[ CAS No. 6404-31-5 ] {[proInfo.proName]}

Name: 6404-31-5|((Benzyloxy)carbonyl)-D-proline|97%
Brand: Ambeed
SKU: A154146
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Quality Control of [ 6404-31-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 6404-31-5 ]

Product Details of [ 6404-31-5 ]

CAS No. :	6404-31-5	MDL No. :	MFCD00063228
Formula :	C₁₃H₁₅NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JXGVXCZADZNAMJ-LLVKDONJSA-N
M.W :	249.26	Pubchem ID :	111208
Synonyms :		Chemical Name :	((Benzyloxy)carbonyl)-D-proline

Calculated chemistry of [ 6404-31-5 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.38
Num. rotatable bonds :	5
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	68.39
TPSA :	66.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.59 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.09
Log Po/w (XLOGP3) :	1.74
Log Po/w (WLOGP) :	1.34
Log Po/w (MLOGP) :	1.31
Log Po/w (SILICOS-IT) :	1.03
Consensus Log Po/w :	1.5

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.4
Solubility :	0.996 mg/ml ; 0.004 mol/l
Class :	Soluble
Log S (Ali) :	-2.76
Solubility :	0.433 mg/ml ; 0.00174 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.08
Solubility :	2.05 mg/ml ; 0.00822 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.63

Safety of [ 6404-31-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 6404-31-5 ]

* 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 [ 6404-31-5 ]
Downstream synthetic route of [ 6404-31-5 ]

[ 6404-31-5 ] Synthesis Path-Upstream 1~19

1
[ 6404-31-5 ]
[ 62937-45-5 ]

Reference： [1] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842

2
[ 501-53-1 ]
[ 344-25-2 ]
[ 6404-31-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydroxide In water at 0 - 20℃;	Step-1 : Preparation of (R)-l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) To a stirred solution of D-Proline (1.2 g, 10.42 mmol) in 2 N aqueous NaOH solution (20.85 mL, 41.7 mmol) at 0 °C was added benzyl chloroformate (1.488 mL, 10.42 mmol) and allowed to warm to room temperature overnight. The reaction was washed with MTBE (2 x 25 mL), acidified with cone HCl and extracted with ethyl acetate (2 x 200 mL). The ethyl acetate layers were combined washed with water (50 mL), brine (25 mL) dried and concentrated in vacuum to afford (R)-l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) (2.41 g, 9.67 mmol, 93 percent yield) which was used as such in next step; Η NMR (300 MHz, DMSO-i) δ 12.66 (s, 1H), 7.42 - 7.25 (m, 5H), 5.14 - 4.97 (m, 2H), 4.20 (ddd, J = 22.7, 8.8, 3.5 Hz, 1H), 3.50 - 3.25 (m, 2H), 2.32 - 2.08 (m, 1H), 1.97 - 1.75 (m, 3H); MS (ES+) 250.2 (M+l), 272.2 (M+Na), (ES-) 248.2 (M-l), 284.2 (M+Cl), 497.4 (2M-1).

Reference： [1] Patent: WO2015/62486, 2015, A1, . Location in patent: Paragraph 00191
[2] Patent: WO2017/59178, 2017, A1, . Location in patent: Page/Page column 73
[3] Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842
[4] Angewandte Chemie - International Edition, 2006, vol. 45, # 28, p. 4593 - 4597
[5] European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2807 - 2814

3
[ 640-68-6 ]
[ 501-53-1 ]
[ 6404-31-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 0℃;	20.0mmol D-valine was dissolved in 12.0mL, 2mol/L NaOH solution, 22mmol benzyl chloroformate was added dropwise at 0 °C, then added with NaOH solution, extracted, washed, dried, concentrated, separated by silica gel column. Got(R)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxylic acid in a yield of 95percent.

Reference： [1] Patent: CN108610358, 2018, A, . Location in patent: Paragraph 0065; 0066

4
[ 99464-81-0 ]
[ 344-25-2 ]
[ 6404-31-5 ]

Reference： [1] Synthesis, 1986, # 8, p. 627 - 632

5
[ 50463-82-6 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

6
[ 501-53-1 ]
[ 6404-31-5 ]

Reference： [1] Organic Letters, 2010, vol. 12, # 10, p. 2222 - 2225

7
[ 1148-11-4 ]
[ 6404-31-5 ]
[ 147-85-3 ]

Reference： [1] Advanced Synthesis and Catalysis, 2003, vol. 345, # 6-7, p. 830 - 834

8
[ 136963-32-1 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

9
[ 200499-54-3 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

10
[ 200499-52-1 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

11
[ 501-53-1 ]
[ 609-36-9 ]
[ 6404-31-5 ]
[ 1148-11-4 ]

Reference： [1] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 5, p. 449 - 461

12
[ 13139-17-8 ]
[ 344-25-2 ]
[ 6404-31-5 ]

Reference： [1] Journal of Organic Chemistry, 2004, vol. 69, # 11, p. 3849 - 3856

13
[ 100-51-6 ]
[ 6404-31-5 ]

Reference： [1] Synthesis, 1986, # 8, p. 627 - 632

14
[ 200499-55-4 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

15
[ 200499-58-7 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

16
[ 200499-57-6 ]
[ 6404-31-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 22, p. 3351 - 3356

17
[ 6404-31-5 ]
[ 143322-57-0 ]

Reference： [1] Patent: US2011/166364, 2011, A1,
[2] Patent: US2012/71669, 2012, A1,
[3] Patent: EP944595, 2003, B1,

18
[ 10075-50-0 ]
[ 79-37-8 ]
[ 925-90-6 ]
[ 61350-62-7 ]
[ 6404-31-5 ]
[ 143322-56-9 ]

Reference： [1] Patent: US5545644, 1996, A,
[2] Patent: US5559129, 1996, A,
[3] Patent: US5559246, 1996, A,
[4] Patent: US5578612, 1996, A,
[5] Patent: US5607951, 1997, A,

19
[ 6404-31-5 ]
[ 143322-56-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3419 - 3421
[2] Patent: US2011/166364, 2011, A1,
[3] Patent: US2012/71669, 2012, A1,
[4] Patent: EP944595, 2003, B1,

[ 6404-31-5 ] Synthesis Path-Downstream 1~18

1
[ 6404-31-5 ]
[ 62937-47-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: Z-D-proline With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 24h; Inert atmosphere;
68%	Stage #1: Z-D-proline With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 20℃; for 24h;
	With ammonia; triethylamine; isobutyl chloroformate 1.) chloroform, 0 deg C, 2 h, 2.) chloroform, RT, overnight; Yield given. Multistep reaction;

	Stage #1: Z-D-proline With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at 0℃; for 0.0833333h; Stage #2: With ammonia In tetrahydrofuran at 20℃;	33 Example 33 (R)-Benzyl 2-carbamoylpyrrolidine-1-carboxylate. A solution of the carboxylic acid (3.00 g, 12.03 mmol) and N-methylmorpholine (1.21 g, 12.03 mmol) in 40 mL of dry THF was cooled to 0° C. and isobutyl chloroformate (1.643 g, 12.03 mmol) was added dropwise. After 5 min, ammonia gas was passed through the reaction mixture for 15 min and the reaction mixture was stirred overnight at RT. After filtration, the solvent was evaporated and the residue was partitioned between water and EtOAc. The EtOAc layer was successively washed with 1 N HCl, water, sat. NaHCO3, water and brine. After evaporation of the organic layer, the residue was purified by chromatography (silica/hexane:EtOAc (1:4) EtOAc→EtOAc:methanol (95:5)) to provide 1.56 g of the desired amide. 1H NMR (300 MHz, CDCl3): δ 7.40-7.20 (m, 5H), 6.7 (bs) and 5.8-6.2 (bm) combined 2H, 5.15 (dod, 2H), 4.30 (bs, 1H), 3.60-3.35 (bm, 2H), 2.40-1.80 (m, 4H).
	With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane for 12h;	1.2.1 [0287] To a solution of the commercially available (R)-l-(benzyloxycarbonyl)pyrrolidine- 2-carboxylic acid (Synthetech, 9.97g, 40.0 mmoles) in 1, 4-dioxane (60mL) was added pyridine (2mL), (Boc)20 ( 11.35mL, 52 mmoles) and NH4HC03 ( 3.98g, 50.4 mmoles) and stirred for 12h. All solvent was evaporated, diluted with EtOAc and washed with water, 5% H2S04 and brine. The organic layer was dried over anhydrous Na2S04 and concentrated. (R)- benzyl 2-carbamoylpyrrolidine-l-carboxylate was generated in quantitative yield and used in the following step without further purification.
	With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane for 12h;	1.2.1; 1.2.7 To a solution of the commercially available (R)-l-(benzyloxycarbonyl)pyrrolidine- 2-carboxylic acid (Synthetech, 9.97g, 40.0 mmoles) in 1, 4-dioxane (60mL) was added pyridine (2mL), di-tert-butyl dicarbonate ((Boc)20) ( 11.35mL, 52 mmoles) and NH4HCO3 ( 3.98g, 50.4 mmoles) and stirred for 12h. All solvent was evaporated, diluted with EtOAc and washed with water, 5% H2S04 and brine. The organic layer was dried over anhydrous Na2S04 and concentrated. (R)-benzyl 2-carbamoylpyrrolidine-l-carboxylate was generated in quantitative yield and used in the following step without further purification.
5.005 g	With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In acetonitrile at 20℃; for 6h; Inert atmosphere; Schlenk technique;
	With pyridine; di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate In 1,4-dioxane at 20℃; for 16h; Inert atmosphere;	1.1 Step 1: Synthesis of (R)-benzyl 2-carbamoylpyrrolidine-l-carboxylate. To a solution of ( ?)- l-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (15 g, 60.2 mmol ) in dioxane (200 mL) was added pyridine (6.19 g, 78.26 mmol), di-tert-butyl dicarbonate (16.9 g, 78.26 mmol), followed by ammonium bicarbonate (6.19 g, 78.26 mmol). The resulting mixture was stirred for 16 h at room temperature. Upon removal of the solvent, the residue was diluted with 150 mL ethyl acetate, washed with water (200 mL x 3), 1 N hydrochloride acid (200 mL) and brine (200 mL). The organic layer was dried with over anhydrous sodium sulfate and concentrated to afford (K)-benzyl 2-carbamoylpyrrolidine-l-carboxylate (16.15 g) as yellow oil. MS(ESI) m/z 249.1 [M + H]+.
	Stage #1: Z-D-proline With 1,1'-carbonyldiimidazole In tetrahydrofuran at 15℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0℃; for 2h;	43.43A (R)-benzyl 2-carbamoylpyrrolidine-1-carboxylate To a solution of (R)-l-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (25 g) in tetrahydrofuran (250 mL) was added carbonyldiimidazole (48.8 g) with stirring at 15 °C for 2 hours. Ammonium hydroxide (200 mL) was added to the reaction and stirring was continued at 0 °C for 2 hours. The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted five times with dichloromethane and the combined organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography on silica gel, eluting with 1-2.5% methanol in dichloromethane to give the title compound.
	Stage #1: Z-D-proline With 1,1'-carbonyldiimidazole In tetrahydrofuran at 20℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran at 0℃;	84.84B benzyl (R)-2-carbamoylpyrrolidine-1-carboxylate Example 84B benzyl (R)-2-carbamoylpyrrolidine-1-carboxylate To a mixture of Example 84A (25 g) in tetrahydrofuran (250 mL) was added di(1H-imidazol-1-yl)methanone (48.8 g) at 20° C. and the reaction mixture was stirred for 2 hours. Saturated ammonium hydroxide mixture (200 mL) was added to the reaction mixture dropwise at 0° C. The reaction mixture was extracted with dichloromethane (5*50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced to give a residue which was purified by column chromatography on silica gel (eluted with dichloromethane:methanol=100:1 to 40:1) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (br s, 5H), 5.18-5.11 (m, 2H), 4.32 (br s, 1H), 3.61-3.35 (m, 2H), 2.35-1.76 (m, 4H).

Reference： [1]Bourgeois, Frederic; Medlock, Jonathan A.; Bonrath, Werner; Sparr, Christof [Organic Letters, 2020, vol. 22, # 1, p. 110 - 115]
[2]Cobb, Alexander J. A.; Shaw, David M.; Longbottom, Deborah A.; Gold, Johan B.; Ley, Steven V. [Organic and Biomolecular Chemistry, 2005, vol. 3, # 1, p. 84 - 96]
[3]Morikawa; Honda; Endoh -i.; Matsumoto; Akamatsu -i.; Mitsui; Koizumi [Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842]
[4]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - US2009/93472, 2009, A1 Location in patent: Page/Page column 25
[5]Current Patent Assignee: COMENTIS, INC. - WO2011/130383, 2011, A1 Location in patent: Page/Page column 83-84
[6]Current Patent Assignee: COMENTIS, INC.; ASTELLAS PHARMA INC. - WO2012/54510, 2012, A1 Location in patent: Page/Page column 91
[7]Lang, Jan Hendrik; Jones, Peter G.; Lindel, Thomas [Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12714 - 12717]
[8]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - WO2019/28362, 2019, A1 Location in patent: Paragraph 00319; 00320; 00337
[9]Current Patent Assignee: ABBVIE INC - WO2019/35927, 2019, A1 Location in patent: Paragraph 00425
[10]Current Patent Assignee: ABBVIE INC - US2019/55264, 2019, A1 Location in patent: Paragraph 0907

2
[ 501-53-1 ]
[ 344-25-2 ]
[ 6404-31-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide In water; toluene at 20℃; for 1h; Inert atmosphere;
93%	With sodium hydroxide In water at 0 - 20℃;	1 Step-1 : Preparation of (R)-l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) Step-1 : Preparation of (R)-l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) To a stirred solution of D-Proline (1.2 g, 10.42 mmol) in 2 N aqueous NaOH solution (20.85 mL, 41.7 mmol) at 0 °C was added benzyl chloroformate (1.488 mL, 10.42 mmol) and allowed to warm to room temperature overnight. The reaction was washed with MTBE (2 x 25 mL), acidified with cone HCl and extracted with ethyl acetate (2 x 200 mL). The ethyl acetate layers were combined washed with water (50 mL), brine (25 mL) dried and concentrated in vacuum to afford (R)-l-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (12a) (2.41 g, 9.67 mmol, 93 % yield) which was used as such in next step; Η NMR (300 MHz, DMSO-i) δ 12.66 (s, 1H), 7.42 - 7.25 (m, 5H), 5.14 - 4.97 (m, 2H), 4.20 (ddd, J = 22.7, 8.8, 3.5 Hz, 1H), 3.50 - 3.25 (m, 2H), 2.32 - 2.08 (m, 1H), 1.97 - 1.75 (m, 3H); MS (ES+) 250.2 (M+l), 272.2 (M+Na), (ES-) 248.2 (M-l), 284.2 (M+Cl), 497.4 (2M-1).
	With sodium hydroxide In water Ambient temperature;

	With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 6h;
	Stage #1: benzyl chloroformate; D-Prolin With sodium hydroxide In water for 0.25h; Cooling with ice; Stage #2: With hydrogenchloride In water
	With triethylamine In dichloromethane at 15℃; for 2h;	84.84A ((benzyloxy)carbonyl)-D-proline Example 84A ((benzyloxy)carbonyl)-D-proline To a mixture of D-proline (25 g) in dichloromethane (500 mL) was added triethylamine (26.4 g) at 0° C. Benzyl carbonochloridate (48.2 g) was added to the reaction. The reaction mixture was stirred at 15° C. for 2 hours. The reaction mixture was quenched by addition of saturated aqueous NH4Cl (250 mL). The mixture was extracted with dichloromethane (3*250 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the residue which was purified by column chromatography on silica gel (eluted with ethyl acetate) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.39-7.17 (m, 5H), 5.18-5.01 (m, 2H), 4.35-4.24 (m, 1H), 3.64-3.54 (m, 1H), 3.52-3.38 (m, 1H), 2.25-2.09 (m, 1H), 2.08-1.98 (m, 1H), 1.97-1.86 (m, 1H), 1.85-1.74 (m, 1H).
	With sodium hydrogencarbonate In water; toluene at 0 - 20℃; for 4h;

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - WO2015/62486, 2015, A1 Location in patent: Paragraph 00191
[2]Current Patent Assignee: BIOCRYST PHARMACEUTICALS INC - WO2017/59178, 2017, A1 Location in patent: Page/Page column 73
[3]Morikawa; Honda; Endoh -i.; Matsumoto; Akamatsu -i.; Mitsui; Koizumi [Journal of Pharmaceutical Sciences, 1991, vol. 80, # 9, p. 837 - 842]
[4]Hayashi, Yujiro; Matsuzawa, Masayoshi; Yamaguchi, Junichiro; Yonehara, Sayaka; Matsumoto, Yasunobu; Shoji, Mitsuru; Hashizume, Daisuke; Koshino, Hiroyuki [Angewandte Chemie - International Edition, 2006, vol. 45, # 28, p. 4593 - 4597]
[5]Location in patent: experimental part Diakos, Connie I.; Zhang, Mei; Beale, Philip J.; Fenton, Ronald R.; Hambley, Trevor W. [European Journal of Medicinal Chemistry, 2009, vol. 44, # 7, p. 2807 - 2814]
[6]Current Patent Assignee: ABBVIE INC - US2019/55264, 2019, A1 Location in patent: Paragraph 0906
[7]Kundu, Gourab; Rissanen, Kari; Schoenebeck, Franziska; Sperger, Theresa [Angewandte Chemie - International Edition, 2020, vol. 59, # 49, p. 21930 - 21934][Angew. Chem., 2020, vol. 132, # 49, p. 22114 - 22118,5]

3
[ 6404-31-5 ]
[ 344-25-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With hydrogen In methanol for 5h;

Reference： [1]Mazzini, Claudio; Sambri, Letitia; Regeling, Henk; Zwanenburg, Binne; Chittenden, Gordon J. F. [Journal of the Chemical Society. Perkin transactions I, 1997, # 22, p. 3351 - 3356]

4
[ 6404-31-5 ]
[ 620601-77-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 1-hydroxybenzotriazole; EDCI / tetrahydrofuran / 0.5 h / 20 °C 1.2: 68 percent / aq. NH₃ / tetrahydrofuran / 24 h / 20 °C 2.1: 64 percent / p-TsCl; pyridine / CH₂Cl₂ / 72 h / 20 °C
	Multi-step reaction with 2 steps 1: di-<i>tert</i>-butyl dicarbonate; ammonium bicarbonate; pyridine / acetonitrile / 6 h / 20 °C / Inert atmosphere; Schlenk technique 2: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 0 - 20 °C / Inert atmosphere; Schlenk technique

Reference： [1]Cobb, Alexander J. A.; Shaw, David M.; Longbottom, Deborah A.; Gold, Johan B.; Ley, Steven V. [Organic and Biomolecular Chemistry, 2005, vol. 3, # 1, p. 84 - 96]
[2]Lang, Jan Hendrik; Jones, Peter G.; Lindel, Thomas [Chemistry - A European Journal, 2017, vol. 23, # 52, p. 12714 - 12717]

5
[ 6404-31-5 ]
[ 702700-79-6 ]

Reference： [1]Organic and Biomolecular Chemistry,2005,vol. 3,p. 84 - 96
[2]Chemistry - A European Journal,2017,vol. 23,p. 12714 - 12717

6
[ 6404-31-5 ]
[ 143322-56-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3419 - 3421
[2]Patent: US2011/166364,2011,A1
[3]Patent: US2012/71669,2012,A1
[4]Patent: EP944595,2003,B1

7
[ 6404-31-5 ]
[ 62937-45-5 ]

Reference： [1]Journal of Pharmaceutical Sciences,1991,vol. 80,p. 837 - 842

8
[ 10075-50-0 ]
[ 79-37-8 ]
[ 925-90-6 ]
[ 61350-62-7 ]
[ 6404-31-5 ]
[ 143322-56-9 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In dichloromethane; water; N,N-dimethyl-formamide; toluene;	EXAMPLE 56 (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-bromo-1H-indole Two solutions containing the reactants were prepared separately as follows: To a stirred solution of N-benzyloxycarbonyl-D-proline (291.93 g) in dichloromethane (291.9 mL) and toluene (370.8 mL) containing N,N-dimethylformamide (1.46 mL) was added oxalyl chloride (102.2 mL) in toluene (291.9 mL) and the resulting solution was stirred at ambient temperature overnight. The solution was then purged by passing a stream of dry nitrogen gas for five hours. This solution of N-benzyloxycarbonyl-D-proline acid chloride was ready for use. In parallel, a solution of ethyl magnesium bromide (800 mL of a 3M solution in ether) was added dropwise over one hour to a stirred solution of 5-bromoindole (459.15 g) in dichloromethane (4391.4 mL). The mixture was stirred and heated at reflux for 30 minutes then cooled to -20 C. The above solution of N-benzyloxycarbonyl-D-proline acid chloride was added dropwise with stirring (over one hour) and stirring was continued for a further 30 minutes. Then a solution of ammonium chloride (1122.3 g) in water (5855.3 mL) was added at this temperature and the mixture allowed to warm to room temperature. Further ammonium chloride (1452.3 g) in water (2000 mL) was added to allow separation of the phases. The phases were separated and the aqueous phase extracted with dichloromethane (1.95 L) then discarded. The combined organic phases were washed with aqueous sodium bicarbonate solution (2.7 L), then with brine (1 L) before concentration to low volume (about 1 L). This concentrate was diluted with ethyl acetate (1250 mL) and then further diluted with hexane (1250 mL). The resulting slurry was stirred at ambient temperature before collection of the title compound (361.4 g) by filtration (washing with 1:1 ethyl acetate:hexane-2*300 ml) and drying in vacuo. This material is as described in Example 26.

Reference： [1]Patent: US5545644,1996,A

9
[ 6404-31-5 ]
[ 72597-18-3 ]

Yield	Reaction Conditions	Operation in experiment
97%		1) (2R)-N-Benzyloxycarbonyl-2-hydroxymethylpyrrolidine Borane dimethylsulfide (3.23 mL) was added to a solution of N-benzyloxycarbonyl-D-proline (4.02 g) in tetrahydrofuran (50 mL) at room temperature, and the resultant mixture heated to reflux for 2 hours. Under ice cooling, an aqueous 1 N hydrochloric acid solution was added to the reaction solution to treat excessive borane dimethylsulfide, then chloroform was added to the reaction solution, which was then partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane-ethyl acetate), to obtain (2R)-N-benzyloxycarbonyl-2-hydroxymethylpyrrolidine (3.68 g, 97%) as an oily product. 1H-NMR(400MHz, CDCl3)delta: 1.57-2.05(4H, m), 3. 36-3. 68 (4H, m), 4.01(1H, br s), 4.39(1H, br s), 5.15(2H, s), 7.32(5H, m). ESI-MSm/z: 236(M+H)+.

Reference： [1]Patent: EP1785418,2007,A1 .Location in patent: Page/Page column 70

10
[ 6404-31-5 ]
[ 95034-05-2 ]
[ 1160838-90-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane

Reference： [1]Freire, Felix; Gellman, Samuel H. [Journal of the American Chemical Society, 2009, vol. 131, p. 7970 - 7972]

11
[ 6404-31-5 ]
[ 143322-57-0 ]

Reference： [1]Patent: US2011/166364,2011,A1
[2]Patent: US2012/71669,2012,A1
[3]Patent: EP944595,2003,B1

12
[ 6404-31-5 ]
[ 177834-92-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide; toluene / 2.5 h / 20 - 25 °C 2.1: methylmagnesium chloride / tert-butyl methyl ether; tetrahydrofuran / 0.75 h / 20 °C 2.2: 0.5 h / 3 - 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 3.5 h / 60 °C / Reflux 4.1: isopropyl alcohol; water / 4 h / 20 - 35 °C 5.1: potassium hydroxide / toluene; water / 0.25 h / 21 - 25 °C 5.2: 4 h / 100 °C 6.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 5 h / 115 °C 7.1: potassium carbonate; water / methanol 8.1: hydrogen bromide / water / pH 1.5 9.1: hydrogen / 5% Pd(II)/C(eggshell) / water / 20 - 50 °C / Autoclave
	Multi-step reaction with 5 steps 1.1: oxalyl dichloride / N,N-dimethyl-formamide / dichloromethane / 25 - 30 °C 2.1: ethylmagnesium bromide / diethyl ether / 2.25 h / 25 °C / 760.05 Torr / Reflux 2.2: 1 h / -30 °C 2.3: 0.17 h / -30 - 30 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 39 h / 25 °C / 760.05 Torr / Inert atmosphere; Reflux 4.1: triethylamine / palladium diacetate; tris-(o-tolyl)phosphine / acetonitrile / 75 - 80 °C 5.1: hydrogen / 10% Pd/C / methanol / 40 °C / 3677.86 Torr 5.2: 5 h / 25 - 70 °C

Reference： [1]Current Patent Assignee: HOLDING F.I.S. S.P.A. - US2011/166364, 2011, A1
[2]Current Patent Assignee: U S V LTD. - US2012/71669, 2012, A1

13
[ 6404-31-5 ]
[ 566159-08-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 7 h / 0 - 25 °C 2: palladium 10% on activated carbon; hydrogen / methanol / 760.05 Torr

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; Chugai Pharmaceutical (in: Roche) - EP2842946, 2015, A1

14
[ 578-66-5 ]
[ 6404-31-5 ]
(2R)-2-(quinolin-8-ylcarbamoyl)pyrrolidine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;	2 After that, 10 mmol of (R)-1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid was dissolved in dry dichloromethane, and 10 mmol of 8-aminoquinoline and 3 mmol of 4-dimethylaminopyridine were added, and the mixture was cooled to 0 ° C. Then, 15 mmol of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was slowly added, and the mixture was reacted at room temperature overnight, washed, dried, concentrated, and separated by silica gel column.(R)-2-(Quinoline-8-carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester in a yield of 90%.
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 36h; Inert atmosphere;
83%	Stage #1: 8-amino quinoline; Z-D-proline With benzotriazol-1-ol In dichloromethane at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; Inert atmosphere;

Reference： [1]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN108610358, 2018, A Location in patent: Paragraph 0065; 0067
[2]Affron, Dominic P.; Davis, Owen A.; Bull, James A. [Organic Letters, 2014, vol. 16, # 18, p. 4956 - 4959]
[3]Bunch, Lennart; Kayser, Silke; Nielsen, Birgitte; Pickering, Darryl S.; Poulie, Christian B. M.; Staudt, Markus; Temperini, Piero [ACS Chemical Neuroscience, 2020]

15
[ 640-68-6 ]
[ 501-53-1 ]
[ 6404-31-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide at 0℃;	2 20.0mmol D-valine was dissolved in 12.0mL, 2mol/L NaOH solution, 22mmol benzyl chloroformate was added dropwise at 0 °C, then added with NaOH solution, extracted, washed, dried, concentrated, separated by silica gel column. Got(R)-1-(Benzyloxycarbonyl)pyrrolidine-2-carboxylic acid in a yield of 95%.

Reference： [1]Current Patent Assignee: SHANGHAI JIAO TONG UNIVERSITY - CN108610358, 2018, A Location in patent: Paragraph 0065; 0066

16
[ 6404-31-5 ]
[ 223673-36-7 ]
(R)-2-((4-(2-((tert-butoxycarbonyl)((R)-2-hydroxy-2-phenylethyl)amino)ethyl)phenyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%		(2R)-1-((Benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (0.84 g, 3.37 mmol)Add to a 100ml single-mouth bottle,Add dichloromethane (10 mL) andN,N-diisopropylethylamine (2.40 mL, 14 mmol),After cooling at -20 C, HATU (1.39 g, 3.65 mmol) was added and stirred for 1 hour.Then <strong>[223673-36-7](R)-(4-aminophenethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester</strong> (1.0 g, 2.80 mmol),After reacting for 1 hour, transfer to room temperature for 3 hours to stop the reaction, and add water (5 mL) to quench, thenExtracted with dichloromethane (20 mL x 2), EtOAc (EtOAc)v) = 3/1) The title compound was obtained as a pale red liquid (1.55 g, 94%).
94%		will(2R)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid(0.84 g, 3.37 mmol) was added to a 100 mL single-mouth bottle and dichloromethane (10 mL) was added.And N,N-diisopropylethylamine (2.40 mL, 14 mmol), cooled at -20 C, then added HATU (1.39 g, 3.65 mmol) and stirred for 1 hour.Then join(R)-(4-Aminophenylethyl)(2-hydroxy-2-phenylethyl)carbamic acid tert-butyl ester(1.0 g, 2.80 mmol) was reacted for 1 hour, then transferred to room temperature, and the reaction was stopped for 3 hours.Quenched with water (5 mL),It was then extracted with dichloromethane (20 mL x 2) and the organic phase was collected.Concentrated under reduced pressure and the residue was purified by column chromatography ( petroleum ether / ethyl acetate (v/v) = 3/1)The title compound was obtained as a light red liquid(1.55g,94%).

Reference： [1]Patent: CN109776373,2019,A .Location in patent: Paragraph 0344; 0346; 0347
[2]Patent: CN109776374,2019,A .Location in patent: Paragraph 0297; 0298; 0299; 0300; 0301; 0303

17
[ 6404-31-5 ]
[ 14316-16-6 ]
(R)-2-((2-((4-methylphenyl)sulfonamido)ethyl)carbamoylbenzyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: Z-D-proline With triethylamine; isobutyl chloroformate In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: N-tosylethylenediamine In dichloromethane at 0 - 20℃; Inert atmosphere;

Reference： [1]Bourgeois, Frederic; Medlock, Jonathan A.; Bonrath, Werner; Sparr, Christof [Organic Letters, 2020, vol. 22, # 1, p. 110 - 115]

18
[ 801315-74-2 ]
[ 6404-31-5 ]
tert-butyl 4-({1-[(benzyloxy)carbonyl]-D-prolyl}amino)-1H-indazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 1-[(benzyloxy)carbonyl]-D-proline With 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: tert-butyl 4-amino-1H-indazole-1-carboxylate In N,N-dimethyl-formamide at 20℃;	tert-Butyl 4-[N-(tert-butoxycarbonyl)-N-methyl-D-alanyl]amino}-1H-indazole-1-carboxylate (S19) General procedure: To a solution of N-(tert-butoxycarbonyl)-N-methyl-D-alanine (0.500 g, 2.46 mmol) in DMF (7 mL), COMU (1.16 g, 2.71 mmol) and DIPEA (0.558 mL, 3.20 mmol) were added at 0°C, and the mixture was stirred at rt for 5 min. S18 (0.632 g, 2.71 mmol) was then added, and the mixture was stirred at rt overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with EtOAc three times. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and with saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was subjected to amino silica gel column chromatography (hexane/EtOAc) then to silica gel column chromatography (hexane/EtOAc) to obtain S19 (0.517 g, 1.23 mmol, 50% yield) as a colorless oil.
73%	Stage #1: 1-[(benzyloxy)carbonyl]-D-proline With 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: tert-butyl 4-amino-1H-indazole-1-carboxylate In N,N-dimethyl-formamide at 20℃;	tert-Butyl 4-[N-(tert-butoxycarbonyl)-N-methyl-D-alanyl]amino}-1H-indazole-1-carboxylate (S19) General procedure: To a solution of N-(tert-butoxycarbonyl)-N-methyl-D-alanine (0.500 g, 2.46 mmol) in DMF (7 mL), COMU (1.16 g, 2.71 mmol) and DIPEA (0.558 mL, 3.20 mmol) were added at 0°C, and the mixture was stirred at rt for 5 min. S18 (0.632 g, 2.71 mmol) was then added, and the mixture was stirred at rt overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with EtOAc three times. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and with saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was subjected to amino silica gel column chromatography (hexane/EtOAc) then to silica gel column chromatography (hexane/EtOAc) to obtain S19 (0.517 g, 1.23 mmol, 50% yield) as a colorless oil.
4.06 g	Stage #1: 1-[(benzyloxy)carbonyl]-D-proline With 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: tert-butyl 4-amino-1H-indazole-1-carboxylate In N,N-dimethyl-formamide at 20℃;	A-6.4 (Step 4) tert-butyl 4-({1-[(benzyloxy) carbonyl] -D-prolyl} amino) -1H-indazole-1-carboxylate To a solution of 1-[(benzyloxy) carbonyl] -D-proline (3.00 g, CAS number: 6404-31-5) in N, N-dimethylformamide (60 mL), COMU (5.67 g), N, N-Diisopropylethylamine (2.73 mL) was added, and the mixture was stirred at room temperature for 15 minutes, then the compound (2.81 g) obtained in the above Step 3 was added,Stir overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, followed by extraction with ethyl acetate three times. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate.After filtration and concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate and then n-hexane / ethyl acetate) to give the title compound (4.06 g) as a solid.

4.06 g

Stage #1: 1-[(benzyloxy)carbonyl]-D-proline With 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinomethylene)]methanaminium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: tert-butyl 4-amino-1H-indazole-1-carboxylate In N,N-dimethyl-formamide at 20℃;

4.1 (Step 1)
tert-Butyl 4-({1-[(benzyloxy)carbonyl]-D-prolyl}amino)-1H-indazole-1-carboxylate
To a solution of 1-[(benzyloxy)carbonyl]-D-proline (3.00 g)in N,N-dimethylformamide (60 mL), COMU (5.67 g)and N,N-diisopropylethylamine (2.73 mL)were added, and the mixture was stirred at room temperature for 15 minutes. The compound obtained in Reference Example A-2 (2.81 g)was then added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate three times. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and with saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue obtained was purified by silica gel column chromatography (chloroform/ethyl acetate, then hexane/ethyl acetate)to obtain the title compound (4.06 g)as a solid. 1H-NMR (DMSO-D6)δ: 1.65 (9H, s), 1.85-2.08 (3H, m), 2.23-2.39 (1H, m), 3.44-3.59 (2H, m), 4.52-4.61 (1H, m), 4.97-5.14 (2H, m), 7.06-7.39 (5H, m), 7.55 (1H, td, J = 8.2, 2.8 Hz), 7.81 (2H, dd, J = 14.8, 8.2 Hz), 8.52 (1H, d, J = 32.0 Hz), 10.36 (1H, s). MS (m/z):465 (M+H)+.

Reference： [1]Asano, Masayoshi; Banjo, Toshihiro; Haruta, Makoto; Hashimoto, Kazuyuki; Higuchi, Saito; Isoyama, Takeshi; Kagoshima, Yoshiko; Kanada, Ryutaro; Kihara, Kawori; Kuroha, Mutsumi; Murata, Takeshi; Naito, Hiroyuki; Obata, Kenichi; Sato, Kazumi; Suzuki, Kanae; Suzuki, Takashi; Takahashi, Mizuki; Togashi, Noriko; Tominaga, Yuichi; Ubukata, Osamu; Yamamoto, Yuka [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 66]
[2]Asano, Masayoshi; Banjo, Toshihiro; Haruta, Makoto; Hashimoto, Kazuyuki; Higuchi, Saito; Isoyama, Takeshi; Kagoshima, Yoshiko; Kanada, Ryutaro; Kihara, Kawori; Kuroha, Mutsumi; Murata, Takeshi; Naito, Hiroyuki; Obata, Kenichi; Sato, Kazumi; Suzuki, Kanae; Suzuki, Takashi; Takahashi, Mizuki; Togashi, Noriko; Tominaga, Yuichi; Ubukata, Osamu; Yamamoto, Yuka [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 66]
[3]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - JP2020/45306, 2020, A Location in patent: Paragraph 0259; 0260; 0264
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP3643703, 2020, A1 Location in patent: Paragraph 0527; 0528

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H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 6404-31-5 ] {[proInfo.proName]}

Quality Control of [ 6404-31-5 ]

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[ 6404-31-5 ] Synthesis Path-Upstream 1~19

[ 6404-31-5 ] Synthesis Path-Downstream 1~18

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Amino Acid Derivatives

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[ 6404-31-5 ]