tert-Butoxycarbonyl)-3-methylpiperidine-3-carboxylic acid

Similarity: 0.95

A273936 [88495-54-9]

(S)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid

Similarity: 0.95

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CAS No.: 194726-40-4

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