[ CAS No. 41447-17-0 ] {[proInfo.proName]}

Name: 41447-17-0|(R)-1-Methylpiperidine-2-carboxylic acid|97%
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Quality Control of [ 41447-17-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 41447-17-0 ]

Product Details of [ 41447-17-0 ]

CAS No. :	41447-17-0	MDL No. :	MFCD13183995
Formula :	C₇H₁₃NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BPSLZWSRHTULGU-ZCFIWIBFSA-N
M.W :	143.18	Pubchem ID :	11286529
Synonyms :

Calculated chemistry of [ 41447-17-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.23
TPSA :	40.54 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) :	-9.05 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.44
Log Po/w (XLOGP3) :	-2.64
Log Po/w (WLOGP) :	0.17
Log Po/w (MLOGP) :	0.35
Log Po/w (SILICOS-IT) :	0.31
Consensus Log Po/w :	-0.07

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	1.0
Solubility :	1440.0 mg/ml ; 10.0 mol/l
Class :	Highly soluble
Log S (Ali) :	2.34
Solubility :	31100.0 mg/ml ; 217.0 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.11
Solubility :	111.0 mg/ml ; 0.776 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.78

Safety of [ 41447-17-0 ]

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 [ 41447-17-0 ]

* 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 [ 41447-17-0 ]
Downstream synthetic route of [ 41447-17-0 ]

[ 41447-17-0 ] Synthesis Path-Upstream 1~6

1
[ 50-00-0 ]
[ 1723-00-8 ]
[ 41447-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 5%-palladium/activated carbon; hydrogen In methanol; water for 20 h;	37percent Aqueous solution of formaldehyde (1.26 mL, 16.9 mmol) was added to a mixture of (2R)-piperidine-2-carboxylic acid (2.00 g, 15.5 mmol) and 5percent Pd/C (500 mg) in MeOH (20 mL). After the reaction mixture was purged with H₂ gas, additional formaldehyde (0.60 mL, 8.06 mmol) was added, and stirred under H₂ atmosphere for 20 h. The reaction mixture was filtered through a pad of Celite, and washed with MeOH (200 mL). The filtrate was concentrated by rotary evaporation to afford analytically pure amino acid 8 (2.23 g, quantitative yield) as a white solid, which was used in the next step without further purification. TLC: R_f 0.25 (1:1 CH₂Cl₂/MeOH). Mp: 208-210 °C. [α]_D^27.1 = + 67.6 (c 1.27, MeOH). IR (KBr, film): 3407, 2950, 1615, 1399 cm^-1. 1H NMR (400 MHz, CDCl3): d8.22 (br s, 1H), 3.64 (d, 1H, J = 12.0 Hz), 3.28 (m, 1H), 2.86 (s,3H), 2.70 (m, 1H), 2.34 (d, 1H, J = 14.4 Hz), 2.00–1.74 (m, 4H),1.46 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d 170.4, 68.3, 53.3,42.3, 28.0, 23.1, 21.8. HRMS (ESI) m/z calculated for C7H13NO2143.0946, found 143.0947.
90%	With palladium 10% on activated carbon; hydrogen In methanol; water	To a solution of D-pipecolinic acid (10.0 g, 77.4 mmol, 1.0 eq.) in methanol (100 mL) was added formaldehyde (37percent aqueous solution, 30.8 mL, 154.8 mmol, 2.0 eq.), followed by Pd/C (10 wtpercent, 1.0 g). The reaction mixture was stirred under H₂ (1 atm) overnight, and then filtered through Celite, with washing of the filter pad with methanol. The filtrate was concentrated under reduced pressure to afford compound 126 (10.0 g, 90percent yield) as a white solid.

Reference： [1] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 21, p. 6827 - 6843
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 43, p. 7235 - 7239
[3] Patent: WO2016/59622, 2016, A2, . Location in patent: Page/Page column 95-96
[4] Journal of Organic Chemistry, 2016, vol. 81, # 21, p. 10302 - 10320
[5] Patent: WO2018/86139, 2018, A1, . Location in patent: Page/Page column 143
[6] Journal of the American Chemical Society, 2006, vol. 128, # 50, p. 16018 - 16019

2
[ 124-38-9 ]
[ 150130-31-7 ]
[ 41447-17-0 ]

Reference： [1] Tetrahedron, 1994, vol. 50, # 20, p. 6077 - 6088

3
[ 79-22-1 ]
[ 150130-31-7 ]
[ 41447-17-0 ]

Reference： [1] Tetrahedron, 1994, vol. 50, # 20, p. 6077 - 6088

4
[ 616-38-6 ]
[ 150130-31-7 ]
[ 41447-17-0 ]

Reference： [1] Tetrahedron, 1994, vol. 50, # 20, p. 6077 - 6088

5
[ 7730-87-2 ]
[ 41447-17-0 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1957, vol. 22, p. 286,288, 289

6
[ 41447-17-0 ]
[ 68474-13-5 ]

Reference： [1] Tetrahedron, 1994, vol. 50, # 20, p. 6077 - 6088

[ 41447-17-0 ] Synthesis Path-Downstream 1~60

1
[ 41447-17-0 ]
[ 68474-13-5 ]

Reference： [1]Tetrahedron,1994,vol. 50,p. 6077 - 6088

2
[ 50-00-0 ]
[ 1723-00-8 ]
[ 41447-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 5%-palladium/activated carbon; hydrogen; In methanol; water; for 20h;	37% Aqueous solution of formaldehyde (1.26 mL, 16.9 mmol) was added to a mixture of (2R)-piperidine-2-carboxylic acid (2.00 g, 15.5 mmol) and 5% Pd/C (500 mg) in MeOH (20 mL). After the reaction mixture was purged with H2 gas, additional formaldehyde (0.60 mL, 8.06 mmol) was added, and stirred under H2 atmosphere for 20 h. The reaction mixture was filtered through a pad of Celite, and washed with MeOH (200 mL). The filtrate was concentrated by rotary evaporation to afford analytically pure amino acid 8 (2.23 g, quantitative yield) as a white solid, which was used in the next step without further purification. TLC: Rf 0.25 (1:1 CH2Cl2/MeOH). Mp: 208-210 C. [alpha]D27.1 = + 67.6 (c 1.27, MeOH). IR (KBr, film): 3407, 2950, 1615, 1399 cm-1. 1H NMR (400 MHz, CDCl3): d8.22 (br s, 1H), 3.64 (d, 1H, J = 12.0 Hz), 3.28 (m, 1H), 2.86 (s,3H), 2.70 (m, 1H), 2.34 (d, 1H, J = 14.4 Hz), 2.00-1.74 (m, 4H),1.46 (m, 1H). 13C NMR (100 MHz, DMSO-d6): d 170.4, 68.3, 53.3,42.3, 28.0, 23.1, 21.8. HRMS (ESI) m/z calculated for C7H13NO2143.0946, found 143.0947.
90%	With palladium 10% on activated carbon; hydrogen; In methanol; water; under 760.051 Torr;	To a solution of D-pipecolinic acid (10.0 g, 77.4 mmol, 1.0 eq.) in methanol (100 mL) was added formaldehyde (37% aqueous solution, 30.8 mL, 154.8 mmol, 2.0 eq.), followed by Pd/C (10 wt%, 1.0 g). The reaction mixture was stirred under H2 (1 atm) overnight, and then filtered through Celite, with washing of the filter pad with methanol. The filtrate was concentrated under reduced pressure to afford compound 126 (10.0 g, 90% yield) as a white solid.
90%	With palladium 10% on activated carbon; hydrogen; In methanol; water; under 760.051 Torr;	To a solution of D-pipecolinic acid (10.0 g, 77.4 mmol, 1.0 eq. ) in methanol (100 mL) was added formaldehyde (37%aqueous solution, 30.8 mL, 154.8 mmol, 2.0 eq. ) , followed by Pd/C (10 wt%, 1.0 g) . The reaction mixture was stirred under H 2 (1 atm) overnight, and then filtered through Celite, with washing of the filter pad with methanol. The filtrate was concentrated under reduced pressure to afford compound 22 (10.0 g, 90%yield) as a white solid.

90%

With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr;

To a solution of D-pimidic acid (10.0 g, 77.4 mmol) in methanol (100 mL) was added formaldehyde (37% aqueous solution, 30.8 mL, 154.8 mmol) and Pd / C (10 wt%, 1.0 g). The reaction solution was stirred under H2 (1 atm) environment overnight, and then filtered through celite and washed with methanol. The filtrate was concentrated to give the title compound (10.0 g, 90% yield) as a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6827 - 6843
[2]Angewandte Chemie - International Edition,2006,vol. 45,p. 7235 - 7239
[3]Patent: WO2016/59622,2016,A2 .Location in patent: Page/Page column 95-96
[4]Journal of Organic Chemistry,2016,vol. 81,p. 10302 - 10320
[5]Patent: WO2018/86139,2018,A1 .Location in patent: Page/Page column 143
[6]Patent: WO2019/127607,2019,A1 .Location in patent: Page/Page column 10; 160-161
[7]Patent: CN110621673,2019,A .Location in patent: Paragraph 0803-0805
[8]Journal of the American Chemical Society,2006,vol. 128,p. 16018 - 16019

3
[ 771-61-9 ]
[ 41447-17-0 ]
[ 921928-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In ethyl acetate; for 24h;	<strong>[41447-17-0](R)-1-methylpiperidine-2-carboxylic acid</strong> (92 mg, 643 mumol), 2,3,4,5,6-pentafluorophenol (122 mg, 662 mumol), and dicyclohexylmethanediimine (198 mg, 960 mumol) in ethyl acetate (1.0 ml) was stirred for 24 h. The heterogeneous mixture was filtered and the solid was washed with ethyl acetate. The perfluorophenyl (R)-1-methylpiperidine-2-carboxylate contained in the filtrate was used crude in the subsequent reaction.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; for 16h;	f. EXAMPLE. EC1005 is re ared accordin to the followin rocess. Into an appropriately sized hydrogenation flask place R-N-methyl pipecolinate (MEP), pentafluorophenol, N-methyl pyrrolidinone (NMP), and ethyl dimethylaminopropyl carbodiimide (EDC). The mixture is stirred for at least 16h. EC1004 dissolved in N-methyl pyrrolidinone (NMP) and 10 wt% Pd/C are added. The reaction mixture is stirred/shaken under hydrogen pressure until the reaction is complete by LC analysis. The Pd/C is removed by filtration through celite. The celite is washed with ethyl acetate and the combined organics are washed three times with a 1% sodium bicarbonate/10% sodium chloride solution. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is dissolved in DCM and purified by silica gel chromatography using ethyl acetate and petroleum ether as eluents. Fractions are collected, checked for purity, combined and dried on a rotary evaporator. The EC1005 oil is assayed by LC and stored in a freezer until use
	With dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃; for 16h;	To a solution of <strong>[41447-17-0]D-N-methyl pipecolinic acid</strong> (2.65 g, 18.5 mmol) in EtOAc (50 mL) were added pentafluorophenol (3.75 g, 20.4 mmol) and DCC (4.21 g, 20.4 mmol). The reaction mixture was stirred at r.t. for 16 h, and then filtered over Celite. The filter pad was washed with 10 mL of EtOAc. The filtrate was used immediately without further purification or concentration.

	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; at 20℃;	60 mg of MEP (0.42 mmole, 1.4 equiv compared to EC1794) was suspended in 1.0 mL NMP. To the suspension, 83 mg of pentafluorophenol (0.45 mmole, 1.5 equiv.) and 86 mg of EDC (0.45 mmole, 1.5 equiv) were added. The reaction mixture was stirred overnight at room temperature.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one;	Into an appropriately sized hydrogenation flask place R-N-methyl pipecolinate (MEP), pentafluorophenol, N-methyl pyrrolidinone (NMP), and ethyl dimethylaminopropyl carbodiimide (EDC). The mixture is stirred for at least 16 h. EC1004 dissolved in N-methyl pyrrolidinone (NMP) and 10 wt % Pd/C are added. The reaction mixture is stirred/shaken under hydrogen pressure until the reaction is complete by LC analysis. The Pd/C is removed by filtration through celite. The celite is washed with ethyl acetate and the combined organics are washed three times with a 1% sodium bicarbonate/10% sodium chloride solution. The organic layer is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is dissolved in DCM and purified by silica gel chromatography using ethyl acetate and petroleum ether as eluents. Fractions are collected, checked for purity, combined and dried on a rotary evaporator. The EC1005 oil is assayed by LC and stored in a freezer until use.
	With dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃; for 16h;	To a solution of <strong>[41447-17-0]D-N-methyl pipecolinic acid</strong> (2.65 g, 18.5 mmol) in EtOAc (50 mL) were added pentafluorophenol (3.75 g, 20.4 mmol) and DCC (4.21 g, 20.4 mmol) . The reaction mixture was stirred at r.t. for 16 h, and then filtered over Celite. The filter pad was washed with 10 mL of EtOAc. The filtrate was used immediately without further purification or concentration.
	With dicyclohexyl-carbodiimide; In ethyl acetate; at 20℃; for 16h;	To a solution of D-N-methylpyridine acid (2.65 g, 18.5 mmol) in ethyl acetate (50 mL) was added pentafluorophenol (3.75 g, 20.4 mmol) and DCC (4.21 g, 20.4 mmol).The reaction was stirred at room temperature for 16 hours, filtered through celite, and washed with 10 mL of ethyl acetate.The filtrate was used without further purification.Use directly.

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 16018 - 16019
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 1530 - 1533
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 238 - 240
[4]Patent: US2014/363454,2014,A1 .Location in patent: Paragraph 0266
[5]Patent: WO2016/49313,2016,A1 .Location in patent: Page/Page column 58-59; 63
[6]Patent: WO2016/59622,2016,A2 .Location in patent: Page/Page column 96
[7]Patent: WO2016/89879,2016,A1 .Location in patent: Page/Page column 100
[8]Patent: US2017/348376,2017,A1 .Location in patent: Paragraph 0249; 0255; 0256
[9]Patent: WO2018/86139,2018,A1 .Location in patent: Page/Page column 143
[10]Patent: WO2019/127607,2019,A1 .Location in patent: Page/Page column 10; 161
[11]Patent: CN110621673,2019,A .Location in patent: Paragraph 0806-0808
[12]Patent: WO2020/73345,2020,A1 .Location in patent: Page/Page column 224

4
4-nitrophenyl L-isoleucinate hydrobromide [ No CAS ]
[ 41447-17-0 ]
[ 919518-56-2 ]

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 7235 - 7239

5
[ 943218-34-6 ]
[ 41447-17-0 ]
[ 919518-62-0 ]

Yield	Reaction Conditions	Operation in experiment
14.1 mg	With triethylamine; HATU; In N,N-dimethyl-formamide; at 0 - 25℃; for 24h;	(25,4/?)-Methyl 4-(2-((l/?,3/?)-l-acetoxy-4-methyl-3-((25,35)-3-methyl-2-((/i)-l-methylpipe ridine -2-carboxamido)pentanamido)pent yl)thiazole-4-carboxamido)-2-methyl-5-phenyl pentanoate (Tb53): To an ice-cooled stirred solution of Fmoc-derivative 83 (16.0 mg, 0.023 mmol) in CH2CI2 (2.5 mL) was added tris(2-aminoethyl)amine (0.04 mL, 0.3 mmol). The reaction mixture was stirred for 2 h at 25 C and then diluted with ethyl acetate (5 mL). The solution was washed with saturated aqueous NaHCCh solution (5 mL) and brine (5 mL), dried over Na2S04, and concentrated. The crude amine so obtained was used for the next step without further purification. To an ice-cooled stirred solution of (D)- V-methyl-pipecolinic acid 10 (6.6 mg, 0.05 mmol) in DMF (0.5 ml) at 0 C was added HATU (26 mg, 0.07 mmol) followed by the above obtained crude amine (10 mg, 0.02 mmol) and Et3N (0.02 mL, 0.14 mmol) and the reaction mixture was stirred at 25 C for 24 h. The reaction mixture was diluted with H20 (2 mL) and the resulting solution was extracted with EtOAc (3 ^ 5 mL). The combined organic extracts were washed with saturated aqueous NaHCCh solution (2 mL) and brine (5 mL), dried over Na2S04 and evaporated under reduced pressure. The obtained residue was purified by flash column chromatography (silica gel, 3?15% MeOH in CH2CI2) to afford analog Tb53 (14.1 mg, 85% for the two steps) as a white amorphous solid. Tb53: Rf = 0.50 (silica gel, 10% MeOH in CH2C12); [alpha] 2 = +4.64 (c = 0.69, MeOH); FT-IR (neat) fm{; : 3640, 3401, 2963, 2939, 2878, 1734, 1656, 1545, 1499, 1455, 1383, 1255, 1232, 1147, 1117, 1087, 1050, 1033, 842, 787, 741, 702 cm"1; NMR (600 MHz, CD3OD) delta 8.09 (s, 1H), 7.34 - 7.19 (m, 4H), 7.17 (t, J = 6.8 Hz, 1H), 5.93 (dd, J = 11.0, 2.5 Hz, 1H), 4.39 - 4.30 (m, 1H), 4.21 (d, J = 8.4 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.59 (s, 3H), 3.06 (d, J = 10.1 Hz, 1H), 2.92 - 2.84 (m, 2H), 2.81 (s, 1H), 2.64 - 2.56 (m, 1H), 2.34 (s, 3H), 2.32 - 2.20 (m, 2H), 2.15 (s, 3H), 2.09 - 2.03 (m, 1H), 1.99 (ddd, J = 13.6, 9.8, 3.6 Hz, 1H), 1.93 - 1.84 (m, 2H), 1.83 - 1.77 (m, 2H), 1.72 (ddd, J = 14.1, 10.4, 3.9 Hz, 2H), 1.68 - 1.55 (m, 3H), 1.41 - 1.34 (m, 1H), 1.26 - 1.17 (m, 1H), 1.14 (d, J = 7.1 Hz, 3H), 0.99 (d, J = 6.7 Hz, 3H), 0.97 - 0.73 (m, 9H) ppm; 13C NMR: (CD3OD, 150 MHz) delta = 176.3, 172.1, 171.7, 169.8, 169.7, 160.7, 148.8, 137.4, 128.4, 127.4, 125.5, 123.2, 69.2, 68.1, 57.4, 54.5, 50.3, 49.9, 48.3, 42.3, 40.4, 36.9, 36.1, 35.7, 35.5, 31.9, 29.3, 23.8, 23.7, 21.9, 18.8, 17.6, 16.4, 16.1, 14.3, 9.1 ppm; HRMS calcd for C38H57N507S [M+Na] + 750.3871 found 750.3860.

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 7235 - 7239
[2]Patent: WO2016/138288,2016,A1 .Location in patent: Page/Page column 157

6
[ 41447-17-0 ]
(αS,γR)-γ-[({2-[(1R,3R)-1-hydroxy-4-methyl-3-[(2S,3S)-3-methyl-2-([(2R)-1-methylpiperidin-2-yl]carbonyl}amino)-1-oxopentyl]amino}pentyl]-1,3-thiazol-4-yl}carbonyl)amino]-α-methyl-5-phenylpentanoic acid [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 7235 - 7239
[2]Angewandte Chemie - International Edition,2006,vol. 45,p. 7235 - 7239
[3]Patent: WO2016/138288,2016,A1
[4]Tetrahedron,2016,vol. 72,p. 5928 - 5933

7
[ 1193888-66-2 ]
[ 41447-17-0 ]
ethyl 2-((1R,3R)-3-((2S,3S)-N,3-dimethyl-2-((R)-1-methylpiperidine-2-carboxamido)pentanamido)-1-hydroxy-4-methylpentyl)thiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	To a solution of ethyl 2-{(1 R,3R)-1 -hydroxy-3-[L-isoleucyl(methyl)amino]-4-methylpentyl}-1 ,3- thiazole-4-carboxylate (17, 514.8 mg, 3.6 mmol) and DIPEA (1 .2 g, 9mmol) in DMF (20 mL) at 0 C was added TPTU (1 .1 g, 3.6 mmol). After stirring 15 min at 0 C, a solution of (2f?)-1 - methylpiperidine-2-carboxylic acid (CAS 41447-17-0) (1 .2 g, 3 mmol) in DMF (5 mL) was added. The resulting solution was stirred at rt overnight and poured into H20 (50 mL) and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHC03 (20 mL) and brine (20 mL), dried over Na2S04, and concentrated under vacuum to afford title compound 18 (1 .4 g, 85%) as a yellow oil

Reference： [1]Patent: WO2017/134547,2017,A1 .Location in patent: Page/Page column 80
[2]Journal of Organic Chemistry,2008,vol. 73,p. 4362 - 4369

8
[ 1005192-38-0 ]
[ 41447-17-0 ]
[ 1106949-47-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;palladium 10% on activated carbon; In ethyl acetate; for 26h;	Synthesis of '2-[I -hydroxy-4-methyl-3-(methyl-{3-methyl-2-[(l -methyl-piperidine-2-carbonyl)- aminoj-pentanoyl} -amino) -pentylJ-thiazole-4-carboxylic acid methyl ester (23)Pd/C (10 wt%, 242 mg) and azide 21 (359 mg, 0.683 mmol) were added to a 0.32 M solution of 22 (2.17 mmol) in 6.80 ml, of EtOAc (filtered through activated alumina). The reaction mixture was stirred under a hydrogen atmosphere for 26 h and then filtered through a plug of Celite. with washing of the filter pad with EtOAc. Normal-phase HPFC purification (99:1 to 95:5 EtOAc:MeOH) provided 483 mg of Mep-coupled product. The product was dissolved in 35.0 ml, of deoxygenated AcOH/H2O/THF (3: 1 : 1, v/v/v, 0.02 M) and stirred at rt for 28 h. Concentration followed by normal-phase HPFC purification (98:2 to 85:15 EtOAc:MeOH) afforded 302 mg (87%, over two steps) of 23 as an amorphous solid. The 1H NMR corresponds to a 7.5:1 mixture of rotamers, with the major isomer reported.[OC]23D = - 4.8 (c = 1.0, MeOH). IR: 1095, 1212, 1238, 1495, 1622, 1722, 2936 cm'1. 1H NMR (500 MHz, MeOD): delta 0.81 (d, 3H, J= 6.5 Hz), 0.91 (t, 3H, J= 7.5 Hz), 0.97 (d, 3H, J= 6.5 Hz), 0.99 (d, 3H, J = 6.5 Hz), 1.16-1.34 (m, 2H), 1.49-1.66 (m, 4H), 1.75 (d, 2H, J= 10.5 Hz), 1.77-1.86 (br s, IH), 1.89-2.01 (m, 2H), 2.02-2.09 (m, IH), 2.17 (s, 3H), 2.18-2.26 (m, IH), 2.57 (d, IH, J = 9.0 Hz), 2.85-2.95 (m, IH), 3.17 (s, 3H), 3.91 (s, 3H), 4.40-4.55 (br s, IH), 4.68 (d. IH, J = 9.5 Hz). 4.75 (d. IH, J= 9.0 Hz), 8.32 (s, IH). 13C NMR (125 MHz, MeOD): delta 11.2, 16.2. 20.5, 20.7, 24.4, 25.9, 26.3, 31.1, 31.6, 32.1, 37 7, 38.8, 44.9, 52.8, 55.0, 56.7, 69.9, 70.6, 129.3, 147 5, 163.2, 175.4, 175.7, 180.6. HRMS (FAB) calcd for C25H43N4O5S (M+H) 511.2954. Found: 511.2947.

Reference： [1]Patent: WO2009/12958,2009,A2 .Location in patent: Page/Page column 17; 43-44

9
[ 1200041-15-1 ]
[ 41447-17-0 ]
[ 1200041-17-3 ]

Yield	Reaction Conditions	Operation in experiment
50%		Alkylated dipeptide 3 (4.3 g, 7.0 mmol), N-methyl pipecolinate (MEP) (4.0 g, 28.0 mmol, 4 equiv) and pentafluorophenol (5.7 g, 30.8 mmol. 4.4 equiv) were added to a flask. N-methylpyrrolidone (NMP, 86 mE) was added to the mixture. To the mixture was added diisopropylcarbodiimide (DIC, 4.77 mE, 30.8 mmol, 4.4 equiv) was added to the mixture. The mixture was stirred at room temperature for 1 h. Pd/C (10%, dry, 1.7 g) was added. The flask was shaken under hydrogen (30-35 psi) for 5 hours. The reaction mixture was analyzed by HPEC. The starting material was found to be less than 3%. The mixture was filtered through diatomaceous earth. The diatomaceous earth was extracted with 200 mE ethyl acetate. The filtrate and the ethyl acetate extract were combined and transferred to a separatory thnnel and washed with 1% NaHCO3/10% NaC1 solution (200 mEx4). The organic layer was isolated and evaporated on a rotary evaporator under reduced pressure. The crude product was dissolved in 40 mE of MeOH/H20 (3:1). The crude product solution was loaded onto a Biotage Cl 8 column (Flash 65i, 350 g, 450 mE, 65x200 mm) and eluted with bufferA [10mM NH4OAc/ACN (1:1)1 and B (ACN, acetonitrile). The fractions were collected and organic solvent was removed by evaporating on a rotary evaporatot 100 mE of 10% NaC1 solution and 100 mE of methyl tert-butyl ether (MTBE) were added to the flask and the mixture was transferred to a separatory funnel. The organic layer was isolated and dried over anhydrous Na2504, filtered and evaporated on a rotary evaporator to dryness. 2.5 g of tripeptide intermediate 4 wasobtained (yield 50%).

Reference： [1]Organic Letters,2009,vol. 11,p. 5567 - 5569
[2]Patent: US2014/249315,2014,A1 .Location in patent: Paragraph 0216

10
[ 1265905-29-0 ]
[ 41447-17-0 ]
[ 1265905-33-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With 2,3,4,5,6-pentafluorophenol; 10% palladium on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 40h;	General procedure: To a solution of compound of 14 (1.10 g, 1.76 mmol) and pentafluorophenyl ester of D-Mep3 [prepared from D-Mep (755 mg, 5.27 mmol) in AcOEt (6 mL)] was added 10% Pd-C, and the mixture was stirred at room temperature under a hydrogen atmosphere for 40 h. The mixture was filtrated through a pad of Celite, and then concentrated in vacuo. Flash chromatography (silica gel, AcOEt:MeOH = 30:1) of the residue gave N-Methyl-D-pipecorinyl-L-isoleucinyl-1'-epi-N-[(3-methylbutanoyloxy)methyl]-(O-triethylsilyl)-tubuvaline methyl ester (765 mg, 60%) as a colorless oil: [alpha]26D +10.8 (c 0.51, CHCl3); 1H NMR (400 MHz, CD3OD) delta 0.55-0.68 (m, 6H), 0.76 (d, J = 6.7 Hz, 3H), 0.88-1.02 (m, 24H), 1.12-1.25 (m, 1H), 1.25-1.40 (m, 1H), 1.48-1.70 (m, 4H), 1.72-1.84 (m, 2H), 1.85-2.00 (m, 2H), 2.04-2.14 (m, 1H), 2.15-2.30 (m, 5H), 2.22 (s, 3H), 2.70 (br dd, J = 2.4, 11.1 Hz, 1H), 2.98 (br d, J = 11.6 Hz, 1H), 3.90 (s, 3H), 4.05 (br, 1H), 4.55 (br d, J = 8.6 Hz, 1H), 5.07 (t, J = 6.7 Hz, 1H), 5.42 (d, J = 12.2 Hz, 1H), 6.01 (d, J = 11.6 Hz, 1H), 8.37 (s, 1H); 13C NMR (100 MHz, CD3OD) delta 5.7, 7.1, 10.9, 16.4, 20.0, 20.7, 22.76, 22.79, 24.0, 25.7, 25.9, 26.7, 31.4, 32.9, 38.0, 42.7, 44.3, 44.5, 52.7, 55.3, 56.5, 70.1, 72.1, 129.6, 147.3, 163.1, 173.4, 174.7, 175.9, 177.4; IR (ATR) 1090, 1239, 1498, 1663, 1740, 2958 cm-1; MS (ESI+) m/z 725 [M+H]+; HRMS (ESI+) calcd for C36H65N4O7SSi [M+H]+ 725.4343, found 725.4350.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 431 - 434

11
[ 1265905-31-4 ]
[ 41447-17-0 ]
[ 1265905-34-7 ]

Yield	Reaction Conditions	Operation in experiment
40%	With 2,3,4,5,6-pentafluorophenol; 10% palladium on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 40h;	General procedure: To a solution of compound of 14 (1.10 g, 1.76 mmol) and pentafluorophenyl ester of D-Mep3 [prepared from D-Mep (755 mg, 5.27 mmol) in AcOEt (6 mL)] was added 10% Pd-C, and the mixture was stirred at room temperature under a hydrogen atmosphere for 40 h. The mixture was filtrated through a pad of Celite, and then concentrated in vacuo. Flash chromatography (silica gel, AcOEt:MeOH = 30:1) of the residue gave N-Methyl-D-pipecorinyl-L-isoleucinyl-1'-epi-N-[(3-methylbutanoyloxy)methyl]-(O-triethylsilyl)-tubuvaline methyl ester (765 mg, 60%) as a colorless oil

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 431 - 434

12
[ 1265905-32-5 ]
[ 41447-17-0 ]
[ 1265905-35-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 2,3,4,5,6-pentafluorophenol; 10% palladium on activated carbon; hydrogen; In ethyl acetate; at 20℃; for 40h;	General procedure: To a solution of compound of 14 (1.10 g, 1.76 mmol) and pentafluorophenyl ester of D-Mep3 [prepared from D-Mep (755 mg, 5.27 mmol) in AcOEt (6 mL)] was added 10% Pd-C, and the mixture was stirred at room temperature under a hydrogen atmosphere for 40 h. The mixture was filtrated through a pad of Celite, and then concentrated in vacuo. Flash chromatography (silica gel, AcOEt:MeOH = 30:1) of the residue gave N-Methyl-D-pipecorinyl-L-isoleucinyl-1'-epi-N-[(3-methylbutanoyloxy)methyl]-(O-triethylsilyl)-tubuvaline methyl ester (765 mg, 60%) as a colorless oil

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 431 - 434

13
C₁₇H₃₁N₅O₃ [ No CAS ]
[ 41447-17-0 ]
[ 1433634-51-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		To a solution of compound 13 (0.41 g, 0.9 mmol) in MeOH (5.6 mL) was added 3.5 N HCl in dioxane (2.57 mL, 9 mmol). The reaction mixture was stirred at room temperature for 3 h, and then was concentrated to give the corresponding amine as a colorless solid. To a solution of <strong>[41447-17-0]D-N-methyl pipecolinic acid</strong> (0.2 g, 1.4 mmol) in EtOAc (3 mL) was added pentafluorophenol (0.28 g, 1.5 mmol) and DCC (0.31 g, 1.5 mmol). The reaction mixture was stirred at room temperature for 24 h. The precipitate was then filtered and washed with EtOAc (2 mL). The activated ester in EtOAc was used immediately without further purification. To above amine was added the solution of above activated ester, followed by addition of DIEA (0.75 mL, 4.5 mmol). After stirring at room temperature for 30 h, the solvent was evaporated under reduced pressure. The resulting residue was purified by flash chromatography (1 : 30, MeOH/CH2Cl2) to provide the desired product (0.34 g, 80% yield) as a colorless solid. 1H NMR (400 MHz, CD3OD) delta 8.64 (s, 1H), 4.80-4.73 (m, 1H), 4.19 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.86-3.81 (m, 1H), 3.03-2.95 (m, 1H), 2.68-2.65 (m, 1H), 2.24 (s, 3H), 2.18-2.11 (m, 2H), 2.04-1.97 (m, 1H), 1.92-1.86 (m, 1H), 1.82-1.75 (m, 3H), 1.65-1.53 (m, 4H), 1.61 (d, J = 6.8 Hz, 3H), 1.27-1.17 (m, 2H), 0.99 (d, J = 6.8 Hz, 3H), 0.95-0.85 (m, 9H). 13C NMR (100 MHz, CD3OD) delta 175.3, 173.9, 162.5, 140.7, 127.8, 70.6, 59.3, 57.2, 56.7, 52.8, 52.6, 44.7, 40.2, 37.5, 33.9, 31.5, 26.1, 26.1, 24.3, 20.4, 19.8, 18.4, 16.3, 11.0. HRMS (ESI) for [C24H43N6O4]+: calcd. 479.3340, found 479.3346.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 2986 - 2988

14
C₂₈H₄₉N₅O₆SSi [ No CAS ]
[ 41447-17-0 ]
C₃₅H₆₂N₄O₇SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.64 g		EXAMPLE. S nthesis of tripeptide methyl ester 10. Based on 16.5 g of alkylated dipeptide 9 (26.97 mmol.), N-methyl pipecolinate (MEP) (5.51 g, 1.4 equiv.) and pentafluorophenol (7.63 g, 1.5 equiv.) were added to a 300 mL hydrogenation flask. NMP (115 mL) was then added, followed by EDC (7.78 g, 1.5 equiv.). The mixture was stirred at room temperature for overnight. 16.5 g of alkylated dipeptide 9 was dissolved in 16.5 mL NMP, transferred the solution into the hydrogenation flask, washed the residual 9 with 8 mL NMP, and transferred into the hydrogenation flask. Dry 10% Pd/C (1.45, 0.05 eq.) was added. The reaction mixture was vacuumed/back filled with hydrogen 3 times, and the flask was shaken under hydrogen (-35 psi) for 3.5 hours. The reaction mixture was analyzed by HPLC. The reaction mixture was filtered through 40 g of celite in a 350 mL sintered glass funnel and washed with 250 mL of EtOAc. The filtrate and the wash were transferred to a separatory funnel and washed with a 1% NaHCO3/10% NaCl solution (200 mL x 3). The organic layer was isolated and dried over 45.2 g of Na2S04. The solution was filtered and rotovaped under reduced pressure. A sticky amber residue was obtained and dried under high vacuum overnight to give 19.3 g of crude product. The crude product was dissolved in 10 mL of dichloromethane, split into two portions, and purified with a 330 g Teledyne Redisep Silica Gold column. The combined fractions of two purifications were evaporated and dried under high vacuum to give 7.64 g of 10 as a pale yellow solid (overall yield: 39% over 3 steps from compound 7).

Reference： [1]Patent: WO2014/78484,2014,A1 .Location in patent: Page/Page column 76-77

15
C₃₄H₅₃N₅O₆SSi [ No CAS ]
[ 41447-17-0 ]
C₄₁H₆₆N₄O₇SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5 mg		239mg of MEP (1.67 mmole, 1.5 eq), 316mg of EDC (1.65 mmole, 1.5 eq), and 300mg of pentafluorophenol (1.63 mmole, 1.5 eq) were dissolved in 8 mE of N-methyl-2- pyrrolidone. The reaction was stirred overnight. 759 mg (1.1 mmole) of the alkylated dipeptide 20 in 1 mE NMP was then added. An additional 0.8 mE of NMP was used to rinse the flask/syringe to transfer residue to the hydrogenation flask. 60 mg (0.05 eq) of 10% Pd/C was then added and the reaction mixture was hydrogenated at 35 PSI, overnight. EC/MS showed the major product is the benzyl ester, along with 10% free acid. The reaction was filtered through celite, and the filter cake was washed with EtOAc. The filtrate was extracted with brine, washed with brine, and concentrated. Combiflash purification with petroleum ether/EtOAc resulted in the recovery of2l 5mg (25%) ofbenzyl ester 21. ECMS: [M+H] mlz=787.66. ?H NMR (CDC13, oe in ppm): 8.09 (s, 1H), 7.44- 7.40 (m, 2H), 7.39-7.30 (m, 3H), 7.07 (d, J=15.5 Hz, 1H),5.93 (d, J=12.3 Hz, 1H), 5.42 (d, J=12.3 Hz, 1H), 5.34 (s, 2H),4.93 (dd, J=8.4, 2.7 Hz, 1H), 4.70-4.60 (m, 1H), 4.50-4.30 (br, 1H), 2.88 (m, 1H), 2.60-2.28 (m, 4H), 2.21 (s, 3H), 2.08-1.89 (m, 4H), 1.80-1.40 (m, 8H), 1.36-1.1.07 (m, 3H), 1.00-0.80 (m, 21H), 0.77 (d, 3H), 0.65 (t, 6H). ?3C NMR (CDC13, 6 in ppm): 177.5, 175.1, 174.1, 173.0, 161.1, 146.5, 135.8, 128.6, 128.4, 128.3, 127.6, 77.2, 70.7, 69.5, 69.2, 66.7, 57.3, 55.4,53.5, 53.4, 44.8, 41.3,36.8,35.9,31.4,30.3,25.0,24.7,23.2,20.2, 19.4, 18.1, 16.2, 13.6, 10.6, 6.8, 5.1, 4.7.

Reference： [1]Patent: US2014/249315,2014,A1 .Location in patent: Paragraph 0235; 0239

16
C₂₉H₅₃N₅O₅SSi [ No CAS ]
[ 41447-17-0 ]
C₃₆H₆₆N₄O₆SSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		0.38 g of MEP (2.65 mmole, 1.4 equiv.) was suspended in 1.2 mE NMP, 0.53 g of PFP (2.88 mmole, 1.5equiv.) and 0.55 g of EDC (2.87 mmole, 1.5 equiv.) wereadded. The reaction mixture was stirred overnight in a hydrogenation vessel. 1.17 g (1.91 mmole) of alkylated dipeptide EC1760 was dissolved in 0.3 mE NMP and transferred to the above hydrogenation vessel, and the residue of the dipeptide was rinsed with 0.3 mE NMP and transferred to the hydrogenation vessel. 154 mg of 10% Pd/C (dry, 0.05 equiv.) was added to the solution. The hydrogenation was carried out at 35 PSI. After 5 hrs, EC/MS showed there was no starting material. The reaction mixture was filtered through celite pad and the reaction vessel was washed with EtOAc and filtered through celite pad. The combined solution was washed with 10% NaC1/1% Na2CO3 solution to remove PFP, then with brine. The organic phase was dried over Na2504. Na2504 was filtered off and the solvent was evaporated under vacuum to give 1.20 g (88%) of crude product EC1761.

Reference： [1]Patent: US2014/249315,2014,A1 .Location in patent: Paragraph 0239; 0242

17
ethyl 2-((2R,4R)-4-((2S,3S)-2-amino-3-methylpentanamido)tetrahydro-2H-pyran-2-yl)thiazole-4-carboxylate [ No CAS ]
[ 41447-17-0 ]
ethyl 2-((2R,4R)-4-((2S,3S)-3-methyl-2-((R)-1-methylpiperidine-2-carboxamido)pentanamido)tetrahydro-2H-pyran-2-yl)thiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With triethylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In tetrahydrofuran; at 0 - 20℃; for 4.5h;Inert atmosphere;	Amine 12b (345 mg, 934 mumol) and d-Mep (13) (160 mg, 1.12 mmol) were dissolved in distilled THF (3.4 mL). The mixture was treated sequentially with Et3N (365 muL, 2.62 mmol) and DEPBT (670 mg, 2.24 mmol) at 0 C. After stirring at 0 C for 1 h and at room temperature for 3 h 30 min, the reaction was quenched with H2O (8 mL). According to the procedure described for the synthesis of 14a, it was worked up and purified by column chromatography (15:1:0.03 CH2Cl2/MeOH/Et3N) to afford 14b (315 mg, 68%) as a white solid. TLC: Rf 0.5 (7:1 CH2Cl2/MeOH). Mp: 143.7-145.7 C. [alpha]D22.9 = + 24.2 (c 1.01, CHCl3). IR (KBr, film): 3296, 2936, 1645, 1205 cm-1. 1H NMR (400 MHz, CDCl3): delta 8.14 (s, 1H), 7.09 (d, 1H, J = 8.4 Hz), 6.63 (d, 1H, J = 6.4 Hz), 4.90 (dd, 1H, J = 10.8, 2.8 Hz), 4.40 (q, 2H, J = 7.2 Hz), 4.31 (m, 1H), 4.15 (t, 1H, J = 8.4 Hz), 4.04 (ddd, 1H, J = 12.0, 4.4, 2.8 Hz), 3.83 (td, 1H, J = 12.0, 2.4 Hz), 2.92 (dm, 1H, J = 11.2 Hz), 2.50 (dd, 1H, J = 11.2, 3.6 Hz), 2.30 (d, 1H, J = 14.4 Hz), 2.22 (s, 3H), 2.13-1.93 (m, 5H), 1.76-1.72 (m, 2H), 1.64-1.50 (m, 3H), 1.44 (m, 1H), 1.39 (t, 3H, J = 7.2 Hz), 1.25-1.12 (m, 2H), 0.98 (d, 3H, J = 6.8 Hz), 0.94 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): delta 175.7, 172.8, 170.8, 161.6, 147.2, 127.8, 72.9, 69.8, 63.8, 61.6, 58.0, 55.6, 45.3, 42.5, 36.1, 36.0, 31.4, 30.1, 25.4, 25.3, 23.4, 16.2, 14.6, 11.4. HRMS (ESI) m/z calculated for C24H38N4O5S 494.2563, found 494.2565.