[ CAS No. 88495-54-9 ] {[proInfo.proName]}

Name: 88495-54-9|(S)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid|97%
Brand: Ambeed
SKU: A273936
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Quality Control of [ 88495-54-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 88495-54-9 ]

SDS Specification

Alternatived Products of [ 88495-54-9 ]

Product Details of [ 88495-54-9 ]

CAS No. :	88495-54-9	MDL No. :	MFCD02179172
Formula :	C₁₁H₁₉NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NXILIHONWRXHFA-QMMMGPOBSA-N
M.W :	229.27	Pubchem ID :	6951168
Synonyms :		Chemical Name :	(S)-1-(tert-Butoxycarbonyl)piperidine-3-carboxylic acid

Calculated chemistry of [ 88495-54-9 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	63.17
TPSA :	66.84 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) :	-6.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.82
Log Po/w (XLOGP3) :	1.13
Log Po/w (WLOGP) :	1.34
Log Po/w (MLOGP) :	1.03
Log Po/w (SILICOS-IT) :	0.5
Consensus Log Po/w :	1.16

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.71
Solubility :	4.48 mg/ml ; 0.0195 mol/l
Class :	Very soluble
Log S (Ali) :	-2.13
Solubility :	1.71 mg/ml ; 0.00746 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.66
Solubility :	50.7 mg/ml ; 0.221 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.73

Safety of [ 88495-54-9 ]

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

Application In Synthesis of [ 88495-54-9 ]

* 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 [ 88495-54-9 ]
Downstream synthetic route of [ 88495-54-9 ]

[ 88495-54-9 ] Synthesis Path-Upstream 1~4

1
[ 86447-11-2 ]
[ 88495-54-9 ]
[ 163438-09-3 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 23, p. 6072 - 6075[2] Angew. Chem., 2013, vol. 125, # 23, p. 6188 - 6191

2
[ 88495-54-9 ]
[ 851956-01-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogenchloride In 1,4-dioxane; dichloromethane at 20℃; for 2 h;	Example 129 (3S)-N-1-Adamantyl-1-phenylpiperidine-3-carboxamide Step 1. (3S)-Piperidine-3-carboxylic acid hydrochloride A mixture of (3S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (4.0 g, 0.017 mol) in methylene chloride (10 mL, 0.2 mol) and 4.0 M of hydrogen chloride in 1,4-dioxane (30 mL) was stirred at rt for 2 hours. The volatiles were removed in vacuo to afford the desired product in quantitative yield. The crude product was used in the following step without further purification. LCMS: m/z 166.2 (M+H)+.
14.4 kg	With hydrogenchloride In acetic acid at 15℃; for 4 h; Large scale	(S)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (20 kg, 87.2 mol) was slurried in acetic acid (189 kg) and cooled to 15° C. An excess of hydrogen chloride gas (9.6 kg) was charged and stirred for ˜4 hours to complete deprotection. The slurry was isolated and filter-cake rinsed with acetic acid (2*31.5 kg). The filter cake was then vacuum dried to obtain product (14.4 kg).

Reference： [1] Patent: US2006/4049, 2006, A1, . Location in patent: Page/Page column 49
[2] Patent: WO2012/131379, 2012, A1, . Location in patent: Page/Page column 25
[3] Patent: US2014/206703, 2014, A1, . Location in patent: Paragraph 0106; 0107

3
[ 88495-54-9 ]
[ 858643-92-2 ]

Reference： [1] Patent: WO2011/117254, 2011, A1,

4
[ 88495-54-9 ]
[ 1235439-55-0 ]

Reference： [1] Patent: WO2011/117254, 2011, A1,

[ 88495-54-9 ] Synthesis Path-Downstream 1~22

1
[ 88495-54-9 ]
[ 37675-18-6 ]
[ 253790-54-4 ]

Reference： [1]Helvetica Chimica Acta,1999,vol. 82,p. 1539 - 1558

2
[ 164323-85-7 ]
[ 88495-54-9 ]
Boc-(S)-Nip-(R)-Nip-OCH₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 20℃; for 40h;

Reference： [1]Chung, Yong Jun; Huck, Bayard R.; Christianson, Laurie A.; Stanger, Heather E.; Krauthaeuser, Susanne; Powell, Douglas R.; Gellman, Samuel H. [Journal of the American Chemical Society, 2000, vol. 122, # 17, p. 3995 - 4004]

3
[ 276248-50-1 ]
[ 88495-54-9 ]
Boc-(S)-Nip-(S)-Nip-OCH₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine In N,N-dimethyl-formamide at 20℃; for 40h;

4
[ 24424-99-5 ]
[ 88466-74-4 ]
[ 88495-54-9 ]

Reference： [1]Helvetica Chimica Acta,2005,vol. 88,p. 2235 - 2249

5
[ 37675-18-6 ]
[ 88495-54-9 ]

Reference： [1]Helvetica Chimica Acta,1999,vol. 82,p. 1539 - 1558

6
[ 459-59-6 ]
[ 88495-54-9 ]
[ 851882-98-9 ]

Yield	Reaction Conditions	Operation in experiment
47%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In 1,4-dioxane at 20 - 80℃; for 51h;	63(A) Example 63 (S)-1- (4-Fluoro-benzoyl)-piperidine-3-carboxylic acid (4-fluoro-phenyl)-methyl- amide; 63 (A) (S)-3- [ (4-Fluoro-phenyl)-methyl-carbamoyl]-piperidine-l-carboxylic acid tert-butyl ester A mixture of S-1-Boc-piperidine-3-carboxylic acid (0.3 g, 1.30 mmol), EDCI. HC1 (0.376 g, 1.96 mmol), HOBT (0. 198 g, 1.30 mmol) in dioxane (4 mL) was stirred at R. T. for lh, under nitrogen atmosphere. N-Methyl-4-fluoro-aniline (164 mg, 1.30 mmol) was then added and the reaction mixture was heated at 80°C for 2h and then kept under stirring at room temperature for 2 days. The solvent was evaporated under reduced pressure and the residue was diluted with water and ethyl acetate. The phases were separated, the organic layer was washed with Na2C03 2M (aq. ), dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by filtration through a silica gel cartridge (silica gel: 10 g, eluent gradient: from petroleum ether/ethyl acetate 9/1 to petroleum ether/ethyl acetate 7/3) to provide 0.209 g of (S)-3- [ (4-Fluoro-phenyl)-methyl-carbarnoyl]-piperidine-l- carboxylic acid tert-butyl ester. Yield: 47%; LCMS (Tr): 7.0 min (Method A); MS (ES+) gave m/z: 337.2. 'H-NMR (CDC13, 300 MHz), 8 (ppm): 7.22-7. 07 (m, 4H); 4.00 (m, 2H); 3.22 (s, 3H); 2.89 dd, 1H) ; 2.63 (m, 1H) ; 2.27 (m, 1H) ; 1.78-1. 65 (m, 2H); 1.61-1. 50 (m, 2H); 1.40 (s, 9H).

Reference： [1]Current Patent Assignee: ADDEX THERAPEUTICS SA - WO2005/44797, 2005, A1 Location in patent: Page/Page column 95

7
[ 883022-90-0 ]
[ 88495-54-9 ]
[ 851882-70-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 18h; Heating / reflux;	49(A) Example 49 (S)-3- [3- (2, 4-Difluoro-phenyl)- [ 1, 2,4] oxadiazol-5-yl]-piperidin-1-yl}- (4-fluoro- phenyl)-methanone 49 (A) S-3- [3- (2, 4-Difluoro-phenyl) - [1, 2,4] oxadiazol-5-yl]-piperidine-l- carboxylic acid tert-butyl ester To a mixture of 2, 4-difluorobenzonitrile (1.39 g, 10 mmol) and DIEA (5.13 ml, 30 mmol) in EtOH (15 ml) was added 2.12 g of hydroxylamine hydrochloride (30 mmol) and the reaction was heated at 70 °C for 48h. Half of the solvent was removed under reduced pressure. The mixture was poured in DCM (100ml) and water (30ml). 2. 5ml of NaOH 1N was added until pH = 9-10. The organic layer was separated and the aqueous phase was extracted with DCM. The organic layers were combined, washed with water, dried over MgS04, filtered and evaporated under reduced pressure to afford N-hydroxy-2,4-difluoro-benzamidine which was used without further purification for the next step. A mixture of N-hydroxy-2, 4-difluoro-benzamidine (10 mmol), S-1-Boc-piperidine-3- carboxylic acid (2.3 g, 10 mmol), EDCI. HC1 (2.87 g, 15 mmol), HOBT (1.35 g, 10 mmol) and DIEA (3.4 mL, 20 mmol) in dioxane (10 mL) was stirred overnight at room temperature, under nitrogen atmosphere. Then, the reaction mixture was refluxed for 18h and the solvent was evaporated under reduced pressure. The residue was diluted with water (50 mL) and ethyl acetate (50 mL), the phases were separated and the organic layer was washed sequentially with water (50 mL x 2 times) and with NaOH IN (50 mL x 2 times). The organic layer was dried over Na2S04 and concentrated under reduced pressure. Purification of the crude by flash chromatography (silica gel, eluent: DCM/hexane/MeOH 50/50/0.2) gave 2.4 g of S-3- [3- (2, 4-difluoro-phenyl)- [1, 2,4] oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester. Yield: 66%; LCMS (Tr): 7.93 min (Method A); MS (ES+) gave m/z: 366.2. 'H-NMR (CDCl3, 333K, 300 MHz), 8 (ppm): 8. 05 (m, 1H); 6. 98 (m, 2H); 4.27 (d br, 1H) ; 3.92 (m, 1H); 3.31 (dd, 1H) ; 3.17 (tt, 1H); 3.03 (ddd, 1H) ; 2.25 (m, 1H); 1.95- 1.78 (m, 2H); 1.77-1. 53 (m, 1H) ; 1.46 (s, 9H).

Reference： [1]Current Patent Assignee: ADDEX THERAPEUTICS SA - WO2005/44797, 2005, A1 Location in patent: Page/Page column 80-81

8
[ 88495-54-9 ]
[ 88466-77-7 ]

Yield	Reaction Conditions	Operation in experiment
100%		Triethylamine (1.2ImL, 8.72 mmol) and then ethyl chloroformate (0.8 mL, 8.30 mmol) were added dropwise at 00C to a solution of (S)-l-Boc-piperidine-3- carboxylic acid (2 g, 8.72 mmol) in chloroform (40 mL), under nitrogen atmosphere. After stirring 10 min at 0C, NH3 (gas) was bubbled into the solution for Ih. The reaction mixture was then stirred at room temperature for 3h, 5% NaHCO3 (aq) was added and the phases were separated. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound, which was used for the next step without further purification.Yield: quantitative; LCMS (RT): 3.31 min (Method A); MS (ES+) gave m/z: 229.0 (MH+).
		Triethylamine (1.2ImL5 8.72 mmol) and then ethyl chloroformate (0.8 mL, 8.30 mmol) were added dropwise at 0C to a solution of (S)-l-Boc-piperidine-3- carboxylic acid (2 g, 8.72 mmol) in chloroform (40 mL), under nitrogen atmosphere. After stirring 10 min at O0C, NH3 (gas) was bubbled into the solution for Ih. The reaction mixture was then stirred at room temperature for 3h, 5% NaHCO3 (aq) was added and the phases were separated. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford the title compound, which was used for the next step without further purification. Yield: quantitative; LCMS (RT): 3.31 min (Method A); MS (ES+) gave m/z: 229.0.

Reference： [1]Patent: WO2006/123257,2006,A2 .Location in patent: Page/Page column 37; 50
[2]Patent: WO2006/129199,2006,A1 .Location in patent: Page/Page column 46

9
[ 88495-54-9 ]
[ 74-88-4 ]
[ 88466-76-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;	118.1 To a solution of 1-(tert-butoxycarbonylpiperidine)-(3S)-carboxylic acid (2.75 g) in DMF (20 mL), potassium carbonate (2.49 g) and methyl iodide (1.12 mL) were added at room temperature, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and to the resultant residue, water (15.0 mL) and ethyl acetate (20 mL) were added for phase separation. The aqueous layer was extracted with ethyl acetate (3 × 10.0 mL), and the extracts were combined and dried with sodium sulfate anhydrate. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage 40M), whereby the title compound (2.88 g) was yielded. 1H-NMR (CDCl3) δ: 1.46(9H,s),1.56-1.74(3H,m),2.00-2.08(1H,m),2.45(1H,tdd,J=10.2,3.9,3.9Hz),2.81(1H,ddd,J=11.5,3 .2,13.7Hz),2.88-3.10(1H,br m),3.69(3H,s),3.91(1H,d,J=13.7Hz),4.29-4.00(1H,br m).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP2017263, 2009, A1 Location in patent: Page/Page column 301

10
[ 88495-54-9 ]
[ 858643-92-2 ]

Reference： [1]Patent: WO2011/117254,2011,A1

11
[ 88495-54-9 ]
[ 1235439-55-0 ]

Reference： [1]Patent: WO2011/117254,2011,A1

12
[ 300-08-3 ]
[ 88495-54-9 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 6072 - 6075
Angew. Chem.,2013,vol. 125,p. 6188 - 6191

13
[ 86447-11-2 ]
[ 88495-54-9 ]
[ 163438-09-3 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 6072 - 6075
Angew. Chem.,2013,vol. 125,p. 6188 - 6191

14
[ 67-56-1 ]
[ 88495-54-9 ]
[ 276248-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	With methanesulfonic acid at 25℃; for 16h;	C.6 Production of (S)-nipecotic acid Comparative Example 6 Production of (S)-nipecotic acid Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)-N-(tert-butoxycarbonyl)nipecotic acid (1145 mg, 5 mmol) and methanol (5 mL). When the mixture was stirred at 25° C. for 16 hours, (S)-methyl nipecotate was produced, and the object (S)-nipecotic acid was not produced.

Reference： [1]Current Patent Assignee: KANEKA CORPORATION - US2014/343289, 2014, A1 Location in patent: Paragraph 0056

15
[ 452-69-7 ]
[ 88495-54-9 ]
(S)-tert-butyl 3-((4-fluoro-3-methylphenyl)carbamoyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0℃; for 2h;	A mixture of (S)-l-boc-piperidine-3-carboxylic acid CAS [88495-54-9 ] (9 g, 39.3 mmol), 4-fluoro-3-methylaniline (4.91 g, 39.3 mmol), and CH2CI2 (90 mL) was cooled to 0 C followed by the addition of diisopropylethylamine (20.5 mL, 117.8 mmol) and HATU (17.9 g, 47.1 mmol). The reaction mixture stirred at 0 C for 2 hours followed by the addition of citric acid (sat., aq., 100 mL), NaHC03 (sat., aq., 100 mL), and brine. The organic layer was dried over Na2S04, the solids were removed by filtration and the solvents were removed under reduced pressure. The crude was purified using a petroleum ether/ ethyl acetate gradient (from 100/1 to 3/1). The best fractions were pooled and the solvent was removed under reduced pressure. 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 1.26 - 1.37 (m, 1 H), 1.39 (s, 9 H), 1.59 (qd, J=12.1, 3.4 Hz, 1 H), 1.69 (d, J=13.2 Hz, 1 H), 1.91 (d, J=12.6 Hz, 1 H), 2.19 (d, J=1.8 Hz, 3 H), 2.40 (tt, J=l 1.0, 3.7 Hz, 1 H), 2.75 (t, J=11.7 Hz, 1 H), 2.97 (br. s., 1 H), 3.86 (d, J=13.1 Hz, 1 H), 4.03 (br. s., 1 H), 7.05 (t, J=9.3 Hz, 1 H), 7.31 - 7.42 (m, 1 H), 7.51 (dd, J=7.0, 2.3 Hz, 1 H), 9.97 (s, 1 H) Subsequent deprotection of the boc group was possible via addition of CH2CI2 (100 mL) and HC1 (100 mL, in dioxane) at room temperature for 24 hours to afford the (S)-N-(4- fluoro-3-methylphenyl)piperidine-3-carboxamide hydrochloride intermediate. 1H NMR (400 MHz, CHLOROFORM-^) delta ppm 1.49 - 1.87 (m, 3 H), 1.95 - 2.08 (m, 1 H), 2.19 (d, J=2.0 Hz, 3 H), 2.80 - 2.93 (m, 2 H), 3.00 (q, J=10.4 Hz, 1 H), 3.17 (d, J=12.0 Hz, 1 H), 3.29 (d, J=11.0 Hz, 1 H), 7.07 (t, J=9.2 Hz, 1 H), 7.35 - 7.45 (m, 1 H), 7.52 (dd, J=7.0, 2.3 Hz, 1 H), 8.90 (d, J=11.2 Hz, 1 H), 9.12 (m, J=9.5 Hz, 1 H), 10.31 (s, 1 H)

Reference： [1]Patent: WO2015/59212,2015,A1 .Location in patent: Page/Page column 27; 28

16
[ 88495-54-9 ]
[ 915226-39-0 ]

Reference： [1]Patent: WO2006/123257,2006,A2
[2]Patent: WO2006/129199,2006,A1

17
[ 88495-54-9 ]
[ 1008563-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-methylcyclohexylamine; chloroformic acid ethyl ester / dichloromethane / 4.25 h / -78 - 20 °C 2: tetrahydrofuran; diethyl ether / 0.5 h / 0 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/23258, 2008, A1

18
[ 17083-23-7 ]
[ 88495-54-9 ]
Boc-L-Pic⁽³⁾-L-Tyr(t-Bu)-O-t-Bu [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 18926 - 18931

19
[ 2106-04-9 ]
[ 88495-54-9 ]
C₁₂H₁₄ClFN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 3-chloro-2-fluoroaniline; (3S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 13h; Inert atmosphere; Stage #2: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 22h; Inert atmosphere;	162 Example 162: Synthesis of Intermediate 2.124 To a precooled (0 °C) solution of intermediate 2.38 (150. mg, 0.654 mmol), N,N’-dicyclohexylcarbodiimide (202 mg, 0.981 mmol) and 4-dimethylaminopyridine (24 mg, 0.20 mmol) in CH2Cl2 (5 mL) under N2 atmosphere was added 3-chloro-2-fluoroaniline (0.1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 13 h, then concentrated in vacuo. The crude residue was diluted with ether and filtered. The filtrate was washed sequentially with sat. aq. NH4Cl, sat. aq. NaHCO3, and brine, dried over Na2SO4, and concentrated in vacuo to afford the product. (0567) [00185] To a precooled (0 °C) solution of intermediate (136 mg, 0.381 mmol) in CH2Cl2 (1.9 mL) under N2 atmosphere was added dropwise trifluoroacetic acid (0.15 mL, 1.9 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 22 h, then concentrated in vacuo. The crude residue was taken up in CH2Cl2 and diluted with H2O. The layers were separated, and the organic phase was extracted with H2O (3x). The combined aqueous layers were cooled to 0 °C and neutralized with powdered NaHCO3. The aqueous phase was extracted with CH2Cl2 (3x), dried over Na2SO4, and concentrated in vacuo to afford the desired product as a clear colorless oil (83 mg, 85% yield). [ a]D23 -0.72 (c.0.12, CH3OH); 1H NMR (500 MHz, Chloroform-d) d 9.68 (s, 1H), 8.80 (s, 1H), 8.20 (s, 1H), 8.00 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.05 (t, J = 8.3 Hz, 1H), 3.52 (d, J = 12.2 Hz, 1H), 3.34 (s, 1H), 3.27 (s, 1H), 3.08 (s, 2H), 2.14 (s, 1H), 1.97 (d, J = 40.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) d 174.31, 149.59, 147.64, 128.28, 128.20, 124.50, 124.46, 124.16, 120.41, 120.28, 120.11, 77.00, 47.79, 46.46, 41.87, 27.47, 22.34; IR (ATR) vmax 3025, 2924, 2850, 2809, 1668, 1606, 1542, 1457, 1102, 782, 653, 485 cm-1; AMM 257.0869 (ESI) m/z [calc for C12H15ClFN2O (M+H)+ 257.0857].

Reference： [1]Current Patent Assignee: UNIVERSITY OF PENNSYLVANIA; VAL-CHUM LIMITED PARTNERSHIP - WO2020/28482, 2020, A1 Location in patent: Paragraph 00184-00185

20
[ 21397-08-0 ]
[ 88495-54-9 ]
C₁₂H₁₄ClFN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%		To a precooled (0 C) solution of intermediate 2.38 (200. mg, 0.872 mmol), N,N?-dicyclohexylcarbodiimide (270 mg, 1.31 mmol) and 4-dimethylaminopyridine (32 mg, 0.26 mmol) in CH2Cl2 (7 mL) under N2 atmosphere was added <strong>[21397-08-0]2-chloro-3-fluoroaniline</strong> (0.1 mL). The resulting mixture was allowed to warm to room temperature and stirred for 25 h, then concentrated in vacuo. The crude residue was diluted with ether and filtered. The filtrate was washed sequentially with sat. aq. NH4Cl, sat. aq. NaHCO3, and brine, dried over Na2SO4, and concentrated in vacuo to afford the product which was carried forward. (0579) [00190] To a precooled (0 C) solution of intermediate (97 mg, 0.27 mmol) in CH2Cl2 (1.4 mL) under N2 atmosphere was added dropwise trifluoroacetic acid (0.1 mL, 1 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 32 h, then concentrated in vacuo. The crude residue was taken up in CH2Cl2 and diluted with H2O. The layers were separated, and the organic phase was extracted with H2O (3x). The combined aqueous layers were cooled to 0 C and neutralized with powdered NaHCO3. The aqueous phase was extracted with CH2Cl2 (3x), dried over Na2SO4, and concentrated in vacuo to afford the desired product as a clear colorless oil (33 mg, 47% yield, 2 steps). [ a]D23 +0.95 (c. 0.078, CH3OH); 1H NMR (500 MHz, Chloroform-d) d 11.21 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.21 (td, J = 8.3, 6.1 Hz, 1H), 6.87 (td, J = 8.6, 1.4 Hz, 1H), 3.35- 3.23 (m, 1H), 3.11 (dt, J = 11.4, 3.9 Hz, 1H), 2.93 (dd, J = 11.9, 3.1 Hz, 1H), 2.75 (td, J = 11.1, 3.0 Hz, 1H), 2.61 (dq, J = 6.6, 3.5 Hz, 1H), 2.17 (s, 1H), 2.05 (dd, J = 13.5, 3.9 Hz, 1H), 1.93- 1.70 (m, 2H), 1.57 (dp, J = 10.6, 3.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) d 174.52, 159.36, 157.40, 137.59, 127.81, 127.74, 117.40, 117.37, 110.99, 110.82, 47.89, 46.63, 42.30, 29.82, 27.71, 22.58; IR (ATR) vmax 2937, 2859, 1668, 1590, 1538, 1470, 1434, 1251, 1199, 777, 642 cm-1; AMM (ESI) m/z 257.0869 [calc for C12H15ClFN2O (M+H)+ 257.0857].

Reference： [1]Patent: WO2020/28482,2020,A1 .Location in patent: Paragraph 00189-00190

21
[ 88495-54-9 ]
[ 169280-56-2 ]
tert-butyl (S)-3-(((2S,3R)-4-(4-amino-N-isobutylphenylsulfonamido)-3-hydroxy-1-phenylbutan-2-yl)carbamoyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.4%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 8h; Inert atmosphere;	4.1.15. (R)-N-((2S, 3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl)-1-methylpiperidine-3-carboxamide (3m) General procedure: To a stirred solution of 10e (18.0 mg, 0.10 mmol) and 7a(44.7 mg, 0.11 mmol) in anhydrous DMF (1 mL) was added EDCI(28.8 mg, 0.15 mmol), HOBt (14.9 mg, 0.11 mmol) and DMAP (2.40 mg, 0.02 mmol) at 0 C under argon atmosphere. The reactionmixture was warmed to 25 C and stirred for 8 h. After this period,the reaction was diluted with 5 mL ethyl acetate, washed with H2Oand saturated aqueous NaCl and dried over anhydrous Na2SO4, andthen concentrated under reduced pressure. The crude product waspurified by silica gel column chromatography to furnish 3m as ayellow powder: yield 30.2 mg (56.8%);

Reference： [1]Zhu, Mei; Zhou, Huiyu; Ma, Ling; Dong, Biao; Zhou, Jinming; Zhang, Guoning; Wang, Minghua; Wang, Juxian; Cen, Shan; Wang, Yucheng [European Journal of Medicinal Chemistry, 2021, vol. 220]

22
[ 1232149-37-9 ]
[ 88495-54-9 ]
tert-butyl (S)-3-((4-amino-7-bromoquinolin-3-yl)carbamoyl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2021/142203,2021,A1 .Location in patent: Page/Page column 52; 54-55

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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 88495-54-9 ] {[proInfo.proName]}

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[ 88495-54-9 ] Synthesis Path-Upstream 1~4

[ 88495-54-9 ] Synthesis Path-Downstream 1~22

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Amides

Carboxylic Acids

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Aliphatic Heterocycles

Piperidines

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[ 88495-54-9 ]

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[ 88495-54-9 ]