40350-83-2|4-Benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester| Ambeed

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Quality Control of [ 40350-83-2 ] Purity: 98% SDS Specification

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Product Details of [ 40350-83-2 ]

CAS No. :	40350-83-2
Formula :	C₁₇H₂₃NO₅
M.W :	321.37
SMILES Code :	O=C(N1C(C(O)=O)CC(OCC2=CC=CC=C2)C1)OC(C)(C)C
InChI Key :	DGIGGVANZFKXLS-UHFFFAOYSA-N
Pubchem ID :	4179828

Safety of [ 40350-83-2 ]

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

Application In Synthesis of [ 40350-83-2 ]

* 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 [ 40350-83-2 ]

[ 40350-83-2 ] Synthesis Path-Downstream 1~35

1
[ 67-56-1 ]
[ 40350-83-2 ]
[ 113490-76-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; at 20℃; for 12h;	[1118] a mixture of <strong>[40350-83-2](2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid</strong> (500 mg, 1.56 mmol) in MeOH (3 ml), hci/MeOH (15 ml) was stirred at 20 C for 12 hours. Lcms showed starting material was consumed completely and one main peak with desired ms was detected. The reaction mixture was diluted with aqueous NaHCO3, adjusted the h ~ 7, and extracted with DCM (30 ml x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 220a (340 mg, crude, yellow oil): 1H NMR (400mhz, CDCl3) delta 7.37 - 7.20 (m, 5h), 4.52 - 4.41 (m, 2h), 4.12 (br s, 1h), 4.00 (br t, = 7.6 hz, 1h), 3.77 -3.62 (m, 3h), 3.11 (br s, 2h), 2.66 (br s, 1h), 2.29 (br dd, = 7.8, 13.1 hz, 1h), 1.98 (td, = 6.6, 13.4 hz, 1h). MS (ESI) m/z (M+H)+ 236.1.

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 875 - 885.
[2]Patent: WO2018/64119,2018,A1 .Location in patent: Paragraph 1118.

2
[ 100-39-0 ]
[ 13726-69-7 ]
[ 40350-83-2 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Synthesis of 1m-p 200 mg (0.86 mmol) of (2S,4R), (2S,4S), (2R,4R), or (2R,4S)-Boc-Hyp was dissolved in 3 ml of tetrahydrofuran, cooled to 0 C., and 103 mg (3 eq.) of 60% sodium hydride was added. The mixture was stirred cold for 20 minutes, then 226 ul (2.2 eq) of benzyl bromide was added. The mixture was allowed to warm to room temperature and stirred for 16 hours, at which time it was cooled to 0 C. and 1 ml of water was added, followed by 500 uL of 5% citric acid and 2 mL of saturated sodium bicarbonate solution. The organic layer was separated, and the aqueous phase was washed twice with 1 ml portions of ethyl acetate. The aqueous layer was then acidified to pH2.0 with citric acid, and extracted three times with 2 ml portions of ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, the solvent removed under reduced pressure, the residues were dissolved in 2 ml of methylene chloride, and 2 ml of 4M HCl in dioxane was added. The mixture was stirred for 12 hours, and the solvent removed under reduced pressure, yielding the HCl salts 3m-p. 300 uM of each was then converted first to 5m-p, then the final product 1m-p as the TFA salt via the methods described earlier for 1h-1.
	With sodium hydride; In tetrahydrofuran; mineral oil; at 0℃; for 6h;Reflux;	The Boc-protected L-Hyp 3 was dissolved in THF (100mL) and then cannulated into a slurry of NaH (60% inmineral oil, 11.2 g, 155 mmol) in THF (200 mL) at 0 C.Benzyl bromide (15.0 g, 87.7 mmol) was added dropwise tothe reaction mixture. The flask was warmed to room temperatureand then the mixture was heated under reflux for 6h. The reaction mixture was cooled to room temperature andpoured over ice. The organic solvent was evaporated underreduced pressure and the aqueous solution was washed withEtOAc. The aqueous phase was acidified with 2N HCl untilthe pH was 2, and then it was extracted with EtOAc. Theorganic phase was concentrated under reduced pressure toyield 4 as a brownish yellow oil. This brownish yellow oilwas dissolved in dry THF (300 mL) and cooled to 0 C.BH3·DMS (5.7 mL, 58 mmol) was added dropwise to thereaction mixture, which was then kept stirring at 0 C for anadditional 1 h. The flask was removed from the ice bath, andthe mixture stirred overnight at room temperature. Thereaction mixture was poured over ice and sequentiallyextracted with EtOAc, washed with saturated aqueousNaHCO3, washed with brine, and dried (Na2SO4). Thesolution was concentrated under reduced pressure andpurified through flash column chromatography (FCC; gradientEtOAc/hexanes, from 30 to 50%) to yield 5 [26] as aslightly yellow oil (16.3 g, 70% over three steps).

References: [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 5351 - 5355.
[2]Organic and Biomolecular Chemistry,2017,vol. 15,p. 894 - 910.
[3]Tetrahedron,1986,vol. 42,p. 6039 - 6045.
[4]Journal of Medicinal Chemistry,1988,vol. 31,p. 875 - 885.
[5]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2151 - 2154.
[6]Patent: US2015/202333,2015,A1 .Location in patent: Paragraph 0060; 0061.
[7]Journal of Antibiotics,2019,vol. 72,p. 389 - 396.

3
4-Hyp(CH₂Ph) ethyl ester [ No CAS ]
[ 40350-83-2 ]
[ 111104-02-0 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1987,p. 613 - 618.

4
[ 40350-83-2 ]
[ 109953-95-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		32A. (2S,4R)-tert-butyl 4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate To a solution of <strong>[40350-83-2](2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid</strong> (1.00 g, 3.11 mmol) in tetrahydrofuran (10 mL) at -10 C. (ice water-brine) was added N-methyl morpholine (0.359 mL, 3.27 mmol). To this solution was added slowly isobutyl chloroformate (0.429 mL, 3.27 mmol). After 30 min, the mixture was filtered and added to a solution of NaBH4 (0.247 g, 6.53 mmol) in water (1.5 mL) at 0 C. After 30 min, the reaction was quenched via addition of NH4Cl (sat.). The resulting mixture was extracted with EtOAc, and the combined organic layer was washed with brine, dried and concentrated to give 1.12 g colorless oil. Purification via silica gel chromatography gave 32A (colorless oil, 1.04 g, 3.38 mmol, 109% yield). LC-MS Anal. Calc'd for C17H25NO4: 307.18. found [M-Boc+H] 208.0. 1H NMR (400 MHz, chloroform-d) delta ppm 7.27-7.39 (5H, m), 4.91 (1H, d, J=7.1 Hz), 4.47-4.55 (2H, m), 4.05 (1H, br. s.), 3.60-3.76 (2H, m), 3.51-3.59 (1H, m), 3.41 (1H, dd, J=12.1, 4.4 Hz), 2.19 (1H, dd, J=13.7, 7.1 Hz), 1.57-1.69 (1H, m), 1.52 (1H, d, J=7.7 Hz), 1.47 (9 H, s).
97%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 3.5h;	EXAMPLE 85; Step 1; (2S,4R)-4-Benzyloxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester; (2S,4R)-4-Benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (960 mg, 3 mmol) in THF (5 mL) was cooled to 0 C. using ice-water bath. Then 1M solution of BH3 (6 mL, 6 mmol) in THF was added under nitrogen over period of 30 min. Reaction was stirred at 0 C. for 2 h and at rt for another 1 h. Reaction mixture was poured over ice water and product was extracted with EtOAc. Organic layers were combined, washed with water, brine, saturated sodium bicarbonate, dried over anhydrous MgSO4 and concentrated to give the crude product. It was used in next step without purification (900 mg, 97%).; EXAMPLE 86; Step 1; (2S,4R)-4-Benzyloxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester; (2S,4R)-4-Benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (960 mg, 3 mmol) in THF (5 mL) was cooled to 0 C. using ice-water bath. Then 1M solution of BH3 (6 mL, 6 mmol) in THF was added under nitrogen over period of 30 min. Reaction was stirred at 0 C. for 2 h and at rt for another 1 h. Reaction mixture was poured over ice water and product was extracted with EtOAc. Organic layers were combined, washed with water, brine, saturated sodium bicarbonate, dried over anhydrous MgSO4 and concentrated to give the crude product. It was used in next step without purification (900 mg, 97%); MS; m/z 286.2 (M+H); 1H NMR (400 MHz, DMSO-d6); delta 1.90 (m, 1H), 3.09(m, 1H), 4.12(m, 2H), 4.27(m, 1H), 5.46(br s, 2H), 6.92 (d, J=6.8 Hz, 2H), 7.02(s, 4H), 7.08(t, J=5.6 Hz, 1H), 7.35(m, 2H), 9.09(br s, 1H), 9.62(br s, 3H);
82%		To a solution of <strong>[40350-83-2](2S,4R)-4-(benzyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid</strong> (5.00 g, 15.56 mmol) in tetrahydrofuran (50 mL) at -10 C. was added N-methylmorpholine (1.882 mL, 17.11 mmol). To this solution was added slowly isobutyl chloroformate (2.34 g, 2.25 mL, 17.11 mmol). The resulting mixture was stirred for 30 minutes and filtered, and the filtrate was added to a solution of sodium borohydride (1.18 g, 31.1 mmol) in water (1.5 mL) at 0 C. The resulting mixture was stirred at 0 C. for 30 minutes, and the reaction was quenched by the addition of a saturated solution of NH4Cl. The mixture was extracted with ethyl acetate, and the organic extract was washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-2% methanol in dichloromethane to give the title compound as a colorless oil (3.93 g, 82%). 1H NMR (400 MHz, pyridine-d5, 90 C.) delta ppm 7.36 (d, J=7.4 Hz, 2H), 7.30 (t, J=7.3 Hz, 2H), 7.23 (t, J=7.2 Hz, 1H), 4.50 (s, 2H), 4.20-4.29 (m, 2H), 3.92-4.00 (m, 1H), 3.80-3.87 (m, 2H), 3.50-3.59 (m, 1H), 2.16-2.30 (m, 2H), 1.47 (s, 9H)

		Example 45: Synthesis of (2R,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-(5-bromo- pyrimidin-2-yl)-amino]-2-ethyl-pyrrolidine-1-carboxylic acid tert-butyl ester; To a solution of (2S,4R)-4-benzyloxy-pyrrolidine-1 ,2-dicarboxylic acid 1-ferf-butyl ester (77.8 mmol; 25.O g) in THF (135 mL) is added 0.93 M THF solution of borane THF complex (116.7 mmol; 125 mL) at 0 0C under nitrogen. The solution is stirred for 1.5 hours at room temperature, quenched by dropwise addition of 40 ml of MeOH. After concentrating, the mixture is diluted with 400 ml of dichloromethane and 250 ml of saturated aqueous ammonium chloride solution. The product is extracted twice with 100 ml of dichloromethane. The combined organic layer is washed with 250 ml of brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude product (24.3 g).
16.3 g	With BH3*DMS; In tetrahydrofuran; at 0 - 20℃;	The Boc-protected L-Hyp 3 was dissolved in THF (100mL) and then cannulated into a slurry of NaH (60% inmineral oil, 11.2 g, 155 mmol) in THF (200 mL) at 0 C.Benzyl bromide (15.0 g, 87.7 mmol) was added dropwise tothe reaction mixture. The flask was warmed to room temperatureand then the mixture was heated under reflux for 6h. The reaction mixture was cooled to room temperature andpoured over ice. The organic solvent was evaporated underreduced pressure and the aqueous solution was washed withEtOAc. The aqueous phase was acidified with 2N HCl untilthe pH was 2, and then it was extracted with EtOAc. Theorganic phase was concentrated under reduced pressure toyield 4 as a brownish yellow oil. This brownish yellow oilwas dissolved in dry THF (300 mL) and cooled to 0 C.BH3·DMS (5.7 mL, 58 mmol) was added dropwise to thereaction mixture, which was then kept stirring at 0 C for anadditional 1 h. The flask was removed from the ice bath, andthe mixture stirred overnight at room temperature. Thereaction mixture was poured over ice and sequentiallyextracted with EtOAc, washed with saturated aqueousNaHCO3, washed with brine, and dried (Na2SO4). Thesolution was concentrated under reduced pressure andpurified through flash column chromatography (FCC; gradientEtOAc/hexanes, from 30 to 50%) to yield 5 [26] as aslightly yellow oil (16.3 g, 70% over three steps).

References: [1]Patent: US2011/82165,2011,A1 .Location in patent: Page/Page column 29.
[2]Patent: US2007/66820,2007,A1 .Location in patent: Page/Page column 54; 55.
[3]Patent: US2014/171423,2014,A1 .Location in patent: Paragraph 0901.
[4]Tetrahedron,1986,vol. 42,p. 6039 - 6045.
[5]Patent: WO2009/71509,2009,A1 .Location in patent: Page/Page column 122.
[6]Journal of Antibiotics,2019,vol. 72,p. 389 - 396.

5
[ 40350-83-2 ]
O-benzyl-trans-4-hydroxy-L-proline hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 2461 - 2480.

6
[ 40350-83-2 ]
(±)-1-azafagomine [ No CAS ]
[ 541-88-8 ]
(2S,4R)-1-((2S,4R)-1-{(2S,4R)-1-[2-((3R,4R,5R)-4,5-Dihydroxy-3-hydroxymethyl-tetrahydro-pyridazin-1-yl)-acetyl]-4-hydroxy-pyrrolidine-2-carbonyl}-4-hydroxy-pyrrolidine-2-carbonyl)-4-hydroxy-pyrrolidine-2-carboxylic acid amide [ No CAS ]

References: [1]Tetrahedron Letters,1999,vol. 40,p. 3033 - 3036.

7
[ 15761-39-4 ]
[ 13734-34-4 ]
[ 40350-83-2 ]
Boc-L-Arg(Tos)-OH [ No CAS ]
Boc-Ser(OBzl), Boc-Leu, Boc-Cys(Meb), Boc-Gly [ No CAS ]
[ 140661-85-4 ]