52558-24-4|(S)-3-((tert-Butoxycarbonyl)amino)-2-hydroxypropanoic acid| Ambeed

Structure of Boc-IsoSer-OH
CAS No.: 52558-24-4

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Quality Control of [ 52558-24-4 ] Purity: 98% SDS Specification

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Product Details of [ 52558-24-4 ]

CAS No. :	52558-24-4
Formula :	C₈H₁₅NO₅
M.W :	205.21
SMILES Code :	O=C(O)[C@@H](O)CNC(OC(C)(C)C)=O
MDL No. :	MFCD17011798
InChI Key :	JJCAYTVAYSGVLA-YFKPBYRVSA-N
Pubchem ID :	11264189

Safety of [ 52558-24-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 52558-24-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.75
Num. rotatable bonds	6
Num. H-bond acceptors	5.0
Num. H-bond donors	3.0
Molar Refractivity	48.02
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	95.86 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.24
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.13
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-0.04
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.3
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.69
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.01

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-0.63
Solubility	47.6 mg/ml ; 0.232 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.43
Solubility	7.64 mg/ml ; 0.0372 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-0.09
Solubility	167.0 mg/ml ; 0.813 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.64 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.79

Application In Synthesis of [ 52558-24-4 ]

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

Downstream synthetic route of [ 52558-24-4 ]

[ 52558-24-4 ] Synthesis Path-Downstream 1~35

1
[ 565-71-9 ]
[ 24424-99-5 ]
[ 52558-24-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 9h;	(S)-isoserine 15a (21 g, 0.20 mol) was dissolved in tetrahydrofuran (100 mL)And a mixed solvent of 10percent aqueous sodium hydroxide solution (100 mL),Di-tert-butyl dicarbonate (50 mL, 0.22 mol) was added dropwise.The reaction was carried out at room temperature for 9 hours.The aqueous phase was adjusted to pH 2 with 4 mol/L hydrochloric acid, and extracted with dichloromethane/methanol (v/v = 5/1, 50 mL × 3) and dried over anhydrous sodium sulfate.Filter by suction, concentrate under reduced pressure,The title compound 15b was obtained as a colorless oil (35 g, yield: 85percent).
81.5%		To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1:1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to O0C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-ammo-2(S)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (IOO MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.
81.5%		To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H20 (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by Boc20 (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHC03 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHS04. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2S04, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(S)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.

81.5%		To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: 3/40 (100 mL, 1:1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by B0C2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHC<3/4 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHS04. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SC filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): [H NM (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.
81.5%	With 4-methyl-morpholine; In 1,4-dioxane; water; at 0 - 20℃;	N-Boc-3-amino-2(S)-hydroxy-propionic acid ; <n="62"/>To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.
81.5%		N-Boc-3-amino-2 (^-hydroxy-propionic acid OHTo a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.
81.5%	With 4-methyl-morpholine; In 1,4-dioxane; water; at 0 - 20℃;	N-Boc-3-amino-2(5)-hydroxy-propionic acid To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1:1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.
80%		Part I - Synthesis of (S)-3-((ter^butoxycarbonyl)amino)-2-hydroxypropanoic acid [0261] To (L)-isoserine (1.0 g, 9.5 mmol) in tetrahydrofuran (10 mL) and 2M sodium hydroxide (9.75 mL, 19.5 mmol) was added di-tert-butyl dicarbonate (0.78 g, 10 mmol). The resulting mixture was stirred vigorously at ambient temperature overnight. Then, the reaction mixture was acidified with 1M hydrogen chloride (20 mL) and stirred for 20 minutes until gas evolution ceased. The resulting mixture was partitioned between ethyl acetate and water, washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo to yield title compound. (1.57 g, 80percent yield)
		To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H20 (100 mL, 1 : 1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by Boc20 (1 1.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHC03 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHS04. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2S04, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.

References: [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2012,vol. 27,p. 302 - 310.
[2]Journal of Organic Chemistry,2018,vol. 83,p. 4973 - 4980.
[3]Patent: CN108341752,2018,A .Location in patent: Paragraph 0507; 0508; 0509; 0510.
[4]Patent: WO2010/132757,2010,A2 .Location in patent: Page/Page column 98-99.
[5]Patent: WO2011/44503,2011,A1 .Location in patent: Page/Page column 67.
[6]Patent: WO2011/44538,2011,A1 .Location in patent: Page/Page column 94.
[7]Patent: WO2009/67692,2009,A1 .Location in patent: Page/Page column 60-61.
[8]Patent: WO2010/42851,2010,A1 .Location in patent: Page/Page column 55-56.
[9]Patent: WO2010/132777,2010,A2 .Location in patent: Page/Page column 63-64.
[10]Patent: WO2013/169704,2013,A2 .Location in patent: Paragraph 0261.
[11]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 239 - 252.
[12]Patent: WO2011/44498,2011,A1 .Location in patent: Page/Page column 69-70.
[13]Journal of Enzyme Inhibition and Medicinal Chemistry,2013,vol. 28,p. 717 - 726.

2
[ 162085-96-3 ]
[ 52558-24-4 ]
[ 412352-75-1 ]

References: [1]Journal of the American Chemical Society,2002,vol. 124,p. 2148 - 2152.

3
[ 52558-24-4 ]
H-Leu-Tyr(Me)-NHMe*HCl [ No CAS ]
[ 458531-93-6 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 239 - 252.

4
[ 169688-48-6 ]
[ 52558-24-4 ]

References: [1]Synlett,2002,p. 2101 - 2103.

5
methyl (5S)-3-tert-butoxycarbonyloxazolidin-2-one-5-carboxylate [ No CAS ]
[ 52558-24-4 ]

References: [1]Synlett,2002,p. 2101 - 2103.

6
[ 24424-99-5 ]
[ 52558-24-4 ]

References: [1]Synlett,2002,p. 2101 - 2103.

7
[ 52558-24-4 ]
((R)-2-Mercapto-2-{(S)-1-[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-3-methyl-butylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester [ No CAS ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 239 - 252.

8
[ 52558-24-4 ]
[ 458531-95-8 ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 239 - 252.

9
[ 52558-24-4 ]
Methanesulfonic acid (S)-2-tert-butoxycarbonylamino-1-{(S)-1-[(S)-2-(4-methoxy-phenyl)-1-methylcarbamoyl-ethylcarbamoyl]-3-methyl-butylcarbamoyl}-ethyl ester [ No CAS ]

References: [1]Chemical and pharmaceutical bulletin,2002,vol. 50,p. 239 - 252.

10
[ 21715-90-2 ]
[ 52558-24-4 ]
C₁₇H₂₂N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 2h;	6'-Trifluoroacetyl-2',3-diPNZ-l-(N-Boc-3-amino-2(S)-hydroxy-propionyl)- sisomicin; To a stirring solution of N-Boc-3-amino-2(5)-hydroxy-propionic acid(1.30 g, 6.34 mmol) in DMF (14 ml) was slowly added HONB (1.14 g, 6.34 mmol) and EDC (1.21 g, 6.34 mmol) and the reaction mixture was stirred for 2 hours, when MS <n="63"/>showed complete formation of the activated ester (MS m/e [M+Na]+ calcd 389.1, found 389.1). 6'-trifluoroacetyl-2',3-diPNZ-sisomicin (4.76 g, 5.28 mmol) was then added and the reaction was allowed to stir overnight. The reaction was quenched with sat. aq. NaHCO3 (10 ml) and was extracted with EtOAc (5 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield a crude, which was purified by RP HPLC Method 2-Column B to yield the desired 6'- trifluoroacetyl-2',3-diPNZ-l -(N-Boc-3-amino-2(,S)-hydroxy-propionyl)-sisomicin (1.66 g, 1.52 mmol, 29% yield, >95% purity): MS m/e [M+H]+ calcd 1089.4, found 1089.2, [M+Na]+ 1111.3.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 2h;	6'-PNZ-2',3,3"-triBoc-l-(N-Boc-3-amino-2(S)-hydroxy-propionyl)-sisomicin; To a stirring solution of N-Boc-3-amino-2(5)-hydroxy-propionic acid (0.93 g, 4.53 mmol) in DMF (8 ml) was slowly added HONB (0.82 g, 4.53 mmol) and EDC (0.87 g, 4.53 mmol) and the reaction mixture was stirred for 2 hours. 6'-PNZ- 2',3,3"-triBoc-sisomicin (3.0 g, 3.23 mmol) was then added and the reaction was allowed to stir overnight. The reaction was quenched with H2O (10 ml) and was extracted with EtOAc (5 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired 6'-PNZ-2',3,3"-triBoc- l-(N-Boc-3-amino-2(,S)-hydroxy-propionyl)-sisomicin (MS m/e [M+H]+ calcd 1114.5, found 1113.9, [M+Na]+ 1136.3), which was carried through to the next step without further purification.

References: [1]Patent: WO2009/67692,2009,A1 .Location in patent: Page/Page column 61-62.
[2]Patent: WO2009/67692,2009,A1 .Location in patent: Page/Page column 71.

11
[ 21715-90-2 ]
[ 52558-24-4 ]
C₁₇H₂₂N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 0 - 20℃; for 6.33333h;Product distribution / selectivity;	6'-Trifluoroacetyl-2',3-di-PNZ-l-[(R)-3-(fer-butoxycarbonylamino)-2-hydroxy- propionyl] -sisomicin ; <n="59"/>(i?)-3-(tert-Butoxycarbonylamino)-2-hydroxypropionic acid (1.3 g, 6.3 mmol) and HONB (1.35 g, 7.5 mmol) were dissolved in THF (40 mL), the solution was cooled to 0C, and EDC (1.33 g, 6.9 mmol) was added. After 20 minutes the reaction was allowed to warm to room temperature. After 6 hours, a solution of 6'- trifluoroacetyl-2',3-di-PNZ-sisomicin (5.23 g, 5.8 mmol) in DMF (25 mL) was added, and the solution was allowed to stir overnight. The reaction was concentrated to remove the THF, and was partitioned between water and ethyl acetate. The phases were separated, and the ethyl acetate phase was washed once each with water, sat. NaHCO3, water, and brine. The ethyl acetate phase was then dried over Na2SO4, filtered, and concentrated to a residue. The residue was chromatographed by RP HPLC Method 2- Column B to give 6'-trifluoroacetyl-2',3-di-PNZ-l-[(i?)-3-(tert-butoxycarbonylamino)- 2-hydroxy-propionyl]-sisomicin as an off-white foam (1.64 g, 1.51 mmol, 24% yield): MS m/e [M+H]+ calcd 1089.4, found 1089.2.

References: [1]Patent: WO2009/67692,2009,A1 .Location in patent: Page/Page column 57-58.

12
[ 565-71-9 ]
[ 24424-99-5 ]
[ 56-40-6 ]
[ 52558-24-4 ]

Yield	Reaction Conditions	Operation in experiment
81.5%		N-Boc-3-amino-2 (^-hydroxy-propionic acid OHTo a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.

References: [1]Patent: WO2010/42850,2010,A1 .Location in patent: Page/Page column 55-56.

13
[ 1195164-50-1 ]
[ 52558-24-4 ]
C₁₇H₂₂N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 2h;	'-TrifluoroacetyWjS-diPNZ-l^N-Boc-S-amino-ZCSJ-hydroxy-propionyl)- sisomicin To a stirring solution of N-Boc-S-amino-l^-hydroxy-propionic acid (1.30 g, 6.34 mmol) in DMF (14 ml) was slowly added HONB (1.14 g, 6.34 mmol) and EDC (1.21 g, 6.34 mmol) and the reaction mixture was stirred for 2 hours, when MS showed complete formation of the activated ester (MS m/e [M+Na]+ calcd 389.1, found 389.1). 6'-trifluoroacetyl-23-diPNZ-sisomicin (4.76 g, 5.28 mmol) was then added and the reaction was allowed to stir overnight. The reaction was quenched with sat. aq. NaHCO3 (10 ml) and was extracted with EtOAc (5 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to yield a crude, which was purified by RP HPLC Method 2-Column B to yield the desired 6'- trifluoroacetyl-2',3-diPNZ-l -(N-Boc-3-amino-2(5)-hydroxy-propionyl)-sisomicin (1.66 g, 1.52 mmol, 29% yield, >;95% purity): MS m/e [M+H]+ calcd 1089.4, found 1089.2, [M+Na]+ 1111.3.

References: [1]Patent: WO2010/132777,2010,A2 .Location in patent: Page/Page column 64-65.

14
[ 1154758-59-4 ]
[ 52558-24-4 ]
[ 1154758-60-7 ]

Yield	Reaction Conditions	Operation in experiment
		6'-PNZ-2',3,3"-triBoc-l-(N-Boc-3-amino-2(S)-hydroxy-propionyl)-sisomicinTo a stirring solution of N-Boc-3-amino-2(S)-hydroxy-propionic acid (0.93 g, 4.53 mmol) in DMF (8 ml) was slowly added HONB (0.82 g, 4.53 mmol) andEDC (0.87 g, 4.53 mmol) and the reaction mixture was stirred for 2 hours. 6'-PNZ-2',3,3"-triBoc-sisomicin (3.0 g, 3.23 mmol) was then added and the reaction was allowed to stir overnight. The reaction was quenched with H2O (10 ml) and was extracted with EtOAc (5 x 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired 6'-PNZ-2',3,3"-triBoc- l-(N-Boc-3-amino-2(S)-hydroxy-propionyl)-sisomicin (MS m/e [M+H]+ calcd 1114.5, found 1113.9, [M+Na]+ 1136.3), which was carried through to the next step without further purification.

References: [1]Patent: WO2010/132777,2010,A2 .Location in patent: Page/Page column 74.

15
2',3-diPNZ-1-(N-PNZ-4-amino-2(R)-hydroxy-butyryl)-3''-boc-sisomicin [ No CAS ]
[ 52558-24-4 ]
[ 1154759-14-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;	'-CN-Boc-S-amino-l-hydroxy-propionyO-lSS-diPNZ-l-^-Boc-S-amino-lr°- hydroxy-propionyl)-3"-Boc sisomicinTreatment of 2',3-diPNZ-l-(N-Boc-3-amino-2(5)-hydroxy-propionyl)- 3"-Boc-sisomicin (0.078 mmol) with N-Boc-3-amino-2-hydroxy-propionic acid following Procedure 4-Method A gave the corresponding 6'-(N-Boc-3-amino-2- hydroxy-propionyl)-2',3-diPNZ-l-(N-Boc-3-amino-2(5)-hydroxy-propionyl)-3"-Boc sisomicin (MS m/e [M+Na]+ calcd 1302.5, found 1302.4), which was carried through to the next step without further purification; Procedure 4: BOP and PyBOP couplingMethod A: To a stirring solution of sisomicin derivative (0.078 mmol) in DMF (1 mL) was added the acid (0.16 mmol), followed by PyBOP (0.16 mmol) and DIPEA (0.31 mmol) and the reaction was stirred overnight. The reaction mixture was diluted with EtOAc (3 mL) and H2O (3 mL), and the aqueous layer was separated and extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness.

References: [1]Patent: WO2010/132777,2010,A2 .Location in patent: Page/Page column 126; 43.

16
[ 1215860-58-4 ]
[ 52558-24-4 ]
[ 1287277-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	To a stirring solution of 1 (0.475 g, 0.39 mmol) in DMF (7 mL) at 0C was added DIPEA (0.204 mL, 1.71 mmol), followed by N-Cbz-2(5)-hydroxy-propionic acid (0.187 g, 0.78 mmol) and PyBOP (0.325 g, 0.62 mmol) and the reaction was stirred overnight at room temperature. The reaction was diluted with EtOAc, and washed with sat. aq. NH4CI, sat. aq. NaHCC>3, brine (2 x), dried over Na2S<¾, filtered and concentrated to a crude, which was purified on a 2-inch reverse phase HPLC column (Method 2) to yield 2: MS m/z calcd for C74H83N7O23 (M+Na+) 1460.5, found 1460.4.

References: [1]Patent: WO2011/44538,2011,A1 .Location in patent: Page/Page column 198.

17
[ 1186120-59-1 ]
[ 52558-24-4 ]
[ 1335122-95-6 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 5190 - 5198.

18
[ 24424-99-5 ]
[ 1346507-66-1 ]
[ 52558-24-4 ]
[ 1346507-67-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of compound LXXIII (20.2 g, 24.2 mmol) in DMSO (100 mL) was added CF3COOEt (2.85 mL, 24.0 mmol). The mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into water (300 mL) and brine (30 mL) and then extracted with EtOAc (5 x 100 mL). The organic extract was washed with 5% aq. NaCl, dried over Na2S04 and concentrated to dryness. The residue was dissolved in pyridine (150 mL). (S)-3-(iert-Butoxycarbonylamino)-2-hydroxypropanoic acid LXXIV (8.43 g, 41.1 mmol) and N-hydroxysuccinimide (4.73 g, 41.1 mmol) were dissolved in THF (150 mL) and cooled to 0C. The solution was treated with DCC (8.47 g, 41.1 mmol), warmed up to room temperature and stirred for 3 h while a precipitate formed. The solid was filtered off and the clear solution of active ester was added to the above pyridine solution. The mixture was stirred at room temperature for 3 h and then concentrated to dryness. The resultant yellow foam was dissolved in methanol (120 mL), treated with ammonia (50 mL) and stirred for 1 h. The mixture was concentrated to dryness and the residue was dissolved in EtOAc (300 mL), washed with brine, dried over Na2S04, filtered and evaporated under vacuum. The residue was then dissolved in MeOH (120 mL). Et3N (5 mL, 36.0 mmol) was added followed by B0C2O (7.5 g, 34.4 mmol). The mixture was left stirring at room temperature for 18 h. The mixture was evaporated to dryness, the residue was washed with water and the organic phase was dried over Na2S04, filtered and concentrated. The crude product was purified on a silica gel column (50:1 DCM:MeOH?15:l DCM:MeOH) to produce rerf-butyl (2R,3R,6S)-2-((lR,2S,3S,4R,6S)-3-((2R,3R,4R,5R)-3,5-dihydroxy-5- methyl-4-(N-methyl-ierf-butoxycarbonylamino)tetrahydro-2H-pyran-2-yloxy)-2-hydroxy-4- ((S)-2-hydroxy-3-ierf-butoxycarbonylaminopropanamido)-6-ieri-butoxycarbonylamino cyclohexyloxy)-6-((2-nitrophenylsulfonamido)methyl)tetrahydro-2H-pyran-3-ylcarbamate LXXV (18.1 g, 16.1 mmol, 66% yield). ESIMS found for C48H79N702iS m/z 1122 (M+H).

References: [1]Patent: WO2011/143497,2011,A1 .Location in patent: Page/Page column 58; 59.

19
[ 1346508-00-6 ]
[ 52558-24-4 ]
[ 1346508-01-7 ]

Yield	Reaction Conditions	Operation in experiment
42%		To a solution (S)-3-(ieri-butoxycarbonylamino)-2-hydroxypropanoic acid LXXIV (5.20 g, 25.2 mmol) and N-hydroxysuccinimide (3.20 g, 27.7 mmol) in THF (100 mL) at 0C was added DCC (5.70 g, 27.7 mmol). The mixture was allowed to warm to room temperature and stir for 1.5 h, during which time a precipitate formed. The solid was removed by filtration, and the clear solution of active ester was added to a solution of compound CIII (14.95 g, 15.5 mmol) in pyridine (100 mL). The mixture was allowed to stir at room temperature for 18 h before concentrating to dryness. The residue was dissolved in EtOAc (100 mL) and washed with water (100 mL). The organic phase was dried over Na2S04, filtered, concentrated and dried under vacuum. The crude product was purified by column chromatography on silica gel (1:1 hexane/EtOAc?l:2 hexane/EtOAc- >100% EtOAc) to yield tert-butyl (2R,3R,4R,5R)-2-((lS,2S,3 ,4S,6R)-3-((2R,3R,6S)-6-((N-(((R)-2,2- dimethyl-l,3-dioxolan-4-yl)methyl)ierr-butoxycarbonylamino)methyl)-3-¾ri- butoxycarbonylaminotetrahydro-2H-pyran-2-yloxy)-2-hydroxy-6-((S)-2-hydroxy-3-ieri- butoxycarbonylaminopropanamido)-4-fert-butoxycarbonylaminocyclohexyloxy)-3,5- dihydroxy-5-methyltetrahydro-2H-pyran-4-yl(methyl)carbamate CIV (8.26 g, 7.13 mmol, 42% yield). ESIMS found for C53H94N602i mlz 1173 (M+Na).

References: [1]Patent: WO2011/143497,2011,A1 .Location in patent: Page/Page column 78.

20
[ 70691-56-4 ]
[ 52558-24-4 ]
C₃₀H₄₁N₃O₇ [ No CAS ]