Name: 135042-17-0|(2R,4S)-1-tert-Butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate|97%
Brand: Ambeed
SKU: A139174
Price: 7.0 USD
Availability: InStock
Rating: 97 (35 reviews)

1
[ 135042-16-9 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
93.9%	With sodium methylate In methanol for 1h; Ambient temperature;

Reference： [1]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]

2
[ 135042-17-0 ]
[ 87-42-3 ]
[ 135042-18-1 ]

Yield	Reaction Conditions	Operation in experiment
77.6%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]

3
[ 135042-17-0 ]
[ 507-09-5 ]
[ 161458-04-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran 1.) 0 deg C, 1 h, 2.) RT, 1 h;

Reference： [1]Kolodziej, Stephen A.; Nikiforovich, Gregory V.; Skeean, Richard; Lignon, Marie-Francoise; Martinez, Jean; Marshall, Garland R. [Journal of Medicinal Chemistry, 1995, vol. 38, # 1, p. 137 - 149]

4
[ 100-02-7 ]
[ 135042-17-0 ]
(2R,4R)-4-(4-Nitro-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

5
[ 371-41-5 ]
[ 135042-17-0 ]
(2R,4R)-4-(4-Fluoro-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

6
[ 90-15-3 ]
[ 135042-17-0 ]
(2R,4R)-4-(Naphthalen-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

7
[ 540-38-5 ]
[ 135042-17-0 ]
(2R,4R)-4-(4-Iodo-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

8
[ 367-27-1 ]
[ 135042-17-0 ]
(2R,4R)-4-(2,4-Difluoro-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

9
[ 135042-17-0 ]
[ 106-48-9 ]
[ 198969-21-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

10
[ 135042-17-0 ]
[ 120-83-2 ]
(2R,4R)-4-(2,4-Dichloro-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]

11
[ 135042-17-0 ]
[ 108-95-2 ]
[ 198969-19-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran Ambient temperature;
59%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Inert atmosphere;	6.6B 6B. (2R,4R)- 1 -tert-Butyl 2-methyl 4-phenoxypyrrolidine- 1 ,2-dicarboxylate: [00204j 6B. (2R,4R)- 1 -tert-Butyl 2-methyl 4-phenoxypyrrolidine- 1 ,2-dicarboxylate:To a stirred mixture of 6A (0.500 g, 2.04 mmol), phenol (0.211 g, 2.24 mmol), and Ph3P (0.588 g, 2.24 mmol) in THF (8.6 mL) at rt under argon was added DIAD (0.46 mL, 2.2 mmol). The mixture was stirred at rt overnight. The reaction was quenched with sat. aq.NaHCO and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by silica chromatography to give (2R,4R)- 1 -tert-butyl 2-methyl 4-phenoxypyrrolidine- 1 ,2-dicarboxylate as acolorless oil (0.385 g, 1.12 mmol, 59% yield). 1H NMR (500 MHz, methanol-d4) ö7.33 - 7.25 (m, 2H), 6.98 (q, J=7.2 Hz, 1H), 6.87 - 6.75 (m, 2H), 4.91 (ddd, J=7.2, 4.7,2.2 Hz, 1H), 4.60 - 4.40 (m, 1H), 3.84 - 3.65 (m, 5H), 2.54 - 2.42 (m, 2H), 1.50, 1.45 (two s, 9H).

Reference： [1]Bellier, Bruno; McCort-Tranchepain, Isabelle; Ducos, Bertrand; Danascimento, Sophie; Meudal, Hervé; Noble, Florence; Garbay, Christiane; Roques, Bernard P. [Journal of Medicinal Chemistry, 1997, vol. 40, # 24, p. 3947 - 3956]
[2]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/78609, 2014, A1 Location in patent: Paragraph 00204

12
[ 135042-17-0 ]
[ 185304-06-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With diphenyl-phosphinic acid; triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran

Reference： [1]Gomez-Vidal, Jose A.; Silverman, Richard B. [Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484]

13
[ 198969-28-7 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium azide In methanol at 40℃;

Reference： [1]Gomez-Vidal, Jose A.; Silverman, Richard B. [Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484]

14
[ 361367-93-3 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium azide; crown ether In methanol at 40℃;
90%	With sodium methylate In methanol at 0℃; for 0.5h;	15 4.15 N-tert-Butoxycarbonyl-trans-4-hydroxy-d-proline methyl ester (5) To a solution of compound 15 (4.45 g, 11.7 mmol) in anhydrous MeOH (59 mL) was added CH3ONa (0.5 g, 9.26 mmol) at 0 °C. The reaction mixture was stirred for 30 min at the same temperature, at the end of which time TLC indicated it was finished. The reaction was neutralized with Amberlite IR-120 H+ resin. After filtration, the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (1.5:1, petroleum ether-EtOAc) to give compound 5 (2.58 g, 90%) as a colorless syrup. 5: Rf=0.21 (1:1, petroleum ether-EtOAc); [α]D22 +108 (c 1.0, EtOH); 1H NMR (600 MHz, CDCl3): δ 4.47 (s, 1H), 4.39 (4.44)* (t, 1H, J=7.8 Hz), 3.74 (3.73) (s, 3H), 3.64-3.59 (m, 1H), 3.54 (3.45) (d, 1H, J=10.8 Hz), 3.0 (2.9) (s 1H), 2.33-2.22 (m, 1H), 2.10-2.02 (m, 1H), 1.46 (1.41) (s, 9H); The specific rotation and 1H NMR data corresponded to the literature values.
79%	With methanol; sodium azide at 45℃; for 24h;

63%

With sodium azide; 15-crown-5 In methanol at 40℃; for 2.5h;

91.2 Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4R-fluoropyrrolidine-2R-carboxylic acid hydroxyamide; Step 2 4S-(4-NITROBENZOYLOXY) PYRROLIDINE-1, 2RDICARBOXYLIC] acid 1-tert-butyl ester 2-methyl ester was dissolved in [MEOH] (200 mL) and treated with NaN3 (2.17 g, 33 mmol, 3.7 eq. ) followed by [15-CROWN-5] (4.0 mL, 20 mmol, 2. [1] eq. ). The resulting solution was warmed to 40 [°C] for 2.5 h, then concentrated. The residue was partitioned between [H20] (150 mL) and EtOAc (200 mL). The layers were separated, the organic layer washed with [H2O] (150 [ML),] brine (100 mL), dried [MGS04] and concentrated concentrated in vacuo. The product was purified via flash column chromatography on silica gel [(50-100%] EtOAc/hexanes as eluent) to give 4S- [HYDROXYPYRROLIDINE-1,] 2R-dicarboxylic acid [1-TERT-BUTYL] ester 2-methyl ester (1.40 g, 5.71 mmol, 63% yield).

Reference： [1]Gomez-Vidal, Jose A.; Silverman, Richard B. [Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484]
[2]Zhu, Kai; Yang, Jin-Song [Tetrahedron, 2016, vol. 72, # 22, p. 3113 - 3123]
[3]Pandey, Anil K.; Naduthambi, Devan; Thomas, Krista M.; Zondlo, Neal J. [Journal of the American Chemical Society, 2013, vol. 135, # 11, p. 4333 - 4363]
[4]Current Patent Assignee: ABBVIE INC - WO2004/7444, 2004, A2 Location in patent: Page 137

15
[ 135042-17-0 ]
[ 98-74-8 ]
[ 629616-71-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	In pyridine at 4℃; for 14h;

Reference： [1]Lerner, Christian; Siegrist, Romain; Schweizer, Eliane; Diederich, Francois; Gramlich, Volker; Jakob-Roetne, Roland; Zuercher, Gerhard; Borroni, Edilio [Helvetica Chimica Acta, 2003, vol. 86, # 4, p. 1045 - 1062]

16
[ 13154-24-0 ]
[ 135042-17-0 ]
[ 728895-97-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 1H-imidazole In N,N-dimethyl-formamide

Reference： [1]Geng, Xudong; Geney, Raphael; Pera, Paula; Bernacki, Ralph J.; Ojima, Iwao [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 13, p. 3491 - 3494]

17
[ 135042-17-0 ]
(1R,4R)-2,5-Diaza-bicyclo[2.2.1]heptane-2,6-dicarboxylic acid 2-tert-butyl ester 6-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: pyridine / CH₂Cl₂ 2: LiBH₄ / tetrahydrofuran / 22 °C 3: (COCl)2; DMSO; TEA / CH₂Cl₂ / -78 - 0 °C 4: CH₂Cl₂ 5: DBU / 1,2-dichloro-ethane / 80 °C 6: aq. NaOH 7: HCl 8: H₂ / Pd/C / ethyl acetate

Reference： [1]Balog, Aaron; Salvati, Mark E.; Shan, Weifang; Mathur, Arvind; Leith, Leslie W.; Wei, Donna D.; Attar, Ricardo M.; Geng, Jieping; Rizzo, Cheryl A.; Wang, Chihuei; Krystek, Stanley R.; Tokarski, John S.; Hunt, John T.; Gottardis, Marco; Weinmann, Roberto [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6107 - 6111]

18
[ 135042-17-0 ]
(1R,6S,7R)-4-(4-Nitro-naphthalen-1-yl)-3,5-dioxo-2,4,8-triaza-tricyclo[5.2.1.0^2,6]decane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: pyridine / CH₂Cl₂ 2: LiBH₄ / tetrahydrofuran / 22 °C 3: (COCl)2; DMSO; TEA / CH₂Cl₂ / -78 - 0 °C 4: CH₂Cl₂ 5: DBU / 1,2-dichloro-ethane / 80 °C 6: aq. NaOH 7: HCl 8: H₂ / Pd/C / ethyl acetate 9: 1,2-dichloro-ethane / 22 °C 10: DBU / 1,2-dichloro-ethane / 2 h / 60 °C

Reference： [1]Balog, Aaron; Salvati, Mark E.; Shan, Weifang; Mathur, Arvind; Leith, Leslie W.; Wei, Donna D.; Attar, Ricardo M.; Geng, Jieping; Rizzo, Cheryl A.; Wang, Chihuei; Krystek, Stanley R.; Tokarski, John S.; Hunt, John T.; Gottardis, Marco; Weinmann, Roberto [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6107 - 6111]

19
[ 135042-17-0 ]
(1R,6R,7R)-4-(4-Nitro-naphthalen-1-yl)-3,5-dioxo-2,4,8-triaza-tricyclo[5.2.1.0^2,6]decane-8-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: pyridine / CH₂Cl₂ 2: LiBH₄ / tetrahydrofuran / 22 °C 3: (COCl)2; DMSO; TEA / CH₂Cl₂ / -78 - 0 °C 4: CH₂Cl₂ 5: DBU / 1,2-dichloro-ethane / 80 °C 6: aq. NaOH 7: HCl 8: H₂ / Pd/C / ethyl acetate 9: 1,2-dichloro-ethane / 22 °C 10: DBU / 1,2-dichloro-ethane / 2 h / 60 °C

Reference： [1]Balog, Aaron; Salvati, Mark E.; Shan, Weifang; Mathur, Arvind; Leith, Leslie W.; Wei, Donna D.; Attar, Ricardo M.; Geng, Jieping; Rizzo, Cheryl A.; Wang, Chihuei; Krystek, Stanley R.; Tokarski, John S.; Hunt, John T.; Gottardis, Marco; Weinmann, Roberto [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6107 - 6111]

20
[ 135042-17-0 ]
(1R,4R)-5-(4-Nitro-naphthalen-1-ylcarbamoyl)-2,5-diaza-bicyclo[2.2.1]heptane-2,6-dicarboxylic acid 2-tert-butyl ester 6-methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: pyridine / CH₂Cl₂ 2: LiBH₄ / tetrahydrofuran / 22 °C 3: (COCl)2; DMSO; TEA / CH₂Cl₂ / -78 - 0 °C 4: CH₂Cl₂ 5: DBU / 1,2-dichloro-ethane / 80 °C 6: aq. NaOH 7: HCl 8: H₂ / Pd/C / ethyl acetate 9: 1,2-dichloro-ethane / 22 °C

Reference： [1]Balog, Aaron; Salvati, Mark E.; Shan, Weifang; Mathur, Arvind; Leith, Leslie W.; Wei, Donna D.; Attar, Ricardo M.; Geng, Jieping; Rizzo, Cheryl A.; Wang, Chihuei; Krystek, Stanley R.; Tokarski, John S.; Hunt, John T.; Gottardis, Marco; Weinmann, Roberto [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6107 - 6111]

21
[ 135042-17-0 ]
5R-(5α,8α,8aα)-4-[Octahydro-7-[(1,1-dimethylethoxy)carbonyl]-1,3-dioxo-5,8-methanoimidazo[1,5-a]pyrazin-2-yl]-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: pyridine / CH₂Cl₂ 2: LiBH₄ / tetrahydrofuran / 22 °C 3: (COCl)2; DMSO; TEA / CH₂Cl₂ / -78 - 0 °C 4: CH₂Cl₂ 5: DBU / 1,2-dichloro-ethane / 80 °C 6: aq. NaOH 7: HCl 8: H₂ / Pd/C / ethyl acetate 9: 1,2-dichloro-ethane / 22 °C 10: DBU / 1,2-dichloro-ethane / 2 h / 60 °C

Reference： [1]Balog, Aaron; Salvati, Mark E.; Shan, Weifang; Mathur, Arvind; Leith, Leslie W.; Wei, Donna D.; Attar, Ricardo M.; Geng, Jieping; Rizzo, Cheryl A.; Wang, Chihuei; Krystek, Stanley R.; Tokarski, John S.; Hunt, John T.; Gottardis, Marco; Weinmann, Roberto [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6107 - 6111]

22
[ 135042-17-0 ]
5R-(5α,8α,8aβ)-4-[Octahydro-7-[(1,1-dimethylethoxy)carbonyl]-1,3-dioxo-5,8-methanoimidazo[1,5-a]pyrazin-2-yl]-2-(trifluoromethyl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: pyridine / CH₂Cl₂ 2: LiBH₄ / tetrahydrofuran / 22 °C 3: (COCl)2; DMSO; TEA / CH₂Cl₂ / -78 - 0 °C 4: CH₂Cl₂ 5: DBU / 1,2-dichloro-ethane / 80 °C 6: aq. NaOH 7: HCl 8: H₂ / Pd/C / ethyl acetate 9: 1,2-dichloro-ethane / 22 °C 10: DBU / 1,2-dichloro-ethane / 2 h / 60 °C

Reference： [1]Balog, Aaron; Salvati, Mark E.; Shan, Weifang; Mathur, Arvind; Leith, Leslie W.; Wei, Donna D.; Attar, Ricardo M.; Geng, Jieping; Rizzo, Cheryl A.; Wang, Chihuei; Krystek, Stanley R.; Tokarski, John S.; Hunt, John T.; Gottardis, Marco; Weinmann, Roberto [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 24, p. 6107 - 6111]

23
[ 135042-17-0 ]
[ 135042-19-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 85 percent / pyridine / 14 h / 4 °C 2: 60 percent / K₂CO₃; 18-crown-6 / dimethylformamide / 6 h / 80 °C 3: 85 percent / LiCl; NaBH₄ / tetrahydrofuran; ethanol / 12 h / 0 - 55 °C
	Multi-step reaction with 2 steps 1: 77.6 percent / triphenylphosphine, diethylazodicarboxylate (DEAD) / tetrahydrofuran / Ambient temperature 2: 1.) LiBHEt₃, 2.) NH₃ / 1.) THF, 0 deg C, 2.) 80 deg C

Reference： [1]Lerner, Christian; Siegrist, Romain; Schweizer, Eliane; Diederich, Francois; Gramlich, Volker; Jakob-Roetne, Roland; Zuercher, Gerhard; Borroni, Edilio [Helvetica Chimica Acta, 2003, vol. 86, # 4, p. 1045 - 1062]
[2]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]

24
[ 135042-12-5 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: methanol 2: 95 percent / DEAD; PPh₃ / tetrahydrofuran 3: 100 percent / sodium azide / methanol / 40 °C
	Multi-step reaction with 3 steps 1: 92.4 percent / dioxane; diethyl ether / 0.25 h / 5 °C 2: 93.9 percent / Ph₃P, DEAD / tetrahydrofuran / 42 h / Ambient temperature 3: 93.9 percent / NaOMe / methanol / 1 h / Ambient temperature
	Multi-step reaction with 3 steps 1: acetone / 2 h / 20 °C / Alkaline conditions 2: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 7 h / 0 - 20 °C 3: sodium azide; methanol / 24 h / 45 °C

Reference： [1]Gomez-Vidal, Jose A.; Silverman, Richard B. [Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484]
[2]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]
[3]Pandey, Anil K.; Naduthambi, Devan; Thomas, Krista M.; Zondlo, Neal J. [Journal of the American Chemical Society, 2013, vol. 135, # 11, p. 4333 - 4363]

25
[ 114676-69-6 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 95 percent / DEAD; PPh₃ / tetrahydrofuran 2: 100 percent / sodium azide / methanol / 40 °C
	Multi-step reaction with 2 steps 1: DEAD, Ph₃P / tetrahydrofuran / 5 h / Ambient temperature 2: conc. aq. NH₃ / 2 h / Ambient temperature
	Multi-step reaction with 2 steps 1: 76 percent / diisopropyl azodicarboxylate, triphenylphosphine / tetrahydrofuran 2: 0.64 g / 1 N NaOH / methanol

	Multi-step reaction with 2 steps 1: 93.9 percent / Ph₃P, DEAD / tetrahydrofuran / 42 h / Ambient temperature 2: 93.9 percent / NaOMe / methanol / 1 h / Ambient temperature
	Multi-step reaction with 2 steps 1: diethylazodicarboxylate; triphenylphosphine / tetrahydrofuran / 0 - 20 °C 2: sodium methylate / methanol / 0.5 h / 0 °C

Reference： [1]Gomez-Vidal, Jose A.; Silverman, Richard B. [Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484]
[2]Lowe, Gordon; Vilaivan, Tirayut [Journal of the Chemical Society. Perkin transactions I, 1997, # 4, p. 539 - 546]
[3]Kolodziej, Stephen A.; Nikiforovich, Gregory V.; Skeean, Richard; Lignon, Marie-Francoise; Martinez, Jean; Marshall, Garland R. [Journal of Medicinal Chemistry, 1995, vol. 38, # 1, p. 137 - 149]
[4]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]
[5]Zhu, Kai; Yang, Jin-Song [Tetrahedron, 2016, vol. 72, # 22, p. 3113 - 3123]

26
[ 2584-71-6 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: TEA / dioxane; H₂O; methanol / 3 h 2: methanol 3: 95 percent / DEAD; PPh₃ / tetrahydrofuran 4: 100 percent / sodium azide / methanol / 40 °C
	Multi-step reaction with 5 steps 1: SOCl₂ 2: -5 °C 3: Na₂CO₃ / dioxane; H₂O / Ambient temperature 4: 76 percent / diisopropyl azodicarboxylate, triphenylphosphine / tetrahydrofuran 5: 0.64 g / 1 N NaOH / methanol
	Multi-step reaction with 4 steps 1: 82.5 percent / aq. NaOH / tetrahydrofuran / Ambient temperature 2: 92.4 percent / dioxane; diethyl ether / 0.25 h / 5 °C 3: 93.9 percent / Ph₃P, DEAD / tetrahydrofuran / 42 h / Ambient temperature 4: 93.9 percent / NaOMe / methanol / 1 h / Ambient temperature

Reference： [1]Gomez-Vidal, Jose A.; Silverman, Richard B. [Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484]
[2]Kolodziej, Stephen A.; Nikiforovich, Gregory V.; Skeean, Richard; Lignon, Marie-Francoise; Martinez, Jean; Marshall, Garland R. [Journal of Medicinal Chemistry, 1995, vol. 38, # 1, p. 137 - 149]
[3]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]

27
[ 24424-99-5 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 1) SnCl₂, 2) Na₂CO₃ / 1) dioxane, H₂O 2: I₂ / ethanol; H₂O / 41 h / Ambient temperature
	Multi-step reaction with 4 steps 1: 82.5 percent / aq. NaOH / tetrahydrofuran / Ambient temperature 2: 92.4 percent / dioxane; diethyl ether / 0.25 h / 5 °C 3: 93.9 percent / Ph₃P, DEAD / tetrahydrofuran / 42 h / Ambient temperature 4: 93.9 percent / NaOMe / methanol / 1 h / Ambient temperature

Reference： [1]Kitagawa, Osamu; Hanano, Tokushi; Kikuchi, Norihiko; Taguchi, Takeo [Tetrahedron Letters, 1993, vol. 34, # 13, p. 2165 - 2168]
[2]Peterson, Mark L.; Vince, Robert [Journal of Medicinal Chemistry, 1991, vol. 34, # 9, p. 2787 - 2797]

28
[ 135042-17-0 ]
[ 647857-43-0 ]

Yield	Reaction Conditions	Operation in experiment
35%	Stage #1: (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With (bis-(2-methoxyethyl)amino)sulfur trufluoride In dichloromethane at -78 - 23℃; for 5.53333h; Stage #2: With sodium hydrogencarbonate In dichloromethane; water	91.3 Preparation of 1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-4R-fluoropyrrolidine-2R-carboxylic acid hydroxyamide; Step 3 To a stirred solution of 4S-hydroxypyrrolidine-1, 2R-dicarboxylic acid 1- [TERT-BUTYL] ester 2-methyl ester (716 mg, 2.92 mmol, 1 eq. ) in [CH2C12] (15 [ML)] [AT-78 °C] was added aqueous [(MEO)] 2DAST (2.15 mL, 11.7 mmol, 4 eq. ) over the course of 2 min. After 2 h the reaction mixture was warmed to [0 °C,] and after a further 2 h warmed to 23 [°C.] After 1.5 h at 23 [°C] the reaction was quenched with [NAHC03.] The mixture was then filtered through a pad of Celite and concentrated [IN VACUO.] The product was purified via flash column chromatography on silica gel (40% [ETOAC/HEXANES] as eluent) to give [4R-FLUOROPYRROLIDINE-1,] 2R-dicarboxylic acid [1-] [TERT-BUTYL] ester 2-methyl ester (255 mg, 1.03 mmol, 35% yield

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2004/7444, 2004, A2 Location in patent: Page 137-138

29
[ 92-69-3 ]
[ 135042-17-0 ]
[ 1372656-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 8h;	100.1 Preparation of 4R-(biphenyl-4-yloxy)-1-(3,4-dimethoxy-5-trifluoromethylthiobenzoyl)-pyrrolidine-2R-carboxylic acid hydroxyamide; Step 1 To a mixture of of 4S-hydroxypyrrolidine-1, [2R-DICARBOXYLIC] acid 1-tert- butyl ester 2-methyl ester (1.0 g, 4.08 mmol, [1] eq.; Product from Step 2 of Example 91), biphenyl- [4-OL] (860 mg, 4. 89 mmol, 1.2 eq. ), and Ph3P (1.64 g, 6.12 mmol, 1.5 eq. ) in dry THF (50 mL) at 0 [°C] was added DIAD (1.27 mL, 6.12 mmol, 1. [5] eq. ) dropwise. The reaction was allowed to warm to rt and stirred for 8 h. The solvent was removed in vacuo and the residue was pre-adsorbed on to silica gel and chromatographed on silica gel using in 30% EtOAc/hexanes as an eluent to afford 4R-(biphenyl-4-yloxy)pyrrolidine-1, 2R-dicarboxylic acid 1-tert-butyl ester 2-methyl ester.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2004/7444, 2004, A2 Location in patent: Page 149

30
[ 69739-34-0 ]
[ 135042-17-0 ]
[ 791602-89-6 ]

Yield	Reaction Conditions	Operation in experiment
59%	With triethylamine In dichloromethane at 20℃; for 2h;	20 tert-Butyldimethylsilyl triflate (1.44 ml) was added to a stirred solution of 1-tert-butyl 2-methyl (2R, 4S)-4-hydroxypyrrolidine-1, 2-dicarboxylate (1.03 g) and triethylamine (1.76 ml) in DCM (50 ml) at room temperature, under an atmosphere of nitrogen. The reaction mixture was stirred for 2 hours and then the mixture was washed with saturated aqueous potassium hydrogensulfate, dried (NA2S04), and concentrated in vacuo to give a clear oil. Purification by column chromatography, using 0-30% ethyl acetate in hexane as eluent, gave 1-tert-butyl 2- methyl (2R, 4S)-4-{ [tert-butyl (dimethyl) silyl] OXY} PYRROLIDINE-1, 2-dicarboxylate as a clear oil (891 mg, 59%) ; NMR spectrum (CDC13) 4.43-4. 32 (m, 2H), 3.75-3. 72 (m, 2H), 3.65-3. 56 (m, 1H), 3.43-3. 31 (m, 1H), 2.21-2. 15 (m, 1H), 2.07-1. 98 (m, 1H), 1.47 (s, 3H), 1.42 (s, 6H), 0.88 (s, 9H), 0.07 (s, 6H).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/96226, 2004, A1 Location in patent: Page/Page column 102

31
[ 147266-92-0 ]
[ 18107-18-1 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	In methanol; hexane; dichloromethane; at 20℃;	(Trimethylsilyl) diazomethane (2N solution in hexane, 2.9 ML) was added dropwise over 5 minutes to a stirred solution of (4S)-L- (TERT-BUTOXYCARBONYL)-4-HYDROXY-D-PROLINE (1.0 g) in DCM (20 ml) and methanol (5 ml) at room temperature until a permanent faint yellow colour persisted. The reaction mixture was concentrated in vacuo and purified by column chromatography, using 0-50% ethyl acetate in hexane as eluent, to give 1-tert-butyl 2-methyl (2R, 4S)-4-hydroxypyrrolidine-1, 2-dicarboxylate as a clear oil (1.03 g, 97%); NMR spectrum (CDC13) 4.90-4. 37 (m, 2H), 3.73 (s, 3H), 3.64 (dd, 1H), 3.53-3. 43 (m, 1H), 2.34-2. 27 (m, 1H), 2.12-1. 97 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).

Reference： [1]Patent: WO2004/96226,2004,A1 .Location in patent: Page/Page column 102

32
[ 135042-17-0 ]
[ 647857-43-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With diethylamino-sulfur trifluoride In dichloromethane at -78 - 20℃; for 20.5h; Heating / reflux;	7 Add (diethylamino)sulfur trifluoride (10.5 mL, 80 mmol) to a -78 °C cooled solution of 4-(S)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2- methyl ester (9.83 g, 40 mmol) in dichloromethane (60 mL). Stir 2 h, then remove cooling bath and stir 18 h at room temperature. Heat to reflux for 30 min, then cool in ice bath and add saturated aqueous sodium bicarbonate solution. Warm to room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25 °C) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) and then concentrate at 120 mbar at 25 °C to give the title compound as an oil (9.09 g, 92%). MS (ES): m/z = 148.1 [M+H, Product-Boc]

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/108358, 2005, A2 Location in patent: Page/Page column 39

33
[ 481704-21-6 ]
[ 24424-99-5 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 0 - 20℃; for 1h;	Add di-tert-butyl dicarbonate (11.2 g, 51.35 mmol) to a solution of 4-(S)- hydroxypyrrolidine-2- (R)-carboxylic acid methyl ester hydrochloride (7.17 g, 39.5 mmol) in 1,4-dioxane (80 mL). Cool in an ice bath and add N,N-diisopropylethylamine (11.7 mL, 67.2 mmol). Remove ice bath and stir 1 h at room temperature. Concentrate and dissolve in ethyl acetate, wash with 5percent aqueous citric acid solution (2 x100 mL), water, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compound as a white solid (9.83 g, 100percent). MS (ES): m/z = 246.1 [M+H].

Reference： [1]Patent: WO2005/108358,2005,A2 .Location in patent: Page/Page column 38-39

34
aqueous 1N-sodium hydroxide [ No CAS ]
[ 148017-31-6 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	In methanol	P.7.B.2 Step B-2. Step B-2. Removal of a formyl group To a solution of (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.08 g: 7.6 mmole) in methanol (21.0 ml), aqueous 1N-sodium hydroxide (7.6 ml) is added under ice cooling. The mixture is stirred at the same temperature for 25 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (1.86 g). Yield: 100%. Colorless oil. NMR δ(CDCl3) ppm: 1.44(d, J=9.2 Hz, 9H), 1.9 to 2.4(m, 2H), 3.4 to 3.7(m, 2H), 3.74 (s, 3H), 4.3 to 4.6(m, 2H).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - US5317016, 1994, A

35
[ 135042-17-0 ]
[ 124-63-0 ]
(2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine In dichloromethane	P.7.B.3 Step B-3. Step B-3. Preparation of a mesyl compound To a solution of (2R,4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (3.17 g: 12.9 mmole) in dichloromethane (16 ml) in a nitrogen atmosphere under ice cooling, triethylamine (2.15 ml: 15.5 mmole) and methanesulfonyl chloride (1.19 ml: 15.5 mmole) are added. The mixture is stirred to react for 30 minutes to give (2R,4S)-1-t-butoxycarbonyl-4-methanesulfonyloxy-2-methoxycarbonylpyrrolidine as oil (4.13 g). Yield: 99%. NMR δ(CDCl3) ppm: 1.46(d, J=8.4 Hz, 9H), 2.3(m, 1H), 2.5 to 2.8(m, 1H), 3.08(s, 3H), 3.8 to 4.0(m, 5H), 4.3 to 4.6(m, 1H), 5.3(m, 1H).

Reference： [1]Current Patent Assignee: SHIONOGI & CO., LTD. - US5317016, 1994, A

36
[ 135042-17-0 ]
[ 18162-48-6 ]
[ 791602-89-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1H-imidazole In N,N-dimethyl-formamide	46.2 Synthesis of (2R,4S)-l-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-l ,2- dicarboxylate (46b) To a solution of 46b (5 g; 20.38 mmol) in DMF (60 mL), imidazole (6.94 g; 101.90 mmol) was added followed by TBDMSCI (4.61 g; 30.57 mmol) and reaction was stirred overnight. AfterLCMS indicated completion of the reaction, reaction mixture extracted between water and EtOAc.Organic layer was washed with water, brine, dried over anhydrous MgS04, and concentrated.Crude product was purified by column chromatography (hexane/EtOAc 8: 1) to give 6.70 g of 46b as a colorless oil (18.63 mmol; 92% yield).ESI-MS m/z for C17H33NO5S1 found 260.2 (M-Boc+l)+, 382.1 (M+Na)+. NMR (CDCI3, 700MHz) δ [4.43-4.40 (m); 4.33 (d, J=7.7Hz); 2H], [3.74 (s); 3.72 (s); 3H], [3.61 (dd, J=11.2, 4.6Hz); 3.57 (dd, J=11.0, 4.8Hz); 1H], [3.40 (dd, J=11.4, 1.3Hz); 3.37 (dd, J=11.2, 2.4Hz); 1H], 2.20-2.14 (m, 1H), 2.04-1.98 (m, 1H), [1.46(s); 1.41(s); 9H], 087 (s, 9H), 0.06 (s, 6H).
92%	With 1H-imidazole In N,N-dimethyl-formamide	55.2 Synthesis of (2R,4S)-1-tert-butyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (55b). To a solution of 55a (5 g; 20.38 mmol) in DMF (60 mL), imidazole (6.94 g; 101.90 mmol) was added followed by TBDMSCl (4.61 g; 30.57 mmol) and reaction was stirred overnight. When LC-MS analysis indicated completion of the reaction, reaction mixture was taken between water and EtOAc. Organic layer was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Crude product was purified by column chromatography (hexane/EtOAc 8:1 v/v) to give 55b as a colorless oil in 92% yield (6.7 g; 18.63 mmol).ESI-MS m/z for C17H33NO5Si found 260.2 (M+H-Boc)+, 382.1 (M+Na)+;1H NMR (700 MHz, CDCl3) d [4.43-4.40 (m); 4.33 (d, J = 7.7Hz); 2H], [3.74 (s); 3.72 (s); 3H], [3.61 (dd, J = 11.2, 4.6Hz); 3.57 (dd, J = 11.0, 4.8Hz); 1H], [3.40 (dd, J = 11.4, 1.3Hz); 3.37 (dd, J = 11.2, 2.4Hz); 1H], 2.20-2.14 (m, 1H), 2.04-1.98 (m, 1H), [1.46(s); 1.41(s); 9H], 087 (s, 9H), 0.06 (s, 6H).
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1.5h;	3 Intermediate 31-(1,1 -dimethylethyl) 2-methyl (2R,4S)-4-[(1,1 -dimethylethyl)(dimethyl)silyl]oxy}-1,2- pyrrolidinedicarboxylateTo 1-(1 ,1-dimethylethyl) 2-methyl (2R,4S)-4-hydroxy-1 ,2-pyrrolidinedicarboxylate(1.4406 g, 5.9 mmol) in DMF (~4 ml.) was added imidazole (0.4399 g, 6.46 mmol) and TBSCI (1.8512 g, 12.3 mmol). The resultant mixture was stirred at room temperature for 1.5 hours and diluted in ether and water. The organic layers were washed with 1 N HCI and NaHCOs solution, dried on MgSO4 and the ether removed under vacuum to afford the title compound as a yellow liquid (2.3591 g). LC-MS: m/z, 360 (M+H).

With 1H-imidazole

Reference： [1]Current Patent Assignee: ONCOARENDI THERAPEUTICS SA - WO2017/37670, 2017, A1 Location in patent: Page/Page column 202-204
[2]Current Patent Assignee: MOLECURE SA - WO2021/9209, 2021, A1 Location in patent: Paragraph 0430; 0431
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/26197, 2009, A1 Location in patent: Page/Page column 29
[4]Location in patent: scheme or table Laine, Dramane; Palovich, Michael; McCleland, Brent; Petitjean, Emilie; Delhom, Isabelle; Xie, Haibo; Deng, Jianghe; Lin, Guoliang; Davis, Roderick; Jolit, Anais; Nevins, Neysa; Zhao, Baoguang; Villa, Jim; Schneck, Jessica; McDevitt, Patrick; Midgett, Robert; Kmett, Casey; Umbrecht, Sandra; Peck, Brian; Davis, Alicia Bacon; Bettoun, David [ACS Medicinal Chemistry Letters, 2011, vol. 2, # 2, p. 142 - 147]

37
[ 24424-99-5 ]
[ 178962-09-9 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydrogencarbonate In methanol at 20℃; Inert atmosphere;
	With triethylamine In dichloromethane at 0 - 20℃;	2 Intermediate 21-(1,1 -dimethylethyl) 2-methyl (2R,4S)-4-hydroxy-1,2-pyrrolidinedicarboxylateTo methyl (4S)-4-hydroxy-D-prolinate (1.1 147 g, 7.6 mmol) in DCM (8 ml.) was added triethylamine (3.19 ml_, 22.9 mmol) while the bath cooled down to O0C. To the resultant mixture, di-tert-butyl dicarbonate (1.8318 g, 8.4 mmol) was added, stirred from O 0C to room temperature over the weekend. The resultant mixture was washed with 1 N HCI and NaHCOs solution, dried over MgSO4 and evaporated to afford the title compound as a yellow oil (1.4406 g). LC-MS: m/z, 246 (M+H).
	With triethylamine

With triethylamine In dichloromethane

Reference： [1]Jing, Qing; Li, Huiying; Roman, Linda J.; Martasek, Pavel; Poulos, Thomas L.; Silverman, Richard B. [ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 56 - 60]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/26197, 2009, A1 Location in patent: Page/Page column 28-29
[3]Location in patent: scheme or table Laine, Dramane; Palovich, Michael; McCleland, Brent; Petitjean, Emilie; Delhom, Isabelle; Xie, Haibo; Deng, Jianghe; Lin, Guoliang; Davis, Roderick; Jolit, Anais; Nevins, Neysa; Zhao, Baoguang; Villa, Jim; Schneck, Jessica; McDevitt, Patrick; Midgett, Robert; Kmett, Casey; Umbrecht, Sandra; Peck, Brian; Davis, Alicia Bacon; Bettoun, David [ACS Medicinal Chemistry Letters, 2011, vol. 2, # 2, p. 142 - 147]
[4]Location in patent: scheme or table Rawson, David J.; Brugier, Delphine; Harrison, Anthony; Hough, Jo; Newman, Julie; Otterburn, Joe; Maw, Graham N.; Price, Jenny; Thompson, Lisa R.; Turnpenny, Paul; Warren, Andrew N. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 12, p. 3771 - 3773]

38
[ 135042-17-0 ]
[ 256487-77-1 ]

Yield	Reaction Conditions	Operation in experiment
9.92 g	With Dess-Martin periodane; In dichloromethane; at 20℃;	(2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1 ,2-dicarboxylate (10 g, 40.8 mmol, 1.0 equiv) was suspended in DCM (Volume: 408 ml) and Dess-Martin periodinane (20.75 g, 48.9 mmol) was added in one portion. The reaction mixture was stirred at room temperature overnight and then diluted with water and DCM and filtered. The organic layer was separated and washed with water twice and dried (MgS04), filtered and concentrated in vacuo to afford the crude product which was purified by silica gel chromatography (0-20% EtOAc/heptanes) to afford 9.92g of the desired product (R)-1- tert-butyl 2-methyl 4-oxopyrrolidine-1 ,2-dicarboxylate 32 which solidified upon standing. [M-C4H9+] = 188.1 , Rt = 0.65.

Reference： [1]Organic Letters,2009,vol. 11,p. 1245 - 1248
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3771 - 3773
[3]Patent: WO2014/47020,2014,A1 .Location in patent: Page/Page column 69

39
[ 135042-17-0 ]
[ 124-63-0 ]
[ 84520-67-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In dichloromethane; at 0 - 20℃;	Step C: Methyl (I S A R Vl-Boc-4-rfmethylsulfonvDoxylpyrrolidin-2-carboxylate[294] Methyl (2S,4No.)-l-Boc-4-hydroxypyrrolidin-2-carboxylate (8 g, 32.65 mmol) obtained in the Step B was dissolved in DCM (80 ml) and TEA (11.99 ml, 81.56 mmol) was added thereto, and methanesulfonyl chloride (3.77 ml, 48.9 mmol) was added dropwise at O0C. After the reaction mixture was stirred at room temperature for 3 hours, the organic extracts were washed with IN HCl, saturated NaHCO3 aqueous solution and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (9.4 g, 90 %).[295] MS [M+H] = 324 (M+ 1 )

Reference： [1]Patent: WO2010/56022,2010,A2 .Location in patent: Page/Page column 22

40
[ 147266-92-0 ]
[ 74-88-4 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;	Step B: Methyl (25.4fl)-l-Boc-4-hydroxypyrrolidine-2-carboxylate [290] (4/?H-Boc-4-hydroxy-L-proline (8 g, 34.63 mmol) obtained in the Step A was dissolved in DMF (80 ml) and K2CO3 (14 g, 101 mmol) was added thereto, and methyl iodide (2.6 ml, 51.9 mmol) was added dropwise at O0C. The reaction mixture was stirred at room temperature for 5 hours, concentrated in vacuo, and extracted with EtOAc. The organic extracts were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (8.0 g, 95 %).[291 ] MS [M+H] = 246 (M+ 1 )
88%	With potassium carbonate; In acetonitrile;	To a solution of N-Boc-/rarcs-4-hydroxy- -proline (10.00 g; 43.25 mmol) in MeCN (100 mL), potassium carbonate (11.95 g; 86.50 mmol) was added followed by methyl iodide (5.40 mL, 86.50 mmol) and resulting mixture was stirred overnight. LCMS indicated presence of substrate. Another portion of potassium carbonate (5.98 g; 43.25 mmol) and methyl iodide was added (2.7 mL; 43.25 mmol) and reaction was stirred for 2 days after which time LCMS indicated completion of the reaction. Reaction mixture was filtered and solid residue was washed with EtOAc. After evaporation of organic phase 9.37 g (38.22 mmol; 88% yield) of product was obtained as a yellowish oil.ESI-MS m/z for C11H19NO5 found 145.9 (M-Boc+l)+, 268.0 (M+Na)+.

Reference： [1]Patent: WO2010/56022,2010,A2 .Location in patent: Page/Page column 21-22
[2]Patent: WO2017/37670,2017,A1 .Location in patent: Page/Page column 202; 203

41
[ 135042-17-0 ]
[ 477293-60-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147

42
[ 3398-22-9 ]
[ 135042-17-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 142 - 147
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3771 - 3773

43
[ 77449-94-6 ]
[ 135042-17-0 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 4333 - 4363

44
[ 135042-17-0 ]
[ 142347-81-7 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 4333 - 4363

45
[ 135042-17-0 ]
[ 77450-03-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With lithium borohydride In tetrahydrofuran at 20℃; for 4h; Inert atmosphere;

Reference： [1]Jing, Qing; Li, Huiying; Roman, Linda J.; Martasek, Pavel; Poulos, Thomas L.; Silverman, Richard B. [ACS Medicinal Chemistry Letters, 2014, vol. 5, # 1, p. 56 - 60]

46
2-((2R,4R)-1-(4-((1-(3-methoxyphenyl)piperidin-4-yl)oxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetic acid hydrochloride [ No CAS ]
[ 135042-17-0 ]
[ 1610036-44-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With silver(l) oxide In N,N-dimethyl-formamide at 0 - 20℃; for 168h;	125A 25A. (2R,4S)- 1 -tert-Butyl 2-methyl 4-(benzyloxy)pyrrolidine- 1,2-dicarboxylate: [004801 1 25A. (2R,4S)- 1 -tert-Butyl 2-methyl 4-(benzyloxy)pyrrolidine- 1,2-dicarboxylate: To a solution of (2R,4S)- 1 -tert-butyl 2-methyl 4-hydroxypyrrolidine- 1,2- dicarboxylate (4.19 g, 17.1 mmol) in DMF (27 mL) at 0 °C was added benzyl bromide (4.5 mL, 38 mmol) followed by Ag20 (4.35 g, 18.8 mmol). The reaction mixture waswarmed to rt and stirred for 1 week. The reaction mixture was diluted with ether andfiltered. The filtrate was diluted with Et20 and washed with water, brine, dried (MgSO4), and concentrated. The crude product was purified by silica chromatography to provide125A (5.21 g, 15.6 mmol, 91% yield) as a colorless oil. LC-MS Anal. Calc’d forC18H25N05: 335.40, found [M+H] 336.0. 1H NMR (500 MHz, CDC13) ö 7.39 - 7.27 (m,5H), 4.57 - 4.41 (m, 2H), 4.39 - 4.30 (m, 1H), 4.23 - 4.12 (m, 1H), 3.76 - 3.71 (m, 3H),3.70 - 3.48 (m, 2H), 2.46 - 2.29 (m, 1H), 2.12 - 2.00 (m, 1H), 1.51 - 1.37 (m, 9H).

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2014/78609, 2014, A1 Location in patent: Paragraph 00480

47
ethyl 2-O-(2-naphthylmethyl)-3-O-benzyl-5-O-(2-quinolinecarbonyl)-1-thio-α-L-arabinofuranoside [ No CAS ]
[ 135042-17-0 ]
N-tert-butoxycarbonyl-trans-4-hydroxy-4-O-[2-O-(2-naphthylmethyl)-3-O-benzyl-5-O-(2-quinolinecarbonyl)-β-L-arabinofuranosyl]-D-proline methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: ethyl 2-O-(2-naphthylmethyl)-3-O-benzyl-5-O-(2-quinolinecarbonyl)-1-thio-α-L-arabinofuranoside; (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate In 1,2-dichloro-ethane for 1h; Inert atmosphere; Molecular sieve; Stage #2: With N-iodo-succinimide; trifluorormethanesulfonic acid In 1,2-dichloro-ethane at -30 - 0℃; Inert atmosphere; Molecular sieve;	16 4.16 N-tert-Butoxycarbonyl-trans-4-hydroxy-4-O-[2-O-(2-naphthylmethyl)-3-O-benzyl-5-O-(2-quinolinecarbonyl)-β-l-arabinofuranosyl]-d-proline methyl ester (16) A mixture of a glycosyl donor 3a (1.468 mg, 2.53 mmol), glycosyl acceptor 5 (0.618 g, 2.52 mmol), and freshly activated 4 Å molecular sieves (4.17 g) in dry ClCH2CH2Cl (361 mL) was stirred under nitrogen for 1 h. The mixture was cooled to -30 °C, then NIS (1.14 g, 5.07 mmol) and TfOH (45 μL, 0.51 μmol) were added and the resulting mixture was gradually warmed to 0 °C. The reaction mixture was stirred for 1.5 h at the same temperature, at the end of which time TLC indicated it was finished. Then the reaction was quenched with Et3N, diluted with CH2Cl2, filtered, and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (3:1, petroleum ether-EtOAc) to afford 16 (1.65 g, 86%) as a colorless syrup. 16: Rf=0.32 (1:1, petroleum ether-EtOAc); [α]D20 +53.2 (c 1.0, CHCl3); 1H NMR (600 MHz, CDCl3): δ 8.27-8.25 (m, 2H), 8.16 (8.13) (d, 1H, J=7.8 Hz), 7.88-7.74 (m, 6H), 7.64 (q, 1H, J=7.2 Hz), 7.51-7.48 (m, 3H), 7.31-7.20 (m, 5H), 4.95 (4.93)* (d, 1H, J=4.8 Hz, H1'-Araf), 4.81-4.72 (m, 4H), 4.63-4.48 (m, 2H), 4.40-4.29 (m, 4H), 4.17 (dd, 1H, J=6.6, 4.8 Hz), 3.77-3.50 (m, 2H), 3.73 (3.71) (s, 3H), 2.31-2.27 (2.20-2.15) (m, 1H), 2.06-1.98 (m, 1H), 1.38 (1.37) (s, 9H); 13C NMR (100 MHz, CDCl3): δ 173.4 (173.1), 164.8 (164.7), 154.2 (153.4), 147.6 (147.4), 137.7, 137.24 (137.20), 134.9 (134.7), 133.10 (133.08), 133.0, 130.7, 130.3 (130.2), 129.3, 128.7 (128.5), 128.4, 128.3, 127.9, 127.7, 127.4, 127.1 (126.9), 126.28 (126.25), 126.2 (126.1), 126.0 (125.9), 121.2 (121.0), 99.5 (99.4), 84.0 (83.8), 82.6 (82.4), 80.2 (80.1), 78.8 (78.6), 74.7 (74.9), 72.8 (72.9), 72.7, 67.0 (66.9), 57.7 (57.3), 52.2 (52.0), 35.9 (34.7), 29.6, 28.1 (28.2); HRMS (ESI): m/z calcd for C44H46N2O10Na [M+Na]+: 785.3052, found: 785.3057. Values in parentheses signify a second signal due to a minor rotamer.

Reference： [1]Zhu, Kai; Yang, Jin-Song [Tetrahedron, 2016, vol. 72, # 22, p. 3113 - 3123]

48
[ 135042-17-0 ]
[ 74-88-4 ]
1-tert-butyl 2-methyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With silver(l) oxide In acetonitrile at 20℃; for 16h;	1 Step 1 To a solution of 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (167) (3 g, 12.23 mmol) in CH3CN (80 mL) was added Ag2O (8.5 g, 36.7 mmol) and CH3I (17.4 g, 122 mmol) and the mixture was stirred at 20° C. for 16 h. LCMS analysis showed remaining starting material. More Ag2O (4 g) and CH3I (9 g) was added and the reaction was stirred at 20° C. for an additional 16 h. LCMS analysis showed consumption of the starting material. The mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (SiO2, 1:1 petroleum ether/EtOAc) to afford 1-tert-butyl 2-methyl (2R,4S)-4-methoxypyrrolidine-1,2-dicarboxylate (168) as colorless oil (2.5 g, 79% yield). 1H NMR (400 MHz, DMSO-d6) δ 4.21 (dd, J=9.2, 4.0 Hz, 1H), 3.92-3.86 (m, 1H), 3.59 (d, J=11.5 Hz, 3H), 3.48 (dd, J=11.4, 5.6 Hz, 1H), 3.21 (dd, J=11.4, 3.1 Hz, 1H), 3.13 (t, J=3.8 Hz, 3H), 2.33 (d, J=14.0 Hz, 1H), 1.98 (dd, J=13.8, 4.1 Hz, 1H), 1.34 (d, J=26.9 Hz, 9H). LCMS (ESI) m/z 282 (M+Na).

Reference： [1]Current Patent Assignee: PFIZER INC - US2019/233440, 2019, A1 Location in patent: Paragraph 0478; 0479

49
[ 110-89-4 ]
[ 135042-17-0 ]
1-tert-butyl 2-methyl (2R,4R)-4-(piperidin-1-yl)pyrrolidine-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 5℃; for 1h; Inert atmosphere; Stage #2: piperidine In tetrahydrofuran at 120℃; for 1.83333h; Microwave irradiation;	1 Synthesis of 1 -tert-butyl 2-lithio (2R,4R)-4-(piperidin-1 -yl)pyrrolid me-i ,2-dicarboxylate Step 1: To a solution of (2R,45)-1-tert-butyl-2-methyl-4-hydroxypyrrolidine-1 2- dicarboxylate (267 mg, 1.09 mmol) and Et3N (0.18 mL, 1.31 mmol) in anhydrous DCM (5 mL), under N2 at 0°C was added mesyl chloride (0.10 mL, 1.31 mmol). The temperature maintained below 5°C for 1 h, then the reaction was diluted with DCM (20 mL) and washed sequentially with 1 MHCI (30 mL), sat. NaHCO3(aq) and brine (30 mL) before drying over Na2CO3 and concentrated in vacuo. The crude mesylate was then dissolved in THF (1 mL) and piperidine (1 mL) and heated at 120 °Cwith microwave heating. After 110 mm the reaction was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with brine (40 mL), dried over Na2CO3 and concentrated in vacuo. The crude product purified using SCX-2 to give 1-tert-butyl 2-methyl (2R,4R)-4-(piperidin-1 -yl)pyrrolidine-1 ,2-dicarboxylate (137 mg, 40%)Thermo_MeOH_UHPLC_1 .2 mm LCMS: Rt= 0.6 mm mlz 313.44 [M+H]

Reference： [1]Current Patent Assignee: UNIVERSITY OF LEEDS - WO2019/186164, 2019, A1 Location in patent: Paragraph 00414; 00415

50
[ 13726-69-7 ]
[ 74-88-4 ]
[ 135042-17-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In acetonitrile for 48h;	55.1 Synthesis of (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (55a). To a solution of N-Boc-trans-4-hydroxy-D-proline (10.00 g; 43.25 mmol) in acetonitrile (100 mL), potassium carbonate (11.95 g; 86.50 mmol) was added followed by methyl iodide (5.40 mL, 86.50 mmol) and resulting mixture was stirred overnight. LC-MS indicated presence of substrate. Another portion of potassium carbonate (5.98 g; 43.25 mmol) and methyl iodide was added (2.7 mL; 43.25 mmol) and reaction was stirred for 2 days after which time LC-MS indicated completion of the reaction. Reaction mixture was filtered and solid residue was washed with EtOAc. After evaporation of filtrate the product 55a was obtained as a yellowish oil in 88% yield (9.37 g; 38.22 mmol).ESI-MS m/z for C11H19NO5 found 145.9 (M+H-Boc)+, 268.0 (M+Na)+

Reference： [1]Current Patent Assignee: MOLECURE SA - WO2021/9209, 2021, A1 Location in patent: Paragraph 0430

51
[ 31076-84-3 ]
[ 135042-17-0 ]
1-(tert-butyl) 2-methyl (2R,4S)-4-((4-acetylbenzoyl)oxy)pyrrolidine-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With pyridine; dmap In dichloromethane at 20℃; for 24h; Inert atmosphere; Schlenk technique;

Reference： [1]Cai, Yuan; Ruan, Lin-Xin; Rahman, Abdul; Shi, Shi-Liang [Angewandte Chemie - International Edition, 2021, vol. 60, # 10, p. 5262 - 5267][Angew. Chem., 2021, vol. 133, # 10, p. 5322 - 5327,6]

52
[ 593-51-1 ]
[ 135042-17-0 ]
(2R,4R)-tert-butyl 4-(2-fluoro-4-iodophenoxy)-2-(methylcarbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.5%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 2h; Cooling with ice; Inert atmosphere;	4.3 Step 3. Synthesis of compound 4-4 Put (2S,4R)-1-(tert-butoxycarbonyl)-4-(2-fluoro-4-iodophenoxy)pyrrolidine-2-carboxylic acid 4-3 (1g, 2.22mmol) in an ice bath Dissolve in 70ml N,N-dimethylformamide (DMF), add DIPEA (287mg, 2.22mmol), HOBT (300mg, 2.22mmol), EDCl (425mg, 2.22mmol). After stirring thoroughly, methylamine hydrochloride was added, and the reaction was stirred for two hours. After the reaction, it was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product (2S,4R)-tert-butyl 4-(2-fluoro-4- Iodophenoxy)-2-(methylcarbamoyl)pyridine-1-carboxylate 4-4 (746 mg, 72.5%).

Reference： [1]Current Patent Assignee: CHENGDU HITGEN PHARMACEUTICAL DEV - CN113549065, 2021, A Location in patent: Paragraph 0063; 0096-0097; 0102-0103

53
[ 2713-28-2 ]
[ 135042-17-0 ]
(2R,4R)-1-tert-butyl 2-methyl 4-(2-fluoro-4-iodophenoxy)pyrrolidine-1,2-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.6%	Stage #1: 2-fluoro-4-iodophenol; (2R,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate With triphenylphosphine In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran at 20℃; Inert atmosphere;	4.1 Step 1. Synthesis of compound 4-2 Add 2-fluoro-4-iodophenol 4-1a (1.43g, 6mmol) and triphenylphosphine (1.62g, 6mmol) to a 250ml three-necked flask, deoxygenate and protect with nitrogen, and put it into the three-necked flask under ice bath conditions. Add 100ml of ultra-dry tetrahydrofuran and stir until the reactants are completely dissolved. After dissolving, add (2R, 4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate 4-1 (1.47g, 6mmol) dissolved in ultra-dry tetrahydrofuran. Add it to a three-necked flask and stir well for about 15 minutes, then slowly add DIAD (1.21g, 6mmol) dropwise to the reaction flask. Stir overnight under nitrogen protection. After the reaction, it was extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product (2R, 4R)-1-tert-butyl 2-methyl 4-( 2-Fluoro-4-iodophenol)pyrrolidine-1,2-dicarboxylate 4-2 (1.58 g, 56.6%).

Reference： [1]Current Patent Assignee: CHENGDU HITGEN PHARMACEUTICAL DEV - CN113549065, 2021, A Location in patent: Paragraph 0063; 0096-0099

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CAS No. :	135042-17-0	MDL No. :	MFCD09954932
Formula :	C₁₁H₁₉NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MZMNEDXVUJLQAF-JGVFFNPUSA-N
M.W :	245.27	Pubchem ID :	6951201
Synonyms :

Num. heavy atoms :	17
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.82
Num. rotatable bonds :	5
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	63.85
TPSA :	76.07 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.38 cm/s

Log Po/w (iLOGP) :	2.43
Log Po/w (XLOGP3) :	0.58
Log Po/w (WLOGP) :	0.15
Log Po/w (MLOGP) :	0.22
Log Po/w (SILICOS-IT) :	-0.11
Consensus Log Po/w :	0.65

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

Log S (ESOL) :	-1.4
Solubility :	9.85 mg/ml ; 0.0402 mol/l
Class :	Very soluble
Log S (Ali) :	-1.75
Solubility :	4.36 mg/ml ; 0.0178 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.27
Solubility :	131.0 mg/ml ; 0.535 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.36

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:

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[ CAS No. 135042-17-0 ] {[proInfo.proName]}

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[ 135042-17-0 ]