[ CAS No. 163768-50-1 ] {[proInfo.proName]}

Name: 163768-50-1|(S)-2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(Dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoic acid|99%
Brand: Ambeed
SKU: A516438
Rating: 90 (40 reviews)

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Cat. No.: {[proInfo.prAm]}

2D 3D

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Quality Control of [ 163768-50-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 163768-50-1 ]

SDS Specification

Alternatived Products of [ 163768-50-1 ]

Product Details of [ 163768-50-1 ]

CAS No. :	163768-50-1	MDL No. :	MFCD25976745
Formula :	C₄₀H₆₇N₅O₈	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LGNCNVVZCUVPOT-FUVGGWJZSA-N
M.W :	745.99	Pubchem ID :	67472795
Synonyms :

Calculated chemistry of [ 163768-50-1 ]

Physicochemical Properties

Num. heavy atoms :	53
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.72
Num. rotatable bonds :	25
Num. H-bond acceptors :	9.0
Num. H-bond donors :	3.0
Molar Refractivity :	210.87
TPSA :	157.82 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-9.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.68
Log Po/w (XLOGP3) :	2.57
Log Po/w (WLOGP) :	3.07
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	4.86
Consensus Log Po/w :	3.0

Druglikeness

Lipinski :	2.0
Ghose :	None
Veber :	2.0
Egan :	1.0
Muegge :	3.0
Bioavailability Score :	0.17

Water Solubility

Log S (ESOL) :	-4.52
Solubility :	0.0226 mg/ml ; 0.0000303 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.53
Solubility :	0.00219 mg/ml ; 0.00000294 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.87
Solubility :	0.001 mg/ml ; 0.00000135 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	7.09

Safety of [ 163768-50-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 163768-50-1 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 163768-50-1 ]

[ 163768-50-1 ] Synthesis Path-Downstream 1~35

1
[ 163768-50-1 ]
(4-aminophenyl)arsenous acid [ No CAS ]
[ 920017-32-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline In chloroform for 2h;	III.4; 19 [0477] To a solution of auristatin F (10 mg, 13 μmol) and p-aminoplienyl arsenoxide (3 mg, 16 μmol) in chloroform (200 μL) was added EEDQ (5 mg, 20 μmol). The reaction mixture was stirred for 2 hours before being concentrated by passing nitrogen gas over the reaction mixture. The resulting residue was dissolved in DMSO (0.5 mL) and purified via reverse-phase preparative chromatography (see infra). Product containing fractions were concentrated to give the 4.7 mg (35%) of the desired aldehyde: MS m/z (ES+), 929.5 (M+H).[0478] Preparative HPLC purifications was performed on a Varian instrument equipped with Cl 2 Phenomenex Synergy MAX-RP 4μ 250 x 21.2 mm reversed phase column, eluting with 0.05% formic acid in a water and acetonitrile gradient at a flow rate of 4.6 mL/min with a gradient of 10% organic for 3 min followed by a ramp up to 50% organic over 50 min.

Reference： [1]Current Patent Assignee: SEAGEN INC - WO2007/8848, 2007, A2 Location in patent: Page/Page column 146

2
[ 581065-95-4 ]
[ 163768-50-1 ]
[ 76-05-1 ]
[ 1415329-56-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of compound 23-3 (33mg, 0.102 mmol), compound 12-7 (40 mg, 0.051 mmol) and 54 mu^ of diisopropylethylamine in 1 mL of DMF was added 38 mg of HATU. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by HPLC to give 52 mg of compound 23-4. MS (ESI) m/z 525[M+2H], 1049[M+H].

Reference： [1]Patent: WO2012/166560,2012,A1 .Location in patent: Page/Page column 183

3
[ 163768-50-1 ]
C₁₈H₂₆N₄O₅*2ClH [ No CAS ]
[ 76-05-1 ]
2C₂HF₃O₂*C₉₈H₁₅₆N₁₄O₁₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine; C₁₈H₂₆N₄O₅*2ClH With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: trifluoroacetic acid	22 To a solution of compound 19-4 (7.6 mg, 0.017 mmol), compound 12-7 (40 mg, 0.051 mmol) and DIEA (0.030 mL, 0.17 mmol) in 2 mL of DMF was added 32 mg (0.085 mmol) of HATU. The reaction mixture was stirred at room temperature for 2 hour. The reaction mixture was purified by HPLC, eluting with 20-70% CH3CN/H20 in 20 min at 254 nm, to give 24 mg (68%) of compound 22-1. MS (ESI) m/z 612 [M+3H], 917 [M+2H], 1834[M+H].

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1 Location in patent: Page/Page column 181

4
[ 50-00-0 ]
[ 745017-94-1 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of compound 12-6 in DMF was added formylaldehyde (3eq) and 20 eq of acetic acid, followed by addition of 2 eq of sodium cyanoborohydride. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with water and purified by HPLC to give compound 12-7.
	With sodium cyanoborohydride; acetic acid; In N,N-dimethyl-formamide; for 2h;	To a solution of compound 12-6 in DMF was added formylaldehyde15 (3eq) and 20 eq of acetic acid, followed by addition of 2 eq of sodium cyanoborohydride. Theresulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was dilutedwith water and purified by HPLC to give compound 12-7.

Reference： [1]Patent: WO2012/166560,2012,A1 .Location in patent: Page/Page column 165
[2]Patent: WO2013/185117,2013,A1 .Location in patent: Paragraph 00454

5
[ 163768-50-1 ]
[ 1415329-31-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 2 h / 20 °C 2: hydrazine / N,N-dimethyl-formamide / 1 h / 20 °C
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 2 h / 20 °C 2: hydrazine / N,N-dimethyl-formamide / 1 h / 20 °C

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1

6
[ 163768-50-1 ]
[ 1415328-85-6 ]
[ 1415328-86-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;	12 To a solution of compound 12-10 (20 mg, 0.026 mmol) in 1 mL of DMF was added 11.2 mg of compound 12-10, 15 mg of HATU and 23 μ^ of DIEA. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was purified by HPLC to give 20 mg (70%>) of compound 12-4. MS (ESI) m/z 490 [M+2H], 978[M+H].
70%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h;	12 Compound 12-11: To a solution of compound 12-10 (20 mg, 0.026 mmol) in 1 mL ofDMF was added 11.2 mg of compound 12-10, 15 mg of HATU and 23 IlL of DIEA. The reactionmixture was stirred at room temperature for 2 hours. The reaction mixture was purified by HPLC togive 20 mg (70%) of compound 12-4. MS (ESI) m/z 490 [M+2H], 978[M+H].

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1 Location in patent: Page/Page column 165
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1 Location in patent: Paragraph 00456

7
[ 7524-50-7 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 4 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 4 h / 20 °C 4: water; lithium hydroxide / methanol / 2 h / 20 °C 5: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6: sodium cyanoborohydride; acetic acid / N,N-dimethyl-formamide / 2 h / 20 °C

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1

8
[ 1415246-54-6 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 4 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 4 h / 20 °C 4: water; lithium hydroxide / methanol / 2 h / 20 °C 5: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6: sodium cyanoborohydride; acetic acid / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 6 steps 1: HATU / N,N-dimethyl-formamide / 4 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3: HATU; 4-methyl-morpholine / N,N-dimethyl-formamide / 4 h / 20 °C 4: lithium hydroxide / 2 h / 20 °C 5: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 6: acetic acid; sodium cyanoborohydride / N,N-dimethyl-formamide / 2 h

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1

9
[ 1415246-55-7 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 2: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 4 h / 20 °C 3: water; lithium hydroxide / methanol / 2 h / 20 °C 4: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 5: sodium cyanoborohydride; acetic acid / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 5 steps 1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 2: HATU; 4-methyl-morpholine / N,N-dimethyl-formamide / 4 h / 20 °C 3: lithium hydroxide / 2 h / 20 °C 4: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 5: acetic acid; sodium cyanoborohydride / N,N-dimethyl-formamide / 2 h

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1

10
[ 1415246-58-0 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 4-methyl-morpholine; HATU / N,N-dimethyl-formamide / 4 h / 20 °C 2: water; lithium hydroxide / methanol / 2 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 4: sodium cyanoborohydride; acetic acid / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 4 steps 1: HATU; 4-methyl-morpholine / N,N-dimethyl-formamide / 4 h / 20 °C 2: lithium hydroxide / 2 h / 20 °C 3: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 4: acetic acid; sodium cyanoborohydride / N,N-dimethyl-formamide / 2 h

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1

11
[ 1415246-61-5 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: water; lithium hydroxide / methanol / 2 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3: sodium cyanoborohydride; acetic acid / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 3 steps 1: lithium hydroxide / 2 h / 20 °C 2: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 3: acetic acid; sodium cyanoborohydride / N,N-dimethyl-formamide / 2 h

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1

12
[ 1369427-27-9 ]
[ 163768-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 2: sodium cyanoborohydride; acetic acid / N,N-dimethyl-formamide / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 2 h / 20 °C 2: acetic acid; sodium cyanoborohydride / N,N-dimethyl-formamide / 2 h

Reference： [1]Current Patent Assignee: AMBRX, INC. - WO2012/166560, 2012, A1
[2]Current Patent Assignee: AMBRX, INC. - WO2013/185117, 2013, A1

13
[ 581065-95-4 ]
[ 163768-50-1 ]
trifluoroacetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52 mg	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 4h;	To a solution of compound 23-3 (33mg, 0.102 mmol), compound 12-7(40 mg, 0.051 mmol) and 54 ~tL of diisopropylethylamine in 1 mL of DMF was added 38 mg ofHATU. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was10 purified by HPLC to give 52 mg of compound 23-4. MS (ESI) m/z 525[M+2H], 1049[M+H].

Reference： [1]Patent: WO2013/185117,2013,A1 .Location in patent: Paragraph 00 513

14
[ 163768-50-1 ]
[ 1415659-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.75 h / 23 °C 2.1: dmap; diisopropyl-carbodiimide / 0.17 h / 0 °C / Cooling 2.2: 18 h / 23 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 23 °C
	Multi-step reaction with 3 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.75 h / 23 °C 2.1: diisopropyl-carbodiimide; dmap / dichloromethane / 0.17 h / 0 °C 2.2: 18 h / 23 °C 3.1: trifluoroacetic acid / dichloromethane / 1 h / 23 °C

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - WO2014/8375, 2014, A1
[2]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2

15
[ 163768-50-1 ]
[ 1415659-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: HATU; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.75 h / 23 °C 2.1: dmap; diisopropyl-carbodiimide / 0.17 h / 0 °C / Cooling 2.2: 18 h / 23 °C
	Multi-step reaction with 2 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.75 h / 23 °C 2.1: diisopropyl-carbodiimide; dmap / dichloromethane / 0.17 h / 0 °C 2.2: 18 h / 23 °C

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - WO2014/8375, 2014, A1
[2]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2

16
[ 163768-50-1 ]
[ 156-87-6 ]
[ 1415659-09-4 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 23℃; for 0.75h;	17 Synthesis of Auristatin F-hydroxypropylamide Auristatin F (150 mg, 0.201 mmol), HATU (153.0 mg, 0.402 mmol), and20 diisopropylethylamine (1 08 flL, 0.603 mmol) were taken up in DMF (5 mL) and 3-aminopropan-1-ol ( 45.9 flL, 0.603 mmol) was added. The mixture was stirred at 23 °C for 45 minutes at which time LCMS analysis showed complete disappearance of the startingmaterial. Reduction of the volume to 1.4 mL under high vacuum followed by purification viapreparative HPLC (1 0-90 solvent B gradient over 20 minutes eluting with 0.1 %TFA/Water,0.1% TF A/CH3CN) to give the title compound as white solid; 109 mg, 68 %yield.
68%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 23℃; for 0.75h;	48 Auristatin F (150 mg, 0.201 mmol), HATU (153.0 mg, 0.402 mmol), and diisopropylethylamine (108 μL, 0.603 mmol) were taken up in DMF (5 mL) and 3-aminopropan-1-ol (45.9 μL, 0.603 mmol) was added. The mixture was stirred at 23° C. for 45 minutes at which time LCMS analysis showed complete disappearance of the starting material. Reduction of the volume to 1.4 mL under high vacuum followed by purification via preparative HPLC (10-90 solvent B gradient over 20 minutes eluting with 0.1% TFA/Water, 0.1% TFA/CH3CN) afforded the title compound as white solid (109 mg, 68% yield).

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - WO2014/8375, 2014, A1 Location in patent: Paragraph 00466
[2]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2 Location in patent: Page/Page column 515; 516

17
[ 163768-50-1 ]
[ 1353016-71-3 ]
C₅₈H₇₈N₆O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl acetamide;pH 7.5;	Fig. 13 shows the synthesis of an antibody conjugate via the phosphamide linkers containing two function groups, wherein one group is linked to a cytotoxic agent, MMAF for targeted killing, and the other one is linked to a fluorochrome group for monitoring the interaction of the conjugate with a targeted cell.

Reference： [1]Patent: US2015/284416,2015,A1 .Location in patent: Paragraph 0050

18
[ 163768-50-1 ]
1-aminopropan-2-yl-auristatin-F trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: benzotriazol-1-ol; diisopropyl-carbodiimide / dichloromethane / 0.17 h / 0 °C 1.2: 45 °C / Sealed tube 2.1: dichloromethane / 0.5 h / 23 °C

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2

19
[ 163768-50-1 ]
(S)-2-hydroxypropylamide auristatin-F trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.75 h / 23 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.33 h 2.2: 20 °C

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2

20
[ 163768-50-1 ]
[ 1415659-17-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: diisopropyl-carbodiimide; dmap / dichloromethane / 20 °C / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 2 h / 20 °C / Cooling

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2

21
[ 163768-50-1 ]
[ 1415659-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.75 h / 23 °C 2.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.33 h 2.2: 20 °C

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2

22
[ 163768-50-1 ]
tert-butyl 2-hydroxypropylcarbamate [ No CAS ]
1-(tert-butoxycarbonylamino)propan-2-yl-auristatin F [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane at 0℃; for 0.166667h; Stage #2: tert-butyl 2-hydroxypropylcarbamate In dichloromethane at 45℃; Sealed tube;	39 To Auristatin F (150.0 mg, 0.201 mmol) and HOBt (32.6 mg, 0.241 mmol) in 5 mL dichloromethane was added diisopropylcarbodiimide (68.5 μL, 0.442 mmol). The mixture was stirred at 0° C. for 10 minutes at which point a precipitate was observed. tert-Butyl-2-hydroxypropylcarbamate (881.0 mg, 5.03 mmol) in 2 mL dichloromethane was added. The reaction mixture was stirred at 45° C. in a sealed vial and the progress of the reaction monitored via LCMS. Additional HOBt (30.0 mg, 0.222 mmol) was added at 2.5 and 6 hours and the mixture stirred for 18 hours. Additional HOBt (54.3 mg, 0.402 mmol) and diisopropylcarbodiimide (43.1 mg, 0.342 mmol) were added and the mixture stirred at 45° C. for an additional 9 hours at which time LCMS analysis showed complete disappearance of the starting material. The solvent was removed under reduced pressure and the residue dissolved in 3 mL DMF. The sample was purified via preparatory HPLC; (10-90 solvent B gradient over 10 minutes, eluting with 0.1% TFA/Water, 0.1% TFA/CH3CN). The water was removed via lyophilization to give the title compound as a white solid. (1348) 1-(Tert-butoxycarbonylamino)propan-2-yl-auristatin F (150 mg, 0.166 mmol) was taken up in dichloromethane (5 mL) and 2,2,2-trifluoroacetic acid (0.256 mL, 3.32 mmol) was added. The mixture was stirred at 23° C. for 30 minutes at which time LC/MS indicated complete conversion. The solvent was reduced to 1 mL under reduced pressure. Dropwise addition of the solution to stirring diethyl ether gave the title compound (27.5 mg, 0.027 mmol. 16%) as a white solid which was collected via filtration.

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2 Location in patent: Page/Page column 501-503

23
[ 163768-50-1 ]
[ 58885-58-8 ]
[ 76-05-1 ]
(x)C₂HF₃O₂*C₄₈H₈₂N₆O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine; N-tert-butoxycarbonyl-3-aminopropanol With dmap; diisopropyl-carbodiimide In dichloromethane at 20℃; Cooling with ice; Stage #2: trifluoroacetic acid In water; acetonitrile	64 To a solution of auristain F (100 mg, 0.134 mmol) in DCM (5 ml) cooled in an ice/salt bath was added DIC (0.052 ml, 0.335 mmol), tert-butyl 3-hydroxypropylcarbamate (117 mg, 0.670 mmol) and DMAP (82 mg, 0.670 mmol) and the resulting mixture was stirred cold for 2 h and then overnight at room temperature. The reaction mixture was purified by HPLC followed by lyophilized to give the tert-butyl carbamate protected title compound as a white amorphous solid (121 mg, 89% yield) M/z=903.5. (1406) To an ice cold solution of the tert-butyl carbamate protected title compound 2,2,2-trifluoroacetate (121 mg, 0.119 mmol) in DCM (4 ml) was added TFA (500 μl, 6.49 mmol) and the resulting mixture was stirred cold for 1 h and then at room temperature for 1 h. After removal of the excess TFA, the title compound was isolated by precipitation into ethyl ether as a white amorphous solid (109 mg, 93% yield); M/z=803.4.

Reference： [1]Current Patent Assignee: MERSANA THERAPEUTICS, INC. - US9144615, 2015, B2 Location in patent: Page/Page column 537; 538

24
[ 163768-50-1 ]
[ 660-88-8 ]
auristatin F-C₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 0.666667h; Stage #2: 5-aminopentanoic acid In N,N-dimethyl-formamide at 20℃; for 4h;	50 Auristatin F (0.1 g, 0.116 mmol) and HATU (40 mg, 0.104 mmol) was dissolved in DMF (3 ml) and DIPEA (40 μΙ) was added to it. The reaction mixture was stirred at room temperature for 40 min and then added dropwise to a solution of 5- Aminovaleric acid (15 mg, 0.127 mmol) in DMF (2 ml). The reaction mixture was stirred at room temperature for 4h and evaporated in vacuo. The crude product was purified on Biotage flash purification system using C18 column to yield the compound Auristatin F-Cs acid 87 as a white solid (85 mg, 84%). LC-MS ESI m/z 867.5 [M+Na]+

Reference： [1]Current Patent Assignee: ANTIKOR BIOPHARMA - WO2016/46574, 2016, A1 Location in patent: Page/Page column 147

25
[ 163768-50-1 ]
[ 660-88-8 ]
C₄₉H₇₉N₇O₁₁ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.67 h / 20 °C 1.2: 4 h / 20 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C

Reference： [1]Current Patent Assignee: ANTIKOR BIOPHARMA - WO2016/46574, 2016, A1

26
[ 163768-50-1 ]
[ 107-18-6 ]
(S)-allyl 2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropanamido)-3-phenylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; carbon dioxide; diallyl dicarbonate at 0 - 20℃; for 2.25h;	45 Example 45:Preparation of drug-linker compounds with quaternized auristatin F incorporating glucuronide units Auristatin F C-terminal protection:The round bottom flask was charged with auristatin F 184 (150 mg, 201 μmol) and dissolved in allyl alcohol (10 mL).The reaction was cooled to 0 & lt; 0 & gt; C and allyl pyrocarbonate (149 mg, 804 [mu] mol) was added followed by DMAP (7.3 mg, 60 [mu] mol).The reaction spewed CO2 intensely and slowed after 15 minutes.The reaction was stirred for 2 hours at RT and then analyzed by UPLC, resulting in> 90% conversion.The reaction was concentrated in vacuo and the crude was purified by silica gel chromatography (0-25% MeOH). Concentrate the parts in dry conditionA solution of 111 mg (71%) of (S) -allyl 2 - ((2R, 3R) -3 - ((S) -1 - ((3R, 4S, 5S) -4- (S) -2- (dimethylamino) -3-methylbutane2-yl) -3-methoxy-2-methylpropanamido) -3- (2-pyridyl) Phenylpropanoate (185).

Reference： [1]Current Patent Assignee: SEAGEN INC - KR2017/53648, 2017, A Location in patent: Paragraph 0680; 1418-1419

27
[ 163768-50-1 ]
C₂₄H₄₈N₆O₇SSi₂ [ No CAS ]
C₆₄H₁₁₃N₁₁O₁₄SSi₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide	20 Example 20: (S)-N-((3R,4S,5S)-1-((S)-2-((7S,10R,11R)-7-benzyl-2-hydroxy-2,10-dimethyl- 6,9-dioxo-12-oxa-5,8-diaza-2-silatridecan-11-yl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1- oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide Example 20: (S)-N-((3R,4S,5S)-1-((S)-2-((7S,10R,11R)-7-benzyl-2-hydroxy-2,10-dimethyl- 6,9-dioxo-12-oxa-5,8-diaza-2-silatridecan-11-yl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1- oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide [00139] The title compound can be prepared according to the scheme shown below.

Reference： [1]Current Patent Assignee: BLINKBIO - WO2017/214491, 2017, A1 Location in patent: Paragraph 00139

28
[ 163768-50-1 ]
(S)-N-((3R,4S,5S)-1-((S)-2-((7S,10R,11R)-7-benzyl-2-hydroxy-2,10-dimethyl-6,9-dioxo-12-oxa-5,8-diaza-2-silatridecan-11-yl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-oxoheptan-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide 2: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid sodium salt / dimethyl sulfoxide; water / pH 5

Reference： [1]Current Patent Assignee: BLINKBIO - WO2017/214491, 2017, A1

29
[ 163768-50-1 ]
[ 144222-22-0 ]
C₅₁H₈₇N₇O₉ [ No CAS ]
auristatin F piperidinyl amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 95.9 %Chromat. 2: 4.1 %Chromat.	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 1h; Cooling with ice; Overall yield = 100 %; Overall yield = 44.5 mg;	6.6.25.6.25.1 6.25.1. Synthesis of the ligand AF-pip (L8) Auristatin F (AF) (30.0 mg, 40 pmol, 1.0 eq.), dissolved in DMF (1.00 mL), was added to tert- butyl 4-(aminomethyl)piperidine-l-carboxylate (22.9 mg, 60 pmol, 1.5 eq). HATU (12.9 mg, 60 pmol, 1.5 eq.) and DIPEA (13.96 pL, 101 pmol, 2.5 eq.) were subsequently added and the mixture was stirred for 1 h in an ice bath. The reaction mixture was concentrated, dissolved in water/MeCN (3.5: 1, 3 mL), and filtered through a 0.2 pm syringe filter. Purification was performed by preparative reverse-phase HPLC (Grace Alltima C18 5 pm column, 22 x 250 mm; gradient: 20 to 100% MeCN/0.1% TFA in water/0.1% TFA in 36 min). Product fractions were concentrated resulting in a colorless solid (44.5 mg, quant.). HPLC (Grace Alltima C18 5 mih column, 25 x 4.6 mm) indicated that the product compound L8-Boc was 100.0% pure (95.9% compound L8-Boc: retention time 14.9 min and 4.1% Boc- deprotected compound compound L8: retention time 9.3 min; gradient: 20 to 100% MeCN/0.l% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). The obtained compound L8-Boc was dissolved in DCM (2 mL) and TFA (2 mL) was added. The mixture was stirred for 45 min at room temperature, followed by concentration under reduced pressure. The residue was dissolved in 10% MeOH/DCM (2 mL) and loaded on an ISOLUTE SCX-2 column, pre-washed with DCM (10 mL). The column was washed with 10% MeOH/DCM (20 mL), and the product was eluted with 1 M methanolic ammonia in DCM (1 : 1). The combined product fractions were concentrated and co-evaporated with MeOH several times to remove traces of ammonia affording a colorless solid (22.7 mg, 63.0% yield). (0440) HPLC (Grace Alltima C18 5 mih column, 25 x 4.6 mm) indicated that the product was 100% pure (retention time 9.3 min; gradient: 20 to 100% MeCN/0.1% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). HRMS (ESI+) C46H81N7O7 [M+2H]2+ calc 421.8093, found 421.8071

Reference： [1]Current Patent Assignee: LINXIS BV - WO2019/125153, 2019, A1 Location in patent: Page/Page column 86-87

30
[ 163768-50-1 ]
[ 144222-22-0 ]
auristatin F piperidinyl amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22.7 mg	Stage #1: ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine; tert-butyl 4-(aminomethyl)piperidine-1-carboxylate With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 0.75h;	6.6.25.6.25.1 6.25.1. Synthesis of the ligand AF-pip (L8) Auristatin F (AF) (30.0 mg, 40 pmol, 1.0 eq.), dissolved in DMF (1.00 mL), was added to tert- butyl 4-(aminomethyl)piperidine-l-carboxylate (22.9 mg, 60 pmol, 1.5 eq). HATU (12.9 mg, 60 pmol, 1.5 eq.) and DIPEA (13.96 pL, 101 pmol, 2.5 eq.) were subsequently added and the mixture was stirred for 1 h in an ice bath. The reaction mixture was concentrated, dissolved in water/MeCN (3.5: 1, 3 mL), and filtered through a 0.2 pm syringe filter. Purification was performed by preparative reverse-phase HPLC (Grace Alltima C18 5 pm column, 22 x 250 mm; gradient: 20 to 100% MeCN/0.1% TFA in water/0.1% TFA in 36 min). Product fractions were concentrated resulting in a colorless solid (44.5 mg, quant.). HPLC (Grace Alltima C18 5 mih column, 25 x 4.6 mm) indicated that the product compound L8-Boc was 100.0% pure (95.9% compound L8-Boc: retention time 14.9 min and 4.1% Boc- deprotected compound compound L8: retention time 9.3 min; gradient: 20 to 100% MeCN/0.l% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). The obtained compound L8-Boc was dissolved in DCM (2 mL) and TFA (2 mL) was added. The mixture was stirred for 45 min at room temperature, followed by concentration under reduced pressure. The residue was dissolved in 10% MeOH/DCM (2 mL) and loaded on an ISOLUTE SCX-2 column, pre-washed with DCM (10 mL). The column was washed with 10% MeOH/DCM (20 mL), and the product was eluted with 1 M methanolic ammonia in DCM (1 : 1). The combined product fractions were concentrated and co-evaporated with MeOH several times to remove traces of ammonia affording a colorless solid (22.7 mg, 63.0% yield). (0440) HPLC (Grace Alltima C18 5 mih column, 25 x 4.6 mm) indicated that the product was 100% pure (retention time 9.3 min; gradient: 20 to 100% MeCN/0.1% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). HRMS (ESI+) C46H81N7O7 [M+2H]2+ calc 421.8093, found 421.8071

Reference： [1]Current Patent Assignee: LINXIS BV - WO2019/125153, 2019, A1 Location in patent: Page/Page column 86-87

31
[ 163768-50-1 ]
tert-butyl 4-(12-amino-3-oxo-7.10-dioxa-2.4-diazadodecyl)piperidine-1-carboxylate [ No CAS ]
tert-butyl 4-((15S,18R,19R)-15-benzyl-19-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutanamido)-N,3-dimethylbutanamido)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-18-methyl-3,14,17-trioxo-7,10,20-trioxa-2,4,13,16-tetraazahenicosyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide for 1.5h; Cooling with ice;	6.6.13.6.13.1 6.13.1. Synthesis of the ligand AF-PEG2-urea-pip (L7) Auristatin F (AF) (40.0 mg, 54 pmol, 1.0 eq.), dissolved in DMF (1.33 mL), was added to tert- butyl 4-(l2-amino-3 -oxo-7, lO-dioxa-2, 4-diazadodecyl)piperi dine- l-carboxylate (62.5 mg, 161 pmol, 3.0 eq.; synthesis is described in Sijbrandi el a/. , Cancer Res. 2017, 72, 257-267) in DMF (1 mL). HATU (40.8 mg, 107 pmol, 2.0 eq.) and DIPEA (29 pL, 161 pmol, 3.0 eq.) were subsequently added and the mixture was stirred for 1.5 h in an ice bath. The reaction mixture was concentrated, dissolved in water/MeCN (3.5: 1, 3 mL), and filtered through a 0.2 mih syringe filter. Purification was performed by preparative reverse-phase HPLC (Grace Alltima C18 5 mih column, 22 x 250 mm; gradient: 30 to 50% MeCN/0.1% TFA in water/0.1% TFA in 36 min). Product fractions were concentrated under reduced pressure resulting in a colorless solid (56 mg, 85% yield). HPLC (Grace Alltima C18 5 mih column, 25 x 4.6 mm) indicated that the product compound L7-Boc was 100% pure (retention time 19.8 min; gradient: 5 to 50% MeCN/0.1% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). HRMS (ESI+) C5SHIO2N9OI2 [M+H]+ calc 1116.7642, found 1116.7774 The obtained compound L7-Boc was dissolved in DCM (2 mL) and TFA (2 mL) was added. The mixture was stirred for 45 min at room temperature, followed by concentration under reduced pressure. The residue was dissolved in 10% MeOH/DCM (2 mL) and loaded on an ISOLUTE SCX-2 column, pre- washed with DCM (10 mL). The column was washed with 10% MeOH/DCM (20 mL), and the product was eluted with 1 M methanolic ammonia in DCM (1 : 1). The combined product fractions were concentrated under reduced pressure and co- evaporated with MeOH several times to remove traces of ammonia affording a colorless solid (34 mg, 73% yield). HPLC (Grace Alltima C18 5 pm column, 25 x 4.6 mm) indicated that the product was 99% pure (retention time 9.2 min; gradient: 20 to 100% MeCN/0.1% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). FIRMS (ESI+) C53H94N9O10 [M+H]+ calc 1016.7118, found 1016.6976
	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide; acetonitrile at 0 - 4℃; for 0.333333h;

Reference： [1]Current Patent Assignee: LINXIS BV - WO2019/125153, 2019, A1 Location in patent: Page/Page column 69-70
[2]Aydin, Ibrahim; Houthoff, Hendrik-Jan; Laarhoven, Paul; Merkul, Eugen; Muns, Joey A.; Peters, Ruud J. R. W.; Sijbrandi, Niels J.; Van Dongen, Guus A. M. S. [Green Chemistry, 2020, vol. 22, # 7, p. 2203 - 2212]

32
[ 163768-50-1 ]
tert-butyl 4-(12-amino-3-oxo-7.10-dioxa-2.4-diazadodecyl)piperidine-1-carboxylate [ No CAS ]
N-(3-oxo-1-(piperidin-4-yl)-7,10-dioxa-2,4-diazadodecan-12-yl)-auristatin F amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 1.5 h / Cooling with ice 2: trifluoroacetic acid / dichloromethane / 0.75 h / 20 °C

Reference： [1]Current Patent Assignee: LINXIS BV - WO2019/125153, 2019, A1

33
[ 6066-82-6 ]
[ 163768-50-1 ]
C₄₄H₇₀N₆O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide In dichloromethane	17 EXAMPLE 17 SYNTHESIS OF NHS ACTIVATED AURISTATIN F (AF-NHS) Auri statin F was converted to an NHS activated using standard coupling conditons as indicated in the reaction scheme above.

Reference： [1]Current Patent Assignee: SONY CORPORATION - WO2020/210694, 2020, A1 Location in patent: Page/Page column 142-143

34
[ 163768-50-1 ]
[ 220298-96-4 ]
tert-butyl (4-((2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-3-phenylpropionamido)methyl)phenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.0 mg	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃;	1.1 Step 1: Synthesis of tert-butyl (4-((2-((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5 methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionamido)-3-phenylpropionamido)methyl)phenyl)carbamate. At room temperature, 1-hydroxybenzotriazole (2.0 mg, 14.74 μmol) was dissolved in N,N-dimethylformamide (4 mL), cooled to 0°C., and then tert-butyl 4-methylaminobenzyl carbamate (4.0 mg, 16.1 μmol), N,N-diisopropylethylamine (8.5 mg, 66.8 μmol), ((2R,3R)-3-((S)-1-((3R,4S,5S)-4-((S)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutyrylamino)-3-methoxy-5-methylheptanoyl)pyrrolidin-2-yl)-3-methoxy-2-methylpropionyl)-L-phenylalanine (10.0 mg, 13.5 μmol, commercially available) were successively added. After being stirred for 5 min, 1H-benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (10.0 mg, 20.1 μmol) was added thereto, and stirred at 0°C. for 1 h. The reaction of raw materials was monitored by high performance liquid chromatography-mass spectrometry. After the raw materials were consumed up, the reaction solution was purified by preparative liquid chromatography (method D) to obtain the title compound (9.0 mg of white solid). [0286] ESI-MS (m/z): 950.5 [M+H] +.

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2020/347075, 2020, A1 Location in patent: Paragraph 0285-0286

35
[ 163768-50-1 ]
[ 220298-96-4 ]
(2S)-N-((3R,4S,5S)-1-((2S)-2-((1R,2R)-3-((1-((4-aminobenzyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-1-methoxy-2-methyl-3-propionyl)pyrrolidin-1-yl)-3-methoxy-5-methyl-1-heptanoyl-4-yl)-2-((S)-2-(dimethylamino)-3-methylbutyrylamino)-N,3-dimethylbutanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; benzotriazol-1-ol / N,N-dimethyl-formamide / 0 - 20 °C 2: hydrogenchloride / 1,4-dioxane / 3 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - US2020/347075, 2020, A1

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Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
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P243	Take precautionary measures against static discharge.
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P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
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P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
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P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
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P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
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. 163768-50-1 ] {[proInfo.proName]}

Quality Control of [ 163768-50-1 ]

Related Doc. of [ 163768-50-1 ]

Product Details of [ 163768-50-1 ]

Calculated chemistry of [ 163768-50-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 163768-50-1 ]

Application In Synthesis of [ 163768-50-1 ]

[ 163768-50-1 ] Synthesis Path-Downstream 1~35

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry