[ CAS No. 183673-71-4 ] {[proInfo.proName]}

Name: 183673-71-4|4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid|97%
Brand: Ambeed
SKU: A319862
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Quality Control of [ 183673-71-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 183673-71-4 ]

Product Details of [ 183673-71-4 ]

CAS No. :	183673-71-4	MDL No. :	MFCD01318728
Formula :	C₁₁H₂₀N₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YNHLVALLAURVJF-UHFFFAOYSA-N
M.W :	244.29	Pubchem ID :	693797
Synonyms :	1-Boc-4-Aminopiperidine-4-carboxylic acid	Chemical Name :	4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid

Calculated chemistry of [ 183673-71-4 ]

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	65.92
TPSA :	92.86 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-9.33 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.93
Log Po/w (XLOGP3) :	-2.17
Log Po/w (WLOGP) :	0.42
Log Po/w (MLOGP) :	-2.0
Log Po/w (SILICOS-IT) :	-0.21
Consensus Log Po/w :	-0.41

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	0.28
Solubility :	462.0 mg/ml ; 1.89 mol/l
Class :	Highly soluble
Log S (Ali) :	0.75
Solubility :	1380.0 mg/ml ; 5.63 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.51
Solubility :	74.8 mg/ml ; 0.306 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.28

Safety of [ 183673-71-4 ]

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 [ 183673-71-4 ]

* 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 [ 183673-71-4 ]
Downstream synthetic route of [ 183673-71-4 ]

[ 183673-71-4 ] Synthesis Path-Upstream 1~14

1
[ 183673-68-9 ]
[ 183673-71-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2448 - 2451
[2] Organic Syntheses, 2005, vol. 81, p. 213 - 224
[3] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651
[4] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2519 - 2522

2
[ 321997-89-1 ]
[ 183673-71-4 ]

Reference： [1] Patent: WO2015/150337, 2015, A1, . Location in patent: Page/Page column 36

3
[ 24424-99-5 ]
[ 183673-71-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2448 - 2451
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2519 - 2522
[3] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651

4
[ 13625-39-3 ]
[ 183673-71-4 ]

5
[ 40064-34-4 ]
[ 183673-71-4 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651
[2] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651

6
[ 79099-07-3 ]
[ 183673-71-4 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651

7
[ 183673-70-3 ]
[ 183673-71-4 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651

8
[ 41979-39-9 ]
[ 183673-71-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2448 - 2451

9
[ 73390-11-1 ]
[ 183673-71-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 18, p. 2519 - 2522

10
[ 28920-43-6 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium carbonate In tetrahydrofuran at 0 - 25℃; for 12 h;	4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(tert- butoxycarbonyl)piperidine-4-carboxylic acid (Scheme 1, compound 8) [0225] A solution of 4-amino-1 -(terf-butoxycarbonyl)piperidine-4- carboxylic acid (5 g, 20.5 mmol) in THF (300 mL) and Na₂CO₃ (6.45 g, 61 .5 mmol, 3.0 eq in 64.5 mL of water) was cooled to 0°C before the dropwise addition of a solution of Fmoc chloride (5.3 g, 30.7 mmol, 1 .5 eq) in THF (30 mL). The resulting mixture was slowly warmed to 25°C and stirred for an additional 12 hours. Upon completion, the reaction contents were carefully acidified with HCI (1 M), and the crude material was extracted with EtOAc (three times). The combined organic layers were dried (Na₂SO₄), concentrated, and the crude material was purified by combiflash 0 to 10percent MeOH in DCM to provide 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1 -(te/t- butoxycarbonyl)piperidine-4-carboxylic acid (Scheme 1 , compound 8) (4.02 g, 42percent yield). [0226] ¹ H NMR (400 MHz, Ch lore-form -c/) δ 7.75 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.5 Hz, 2H), 7.45-7.34 (m, 2H), 7.30 (td, J = 6.9, 6.3, 1 .4 Hz, 2H), 4.68-4.26 (m, 2H), 4.19 (t, J = 6.5 Hz, 1 H), 3.96-3.65 (m, 3H), 3.08 (s, 2H), 1 .91 -1 .77 (m, 2H), 1 .48 (s, 9H). ¹³C NMR (101 MHz, CDCI₃) 177.19, 154.73, 143.67, 141 .32, 127.72, 127.08, 124.95, 1 19.97, 80.06, 67.90, 66.86, 57.49, 47.19, 31 .98, 28.42, 25.57. HRMS (m/z): [M+] cald for C26H30N2O6, 466.53, found 466.2

Reference： [1] Organic Syntheses, 2005, vol. 81, p. 213 - 224
[2] Patent: WO2015/184349, 2015, A2, . Location in patent: Paragraph 0225-0226

11
[ 82911-69-1 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 18, p. 5694 - 5706

12
[ 102774-86-7 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

Reference： [1] Journal of Organic Chemistry, 1996, vol. 61, # 22, p. 7650 - 7651

13
[ 13139-17-8 ]
[ 183673-71-4 ]
[ 288154-16-5 ]

Reference： [1] Patent: US2004/38998, 2004, A1,
[2] Patent: US2004/53928, 2004, A1,

14
[ 501-53-1 ]
[ 183673-71-4 ]
[ 288154-16-5 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 9, p. 2448 - 2451

[ 183673-71-4 ] Synthesis Path-Downstream 1~85

1
[ 102774-86-7 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651

2
[ 183673-68-9 ]
[ 183673-71-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451
[2]Organic Syntheses,2005,vol. 81,p. 213 - 224
[3]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651
[4]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

3
[ 183673-71-4 ]
[ 2937-50-0 ]
[ 495414-58-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

4
[ 67-56-1 ]
[ 183673-71-4 ]
[ 590-86-3 ]
[ 630132-95-5 ]

Reference： [1]Organic Letters,2005,vol. 7,p. 5521 - 5524

5
[ 188440-21-3 ]
[ 183673-71-4 ]
[ 1026484-91-2 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 550 - 565

6
[ 183673-71-4 ]
[ 18908-07-1 ]
4-[3-(3-methoxy-phenyl)-ureido]-piperidine-1,4-dicarboxylic acid mono-<i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2171 - 2178

7
[ 501-53-1 ]
[ 183673-71-4 ]
[ 288154-16-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451

8
[ 24424-99-5 ]
[ 183673-71-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522
[3]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651

9
[ 41979-39-9 ]
[ 183673-71-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451

10
[ 13625-39-3 ]
[ 183673-71-4 ]

11
[ 183673-71-4 ]
C₃₂H₃₄N₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451

12
[ 183673-71-4 ]
[ 940290-02-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451

13
[ 183673-71-4 ]
[ 940290-03-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451

14
[ 183673-71-4 ]
[ 940290-04-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2448 - 2451

15
[ 183673-71-4 ]
[ 937806-34-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2171 - 2178

16
[ 183673-71-4 ]
4'-[3-(3-methoxy-phenyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-8-ylmethyl]-biphenyl-3-carbonitrile [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 2171 - 2178

17
[ 183673-71-4 ]
[ 630131-43-0 ]

Reference： [1]Organic Letters,2005,vol. 7,p. 5521 - 5524

18
[ 73390-11-1 ]
[ 183673-71-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

19
[ 183673-71-4 ]
3-(3,5-bis-trifluoromethyl-phenyl)-8-(naphthalene-1-carbonyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

20
[ 183673-71-4 ]
3-(3,5-bis-trifluoromethyl-benzyl)-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid <i>m</i>-tolylamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

21
[ 183673-71-4 ]
3-(3,5-bis-trifluoromethyl-phenyl)-8-(2,4,6-trimethyl-benzoyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

22
[ 183673-71-4 ]
3-biphenyl-3-ylmethyl-8-(3,5-bis-trifluoromethyl-benzoyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

23
[ 183673-71-4 ]
3-(3,5-bis-trifluoromethyl-benzyl)-8-(2-naphthalen-1-yl-ethanesulfonyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2519 - 2522

24
[ 79099-07-3 ]
[ 183673-71-4 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651

25
[ 40064-34-4 ]
[ 183673-71-4 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651
[2]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651

26
[ 183673-70-3 ]
[ 183673-71-4 ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 7650 - 7651

27
[ 183673-71-4 ]
[ 590-86-3 ]
[ 630132-94-4 ]

Yield	Reaction Conditions	Operation in experiment
83%		A slurry of 1-tert-butyl 4-amino-piperidine-1, 4-dicarboxylate (0.489 g, 2.00 mmol) in anhydrous methanol (10.0 mL) was treated with isovaleraldehyde (0.215 mL, 2.00 mmol). After stirring 3 h at ambient temperature, sodium cyanoborohydride (0.088 g, 1.40 mmol) was added. After stirring 3 d at ambient temperature, the title compound was collected by filtration as a white solid (0.523 g, 83percent). MS (ES+) [M/E] 315 [M+H] +.

Reference： [1]Patent: WO2003/99801,2003,A1 .Location in patent: Page 47

28
[ 186581-53-3 ]
[ 183673-71-4 ]
[ 321997-89-1 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; dichloromethane; at 20℃; for 0.5h;	Intermediate 65: Methyl 1-BOC-4-amino-4-piperidinecarboxylate To a solution of l-BOC-4-amino-4-piperidinecarboxylic acid (2.00 g, 8.2 mol) in MeOH (300 mL) and DCM (300 mL) was added diazomethane slowly until the reaction solution became to pale yellow. The reaction mixture was stirred at room temperature for additional 30 min. and concentrated in vacuo to give the title compound. MS [M+H] = 393 (M+1)

Reference： [1]Patent: WO2005/47253,2005,A1 .Location in patent: Page/Page column 49

29
[ 183673-71-4 ]
[ 18107-18-1 ]
[ 321997-89-1 ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine; In methanol; hexane; acetonitrile;	(a) Methyl 4-amino-1-tert-butoxycarbonylpiperidine-4-carboxylate 4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylate (5g) in acetonitrile (22ml) and methanol (2ml) was treated with di-isopropylethylamine (3.65ml) and trimethylsilyldiazomethane (2M in hexane, 13.9ml). After overnight stirring and evaporation of solvent, the crude product was chromatographed on silica gel (0-50% ethyl acetate/petrol) to give a yellow oil (4g, 76%). MS (+ve ion electrospray) m/z 259 (MH+).

Reference： [1]Patent: EP1214314,2005,B1 .Location in patent: Page/Page column 17

30
[ 541-41-3 ]
[ 183673-71-4 ]
[ 392331-43-0 ]

Yield	Reaction Conditions	Operation in experiment
48%	With pyridine; sodium hydroxide; In ethanol; dichloromethane;	92b) 1-(tert-Butoxycarbonyl)-4-(ethoxycarbonylamino)-4-piperidinecarboxylic Acid Ethyl chlorocarbonate (0.95 ml) was added dropwise to a solution of <strong>[183673-71-4]4-amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid</strong> (0.98 g) obtained in Example 92a) and pyridine (0.8 g) in methylene chloride (50 ml) at -30° C., and the mixture was stirred further at room temperature for 5 hours. The reaction mixture was concentrated, the residue was diluted with water, adjusted to pH 3 with an aqueous potassium hydrogensulfate, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column to obtain colorless oil (0.9 g). A 1 N aqueous sodium hydroxide solution (6 ml) was added to a solution of the resulting oil in ethanol (5 ml), the mixture was stirred at room temperature for 18 hours, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, the mixture was adjusted to pH 3 with an aqueous potassium hydrogensulfate solution, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound (0.61 g, 48percent). NMR (CDCl3) delta: 1.25 (3H, t, J=7.1), 1.46 (9H, s), 1.90-2.20 (4H, m), 3.00-3.22 (2H, m), 3.76-3.98 (2H, m), 4.13 (2H, q, J=7.1), 5.11 (1H, bs), 7.47 (1H, bs). IR (KBr): 1698, 1674, 1534, 1433 cm-1.

Reference： [1]Patent: US2003/187023,2003,A1

31
[ 98-74-8 ]
[ 183673-71-4 ]
[ 18107-18-1 ]
[ 321997-89-1 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; hexane;	a) 4-Amino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester. To a slurry of 4-amino-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (13.9 g) in methanol (150 mL) and tetrahydrofuran (100 mL) cooled to 0 C. is added dropwise over 4 hours 2 M trimethylsilyldiazomethane in hexane (57 mL) followed by 4-nitrophenylsulfonyl chloride (2.0 g). The solvents are evaporated under vacuum and the crude product is used in the next step without further purification.

Reference： [1]Patent: US2003/139414,2003,A1

Yield	Reaction Conditions	Operation in experiment
		Step 4 Synthesis of 1-Boc-4-aminopiperidine-4-carboxylic acid (8) In a 2L Erlenmeyer flask equipped with a stirring bar, 1-Boc-4-piperidinespiro-5'-(di-t-Boc)-hydantoin (5) (4.23 g, 9.0 mmol) was suspended in THF (800 mL). To this suspension was added 1N LiOH (72 mL, 72 mmol) with vigorous stirring. The resulting white suspension was stirred for 24 hrs. The final reaction mixture was concentrated with reduced pressure, extracted with Et2O (2*125 mL), and the pH adjusted to 7 with a solution of 20percent citric acid. The resulting solid was filtered and dried in vacuo to yield 1-Boc-4-aminopiperidine-4-carboxylic acid 8 (1.54 g, 70percent). 1H NMR (250 MHZ, C5D5N) d 4.45 (br, 1H), 4.23 (br, 1H), 3.71(br, 2H), 2.87 (dt, 2H), 2.35 (br, 1H), 1.86 (br d, 2H), 1.55, 1.54 (2s, 9H).

33
[ 183673-71-4 ]
[ 286459-94-7 ]
[ 287408-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; triethylamine; In 1,4-dioxane; water; ethyl acetate;	Step 1 4-Amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (1.0 g, 4.09 mmol) in dioxane (5 mL) and water (2.5 mL) was treated with triethylamine (0.63 mL, 4.5 mmol) and 0.8 mL of 5 N aqueous sodium hydroxide and 4-(2-butynyloxy)phenyl sulfonyl chloride (1.0 g, 4.09 mmol) was then added. After 40h, ethyl acetate and 1N aqueous hydrochloric acid was added. The organic phase was washed an additional 2* with 1N aqueous hydrochloric acid and once with brine, then dried over anhydrous magnesium sulfate to give an oil (0.98 g) which was chromatographed on silica gel eluding with dichloromethane/methanol to give 1-(tert-butoxycarbonyl)4-([4-(2-butynyloxy)phenyl]sulfonyl} amino)-4-piperidinecarboxylic acid as a white powder (0.36 g). Electrospray Mass Spec 453.1(+H)+.

Reference： [1]Patent: US6225311,2001,B1

34
[ 13139-17-8 ]
[ 183673-71-4 ]
[ 288154-16-5 ]

Yield	Reaction Conditions	Operation in experiment
	With aq. sodium hydroxide; In 1,2-dimethoxyethane; aqueous sodium hydroxide;	(a) Allyl 4-benzyloxycarbonylaminopiperidine-4-carboxylate. 4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (18.0 g) was dissolved in 0.03M aqueous sodium hydroxide (750 mL), and 1,2-dimethoxyethane (100 mL). The pH was adjusted to 9.5 with dilute hydrochloric acid, and the suspension was added to an ice-cold solution of N-(benzyloxycarbonyloxy)succinimide (28.8 g) in 1,2-dimethoxyethane (100 mL). The pH was kept at 9.5 by addition of aq. sodium hydroxide, and the mixture was stirred at room temperature. More N-(benzyloxycarbonyloxy)succinimide (3 g) was added after 7 h, then stirring continued overnight. After evaporation to remove the 1,2-dimethoxyethane, the aqueus residue was extracted with ether then acidified to pH 4 and extracted with ethyl acetate. This extract was washed with dilute hydrochloric acid, water and brine, dried and evaporated. Trituration of the oily residue gave 4-benzyloxycarbonylamino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (23 g).
	In sodium hydroxide; 1,2-dimethoxyethane;	(a) Methyl 4-benzyloxycarbonylamino-1-tert-butoxycarbonylpiperidine-4-carboxylate. 4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (18.0 g) was dissolved in 0.03M aqueous sodium hydroxide (750 ml), and 1,2-dimethoxyethanol (DME, 100 ml). The pH was adjusted to 9.5 with dilute hydrochloric acid, and the suspension was added to an ice-cold solution of N-(benzyloxycarbonyloxy)succinimide (28.8 g) in DME (100 ml). The pH was kept at 9.5 by addition of aqueous sodium hydroxide, and the mixture was stirred at room temperature. More N-(benzyloxycarbonyloxy)succinimide (3 g) was added after 7 hours, then stirring was continued overnight. After evaporation, the aqueous residue was extracted with ether then acidified to pH4 and extracted with ethyl acetate. This extract was washed with dilute hydrochloric acid, water and brine, dried and evaporated. Trituration of the oily residue gave 4-benzyloxycarbonylamino-1-tert-butoxycarbonylpiperidine-4-carboxylic acid (23 g).

Reference： [1]Patent: US2004/38998,2004,A1
[2]Patent: US2004/53928,2004,A1

35
C₁₆H₁₈ClNO₄S₂ [ No CAS ]
[ 183673-71-4 ]
[ 286459-94-7 ]
[ 287408-73-5 ]

Yield	Reaction Conditions	Operation in experiment
		4-Amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid (1.0 g, 4.09 mmol) in dioxane (5 mL) and water (2.5 mL) was treated with triethylamine (0.63 mL, 4.5 mmol) and 0.8 mL of 5N aqueous sodium hydroxide and 4-(2-butynyloxy)phenyl sulfonyl chloride (1.0 g, 4.09 mmol) was then added. After 40h, ethyl acetate and 1N aqueous hydrochloric acid was added The organic phase was washed an additional 2X with 1N aqueous hydrochloric acid and once with brine, then dried over anhydrous magnesium sulfate to give an oil (0.98 g) which was chromatographed on silica gel eluting with dichloromethane/methanol to give 1-(tert-butoxycarbonyl)-4-([4-(2-butynyloxy)phenyl]sulfonyl} amino)-4-piperidinecarboxylic acid as a white powder (0.36 g). Electrospray Mass Spec 453.1 (M+H)+.

Reference： [1]Patent: EP1144368,2004,B1 .Location in patent: Page 116

36
[ 24424-99-5 ]
[ 183673-71-4 ]
[ 189321-65-1 ]

Yield	Reaction Conditions	Operation in experiment
59%		1-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid4-Amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3.00 g, 12.3 mmol, Alfa Aesar) was dissolved in NaOH (2 N aqueous solution, 14 mL, 28 mmol) and t-butanol (14 mL). Boc2O (3.21 g, 14.7 mmol) was added in one portion and the reaction mixture was stirred at ambient temperature for about 18 h.The white solid that formed during that time was filtered and washed with Et2O.The filtrate was collected and extracted with water.The aqueous layer was acidified to about pH 2 with 1 N aqueous HCl which triggered the precipitation of a white solid that was collected by filtration.The filter cake was dissolved in EtOAc and the resulting solution was dried over MgSO4, filtered, and evaporated under reduced pressure to give 1-(tert-butoxycarbonyl)-4-(tert-butoxycarbonylamino)piperidine-4-carboxylic acid (2.50 g, 59percent): LC/MS (Table 1, Method b) Rt=1.33 min; MS m/z: 345 (M+H)+.

Reference： [1]Patent: US2011/152243,2011,A1 .Location in patent: Page/Page column 104

37
thiazol-5-ylmethyl ((2R,5R)-5-amino-1,6-diphenylhexan-2-yl)carbamate hydrochloride [ No CAS ]
[ 183673-71-4 ]
[ 1383620-90-3 ]

Yield	Reaction Conditions	Operation in experiment
19%		Preparation of compound 20:Commercially available compound 19 (244 mg, 1 mmol) with HOBt (153 mg, lmmol) and compound 2 (446 mg, lmmol) were combined in anhydrous DMF (lOmL).ED AC (210 mg, 1.1 mmol) was added and the reaction was stirred for 45 minutes. TEA(350 2.5 mmol) was added and the reaction was stirred for an additional 16 hours.The reaction material was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate solution (2x) and saturated sodium chloride solution. The organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified with CombiFlash (0-5percent MeOH in DCM) and then Prep Cie HPLC to give compound 20 (120mg, 19percent). Mass Spectrum (m/e): (M+H)+ 636.0, (M-ny 633.9.

Reference： [1]Patent: WO2012/88156,2012,A1 .Location in patent: Page/Page column 68-70

38
thiazol-5-ylmethyl ((2R,5R)-5-amino-1,6-diphenylhexan-2-yl)carbamate hydrochloride [ No CAS ]
[ 183673-71-4 ]
[ 1383620-88-9 ]

Reference： [1]Patent: WO2012/88156,2012,A1

39
[ 183673-71-4 ]
[ 1022305-60-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5694 - 5706

40
[ 183673-71-4 ]
[ 1453814-65-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5694 - 5706

41
[ 183673-71-4 ]
[ 1453814-66-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5694 - 5706

42
[ 82911-69-1 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In tetrahydrofuran; water; at 20℃; for 18h;pH 8 - 9;	General procedure: To 250 mL round-bottomed flask add 1a or 1c or 1g or 1h, 2.5 equiv Fmoc-OSu, 50 mL THF/H2O (1:1, v/v), pH of the solution was adjusted with saturated sodium carbonate to 8?9, and the reaction continued at room temperature for about 18h. After that, the solution was extracted twice with ether, and pH of aqueous layer was adjusted with concentrated HCl to 5, white precipitation was obtain and dried in vacuum to gave corresponding product (2a or 2c or 2g or 2h).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5694 - 5706

43
[ 82911-69-1 ]
[ 183673-71-4 ]
[ 1453814-64-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5694 - 5706

44
[ 32315-10-9 ]
[ 183673-71-4 ]
[ 1567899-06-2 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1526 - 1529

45
[ 183673-71-4 ]
[ 1567898-59-2 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1526 - 1529

46
[ 1446358-48-0 ]
[ 183673-71-4 ]
C₂₈H₂₉F₂N₇O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With triethylamine; In dimethyl sulfoxide; at 120℃; for 18h;	General procedure: General procedure B A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.), and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1 ratio) at 90 °C until complete consumption of starting material was observed by LC/MS. The solution was diluted withiN hydrochloric acid and dichloromethane. The layers were then separated and thelayer was extracted with dichloromethane. The organics were combined, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification yielded theproduct The title compound was prepared following general procedure B, except 4-amino-i -(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 equiv.) was the aminereactant, 5 equivalents oftriethylamine was used, and the contents were heated to 120 °C for 18 h as a solution in DMSO. Without workup, the crude material was purified via reverse phase HPLC to deliver the desired compound, Compound 1-110 (8.2 mg, 26percent yield) as a solid. 1H NMR (500 MHz, METHANOL-d4) oe 8.83 (s, 1H), 8.3 1-8.36 (m, 1H), 7.39 (s, 1H),7.26-7.36 (m, 1H), 7.02-7.14 (m, 2H), 6.91 (s, 2H), 6.00 (s, 2H), 3.75-3.88 (m, 2H), 3.36-3.49 (m, 2H), 2.29 (br. s., 4H), 1.50 (s, 9H).

Reference： [1]Patent: WO2014/144100,2014,A2 .Location in patent: Paragraph 00274

47
[ 183673-71-4 ]
C₂₈H₅₄N₂O₅Sn [ No CAS ]