91103-47-8|Boc-D-Ala-OMe| Ambeed

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Quality Control of [ 91103-47-8 ] Purity: 97% SDS Specification

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Product Details of [ 91103-47-8 ]

CAS No. :	91103-47-8
Formula :	C₉H₁₇NO₄
M.W :	203.24
SMILES Code :	[H][C@](C)(NC(=O)OC(C)(C)C)C(=O)OC
MDL No. :	MFCD00191865
InChI Key :	GJDICGOCZGRDFM-ZCFIWIBFSA-N
Pubchem ID :	637612

Safety of [ 91103-47-8 ]

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

Computational Chemistry of [ 91103-47-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	0
Fraction Csp3	0.78
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	51.18
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	64.63 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.67
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	0.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.07
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.	0.83
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	0.39
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.15

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.22
Solubility	12.2 mg/ml ; 0.0602 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.	-1.76
Solubility	3.54 mg/ml ; 0.0174 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	-1.35
Solubility	9.1 mg/ml ; 0.0448 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	Yes
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.	-6.96 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.	0.55

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	1.0 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)	2.73

Application In Synthesis of [ 91103-47-8 ]

* 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 [ 91103-47-8 ]

[ 91103-47-8 ] Synthesis Path-Downstream 1~35

1
[ 338-69-2 ]
[ 91103-47-8 ]

References: [1]Liebigs Annalen der Chemie,1992,p. 131 - 138.

2
[ 78-38-6 ]
[ 91103-47-8 ]
((R)-3-tert-Butoxycarbonylamino-1-methyl-2-oxo-butyl)-phosphonic acid diethyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 1886 - 1890.

3
[ 24424-99-5 ]
[ 14316-06-4 ]
[ 91103-47-8 ]

Yield	Reaction Conditions	Operation in experiment
73%	With sodium hydrogencarbonate; In water; at 20℃;	To a solution of D-alanine methyl ester hydrochloride (5 g, 35.8 mmol) and sodium hydrogen carbonate (9.0 g, 107 mmol) in water (100 mL) was added di-tert-butyl dicarbonate (11.7 g, 53.7 mmol) and the resulting solution was stirred at RTovernight. The reaction mixture was extracted with DCM (3 x 100 mL) and the combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. Crude NMR revealed large amounts of un-reacted di-tert-butyl dicarbonate, hence the material was taken up in DCM (50 mL) and treated with N,N-dimethyl ethylenediamne (5 mL), and stirred for 30 mins. The solution waswashed with 1M HCI (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to afford 5.35 g (73% yield) of the title compound as a colourless oi I.1H NMR (500 MHz, Chloroform-d) 6 5.04 (5, 1 H), 4.31 (m, 1 H), 3.73 (5, 3H), 1 .44 (5, 9H), 1.37 (d, J = 7.2 Hz, 3H).
17.6 g	With triethylamine; In dichloromethane; at 20 - 25℃; for 24h;	A suspension of D-alanine methyl ester hydrochloride (13.9 g, 100 mmol) in 250 mL of dichloromethane was combined with triethylamine (42 mL, 300 mmol) and di-tert-butyl dicarbonate (24.5 g, 110 mmol). After stirring for 24 hours at ambient temperature, the reaction mixture was combined with 5% NaHaPCL solution and the layers were separated. The organic portion was washed successively with a saturated aqueous sodium bicarbonate solution, a 10% aqueous citric acid solution, water and brine. The organic portion was dried over NaiSCri. filtered and concentrated to give 17.6 g of methyl (2R)-2-[(tert-butoxycarbonyl)amino]propanoate as a colorless oil.

References: [1]Journal of the Chemical Society. Perkin transactions I,1985,p. 2299 - 2306.
[2]Patent: WO2016/91776,2016,A1 .Location in patent: Page/Page column 387.
[3]Heterocycles,1988,vol. 27,p. 2077 - 2080.
[4]Journal of Organic Chemistry,1998,vol. 63,p. 92 - 98.
[5]Journal of the Chemical Society. Perkin transactions I,1999,p. 387 - 398.
[6]Patent: WO2019/224765,2019,A1 .Location in patent: Page/Page column 32.

4
[ 91103-47-8 ]
C₉H₁₂LiO₃P [ No CAS ]
[ 112392-61-7 ]

References: [1]Tetrahedron Letters,1987,vol. 28,p. 611 - 612.

5
[ 91103-47-8 ]
[ 79069-13-9 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1989,p. 1479 - 1481.
[2]Journal of Organic Chemistry,1987,vol. 52,p. 1252 - 1255.
[3]Angewandte Chemie - International Edition,2012,vol. 51,p. 5239 - 5243.

6
[ 91103-47-8 ]
[ 82353-56-8 ]

Yield	Reaction Conditions	Operation in experiment
85%		Example 46(1-Methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester The title compound from Example 45 (3.53 g, 17.4 mmol) was dissolved in toluene (35 mL) at -78 C. and DIBAL-H (26.6 mL, 39.9 mmol) was added dropwise over 1 hour. Methanol (70 mL) was added to the reaction over 10 min. at -78 C. The reaction was moved to an ice bath and 10% w/v citric acid in water (250 mL) was added and the reaction was allowed to stir for 1 hour. The reaction was extracted with portions of ethyl acetate and the organic extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (2.57 g, 85%) as a white semi-solid.1H NMR (300 MHz, CDCl3): delta (ppm) 9.51 (s, 1H), 5.21 (broad s, 1H), 4.24 (broad s, 1H), 1.53 (s, 9H), 1.35 (d, 3H).
82%		Step 1: (R)-tert-butyl 1-oxopropan-2-ylcarbamateTo a cooled solution of <strong>[91103-47-8](R)-methyl 2-(tert-butoxycarbonylamino)propanoate</strong> (40.0 g, 98.0 mmol) in DCM (200 mL) at -78 C. was added diisobutylaluminum hydride (208 mL, 1.0 M in THF) dropwise over 30 min. The reaction mixture was stirred at -78 C. for 1.5 h then quenched with water (50 mL). After warmed to rt, the white precipitate was removed by filtration over Celite. The organic layer was then washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography (petroleum ether: EtOAc, 10:1) to give (R)-tert-butyl 1-oxopropan-2-ylcarbamate (28.0 g, 82%). 1H NMR (DMSO-d6, 400 MHz) delta 9.43 (s, 1H), 7.33 (d, J=6.0 Hz, 1H), 3.85 (m, 1H), 1.39 (s, 9H), 1.12 (d, J=7.2 Hz, 3H).
65%	With diisobutylaluminium hydride; In toluene; at -78℃; for 2h;	EXAMPLE 49; (R)-5-Chloro-thiophene-2-carboxylic acid (1 - {3-[4-(N,N-dimethyl-carbamimidoyl)-phenyl]- isoxazol-5-yl}-ethyl)-amide; Step l :; [0553] Methyl ester 8 (4.03 g, 19.9 mmol) was diluted with 40 mL of toluene and cooled to -780C. Diisobutylaluminum hydride in toluene (26 mL, 40 mmol) was added slowly to the precooled mixture down the side of the flask. The reaction was stirred at -780C for two hours at which time it was treated slowly with ca. 5 mL of methanol precooled to -780C (vigorous reaction). The mixture was then warmed to it and partitioned with saturated sodium potassium tartrate and ethyl acetate. The layers were separated, the organic phase was extracted with ethyl acetate and the combined organic layers were dried over MgSO4. After filtration and concentration in vacuo the crude material was purified by filtration through a short plug of silica gel eluted with dichloromethane affording the aldehyde 9 as a colorless oil (2.23g, 65%). 1H NMR (DMSO-J6, 400 MHz): delta 9.38 (s, IH), delta 7.30 (d, IH), delta 3.79 (m, IH), delta 1.31 (s, 9H), 1.06 (d, 3H).

With diisobutylaluminium hydride; In toluene; at -78℃; for 2h;

To a stirred solution of (S)-methyl 2-(tert-butoxycarbonylamino)propanoate (3.87 g, 19 mmol) in dry toluene (10 ml) was slowly added DIBAL-H (1.0 M in toluene solution; 24.8 ml, 24.8 mmol) at -78C. After stirring of the mixture at -78C for 2 h, excess of DIBAL-H was quenched with 1.5N HCl (5 ml). The resulting mixture was filtered and the organic layer of the filtrate was washed with saturated NaHCO3 aq and water, dried over with anhydrous MgSO4, and solvent was removed in vacuo. The residue was purified by silica gel column chromatography to give compound (1.74 g) in 53% yield.

References: [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 1886 - 1890.
[2]Bulletin des Societes Chimiques Belges,1987,vol. 96,p. 629 - 630.
[3]Patent: US2007/259860,2007,A1 .Location in patent: Page/Page column 34-35.
[4]Patent: US2011/213003,2011,A1 .Location in patent: Page/Page column 73.
[5]Organic and Biomolecular Chemistry,2003,vol. 1,p. 2983 - 2997.
[6]Journal of the American Chemical Society,2016,vol. 138,p. 15798 - 15800.
[7]Liebigs Annalen der Chemie,1992,p. 131 - 138.
[8]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2702 - 2706.
[9]Heterocycles,1988,vol. 27,p. 2077 - 2080.
[10]Patent: WO2006/2099,2006,A2 .Location in patent: Page/Page column 94-95.
[11]Tetrahedron,2016,vol. 72,p. 4518 - 4522.
[12]Journal of the Chemical Society. Perkin transactions I,1985,p. 2299 - 2306.
[13]Journal of Medicinal Chemistry,1989,vol. 32,p. 165 - 170.
[14]Journal of Organic Chemistry,1998,vol. 63,p. 92 - 98.
[15]Tetrahedron Asymmetry,2001,vol. 12,p. 1543 - 1545.
[16]Journal of Organic Chemistry,1987,vol. 52,p. 1252 - 1255.
[17]Tetrahedron,2009,vol. 65,p. 357 - 363.
[18]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 2812 - 2815.
[19]Angewandte Chemie - International Edition,2012,vol. 51,p. 5239 - 5243.
[20]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 37 - 41.

7
[ 147751-23-3 ]
[ 91103-47-8 ]

References: [1]Journal of Organic Chemistry,1993,vol. 58,p. 2900 - 2903.

8
[ 91103-47-8 ]
[ 756-79-6 ]
[ 120962-15-4 ]

References: [1]Journal of Organic Chemistry,2000,vol. 65,p. 5615 - 5622.
[2]Journal of Medicinal Chemistry,1989,vol. 32,p. 1886 - 1890.

9
[ 3744-87-4 ]
[ 74-88-4 ]
[ 91103-47-8 ]

Yield	Reaction Conditions	Operation in experiment
96%		Intermediate 57 Boc-D-AlaOMe Boc-D-AlaOH (10.0 g, 52.9 mmol) was dissolved in dry DMF (60 mL), then potassium carbonate (8.0 g, 58.0 mmol) was added, the mixture was stirred at rt for 15 min, and methyl iodide (6.58 mL, 106.0 mmol) was added dropwise. The stirring was maintained for 18h. Then, the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (lOOmL). The organic layer was washed with water, brine, dried over MgSCU, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, DCM/MeOH 0 to 1%) to give 10.36 g (51.0 mmol, 96% yield) of the title compound. *Eta NMR (DMSO-d6) delta 7.46 (1H, d), 4.35 (1H, m), 3.66 (3H, s), 1.30 (9H, s), 1.18 (3H, d).
82%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Example 452-tert-Butoxycarbonylamino-propionic acid methyl ester Boc-D-Ala-OH (4.0 g, 21 mmol) and potassium carbonate (11.7 g, 84.6 mmol) was dissolved in dimethylformamide (90 mL) and iodomethane (1.6 mL, 25 mmol) was added to the reaction mixture. The reaction was allowed to stir at room temperature. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with portions of water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a colorless oil (3.53 g, 82%).1H NMR (300 MHz, CDCl3): delta (ppm) 5.14 (broad s, 1 h), 4.33 (broad s, 1H), 3.51 (s, 3H), 1.49 (s, 9H).

References: [1]Patent: WO2016/8946,2016,A1 .Location in patent: Page/Page column 72-73.
[2]Patent: US2007/259860,2007,A1 .Location in patent: Page/Page column 34.
[3]Journal of Organic Chemistry,1987,vol. 52,p. 1252 - 1255.
[4]Angewandte Chemie - International Edition,2012,vol. 51,p. 5239 - 5243.

10
[ 67-56-1 ]
[ 139928-91-9 ]
[ 91103-47-8 ]

References: [1]Chemical Communications,1997,p. 1017 - 1018.

11
[ 75-16-1 ]
[ 91103-47-8 ]
[ 186466-64-8 ]

Yield	Reaction Conditions	Operation in experiment
100%		Intermediate 2-((( 1 R)-2-fluoro- 1 ,2-dimethylpropyl)amino)pyrrolo [ 1 ,2-b]pyridazine-3 -carboxamide [00195] To a solution of <strong>[91103-47-8](R)-methyl 2-(tert-butoxycarbonylamino)propanoate</strong> (10 g, 49.2 mmol) in THF (80 mL) at 0 C was added methyl magnesium bromide (65.6 mL, 197 mmol) dropwise. The reaction mixture was warmed up to RT and stirred for 16 hrs. The reaction mixture was poured into 200 mL of ice water. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were concentrated to yield a crude product to which was added 100 mL of diethyl ether. Filtration and concentration yielded the title compound (lOg, 100%). 1H-NMR (400 MHz, CDC13) delta ppm 3.60 (1 H, ddd, J=14.5, 7.1, 6.8 Hz), 1.46 (9 H, s), 1.24 (3 H, s), 1.18 (3 H, s), 1.14 (3 H, d, J=7.0 Hz).
99%		Example 32.Step 1To a solution of Boc-D-alanine methyl ester (5.00 g, 24.6 mmol) in THF (100 mL) at 0 C was slowly added methyl magnesium bromide (3.0 M in Et20, 28.7 mL, 86.1 mmol). The resultant white slurry was stirred at 0 C for 1 h then at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4C1, diluted with H20 and extracted with EtOAc. The combined organics were washed with brine, dried over MgS04 and concentrated to give 4.93 g (99%) ((R)-2-hydroxy-l,2-dimethyl -propyl)-carbamic acid tert-butyl ester as a colorless viscous oil.
0.86 g	In diethyl ether; at 0 - 20℃; for 3h;Inert atmosphere;	Step (i): Preparation of tert-butyl [(2R)-3-hydroxy-3-methylbutan-2-yl]carbamate (Compound 228b) Under a nitrogen atmosphere, 3 mol/L methylmagnesium bromide/diethyl ether (5.90 mL) was added to a solution of Boc-D-alanine methyl ester (1.0 g) in diethyl ether (25 mL) at 0 C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with aqueous ammonium chloride and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The concentrated residue was purified by silica gel column chromatography (eluate: hexane/ethyl acetate=70/30) to give Compound 228b (0.86 g).

0.86 g

In diethyl ether; at 0 - 20℃; for 3h;Inert atmosphere;

Under a nitrogen atmosphere, a solution of Boc-D-alanine methyl ester (1.0 g) in diethyl ether (25 ml)A 3 mol / L methyl magnesium bromide-diethyl ether solution (5.90 ml) was added at 0 C.,And the mixture was stirred at room temperature for 3 hours.After quenching with ammonium chloride solution,The mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate.The residue obtained by concentration was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 70/30) to prepare compound 228b (0.86 g).

References: [1]Patent: WO2012/125887,2012,A1 .Location in patent: Page/Page column 87-88.
[2]Patent: WO2011/144585,2011,A1 .Location in patent: Page/Page column 139.
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 345 - 356.
[4]Chemical and Pharmaceutical Bulletin,1997,vol. 45,p. 185 - 188.
[5]Journal of Medicinal Chemistry,2013,vol. 56,p. 7976 - 7996.
[6]Patent: US2017/107211,2017,A1 .Location in patent: Paragraph 0544; 0545.
[7]Patent: JP2018/154620,2018,A .Location in patent: Paragraph 0207; 0208.

12
[ 24424-99-5 ]
[ 204126-98-7 ]
[ 91103-47-8 ]

References: [1]Journal of Organic Chemistry,1998,vol. 63,p. 2371 - 2374.

13
[ 108-86-1 ]
[ 91103-47-8 ]
[ 223906-32-9 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 387 - 398.

14
[ 91103-47-8 ]
[ 74-88-4 ]
[ 186466-64-8 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1999,p. 387 - 398.

15
[ 186581-53-3 ]
[ 3744-87-4 ]
[ 91103-47-8 ]

References: [1]Tetrahedron Letters,2002,vol. 43,p. 9691 - 9693.

16
[ 91103-47-8 ]
[ 76-05-1 ]
[ 42460-91-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	In dichloromethane; at 20℃; for 1h;	Intermediate 58 TFA.D-AlaOMe The compound 57 (10.36 g, 51.0 mmol) was dissolved in TFA/DCM mixture (1/1) (100 mL). After stirring for lh at rt, the solvents were removed under vacuo; the residue was coevaporated 3 times with toluene. The crude compound was triturated with Et20 to provide 11.0 g (51.0 mmol, 99% yield) of the compound. This compound was used for the next step without any further purification.

References: [1]Patent: WO2016/8946,2016,A1 .Location in patent: Page/Page column 73.
[2]Journal of the American Chemical Society,2003,vol. 125,p. 13018 - 13019.

17
[ 1826-67-1 ]
[ 91103-47-8 ]
[ 640285-87-6 ]

References: [1]Organic Letters,2003,vol. 5,p. 4887 - 4890.

18
[ 91103-47-8 ]
[ 41863-52-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With hydrazine hydrate; In ethanol; at 20℃; for 5h;	To a solution of Intermediate LV (5.35 g, 26.3 mmol) in ethanol (140 mL) wasadded hydrazine hydrate (19.8 mL) and the reaction was stirred at RT for 5 h. Thereaction mixture was concentrated under reduced pressure and the residue was triturated with heptane. The resulting precipitate was collected by filtration and dried in the vacuum oven to afford 5.00 g (93% yield) of the title compound as a white crystalline powder.1H NMR (250 MHz, DMSO): 6 [ppm] 8.96 (5, 1H), 6.81 (d, J = 7.7 Hz, 1H), 4.17 (5,2H), 4.03-3.81 (m, 1H), 1.36 (5, 9H), 1.14 (d, J = 7.1 Hz, 3H).
25%	With hydrazine hydrate; In ethanol;	Boc-D-alanine methyl ester (2.0 g) was dissolved in ethanol (50 mL)And stirred overnight added hydrazine monohydrate (0.6 mL).After completion of the reaction was partitioned with ethyl acetate and water.The organic layer was washed with a saturated saline solution, and dried over anhydrous sodium sulfate.Concentrated to dryness Insoluble materials were filtered off, the resulting residue was purified by silica gel column chromatography to give the title compound 500mg (25% yield).
	With hydrazine; In methanol; at 20℃; for 12h;	Hydrazine monohydrate (30 ml) was added to a solution of N-(t-butoxycarbonyl)-D-alanine methyl ester (41.8 g) in methanol (180 ml), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated, and the resulting crude crystal was washed with a mixed solvent of hexane and ethyl acetate (1:1, 300 ml) and then dried to give the titled compound as a colorless powder (32.6 g). 1H NMR (300 MHz, DMDO-d6) delta ppm: 1.14 (d, J = 7.2 Hz, 3H), 1.37 (s, 9H), 3.30-4.09 (m, 3H), 6.70-6.90 (m, 1H), 8.96 (br s, 1H)

	With hydrazine; In ethanol; at 20℃; for 16h;	To a solution of Boc-D-alanine methyl ester (10 g, 49 mmol) in ethanol (250 mL) was added NH2NH2-H2O (35.6 mL, 735 mmol) and stirred at rt for 16 h. The solvent was removed by evaporation and the residue triturated with hexane to yield a white foamy solid,which was filtered <n="64"/>and dried under vacuum. Yield: 9.8 g. 1HNMR (300 MHz, DMSO-^6) : 8.97 (s, IH)5 6.86-6.84 (m, IH), 4.18 (s, 2H), 3.96-3.86 (m, IH), 1.36 (s, 9H), 1.13 (d, J= 7.14 Hz, 3H). M/Z= 203
11.4 g	With hydrazine hydrate; In methanol; at 80℃; for 6h;	Step A (R)-tert-butyl (1-hydrazinyl-1-oxopropan-2-yl)carbamate (18a)A solution of N-Boc D-Alanine methyl ester (15 g, 73.891 mmol) and hydrazine hydrate (1 1.08 g, 221.674 mmol) in methanol (200 mL) was heated at 80C for 6h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The crude mass was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous Na2SO4 and evaporated to dryness to afford 18a (11.4 g) which was used as such for next step.
	With hydrazine hydrate; In tetrahydrofuran; at 110℃; for 10h;Sealed tube;	[0215] To a stuffed solution of compound III (10 g; 41.84 mmol; 1 eq) in THF (30 mL) in a reaction tube was added hydrazine hydrate (6.08 mL; 125.52 mmol; 3 eq). The reaction tube was sealed and heated at 110 C for 10 h. The mixture was concentrated in vacuo to obtain crude title compound (11 g, 100%) as an off white solid. 1H NMR (400 MHz, DMSO-d6) oe 8.98 (brs, 1H), 7.10 (brs, 1H), 6.82 (d, 1H, J= 7Hz), 6.48 (brs, 1H), 4.11 (m, 1H), 1.30 (m, 9H), 1.10 (m, 3H).
8 g	With hydrazine hydrate; In ethanol; at 100℃; for 0.5h;	Methyl N-(tert-butoxycarbonyl)-D-alaninate (8.00 g, 39.4 mmol) was dissolved in ethanol (10 mL), followed by hydrazine hydrate (20 mL, 410 mmol). The mixture was stirred at 100 SC for 30 min (Caution Use appropriate safety measures). The solvent was removed to obtain tert-butyl [(2R)-1-hydrazinyl-1-oxopropan-2-yl]carbamate (8.00 g, 39.4 mmol).

References: [1]RSC Medicinal Chemistry,2020,vol. 11,p. 528 - 531.
[2]Patent: WO2016/91776,2016,A1 .Location in patent: Page/Page column 387.
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 4430 - 4448.
[4]Patent: JP5851663,2016,B1 .Location in patent: Paragraph 0248.
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[11]Patent: WO2018/77923,2018,A1 .Location in patent: Page/Page column 251.

19
[ 91103-47-8 ]
[ 716329-44-1 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2543 - 2546.
[2]Patent: JP5851663,2016,B1 .

20
[ 91103-47-8 ]
[ 645414-83-1 ]

References: [1]Organic Letters,2003,vol. 5,p. 4887 - 4890.

21
[ 91103-47-8 ]
[ 640285-98-9 ]

References: [1]Organic Letters,2003,vol. 5,p. 4887 - 4890.

22
[ 91103-47-8 ]
tert-butyl (2R)-(3-hydroxyhept-6-en-2-yl)carbamate [ No CAS ]