[ CAS No. 64187-48-0 ] {[proInfo.proName]}

Name: 64187-48-0|(2S,4R)-1-Benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate|97%
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SKU: A101081
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Quality Control of [ 64187-48-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 64187-48-0 ]

SDS Specification

Alternatived Products of [ 64187-48-0 ]

Product Details of [ 64187-48-0 ]

CAS No. :	64187-48-0	MDL No. :	MFCD00055851
Formula :	C₁₄H₁₇NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	279.29	Pubchem ID :	-
Synonyms :		Chemical Name :	(2S,4R)-1-Benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate

Calculated chemistry of [ 64187-48-0 ]

Physicochemical Properties

Num. heavy atoms :	20
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.43
Num. rotatable bonds :	6
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	73.87
TPSA :	76.07 Å²

Pharmacokinetics

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) :	-7.23 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.44
Log Po/w (XLOGP3) :	1.09
Log Po/w (WLOGP) :	0.4
Log Po/w (MLOGP) :	0.76
Log Po/w (SILICOS-IT) :	0.66
Consensus Log Po/w :	1.07

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.08
Solubility :	2.3 mg/ml ; 0.00824 mol/l
Class :	Soluble
Log S (Ali) :	-2.28
Solubility :	1.47 mg/ml ; 0.00525 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.98
Solubility :	2.96 mg/ml ; 0.0106 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.33

Safety of [ 64187-48-0 ]

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

Application In Synthesis of [ 64187-48-0 ]

* 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 [ 64187-48-0 ]
Downstream synthetic route of [ 64187-48-0 ]

[ 64187-48-0 ] Synthesis Path-Upstream 1~7

1
[ 64187-48-0 ]
[ 13504-86-4 ]

Reference： [1] Bioscience, Biotechnology, and Biochemistry, 1995, vol. 59, # 6, p. 1161 - 1162
[2] Patent: JP5703654, 2015, B2,

2
[ 64187-48-0 ]
[ 16217-15-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: With dimethyl sulfoxide In dichloromethane at -65℃; Inert atmosphere Stage #2: With triethylamine In dichloromethane at -65 - 20℃; for 1.33333 h; Inert atmosphere	Method U: A solution of anhydrous DMSO (22.7 mL, 320 mmol) in anhydrous DCM (600 mL) is stirred at -78° C. under nitrogen. Oxalyl chloride (13.9 mL, 159 mmol) is slowly added at a rate to maintain a temperature below -65° C. The mixture is stirred for an additional 15 min, and alcohol (126 mmol) in DCM (125 mL) is added. After an additional 30 min of stirring, triethylamine (85.0 mL, 610 mmol) is added. The mixture is stirred while slowly warming to rt (ca. 80 min). This is diluted with DCM and washed with 10percent citric acid solution. The DCM layer is separated, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product is purified by column chromatography (SiO₂, 30percent-50percent ethyl acetate in hexanes).Step 1: (S)-1-Benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate is prepared from (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (benzyloxycarbonyl (CBZ)-hydroxyproline methyl ester) following Method U (yield=73percent). 1H NMR (300 MHz, CDCl₃) δ 7.42-7.29 (m, 5H), 5.20-5.09 (m, 2H), 4.94-4.81 (m, 1H), 4.07-3.59 (m, 5H), 3.04-2.87 (m, 1H), 2.67-2.56 (m, 1H).
72%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	Step 1. To solution of methyl sulfoxide (28.0 ml, 395 mmol) in dichloromethane (150 ml) at -78 ° C. was added oxalyl chloride (99 ml, 198 mmol) dropwise. The formed solution was stirred at this temperature for 30 minutes. A solution of (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (25.08 g, 90 mmol) in dichloromethane (150 ml) was added dropwise at -78° C. The formed white slurry was stirred at -78° C. for 2 hours before addition of N,N-diisopropylethylamine (78 ml, 449 mmol) dropwise. The final pink solution was stirred at room temperature for 3 hours, washed with iced 1M HCl, 5percent citric acid, and brine, dried over MgSO₄, filtered, and concentrated. The residual light brown oil was purified by column, eluted with 4:1, 3: 1, then 2:1 hexane-ethyl acetate to afford the desired product (17.8 g, 72percent yield) as light brown viscous oil. ¹H NMR (CDCl₃) δ 2.58-2.63 (m, 1H), 2.90-2.99 (m, 1H), 3.62, 3.77 (s, 3H, rotamers), 3.95-4.02 (m, 2H), 4.82-4.89 (m, 1H), 5.11-5.24 (m, 2H), 7.32-7.39 (m, 5H).
72%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	To solution of Methyl Sulfoxide (28.0 ml, 395 mmol) in DCM (150 ml) at -78° C. was added oxalyl chloride (99 ml, 198 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (25.08 g, 90 mmol) in DCM (150 ml) was added dropwise at -78° C. The formed white slurry was stirred at -78° C. for 2 hr before addition of INN-Diisopropylethylamine (78 ml, 449 mmol) dropwise. The final pink solution was stirred at room temperature for 3 h. Washed with iced 1M HCl, 5percent citric acid, and brine, dried over MgSO₄, filtered, and concentrated. The residual light brown oil was purified by column, eluted with 4:1, 3:1, then 2:1 hexane-EtOAc to afford the desired product (17.8 g, 72percent yield) as light brown viscous oil. ¹H NMR (CDCl₃) δ 2.58-2.63 (m, 1H), 2.90-2.99 (m, 1H), 3.62, 3.77 (s, 3H, rotamers), 3.95-4.02 (m, 2H), 4.82-4.89 (m, 1H), 5.11-5.24 (m, 2H), 7.32-7.39 (m, 5H).

71%	With sulfuric acid; water; chromic acid In acetone at 20℃; for 0.583333 h;	General procedure: To a solution of the respective N-protected 4-hydroxypyrrolidine derivative of (2S,4R)-12e, (2R,4R)-12e, (2S,4R)-15e, and (2R,4R)-15e (1 equiv) in acetone (15 mL), chromic acid in aq H₂SO₄ (2.67 M, 8.50 equiv) was added at rt for 5 min. The brown mixture was stirred at rt for 30 min followed by the addition of MeOH (9 equiv) to destroy excessive oxidizing agent. The supernatant was decanted, diluted by CH₂Cl₂ (70 mL), washed with sat. aq NH₄Cl, dried (MgSO₄) and concentrated in vacuo. The residual oil was purified by CC (n-heptane/acetone, 3:1).
70%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2 h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 3 h;	Step 1.To solution of methyl sulfoxide (23.90 ml, 337 mmol) in DCM (100 ml) at -78 ⁰C was added oxalyl chloride (2 M in DCM, 84 ml, 168 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2 S,4R)-1 -benzyl 2- methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (21.38 g, 77 mmol) in DCM (100 ml) was added dropwise at -78 ⁰C. The formed slurry was stirred at -78 ⁰C for 2 hr before additon of N,N-Diisopropylethylamine (66.7 ml, 383 mmol) dropwise. The final solution was stirred at room temperature 3 h. The mixture was washed with iced IM HCl, 5percent citric acid, and then brine, dried over MgSO4, filtered, and evaporated. The residual light brown oil was purified by silica gel column chromatography, eluted with 4: 1, 3: 1, then 2: 1 hexane-EtOAc to afford (S)-I -benzyl 2-methyl 4- oxopyrrolidine-l,2-dicarboxylate (14.8 g, 70 percent yield) as light brown viscous oil. ¹H NMR (CDCl₃) δ 2.58-2.63 (m, 1 H), 2.90-2.99 (m, 1 H), 3.62, 3.77 (s, 3 H, rotamers), 3.95-4.02 (m, 2 H), 4.82-4.89 (m, 1 H), 5.11-5.24 (m, 2 H), 7.32-7.39 (m, 5 H).
63%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1 h; Stage #2: With triethylamine In dichloromethane	Intermediate 23: 2-methyl 1 -(phenylmethyl) (2S)-4-oxo-1 ,2-pyrrolidinedicarboxylate At -78°C, to a stirred solution of oxalyl chloride (5.97g, 47mmol) in DCM (200ml_) was slowly added DMSO (4.8g, 61.5mmol). After 10min stirring, a solution of 2-methyl l-(phenylmethyl) (2S,4R)-4-hydroxy-1 ,2-pyrrolidinedicarboxylate (10.1g, 36.2mmol) in DCM (30ml_) was annulled into the reaction flask. Stirring was continued for 60min before addition of triethylamine (10.98g, 108mmol). Cooling bath was then removed and the reaction mixture was allowed to slowly warm up to 0°C, and quenched with sat. NH₄CI solution. The layers were separated and the aqueous layer was extracted with DCM (2X). The combined organic layers was dried over MgS0₄, filtered and evaporated The crude product was purified by column chromatography (silica gel 0 to 50percent ethyl acetate in hexane) to give 2-methyl 1- (phenylmethyl) (2S)-4-oxo-1 ,2-pyrrolidine dicarboxylate (Intermediate 23) (6.3g, yield: 63percent). ¹H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.29 - 7.56 (m, 5 H) 5.08 - 5.37 (m, 2 H) 4.80 - 5.02 (m, 1 H) 3.89 - 4.08 (m, 2 H) 3.53 - 3.88 (m, 3 H) 2.95 (dd, J=18.82, 10.79 Hz, 1 H) 2.63 (dd, 1 H).

Reference： [1] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7333 - 7342
[2] Patent: US2010/22605, 2010, A1, . Location in patent: Page/Page column 34-35; 41
[3] Patent: US2009/297472, 2009, A1, . Location in patent: Page/Page column 12; 14
[4] Patent: US2010/150866, 2010, A1, . Location in patent: Page/Page column 10
[5] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 3, p. 590 - 596
[6] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 2, p. 470 - 484
[7] Patent: WO2008/64061, 2008, A1, . Location in patent: Page/Page column 96
[8] Patent: WO2011/28596, 2011, A1, . Location in patent: Page/Page column 25-26
[9] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 7, p. 2631 - 2650
[10] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4953 - 4975
[11] Patent: US5631385, 1997, A,
[12] Patent: CN108440507, 2018, A, . Location in patent: Paragraph 0314; 0319; 0320; 0321

3
[ 64187-48-0 ]
[ 57653-35-7 ]

Reference： [1] Journal of Organic Chemistry, 1997, vol. 62, # 16, p. 5542 - 5549
[2] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 6, p. 681 - 686
[3] Patent: WO2014/32, 2014, A1,

4
[ 16217-15-5 ]
[ 64187-48-0 ]
[ 57653-35-7 ]
[ 942308-58-9 ]

Reference： [1] Tetrahedron Letters, 2004, vol. 45, # 32, p. 6097 - 6100

5
[ 64187-48-0 ]
[ 95687-41-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With lithium borohydride In tetrahydrofuran at 0 - 20℃; for 4.5 h;	(2S, 4R)-N-LBeLzyloxvcarbonvo-2-hydroxymethyl-4-hydroxvpvrrolidine (6); To a stirred, cold (0 °C) solution of intermediate (5) (58.4 g, 0.208 mol) in THF (400 mL) was added LiBH4 (3.5 g, 0.16 mol) portion-wise. The reaction mixture was stirred for 30 min at (0-5 °C) then for 4 h at room temperature. At this time, TLC (silica gel plates developed in EtOAc) showed just a trace of starting material. The thick reaction mixture was diluted in succession with H20 (250 mL) and 2 M HC1 (277 mL), and then concentrated in vacuo to remove THF. The resulting aqueous concentrate was extracted with EtOAc (4 x 175 mL). Combined EtOAc extracts were washed with brine (2 x 200 mL), dried over MgS04, and then concentrated in vacuo to give intermediate (5) as an oil (51.9 g, 99percent). Additional reactions were carried out to give a total of 227 g of product suitable for further transformation. In later preparations the more convenient commercial solution of LiBH4 in THF was used

Reference： [1] Patent: EP1193270, 2002, A2, . Location in patent: Page 14, 36, 105
[2] Patent: WO2005/40170, 2005, A2, . Location in patent: Page/Page column 33-34
[3] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 16, p. 1845 - 1847
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 5, p. 1161 - 1174
[5] Tetrahedron, 2009, vol. 65, # 4, p. 862 - 876
[6] European Journal of Organic Chemistry, 2012, # 4, p. 837 - 843
[7] Tetrahedron, 2006, vol. 62, # 10, p. 2321 - 2330
[8] Chemical Communications, 2005, # 4, p. 495 - 497
[9] Organic Process Research and Development, 2018, vol. 22, # 9, p. 1241 - 1256
[10] Collection of Czechoslovak Chemical Communications, 1996, vol. 61, p. S234 - S237
[11] Chemistry - A European Journal, 1997, vol. 3, # 12, p. 1997 - 2010
[12] Nucleosides, Nucleotides and Nucleic Acids, 2003, vol. 22, # 5-8, p. 1285 - 1288
[13] Chemistry - A European Journal, 2010, vol. 16, # 35, p. 10691 - 10706
[14] Patent: WO2011/88045, 2011, A1, . Location in patent: Page/Page column 217-218

6
[ 64187-48-0 ]
[ 203866-13-1 ]

Reference： [1] Patent: WO2005/121135, 2005, A1,

7
[ 64187-48-0 ]
[ 203866-16-4 ]

Reference： [1] Patent: WO2005/121135, 2005, A1,

[ 64187-48-0 ] Synthesis Path-Downstream 1~26

1
[ 64187-48-0 ]
[ 18162-48-6 ]
[ 114358-14-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With 1H-imidazole; at 20℃; for 23h;Inert atmosphere;	SI-1 (1.50 g, 5.38 mmol) was dissolved in dry DCM (8.00 mL) under Ar at RT, TBSCl (1.63 g, 10.8 mmol) and imidazole (0.91 g, 13.4 mmol) were added and the reaction mixture stirred for 23 h. The reaction mixture was quenched with H2O (5.0 mL), the phases separated and the aqueous phase re-extracted with DCM (3 x 8.0 mL), the combined organics washed with saturated brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to give colourless oil, 2.57 g. The crude material was purified by flash column chromatography eluted with petrol: EtOAc 8:1 to give 6a (1.65 g, 78%) as a colourless oil: [a]D23-42.54 (c 1.10 in CHCl3); nmax/cm-1 (CHCl3) 3011, 2956, 2931, 2858, 1746, 1701, 1422, 1355, 1120, 1097; dH (400 MHz; CDCl3, 1:1 mixture of rotamers) 7.42-7.21 (5H, m, ArH), 5.20 (1H, d, J 12.6, PhCHH), 5.10 (0.5H, d, J 12.6, PhCHH), 5.03 (0.5H, d, J 12.6, PhCHH), 4.49 (0.5H, t, J 7.7, CH(C=O)), 4.44 (0.5H, t, J 7.7, CH(C=O)), 4.45-4.40 (1H, m, TBSOCH), 3.75 (1.5H, s, CO2CH3), 3.68 (0.5H, dd, J 6.4, 4.7, NCHH), 3.65 (0.5H, dd, J 6.4, 4.7, NCHH), 3.54 (1.5H, s, CO2CH3), 3.50 (0.5H, ddd, J 11.4, 2.8, 1.5, NCHH), 3.42 (0.5H, ddd, J 11.4, 2.8, 1.5, NCHH), 2.26-2.15 (1H, m, CHCHHCH), 2.08-1.99 (1H, m, CHCHHCH), 0.86 (4.5H, s, C(CH3)3), 0.85 (4.5H, s, C(CH3)3), 0.07-0.02 (6H, m, Si(CH3)2); dC (100 MHz; CDCl3) 173.3, 173.2 (C), 155.1, 154.4 (C), 136.7, 136.5 (C), 128.5, 128.4 (CH), 128.0 (CH), 127.8 (CH), 70.4, 69.7 (CH), 67.1 (CH2), 58.1, 57.9 (CH), 55.2, 54.8 (CH2), 52.3, 52.1 (CH2), 39.9, 38.9 (CH2), 25.7 (CH3), 18.0, 17.9 (C), -4.8, -4.9 (CH3); m/z (ESI) (C20H32NO5Si (M+H) requires 394.2044. Found 394.2041, C20H31NNaO5Si (M+Na) requires 416.1864. Found 416.1858).
	With 1H-imidazole; In dichloromethane; at 0 - 20℃;	A solution of Z-Hyp-OMe (85, 49.4 g, 177 mmol) and imidazole (14.5 g, 214 mmol) were dissolved in DCM (215 mL) and cooled to 0 0C. A solution containing tert-butyldimethylsilyl chloride (TBS-Cl, 29.8 g, 198 mmol) in DCM (100 mL) was added over about 68 minutes at <4 0C. The reaction was allowed to warm and stir overnight at room temperature. TLC analysis indicated only a trace of starting material. The reaction was quenched with water (150 mL). The organic layer was washed with water (150 mL) containing cone. HCl (2-3 mL, pH was about 1) and then with brine ( 113 g). After concentration, the crude product (86) was obtained as an oil (93 g) which was used without further purification.
7.4 g	With 1H-imidazole; In N,N-dimethyl-formamide; at 0 - 20℃; for 7h;	At 0C, tert.-butyldimethylsilyl chloride (4.45 g, 28.6 mmol) was added in portions to a soln of 4 (5.0 g, 17.9 mmol) and imidazole (3.65 g, 53.7 mmol) in DMF (50 mL). The mixture was allowed to warm to rt and stirred for 7 h. Aq. workup (Et.20, 1 M aq. NaH2P04 soln, sat. aq. NaHCOs soln; Na2S04) and FC (hexane / EtOAc) afforded 5 (7.4 g).

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 5192 - 5205
[2]Tetrahedron Letters,2013,vol. 54,p. 55 - 57
[3]Journal of Organic Chemistry,1997,vol. 62,p. 790 - 791
[4]Journal of Organic Chemistry,1997,vol. 62,p. 6773 - 6783
[5]Chemistry Letters,2007,vol. 36,p. 550 - 551
[6]Patent: WO2009/94287,2009,A1 .Location in patent: Page/Page column 76
[7]Organic Process Research and Development,2016,vol. 20,p. 242 - 252
[8]Patent: WO2017/63757,2017,A1 .Location in patent: Page/Page column 43
[9]Chemistry and biodiversity,2017,vol. 14

2
[ 64187-48-0 ]
[ 98-59-9 ]
[ 57653-38-0 ]

Yield	Reaction Conditions	Operation in experiment
96.2%	With pyridine; In 1,2-dimethoxyethane; at 5 - 25℃; for 1h;	Compound II was dissolved in DME. Add into 5L four-mouth flask. Add pyridine. Cool to 5 C. Slowly add dropwise p-toluenesulfonyl chloride. During dropwise addition process control temperature at 25 deg.C or below. After dropping complete, at 25 degree Celcius react for 1 hour. Wherein the compound II, triethylamine and toluene sulfonyl chloride to the equivalence ratio of 1: 2.0: 1.0. After the reaction, by adding 3L salt water, liquid, aqueous phase for DCM extraction (1L × 3 times), the combined organic phase, saturated salt water (2L) washing 3 times, the organic phase dried, concentrated, obtain light yellow solid, yield 96.2%.
93%	With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 15h;	Typical procedure for the preparation of methyl (2S,4R)-1-benzyloxycarbonyl-4-(tosyloxy)pyrrolidine-2-carboxylate (12): A solution of compound 11 (2.22 g, 7.95 mmol), Et3N (0.88 g, 8.7 mmol), and DMAP (0.97 g, 7.95 mmol) in CH2Cl2 (30 mL) was cooled to 0 C. Then, p-toluenesulfonyl chloride (1.67 g, 8.7 mmol) was added in one portion and stirred for 15 h at room temperature. The mixture was washed with water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (EA in PE: 30-40%) to give a colorless oil (3.2 g, yield: 93%). The 1H NMR spectra were in accordance with the literature data [9] . 1H NMR (400 MHz, CDCl3): delta 7.76 (d, 2 H, J = 8.0 Hz), 7.29-7.37 (m, 7 H), 4.99-5.20 (m, 3 H), 4.45-4.48 (m, 1 H), 3.53 and 3.75 (each s, total 3 H), 3.63-3.72 (m, 2 H), 2.55-2.60 (m, 1 H), 2.43 and 2.46 (each s, total 3 H), 2.16-2.21 (m, 1 H).
	With dmap; triethylamine; In dichloromethane; at 20℃;	In 600 ml of dichloromethane was dissolved 77.70 g (245 mmol) of (2S,4R)-1-benzyloxycarbonyl-4-hydroxyproline methyl ester, and to this solution were successively added 37.5 ml (270 mmol) of triethylamine, 49.04 g (257 mmol) of p-toluenesulfonyl chloride and 2.99 g (24.5 mmol) of 4-dimethylaminopyridine. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and to the residue were added ethyl acetate and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate = 1:1) to obtain 106.18 g of (2S,4R)-1-benzyloxycarbonyl-4-(p-toluenesulfonyloxy)proline methyl ester as a yellow oil.

Reference： [1]Patent: CN106083862,2016,A .Location in patent: Paragraph 0070; 0072; 0073
[2]Chinese Chemical Letters,2014,vol. 25,p. 479 - 481
[3]Canadian Journal of Chemistry,1982,vol. 60,p. 2918 - 2920
[4]Journal of the American Chemical Society,2001,vol. 123,p. 10245 - 10254
[5]Carbohydrate Research,1994,vol. 259,p. 219 - 242
[6]Journal of Medicinal Chemistry,2007,vol. 50,p. 4953 - 4975
[7]Patent: EP1541571,2005,A1 .Location in patent: Page/Page column 88

3
[ 64187-48-0 ]
[ 72180-14-4 ]

Yield	Reaction Conditions	Operation in experiment
85.80%	With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 25℃; for 18h;Inert atmosphere;	To a stirring solution of N-Cbz-trans-4-hydroxyl-L-methylprolinate (21.00 g, 57.14 mmol) in anhydrous dichloromethane (90 mL) was added DAST dropwise (21.65 g, 134.29 mmol) at -78 Cunder N2. After stirring for 3 h at -78 C, the mixture was warmed to room temperature (25C) and stirred for another 15 h. The mixture was quenched with sat.aq. NaHCO3 (600 mL)at 0C, and then was extracted with dichloromethane twice (600 mL X 2). The organic phase was washed with sat.aq. NaCl (600 mL X 1), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo at 45 C. The residue was purified by flash column chromatography eluted with Pet. Ether/EtOAc (1/0 to 4/1) to give N-carboxybenzyl-cis-4-fluor-L-methylprolinate (14.00 g, 85.80%). 1HNMR (CDCl3, 400 MHz): delta 7.43-7.27 (m, 5H), 5.31-5.07 (m, 3H), 4.65-4.51 (m, 1H), 3.97-3.62 (m, 5H), 2.51 (d, J = 18.4 Hz, 2H).
	With hexafluoropropene-diethylamine adduct; sodium fluoride; In dichloromethane; at 0 - 20℃; for 20h;	Methyl (2S,4R)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (306 mg, 0.00108 mol) and sodium fluoride (55 mg, 0.00131 mol) were suspended in dichloromethane (1.8 mL), followed by addition of Ishikawa reagent (293 mg, 0.00131 mol) under ice cooling. The reaction mixture was slowly warmed to room temperature and then stirred for 20 hours. After the reaction, the reaction mixture was poured into ice-cold saturated aqueous sodium bicarbonate (5 mL) and then separated into organic and aqueous layers. The aqueous layer was extracted with ethyl acetate. This extracted solution was combined with the organic layer obtained above, washed sequentially with 10% aqueous potassium bisulfate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. After drying, the solvent and the decomposition product of Ishikawa reagent (N,N-diethyl-2,3,3,3-tetrafluoropropionamide) were distilled off under reduced pressure, and the residue was applied to silica gel column chromatography (developing solvent; hexane:ethyl acetate = 5:1 to 0:1) to give the titled compound (227 mg, colorless oil). ESI-MS: m/z 304([M+Na]+). 1H-NMR(CDCl3): delta (ppm) 7.41-7.25(m, 5H), 5.33-5.06(m, 3H), 4.65-4.50(m, 1H), 3.75(s, 1.5H) and 3.65(s, 1.5H), 3.97-3.60(m, 2H), 2.61-2.21(m, 2H).

Reference： [1]Patent: WO2005/121135,2005,A1 .Location in patent: Page/Page column 68
[2]Patent: EP3450430,2019,A1 .Location in patent: Paragraph 0168; 0169
[3]Heterocycles,2014,vol. 88,p. 331 - 346
[4]Chemistry - A European Journal,2011,vol. 17,p. 13433 - 13437
[5]Journal of Medicinal Chemistry,2005,vol. 48,p. 7333 - 7342
[6]Journal of Medicinal Chemistry,1988,vol. 31,p. 875 - 885
[7]Journal of Medicinal Chemistry,2007,vol. 50,p. 4953 - 4975
[8]Patent: EP1657237,2006,A1 .Location in patent: Page/Page column 5-6

4
[ 124-41-4 ]
[ 13500-53-3 ]
[ 64187-48-0 ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 2787 - 2800

5
[ 67-56-1 ]
[ 13504-85-3 ]
[ 64187-48-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; at 0 - 20℃;Inert atmosphere;	[0869] A brown solution of compound M-2-1 (57.5 g, 220 mmol) in MeOH (400 mL) at 0C. under N2 atmosphere was treated with thionyl chloride (45.3 mL, 610 mmol, 2.8 eq.). The reaction mixture was allowed to warm up to room temperature and stirred overnight. The mixture was concentrated under reduced pressure to obtain compound M-2-2 (60.5 g, quant.) as light brown oil. [0870] 1H NMR (400 MHz, CDCl3) delta 7.38-7.28 (m, 5H), 5.23-5.09 (m, 2H), 4.56-4.47 (m, 2H), 3.80 (s, 1H), 3.76-3.66 (m, 2H), 3.58-3.52 (m, 1H) 2.38-2.26 (m, 1H), 2.16-2.08 (m, 1H); EI-MS m/z: 270 (M++1).
96%	With thionyl chloride; at 0 - 20℃; for 2.5h;	Typical procedure for the preparation of methyl (2S,4R)-1-benzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylate (11): SOCl2 (3.83 g, 32.2 mmol) was added to a solution of 10 (7.78 g, 29.3 mmol) in CH3OH (25 mL) dropwise at 0 C, and the mixture was stirred for 2.5 h at room temperature. The solvent was concentrated under vacuum to afford a viscous oil (7.86 g, yield: 96%). The 1H NMR spectra were in accordance with the literature data [8]. 1H NMR (400 MHz, CDCl3): delta 7.30-7.35 (m, 5 H), 5.09-5.21 (m, 2 H), 4.50-4.54 (m, 2 H), 3.75 and 3.54 (each s, total 3 H), 3.65-3.70 (m, 2 H), 2.25-2.35 (m, 1 H), 2.05-2.18 (m, 2 H).
90.4%		Transformer - benzyloxycarbonyl-4-hydroxy-proline of CPME solution 888g (trans - 26% byweight as benzyloxycarbonyl-4-hydroxy-proline, 229.6g containing) methanol 320g (10 mol),95% sulfuric acid 10.3g ( 0.1 mol) was added. After stirred for 5 hours heated to 45-50 C ,After stirring for 0.5 hours was added sodium carbonate 15.9 g (0.15 mol) to remove excessmethanol and concentrated under reduced pressure 40 kPa. CPME400g this concentratedsolution, water 200g was added and stirred, after an aqueous layer was separated and removed,and then concentrated under reduced pressure to CPME layer 24 kPa. The aqueous layer of thedistillate was separated and removed, performed again concentrated under reduced pressure toreturn the upper layer to the flask, trans - obtain a CPME solution 622g containingbenzyloxycarbonyl-4-hydroxyproline methyl ester (trans - benzyloxycarbonyl 35% by weight as4-hydroxy-proline methyl ester, 218.7g (0.78 mol, 90.4% yield) containing).

89%	With sulfuric acid; for 3h;Heating / reflux;	jlloxvcarbonyl)-2-methoxvcarbonyl-4-hydroxygyrrolidine (5).; A stirred solution of carboxylic acid intermediate (4) (62.7 g, 0.236 mol), anhydrous MeOH (350 mL) and concentrated sulfuric acid (2 mL) was heated at reflux for 3 h. At this time, TLC analysis (silica gel plate developed in CH2Cl2/MeOH, 10: 1) indicated complete reaction. The reaction mixture was cooled to room temperature, treated with Et3N (52 mL), and then concentrated in vacuo to a residue, which was dissolved in EtOAc (1 L). The EtOAc extract was washed with brine (3 L and 1 L), dried over MgS04, and then concentrated in vacuo to give intermediate (5) as a colorless oil (58.8 g, 89%). Additional reactions were carried out to give a total of 268 g of product suitable for further transformation
18 g	With sulfuric acid; for 10h;Reflux;	To a stirred solution of (2S,4R)-trans-4-hydroxy-l-proline 8 (10 g, 76 mmol) and NaHCO3 (8.3 g, 99 mmol) in H2O (20 mL) and THF (65 mL) was added, dropwise, benzyl chloroformate (14 mL, 99 mmol) under an N2 atmosphere at 0 C. The reaction mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was diluted with 20% aqueous NaOH and washed with Et2O. The aqueous phase was acidified to pH 3 with concentrated HCl and extracted with AcOEt. The combined organic phase was washed with water, dried over MgSO4, and concentrated at reduced pressure to give N-Cbz-proline. To a solution of the Cbz-proline (19 g, 73 mmol) in MeOH (100 mL) was added, dropwise, concentrated H2SO4 (2 mL) at room temperature. After stirring under reflux for 10 h, the reaction mixture was diluted with saturated aqueous NaHCO3 and extracted with AcOEt. The organic phase was dried over MgSO4 and concentrated at reduced pressure. The residue was purified by flash column chromatography on silica gel (AcOEt) to give 9 (18 g, 87%) as a colorless oil. Analytical data were consistent with those reported in the literature. 27
	With chlorosulphoxide; at -5 - 20℃; for 1h;	Add methanol (200 mL) to a 500 mL round bottom flask.Cool to -5 C in an ice bath, slowly add dropwise chlorosulfoxide (3.51 g, 30.0 mmol) to methanol.After the addition was completed, the ice bath was stirred for 30 minutes.N-Benzyloxycarbonyl-trans-L-hydroxyproline (5.30 g, 20.0 mmol) was dissolved in methanol (50 mL), and then slowly added dropwise to the reaction system. After the addition was completed, the mixture was transferred to room temperature.After 1 h, the reaction was completed, and the reaction solution was evaporated to dryness.The title compound was obtained.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1845 - 1847
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 1161 - 1174
[3]Patent: US2019/367488,2019,A1 .Location in patent: Paragraph 0868-0870
[4]Patent: EP1193270,2002,A2 .Location in patent: Page 14, 36, 105
[5]European Journal of Organic Chemistry,2010,p. 927 - 936
[6]Chemistry - A European Journal,2011,vol. 17,p. 13433 - 13437
[7]Chinese Chemical Letters,2014,vol. 25,p. 479 - 481
[8]Chemical Communications,2003,p. 2606 - 2607
[9]Tetrahedron,2006,vol. 62,p. 2321 - 2330
[10]Bioscience, Biotechnology and Biochemistry,1995,vol. 59,p. 1161 - 1162
[11]Patent: JP5709101,2015,B2 .Location in patent: Paragraph 0055
[12]Patent: WO2005/40170,2005,A2 .Location in patent: Page/Page column 33
[13]Carbohydrate Research,1994,vol. 259,p. 219 - 242
[14]Bioorganic and Medicinal Chemistry,1997,vol. 5,p. 2069 - 2087
[15]Nucleosides, nucleotides and nucleic acids,2001,vol. 20,p. 1193 - 1196
[16]Nucleosides, nucleotides and nucleic acids,2003,vol. 22,p. 1285 - 1288
[17]Tetrahedron Letters,2007,vol. 48,p. 841 - 844
[18]Patent: JP2005/112761,2005,A .Location in patent: Page/Page column 8
[19]Tetrahedron,2013,vol. 69,p. 6866 - 6874
[20]Patent: CN108440507,2018,A .Location in patent: Paragraph 0314; 0316; 0317; 0318
[21]Organic Process Research and Development,2018,vol. 22,p. 1241 - 1256
[22]Journal of Organic Chemistry,2019,vol. 84,p. 1053 - 1063
[23]Patent: WO2020/89687,2020,A2 .Location in patent: Page/Page column 107-108

6
[ 23795-02-0 ]
[ 64187-48-0 ]
(2S,4S)-N-Cbz-4-<4-(2-carbethoxyethyl)phenoxy>proline methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 4508 - 4521

7
[ 41873-65-8 ]
[ 64187-48-0 ]
(2S,4S)-4-(2-Ethoxycarbonylmethyl-phenoxy)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 4508 - 4521

8
[ 1499-56-5 ]
[ 501-53-1 ]
[ 64187-48-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium carbonate; In water; at 10 - 20℃; for 5h;	Water was added to 354g and 358g sodium carbonate to the slurry entire amount. It was addeddropwise over 3 hours benzyloxycarbonyl chloride 484g using a dropping funnel whilemaintaining the temperature at 10 C. After After completion of the dropwise addition is for 2hours and aged at 20 C, trans and liquid separation with toluene 531 g - it was extractedhydroxy -L- proline methyl ester - benzyloxycarbonyl. It separated the transformer further fromthe water layer side in the water layer by adding a toluene 177g - benzyloxycarbonyl - wasextracted and recovered a hydroxy -L- proline methyl ester. After separated the two toluenelayers were combined and concentrated under a reduced pressure of 8kPa at 60 C, trans - togive a crude product 799g benzyloxycarbonyl-4-hydroxy -L- proline methyl ester. Transformer in crude material - the content of benzyloxycarbonyl-4-hydroxy -L- proline methylester was 2.41 mol (91.6% yield). In addition the ratio of the by-product benzyl alcohol and the object was 0.003 (area / area). From trans-4-hydroxy -L- proline trans - yields of upbenzyloxycarbonyl-4-hydroxy -L- proline methyl ester was 88%.
	With triethylamine; In dichloromethane; at 25℃; for 12.25h;Inert atmosphere; Cooling;	Example 1: Synthesis of methyl (4S)-4-{r(3R)-3-r(tert-butoxycarbonyl) aminol-4-(2A5- trifluoro- phenvPbutano yll amino I -L-prolinate; Step 1: 1-benzyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-l, 2-dicarboxylate; Benzylchloroformate (235 ml, 1.7 mol) was added to the chilled solution of trans-4- hydroxy-L-proline methyl ester (120 g, 0.83 mol) (Commercially available) and triethylamine (345 ml, 2.5 mol) in dry dichloromethane (1000 ml) under nitrogen atmosphere over a period of about 15 minutes. After addition, the reaction mixture was stirred at ~ 25C for about 12 hours and the solvent was recovered under reduced pressure The crude was purified using column chromatography (Silica gel 100-200 mesh, 0.25% Methanol: dichloromethane) to give title product (Yield: -108 g).MS (+ve, ion mode); 280.24 (M+l)
	With sodium carbonate; In water; at 10 - 20℃; for 5h;	To 827 g of the slurry of Reference Example 1, 354 g of water and 358 g of sodium carbonate were added. While cooling the temperature to 10 C., 484 g of benzyloxycarbonyl chloride was added dropwise over about 3 hours with a dropping funnel. After completion of the dropwise addition, reaction ripening was carried out at 20 C. for 2 hours, 531 g of toluene was added and liquid separation to extract trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester. From the separated aqueous layer side, 177 g of toluene was further added to extract trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester. The separated two toluene layers were mixed and then concentrated under reduced pressure of 8 kPa at 60 C. to obtain 799 g of crude trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester (2.41 mol (yield: 91.6%) of trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester)

Reference： [1]Chemical Communications,1996,p. 2155 - 2156
[2]Patent: JP5709101,2015,B2 .Location in patent: Paragraph 0043; 0044
[3]Chemistry Letters,2007,vol. 36,p. 550 - 551
[4]Patent: WO2011/92671,2011,A1 .Location in patent: Page/Page column 31
[5]Patent: JP5703654,2015,B2 .Location in patent: Paragraph 0052

9
[ 64187-48-0 ]
[ 95687-41-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; for 4.5h;	(2S, 4R)-N-LBeLzyloxvcarbonvo-2-hydroxymethyl-4-hydroxvpvrrolidine (6); To a stirred, cold (0 C) solution of intermediate (5) (58.4 g, 0.208 mol) in THF (400 mL) was added LiBH4 (3.5 g, 0.16 mol) portion-wise. The reaction mixture was stirred for 30 min at (0-5 C) then for 4 h at room temperature. At this time, TLC (silica gel plates developed in EtOAc) showed just a trace of starting material. The thick reaction mixture was diluted in succession with H20 (250 mL) and 2 M HC1 (277 mL), and then concentrated in vacuo to remove THF. The resulting aqueous concentrate was extracted with EtOAc (4 x 175 mL). Combined EtOAc extracts were washed with brine (2 x 200 mL), dried over MgS04, and then concentrated in vacuo to give intermediate (5) as an oil (51.9 g, 99%). Additional reactions were carried out to give a total of 227 g of product suitable for further transformation. In later preparations the more convenient commercial solution of LiBH4 in THF was used
98%	With lithium borohydride; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	[0872] A brown solution of compound M-2-2 (60.5 g, 220 mmol) in anhydrous THF (500 mL) at 0C. under N2 atmosphere was treated with LiBH4 (3.9 g, 180 mmol, 0.8 eq) and stirred for 30 minutes. And then the mixture was stirred at room temperature for further 2 days. The mixture was quenched with water (200 mL) and 2N HCl (100 mL). The organic solvent was removed by rotary evaporator. The residue was extract with EA (500 mL3) and then the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain compound M-2-3 (54.6 g, 98%) as light brown oil. 1H NMR (400 MHz, CDCl3) delta 7.39-7.30 (m, 5H), 5.21-5.12 (m, 2H), 4.66 (d, J=7.2 Hz, 1H), 4.39 (s, 1H), 4.21 (q, J=7.6, 7.2 Hz, 1H), 3.76 (t, J=9.6 Hz, 2H), 3.66-3.58 (m, 1H), 3.50 (dd, J=8.0, 4.0 Hz, 1H), 2.10-2.23 (m, 1H), 1.78-1.64 (m, 1H); EI-MS m/z: 252 (M++1).
98%	With lithium borohydride; In tetrahydrofuran; at 0 - 20℃; for 48h;Inert atmosphere;	To a solution of compound Mono- 10-2 (60.5 g, 220 mmol) in anhydrous THF (500 mL) was added LiBH4 (3.9 g, 180 mmol) at 0 C under N2 atmosphere. After stirring for 2 days at room temperature, the reaction was quenched with water (200 mL) and 2N HC1 (100 mL). The mixture was extracted with EA (500 mL x 3). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to obtain compound Mono- 10-3 (54.6 g, 98%) as light brown oil. NMR (400 MHz, CDCB) d 7.39-7.30 (m, 5H), 5.21-5.12 (m, 2H), 4.66 (d, J= 12 Hz, 1H), 4.39 (s, 1H), 4.21 (q, J= 7.6, 7.2 Hz, 1H), 3.76 (t, J= 9.6 Hz, 2H), 3.66 - 3.58 (m, 1H), 3.50 (dd, J= 8.0, 4.0 Hz, 1H), 2.10 - 2.23 (m, 1H), 1.78 - 1.64 (m, 1H) ; EI-MS m/z: 252(M++l).

With lithium borohydride; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;

Example 083 A To methyl (2S,4R)- 1 -benzyloxycarbonyl-4- hydroxypyrrolidine-2-carboxylate (4.9 g, 17.54 mmoi) in THF (100 mL) at 0 C under Ar was added lithium borohydridc ( 1.53 g, 70.16 mmol). The mixture was allowed to stir at 0 C then warm to rt and stir for 2 days. The mixture was concentrated under reduced pressure to give a residue (4.4 g) containing (2S,4R)-benzyl 4-hydroxy-2- (hydroxymethyl)pyrrolidine- l-carboxylate. LCMS (ESI) m/z 252 (M + H)+. To the residue in DMF (120 mL) under Ar were added imidazole (1.3 g, 19.3 mmol) and t- butyldiphenylchlorosilane (4.89 mL, 21.0 mmol) and the mixture was stirred at rt for 24 h, at which time more imidazole ( 1.79 g, 26.3 mmol) and t- butyldiphenylchiorosilane (4.48 mL, 1 7.5 mmol) were added, and stirring was continued at rt overnight. Additional imidazole (650 mg) and t- butyldiphenylchlorosilane (2.44 mL) were added. LCMS (ESI) m/z 252 (M + H)+. After a period of continued stirring, the mixture was partitioned between EtOAc (400 mL) and water (200 mL), and the separated EtOAc layer was dried over MgSC>4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 6% to 50% EtOAc hexanes to afford (2S,4R)-benzyl 2-((tert-butyldiphenylsilyloxy) methyl)-4-hydroxypyrrolidine- 1 -carboxylate (2.66 g, 5.43 mmol, 31%). NMR (300 MHz, DMSO-i ) delta 7.54-7.58 (m, 4H), 7.35-7.45 (m, 8H), 7.13-7.25 (m, 3H), 4.92-5.06 (m, 3H), 4.35 (s, 1H), 3.95-4.04 (m, 2H), 3.69-3.73 (m, 1H) , 3.41 (d, 2H), 2.14-2.18 (m, lH), 1.99 (s, 1 H), 1.05 (br, s, 9H) ; LCMS (ESI) m/z 490 (M + H)+.

Reference： [1]Patent: EP1193270,2002,A2 .Location in patent: Page 14, 36, 105
[2]Patent: WO2005/40170,2005,A2 .Location in patent: Page/Page column 33-34
[3]Patent: US2019/367488,2019,A1 .Location in patent: Paragraph 0871-0872
[4]Patent: WO2020/89687,2020,A2 .Location in patent: Page/Page column 107-108
[5]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1845 - 1847
[6]Journal of Medicinal Chemistry,2004,vol. 47,p. 1161 - 1174
[7]Tetrahedron,2009,vol. 65,p. 862 - 876
[8]European Journal of Organic Chemistry,2012,p. 837 - 843
[9]Tetrahedron,2006,vol. 62,p. 2321 - 2330
[10]Chemical Communications,2005,p. 495 - 497
[11]Organic Process Research and Development,2018,vol. 22,p. 1241 - 1256
[12]Collection of Czechoslovak Chemical Communications,1996,vol. 61,p. S234 - S237
[13]Chemistry - A European Journal,1997,vol. 3,p. 1997 - 2010
[14]Nucleosides, nucleotides and nucleic acids,2003,vol. 22,p. 1285 - 1288
[15]Chemistry - A European Journal,2010,vol. 16,p. 10691 - 10706
[16]Patent: WO2011/88045,2011,A1 .Location in patent: Page/Page column 217-218

10
[ 40216-83-9 ]
[ 501-53-1 ]
[ 64187-48-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 0℃; for 2.5h;	NaHCO3 (3.9 g, 27.7 mmol) was dissolved in a mixture solution of dioxane and water 1:1 (40 mL)and then 15 was add to the solution. The resultant mixture waskept stirring for 30 min at 0 oC followed by addition of PhCH2OCOCl (5.9 mL,41.5 mmol). The reaction mixture was allowed to stir at 0 oC for additional 2 h. The reaction solventwas evaporated under vacuum and then CH2Cl2 (30 mL) was added, washed with 1N HCl, driedover Na2SO4, filtered and concentrated under reducedpressure. The residue was purified by flash-chromatography on silica gel(Petroleum ether/ethyl acetate = 1:1) to afford 16 as a colorless viscous liquid (5.6 g, 95% yield).
79%	With sodium carbonate; In 1,4-dioxane; water; at 0℃; for 2.5h;	A solution of (2S, 4R) -methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (5.5 g, 30 mmol) in 1, 4-dioxane (17 mL) was cooled to 0 , and then a solution of sodium carbonate (3.5 g, 33 mmol) in H 2O (17 mL) was added in portions, after that, CbzCl (4.8 mL, 34 mmol) was added over 30 min. The obtaining reaction mixture was stirred at 0 for 2 hours. The mixture was concentrated in vacuo to remove 1, 4-dioxane, the residue was extracted with ethyl acetate (3 x 100 mL) . The combined organic phases were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatograph (PE/EtOAc (V/V) = 1/1) to give the title compound as a colorless oil (6.7 g, 79%) .
79%	With sodium carbonate; In 1,4-dioxane; water; at 0℃; for 2.5h;	(2S,4R)-4-Hydroxypyrrole-2-carboxylic acid methyl ester hydrochloride (5.5 g, 30 mmol) The 1,4-dioxane (17 mL) solution was cooled to 0 C. Then sodium carbonate (3.5 g, 33 mmol) was added in portions. H2O (17mL) solution, Then add CbzCl (4.8 mL, 34 mmol), After 30 minutes, the drop is completed. The resulting reaction solution was stirred at 0 C for 2 hours. The reaction mixture was concentrated to dryness The residue was purified with EtOAc EtOAc m. The title compound was obtained as a colorless oil ( 6.7 g, yield: 79%).

72%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 3h;	Example 2: 1 -benzyl 2-methyl (2S,4R)-4-hvdroxy-l,2-pyrrolidinedicarboxylate Chlorobenzylformate (1.0 mL, 7.9 mmol) was added to a mixture of the compound prepared in Example 1 (1.2 g, 6.6 mmol), NaHC03 (4.0 g) and saturated aqueous NaHC03 (5.0 mL) in THF (20 mL) at 0 C. After stirring at room temperature for 3 h, tris(hydroxymethyl)aminomethane (1.4 g) was added and the reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts were dried and concentrated and purified by flash chromatography (silica gel, 40 g, 20-80% ethyl acetate/hexanes) to give the title compound (1.3 g, 72%) as a pale yellow oil. NMR (300 MHz, CD3OD, rotamers present) 6 7.35-7.29 (m, 5H), 5.18-4.97 (m, 2H), 4.47-4.39 (m, 2H), 3.71 (s, 1.5H), 3.62-3.51 (m, 3.5H), 2.30-2.25 (m, 1H), 2.09-2.00 (m, 1H).
72%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 3h;	Chlorobenzylformate (1.0 mL, 7.9 mmol) was added to a mixture of the compound prepared in Example 1 (1.2 g, 6.6 mmol), NaHCO3 (4.0 g) and saturated aqueous NaHCO3 (5.0 mL) in THF (20 mL) at 0 C. After stirring at room temperature for 3 h, tris(hydroxymethyl)aminomethane (1.4 g) was added and the reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts were dried and concentrated and purified by flash chromatography (silica gel, 40 g, 20-80% ethyl acetate/hexanes) to give the title compound (1.3 g, 72%) as a pale yellow oil. 1H NMR (300 MHz, CD3OD, rotamers present) delta 7.35-7.29 (m, 5H), 5.18-4.97 (m, 2H), 4.47-4.39 (m, 2H), 3.71 (s, 1.5H), 3.62-3.51 (m, 3.5H), 2.30-2.25 (m, 1H), 2.09-2.00 (m, 1H).

Reference： [1]Journal of the American Chemical Society,2001,vol. 123,p. 10245 - 10254
[2]Tetrahedron Letters,2015,vol. 56,p. 4036 - 4038
[3]Journal of the American Chemical Society,1998,vol. 120,p. 7439 - 7449
[4]Patent: WO2019/76310,2019,A1 .Location in patent: Paragraph 00169
[5]Patent: CN109678859,2019,A .Location in patent: Paragraph 0379; 0380-0382
[6]Patent: WO2013/174937,2013,A1 .Location in patent: Page/Page column 74-75
[7]Patent: US2015/152048,2015,A1 .Location in patent: Paragraph 0449-0450
[8]Tetrahedron,2007,vol. 63,p. 7112 - 7119

11
[ 64187-48-0 ]
[ 16217-15-5 ]

Yield	Reaction Conditions	Operation in experiment
73%		Method U: A solution of anhydrous DMSO (22.7 mL, 320 mmol) in anhydrous DCM (600 mL) is stirred at -78 C. under nitrogen. Oxalyl chloride (13.9 mL, 159 mmol) is slowly added at a rate to maintain a temperature below -65 C. The mixture is stirred for an additional 15 min, and alcohol (126 mmol) in DCM (125 mL) is added. After an additional 30 min of stirring, triethylamine (85.0 mL, 610 mmol) is added. The mixture is stirred while slowly warming to rt (ca. 80 min). This is diluted with DCM and washed with 10% citric acid solution. The DCM layer is separated, washed with brine, dried over sodium sulfate, and concentrated under vacuum. The crude product is purified by column chromatography (SiO2, 30%-50% ethyl acetate in hexanes).Step 1: (S)-1-Benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate is prepared from <strong>[64187-48-0](2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate</strong> (benzyloxycarbonyl (CBZ)-hydroxyproline methyl ester) following Method U (yield=73%). 1H NMR (300 MHz, CDCl3) delta 7.42-7.29 (m, 5H), 5.20-5.09 (m, 2H), 4.94-4.81 (m, 1H), 4.07-3.59 (m, 5H), 3.04-2.87 (m, 1H), 2.67-2.56 (m, 1H).
72%		Step 1. To solution of methyl sulfoxide (28.0 ml, 395 mmol) in dichloromethane (150 ml) at -78 C. was added oxalyl chloride (99 ml, 198 mmol) dropwise. The formed solution was stirred at this temperature for 30 minutes. A solution of <strong>[64187-48-0](2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate</strong> (25.08 g, 90 mmol) in dichloromethane (150 ml) was added dropwise at -78 C. The formed white slurry was stirred at -78 C. for 2 hours before addition of N,N-diisopropylethylamine (78 ml, 449 mmol) dropwise. The final pink solution was stirred at room temperature for 3 hours, washed with iced 1M HCl, 5% citric acid, and brine, dried over MgSO4, filtered, and concentrated. The residual light brown oil was purified by column, eluted with 4:1, 3: 1, then 2:1 hexane-ethyl acetate to afford the desired product (17.8 g, 72% yield) as light brown viscous oil. 1H NMR (CDCl3) delta 2.58-2.63 (m, 1H), 2.90-2.99 (m, 1H), 3.62, 3.77 (s, 3H, rotamers), 3.95-4.02 (m, 2H), 4.82-4.89 (m, 1H), 5.11-5.24 (m, 2H), 7.32-7.39 (m, 5H).
72%		To solution of Methyl Sulfoxide (28.0 ml, 395 mmol) in DCM (150 ml) at -78 C. was added oxalyl chloride (99 ml, 198 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of <strong>[64187-48-0](2S,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate</strong> (25.08 g, 90 mmol) in DCM (150 ml) was added dropwise at -78 C. The formed white slurry was stirred at -78 C. for 2 hr before addition of INN-Diisopropylethylamine (78 ml, 449 mmol) dropwise. The final pink solution was stirred at room temperature for 3 h. Washed with iced 1M HCl, 5% citric acid, and brine, dried over MgSO4, filtered, and concentrated. The residual light brown oil was purified by column, eluted with 4:1, 3:1, then 2:1 hexane-EtOAc to afford the desired product (17.8 g, 72% yield) as light brown viscous oil. 1H NMR (CDCl3) delta 2.58-2.63 (m, 1H), 2.90-2.99 (m, 1H), 3.62, 3.77 (s, 3H, rotamers), 3.95-4.02 (m, 2H), 4.82-4.89 (m, 1H), 5.11-5.24 (m, 2H), 7.32-7.39 (m, 5H).

71%	With sulfuric acid; water; chromic acid; In acetone; at 20℃; for 0.583333h;	General procedure: To a solution of the respective N-protected 4-hydroxypyrrolidine derivative of (2S,4R)-12e, (2R,4R)-12e, (2S,4R)-15e, and (2R,4R)-15e (1 equiv) in acetone (15 mL), chromic acid in aq H2SO4 (2.67 M, 8.50 equiv) was added at rt for 5 min. The brown mixture was stirred at rt for 30 min followed by the addition of MeOH (9 equiv) to destroy excessive oxidizing agent. The supernatant was decanted, diluted by CH2Cl2 (70 mL), washed with sat. aq NH4Cl, dried (MgSO4) and concentrated in vacuo. The residual oil was purified by CC (n-heptane/acetone, 3:1).
70%		Step 1.To solution of methyl sulfoxide (23.90 ml, 337 mmol) in DCM (100 ml) at -78 0C was added oxalyl chloride (2 M in DCM, 84 ml, 168 mmol) dropwise. The formed solution was stirred at this temperature for 30 min. A solution of (2 S,4R)-1 -benzyl 2- methyl 4-hydroxypyrrolidine-l,2-dicarboxylate (21.38 g, 77 mmol) in DCM (100 ml) was added dropwise at -78 0C. The formed slurry was stirred at -78 0C for 2 hr before additon of N,N-Diisopropylethylamine (66.7 ml, 383 mmol) dropwise. The final solution was stirred at room temperature 3 h. The mixture was washed with iced IM HCl, 5% citric acid, and then brine, dried over MgSO4, filtered, and evaporated. The residual light brown oil was purified by silica gel column chromatography, eluted with 4: 1, 3: 1, then 2: 1 hexane-EtOAc to afford (S)-I -benzyl 2-methyl 4- oxopyrrolidine-l,2-dicarboxylate (14.8 g, 70 % yield) as light brown viscous oil. 1H NMR (CDCl3) delta 2.58-2.63 (m, 1 H), 2.90-2.99 (m, 1 H), 3.62, 3.77 (s, 3 H, rotamers), 3.95-4.02 (m, 2 H), 4.82-4.89 (m, 1 H), 5.11-5.24 (m, 2 H), 7.32-7.39 (m, 5 H).
63%		Intermediate 23: 2-methyl 1 -(phenylmethyl) (2S)-4-oxo-1 ,2-pyrrolidinedicarboxylate At -78C, to a stirred solution of oxalyl chloride (5.97g, 47mmol) in DCM (200ml_) was slowly added DMSO (4.8g, 61.5mmol). After 10min stirring, a solution of 2-methyl l-(phenylmethyl) (2S,4R)-4-hydroxy-1 ,2-pyrrolidinedicarboxylate (10.1g, 36.2mmol) in DCM (30ml_) was annulled into the reaction flask. Stirring was continued for 60min before addition of triethylamine (10.98g, 108mmol). Cooling bath was then removed and the reaction mixture was allowed to slowly warm up to 0C, and quenched with sat. NH4CI solution. The layers were separated and the aqueous layer was extracted with DCM (2X). The combined organic layers was dried over MgS04, filtered and evaporated The crude product was purified by column chromatography (silica gel 0 to 50% ethyl acetate in hexane) to give 2-methyl 1- (phenylmethyl) (2S)-4-oxo-1 ,2-pyrrolidine dicarboxylate (Intermediate 23) (6.3g, yield: 63%). 1H NMR (400 MHz, CHLOROFORM-c/) delta ppm 7.29 - 7.56 (m, 5 H) 5.08 - 5.37 (m, 2 H) 4.80 - 5.02 (m, 1 H) 3.89 - 4.08 (m, 2 H) 3.53 - 3.88 (m, 3 H) 2.95 (dd, J=18.82, 10.79 Hz, 1 H) 2.63 (dd, 1 H).
		Example 3 (2S)-N-Benzyloxycarbonyl-4-oxoproline methyl ester 25.3 g (88%) of product is obtained as a light-yellow oil from 29.0 g of (2S,4R)-N-benzyloxycarbonyl-4-hydroxyproline methyl ester. Purity: 96% by HPLC and 1 H-NMR.
	With Jones reagent; In acetone; for 1h;	N-Benzyloxycarbonyl-trans-L-hydroxyproline methyl ester (5.30 g, 19.9 mmol)Add to acetone (200 mL),Slowly add Jones reagent (22.2 mL, 60.0 mmol) to acetone.After vigorous stirring for 1 h, the reaction was completed, suction filtration, and the filter cake was washed with acetone.The filtrate was concentrated and separated by column chromatography (petroleum ether: ethyl acetate = 10:1)The title compound was obtained.

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 7333 - 7342
[2]Chemical Biology and Drug Design,2020
[3]Patent: US2010/22605,2010,A1 .Location in patent: Page/Page column 34-35; 41
[4]Patent: US2009/297472,2009,A1 .Location in patent: Page/Page column 12; 14
[5]Patent: US2010/150866,2010,A1 .Location in patent: Page/Page column 10
[6]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 590 - 596
[7]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 470 - 484
[8]Patent: WO2008/64061,2008,A1 .Location in patent: Page/Page column 96
[9]Patent: WO2011/28596,2011,A1 .Location in patent: Page/Page column 25-26
[10]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 2631 - 2650
[11]Journal of Medicinal Chemistry,2007,vol. 50,p. 4953 - 4975
[12]Patent: US5631385,1997,A
[13]Patent: CN108440507,2018,A .Location in patent: Paragraph 0314; 0319; 0320; 0321

12
[ 64187-48-0 ]
[ 2232-08-8 ]
[ 57653-38-0 ]

Yield	Reaction Conditions	Operation in experiment
56%		To a solution of the compound p-toluenesulfonylimidazole (10 g, 45.2 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise methyl trifluoromethanesulfonate (7.9 g, 48.2 mmol) under ice-cooling. After 1 hour of ice bath reaction, a solution of compound 4a (8.4 g, 30.1 mmol) and N-methylimidazole (3.7 g, 45.2 mmol) in tetrahydrofuran (20 mL) was added dropwise to the reaction mixture. The reaction solution was slowly warmed to room temperature and stirred for 24 hours. The solvent was then removed under reduced pressure, and 40 mL of water was added thereto, followed by extraction with ethyl acetate (30 mL of X3). The organic phases were combined and washed with saturated brine (90 mL). The organic phase was dried, filtered, concentrated and concentrated, and purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3: 1). Compound 4b, white solid7.3 g, yield 56%.

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 2725 - 2746
[2]Patent: CN104016993,2016,B .Location in patent: Paragraph 0206-0209

13
[ 5292-43-3 ]
[ 64187-48-0 ]
[ 865436-06-2 ]

Yield	Reaction Conditions	Operation in experiment
77%		Example 1: 2S, 4R-4-carboxymethoxy-2-(pyridin-2-ylaminomethyl)-pyrrolidine-1- carboxylic acid benzyl ester (1); The synthesis of the title compound is depicted in Fig. 1; a) Synthesis of 2S, 4R-4-tert-butoxycarbonylmethoxy-pyrrolidine-1, 2-dicarboxylic acid 1- benzyl ester 2-methyl ester (2); 4.8g (120 mmol) of NaH (60 % in paraffin) were suspended under Ar in 50 mL of absolute THF and cooled down to 0C. 16. 8g (60 mmol) of Z-Hyp-OMe, dissolved in 100 mL of absolute THF, were added slowly to the reaction mixture and stirred for 30min at 0C. 41 mL (278 mmol) of tert-butyl bromoacetate were added to the suspension and the reaction mixture was heated up to 55C stirred for 12h. After addition of 7.5 mL of THF/H20 (1: 1), the reaction mixture was dried with Na2S04 and the precipitate was filtered off. The solvent was removed at the evaporator and the crude reaction mixture was taken up in 200 mL of MeOH. The paraffin oil was removed. After evaporation of the solvent the crude product was chromatographed on silica gel using ethyl acetate/hexane. Yield 12.91g (77 %). NMR-'H (DMSO-d6): 8 = 7.42-7. 24 (m, 5H), 5.09 (s, 2H), 4.96 (d, 1H, J= 9.6), 4.31 (dt, 1H, J= 16.1, 7.8), 4.18 (m, 1H), 3.65 (s, 2H), 3.54 (s, 3H), 3.54 (dt, 1H, J= 4.4, 11.7), 2.37 (m, 1H), 2.00 (m, 1H), 1.42 (s, 9H). NMR-l3C (DMSO-d6) (partial signal doubling due Cbz-rotameres): 6 = 172.6 (Cq), 172.3 (Cq), 169.4 (Cq), 154.1 (Cq), 153.5 (Cq), 136.7 (Cq), 136.5 (Cq), 128.5 (CH), 128. 4 (CH), 128.3 (CH), 127.9 (CH), 127. 8 (CH), 127.5 (CH), 127.3 (CH), 80.8 (Cq), 77.63 (CH2), 76.8 (CH2), 69.2 (CH), 66.2 (CH2), 66.2 (CH2), 57.7 (CH2), 57.3 (CH2), 52.2 (CH2), 52.0 (CH2), 5. 18 (CH), 35.8 (CH2), 34.9 (CH2), 27.7 (CH3). LCMS: m/z : 394.5 [M].

Reference： [1]Patent: WO2005/90329,2005,A1 .Location in patent: Page/Page column 103
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 3786 - 3794

14
[ 64187-48-0 ]
[ 500733-24-4 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 2321 - 2330

15
[ 64187-48-0 ]
[ 189215-90-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: 70 percent / PPh₃; diisopropylazodicarboxylate / tetrahydrofuran / 13 h / -10 - 20 °C 2: NaN₃ / dimethylformamide / 12 h / 60 °C 3: 95 percent / H₂ / Raney-Ni / ethyl acetate / 2 h / 2068.59 Torr
	Multi-step reaction with 3 steps 1: 60 percent / PPh₃; DIAD / tetrahydrofuran 2: 90 percent / NaN₃ / dimethylformamide 3: 93 percent / H₂; Ni / ethyl acetate
	Multi-step reaction with 6 steps 1: 94 percent / PPh₃, DEAD 2: NaOMe / methanol 3: pyridine 4: 97 percent / LiN₃ 5: H₂S / pyridine 6: DIEA

Reference： [1]Lonkar, Pallavi S.; Ganesh, Krishna N.; Kumar, Vaijayanti A. [Organic and Biomolecular Chemistry, 2004, vol. 2, # 18, p. 2604 - 2611]
[2]Umashankara; Babu, I Ramesh; Ganesh, Krishna N [Chemical Communications, 2003, # 20, p. 2606 - 2607]
[3]Jordan, Stephan; Schwemler, Christoph; Kosch, Winfried; Kretschmer, Axel; Schwenner, Eckhardt; Stropp, Udo; Mielke, Burkhard [Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 6, p. 681 - 686]

16
[ 64187-48-0 ]
[ 473806-21-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 60 percent / PPh₃; DIAD / tetrahydrofuran 2: 90 percent / NaN₃ / dimethylformamide 3: 93 percent / H₂; Ni / ethyl acetate 4: 98 percent / methanol; Pd/C
	Multi-step reaction with 7 steps 1: 94 percent / PPh₃, DEAD 2: NaOMe / methanol 3: pyridine 4: 97 percent / LiN₃ 5: H₂S / pyridine 6: DIEA 7: H₂ / Pd/C

Reference： [1]Umashankara; Babu, I Ramesh; Ganesh, Krishna N [Chemical Communications, 2003, # 20, p. 2606 - 2607]
[2]Jordan, Stephan; Schwemler, Christoph; Kosch, Winfried; Kretschmer, Axel; Schwenner, Eckhardt; Stropp, Udo; Mielke, Burkhard [Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 6, p. 681 - 686]

17
[ 64187-48-0 ]
[ 663948-85-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: 99 percent / pyridine / cooling 2: 98.5 percent / NaN₃ / dimethylformamide / 8 h / 70 °C 3: H₂ / Raney Nickel / methanol; H₂O / 1.5 h / 2068.59 Torr 4: 3.17 g / Et₃N / dimethylsulfoxide / 8 h 5: 70 percent / LiBH₄ / tetrahydrofuran / 3.5 h 6: H₂ / Pd-C / methanol / 7 h / 3102.89 Torr
	Multi-step reaction with 6 steps 1: pyridine 2: sodium azide / dimethylformamide / 70 °C 3: hydrogen; Raney nickel / methanol 4: triethylamine / dimethylsulfoxide / 50 °C 5: LiBH₄ / tetrahydrofuran 6: hydrogen / Pd-C / methanol

Reference： [1]Meena; Kumar, Vaijayanti A. [Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 16, p. 3393 - 3399]
[2]Meena; Kumar; Ganesh [Nucleosides, nucleotides and nucleic acids, 2001, vol. 20, # 4-7, p. 1193 - 1196]

18
[ 64187-48-0 ]
[ 618-27-9 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,1995,vol. 59,p. 1161 - 1162
[2]Patent: JP5703654,2015,B2

19
[ 64187-48-0 ]
[ 13504-86-4 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,1995,vol. 59,p. 1161 - 1162
[2]Patent: JP5703654,2015,B2

20
[ 64187-48-0 ]
[ 74-88-4 ]
[ 96522-36-0 ]

Yield	Reaction Conditions	Operation in experiment
96%	With silver(l) oxide; In acetone; at 57℃; for 28h;	(ii) (2S, 4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester To 2.00 g (7.16 mmol) of (2S, 4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester in 20 mL of acetone was added 5.64 g of silver oxide (24.3 mmol) and 1.56 mL of iodomethane (25.0 mmol) and the mixture was stirred at 57 C. for 28 h. The solution was cooled to 25 C., filtered through celite and concentrated. Purification was through 50 mL of silica by eluding with EtOAc:Hexane (8:1) and the purified fractions were concentrated to give a 2.0 g (96%) of (2S,4R)-4-Methoxy-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester as a clear oil. HPLC: Rt 3.79 min. (100% area). 1H NMR (CDCl3, 400 MHz) delta: 7.31-7.23 (5H, m), 5.22-5.00 (2H, m), 4.44-4.40 (1H, m), 4.10-4.02 (1H, m), 3.76 (3H, s), 3.69-3.60 (1H, m), 3.54 (2H, s), 3.29 (3H, bs), 2.42-2.30 (1H, m). LCMS (ESI) (M+Na+) m/z: 316.1.
87%	With silver(l) oxide; In acetone; at 57℃; for 8h;	Comparative Preparation Example 4 (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxyacid 1-benzylester 2-methylester (1.6 g, 6.03 mmol) was dissolved in 16 ml of acetone and then silver oxide (4.7 g, 20.50 mol) and iodomethane (1.3 ml, 21.10 mmol) were added, followed by stirring at 57 C. for 8 hours. After removing silver oxide using cellite, the reaction mixture was washed with methanol and vacuum concentrated. Column chromatography (ethylacetate/n-hexane, 1/9) was performed to obtain (2S,4R)-4-methoxypyrrolidine-1,2-dicarboxyacid 1-benzylester 2-methylester (1.53 g, 87%) as oil. 1H-NMR (600 MHz, CDCl3); delta 7.31?7.23 (m, 5H), 5.22?5.00 (m, 2H), 4.44?4.40 (m, 1H), 4.10?4.02 (m, 1H), 3.76 (s, 3H), 3.69 (m, 1H), 3.54 (s, 2H), 3.29 (brs, 3H), 2.42?2.30 (m, 1H)

Reference： [1]Patent: US2004/19065,2004,A1 .Location in patent: Page/Page column 28-29
[2]European Journal of Organic Chemistry,2012,p. 837 - 843
[3]Patent: US2013/72482,2013,A1 .Location in patent: Paragraph 0706-0708

21
[ 13139-17-8 ]
[ 40216-83-9 ]
[ 64187-48-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In tetrahydrofuran; at 20℃;	L-trans-4-Hydroxyproline methyl ester hydrochloride (9.70 g, 54.0 mmol) was dissolved in dry THF (180 mL) and triethylamine (7.53 mL, 54.0 mmol). N-(Benzyloxycarbonyloxy)succinimide (13.5 g, 54.0 mmol) dissolved in THF (70 mL) was slowly added to the solution. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate and the organic layer was washed successively with water and brine. The organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on silica gel (30% to 70% ethyl acetate/hexane) to provide 12.8 g (85%) of desired product as a colorless oil. LC/MS (M+H)+ m/z=280.0; 1H NMR (CDCl3) delta 7.33 (m, 5H), 5.00-5.25 (m, 2H), 4.52 (m, 2H), 3.69 (m, 2H), 3.56 and 3.78 (s, 3H), 2.05-2.40 (m, 2H).
85%	With triethylamine; In tetrahydrofuran; at 20℃;	Step A1 -Benzyl 2-Methyl (2S,4f?)-4-hydroxypyrrolidine-1 ,2-dicarboxylate. L-trans-4- Hydroxyproline methyl ester hydrochloride (9.70 g, 54.0 mmol) was dissolved in dry THF (180 ml.) and triethylamine (7.53 ml_, 54.0 mmol). N-(Benzyloxycarbonyloxy)succinimide (13.5 g, 54.0 mmoles) dissolved in THF (70 ml.) was slowly added to the solution. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate and the organic layer was washed successively with water and brine. The organic extracts were dried over Na2S04, filtered, and concentrated. The residue was chromatographed on silica gel (30% to 70% ethyl acetate/hexane) to provide 12.8 g (85%) of desired product as a colorless oil. LC/MS (M+H)+ m/z = 280.0; 1H NMR (CDCI3) 57.33 (m, 5H), 5.00-5.25 (m, 2H), 4.52 (m, 2H), 3.69 (m, 2H), 3.56 and 3.78 (s, 3H), 2.05-2.40 (m, 2H).

Reference： [1]Patent: US2005/192302,2005,A1 .Location in patent: Page/Page column 46
[2]Patent: WO2012/114223,2012,A1 .Location in patent: Page/Page column 82-83

22
[ 923590-95-8 ]
[ 64187-48-0 ]
[ 530-62-1 ]
[ 1269195-05-2 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 7804 - 7815

23
[ 32968-78-8 ]
[ 64187-48-0 ]

Reference： [1]Patent: US2015/152048,2015,A1

24
[ 64187-48-0 ]
[ 1260251-31-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 19 steps 1.1: 1H-imidazole / dichloromethane 2.1: lithium borohydride / tetrahydrofuran 5.1: diisobutylaluminium hydride / dichloromethane 6.1: triethylamine / dichloromethane 7.1: sodium hydride / tetrahydrofuran 8.1: palladium diacetate; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; potassium carbonate 9.1: sodium hydroxide / methanol 10.1: tetrabutyl ammonium fluoride / tetrahydrofuran 11.1: triphenylphosphine; 4-nitro-benzoic acid; di-isopropyl azodicarboxylate / tetrahydrofuran 12.1: sodium hydroxide / tetrahydrofuran 13.1: 4-methyl-morpholine; dmap / tetrahydrofuran / 15 - 20 °C / Inert atmosphere; Large scale 14.1: trifluoroacetic acid / neat liquid / Inert atmosphere 14.2: Inert atmosphere 15.1: hydrogen bromide; acetic acid / dichloromethane / 48 h / 20 °C / Inert atmosphere; Large scale 16.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 16.2: 2 h / 0 - 20 °C / Inert atmosphere; Large scale 16.3: 40 h / 20 - 25 °C / Inert atmosphere; Large scale 17.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 17.2: 3 h / 0 - 20 °C / Inert atmosphere; Large scale 18.1: trifluoroacetic acid / dichloromethane / 16 h / 20 - 25 °C / Inert atmosphere; Large scale 19.1: sodium hydroxide / water; methanol / 4 h / 0 - 20 °C / Inert atmosphere; Large scale
	Multi-step reaction with 19 steps 1.1: 1H-imidazole / dichloromethane 2.1: lithium borohydride / tetrahydrofuran 5.1: diisobutylaluminium hydride / dichloromethane 6.1: triethylamine / dichloromethane 7.1: sodium hydride / tetrahydrofuran 8.1: palladium diacetate; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; potassium carbonate 9.1: sodium hydroxide / methanol 10.1: tetrabutyl ammonium fluoride / tetrahydrofuran 11.1: triphenylphosphine; 4-nitro-benzoic acid; di-isopropyl azodicarboxylate / tetrahydrofuran 12.1: sodium hydroxide / tetrahydrofuran 13.1: 4-methyl-morpholine; dmap / tetrahydrofuran / 15 - 20 °C / Inert atmosphere; Large scale 14.1: trifluoroacetic acid / neat liquid / Inert atmosphere 14.2: Inert atmosphere 15.1: hydrogen bromide; 5%-palladium/activated carbon / ethyl acetate; methanol / 6 h / 20 °C / 2585.81 Torr / Large scale 16.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 16.2: 2 h / 0 - 20 °C / Inert atmosphere; Large scale 16.3: 40 h / 20 - 25 °C / Inert atmosphere; Large scale 17.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 17.2: 3 h / 0 - 20 °C / Inert atmosphere; Large scale 18.1: trifluoroacetic acid / dichloromethane / 16 h / 20 - 25 °C / Inert atmosphere; Large scale 19.1: sodium hydroxide / water; methanol / 4 h / 0 - 20 °C / Inert atmosphere; Large scale
	Multi-step reaction with 20 steps 1.1: 1H-imidazole / dichloromethane 2.1: lithium borohydride / tetrahydrofuran 5.1: diisobutylaluminium hydride / dichloromethane 6.1: triethylamine / dichloromethane 7.1: sodium hydride / tetrahydrofuran 8.1: palladium diacetate; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; potassium carbonate 9.1: sodium hydroxide / methanol 10.1: tetrabutyl ammonium fluoride / tetrahydrofuran 11.1: triphenylphosphine; 4-nitro-benzoic acid; di-isopropyl azodicarboxylate / tetrahydrofuran 12.1: sodium hydroxide / tetrahydrofuran 13.1: 4-methyl-morpholine; dmap / tetrahydrofuran / 15 - 20 °C / Inert atmosphere; Large scale 14.1: trifluoroacetic acid / dichloromethane / 4 h / -10 - 5 °C / Inert atmosphere; Large scale 15.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / methanol / 2 h / 10 - 20 °C / Inert atmosphere; Large scale 16.1: hydrogen bromide; acetic acid / dichloromethane / 48 h / 20 °C / Inert atmosphere; Large scale 17.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 17.2: 2 h / 0 - 20 °C / Inert atmosphere; Large scale 17.3: 40 h / 20 - 25 °C / Inert atmosphere; Large scale 18.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 18.2: 3 h / 0 - 20 °C / Inert atmosphere; Large scale 19.1: trifluoroacetic acid / dichloromethane / 16 h / 20 - 25 °C / Inert atmosphere; Large scale 20.1: sodium hydroxide / water; methanol / 4 h / 0 - 20 °C / Inert atmosphere; Large scale

Multi-step reaction with 20 steps 1.1: 1H-imidazole / dichloromethane 2.1: lithium borohydride / tetrahydrofuran 5.1: diisobutylaluminium hydride / dichloromethane 6.1: triethylamine / dichloromethane 7.1: sodium hydride / tetrahydrofuran 8.1: palladium diacetate; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; potassium carbonate 9.1: sodium hydroxide / methanol 10.1: tetrabutyl ammonium fluoride / tetrahydrofuran 11.1: triphenylphosphine; 4-nitro-benzoic acid; di-isopropyl azodicarboxylate / tetrahydrofuran 12.1: sodium hydroxide / tetrahydrofuran 13.1: 4-methyl-morpholine; dmap / tetrahydrofuran / 15 - 20 °C / Inert atmosphere; Large scale 14.1: trifluoroacetic acid / dichloromethane / 4 h / -10 - 5 °C / Inert atmosphere; Large scale 15.1: 2,3-dicyano-5,6-dichloro-p-benzoquinone / methanol / 2 h / 10 - 20 °C / Inert atmosphere; Large scale 16.1: hydrogen bromide; 5%-palladium/activated carbon / ethyl acetate; methanol / 6 h / 20 °C / 2585.81 Torr / Large scale 17.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 17.2: 2 h / 0 - 20 °C / Inert atmosphere; Large scale 17.3: 40 h / 20 - 25 °C / Inert atmosphere; Large scale 18.1: 4-methyl-morpholine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / 1-methyl-pyrrolidin-2-one / 0 - 5 °C / Inert atmosphere; Large scale 18.2: 3 h / 0 - 20 °C / Inert atmosphere; Large scale 19.1: trifluoroacetic acid / dichloromethane / 16 h / 20 - 25 °C / Inert atmosphere; Large scale 20.1: sodium hydroxide / water; methanol / 4 h / 0 - 20 °C / Inert atmosphere; Large scale

Reference： [1]Deng, Yijun; Xie, Qiuzhe; LaPorte, Matthew G.; Chasnoff, Anna T. A.; Mortensen, Mark A.; Patra, Debasis; Putrelo, Seth A.; Antonovich, Robert S.; Cao, Hong; Yan, Jun; Cooper, Arthur J.; Rippin, Susan R.; Alexander, Matthew D.; Kumar, Pavan Tirunahari; Hendi, Mukta S.; Lee, Yu-Hua; Haimowitz, Thomas; Condon, Stephen M. [Organic Process Research and Development, 2016, vol. 20, # 2, p. 242 - 252]
[2]Deng, Yijun; Xie, Qiuzhe; LaPorte, Matthew G.; Chasnoff, Anna T. A.; Mortensen, Mark A.; Patra, Debasis; Putrelo, Seth A.; Antonovich, Robert S.; Cao, Hong; Yan, Jun; Cooper, Arthur J.; Rippin, Susan R.; Alexander, Matthew D.; Kumar, Pavan Tirunahari; Hendi, Mukta S.; Lee, Yu-Hua; Haimowitz, Thomas; Condon, Stephen M. [Organic Process Research and Development, 2016, vol. 20, # 2, p. 242 - 252]
[3]Deng, Yijun; Xie, Qiuzhe; LaPorte, Matthew G.; Chasnoff, Anna T. A.; Mortensen, Mark A.; Patra, Debasis; Putrelo, Seth A.; Antonovich, Robert S.; Cao, Hong; Yan, Jun; Cooper, Arthur J.; Rippin, Susan R.; Alexander, Matthew D.; Kumar, Pavan Tirunahari; Hendi, Mukta S.; Lee, Yu-Hua; Haimowitz, Thomas; Condon, Stephen M. [Organic Process Research and Development, 2016, vol. 20, # 2, p. 242 - 252]
[4]Deng, Yijun; Xie, Qiuzhe; LaPorte, Matthew G.; Chasnoff, Anna T. A.; Mortensen, Mark A.; Patra, Debasis; Putrelo, Seth A.; Antonovich, Robert S.; Cao, Hong; Yan, Jun; Cooper, Arthur J.; Rippin, Susan R.; Alexander, Matthew D.; Kumar, Pavan Tirunahari; Hendi, Mukta S.; Lee, Yu-Hua; Haimowitz, Thomas; Condon, Stephen M. [Organic Process Research and Development, 2016, vol. 20, # 2, p. 242 - 252]

25
[ 64187-48-0 ]
[ 58479-61-1 ]
C₃₀H₃₅NO₅Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 16h;	Compound (2S, 4R) -N-Cbz-2-carboxylic acid ethyl ester-4-hydroxypyrrolidine (20.0 g, 71.6 mmol)Dissolved in 70mL N, N-dimethylformamide,Add imidazole (10.7 g, 158 mmol) and TBDPSCl (23.6 g, 85.9 mmol) at room temperature and stir for 16 hours.The reaction solution was poured into water (700 mL), extracted with ethyl acetate (3 × 60 mL), and the organic phases were combined.It was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtainCompound (2S, 4R) -N-Cbz-2-carboxylic acid ethyl ester 4-O-TBDPS pyrrolidine (34.3 g, yield 92%).

Reference： [1]Patent: CN110483514,2019,A .Location in patent: Paragraph 0593-0599
[2]Chemistry and biodiversity,2017,vol. 14

26
[ 1207294-92-5 ]
[ 64187-48-0 ]
C₃₅H₄₂N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In 2-methoxy-2-methylpropane at 23℃; for 0.25h; Inert atmosphere;

Reference： [1]Macmillan, David W. C.; Sakai, Holt A. [Journal of the American Chemical Society, 2022, vol. 144, # 14, p. 6185 - 6192]

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[ 64187-48-0 ] Synthesis Path-Upstream 1~7

[ 64187-48-0 ] Synthesis Path-Downstream 1~26

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