[ CAS No. 187039-57-2 ] {[proInfo.proName]}

Name: 187039-57-2|(2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid|95%
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Quality Control of [ 187039-57-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 187039-57-2 ]

CAS No. :	187039-57-2	MDL No. :	MFCD04974546
Formula :	C₁₀H₁₇NO₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JLDHXHPQMBNKMC-BQBZGAKWSA-N
M.W :	231.25	Pubchem ID :	14037017
Synonyms :

Calculated chemistry of [ 187039-57-2 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.8
Num. rotatable bonds :	4
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	59.53
TPSA :	87.07 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) :	-7.14 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.51
Log Po/w (XLOGP3) :	0.81
Log Po/w (WLOGP) :	0.06
Log Po/w (MLOGP) :	-0.07
Log Po/w (SILICOS-IT) :	-0.64
Consensus Log Po/w :	0.33

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.52
Solubility :	6.98 mg/ml ; 0.0302 mol/l
Class :	Very soluble
Log S (Ali) :	-2.22
Solubility :	1.39 mg/ml ; 0.00602 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	0.43
Solubility :	621.0 mg/ml ; 2.69 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	3.09

Safety of [ 187039-57-2 ]

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 [ 187039-57-2 ]

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

Upstream synthesis route of [ 187039-57-2 ]
Downstream synthetic route of [ 187039-57-2 ]

[ 187039-57-2 ] Synthesis Path-Upstream 1~11

1
[ 187039-57-2 ]
[ 130966-46-0 ]

Reference： [1] Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484

2
[ 184046-78-4 ]
[ 187039-57-2 ]

Yield	Reaction Conditions	Operation in experiment
88%	With lithium hydroxide In tetrahydrofuran; water at 20℃; for 3 h;	To a solution of 1-Qert-butyl) 2-methyl (2S, 35)-3-hydroxypyrrolidine-1,2-dicarboxylate (0.30 g,1.22 mmol) in tetrahydrofuran (12 mL) was added 0.2N aqueous lithium hydroxide (6.12 mL, 1.22 mmol). The reaction was stirred at ambient temperature for 3 hours. The reaction mixture was diluted with diethyl ether (30 mL) and extracted with 0.2N aqueous lithium hydroxide (3 x 5 mL). The combined aqueous layers were acidified with 5percent aqueous hydrochloric acid until pH=2. The acia?L7F,er was extracted with ethyl acetate (3 x 30 mL). The orT over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a gum (0.25 g, 88percent) which was used in the next step without any further purification: MS (ES+) m/z 230.3 (M+1).

Reference： [1] Patent: WO2016/7534, 2016, A1, . Location in patent: Page/Page column 171; 172

3
[ 24424-99-5 ]
[ 567-36-2 ]
[ 187039-57-2 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With sodium hydroxide In water at 20℃; for 2 h; Stage #2: With hydrogenchloride In water at 0 - 10℃;	Example 24A (2S, 3S)-3-Hydroxy-pyrrolidine-1,2-dicarboxylic Acid 1-tert-butyl Ester 3-Hydroxy-pyrrolidine-2-carboxylic acid (Aldrich, 1.31 g, 10 mmol) was treated with di-tert-butyl dicarbanate (Aldrich, 2.18 g, 10 mmol) and NaOH (5percent, 20 mL, 25 mmol) at room temperature for 2 hours. The mixture was acidified with 5percent HCl solution at 0-10° C. to bring to pH=4. The mixture was extracted with EtOAc (350 mL). The extracts were combined and washed with brine (210 mL). The organic solution was concentrated under vacuum to give the title compound as white solid (2.0 g, 8.6 mmol, 86percent yield). ¹H NMR (300 MHz, CH₃OH-d₄) δ 1.40-1.49 (m, 9H), 1.82-1.93 (m, 1H), 1.97-2.12 (m, 1H), 3.46-3.60 (m, 2H), 4.07-4.18 (m, 1H), 4.38 (dd, J=4.2, 1.9 Hz, 1H); MS (DCl/NH₃) m/z 232 (M+H)⁺.

Reference： [1] Patent: US2005/101602, 2005, A1, . Location in patent: Page/Page column 35-36

4
[ 24424-99-5 ]
[ 4298-08-2 ]
[ 187039-57-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 0 - 20℃; Stage #2: With hydrogenchloride In dichloromethane; water	Method A: To a stirred solution of the carboxylic acid (20.3 mmol) in tetrahydrofuran (75 ml) was added di-tert-butyl dicarbonate (2.5 equivalents (eq.), 50.8 mmol) followed by the addition of sodium bicarbonate (6 eq., 122 mmol) in water (75 ml). The carboxylic acids are commercially available from vendors like Aldrich, Acros, Anaspec, CNH technologies, etc. The addition is typically carried out at low temperatures, e.g. 0° C., after which the reaction was brought to rt and let to stir for 16 h. The reaction was concentrated to remove all solvent, diluted with excess water and extracted with ether. The aqueous layer was acidified with 6N HCl and extracted with DCM (2.x.) and once with n-butanol. All organic extracts were combined, concentrated, and co-evaporated with toluene. The residue was then dried under high vacuum to give the desired Boc-protected carboxylic acid.Step 1: (2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid was prepared from (2S,3S)-3-Hydroxypyrrolidine-2-carboxylic acid following Method A (yield=91percent). The resulting product was used without purification. 1H NMR (DMSO-d6): 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.10 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H). HPLC: Rt=3.868 min following Method R. ES-MS: calcd. for C₁₀H₁₇NO₅ (231.25); found: 230.2 [M-H].
90%	With sodium hydrogencarbonate In 1,4-dioxane; water at 20℃;	Trans-3-hydroxy-L-proline (2.62 g, 20.0 mmol) and sodium bicarbonate (5.04 <n="132"/>g, 60 mmol) were dissolved in water (20 ml). Dioxane was added (20 ml) followed by di- tert-butyl-dicarbonate (8.72 g, 40 mmol). Stirring was continued at room temperature overnight. The reaction was concentrated, and the residue was partitioned between ethyl ether (10 ml) and water (30 ml). The aqueous layer was washed once more with ether, and the organic layers were discarded. Gradual acidification of the aqueous phase with concentrated HCl caused the oily product to precipitate and this was extracted into ethyl acetate by repeated washings (3x10 ml) of the aqueous layer. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated to provide the title compound as a viscous oil (4.17 g, 90percent).
90%	With N-ethyl-N,N-diisopropylamine In methanol at 20℃; for 2 h;	Preparation 8; (2S,3S)- 1 -(tert-butoxycarbonyl)-3 -hydroxypyrrolidine-2-carboxylic acid; A suspension of .pound.rαroe-3-hydroxy-L-proline (5 g, 37.56 mmol) in methanol (100 mL) is treated with diisopropylethylamine (6.55 mL, 37.56 mmol) and subsequently di-t- butyldicarbonate (8.87 g, 39.44 mmol) at room temperature. The resulting suspension is stirred for 2 h at room temperature while becoming a homogeneous solution. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate (120 mL). The organic solution is washed with 1 N aqueous hydrogen chloride. The aqueous layer is discarded and the organic layer is washed with brine, dried over sodium sulfate, concentrated, and dried under vacuum to give 8.0 g (90percent) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ 12.60 (s, br, IH), 5.40 (s, br, IH), 4.20-4.12 (m, IH), 3.87 (d, J = 6.4 Hz, IH), 3.25-3.42 (m, 2H), 1.90-1.75 (s, br, IH), 1.74-1.65 (s, br, IH), 1.30 (d, J = 7.1 Hz, 9H).

85%	With sodium carbonate In 1,4-dioxane; water at 20℃; for 1.5 h;	Boc anhydride (2.95 g, 13.5 mmol) was added to a stirred solution of the (2S, 3S)-3-HYDROXYPYRROLIDINE-2-CARBOXYLIC acid (1.61 g, 12.3 mmol) and sodium carbonate (1.3 g, 12.3 mmol) in a mixture of dioxane (25 ml) and water (12.3 ml). The mixture was stirred for 1.5 h at ambient temperature then evaporated under reduced pressure to afford a residue (-10 ml). The residue was diluted with water (30 ML) then extracted with ethyl acetate (40 ml). The aqueous phase was acidified (PH-2. 5) with dilute aqueous hydrochloric acid (0.1 M) then extracted with chloroform (4 x 50 ml). The combined organic layers were dried (NA2SO4) and evaporated under reduced pressure to afford (2S, 3S)-3-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-TERT-BUTYL ester as a white crystalline solid (2.39 G,-85percent), HPLC- MS (single main peak, 254.1 [M + Na] + and 485.2 [M + H] +).
70%	With sodium hydroxide In tetrahydrofuran; water	EXAMPLE 18A (2S,3 S)-1-(tert-butoxycarbonyl)-3-hydroxy-2-pyrrolidinecarboxylic acid trans-3-Hydroxy (L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in water (34 mL) at ambient temperature. After 10 minutes of stirring, the mixture was treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure, acidified to pH 2-3 with saturated KHSO₄ (aq), and extracted with ethyl acetate (2200 mL). The organic extracts were combined, washed with brine (230 mL), and concentrated to provide the title compound as a white solid (12.3 g, 70percent, yield). mp 156-157° C.
70%	Stage #1: With sodium hydroxide In tetrahydrofuran; water Stage #2: at 20℃; for 10 h; Stage #3: With CHO₄^(1-)*K⁽¹⁺⁾ In water	trans-3-Hydroxy-(L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in H2O (34 mL) and then treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure to remove the THF. The residue was acidified to pH 2-3 with saturated KHSO4 and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with brine (2 x 30 mL) and concentrated to provide the title compound as a white solid (12.3 g, 70percent). mp 156-157 °C.
0.91 g	With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃;	To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol) in CH2Cl2 (19 mL) at roomtemperature was added di-tert-butyl dicarbonate (0.96 mL, 4.2 mmol) and Hunig’s base (1.32 mL, 7.6 mmol) to give atan solution. The reaction was stirred overnight at room temperature and then diluted with CH2Cl2 and washed withsaturated sodium bicarbonate solution. The aqueous layer was concentrated under reduced pressure and then suspendedin methanol and filtered. The solvent was then removed under reduced pressure to prodive the title compound(0.91g, 103percent yield).

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 21, p. 6254 - 6263
[2] Tetrahedron Letters, 2009, vol. 50, # 52, p. 7280 - 7282
[3] Tetrahedron Letters, 1997, vol. 38, # 2, p. 167 - 168
[4] Patent: US2010/22605, 2010, A1, . Location in patent: Page/Page column 16; 33; 36
[5] Patent: WO2008/24725, 2008, A1, . Location in patent: Page/Page column 130-131
[6] Patent: WO2009/140448, 2009, A1, . Location in patent: Page/Page column 32
[7] Patent: WO2004/7501, 2004, A1, . Location in patent: Page 504-505
[8] Journal of the American Chemical Society, 2005, vol. 127, # 45, p. 15923 - 15932
[9] Patent: US2002/19388, 2002, A1,
[10] Patent: EP1428824, 2004, A1, . Location in patent: Page 50
[11] Tetrahedron Letters, 2001, vol. 42, # 4, p. 651 - 653
[12] Patent: US2005/209217, 2005, A1, . Location in patent: Page/Page column 27
[13] European Journal of Organic Chemistry, 2009, # 20, p. 3368 - 3386
[14] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 23, p. 5478 - 5483
[15] Patent: EP2419404, 2015, B1, . Location in patent: Paragraph 0504
[16] Patent: WO2016/25669, 2016, A1, . Location in patent: Page/Page column 72
[17] Patent: WO2017/63757, 2017, A1, . Location in patent: Page/Page column 45

5
[ 24424-99-5 ]
[ 14916-76-8 ]
[ 187039-57-2 ]

Yield	Reaction Conditions	Operation in experiment
97.3%	With sodium hydroxide In 1,4-dioxane	30A. (2S,3S)-3-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester A solution of trans-3-hydroxy-L-proline (9.0 g, 69.2 mmol) in dioxane (94 ml) and water (46 ml) was cooled to 0° C., treated with sodium hydroxide (1.77 g, 44.3 mmol) followed by di-tert-butyl dicarbonate (16.74 g, 7.67 mmol). The mixture was stirred at 0° C. for 5 min, at RT for 6 h then quenched with 2.0 N hydrochloric acid (40 ml, 80 mmol) and extracted with EtOAc (3*350 ml). The combined organic extracts were washed with brine (45 ml) and dried to provide the title compound as a white solid (15.6 g, 97.3percent). MS (ES): m/z 254 [M+Na]⁺.

Reference： [1] Patent: US2003/55094, 2003, A1,

6
[ 58632-95-4 ]
[ 4298-08-2 ]
[ 187039-57-2 ]

Reference： [1] Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484
[2] Patent: US6900238, 2005, B1, . Location in patent: Page/Page column 51

7
[ 34619-03-9 ]
[ 4298-08-2 ]
[ 187039-57-2 ]

Reference： [1] European Journal of Organic Chemistry, 2014, vol. 2014, # 24, p. 5351 - 5355

8
[ 24424-99-5 ]
[ 4298-08-2 ]
[ 7087-68-5 ]
[ 187039-57-2 ]

Reference： [1] Patent: US2010/267634, 2010, A1,

9
[ 187039-57-2 ]
[ 74-88-4 ]
[ 184046-78-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 90℃; for 2 h;	A solution containing 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (37, 16 g, 71 mmol)¹in DMF (100 mL) was cooled to 0° C. To this solution was added K₂CO₃(16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90° C. for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford 14.8 g (87percent) of 38 as a yellow oil.²
87%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 90℃; for 2 h;	A solution containing ester (19, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Sυc. 2005, 45, 15923) in DMF (100 rriL) was cooled to 0 ⁰C. To this solution was added K₂CO₃ (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 °C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂SOa, filtered, and concentrated to afford 14.8 g (87percent) of 20 as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
87%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 90℃; for 2 h;	A solution containing 3-hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester (1, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 ⁰C. To this solution was added K₂CO₃ (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 ⁰C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford 14.8 g (87percent) of S-hydroxypyrrolidine-l^-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).

87%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 90℃; for 2 h;	Scheme I3-Hydroxy-pyrrolidine-l ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2): A solution containing 3-hydroxy-pyrrolidine-l ,2-dicarboxylic acid \\ -tert- butyl ester (1, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 °C. To this solution was added K₂C0₃ (16 g, 1 16 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 °C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂S0₄, filtered, and concentrated to afford 14.8 g (87percent) of 3- hydroxypyrrolidine-l,2-dicarboxylic acid \\-tert-buty\\ ester 2-methyl ester (2) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
87%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 90℃; for 2 h;	A solution containing 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid l-tert-buty\\ ester (16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 °C. To this solution was added K₂CO₃ (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 °C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford 14.8 g (87percent) of 3- hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
87%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃;	3-Hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (61): A solution containing S-hydroxy-pyrrolidine-l^-dicarboxylic acid 1-fert-butyl ester (60, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 ⁰C. To this solution was added K₂CO₃ (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 ⁰C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na₂SO₄, filtered, and concentrated to afford 14.8 g (87percent) of S-hydroxypyrrolidine-l^-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (61) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
82%	With sodium hydrogencarbonate In N,N-dimethyl-formamide at 50℃;	The (2S,3S)-l-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid(4.2 g, 18.2 mmol) and NaHCO₃ (3.1 g, 36.3 mmol) were suspended in DMF (20 ml). Methyl iodide (5.7 ml, 12.9 g, 91.0 mmol) was added to the mixture, which was then heated at 50⁰C overnight. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted once more with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO₄) and concentrated. The residue was purified by silica flash chromatography (gradient elution, using 1 : 1 hexane-ethyl ether to ethyl ether) to provide the title compound as a colorless oil (3.7 g, 82percent).

Reference： [1] Patent: US2008/20986, 2008, A1, . Location in patent: Page/Page column 16
[2] Patent: WO2009/94287, 2009, A1, . Location in patent: Page/Page column 31
[3] Patent: WO2010/138496, 2010, A1, . Location in patent: Page/Page column 38-39
[4] Patent: WO2011/68926, 2011, A1, . Location in patent: Page/Page column 39-40
[5] Patent: WO2010/33531, 2010, A1, . Location in patent: Page/Page column 66
[6] Patent: WO2010/138666, 2010, A1, . Location in patent: Page/Page column 99-100
[7] Patent: WO2008/24725, 2008, A1, . Location in patent: Page/Page column 131
[8] Journal of Organic Chemistry, 2009, vol. 74, # 10, p. 3735 - 3743
[9] Patent: US2015/152068, 2015, A1, . Location in patent: Paragraph 0369; 0370; 0371
[10] Patent: WO2015/79417, 2015, A1, . Location in patent: Page/Page column 77; 78
[11] Patent: WO2016/164580, 2016, A1, . Location in patent: Page/Page column 280; 281

10
[ 186581-53-3 ]
[ 187039-57-2 ]
[ 184046-78-4 ]

Reference： [1] Organic Letters, 2001, vol. 3, # 16, p. 2481 - 2484
[2] Journal of the American Chemical Society, 2005, vol. 127, # 45, p. 15923 - 15932

11
[ 187039-57-2 ]
[ 18107-18-1 ]
[ 184046-78-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	at 0℃; for 2 h;	Method B: The Boc-protected acid (7.35 mmol, 1 eq.) was taken into THF-MeOH (1:1) and the reaction cooled to 0° C. 2M TMSCHN₂in ether (7.35 ml, 2 eq.) was added with stirring in one portion, and the reaction stirred at 0° C. for 2 h. The reaction was monitored by thin layer chromatography (TLC) (eluent: 4:1 hexanes-ethyl acetate). Solvent was removed under vacuum. The residue was purified by SiO₂column chromatography (gradient 20percent-40percent ethyl acetate in hexanes) to provide the desired methyl ester.Step 2: (2S,3S)-1-tert-Butyl 2-methyl 3-hydroxypyrrolidine-1,2-dicarboxylate was prepared from (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid following Method B (quantitative yield). 1H NMR (CDCl₃): 4.44-4.42 (m, 2H), 4.3-4.2 (d, 1H), 3.75 (s, 3H), 3.68-3.56 (m, 2H), 2.18-2.08 (m, 1H), 1.94-1.75 (m, 1H), 1.47-1.41 (d, 9H). HPLC: Rt=4.45 min following Method R, ES-MS: calcd. for C₁₁H₁₉N₂O₆ (245.13); found 268.3 [M+Na].

Reference： [1] Patent: US2010/22605, 2010, A1, . Location in patent: Page/Page column 16; 33; 36

[ 187039-57-2 ] Synthesis Path-Downstream 1~56

1
[ 2687-43-6 ]
[ 187039-57-2 ]
[ 187039-58-3 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 167 - 168

2
[ 24424-99-5 ]
[ 4298-08-2 ]
[ 187039-57-2 ]

Yield	Reaction Conditions	Operation in experiment
91%		Method A: To a stirred solution of the carboxylic acid (20.3 mmol) in tetrahydrofuran (75 ml) was added di-tert-butyl dicarbonate (2.5 equivalents (eq.), 50.8 mmol) followed by the addition of sodium bicarbonate (6 eq., 122 mmol) in water (75 ml). The carboxylic acids are commercially available from vendors like Aldrich, Acros, Anaspec, CNH technologies, etc. The addition is typically carried out at low temperatures, e.g. 0 C., after which the reaction was brought to rt and let to stir for 16 h. The reaction was concentrated to remove all solvent, diluted with excess water and extracted with ether. The aqueous layer was acidified with 6N HCl and extracted with DCM (2×) and once with n-butanol. All organic extracts were combined, concentrated, and co-evaporated with toluene. The residue was then dried under high vacuum to give the desired Boc-protected carboxylic acid.Step 1: (2S,3S)-1-(tert-Butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid was prepared from (2S,3S)-3-Hydroxypyrrolidine-2-carboxylic acid following Method A (yield=91%). The resulting product was used without purification. 1H NMR (DMSO-d6): 5.64-5.63 (d, 1H), 4.42 (bs, 1H), 4.13-4.10 (d, 1H), 3.64-3.48 (m, 2H), 2.11-1.99 (m, 2H), 1.58-1.52 (d, 9H). HPLC: Rt=3.868 min following Method R. ES-MS: calcd. for C10H17NO5 (231.25); found: 230.2 [M-H].
90%	With sodium hydrogencarbonate; In 1,4-dioxane; water; at 20℃;	Trans-3-hydroxy-L-proline (2.62 g, 20.0 mmol) and sodium bicarbonate (5.04 <n="132"/>g, 60 mmol) were dissolved in water (20 ml). Dioxane was added (20 ml) followed by di- tert-butyl-dicarbonate (8.72 g, 40 mmol). Stirring was continued at room temperature overnight. The reaction was concentrated, and the residue was partitioned between ethyl ether (10 ml) and water (30 ml). The aqueous layer was washed once more with ether, and the organic layers were discarded. Gradual acidification of the aqueous phase with concentrated HCl caused the oily product to precipitate and this was extracted into ethyl acetate by repeated washings (3x10 ml) of the aqueous layer. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to provide the title compound as a viscous oil (4.17 g, 90%).
90%	With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃; for 2h;	Preparation 8; (2S,3S)- 1 -(tert-butoxycarbonyl)-3 -hydroxypyrrolidine-2-carboxylic acid; A suspension of £ralphar°-3-hydroxy-L-proline (5 g, 37.56 mmol) in methanol (100 mL) is treated with diisopropylethylamine (6.55 mL, 37.56 mmol) and subsequently di-t- butyldicarbonate (8.87 g, 39.44 mmol) at room temperature. The resulting suspension is stirred for 2 h at room temperature while becoming a homogeneous solution. The solvent is removed in vacuo and the residue is dissolved in ethyl acetate (120 mL). The organic solution is washed with 1 N aqueous hydrogen chloride. The aqueous layer is discarded and the organic layer is washed with brine, dried over sodium sulfate, concentrated, and dried under vacuum to give 8.0 g (90%) of the title compound. 1H NMR (300 MHz, CDCl3) delta 12.60 (s, br, IH), 5.40 (s, br, IH), 4.20-4.12 (m, IH), 3.87 (d, J = 6.4 Hz, IH), 3.25-3.42 (m, 2H), 1.90-1.75 (s, br, IH), 1.74-1.65 (s, br, IH), 1.30 (d, J = 7.1 Hz, 9H).

~ 85%	With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 1.5h;	Boc anhydride (2.95 g, 13.5 mmol) was added to a stirred solution of the (2S, 3S)-3-HYDROXYPYRROLIDINE-2-CARBOXYLIC acid (1.61 g, 12.3 mmol) and sodium carbonate (1.3 g, 12.3 mmol) in a mixture of dioxane (25 ml) and water (12.3 ml). The mixture was stirred for 1.5 h at ambient temperature then evaporated under reduced pressure to afford a residue (-10 ml). The residue was diluted with water (30 ML) then extracted with ethyl acetate (40 ml). The aqueous phase was acidified (PH-2. 5) with dilute aqueous hydrochloric acid (0.1 M) then extracted with chloroform (4 x 50 ml). The combined organic layers were dried (NA2SO4) and evaporated under reduced pressure to afford (2S, 3S)-3-hydroxypyrrolidine-1, 2-dicarboxylic acid 1-TERT-BUTYL ester as a white crystalline solid (2.39 G,-85%), HPLC- MS (single main peak, 254.1 [M + Na] + and 485.2 [M + H] +).
70%	With sodium hydroxide; In tetrahydrofuran; water;	EXAMPLE 18A (2S,3 S)-1-(tert-butoxycarbonyl)-3-hydroxy-2-pyrrolidinecarboxylic acid trans-3-Hydroxy (L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in water (34 mL) at ambient temperature. After 10 minutes of stirring, the mixture was treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure, acidified to pH 2-3 with saturated KHSO4 (aq), and extracted with ethyl acetate (2200 mL). The organic extracts were combined, washed with brine (230 mL), and concentrated to provide the title compound as a white solid (12.3 g, 70%, yield). mp 156-157 C.
70%		trans-3-Hydroxy-(L)-proline (10.0 g, 76.3 mmol) in THF (50 mL) was treated with sodium hydroxide (3.36 g, 84 mmol) in H2O (34 mL) and then treated with di-tert-butyl dicarbonate (16.63 g, 76.3 mmol) portionwise. After stirring at ambient temperature for 10 hours, the mixture was concentrated under reduced pressure to remove the THF. The residue was acidified to pH 2-3 with saturated KHSO4 and extracted with ethyl acetate (2 x 200 mL). The organic extracts were combined, washed with brine (2 x 30 mL) and concentrated to provide the title compound as a white solid (12.3 g, 70%). mp 156-157 C.
	With sodium hydroxide; In 1,4-dioxane; water; at 5 - 20℃; for 16.5h;	A mixture of trans-3-hydroxy-L-proline (5 g), di-tert-butyl dicarbonate (9.15 g), sodium hydroxide (1.52 g), water (78 ml) and dioxan (80 ml) was stirred at 5 C. for 30 mins. and then at ambient temperature for 16 hours. The mixture was evaporated to a smaller volume (30 ml) and diluted with water (150 ml). The pH was adjusted to 2-3 with aqueous sodium bisulphate and saturated with sodium chloride. It was then extracted with ethyl acetate (3*100 ml), the extracts dried and the solution evaporated to dryness to give (2S,3S)-1-(tert-butoxycarbonyl)-2-carboxy-3-hydroxypyrrolidine (compound 64) as a white solid (8.42 g). Compound 64: NMR (DMSOd6) delta: 1.27 (2s, 9H), 1.64-1.76 (m, 2H), 3.24-3.45 (m, 2H), 3.92 (d, 1H), 4.20 (br, 1H), 5.40 (br, 1H), 12.6 (br, 1H).
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 0 - 20℃; for 16h;	To a cold (0 C) mixture of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid 26a (6.37g, 48.6 mmol) in tetrahydrofuran (180 mL) is added di-tert-butyl dicarbonate (26.4 g, 0.121 mmol) followed by addition of solution of NaHCO3 (24.5 g, 0.292 mmol) in water (180 mL). The cooling bath is removed and the mixture is stirred 16 hours at room temperature. The solvent is evaporated in vacuo, the residue is diluted with water and extracted with ether. The ethereal layer is discarded. The aqueous layer is cooled to 0 C, acidified to pH 1 with 6 N hydrochloric acid, extracted with dichloromethane (3x) and n-butanol (2x). The combined organic phase is concentrated in vacuo. The oily residue is co-evaporated twice with toluene anddried on a high vacuum pump to give (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid B16b: ESI-MS calcd. for C10H17NNaO5 ([M+Na]+) 254.1, found 254.1. The product is used without further purification.
0.91 g	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;	To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol) in CH2Cl2 (19 mL) at roomtemperature was added di-tert-butyl dicarbonate (0.96 mL, 4.2 mmol) and Hunig?s base (1.32 mL, 7.6 mmol) to give atan solution. The reaction was stirred overnight at room temperature and then diluted with CH2Cl2 and washed withsaturated sodium bicarbonate solution. The aqueous layer was concentrated under reduced pressure and then suspendedin methanol and filtered. The solvent was then removed under reduced pressure to prodive the title compound(0.91g, 103% yield).
	With water; sodium hydroxide; In 1,4-dioxane; at 20℃; for 2h;	Step 1 : (2S,3S)-l-(tert-Butoxycarbonyl)-3-hvdroxypyrrolidine-2-carboxylic acid.To a solution of (2S,3S)-3-hydroxypyrrolidine-2-carboxylic acid (3.0 g, 23 mmol) in dioxane/H20 (40 mL/20 mL) was added sodium hydroxide (1.83 g, 46 mmol), followed by the dropwise addition of di-tert-butyl dicarbonate (9.49 g, 43 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature (rt) for 2 h. The reaction mixture was extracted with EtOAc (50 mL) and the organic layer was washed with 10% aq. NaOH (30 mL). The combined aqueous layers were acidified with cone. HC1 to pH 2 and extracted with CH2C12. The organic phases were dried (Na2S04) and concentrated to give the crude product, which was used without further purification (5.01 g, 95%). 1H NMR (CD3OD, 400 MHz) delta 4.40- 4.30 (m, 1H), 4.15-4.00 (m, 1H), 3.50-3.40 (m, 2H), 2.00-1.95 (m, 1H), 1.85 (m, 1H), 1.45- 1.35 (m, 9H).
	With sodium hydrogencarbonate; In 1,4-dioxane; water;	(2S,3S)-1-(Tert.-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (15) was prepared by Boc protection of the secondary amino group of 13 by di-tert. -butyl dicarbonate in dioxane in the presence of aq. Na2CC>3 soln applying standard conditions. Data of 15: Ci0Hi7NO5 (231 .2). FI-MS: 230.1 ([M-H]-). 1H-NMR (DMSO-d6): 5.43 (br. s, 1 H); 4.23 (br. m, 1 H); 3.92 (d, J = 12.4, 1 H); 3.46 - 3.29 (m, 2 H); 1 .85 (m, 1 H); 1 .72 (m, 1 H); 1 .40, 1.34 (2 s, 9 H).
		To a stirred solution of (2 S, 3S)-3-hydroxypyrrolidine-2-carboxylic acid (3.00 g, 22.88 mmol) in THF (150 mL) was added water (150 ml_) and NaHCCb (7.70 g, 92 mmol) at 0 C. The reaction mixture was stirred at room temperature for 15 minutes. After B0C2O (7.50 g, 34.4 mmol) was added, the reaction mixture was stirred at 25 C for 16 h. The resulting mixture was added sat'd aqueous NaHCC>3 (50 mL) and washed with ethyl ether (2 x 100 mL). The separated organic phases were deserted. The pH value of the aqueous phase was adjusted to 3 with aqueous HCI (1 M). The aqueous solution was extracted with EA (6 x 200 mL). The organic layers were combined and concentrated under reduced pressure to afford 5.00 g (90% yield) of 123 as an off-white solid. LCMS (ESI) calc?d for C10H17NO5 [M + Na]+: 254.1 , found 253.9. 1H NMR (300 MHz, CDsOD) d 4.47-4.33 (m, 1 H), 4.19-4.08 (m, 1 H), 3.69-3.44 (m, 2H), 2.16-1.97 (m, 1 H), 1.94-1.81 (m, 1 H), 1.45 (d, J = 13.3 Hz, 9H).

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263
[2]Tetrahedron Letters,2009,vol. 50,p. 7280 - 7282
[3]Tetrahedron Letters,1997,vol. 38,p. 167 - 168
[4]Patent: US2010/22605,2010,A1 .Location in patent: Page/Page column 16; 33; 36
[5]Patent: WO2008/24725,2008,A1 .Location in patent: Page/Page column 130-131
[6]Patent: WO2009/140448,2009,A1 .Location in patent: Page/Page column 32
[7]Patent: WO2004/7501,2004,A1 .Location in patent: Page 504-505
[8]Journal of the American Chemical Society,2005,vol. 127,p. 15923 - 15932
[9]Patent: US2002/19388,2002,A1
[10]Patent: EP1428824,2004,A1 .Location in patent: Page 50
[11]Tetrahedron Letters,2001,vol. 42,p. 651 - 653
[12]Patent: US2005/209217,2005,A1 .Location in patent: Page/Page column 27
[13]European Journal of Organic Chemistry,2009,p. 3368 - 3386
[14]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 5478 - 5483
[15]Patent: EP2419404,2015,B1 .Location in patent: Paragraph 0504
[16]Patent: WO2016/25669,2016,A1 .Location in patent: Page/Page column 72
[17]Patent: WO2017/63757,2017,A1 .Location in patent: Page/Page column 45
[18]Patent: WO2019/246352,2019,A1 .Location in patent: Page/Page column 72; 74-75

3
[ 100-39-0 ]
[ 187039-57-2 ]
[ 330945-07-8 ]

Yield	Reaction Conditions	Operation in experiment
100%		To a solution of 200 mg (0.87 mmol) of <strong>[187039-57-2](3S)-1-(tert-butoxycarbonyl)-3-hydroxy-L-proline</strong> in 6.5 ml of methanol and 1.3 ml of water were added 141 mg (0.43 mmol, 0.5 eq.) of caesium carbonate, and the mixture was stirred at RT for 1 h and concentrated under reduced pressure. The residue was co-distilled twice with 10 ml each time of toluene, dried under high vacuum for 2 h and taken up in 8 ml of dimethylformamide, 98 mul (0.825 mmol, 0.95 eq.) of benzyl bromide were added at 0 C. and the mixture was stirred at RT for 1 h. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 286 mg (quant.). LC/MS [Method 1]: Rt=0.92 min; MS (ESIpos): m/z=322 (M+H)+.

Reference： [1]Patent: US2018/346424,2018,A1 .Location in patent: Paragraph 0566; 0567; 0568
[2]Tetrahedron Letters,2001,vol. 42,p. 651 - 653

4
[ 186581-53-3 ]
[ 187039-57-2 ]
[ 184046-78-4 ]

Reference： [1]Organic Letters,2001,vol. 3,p. 2481 - 2484
[2]Journal of the American Chemical Society,2005,vol. 127,p. 15923 - 15932

5
[ 58632-95-4 ]
[ 4298-08-2 ]
[ 187039-57-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In 1,4-dioxane; water; at 0℃; for 12h;	To a solution of commerically available trans-3-hydroxyproline is added 1.1 equivalents BOC-ON (Aldrich) in a 1:1 v/v solution water/dioxanes and NaOH (1N solution) and stirred at 0 C. for 12 hours. The combined organic phases are then washed with water (2×5 mL), 1 N HCl (aq.) (5 mL), saturated sodium bicarbonate solution (aq.) (50 mL), water (5 mL), brine (5 mL) and dried (MgSO4) before concentration in vacuo to give the crude product. Flash chromatography, eluting with 1:1 ethyl acetate/hexane gives the desired protected product. Step 2) As illustrated in FIG. 27 the substrate (70 mg, 0.213 mmol; vida supra), is dissolved in dry methylene chloride (3 mL). EDC, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, (43 mg, 0.224 mmol) is added and the mixture is stirred for 30 minutes at room temperature. tert-butyl amine (73 mg, 0.255 mmol) is added and the reaction stirred for 18 hours. The reaction mixture is diluted with ethyl acetate (20 mL) and added to saturated ammonium chloride (30 mL). The aqueous phase is extracted with ethyl acetate (3×10 mL). The combined organic phases are then washed with water (2×5 mL), 1 N HCl (aq.) (5 mL), saturated sodium bicarbonate solution (aq.) (50 mL), water (5 mL), brine (5 mL) and dried (MgSO4) before concentration in vacuo to give the crude product. Flash chromatography, eluting with 1:1 ethyl acetate/hexane gives the desired product 1050A.

Reference： [1]Organic Letters,2001,vol. 3,p. 2481 - 2484
[2]Patent: US6900238,2005,B1 .Location in patent: Page/Page column 51

6
[ 187039-57-2 ]
[ 73286-71-2 ]

Reference： [1]Organic Letters,2001,vol. 3,p. 2481 - 2484

7
[ 187039-57-2 ]
[ 412278-05-8 ]

Yield	Reaction Conditions	Operation in experiment
		(1) Synthesis of (2S,3S)-2-(aminocarbonyl)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine According to the manner similar to that of Reference Example 3, the title compound (3.19 g) was obtained as a colorless solid from <strong>[187039-57-2](2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid</strong> (3.47 g). MS(ESI pos.)m/z: 253([M+Na]+), (ESI neg.)m/z: 229([M-H]-).

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6254 - 6263
[2]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 6053 - 6061
[3]Patent: EP1333025,2003,A1

8
[ 187039-57-2 ]
[ 74-88-4 ]
[ 184046-78-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 2h;	A solution containing 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (37, 16 g, 71 mmol)1 in DMF (100 mL) was cooled to 0 C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 C. for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14.8 g (87%) of 38 as a yellow oil.2
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 2h;	A solution containing ester (19, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Supsilonc. 2005, 45, 15923) in DMF (100 rriL) was cooled to 0 0C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SOa, filtered, and concentrated to afford 14.8 g (87%) of 20 as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 2h;	A solution containing 3-hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester (1, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 0C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 0C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14.8 g (87%) of S-hydroxypyrrolidine-l^-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).

87%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 2h;	Scheme I3-Hydroxy-pyrrolidine-l ,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (2): A solution containing 3-hydroxy-pyrrolidine-l ,2-dicarboxylic acid -tert- butyl ester (1, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 C. To this solution was added K2C03 (16 g, 1 16 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2S04, filtered, and concentrated to afford 14.8 g (87%) of 3- hydroxypyrrolidine-l,2-dicarboxylic acid -tert-buty ester 2-methyl ester (2) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 2h;	A solution containing 3-hydroxy-pyrrolidine-1,2-dicarboxylic acid l-tert-buty ester (16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14.8 g (87%) of 3- hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
87%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;	3-Hydroxy-pyrrolidine-l,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (61): A solution containing S-hydroxy-pyrrolidine-l^-dicarboxylic acid 1-fert-butyl ester (60, 16 g, 71 mmol. See: Hodges, J.A.; Raines, R.T. J. Am. Chem. Soc. 2005, 45, 15923) in DMF (100 mL) was cooled to 0 0C. To this solution was added K2CO3 (16 g, 116 mmol) followed by iodomethane (5.4 mL, 87 mmol). The reaction mixture was slowly warmed to ambient temperature over 1 h at which time it became a yellow heterogeneous solution. This mixture was heated at 90 0C for 1 h and then cooled to ambient temperature. The solution was diluted with brine, extracted with diethyl ether, dried over anhydrous Na2SO4, filtered, and concentrated to afford 14.8 g (87%) of S-hydroxypyrrolidine-l^-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (61) as a yellow oil (See: Demange, L.; Cluzeau, J.; Menez, A.; Dugave, C. Tetrahedron Lett. 2001, 42, 651).
82%	With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 50℃;	The (2S,3S)-l-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid(4.2 g, 18.2 mmol) and NaHCO3 (3.1 g, 36.3 mmol) were suspended in DMF (20 ml). Methyl iodide (5.7 ml, 12.9 g, 91.0 mmol) was added to the mixture, which was then heated at 500C overnight. After concentrating the reaction in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted once more with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica flash chromatography (gradient elution, using 1 : 1 hexane-ethyl ether to ethyl ether) to provide the title compound as a colorless oil (3.7 g, 82%).
	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃;	(2) (2S,3S) 2-Methyl N-Boc-3-hydroxypyrrolidine-2-carboxylate, INT 38 To a solution of (2S,3S)-N-Boc-3-hydroxypyrrolidine-2-carboxylic acid (4.10 g, 17.73 mmol) in DMF (100 mL) at 0 C. was added potassium carbonate (4.00 g, 28.94 mmol) followed by iodomethane (1.3 mL, 20.79 mmol). The reaction mixture was warmed to RT and stirred at RT for 4 hr, then at 90 C. for 1 hr. After cooling to RT iodomethane (0.70 mL, 11.19 mmol) was added and the reaction mixture was stirred at RT overnight. The mixture was diluted with brine and extracted with EtOAc (3*). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc gradient, 0-50%) to afford INT 38 as a colorless oil. MS (ESI): [M+H]+ 246.2. 1H NMR (CDCl3): delta (ppm) rotamers 4.42 (s, br, 1H), 4.29 and 4.18 (s, total 1H), 3.74 (s, 3H), 3.66-3.53 (m, 3H), 2.13-2.03 (m, 1H), 1.97-1.88 (m, 1H), 1.46 and 1.41 (s, total 9H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃;	(2) (2S,3S) 2-methyl N-Boc-3-hydroxypyrrolidine-2-carboxylate, INT 38 To a solution of (2S,3S)-N-Boc-3-hydroxypyrrolidine-2-carboxylic acid (4.10 g, 17.73 mmol) in DMF (100 mL) at 0 C was added potassium carbonate (4.00 g, 28.94 mmol) followed by iodomethane (1 .3 mL, 20.79 mmol). The reaction mixture was warmed to RT and stirred at RT for 4 hr, then at 90 C for 1 hr. After cooling to RT iodomethane (0.70 mL, 1 1 .19 mmol) was added and the reaction mixture was stirred at RT overnight. The mixture was diluted with brine and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc gradient, 0-50%) to afford INT 38 as a colorless oil.MS (ESI): [M+H]+246.2.1H NMR (CDCI3): delta (ppm) rota me rs 4.42 (s, br, 1 H), 4.29 and 4.18 (s, total 1 H), 3.74 (s, 3H), 3.66-3.53 (m, 3H), 2.13-2.03 (m, 1 H), 1 .97-1.88 (m, 1 H), 1.46 and 1 .41 (s, total 9H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃;	To a solution of (2S,3S)-N-Boc-3-hydroxypyrrolidine-2-carboxylic acid (4.10 g, 17.73 mmol) in DMF(100 mL) at 0 C was added potassium carbonate (4.00 g, 28.94 mmol) followed by iodomethane (1.3mL, 20.79 mmol). The reaction mixture was warmed to RT and stirred at RT for 4 hr, then at 90 C for 1 hr. After cooling to RT iodomethane (0.70 mL, 11.19 mmol) was added and the reaction mixture was stirred at RT overnight. The mixture was diluted with brine and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica; cyclohexane/EtOAc gradient, 0-50%) to afford INT 38 as acolorless oil.MS (ESI): [M+H] 246.2. ?H NMR (CDC13): (ppm) rotamers 4.42 (s, br, 1H), 4.29 and 4.18 (s, total 1H), 3.74 (s, 3H), 3.66-3.53 (m, 3H), 2.13-2.03 (m, 1H), 1.97-1.88 (m, 1H), 1.46 and 1.41 (s, total 9H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 90℃; for 2h;	Potassium carbonate (1.1 g, 8.2 mmol) was added to the stirred solution of (2S,3S)- 1 -(tert- butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (0.95 g, 4.1 mmol) in DMF (5.9 mL) at 0 C, followed by Mel (0.31 mL, 4.9 mmol). The reaction mixture was allowed to warm to room temperature over 1 h and then stirred at 90 C for 1 h. The reaction mixture was cooled to room temperature, diluted with brine, extracted with ether, and the combined organic phase was dried over anhydrous Na2S0 , filtered and concentrated to afford (2S,3S)-l-/er/-butyl 2-methyl 3- hydroxypyrrolidine-l,2-dicarboxylate. LCMS (CiiHi9NNa05+) (ES, m/z): 268 [M+Na]+.

Reference： [1]Patent: US2008/20986,2008,A1 .Location in patent: Page/Page column 16
[2]Patent: WO2009/94287,2009,A1 .Location in patent: Page/Page column 31
[3]Patent: WO2010/138496,2010,A1 .Location in patent: Page/Page column 38-39
[4]Patent: WO2011/68926,2011,A1 .Location in patent: Page/Page column 39-40
[5]Patent: WO2010/33531,2010,A1 .Location in patent: Page/Page column 66
[6]Patent: WO2010/138666,2010,A1 .Location in patent: Page/Page column 99-100
[7]Patent: WO2008/24725,2008,A1 .Location in patent: Page/Page column 131
[8]Journal of Organic Chemistry,2009,vol. 74,p. 3735 - 3743
[9]Patent: US2015/152068,2015,A1 .Location in patent: Paragraph 0369; 0370; 0371
[10]Patent: WO2015/79417,2015,A1 .Location in patent: Page/Page column 77; 78
[11]Patent: WO2016/164580,2016,A1 .Location in patent: Page/Page column 280; 281
[12]Patent: WO2019/177873,2019,A1 .Location in patent: Page/Page column 248

9
[ 187039-57-2 ]
[ 914653-00-2 ]

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

10
[ 187039-57-2 ]
[ 914653-01-3 ]

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

11
[ 187039-57-2 ]
C₁₁H₂₂N₈O₄*3C₂HF₃O₂ [ No CAS ]

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

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[ 187039-57-2 ]
[ 261350-70-3 ]