[ CAS No. 32677-01-3 ] {[proInfo.proName]}

Name: 32677-01-3|H-Glu(OtBu)-OtBu.HCl|98%
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2D 3D

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Quality Control of [ 32677-01-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 32677-01-3 ]

Product Details of [ 32677-01-3 ]

CAS No. :	32677-01-3	MDL No. :	MFCD00058003
Formula :	C₁₃H₂₆ClNO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LFEYMWCCUAOUKZ-FVGYRXGTSA-N
M.W :	295.80	Pubchem ID :	208636
Synonyms :	H-Glu(OtBu)-OtBu hydrochloride	Chemical Name :	H-Glu(OtBu)-OtBu.HCl

Calculated chemistry of [ 32677-01-3 ]

Physicochemical Properties

Num. heavy atoms :	19
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.85
Num. rotatable bonds :	8
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	76.92
TPSA :	78.62 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) :	-6.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	2.19
Log Po/w (WLOGP) :	2.58
Log Po/w (MLOGP) :	1.83
Log Po/w (SILICOS-IT) :	1.68
Consensus Log Po/w :	1.66

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.53
Solubility :	0.882 mg/ml ; 0.00298 mol/l
Class :	Soluble
Log S (Ali) :	-3.47
Solubility :	0.0991 mg/ml ; 0.000335 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.18
Solubility :	1.95 mg/ml ; 0.00658 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.98

Safety of [ 32677-01-3 ]

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 [ 32677-01-3 ]

* 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 [ 32677-01-3 ]
Downstream synthetic route of [ 32677-01-3 ]

[ 32677-01-3 ] Synthesis Path-Upstream 1~5

1
[ 32677-01-3 ]
[ 56-86-0 ]
[ 2419-56-9 ]
[ 45120-30-7 ]

Reference： [1] Patent: US2004/30177, 2004, A1, . Location in patent: Page 3

2
[ 32677-01-3 ]
[ 56-86-0 ]
[ 2419-56-9 ]
[ 45120-30-7 ]

Reference： [1] Patent: US2004/30177, 2004, A1, . Location in patent: Page 3

3
[ 617-65-2 ]
[ 115-11-7 ]
[ 32677-01-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sulfuric acid; nitrogen In sodium hydroxide; chloroform	Example 5 Di-t-butyl L-glutamate Hydrochloride (15A) Glutamic acid 14 (4.4 g, 30 mmol) was suspended in chloroform (120 mL) and sulfuric acid (3 mL, 56 mmol) was added. The suspension was cooled at -78° C. and condensed isobutylene (70 mL) was added. The reaction mixture was stirred allowing to warm to room temperature for 18 h. After 18 hr, all the suspended solid had dissolved to a clear solution. Nitrogen was bubbled through the solution for 10 min, then it was extracted with aqueous NaHCO₃ (2*100 mL) and distilled water (100 mL). The organic layer was dried (MgSO₄), evaporated, and kept in a dessicator over NaOH pellets for 48 h to afford 15 (6.7 g, 86percent) as an oil. ¹H-NMR δ_H: 1.39 (s, 9H, COO-t-Bu), 1.41 (s, 9H, COO-t-Bu), 1.60-1.90 (2 m, 2H, CH₂CH(NH₂)-), 2.15-2.35 (m, 2H, CH₂COO), 2.85 (s, 2H, NH₂), 3.20-3.35 (m, 1H, CH(NH₂)-). MS (ESI): 260 (M⁺+H, 100), 283 (M⁺+Na, 10).

Reference： [1] Patent: US2004/87813, 2004, A1,

4
[ 16881-41-7 ]
[ 32677-01-3 ]

Reference： [1] Recueil des Travaux Chimiques des Pays Bas, 1983, vol. 102, # 11, p. 469 - 474

5
[ 540-88-5 ]
[ 138-15-8 ]
[ 32677-01-3 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 20, p. 3294 - 3302

[ 32677-01-3 ] Synthesis Path-Downstream 1~36

1
[ 5891-45-2 ]
[ 32677-01-3 ]
[ 32719-56-5 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 160 - 165

2
[ 32677-01-3 ]
[ 34897-61-5 ]
[ 32719-56-5 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 1809 - 1813

3
[ 32677-01-3 ]
[ 76-83-5 ]
[ 125127-49-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In dichloromethane at 20℃; for 16h;	1 Preparation of Intermediates II; 1 . Trityl protection; Tritylchloride (2.05 g. 7.36 mmol) was added to a solution of di-ie f-butyl L-glutamate hydrochloride (2.15 g, 7.27 mmol) and triethylamine (5 mL, 36 mmol) in dichloromethane (20 mL). The solution was stirred for overnight (16 h) at room temperature. The solution was washed with sodium bicarbonate solution (3 x 10 mL) and water (2 x 5 mL). After drying over sodium sulphate, the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/n-hexa ne: 2/98 to 3/97) to g ive di-ie f-butyl /V-trityl-L- glutamate (3.2 g, 88%) as a white foam.di-ie f-butyl /v-trityl-L-glutamate1H NMR (400 MHz, CDCI3) δ ppm 1 .17 (s, 9H), 1 .47 (s, 9H), 1 .90-1 .20 (m, 3H), 2.51 (ddd, 1 H), 2.76 (br. d, 1 H), 3.37 (br. s, 1 H), 7.16-7.21 (m, 3H), 7.24-7.29 (m, 6H), 7.51 (br. d, 6H).
21%	With triethylamine In dichloromethane for 18h; Ambient temperature;
18%	With sodium carbonate; triethylamine In dichloromethane at 20℃; for 24h;	4 Di -t- butyl N- trityl glutamate Tree dissolved in triethylamine (40 mL) and trityl chloride (19.0 g, 68.5 mmol) and MeCl2 (100 mL)Di -t- butyl-glutamate hydrochloride (20.0 g, 68 mmol, Sigma (SIGMA), cat : G-7501) was added to. The solution after the sodium carbonate saturated solution was stirred at room temperature for 24 hours (3 ×) and washed with water (3 ×). The organic phase was dried over MgSO4 and the solvent removed in vacuo and purification of the resulting orange color oil by flash (flash) chromatography on silica gel in hexane / MeCl2 (30/70). The obtained white solid was the desired product containing a trityl -OH residue. Dissolving the resulting mixture in a minimal amount of MeCl2, and by the addition of hexane and crystallizing the trityl alcohol. This colorless oil was obtained after filtration and removal of the solvent mixture. Yield: 6.0 g (18%). TLC: Rf = 0.5 (MeCl2).

18%

With triethylamine In dichloromethane at 20℃; for 24h;

4 Example 4 Di-t-butyl N-tritylglutamate Example 4 Di-t-butyl N-tritylglutamate Triethylamine (40 ml) and trityl chloride (19.0 g, 68.5 mmol) were added to di-t-butylglutamic acid hydrochloride (20.0 g, 68 mmol, SIGMA, catNo.: G-7501), dissolved in MeCl2 (100 ml). The solution was stirred at room temperature for 24 h and subsequently washed with saturated sodium carbonate solution (3*) and water (3*). The organic phase was dried over MgSO4, the solvent was removed in vacuo and the resulting orange-colored oil was purified by flash chromatography on silica gel in hexane/MeCl2 (30/70). The white solid obtained contained the product accompanied by a residue of trityl-OH. The trityl alcohol was crystallized by dissolving the product mixture in a minimal amount of MeCl2 and addition of hexane. After filtration and removal of the solvent mixture, a colorless oil was obtained. Yield: 6.0 g, (18%). TLC: Rf=0.5 (MeCl2). Elemental analysis C32H39NO4. found C, 76.4; H, 7.6; N, 2.9; calculated: C, 76.6; H, 7.8; N, 2.8.

Reference： [1]Current Patent Assignee: LIFE HEALTHCARE GROUP HOLDINGS (PTY) LTD - WO2012/150204, 2012, A1 Location in patent: Page/Page column 51-52
[2]Baldwin, Jack E.; North, Michael; Flinn, Anthony; Moloney, Mark G. [Tetrahedron, 1989, vol. 45, # 5, p. 1453 - 1464]
[3]Current Patent Assignee: RUSSIAN ACADEMY OF SCIENCES; LIFE HEALTHCARE GROUP HOLDINGS (PTY) LTD - KR101495924, 2015, B1 Location in patent: Paragraph 0927; 0928
[4]Current Patent Assignee: RUSSIAN ACADEMY OF SCIENCES; LIFE HEALTHCARE GROUP HOLDINGS (PTY) LTD - US9375497, 2016, B2 Location in patent: Paragraph 41

4
[ 540-88-5 ]
[ 138-15-8 ]
[ 32677-01-3 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 3294 - 3302

5
[ 58933-52-1 ]
[ 32677-01-3 ]
[ 162877-53-4 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1998,vol. 46,p. 255 - 273

6
[ 446-31-1 ]
[ 32677-01-3 ]
[ 85803-27-6 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1998,vol. 46,p. 255 - 273

7
[ 1205-30-7 ]
[ 32677-01-3 ]
2-(4-chloro-3-sulfamoyl-benzoylamino)-pentanedioic acid di-<i>tert</i>-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 20℃; for 16h;

Reference： [1]Mincione, Francesco; Starnotti, Michele; Menabuoni, Luca; Scozzafava, Andrea; Casini, Angela; Supuran, Claudiu T. [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 13, p. 1787 - 1791]

8
[ 39978-57-9 ]
[ 32677-01-3 ]
[ 450407-87-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With triethylamine In dichloromethane

Reference： [1]Forsch, Ronald A.; Wright, Joel E.; Rosowsky, Andre [Bioorganic and Medicinal Chemistry, 2002, vol. 10, # 6, p. 2067 - 2076]

9
[ 32677-01-3 ]
[ 94695-48-4 ]
[ 298211-20-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine In dichloromethane
	With triethylamine In dichloromethane at 0 - 20℃; for 18h;	4.i To an ice-cold solution of di-tert-butyl L-glutamate hydrochloride (6.6 g, 22.4 mmol) and Et3N (6.9 ml, 50 mmol) in dry CH2Cl2 (70 ml) was.added, over a period of 1.5 hr, 2,3,4,5-tetrafluorobenzoyl chloride (5.0 g, 23.5 mmol) in dry CH2Cl2 (20 ml) and thirty minutes later the solution was allowed to warm to room temperature. Sixteen hours later the solution was washed with H2O, dried (MgSO4) and evaporated to dryness. 1H NMR δ 1.40 + 1.42 (2s, 18H, t-butyl), 1.85 + 1.95 (2m, 2H, CH2CH), 2.34 (t, 2H, CH2CO, J = 7.5Hz), 4.3 (m, 1H, CH), 7.57 (m, 1H, H6), 8.80 (d, 1H, NH, J = 7. 5Hz) ; 19F NMR δ -138.6 + 139.0 (2m, 2F, F2+5), -152.4 (m, 1H, F4), -154.9 (t, 1F, F3, J = 20Hz).

Reference： [1]Davies, Lawrence C.; Friedlos, Frank; Hedley, Douglas; Martin, Jan; Ogilvie, Lesley M.; Scanlon, Ian J.; Springer, Caroline J. [Journal of Medicinal Chemistry, 2005, vol. 48, # 16, p. 5321 - 5328]
[2]Current Patent Assignee: CANCER RESEARCH UK - EP1165493, 2005, B1 Location in patent: Page 23

10
[ 32677-01-3 ]
[ 177787-26-7 ]
di-tert-butyl 3,4,5-trifluorobenzoyl-L-glutamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine In dichloromethane

11
[ 32677-01-3 ]
[ 56-86-0 ]
[ 2419-56-9 ]
[ 45120-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	With water; sodium acetate; at 50℃; for 25h;pH 4.9;Conversion of starting material;	[0036] A reaction mixture containing 670 mM of L-glu-di-tert-butyl ester HCl and 2 mole equivalents of sodium acetate, pH 4.9, was stirred in a round bottomed flask fitted with a condenser and Therm-o-watch [12R, Cheltenhana, Pa.], at 50 C. Samples were taken over time intervals and analyzed by HPLC for L-glu-alpha-tert-butyl ester alpha-monoester), L-glu-gamma-tert-butyl ester (gamma-monoester), L-glu-di-tert-butyl esters (diester) and L-glutamic acid (diacid). [0037] The results which are present in TABLE I show that under the reaction condition set forth above, approximately half of the substrate (diester) was hydrolyzed within 25 hours. The product of the hydrolytic reaction included alpha-monoester, gamma-monoester, and diacid. However, gamma-monoester was predominant, indicating that the hydrolysis was selective for the alpha-ester group.

Reference： [1]Patent: US2004/30177,2004,A1 .Location in patent: Page 3

12
[ 617-65-2 ]
[ 115-11-7 ]
[ 32677-01-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sulfuric acid; nitrogen In sodium hydroxide; chloroform	5 Di-t-butyl L-glutamate Hydrochloride (15A) Example 5 Di-t-butyl L-glutamate Hydrochloride (15A) Glutamic acid 14 (4.4 g, 30 mmol) was suspended in chloroform (120 mL) and sulfuric acid (3 mL, 56 mmol) was added. The suspension was cooled at -78° C. and condensed isobutylene (70 mL) was added. The reaction mixture was stirred allowing to warm to room temperature for 18 h. After 18 hr, all the suspended solid had dissolved to a clear solution. Nitrogen was bubbled through the solution for 10 min, then it was extracted with aqueous NaHCO3 (2*100 mL) and distilled water (100 mL). The organic layer was dried (MgSO4), evaporated, and kept in a dessicator over NaOH pellets for 48 h to afford 15 (6.7 g, 86%) as an oil. 1H-NMR δH: 1.39 (s, 9H, COO-t-Bu), 1.41 (s, 9H, COO-t-Bu), 1.60-1.90 (2 m, 2H, CH2CH(NH2)-), 2.15-2.35 (m, 2H, CH2COO), 2.85 (s, 2H, NH2), 3.20-3.35 (m, 1H, CH(NH2)-). MS (ESI): 260 (M++H, 100), 283 (M++Na, 10).

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON - US2004/87813, 2004, A1

13
[ 32315-10-9 ]
[ 63628-63-7 ]
[ 32677-01-3 ]
[ 1025796-30-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: bis(trichloromethyl) carbonate; L-glutamic acid di-tert-butyl ester hydrochloride With triethylamine In dichloromethane at -78 - 20℃; for 0.5h; Stage #2: N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With triethylamine In dichloromethane at 20℃; for 12h;	{9S13S)-tri-tert-btttyI 3 l~dioxo-l-phei>yl-2-o:xa-4,ie,12-trtazapeiitad caie-9, 13,15- cteHw -"^ co_:(._& trica r boxy la te (12): 1 .1 (1.0g, 3.38 mtaai, 1.0 equiv.) ami triethylamine f f ( (1 .54 fflL, 1 1.09 mmoU 3.28 equiv.) were dissolved in dichloromethane n (30 mL) and cooled to -78' C, Triphosgeiie i'341 tag, 1.15 mmol, 0,34 equiv.) in dichloromethane (10 mL) was added clropwtse to the reaction mixture. Upon complete addition, the reaction was allowed to warm to room temperature and stirred for 30 minutes. 12 (757 mg, 2.03 mmol, 0.6 equiv) was added, followed by the addition of riethyamine (283 pjL, 2.03 mmo'l, 0,6 equiv.). The reaction was allowed to stir at room temperature overnight for 1 hours. The reaction was then diluted with dichloromethane (50 mL), and washed with water (1.00 mL x. 2). The crude mixture was dried over Na?SQt and concentrated under reduced pressure. Column chromatography (Silica 1 .5:1 hexane: ethyl acetate) yielded 4 (1 .09g, 86%) as a colorless oil with the following spectral characteristics: IR (thin film/ Br) 3342 . 2976 , 1731 5 1650 , 1552 . 1454 , 1368 , 1255 , and 1153 cm" 5; lH NMR (500 MHz, CD() δ 7.35 ( 9H), 1.40-1.30
68.5%	Stage #1: bis(trichloromethyl) carbonate; N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2.5h; Stage #2: L-glutamic acid di-tert-butyl ester hydrochloride In dichloromethane for 12h;	2.2.9. Synthesis of (S)-2-[3((S)-(5-Benzyloxycarbonylamino)-1-tertbutoxycarbonylpent-ylureido]pentanedioic acid Di-tert-butyl ester (9) In a round-bottom flask triphosgene (0.58 g, 2 mmol) was suspendedin DCM (20 mL) and stirred at 0 C. A solution of Cbz-Lys-OtBu (1.82 g,5.4 mmol) and DIPEA (2.1 mL, 12 mmol) in DCM (20 mL) was addeddropwise to the triphosgene solution over 2.5 h. A solution of L-glutamicacid di-tert-butyl ester hydrochloride (1.6 g, 5.4 mmol) containingDIPEA (2.1 mL, 12 mmol) and DCM (20 mL) was then added in oneportion and allowed to stir for 12 h. The mixture was concentrated todryness, diluted with 150 mL of ethyl acetate, washed with 2 N NaHSO4(2 × 200 mL), brine (150 mL), and dried over sodium sulfate to yield ayellow oil. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give 9 (2.35 g, 3.7 mmol, 68.5%) as colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 5H), 5.40-5.27 (m, 3H), 4.98(q, J = 12 Hz, 2H), 4.23 (d, J = 16 Hz, 2H), 3.05 (dp, 2H), 2.22-2.09 (m,3H), 1.97-1.59 (m, 4H), 1.32 (d, J = 8 Hz, 27H). 13C NMR (101 MHz,CDCl3) δ 172.87, 172.58, 172.40, 172.34, 172.17, 157.12, 156.66,136.75, 128.43, 128.01, 127.94, 82.13, 81.97, 81.58, 80.45, 66.45,53.45, 53.26, 52.98, 52.85, 40.69, 32.61, 31.57, 29.33, 28.42, 28.32,28.06, 28.00, 27.98, 22.37. TOF-HRMS calculated for C32H52N3O9,[M+H]+ m/z 622.3698, found 622.3690.
68.5%	Stage #1: bis(trichloromethyl) carbonate; N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 2.5h; Stage #2: L-glutamic acid di-tert-butyl ester hydrochloride In dichloromethane for 12h;	2.2.9. Synthesis of (S)-2-[3((S)-(5-Benzyloxycarbonylamino)-1-tertbutoxycarbonylpent-ylureido]pentanedioic acid Di-tert-butyl ester (9) In a round-bottom flask triphosgene (0.58 g, 2 mmol) was suspendedin DCM (20 mL) and stirred at 0 C. A solution of Cbz-Lys-OtBu (1.82 g,5.4 mmol) and DIPEA (2.1 mL, 12 mmol) in DCM (20 mL) was addeddropwise to the triphosgene solution over 2.5 h. A solution of L-glutamicacid di-tert-butyl ester hydrochloride (1.6 g, 5.4 mmol) containingDIPEA (2.1 mL, 12 mmol) and DCM (20 mL) was then added in oneportion and allowed to stir for 12 h. The mixture was concentrated todryness, diluted with 150 mL of ethyl acetate, washed with 2 N NaHSO4(2 × 200 mL), brine (150 mL), and dried over sodium sulfate to yield ayellow oil. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give 9 (2.35 g, 3.7 mmol, 68.5%) as colorless oil. 1HNMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 5H), 5.40-5.27 (m, 3H), 4.98(q, J = 12 Hz, 2H), 4.23 (d, J = 16 Hz, 2H), 3.05 (dp, 2H), 2.22-2.09 (m,3H), 1.97-1.59 (m, 4H), 1.32 (d, J = 8 Hz, 27H). 13C NMR (101 MHz,CDCl3) δ 172.87, 172.58, 172.40, 172.34, 172.17, 157.12, 156.66,136.75, 128.43, 128.01, 127.94, 82.13, 81.97, 81.58, 80.45, 66.45,53.45, 53.26, 52.98, 52.85, 40.69, 32.61, 31.57, 29.33, 28.42, 28.32,28.06, 28.00, 27.98, 22.37. TOF-HRMS calculated for C32H52N3O9,[M+H]+ m/z 622.3698, found 622.3690.

Stage #1: bis(trichloromethyl) carbonate; L-glutamic acid di-tert-butyl ester hydrochloride With triethylamine In dichloromethane at -78℃; Stage #2: N-[(phenylmethoxy)carbonyl]-L-lysine-1,1-dimethylethylester

Reference： [1]Current Patent Assignee: YALE UNIVERSITY - WO2019/10201, 2019, A1 Location in patent: Page/Page column 66
[2]Fang, Hanyi; Gai, Yongkang; Li, Mengting; Ma, Xiang; Wang, Sheng; Xiang, Guangya [Bioorganic and Medicinal Chemistry, 2022, vol. 60]
[3]Fang, Hanyi; Gai, Yongkang; Li, Mengting; Ma, Xiang; Wang, Sheng; Xiang, Guangya [Bioorganic and Medicinal Chemistry, 2022, vol. 60]
[4]Current Patent Assignee: YALE UNIVERSITY - WO2013/166110, 2013, A1 Location in patent: Sheet 7

14
[ 32315-10-9 ]
[ 32677-01-3 ]
[ 105590-97-4 ]
2-[3-(3-benzyloxycarbonyl-1-tert-butoxycarbonylpropyl)ureido]pentanedioic acid di-tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A 500 mL round bottom flask was charged with compound 2, glutamic acid with tert-butyl protection groups on each hydroxyl group of each carboxylic acid group (6.0 g, 20.28 mmol, 1 equiv) and triphosgene (1.805 g, 6.69 mmol, 0.333 equiv) under an argon atmosphere. Approximatley 210 mL of dichloromethane was added under inert atmosphere to give a clear solution and cooled to -78 C. in dry ice/acetone bath (Suspension VIII-A). Triethylamine (9.9 mL, 8.19 mmol, 3.5 equiv) was added drop wise to the reaction mixture (Suspension VIII-A) in 10 minutes to form a thick white suspension. Reaction mixture was allowed to warm to room temperature and stirred for 3 hours at room temperature (Suspension VIII-A). Another 100 mL round bottom flask was charged with compound 15, glutamic acid with a tert-butyl protection group on the hydroxyl group of the alpha carboxylic acid group and a benzyl group on the hydroxyl of the side chain carboxylic acid (6.69 g, 20.28 mmol, 1.0 equiv) and dissolved in 40 mL of DCM (Solution VIII-B). Triethylamine (5.65 mL, 40.56 mmol, 2.0 equiv) was added to the suspension VIII-B in 2 minutes followed by drop wise addition of suspension VIII-B to suspension VIII-A via cannula over the period of 30 minutes to give a white suspension. The reaction was stirred at 23 C. for 12 hours. 400 mL of 1 M aqueous HCl was added to the reaction and stirred for additional 1 hour. The reaction mixture was extracted using EtOAc three 200 mL extractions. The combined organic extracts were washed with 100 mL of water two times followed by 100 mL of brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 3 as clear thick oil (14.10 g), which was subjected to the next step without further purification.

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 12733 - 12736
Angew. Chem.,2018,vol. 130,p. 12915 - 12918,4
[2]Journal of Drug Targeting,2013,vol. 21,p. 968 - 980
[3]Patent: US2017/66719,2017,A1 .Location in patent: Paragraph 0324; sheet 1
[4]Patent: US2018/99934,2018,A1 .Location in patent: Paragraph 0303-0305

15
[ 53525-65-8 ]
[ 32677-01-3 ]
[ 76-05-1 ]
(S)-2-(1H-imidazole-5-carboxamido)pentanedioic acid trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		a) Synthesis of (S)-2-(lH-imidazole-5-carboxamido)pentanedioic acid TFA (S)-2-(1 H-imidazole-5- carboxamido)pentanedioic acid Diimidazo[l,5-a]piperazine-5,10-dione 376 mg (2 mmol) was dissolved in 20 mL dry THF. H-Glu(Oi-Bu)Oi-Bu HCI 1.2 g (4 mmol) and triethyl amine 3 mL (20 mmol) were added to the solution at 0 C and the reaction was stirred overnight at room temperature. After the solvent was removed under vacuum, the tert-butyl protected intermediate was obtained by flash column chromatography. Then, this intermediate was dissolved in 5 mL TFA/DCM(1/1) for 2 hours at room temperature. After all the solvent was removed under vacuum, compound (S)-2-(lH-imidazole-5- carboxamido) pentanedioic acid was purified by HPLC as a white powder 310 mg, yield 23 %. 1H NMR (400 MHz, D20): delta 8.69 (s,lH), 7.91 (s, 1H), 4.47 (dd, Jl = 7.2 Hz, J2 = 3.9 Hz, 1H), 2.38 (t, 7 = 5.4 Hz, 2H), 2.20-2.11(m, 1H), 2.01-1.94(m, 1H) 13C NMR (100 MHz, D20): 5177.0, 174.6, 162.8(q, TFA), 158.7, 135.5, 126.6, 120.7, 116.4 (q, TFA), 52.4, 29.8, 25.6; HPLC (Waters Atlantis, MeCN/H20 8/92, 10 mL/min): 9.5 min.

Reference： [1]Patent: WO2014/182538,2014,A1 .Location in patent: Page/Page column 27

16
C₁₇H₁₇I₂N₃OPt [ No CAS ]
[ 32677-01-3 ]
[ 6092-80-4 ]
C₃₅H₄₁I₂N₄O₅Pt [ No CAS ]

Reference： [1]European Journal of Inorganic Chemistry,2015,vol. 2015,p. 1665 - 1668

17
[ 55750-62-4 ]
[ 32677-01-3 ]
di-tert-butyl (2S)-2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]pentanedicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 19h;	(0202) (1-15A) Synthesis of di-tert-butyl (2S)-2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]pentanedicarboxylate (compound 1-15A: compound of the following formula) (0203) (0204) A solution of di-tert-butyl (2S)-2-aminopentanedicarboxylate hydrochloride (295 mg, 1.00 mmol) in N,N-dimethylformamide (5.0 mL) was cooled to 0C. N,N-Diisopropylethylamine (0.510 mL, 3.00 mmol) and (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)propanoate (293 mg, 1.10 mmol) were added thereto in this order, and the mixture was stirred at 0C for 1 hour, further heated to room temperature, and stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with 1 M hydrochloric acid and saturated saline in this order, then dried over anhydrous sodium sulfate, and filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. This product was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 - 0:100, v/v) to obtain the title compound 1-15A as a pale yellow oil (400 mg, yield: 98%). 1H-NMR (CDCl3) delta: 6.70 (2H, s), 6.22 (1H, d, J = 7.8 Hz), 4.48-4.42 (1H, m), 3.91-3.79 (2H, m), 2.60-2.52 (2H, m), 2.35-2.18 (2H, m), 2.13-2.04 (1H, m), 1.93-1.84 (1H, m), 1.46 (9H, s), 1.44 (9H, s).

Reference： [1]Patent: EP2949665,2015,A1 .Location in patent: Paragraph 0202; 0203; 0204

18
[ 32315-10-9 ]
[ 32677-01-3 ]
[ 73259-81-1 ]
(R)-2-amino-3-(3-((S)-1,5-di-tert-butoxy-1,5-dioxopentan-2-yl)ureido)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 100%		L-glutamic acid di-tert-butyl ester hydrochloride 600 mg (2 mmol) and triethylamine 1 mL were dissolved in 20 mL anhydrous methylenechloride. The solution was cooled to -78 C. Triphosgene 200 mg (0.66 mmol) was dissolved in 3 mL anhydrous methylene chloride and added by drop. The reaction was slowly warmed up to room temperature and stirred for 30 mi (R)-3-amino-2-((tert- butoxycarbonyl)amino)propanoic acid 400 mg (2 mmol) and triethylamine 0.4 mL were added. The reaction was kept at room temperature for 24 h. The organic layerwas washed with 2N HC1 and dried with sodium sulfate. After the solvent was removed under vacuum, 1.0 g (R)-2-amino-3 -(3 -((S)-i ,5-di-tert-butoxy- 1,5- dioxopentan-2-yl)ureido)propanoic acid was obtained and used for the next steps without further purification. The yield was around 100%. (?H NMR (400 MHz, CDC13): oe 6.17-6.00(br, 3H). 4.31(m, 2H), 3.71-3.51(m, 2H), 2.37-2.32(m, 2H), 2.11-2.06(m, 1H), 1.91-1.80(m, 1H) 1.51-1.41(m, 27H). MS: 446 (M+H)

Reference： [1]Patent: WO2016/65142,2016,A2 .Location in patent: Page/Page column 68

19
[ 63628-63-7 ]
[ 32677-01-3 ]
[ 7693-46-1 ]
C₃₂H₅₁N₃O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: L-glutamic acid di-tert-butyl ester hydrochloride; 4-Nitrophenyl chloroformate With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester With N-ethyl-N,N-diisopropylamine In dichloromethane for 1h; Inert atmosphere;	EC1380 In a dry flask, H-Glu(0u)-0u.HCl (2.48g , 8.41 mmol) and 4-nitrophenyl chloroformate (1.86 g, 9.25 mmol, 1.1 eq) were added, dissolved in CH2CI2 (30ml) under Argon atmosphere. The stirring solution was chilled to 0 °C, followed by the dropwise addition of DIPEA (4.50 ml, 25.2 mmol, 3 eq). The reaction mixture was allowed to warm to room temperature and stirred for 1 hr. To the stirring solution was added H-Lys-(Z)-0u (4.39 g, 11.8 mmol, 1.4 eq), DIPEA (4.50 ml, 25.2 mmol, 3 eq) and stirred for 1 hr. Upon completion, the reaction was quenched with saturated NaHCC and extracted with CH2CI2 three times. The organic extracts were combined, dried over Na2S04, filtered and the solvent was removed via reduced pressure. The product was purified using silica gel chromatography with petroleum ether and ethyl acetate. The Cbz protected amine was transferred to a round bottom flask with 10% Pd/C (10% wt eq), dissolved in MeOH (30 ml) under Hydrogen atmosphere (latm) and stirred for 3 hr. Upon completion, the reaction mixture was filtered through celite and the solvent was removed via reduced pressure to yield the crude amine. The amine was taken up in CH2CI2 (30ml) under Argon atmosphere and chilled to 0 °C. To the chilled solution was added 4-nitrophenyl chloroformate (2.2 g, 10.9 mmol, 1.3 eq) and DIPEA (6.0 ml, 33.6 mmol, 4 eq) subsequently and stirred for 2 hr at room temperature. The reaction mixture was quenched with saturated NH4CI and extract three times with ethyl acetate. The organic extracts were combined, dried over Na2S04, filtered, and solvent was removed under vacuum and purified using silica gel chromatography to yield the desired activated amine, EC1380 (2.54 g, 46%).

Reference： [1]Current Patent Assignee: PURDUE UNIVERSITY SYSTEM; Novartis (w/o Sandoz); NOVARTIS AG - KR2016/79887, 2016, A Location in patent: Paragraph 0482-0484

20
[ 32315-10-9 ]
[ 32677-01-3 ]
[ 5978-22-3 ]
[ 1025796-30-8 ]

Yield	Reaction Conditions	Operation in experiment
92.3%		0A solution of L-glutamic acid di-tertbutyl ester hydrochloride (1.5 g, 5.07 mmol) and triethylamine (2.31 mL, 16.63 mmol) inCH2Cl2 (40 mL) was cooled to -78C in a dry ice/acetone bath. Triphosgene (525 mg,1.77 mmol) dissolved in CH2Cl2 (10 mL) was added dropwise to the reaction. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 minutes. H-Lys(cbz)-OtBu hydrochloride (1.5 g, 4.06 mmol) was then added to the reaction mixture, followed by triethylamine (566 1iL, 4.06 mmol). After stirred overnightfor 17 h, the reaction mixture was diluted with CH2C12 (50 mL) and washed with H20 (60 mL x 2). The organic phase was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluted with 3:2 hexane/EtOAc to obtain the desired product HTK-01018 as colorless oil (2.32 g, 92.3%).

Reference： [1]Patent: WO2017/117687,2017,A1 .Location in patent: Paragraph 0095; 00102; 00103

21
[ 119-24-4 ]
[ 32677-01-3 ]
C₂₇H₃₅N₇O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	the compound 1 tiet acid (4 g, 12.8 mmol) and compound 2 glutamic acid di-tert-butyl ester hydrochloride (4.9 g, 16.6 mmol), added to the dimethyl formamide (100 - 200 ml) in, added HBTU (7.3 g, 19.2 mmol), HOBt (2.6 g, 19.2 mmol) and diisopropyl serotonin reuptake (6.5 g, 50 mmol), the mixture by stirring at room temperature overnight, the reaction liquid is poured into the distilled water (1000 ml), precipitated solid, filtered, distilled water, to obtain the solid crude product. The filtrate is extracted with ethyl acetate, drying, to remove the solvent, to obtain the solid crude product, the two part of the solid merger, vacuum drying, it is crude compound 3 (5 g), yield 70.5%;

Reference： [1]Patent: CN107245082,2017,A .Location in patent: Paragraph 0028

22
[ 32677-01-3 ]
[ 5978-22-3 ]
[ 7693-46-1 ]
[ 1025796-30-8 ]

Yield	Reaction Conditions	Operation in experiment
86%		In a 250mL round-bottom flask, H-Glu(OtBu)-OtBu?HC1 (101) (4.83g, 16.3 mmol,available from Sigma-Aldrich) and 4-nitrophenyl chloroformate (102) (3.47g, 17.2 mmol,available from Sigma-Aldrich) were dissolved in dichloromethane (5OmL) and stirred in an ice bath under argon. Diisopropylethylamine (6.28mL, 36.1 mmol) was added slowly, dropwise and the reaction mixture was stirred in the ice bath for 5 mm, then warmed to room temperature and stirred for 30 mm. H-Lys(Z)-OtBu.HC1 (103) (7.Olg, 18.8 mmol) was added portionwise,followed by dropwise addition of diisopropylethylamine (6.54mL, 37.5 mmol), and stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, then purified by silica gel chromatography in 10-100% ethyl acetate/petroleum ether to yield 104 (8.76g, 86%, ESI mlz = 622.54 [M+H]+).
86%		In a 250 mL round-bottom flask, H-Glu(OtBu)-OtBu.HCl (101) (4.83 g, 16.3 mmol, available from Sigma-Aldrich) and 4-nitrophenyl chloroformate (102) (3.47 g, 17.2 mmol, available from Sigma-Aldrich) were dissolved in dichloromethane (50 mL) and stirred in an ice bath under argon. Diisopropylethylamine (6.28 mL, 36.1 mmol) was added slowly, dropwise and the reaction mixture was stirred in the ice bath for 5 min, then warmed to room temperature and stirred for 30 min. H-Lys(Z)-OtBu.HCl (103) (7.01 g, 18.8 mmol) was added portionwise, followed by dropwise addition of diisopropylethylamine (6.54 mL, 37.5 mmol), and stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, then purified by silica gel chromatography in 10-100% ethyl acetate/petroleum ether to yield 104 (8.76 g, 86%, ESI m/z=622.54 [M+H]+).

Reference： [1]Patent: WO2017/205447,2017,A1 .Location in patent: Page/Page column 71
[2]Patent: US2018/36364,2018,A1 .Location in patent: Paragraph 0225; 0226

23
[ 32677-01-3 ]
[ 105590-97-4 ]
2-[3-(3-benzyloxycarbonyl-1-tert-butoxycarbonylpropyl)ureido]pentanedioic acid di-tert-butyl ester [ No CAS ]

Reference： [1]Molecular Pharmaceutics,2018,vol. 15,p. 1842 - 1852

24
[ 32677-01-3 ]
[ 5978-22-3 ]
[ 1025796-30-8 ]

Reference： [1]Chemical Communications,2018,vol. 54,p. 7810 - 7813

25
[ 32677-01-3 ]
[ 69610-41-9 ]
(S)-di-tert-butyl 2-((((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)amino)pentanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium cyanoborohydride; acetic acid In methanol at 20℃; for 2h;	(S)-di-tert-butyl 2-((((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)methyl)amino)pentanedioate (2) To a solution of (S)-tert-butyl 2-formylpyrrolidine-1-carboxylate (1) (2 g, 10.04 mmol) and H-Glu(OBut)-OBut.HCl (2.96 g, 10.04 mmol) in dry MeOH (126 mL) and AcOH (1.26 mL), NaBH3C N was added portionwise. The reaction mixture was stirred for 2 h at room temperature. After evaporation, the residue was taken up with AcOEt and washed with 1 N KHSO4, NaHCO3, and brine. The organic layer was dried and evaporated. The crude was purified in a chromatographic column using CHCl3/MeOH (97:3) as eluant to give compound 2. Rf= 0.69, CHCl3/MeOH 97:3. Yield: 82%; 1H-NMR (CDCl3) δ: 1.41 (9H, s, C(CH3)3), 1.44 (18H, s, 2 x C(CH3)3), 1.66-2.02 (7H, m, 3 x CH2 + NH), 2.29-2.38 (2H, m, CH2), 2.42-2.59 (2H, m, CH2), 3.04-3.11 (1H, s, CH), 3.26-3.35 (2H, m, CH2), 3.69-3.74 (1H, m, CH); 13C-NMR (CDCl3) δ: 23.18 (CH2), 28.33-28.75 (3 x C(CH3)3), 28.97 (CH2), 29.71 (CH2), 32.31 (CH2), 46.69 (CH2), 50.98 (CH2), 57.40 (CH), 61.69 (CH), 79.46 (C), 80.44 (C), 81.37 (C), 154.92-174.86 (3 x CO). Anal. Calcd for C23H42N2O6: C, 62.42; H, 9.56; N, 6.33; O, 21.69. Found: C, 62.39; H, 9.58; N, 6.29; O, 21.63.

Reference： [1]Marinelli, Lisa; Fornasari, Erika; Di Stefano, Antonio; Turkez, Hasan; Genovese, Salvatore; Epifano, Francesco; Di Biase, Giuseppe; Costantini, Erica; D'Angelo, Chiara; Reale, Marcella; Cacciatore, Ivana [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 2, p. 194 - 198]

26
[ 35661-39-3 ]
[ 32677-01-3 ]
C₃₁H₄₀N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.08%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 0 - 20℃;	3.1 Reaction (1): To a solution of Fmoc-Ala-OH (1475 mg, 5.0 mmol) dissolved in 70 ml dichloromethane, was added HBTU (2086 mg, 5.5mmol) at 0 °C and the mixture was stirred at room temperature for 10-15 min followed by the addition of -Glutamic acid di-fer/-butyl ester hydrochloride (1555 mg, 5.0 mmol) and triethylamine (1670 mg, 16.5 mmol) and stirred for 6-8h. After completion of the reaction (monitored by LC-MS), water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane (3x50 ml). The combined organic layer was washed with brine solution, dried over anhydrous sodium sulfate, filtered, and evaporated to give a viscous liquid which on column purification (0-50% ethyl acetate/hexane) provided desired (S)-di-tert- butyl 2-((S)-3-((9H-fluoren-9-yl)methoxy)-2-methyl-3-oxopropanamido) pentane dioate (1) (2185 mg, 79.08 % yield) as colorless liquid. LC-MS: m/z 575 [M+23].

Reference： [1]Current Patent Assignee: WISTAR INSTITUTE - WO2019/28096, 2019, A1 Location in patent: Page/Page column 25

27
[ 74124-79-1 ]
[ 32677-01-3 ]
[ 105590-97-4 ]
C₁₈H₂₈N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of DSC (1.73 g, 6.76 mmol) in DMF (31.6 ml), a,y-di-tertbutyl L-glutamate (2 g, 6.76 mmol) was added in portions at 0C. After 50 minutes, TEA (937 p1, 6.76 mmol) was added. After complete conversion, a-tert-butyl-y-benzyl L-glutamate (2.23 g, 6.76 mmol) and TEA (1.87 ml, 13.52 mmol) were added at 000. The reaction mixture was stirred overnight at room temperature. DMF was removed in vacuo and the residue was dissolved in MTBE (100 ml). The organic layer was washed with 15% citric acid solution (2x100 ml), water (2xlOOml), saturated NaHCO3 solution (2x1 00 ml) and water (80 ml) in sequence. The organic layer was dried over MgSO4, filtered and concentrated. The resulting yellowish oil was purified by chromatography on silica gel column (0-33% gradient of ethyl acetate (EtOAc) in hexane) to provide the urea HOP 30.21 75 as colorless syrup (3.02 g, 77%).[00153] MS (ESI+): m/zfound: 579.17 calc.: 579.72 [M+H] found: 601.35 calc.:601.70 [M-?-Na] found: 1180.35 calc.: 1180.41 [2M-?-Na].

Reference： [1]Patent: WO2019/57964,2019,A1 .Location in patent: Paragraph 00152; 00153

28
[ 1200-05-1 ]
[ 32677-01-3 ]
[ 5978-22-3 ]
C₃₅H₅₆N₄O₁₀ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2019,vol. 30,p. 1805 - 1813

29
[ 32677-01-3 ]
[ 56502-01-3 ]
Boc-L-β-HoPro-L-Glu(t-Bu)-O-t-Bu [ No CAS ]

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

30
[ 74124-79-1 ]
[ 940941-43-5 ]
[ 32677-01-3 ]
[ 56491-86-2 ]
[ 150629-67-7 ]
[ 133464-46-7 ]
[ 188715-40-4 ]
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine [ No CAS ]
C₆₂H₉₀N₁₂O₂₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: Fmoc-Lys(Dde)-OH With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3.5h; Stage #2: With piperidine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #3: di(succinimido) carbonate; Nα-fluorenylmethyloxycarbonyl-L-lysine-tert-butyl ester; L-glutamic acid di-tert-butyl ester hydrochloride; 1,4,7-triazacyclononane-1,4,7-triacetic acid; (S)-2-[((9H-fluoren-9-yl)methoxy)carbonylamino]-5-(allyloxy)-5-oxopentanoic acid; 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid; N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine Further stages;	1.1-1.8 1) Preparation of compound of formula (1) Soak CTC resin (471mL, 0.5mmol, substitution degree of 1.06mmol/g) in dichloromethane (20mL) for 30 minutes, add Fmoc-Lys(Dde)-OH (533mg, 1mmol) and DIPEA ( 359μl, 2mmol) was stirred at room temperature for 3 hours, then methanol (0.5 mL) was added and stirring continued for 30 minutes, the dichloromethane was removed, and washed with DMF 3 times, and then piperidine DMF solution (20 mL) with a volume percentage of 20% was added. After stirring at room temperature for 30 minutes, the solvent was removed, and then washed with DMF 5 times to obtain the compound of formula (1).2) Preparation of compound of formula (2)Take the compound of formula (1) obtained in step 1), add DSC (256mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 3 hours, remove DMF, wash with DMF 3 times, and add H-Glu (OtBu)-OtBu-HCl (296mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20 mL) were stirred at room temperature for 2 hours, DMF was removed, washed with DMF 3 times, and then 2% hydrazine hydrate DMF was added by volume The solution (20 mL) was stirred at room temperature for 30 minutes, the solvent was removed, and then washed with DMF 5 times to obtain the compound of formula (2).3) Preparation of compound of formula (3)Take the compound of formula (2) obtained in step 2), add Fmoc-D-2-Nal-OH (658mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20 mL), Stir at room temperature for 1.5 hours, remove DMF, wash with DMF 3 times, add piperidine DMF solution (20 mL) with a volume percentage of 20%, stir at room temperature for 30 minutes, remove the solvent, and wash with DMF 5 times to obtain formula (3 ) Compounds.4) Preparation of compound of formula (4)Take the compound of formula (3) obtained in step 3), add Fmoc-D-2-Nal-OH (658mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL) at room temperature Stir for 1.5 hours, remove DMF, and wash with DMF 3 times, then add 20% piperidine DMF solution (20 mL), stir at room temperature for 30 minutes, remove the solvent, and wash with DMF 5 times to obtain the compound of formula (4) .5) Preparation of compound of formula (5)Take the compound of formula (4) obtained in step 4), add Fmoc-D-2-Nal-OH (658mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL) at room temperature Stir for 1.5 hours, remove DMF, and wash with DMF 3 times, add 20% piperidine DMF solution (20 mL), stir at room temperature for 30 minutes, remove the solvent, and wash with DMF 5 times to obtain the compound of formula (5) .6) Preparation of compound of formula (6)Take the compound of formula (5) obtained in step 5), add NOTA (623mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL), stir at room temperature for 1.5 hours, remove DMF, and use DMF wash 3 times, then add H-Glu(OtBu)-OtBu-HCl (296mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 2 hours, remove DMF, and then wash the resin 3 times with DMF , The compound of formula (6) is obtained.7) Preparation of compound of formula (7)Take the compound of formula (6) obtained in step 6), add Pd(PPh3)4 (1.16g, 1mmol) and CHCl3 (30mL), stir at room temperature for 1.5 hours, remove DMF, wash with DMF 3 times, and add Fmoc-Lys-OtBu (638mg, 1.5mmol), HOBt (203mg, 1.5mmol), DIC (232ul, 1.5mmol) and DMF (20mL), stirred at room temperature for 30 minutes, removed DMF, and washed with DMF five times to obtain the compound of formula (7).8) Preparation of NOTA-Bi-PSMA compoundTake the compound of formula (7) obtained in step 7), add DSC (256mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 3 hours, remove DMF, wash with DMF 3 times, and add H-Glu (OtBu)-OtBu-HCl (296mg, 1mmol), DIPEA (359ul, 2mmol) and DMF (20mL), stir at room temperature for 2 hours, remove DMF, wash with DMF 3 times, and then wash with dichloromethane and methanol twice , Dry under reduced pressure, then add 10ml of the mixture of TFA:TIS:water volume ratio 95:2.5:2.5, stir at room temperature for 2.5 hours and then filter, pour the filtrate into cold ether, a large amount of solid initial product precipitates, and then half-prep The NOTA-Bi-PSMA compound was separated by separation method. A proper amount of NOTA-Bi-PSMA compound was detected by mass spectrometry and high performance liquid chromatography, and the mass spectrometry results were measured: the molecular formula was C62H90N12O23, [M+2H]2+=686.8; the high performance liquid chromatography results were measured: purity>98%.

Reference： [1]Current Patent Assignee: NANFANG HOSPITAL - CN112190722, 2021, A Location in patent: Paragraph 0067-0084

31
[ 940941-43-5 ]
[ 1161415-28-6 ]
[ 32677-01-3 ]
C₄₁H₆₀N₅O₉Pol [ No CAS ]
[ 133464-46-7 ]
C₆₂H₉₀N₁₂O₂₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₄₁H₆₀N₅O₉Pol; (S)-2-[((9H-fluoren-9-yl)methoxy)carbonylamino]-5-(allyloxy)-5-oxopentanoic acid With benzotriazol-1-ol; diisopropyl-carbodiimide In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: With piperidine In N,N-dimethyl-formamide Stage #3: tert-butyl N<SUP>2</SUP>-(((9H-fluoren-9-yl)methoxy)carbonyl)-L-lysinate; 2-{4,7-bis-tert-butoxycarbonylmethyl-[1,4,7] triazocyclononan-1-yl}acetic acid; L-glutamic acid di-tert-butyl ester hydrochloride Further stages;	Solid-Phase Synthesis of NOTA-Bi-PSMA NOTA-Bi-PSMA were designed and synthesized using a solid phase platform. The resin-immobilized and bis(t-Bu)-protected precursor-L-Glu-NH-CO-NH-L-Lys-2-Nal-L-Ala-NH2-Me-1,4-trans-CHX, referred to as Compound1-was synthesized on a 2-chlorotrityl chloride resin in analogy to the method described byBenesovaet al(1).Compound1(0.5 mmol) was swelling in 20 mL dichloromethane (DCM) and conditioned inN,N-dimethylformamide (DMF). Subsequently, 3equivFmoc-Glu(OAll)-OH, 1-hydroxybenzotriazole (HOBt) andN,N'-diisopropylcarbodiimide(DIC) were added in 20 mL DMF andstirriedat rt for 1.5 h to complete condensation reaction. The selective removal of the Fmoc-protecting group was performed with 20 mL 20% piperidine/DMF and yielded Compound2. The conjugation of the chelator was performed with 3equivNOTA-bis(tBuester) [1H-1,4,7-triazonine-1,4,7-triacetic acid, hexahydro-, 1,4-bis(1,1-dimethylethyl) ester],HOBtand DIC in DMF. The coupling of the NOTA chelator proceeded over the course of 1.5 h with gentle agitation to yield Compound3. The removal of the carboxy allyl ester (OAll) from Compound3was performed with 2equivPd(PPh3)4in chloroform (CHCl3). In the next step, 3equivFmoc-Lys-OtBu,HOBtand DIC were added in 20 mL DMF and stirred at rt for 1.5 h to complete condensation reaction. And then the Fmoc-protecting group was removed by 20% piperidine/DMF under same method as described above to obtaincompound4. Subsequently, 2equivN,N'-Disuccinimidyl carbonate (DSC) and 4equivN,N-diisopropylethylamine (DIPEA), and 2equivH-Glu(OtBu)-OtBu-HCl was added in DMF and agitated for 2 h. The resulting Compound5was washed with DMF (3 times), DCM (2 times), MeOH (2 times), dried under highvacuum, then dissolved in 10 mL of the mixture consisting of trifluoroacetic acid (TFA),triisopropylsilane(TIPS) andMilliQwater in a ratio of 95:2.5:2.5 (v/v) within 2 h, filtered, and the filtrate was poured into 100 mL ice-ether, large amount ofsolidwas formed, sent to centrifuge, thesolidwas dissolved in acetonitrile (ACN) andMilliQwater in a ratio of 1:1 (v/v) and purified via reverse-phase C18 column (Sepax GP-C18 5μm120A 4.6×250 mm) to obtained.

Reference： [1]Huang, Yong; Li, Hongsheng; Ye, Shimin; Tang, Ganghua; Liang, Yin; Hu, Kongzhen [European Journal of Medicinal Chemistry, 2021, vol. 221]

32
[ 63628-63-7 ]
[ 32677-01-3 ]
[ 1025796-30-8 ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: Nε-benzyloxycarbonyl-L-lysine tert-butyl ester With bis(trichloromethyl) carbonate; triethylamine In dichloromethane at 0℃; for 3h; Stage #2: L-glutamic acid di-tert-butyl ester hydrochloride In dichloromethane at 20℃;	2-[3-(5-benzyloxycarbonylamino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioicacid di-tert-butyl ester (10) Triphosgene (420 mg, 1.40 mmol) was dissolved in dichloromethane (5 mL) and cooledto 0 C. A solution of N(")-benzoyloxycarbonyl-L-lysine (1.42 g, 3.80 mmol) and triethylamine(1.05 mL, 765 mg, 7.60 mmol) in dichloromethane (25 mL) was added dropwiseover a period of 3 hours at 0 C. The reaction mixture was stirred for 40 minutes andL-glutamic acid di-tert-butyl ester hydrochloride (1.13 g, 3.80 mmol) and triethylamine(1.05 mL, 765 mg, 7.60 mmol) in dichloromethane (20 mL) was added. The solution wasstirred over night at room temperature. The solution was evaporated under reducedpressure. Ethyl acetate (25 mL) was added. The organic layer was washed with saturatedNaHCO3-solution (2 10 mL) and brine (2 10 ml), dried over sodium sulfate and evaporatedunder reduced pressure. The residue was purified by column chromatography(hexane/ethyl acetate; 20:1, Rf = 0.26) and the product was obtained as a colorless oil(357.6 mg, 0.58 mmol, 41%).1H-NMR (300 MHz, CDCl3): [ppm] = 7.38-7.22 (m, 5H), 5.16 (d, J = 13.5 Hz, 1H),5.09 (d, J = 3.2 Hz, 2H), 4.32 (dt, J = 7.5, 5.2 Hz, 2H), 3.16 (s, 2H), 2.40-2.15 (m, 2H), 1.93-1.68(m, 2H), 1.43 (m, 29H).13C-NMR (300 MHz, CDCl3): [ppm] = 172.54, 172.25, 172.15, 157.09, 156.61, 136.67,128.47, 128.04, 128.01, 82.29, 81.84, 80.65, 77.24, 66.56, 53.38, 53.03, 40.63, 32.53, 31.52, 29.36,28.28, 28.07, 28.00, 22.26.MS (ESI+): 622.4 [M + H]+, 644.4 [M + Na]+, calculated for C32H51N3O9: 621.36 [M]+.

Reference： [1]Greifenstein, Lukas; Grus, Tilmann; Lahnif, Hanane; Pektor, Stefanie; Rösch, Frank; Schreckenberger, Mathias [Molecules, 2021, vol. 26, # 21]

33
[ 1174157-65-3 ]
[ 32677-01-3 ]
C₁₁H₁₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 1h;	4 [00888] To compound 1 (200 mg, 0.676 mmol) in DCM (4 mL) was added TEA (218 uL, 1.56 mmol) then compound 2 (198 mg, 0.879 mmol) and the mixture was stirred at room temperature for 1 hour. Upon completion all volatiles were removed and crude compound 3 was deprotected using 4N HCl and was used subsequently without further purification.
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 20 °C 2: hydrogenchloride / lithium hydroxide monohydrate

Reference： [1]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56269, 2022, A1 Location in patent: Paragraph 00888
[2]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56277, 2022, A1

34
[ 1174157-65-3 ]
[ 32677-01-3 ]
C₁₉H₃₁NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 1h;	Synthesis of LP106-p To compound 1 (200 mg, 0.676 mmol) in DCM (4 mL) was added TEA (218 uL, 1.56 mmol) then compound 2 (198 mg, 0.879 mmol) and the mixture was stirred at room temperature for 1 hour. Upon completion all volatiles were removed and crude compound 3 was deprotected using 4N HCI to provide acid 5 which was used subsequently without further purification.
	With triethylamine In dichloromethane at 20℃; for 1h;	Synthesis of LP106-p To compound 1 (200 mg, 0.676 mmol) in DCM (4 mL) was added TEA (218 uL, 1.56 mmol) then compound 2 (198 mg, 0.879 mmol) and the mixture was stirred at room temperature for 1 hour. Upon completion all volatiles were removed and crude compound 3 was deprotected using 4N HCl to provide acid 5 which was used subsequently without further purification.

Reference： [1]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56273, 2022, A1 Location in patent: Paragraph 0562; 0563
[2]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56277, 2022, A1 Location in patent: Paragraph 0628-0629

35
[ 1174157-65-3 ]
[ 32677-01-3 ]
C₁₅H₂₃NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1 h / 20 °C 2: hydrogenchloride

Reference： [1]Current Patent Assignee: ARROWHEAD RESEARCH CORP - WO2022/56273, 2022, A1

36
[ 32677-01-3 ]
[ 6160-65-2 ]
[ 2797110-59-7 ]

Yield	Reaction Conditions	Operation in experiment
89.2%	Stage #1: L-glutamic acid di-tert-butyl ester hydrochloride With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: 1,1’-thiocarbonyl diimidazole In dichloromethane at 0 - 20℃; for 24h;	Di-tert-butyl (1H-imidazole-1-carbonothioyl)-L-glutamate (12) Compound S-1 was dissolved in dry DCM (14.9 mL) and cooled to 0 °C. Triethylamine (1.79 mL, 12.8 mmol, 2.53 eq.) and DMAP (24.8 mg, 0.20 mmol, 0.04 eq.) were added and stirred for five minutes. Afterwards, 1,1'-thiocarbonyldiimidazole (S-2) (1.36 g, 7.61 mmol, 1.50 eq.) was added, the solution was allowed to warm to room temperature and stirred overnight. The mixture was dissolved with ∼ 15 mL DCM and washed with NaHCO3 (1x), H2O (1x) and brine (1x). The organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure. This afforded 1.67 g (89.2%) of crude product 12 as a yellow oil, which was used without further purification in the next step. Chemical formula: C17H27N3O4S Molecular weight: 369.48 g/mol Exact mass: 369.17 g/mol tR-value: 13.0 min (10 - 90% B in 15 min, Method A) Capacity factor k: 6.2 ESI-MS: calculated monoisotopic mass (C17H27N3O4S): 369.17; found: ESI (positive ion mode): m/z = 370.2 [M(12)+H]+, 411.2 [M(12)+MeCN+H]+; 1H-NMR (300 MHz, CDCl3) δ(ppm): 8.45 (virt. d, 1H, H(1)), 7.65 (virt. 1H, H(2)), 7.23 (s, 1H, H(3)), 7.18 - 7.01 (m, 1H, H(4)), 4.83 (t, 3J = 5.7 Hz, 1H, H(5)), 2.56 - 2.44 (m, 2H, H(6)), 2.30 - 2.20 (m, 2H, H(7)), 1.48 (s, 9H, H(8, 8', 8")), 1.45 (s, 9H, H(9, 9', 9")).
89.2%	Stage #1: L-glutamic acid di-tert-butyl ester hydrochloride With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: 1,1’-thiocarbonyl diimidazole In dichloromethane at 0 - 20℃; for 24h;	Di-tert-butyl (1H-imidazole-1-carbonothioyl)-L-glutamate (12) Compound S-1 was dissolved in dry DCM (14.9 mL) and cooled to 0 °C. Triethylamine (1.79 mL, 12.8 mmol, 2.53 eq.) and DMAP (24.8 mg, 0.20 mmol, 0.04 eq.) were added and stirred for five minutes. Afterwards, 1,1'-thiocarbonyldiimidazole (S-2) (1.36 g, 7.61 mmol, 1.50 eq.) was added, the solution was allowed to warm to room temperature and stirred overnight. The mixture was dissolved with ∼ 15 mL DCM and washed with NaHCO3 (1x), H2O (1x) and brine (1x). The organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure. This afforded 1.67 g (89.2%) of crude product 12 as a yellow oil, which was used without further purification in the next step. Chemical formula: C17H27N3O4S Molecular weight: 369.48 g/mol Exact mass: 369.17 g/mol tR-value: 13.0 min (10 - 90% B in 15 min, Method A) Capacity factor k: 6.2 ESI-MS: calculated monoisotopic mass (C17H27N3O4S): 369.17; found: ESI (positive ion mode): m/z = 370.2 [M(12)+H]+, 411.2 [M(12)+MeCN+H]+; 1H-NMR (300 MHz, CDCl3) δ(ppm): 8.45 (virt. d, 1H, H(1)), 7.65 (virt. 1H, H(2)), 7.23 (s, 1H, H(3)), 7.18 - 7.01 (m, 1H, H(4)), 4.83 (t, 3J = 5.7 Hz, 1H, H(5)), 2.56 - 2.44 (m, 2H, H(6)), 2.30 - 2.20 (m, 2H, H(7)), 1.48 (s, 9H, H(8, 8', 8")), 1.45 (s, 9H, H(9, 9', 9")).
89.2%	Stage #1: L-glutamic acid di-tert-butyl ester hydrochloride With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 0℃; for 0.0833333h; Stage #2: 1,1’-thiocarbonyl diimidazole In dichloromethane at 0 - 20℃; for 24h;	Di-tert-butyl (1H-imidazole-1-carbonothioyl)-L-glutamate (12) Compound S-1 was dissolved in dry DCM (14.9 mL) and cooled to 0 °C. Triethylamine (1.79 mL, 12.8 mmol, 2.53 eq.) and DMAP (24.8 mg, 0.20 mmol, 0.04 eq.) were added and stirred for five minutes. Afterwards, 1,1'-thiocarbonyldiimidazole (S-2) (1.36 g, 7.61 mmol, 1.50 eq.) was added, the solution was allowed to warm to room temperature and stirred overnight. The mixture was dissolved with ∼ 15 mL DCM and washed with NaHCO3 (1x), H2O (1x) and brine (1x). The organic layer was dried over Na2SO4, filtered and the solvent removed under reduced pressure. This afforded 1.67 g (89.2%) of crude product 12 as a yellow oil, which was used without further purification in the next step. Chemical formula: C17H27N3O4S Molecular weight: 369.48 g/mol Exact mass: 369.17 g/mol tR-value: 13.0 min (10 - 90% B in 15 min, Method A) Capacity factor k: 6.2 ESI-MS: calculated monoisotopic mass (C17H27N3O4S): 369.17; found: ESI (positive ion mode): m/z = 370.2 [M(12)+H]+, 411.2 [M(12)+MeCN+H]+; 1H-NMR (300 MHz, CDCl3) δ(ppm): 8.45 (virt. d, 1H, H(1)), 7.65 (virt. 1H, H(2)), 7.23 (s, 1H, H(3)), 7.18 - 7.01 (m, 1H, H(4)), 4.83 (t, 3J = 5.7 Hz, 1H, H(5)), 2.56 - 2.44 (m, 2H, H(6)), 2.30 - 2.20 (m, 2H, H(7)), 1.48 (s, 9H, H(8, 8', 8")), 1.45 (s, 9H, H(9, 9', 9")).

Reference： [1]Current Patent Assignee: TECHNICAL UNIVERSITY OF MUNICH - EP4023250, 2022, A1 Location in patent: Paragraph 0130-0131
[2]Current Patent Assignee: TECHNICAL UNIVERSITY OF MUNICH - EP4023250, 2022, A1 Location in patent: Paragraph 0130-0131
[3]Current Patent Assignee: TECHNICAL UNIVERSITY OF MUNICH - EP4023250, 2022, A1 Location in patent: Paragraph 0130-0131

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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. 32677-01-3 ] {[proInfo.proName]}

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[ 32677-01-3 ] Synthesis Path-Upstream 1~5

[ 32677-01-3 ] Synthesis Path-Downstream 1~36

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Amino Acid Derivatives

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[ 32677-01-3 ]