[ CAS No. 183673-66-7 ]

Name: 183673-66-7|N-Boc-4-(Fmoc-amino)piperidine-4-carboxylic acid|97%
Brand: Ambeed
SKU: A266792
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Quality Control of [ 183673-66-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 183673-66-7 ]

Product Details of [ 183673-66-7 ]

CAS No. :	183673-66-7	MDL No. :	MFCD01318741
Formula :	C₂₆H₃₀N₂O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BOFOACPQHWDRLH-UHFFFAOYSA-N
M.W :	466.53 g/mol	Pubchem ID :	2734399
Synonyms :

Calculated chemistry of [ 183673-66-7 ]

Physicochemical Properties

Num. heavy atoms :	34
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.42
Num. rotatable bonds :	9
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	130.07
TPSA :	105.17 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.25
Log Po/w (XLOGP3) :	3.88
Log Po/w (WLOGP) :	4.0
Log Po/w (MLOGP) :	2.8
Log Po/w (SILICOS-IT) :	3.0
Consensus Log Po/w :	3.39

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.84
Solubility :	0.00668 mg/ml ; 0.0000143 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.79
Solubility :	0.000764 mg/ml ; 0.00000164 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.95
Solubility :	0.000528 mg/ml ; 0.00000113 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	4.18

Safety of [ 183673-66-7 ]

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

Application In Synthesis of [ 183673-66-7 ]

* 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 [ 183673-66-7 ]
Downstream synthetic route of [ 183673-66-7 ]

[ 183673-66-7 ] Synthesis Path-Upstream 1~11

1
[ 183673-66-7 ]
[ 406235-17-4 ]
[ 161529-14-2 ]

Reference： [1] Patent: US2002/55631, 2002, A1,
[2] Patent: US2002/86887, 2002, A1,

2
[ 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

3
[ 82911-69-1 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

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

4
[ 40064-34-4 ]
[ 183673-66-7 ]

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

5
[ 24424-99-5 ]
[ 183673-66-7 ]

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

6
[ 79099-07-3 ]
[ 183673-66-7 ]

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

7
[ 13625-39-3 ]
[ 183673-66-7 ]

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

8
[ 183673-70-3 ]
[ 183673-66-7 ]

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

9
[ 183673-68-9 ]
[ 183673-66-7 ]

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

10
[ 102774-86-7 ]
[ 183673-71-4 ]
[ 183673-66-7 ]

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

11
[ 183673-66-7 ]
[ 368866-09-5 ]

Reference： [1] Patent: WO2011/153588, 2011, A1, . Location in patent: Page/Page column 49
[2] ChemBioChem, 2016, vol. 17, # 2, p. 137 - 140

[ 183673-66-7 ] Synthesis Path-Downstream 1~58

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

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

2
[ 183673-66-7 ]
[ 18107-18-1 ]
4-(9H-fluoren-9-ylmethoxycarbonylamino)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2669 - 2672

3
[ 183673-66-7 ]
4-(9H-fluoren-9-ylmethoxycarbonylamino)-piperidine-4-carboxylic acid methyl ester; hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2669 - 2672

4
[ 24424-99-5 ]
[ 183673-66-7 ]

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

5
[ 79099-07-3 ]
[ 183673-66-7 ]

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

6
[ 40064-34-4 ]
[ 183673-66-7 ]

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

7
[ 183673-70-3 ]
[ 183673-66-7 ]

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

8
[ 183673-68-9 ]
[ 183673-66-7 ]

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

9
[ 71056-58-1 ]
[ 183673-66-7 ]
C₃₈H₄₂N₄O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-trimethyl-pyridine; 1-hydroxy-7-aza-benzotriazole; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In DMF (N,N-dimethyl-formamide); at 20℃; for 15h;	A solution of amino-indole from example 15 (70 mg, 0.32 mmol), <strong>[183673-66-7]N-Fmoc-amino-(4-N-Boc-piperidinyl)carboxylic acid</strong> (150 mg, 0.32 mmol), HATU (139 mg, 0.35 mmol), HOAt (48 mg, 0.35 mmol) and collidine (155 mg, 1.28 mmol) in DMF (2 mL) was stirred at RT for 15 h. The reaction mixture was diluted with EtOAc, washed with 1% aqueous citric acid (2×), saturated NaHCO3 (2×) and brine, dried over anhydrous MgSO4 and concentrated to dryness to give an orange solid (210 mg) which was used in the next reaction without purification. A solution of the crude solid (210 mg) in DMF (3 mL) and piperidine (95 mL, 0.95 mmol) was stirred at RT for 3 h. The reaction mixture was concentrated to dryness and purified by flash column chromatography, using a solvent gradient from 50% EtOAc in hexane to 100% EtOAc as the eluent, to give the desired compound as a brown solid (110 mg).

Reference： [1]Patent: US2003/236251,2003,A1 .Location in patent: Page 29-30

10
[ 5048-82-8 ]
[ 183673-66-7 ]
[ 877273-27-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In tetrahydrofuran; for 1h;Heating / reflux;	(E)-tert-butyl 4-amino-4-((4-(3-ethoxy-3-oxoprop-1-enyl)phenyl)carbamoyl)piperidine-1-carboxylate. A solution of 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 2.14 mmol), (E)-ethyl 3-(4-aminophenyl)acrylate (409 mg, 2.12 mmol), and EEDQ (582 mg, 2.35 mmol) in THF (12 mL) was stirred at reflux for 1 hour. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed sequentially with dilute HCl, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (40 g) with dichloromethane/ethyl acetate (100:15) to provide impure Fmoc-protected product as a cloudy oil (900 mg). A second purification by flash column chromatography on silica gel (40 g) with hexanes/ethyl acetate (100:20 to 1:1) provided the Fm-c-protected product as a colorless solid: ESI-MS m/z 640 (MH+); 1H NMR (300 MHz, CDCl3) delta 1.30 (t, J=7.14 Hz, 3H), 1.43 (s, 9H), 2.00 (m, 2H), 2.12 (m, 2H), 3.04 (m, 2H), 3.75 (m, J=13.91 Hz, 2H), 3.75 (d, J=13.91 Hz, 2H), 4.22 (q, J=6.95 Hz, 2H), 4.54 (d, J=5.86 Hz, 2H), 4.85 (s, 1H), 6.33 (d, J=16.10 Hz, 1H), 7.23 (m, 2H), 7.35 (t, J=7.50 Hz, 2H), 7.45 (s, 4H), 7.52 (d, J=7.68 Hz, 2H), 7.60 (d, J=16.10 Hz, 1H), 7.73 (d, J=7.68 Hz, 2H), 9.06 (s, 1H).

Reference： [1]Patent: US2006/46983,2006,A1 .Location in patent: Page/Page column 44
[2]Journal of the American Chemical Society,2010,vol. 132,p. 15204 - 15212

Yield	Reaction Conditions	Operation in experiment
87%		Step 3 Synthesis of 1-Boc-piperidine-4-Fmoc-amino-4-carboxylic acid (3) 1 N NaOH (287 mL, 287 mmol) was added all at once to a suspension of tri-Boc-hydantoin 5 (15.0 g, 32.0 mmol) in DME (200 mL), resulting in a homogeneous solution. After 26 hrs, the resulting light yellow solution was extracted with Et2O (375 mL) to remove Boc2NH. The aqueous layer containing 4-amino-1-Boc-piperidine-4-carboxylic acid (8) from above was cooled in an ice bath and the pH adjusted to 9.5 with 12 N HCl. This prechilled solution was added dropwise to a chilled mixture (ice-bath) of Fmoc-OSu (16.0 g, 47.4 mmol) in DME (40 mL). A precipitate formed immediately, and the reaction mixture was allowed to warm to room temperature, keeping the pH at 9.0-9.5 by addition of 1 N NaOH; total reaction time: 18 h. The DME was removed in vacuo (<40 C.) and the resultant aqueous layer was extracted with Et2O (250 mL) to remove unreacted Fmoc-OSu. The aqueous fraction was chilled with an ice bath and adjusted to pH 4 with 12 N HCl and extracted with EtOAc (4*250 mL). The combined EtOAc layers were washed with 1 N HCl (100 mL), brine (100 mL), dried (Na2SO4), and the solvent removed in vacuo to yield a light yellow powder (10.8 g, 87%); mp 80-82 C. 1H NMR (200 MHz, CD3SOCD3) d 8.30 (s, 1H), 7.85-7.96 (d, 2H), 7.70-7.80 (d, 2H), 7.22-7.54 (m, 4H), 4.19-4.32 (m, 3H), 3.55-3.76 (m, 2H), 2.90-3.09 (m, 2H), 1.91-2.15 (m, 2H), 1.65-1.89 (m, 2H), d 1.39 (s, 9H); 13C NMR (50 MHZ, CD3SOCD3) d 175.36, 155.26, 153.83, 143.76, 140.67, 127.54, 126.98, 125.21, 119.99, 79.11, 78.56, 65.26, 56.73, 46.72, 31.26, 28.01; FAB-MS (NBA) 467 (M+H)+, 367 [(M+H)-Boc]+; Analysis calculated for C26H30N2O6.H2O (484.55): C, 64.45; H, 6.66; N, 5.78; found: C, 64.48; H, 6.87; N, 5.74.
63%		Isolated yields of Ngamma-Boc-protected 8 were often low and contaminated with salts, so a one-pot procedure for conversion of tri-Boc hydantoin 5 to 3 was developed. Thus, the above cleavage reaction containing 8 was extracted with ether to remove Boc2NH and then Fmoc-OSu was added along with NaOH to keep the pH~9, giving Compound 3 in 63% overall yield from 4-piperidone.
63%		Step 5 Synthesis of 1-Boc-piperidine-4-Fmoc-amino-4-carboxylic acid (3) From the above cleavage reaction containing Compound 8, the mixture was extracted with ether to remove Boc2NH and then Fmoc-OSu was added along with NaOH to keep the pH~9 giving Compound 3 in 63% overall yield from 4-piperidone. 13C NMR (50 MHZ, CD3SOCD3) d 175.36, 155.26, 153.83, 143.76, 140.67, 127.54, 126.98, 125.21, 119.99, 79.11, 78.56, 65.26, 56.73, 46.72, 31.26, 28.01; FAB-MS (m-nitrobenzylalcohol) 467 (M+H)+, 367 [(M+H)-Boc]+; Analysis calculated for C26H30N2O6.H2O(484.55): C, 64.45; H, 6.66; N, 5.78; found: C, 64.48; H, 6.87; N, 5.74.

flavone and flavonoid derivatives: for example ... 5-(PIPERIDINE-1-CARBONYL)-1H-IMIDAZOLE-4-CARBOXYLIC ACID (2-BZ-4-BR-PH)AMIDE, FMOC-4-CARBOXYMETHYLPIPERAZINE, 4-FMOC-PIPERAZINE-1-YLACETIC ACID, 2-[[2-(4-METHYLPIPERAZINO)PHENYL]METHYLENE]MALONIC ACID, 1-BOC-PIPERIDINE-4-FMOC-AMINO-4-CARBOXYLIC ACID, 5-[(4-CHLOROBENZOYL)AMINO]-2-(3,5-DIMETHYLPIPERIDINO)BENZOIC ACID, 4-CHLORO-N-[4-[4-(2-METHOXYPHENYL)PIPERAZINO]IBUTYL]BENZAMIDE, FMOC-L-ALA[3-(1-N-PIPERAZINYL(4-N-BOC))]; CARBOBENZYLOXYSARCOSYL-L-ALANINE, ...

12
[ 183673-66-7 ]
[ 406235-17-4 ]
[ 161529-14-2 ]

Yield	Reaction Conditions	Operation in experiment
		tert-butyl 4-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate The desired product was prepared by substituting 1-(tert-butoxycarbonyl)-4-(((9H-fluoren-9-ylmethoxy)carbonyl)amino)piperidine-4-carboxylic acid for Fmoc-D-Asp(OtBu)-OH in Example 122A. MS (ESI) m/e 451, 453 (M-H)-, (M+H)+.

Reference： [1]Patent: US2002/55631,2002,A1

13
[ 35661-40-6 ]
[ 96402-49-2 ]
[ 183673-66-7 ]
C₇₃H₇₈N₁₁O₁₀Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Each of the reaction wells contained 0.0675 mmol of Rink Amide MBHA resin(substitution = 0.72 mmol/g, Novabiochem, San Diego, CA). The following Fmoc amino acids (Novabiochem, San Diego, CA; Chem-Impex International, Wood Dale, IL; SyntheTech, Albany, OR; Pharma Core, High Point, NC) were used: Fmoc-Lys(Boc)-OH, EPO <DP n="112"/>Fmoc-Phe-OH, Fmoc-H-Inp-OH, Fmoc-D-lNal-OH, Fmoc-D-2Nal-OH, Fmoc-D- TrP(BoC)-OH, Fmoc-3Pal-OH, Fmoc-4Pal-OH/ FmOc-Om(BoC)-OH, Fmoc-D-Bip-OH, FmOC-ThT(BzI)-OH, Fmoc-Pff-OH, Fmoc-2Thi-OH, Fmoc-Taz-OH, Fmoc-D-Dip-OH, Fmoc-D-Bpa-OH, Fmoc-D-Bal-OH, and Fmoc-Apc(Boc)-OH.Each of the Fmoc amino acids was dissolved in a 0.3 N solution of HOBt in DMF wherein the concentration of the resulting Fmoc amino acid was 0.3 N. A four fold excess (0.27 mmol, 0.9 mL of the 0.3 N solution) of Fmoc amino acid was used for each coupling. DIC (0.27 mmol, 0.6 mL of 0.45N DIC solution in DMF) was used as the coupling reagent for each coupling. Deprotection was performed by using 20percent piperidine in DMF (2 X 1.5 mL per residue). The peptides were cleaved from the resin by treating the peptide-resins with 8percent trsopropylsilane (TIP) in trifluoroacetic acid (TFA) (1.5 mL per reaction well) at room temperature for 2h. The resin was removed by filtration. Each filtrate was diluted to 25 mL with ether in a centrifuge tube. The resulting precipitate in each tube was centrifuged and the solvents were decanted from the precipitate. The precipitate in each tube was then dissolved in methanol (3 mL) and diluted with water (1 mL). The purification of the crude products was done on a reverse-phase preparative HPLC using a column (100 X 21.20 mm, 5mu) of LUNA 5mu C8(2) (Phenomenex, Torrance, CA). For each peptide, the column was eluted with a linear gradient from 85percent A and 15percent B to 25percent A and 75percent B in 15 min with a flow rate of 25 mL/min. A was 0.1percent TFA in water and B was 0.1percent TFA in acetonitrile/water (80/20, v/v). The fractions were checked by analytical HPLC and those containing the pure product were combined and lyophilized to dryness.Yields ranged from 13percent to 71percent and purity of each of Examples 1 - 65 exceeded 94percent based upon analytical HPLC analysis. Electro-spray ionization mass spectrometry (ES-MS) analysis was performed and observed molecular weights were in agreement with calculated molecular weights. The results are detailed in Table I, below

Reference： [1]Patent: WO2007/41278,2007,A2 .Location in patent: Page/Page column 110-111

14
C₇H₈N₃OPol [ No CAS ]
[ 183673-66-7 ]
C₃₃H₃₆N₅O₆Pol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	See the scheme of FIG. 3. The amino acid derivatives used were Boc-D-Phe-OH, Boc-D-Phe-OH, Boc-D-Leu-OH, Boc-D-Dap(Fmoc)-OH, and N-Fmoc-amino-(4-N-Boc-piperidinyl) carboxylic acid. HPLC and MS analyses were performed as described in the synthesis of compound (1). The fully protected resin-bound peptide was synthesized manually starting with 4-Fmoc-hydrazinobenzoyl AM NovaGel resin (3 mmol; Novabiochem). The Fmoc protecting group on the starting resin was first removed by 25% piperidine in DMF and the resin was then treated with a mixture of N-Fmoc-amino-(4-N-Boc-piperidinyl) carboxylic acid (7.5 mmol), PyBOP (7.5 mmol), and DIEA (15 mmol) in DMF overnight at room temperature. The Fmoc group on the attached amino acid was replaced by o-NBS in two steps: (i) Fmoc removal by 25% piperidine in DMF. (ii) o-NBS protection according the procedure described in the synthesis of compound (1). The resulting peptide resin, N-o-NBS-amino-(4-N-Boc-piperidinyl) carboxylic acid-[hydrazinobenzoyl AM NovaGel resin], was split into several portions and a portion of 1 mmol was used to continue the peptide synthesis. PyBOP/DIEA mediated single couplings were performed with a 3-fold excess of amino acid derivatives. The Boc group was removed with 30% TFA in DCM. Upon completion of peptide chain elongation, the resin was treated with 2% DBU in DMF for 2×8 min for Fmoc removal, followed by guanylation of the omega-amino function of D-Dap at Xaa4 according to the procedure described in the synthesis of compound (5), above. The final o-NBS deprotection was carried out according to the procedure described in the synthesis of compound (1).For oxidative cleavage, the dried peptide resin was mixed with a mixture of Cu(OAc)2 (1 mmol), pyridine (4 mmol), and DBU (2 mmol) in 5% H2O in DMF and let air bubble through the resin for 6 h at room temperature. The resin was filtered and washed with DMF and the filtrated was evaporated in vacuo. The residue, Boc-D-Phe-D-Phe-D-Leu-(beta-amidino)D-Dap-[omega(4-aminopiperidine-4-carboxylic acid)]-OH, was treated with 95% TFA in H2O for Boc removal. The solution was evaporated in vacuo and the crude peptide (1 mmol; D-Phe-D-Phe-D-Leu-(beta-amidino)D-Dap-[omega(4-aminopiperidine-4-carboxylic acid)]-OH) was precipitated from diethyl ether.Purification of the above crude peptide was achieved according to the protocol described in the synthesis of compound (2). The purified peptide was an amorphous powder (16 mg). HPLC analysis: tR=16.97 min, purity 99.9%, gradient 5% B to 25% B over 20 min; MS (M+H+): expected molecular ion mass 680.4, observed 680.4.; FIG. 3: General scheme used in the synthesis of compounds (15)-(24). Steps a-n were carried out with the following reactants or conditions: a) 35% piperidine, DMF; b) 1-Boc-4-N-Fmoc-amino-piperidine-4-carboxylic acid, PyBOP, DIEA, DMF; c) (i) 35% piperidine, DMF; (ii) O-NBS-Cl, collidine, NMP; d) 30% TFA in DCM; e) Boc-D-Dap(Fmoc)-OH or Boc-D-Dab(Fmoc)-OH or Boc-D-Orn(Fmoc)-OH, PyBOP, DIEA, DMF; f) Boc-D-Leu-OH, PyBOP, DIEA, DMF; g) Boc-D-Phe-OH, PyBOP, DIEA, DMF; h) Boc-D-Phe-OH, PyBOP, DIEA, DMF; i) 2% DBU/DMF; j) 1H-pyrazole-1-carboxamidine, DIEA, DMF; k) (i) acetone, TMOF, (ii) NaBH(OAc)3, DMF; l) mercaptoethanol, DBU, NMP; m) Cu(OAc)2, pyridine, DBU, DMF/H2O; n) 95% TFA/H2O.

Reference： [1]Patent: US7402564,2008,B1 .Location in patent: Page/Page column 6; 59; sheet 3

15
[ 328-74-5 ]
[ 183673-66-7 ]
[ 1059175-69-7 ]

Yield	Reaction Conditions	Operation in experiment
59%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 0.5h;Microwave irradiation;	EXAMPLE 16; Synthesis of (E)-N-(3,5-bis(trifluoromethyl)phenyl)-4-(3-(4-fluorophenyl)acrylamido) piperidine-4-carboxamide (Compound 32) A. Synthesis of tert-butyl 4-((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(3,5-bis(trifluoromethyl)phenylcarbamoyl)piperidine-1-carboxylate To a solution of 1-N-BOC-4-N-Fmoc-amino-4-carboxylic-piperidine (150 mg, 0.30 mmol), 3,5-bis(trifluoromethyl)aniline (0.15 mL, 0.96 mmol), diisopropylethylamine (DIPEA) (0.12 mL, 0.32 mmol) in DMF (2 mL) was added O-(7-azabenzotriazole-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (120 mg, 0.30 mmol). The solution was stirred in microwave for 0.5 hours at 80 C. and concentrated in vacuo. The residue was diluted with EtOAc, washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography using 2:8 EtOAc-DCM to give desired compound (130 mg, 59%) as a white foam.

Reference： [1]Patent: US2008/227823,2008,A1 .Location in patent: Page/Page column 15-16

16
[ 2711-58-2 ]
[ 183673-66-7 ]
[ 852534-42-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	EXAMPLE 1; Synthesis of (E)-4-(3-(3-bromo-4-fluorophenyl)acrylamido)-N-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperidine-4-carboxamide (Compound 1) A. Synthesis of tert-butyl 4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(2-(5-fluoro-1H-indol-3-yl)ethylcarbamoyl)piperidine-1-carboxylate To a solution of 1-N-BOC-4-N-Fmoc-amino-4-carboxylic-piperidine (4.2 g, 6.43 mmol), 5-fluorotryptamine hydrochloride (1.38 g, 6.43 mmol), diisopropylethylamine (DIPEA) (1.83 g, 14.15 mmol) in DMF (35 mL) was added O-(7-azabenzotriazole-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (2.44 g, 6.43 mmol). The solution was stirred for 2 hours at room temperature and concentrated in vacuo. The residue was diluted with EtOAc, washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography 2:8 EtOAc-DCM to give desired compound (4.0 g, 93%) as white foam.

Reference： [1]Patent: US2008/227823,2008,A1 .Location in patent: Page/Page column 6

17
[ 1246024-64-5 ]
[ 183673-66-7 ]
[ 1246024-65-6 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 13176 - 13178
[2]Chemistry - A European Journal,2017,vol. 23,p. 4818 - 4826

18
[ 15028-41-8 ]
[ 183673-66-7 ]
[ 1246024-75-8 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 13176 - 13178

19
[ 183673-66-7 ]
[ 100-51-6 ]
[ 1246024-63-4 ]

Reference： [1]Journal of the American Chemical Society,2010,vol. 132,p. 13176 - 13178

20
[ 183673-66-7 ]
[ 368866-09-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 1.25h;	Step a: A solution of 1-(ferf-butoxycarbonyl)-4-[(9H-fluoren-9-ylmethoxy)- carbonyl]amino}piperidine-4-carboxylic acid (0.330 g, 0.64 mmol) in 4 M HCI-dioxane (6 mL) was stirred at room temperature. After 1.25 h the residue was co-evaporated with diethyl ether (x2) and dried under high vacuum to afford 4-[(9A7-fluoren-9- ylmethoxy)carbonyl]amino}piperidine-4-carboxylic acid hydrochloride (ii) (0.35 g) as a yellow foam. ESI-MS m/z calculated for [M+H]+: 367.2; found: 367.0.

Reference： [1]Patent: WO2011/153588,2011,A1 .Location in patent: Page/Page column 49
[2]ChemBioChem,2016,vol. 17,p. 137 - 140

21
[ 183673-66-7 ]
[ 1352083-21-6 ]

Reference： [1]Patent: WO2011/153588,2011,A1

22
[ 183673-66-7 ]
C₃₇H₄₁N₅O₄ [ No CAS ]