[ CAS No. 176486-63-8 ] {[proInfo.proName]}

Name: 176486-63-8|(2S,4R)-4-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid|95%
Brand: Ambeed
SKU: A416299
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Quality Control of [ 176486-63-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 176486-63-8 ]

Product Details of [ 176486-63-8 ]

CAS No. :	176486-63-8	MDL No. :	MFCD00673783
Formula :	C₂₅H₂₈N₂O₆	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UPXRTVAIJMUAQR-VFNWGFHPSA-N
M.W :	452.50	Pubchem ID :	2756135
Synonyms :

Calculated chemistry of [ 176486-63-8 ]

Physicochemical Properties

Num. heavy atoms :	33
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.4
Num. rotatable bonds :	9
Num. H-bond acceptors :	6.0
Num. H-bond donors :	2.0
Molar Refractivity :	125.23
TPSA :	105.17 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-6.38 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.43
Log Po/w (XLOGP3) :	3.77
Log Po/w (WLOGP) :	3.61
Log Po/w (MLOGP) :	2.6
Log Po/w (SILICOS-IT) :	2.36
Consensus Log Po/w :	3.15

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.7
Solubility :	0.00912 mg/ml ; 0.0000202 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.67
Solubility :	0.000963 mg/ml ; 0.00000213 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.23
Solubility :	0.00265 mg/ml ; 0.00000586 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	3.0
Synthetic accessibility :	4.54

Safety of [ 176486-63-8 ]

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

Application In Synthesis of [ 176486-63-8 ]

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

Upstream synthesis route of [ 176486-63-8 ]
Downstream synthetic route of [ 176486-63-8 ]

[ 176486-63-8 ] Synthesis Path-Upstream 1~3

1
[ 176486-63-8 ]
[ 132622-69-6 ]

Reference： [1] Patent: WO2003/99274, 2003, A1, . Location in patent: Page 493-494
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6744 - 6751
[3] Patent: US2007/99825, 2007, A1, . Location in patent: Page/Page column 81
[4] Patent: US2008/107623, 2008, A1, . Location in patent: Page/Page column 75-76
[5] Patent: US2008/107624, 2008, A1, . Location in patent: Page/Page column 78-79

2
[ 185304-19-2 ]
[ 176486-63-8 ]

Reference： [1] Patent: US2003/36501, 2003, A1,

3
[ 82911-69-1 ]
[ 132622-69-6 ]
[ 176486-63-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2008, vol. 51, # 6, p. 1771 - 1782

[ 176486-63-8 ] Synthesis Path-Downstream 1~88

1
[ 176486-63-8 ]
[ 914652-89-4 ]

Yield	Reaction Conditions	Operation in experiment
58 g	With pyridine; di-tert-butyl dicarbonate; ammonium bicarbonate; In 1,4-dioxane; at 20℃; for 16h;Inert atmosphere;	To a mixture of (2S,4 ?)-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)- -{tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (59 g crude, 0.13 mol, 1 eq), pyridine (56.6 mL, 0.52 mol, 4 eq), and di-tert-butyl dicarbonate (59.3 mL, 0.26 mol, 2 eq) in dioxane (600 mL), was added ammonium bicarbonate (21 g, 0.26 mol, 2 eq). The mixture was stirred at room temperature for 16 h. TLC showed that the starting material was disappeared. The mixture was concentrated and purified by column chromatography (petroleum ether : ethyl acetate = 2: 1 to ethyl acetate) to give (2S,4 ?)-ieri-butyl-4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2- carbamoyl pyrrolidine- 1-carboxylate (58 g) as white solid. MS (ESI) m/z 452.2[M + H]+; 352.2 [M+H-Boc]+

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263
[2]Patent: WO2019/28362,2019,A1 .Location in patent: Paragraph 00319; 00320; 00364; 00365

2
[ 176486-63-8 ]
[ 914653-05-7 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

3
[ 176486-63-8 ]
[ 914653-06-8 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

4
[ 176486-63-8 ]
[ 914652-92-9 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

5
[ 176486-63-8 ]
[ 914652-93-0 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

6
[ 176486-63-8 ]
[ 914652-96-3 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

7
[ 176486-63-8 ]
[ 914652-97-4 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

8
[ 176486-63-8 ]
trans-4-N-(9-fluorenylmethoxycarbonyl)-amino-L-prolinamide trifluoroacetate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

9
[ 176486-63-8 ]
C₁₂H₂₄N₈O₄*3C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

10
[ 176486-63-8 ]
C₁₈H₂₈N₈O₄*3C₂HF₃O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263

11
[ 1229626-38-3 ]
[ 176486-63-8 ]
[ 630422-48-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 24h;	To a solution of(1R, 2S/1S, 2R 1 : 1 mixture) cyclopropanesulfonic acid (1- amino-2-vinyl-cyclopropanecarbonyl)-amide trifluoroacetic acid salt (626mg, 1. 82mmol) in DCM (17mL) was added and DIEA (555mg, 4.29mmol) in DCM (17mL), HATU (754mg, 1.98mmole), and (2S, 4R)Fmoc-4-amino-1-boc-pyrrolidine- 2-carboxylic acid (747mg, 1. 65mmol). After stirring at rt for 24h, the mixture was washed with 1NHCI (lOmL), 5% aqueous NaHC03 (4mL). Each aqueous layer was extracted with DCM (25 mL). The combined DCM was dried over MgS04 and concentrated. The resulting brown viscous oil was purified by flash column chromatography(Si02, 95: 5 DCM: MeOH) to give a yellow solid 822mg, 75% yield):IH NMR (DMSO-d6)8 1.04-1. 09(m, 3H), 1.15-1. 27(m, 4H), 1.38-1. 44(m, 7H), 1.47 (s, 9H), 1.84 (dd, J=8. 2,5. 2 Hz, 1H), 2.01-2. 30(m, 4H), 2.90-2. 98(m, 1H), 3.64-3. 71(m, 1H), 4.16-4. 22(m, 4H), 4.39 (bs, 2H), 5.13 (dd,J=10. 7,0. 9 Hz, 1H), 3.31 (d, J=17. 1 Hz, 1H), 5.72-5. 79(m, 1H), 7.31 (t, J=7. 3 Hz, 3H), 7.38 (t, J=7. 5 Hz, 3H), 7.64 (d, J=7. 02 Hz, 3H), 7.79 (d, J=7. 63 Hz, 3H); LC-MS m/e(Na+MH+) 687.

Reference： [1]Patent: WO2003/99274,2003,A1 .Location in patent: Page 170-171

12
[ 176486-63-8 ]
[ 132622-69-6 ]

Yield	Reaction Conditions	Operation in experiment
	With pyrrolidine; In acetonitrile; at 20℃; for 3h;	To a solution of (2S, 4R)Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3hr. Then it was concentrated and put on high vacuum togive crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution ofPd2dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8mL) at rt forlh. Then1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg,3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-l-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for lh. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 'H NMR(CD30D, 400 MHz)8 1.44 (m, 9H), 2.51-2. 74 (m, 2H), 3.64 (m,1H), 4.01 (m,1H), 4.49 (m,1H), 4.64 (m,1H), 7.30 (d, J=6.85 Hz,1H), 7.58 (d, J=6.85 Hz,1H), 7.79 (m,1H), 7.91-7. 99 (m, 2H), 8.56 (d, J=8. 56 Hz,1H). LC-MS (retention time: 1.707 min. ), MS m/z 358(MH+).
	With pyrrolidine; In acetonitrile; at 20℃; for 3h;	To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2dba3 (40 mg, 5% mol)and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 1H NMR (CD3OD, 400 MHz) delta 1.44 (m, 9H), 2.51-2.74 (m, 2H), 3.64 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 7.30 (d, J=6.85 Hz, 1H), 7.58 (d, J=6.85 Hz, 1H), 7.79(m, 1H), 7.91-7.99 (m, 2H), 8.56 (d, J=8.56 Hz, 1H). MS m/z 358 (MH+).
	With pyrrolidine; In acetonitrile; at 20℃; for 3h;	To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3 hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2 dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 1H NMR (CD3OD, 400 MHz) delta 1.44 (m, 9H), 2.51-2.74 (m, 2H), 3.64 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 7.30 (d, J=6.85 Hz, 1H), 7.58 (d, J=6.85 Hz, 1H), 7.79 (m, 1H), 7.91-7.99 (m, 2H), 8.56 (d, J=8.56 Hz, 1H). MS m/z 358 (MH+).

With pyrrolidine; In acetonitrile; at 20℃; for 3h;

To a solution of (2S,4R) Fmoc-4-amino-1-boc-pyrrolidine-2-carboxylic acid (400 mg, 0.884 mmol) in acetonitrile (15 mL), five drops of pyrrolidine was added. The reaction mixture was stirred at rt for 3 hr. Then it was concentrated and put on high vacuum to give crude 4-amino-1-boc-pyrrolidine-2-carboxylic acid. In another round-bottomed flask, a solution of Pd2 dba3 (40 mg, 5% mol) and racemic-BINAP (56 mg, 10% mol) was stirred under nitrogen in degassed toluene (8 mL) at rt for 1 h. Then 1-chloroisoquinoline (216 mg, 1.326 mmol) and sodium t-butoxide (340 mg, 3.536 mmol) were added and the reaction mixture was stirred for 30 min. Then 4-amino-1-boc-pyrrolidine-2-carboxylic acid was added and the reaction mixture was heated under reflux for 1 h. Water was added to quench the reaction and the aqueous layer was separated and filtered through filter paper. It was then concentrated and purified by Prep. HPLC to give coupled product as TFA salt. (165 mg, 40% yield) 1H NMR (CD3OD, 400 MHz) delta 1.44 (m, 9H), 2.51-2.74 (m, 2H), 3.64 (m, 1H), 4.01 (m, 1H), 4.49 (m, 1H), 4.64 (m, 1H), 7.30 (d, J=6.85 Hz, 1H), 7.58 (d, J=6.85 Hz, 1H), 7.79 (m, 1H), 7.91-7.99 (m, 2H), 8.56 (d, J=8.56 Hz, 1H). MS m/z 358 (MH+).

Reference： [1]Patent: WO2003/99274,2003,A1 .Location in patent: Page 493-494
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 6744 - 6751
[3]Patent: US2007/99825,2007,A1 .Location in patent: Page/Page column 81
[4]Patent: US2008/107623,2008,A1 .Location in patent: Page/Page column 75-76
[5]Patent: US2008/107624,2008,A1 .Location in patent: Page/Page column 78-79

13
fluorenylmethyl succinyl carbonate [ No CAS ]
[ 185304-19-2 ]
[ 176486-63-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; citric acid;palladium; In 1,4-dioxane; methanol; ethanol; water;	Step 3 N-tert-butoxycarbonyl-trans-4-(N-fluorenylmethyloxycarbonyl_amino)-L-proline A mixture of the compound of step 2 above (8.59 g, 24.8 mmol) and 10% palladium on carbon (900 mg) in ethanol (500 mL) was hydrogenated at 50 psi for 14 h using a Parr hydrogenation apparatus. The mixture was filtered, concentrated, dissolved in methanol (60 mL), refiltered and concentrated to give a colorless oil. The oil was dissolved in water (53 mL) containing sodium carbonate (5.31 g, 50.1 mmol) and a solution of fluorenylmethyl succinyl carbonate (8.37 g, 29.8 mmol) in dioxane (60 mL) was added over 40 min. The reaction mixture was stirred at room temperature for 17 h, then concentrated to remove the dioxane and diluted with water (200 mL). The solution was washed with ether (3*100 mL). The pH of the aqueous solution was adjusted to 2 by the addition of citric acid (caution! foaming!) and water (100 mL). The mixture was extracted with dichloromethane (400 mL, 100 mL, 100 mL) and the combined organic layers were dried (sodium sulfate), filtered and concentrated to give the title compound.

Reference： [1]Patent: US2003/36501,2003,A1

14
[ 6638-79-5 ]
[ 132705-51-2 ]
[ 176486-63-8 ]
[ 176306-36-8 ]

Yield	Reaction Conditions	Operation in experiment
620 mg (84%)	With 2-(Dimethylamino)pyridine; N-ethyl-N,N-diisopropylamine; In dichloromethane;	A. (2S-trans)-4-[[(9-Fluorenylmethoxy)-carbonyl]amino]-2-[(methoxymethylamino)carbonyl]-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester To a solution of (2S-trans)-4-[[(9-Fluorenylmethoxy)carbonyl]amino]-1,2-pyrrolidinedicarboxylic acid 1-(1,1-dimethylethyl) ester (0.70 g, 1.5 mmol) (prepared analogously to the method described in Rosen, T., et al., Synthesis 40 (1988)), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (700 mg, 1.5 mmol) and N,O-dimethylhydroxylamine hydrochloride dissolved in methylene chloride (20 mL) were added dimethylaminopyridine (20 mg, 0.16 mmol) and diisopropylethylamine (790 muL, 0.16 mmol). The solution was stirred for 6 hours and concentrated. The residue was chromatographed on a flash silica gel column (5 x 20 cm) eluding with 1:1/ethyl acetate/hexanes to afford 620 mg (84%) of compound A. MS: (M+H)+ 496+.

Reference： [1]Patent: EP696593,1996,A2

15
(1R,2S)/(1S,2R)-(1-cyclopropanesulfonyl-aminocarbonyl-2-vinyl-cyclo-propyl)-carbamic acid [ No CAS ]
[ 176486-63-8 ]
[ 630422-48-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In dichloromethane; at 20℃;	To a solution of Fmoc-(2S,4R)-4-amino-1-boc-pyrrolidine-2-carboxylic acid (1.0 g, 2.21 mmol) in CH3CN (10 mL) was added intermediate 1 (0.825 g, 3.09 mmol), DIEA (0.714 g, 5.53 mmol) and the coupling reagent PyAOP (1.73 g, 3.32 mmol). The solution was stirred at room temperature overnight. Then it was concentrated, washed with water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give a yellow oil. It was purified by flash column eluting with 20% hexane in ethyl acetate to yield 481110-157 an off-white solid as 1:1 diasteromers (1.48 g, 100% yield). 481110-157: 1H NMR(CD3OD, 300 MHz) delta 7.80 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.0 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.31 (t, J=7.3 Hz, 2H), 5.77 (m, 1H), 5.32 (d, J=17.2 Hz, 1H), 5.13(d, J=10.3 Hz, 1H), 4.39 (m, 2H), 4.0-4.3 (m, 4H), 3.70 (m, 1H), 2.92 (m, 1H), 2.05-2.35 (m, 3H), 1.84 (m, 1H), 1.35-1.50 (m, 10H), 1.20(m, 2H), 1.05(m, 2H). LC-MS (retention time: 1.833 minutes.), MS m/z 665 (MH+).

Reference： [1]Patent: US2007/10455,2007,A1 .Location in patent: Page/Page column 41; 42

16
[ 746657-36-3 ]
[ 176486-63-8 ]
[ 862120-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In acetonitrile; at 20℃;	To a solution of Fmoc(2S,4R)-4-amino-1-boc-pyrrolidine-2-carboxylic acid (0.453 g, 1 mmol) in acetonitrile (10 mL), enantiomer 50177-020 A (0.2 g, 1.29 mmol), DIEA (0.26 mL, 1.5 mmol) and coupling reagent PyAOP (0.78 g, 1.5 mmol) were added. The reaction mixture was stirred at room temperature for overnight. Then it was concentrated, washed with water and extracted with ethyl acetate twice. The organic layers were combined and washed with brine, and dried over MgSO4, and filtered. Evaporation of solvent gave a yellowish oil which was then purified by flash column chromatography (silica gel, 3:1 ethyl acetate:hexanes) to provide a colorless oil as a single diastereoisomer. 50177-024A (0.528 g, 90% yield): 1H NMR(CD3OD, 500 MHz) delta 7.79 (d, J=7.3 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.39 (m, 2H), 7.31 (m, 2H), 5.74 (m, 1H), 5.30 (d, J=17.1 Hz, 1H), 5.11(d, J=10.4 Hz, 1H), 4.38 (m, 2H), 4.0-4.3 (m, 6H), 3.77 (m, 1H), 2.15-2.25 (m, 3H), 1.75 (m, 1H), 1.42-1.46 (m, 9H), 1.30(m, 1H), 1.22(t, J=7.0 Hz, 3H). LC-MS (retention time: 1.803 minutes.), MS m/z 590 (MH+). The above procedure was repeated using enantiomer 50177-020 B in place of enantiomer 50177-020 A to provide, as a single diastereoisomer, 50177-024B (0.43 g, 73% yield): 1H NMR(CD3OD, 500 MHz) delta 7.79 (d, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.39 (m, 2H), 7.31 (m, 2H), 5.73 (m, 1H), 5.30 (dd, J=17.1 Hz, 1.5 Hz, 1H), 5.10(m, 1H), 4.38 (m, 2H), 4.0-4.3 (m, 6H), 3.73 (m, 1H), 2.10-2.25 (m, 3H), 1.8 (m, 1H), 1.41-1.45 (m, 9H), 1.40(m, 1H), 1.22(m, 3H). LC-MS (retention time: 1.800 minutes.), MS m/z 590 (MH+).

Reference： [1]Patent: US2007/10455,2007,A1 .Location in patent: Page/Page column 37

17
[ 4530-20-5 ]
[ 65-85-0 ]
[ 176486-63-8 ]
[ 943134-39-2 ]

Yield	Reaction Conditions	Operation in experiment
		(2S,4R) 1-(2-Amino-acetyl)-4-benzoylamino-pyrrolidine-2-carboxylic acid PAM-resin (Advanced Chemtech) was swelled in DMF, washed with 5% Triethyl amine (TEA) in DMF and washed with DMF until no yellow color could be detected after adding Dhbt-OH to the drained DMF. (2S,4R) Boc-4Amp(Fmoc)-OH was coupled as symmetrical anhydride as follows. 3eq (2S,4R) Boc-4Amp(Fmoc)-OH was dissolved in DCM and cooled to 0 C. DIC (1.5 eq.) was added and the reaction continued for 10 minutes. The solvent was removed in vacuo and the residue dissolved in DMF. The solution was immediately added to the resin followed by 0.1 eq. of DMAP. The coupling was continued over night. Excess coupling reagent was removed by washing with DMF. Deprotection of the Fmoc group was performed by treatment with 20% piperidine in DMF (1×5 and 1×10 min.), followed by washing with DMF until no yellow colour could be detected after addition of Dhbt-OH to the drained DMF. Coupling of benzoic acid was carried out as follows. 3 eq. benzoic acid was dissolved in DMF together with 3 eq. HOBt and 3 eq. DIC and then added to the resin. The coupling was continued over night. Excess coupling reagent was removed by washing with DMF. Prior to the deprotection of the Boc group the resin was treated with DCM. Deprotection of the Boc group was performed by treatment with 50% TFA in DCM v/v (2×2 min, 1×30 min) followed by washing with DCM and then with DMF and then treatment with 5% DIEA in DMF v/v and finally followed by washing with DMF. Coupling of Boc-Gly-OH was carried out as follows. 3 eq. Boc-Gly-OH was dissolved in DMF together with 3 eq. HOBt and 3 eq. DIC and then added to the resin. The coupling was continued 2 hours. Excess coupling reagent was removed by washing with DMF. The coupling was repeated and continued over night. Before cleavage of the peptide from the solid support the peptide resin was washed with DCM and then with ether and finally dried under vacuum. Cleavage of the dipeptide from the PAM-Resin was carried out as follows. The peptide-resin was treated with trifluoroacetic acid (TFA, Riedel-de Haeen) and after 10 min a volume corresponding to 10% of the TFA total volume of trifluoromethanesulfonic acid (TFMSA, Aldrich) was added at room temperature and the reaction was continued for 2 hours. The filtered resins were washed with TFA. The raw material was precipitated from the TFA-solution by adding diethylether. The raw material was collected as a brown oil. The ether solution was further extracted with water and the water phase was evaporated. The total amount of raw material was purified using prep. HPLC (Vydac C18-column): Buffer A: 0.1% TFA in Water; Buffer B: 90% AcCN; 0.1% TFA; 9.9% Water. Flow: 35ml/min. Gradient: 0-47 min 100% A to 75% A (Linear). HPLC purity: 99%. MS: calculated M+H=291.12. found M+H=291.7.

Reference： [1]Patent: US2007/149460,2007,A1 .Location in patent: Page/Page column 33-34

18
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 132-60-5 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-82-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

19
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 132-60-5 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-86-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

20
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-73-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

21
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-74-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

22
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-75-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

23
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-76-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

24
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-78-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

25
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-79-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

26
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-80-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

27
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-84-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 5336-90-3 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-69-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

29
[ 4530-20-5 ]
[ 5336-90-3 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-71-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 132-60-5 ]
[ 6284-80-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-83-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 132-60-5 ]
[ 6284-80-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-87-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 132-60-5 ]
[ 4361-00-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-81-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 132-60-5 ]
[ 4361-00-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-85-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-70-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

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[ 4530-20-5 ]
[ 109130-49-6 ]
[ 108-24-7 ]
[ 176486-63-8 ]
[ 1029683-72-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 2440 - 2444

36
[ 29022-11-5 ]
[ 71989-14-5 ]
[ 119831-72-0 ]
[ 176486-63-8 ]
[ 1073493-29-4 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1771 - 1782

37
[ 82911-69-1 ]
[ 132622-69-6 ]
[ 176486-63-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 2h;Inert atmosphere;	To a solution of (2S,4 ?)-4-amino-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (30 g, 0.13 mol) in tetrahydrofuran (600 niL), aqueous sodium bicarbonate solution (Na2C03, 40 g, 0.377 mol in 240 mL H20) was added. The mixture was cooled to 0 C, and a solution of N- (9-Fluorenylmethoxycarbonyloxy)succinimide (12.3 g, 36.45 mmol) dissolved in tetrahydrofuran (20 mL) was then added. The reaction mixture was stirred for 2 h at room temperature and concentrated in vacuo to remove tetrahydrofuran. The aqueous layer was adjusted pH to 6 by hydrochloric acid (IN) and extracted with ethyl acetate and the organic layers were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude residue (2S,4 ?)- 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-l-(ieri-butoxycarbonyl)pyrrolidine-2- carboxylic acid (59 g) which was used to the next step without further purification as a white solid. MS(ESI) m/z 353.1 [M-Boc]+

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1771 - 1782
[2]Patent: WO2019/28362,2019,A1 .Location in patent: Paragraph 00319; 00320; 00362; 00363

38
[ 17318-03-5 ]
[ 176486-63-8 ]
[ 1018910-35-4 ]

Yield	Reaction Conditions	Operation in experiment
50%		Example 122Synthesis of (2S,4R)-tert-butyl 4-[(9H-fluoren-9-yl)methoxy]carbonylamino}- 2-(3-fluorobenzoyl)pyrrolidine- 1 -carboxylate (XIII-5).N-Boc-trans-4-N-Fmoc-amino-L-proline (0.24 g, 0.19 mL, 0.001 mol) in CH2Cl2 (10 mL) was treated with diphenylphosphinic chloride (0.001 mol) at 0 C in the presence of Et3N (0.10 g, 0.14 mL, 0.001 mol) for 2 h. EtOAc (10 mL) was then added to the mixture, which was then washed successively with H2O (5 mL), saturated NaHCO3 aqueous solution (5 mL), and brine (5 mL), and dried over Na2SO4. The organic layer was concentrated in vacuo, and the resulting residue was dissolved in THF (10 mL). The solution was then cooled to -78 C. 3-Fluorophenylmagnesium bromide solution (1.0 M in THF, 1 mL, 0.001 mol) was added, and the mixture was gradually warmed to room temperature before being poured into a mixture of 0.1 M phosphate buffer (pH = 7.2, 5 mL) and 1 M HCl aqueous solution (5 mL) at 0 C. The aqueous layer was extracted with CH2Cl2 (10 mL x 3). The combined organic layers were washed successively with saturated aqueous NaITCO3 (10 mL) and brine (10 mL) and dried over Na2SO4. The solvent was evaporated in vacuo, and the residue was purified by column chromatography (silica gel, hexanes : EtOAc = 7 : 3) to afford a white solid (XIII-5, 0.27 g, 50%).

Reference： [1]Patent: WO2008/42353,2008,A1 .Location in patent: Page/Page column 75; 76

39
ethyl (1R,2S)-1-amino-2-vinylcyclopropanecarboxylate hydrochloride [ No CAS ]
[ 176486-63-8 ]
[ 862120-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 16h;	(2S,4R) Fmoc-4-amino-1-Boc-pyrrolidine-2-carboxylic acid (5.3 g, 11.8 mmol) was dissolved in DCM (100 ml), HATU (4.94 g, 12.99 mmol), DIEA (4.63 ml, 26.57 mmol) and vinylcyclopropylglycine ethyl ester (2.26 g, 11.81 mmol) were added successively. The mixture was stirred for 16 h at room temperature, and was then diluted with DCM (50 ml), washed with citric acid (10% aq), water, NaHCO3 (sat.aq) and water. The organic phase was dried over Na2SO4 and concentrated to afford a beige solid foam (8.11 g) which was subjected to silica gel column chromatography to afford the title compound (7.14 g, 12.11 mmol).

Reference： [1]Patent: US2009/23758,2009,A1 .Location in patent: Page/Page column 48

40
4-(di-tert-butylphosphoryl)cinnamic acid [ No CAS ]
[ 35661-60-0 ]
[ 71989-31-6 ]
[ 176486-63-8 ]
C₂₅H₃₆N₅O₈P [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 6126 - 6141

41
[ 176486-63-8 ]
[ 935746-27-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5296 - 5300

42
[ 176486-63-8 ]
[ 935746-22-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5296 - 5300

43
[ 176486-63-8 ]
C₃₈H₃₇N₉O₄S [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5296 - 5300

44
[ 176486-63-8 ]
[ 1315589-60-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5296 - 5300

45
[ 557-66-4 ]
[ 176486-63-8 ]
[ 1558040-93-9 ]