[ CAS No. 68766-96-1 ] {[proInfo.proName]}

Name: 68766-96-1|H-D-Pyr-OEt|97%
Brand: Ambeed
SKU: A170025
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2D 3D

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Quality Control of [ 68766-96-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 68766-96-1 ]

SDS Specification

Alternatived Products of [ 68766-96-1 ]

Product Details of [ 68766-96-1 ]

CAS No. :	68766-96-1	MDL No. :	MFCD00010848
Formula :	C₇H₁₁NO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QYJOOVQLTTVTJY-RXMQYKEDSA-N
M.W :	157.16	Pubchem ID :	643508
Synonyms :

Calculated chemistry of [ 68766-96-1 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.71
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.85
TPSA :	55.4 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) :	-7.31 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.59
Log Po/w (XLOGP3) :	-0.07
Log Po/w (WLOGP) :	-0.55
Log Po/w (MLOGP) :	-0.2
Log Po/w (SILICOS-IT) :	0.65
Consensus Log Po/w :	0.28

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-0.57
Solubility :	42.1 mg/ml ; 0.268 mol/l
Class :	Very soluble
Log S (Ali) :	-0.64
Solubility :	35.8 mg/ml ; 0.228 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.17
Solubility :	10.7 mg/ml ; 0.0681 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.1

Safety of [ 68766-96-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 68766-96-1 ]

* 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 [ 68766-96-1 ]
Downstream synthetic route of [ 68766-96-1 ]

[ 68766-96-1 ] Synthesis Path-Upstream 1~7

1
[ 68766-96-1 ]
[ 64-17-5 ]
[ 4042-36-8 ]

Reference： [1] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 545 - 556

2
[ 64-17-5 ]
[ 4042-36-8 ]
[ 68766-96-1 ]

Yield	Reaction Conditions	Operation in experiment
3.7 g	at -5 - 20℃; for 3 h;	To a solution of (f?)-5-oxopyrrolidine-2-carboxylic acid (10 g, 69.84 mmol; available from AldrichNo.422614) in EtOH (100 ml) cooled at -5°C, thionyl chloride (10 ml, 139.68 mmol) was added and the resulting mixture was stirred at RT for 3 hrs. Solvents were evaporated in vacuo and the resulting residue was taken up with EtOAc (350 ml), washed with water/TEA (40/12ml), then with water (40 ml). Collected organics were dried over Na₂S0₄ and evaporated to afford a residue that was loaded on a SNAP-Si cartridge (50 g) and eluted with a mixture DCM/EtOAc from 90/10 to 50/50. Collected fractions after solvent evaporation afforded a first batch of title compound (D23) (6.4 g). The aqueous were saturated with NaCI and extracted with EtOAc (400 ml). The organic was washed with water (20 ml) dried over Na₂SO₄ and evaporated in vacuo to afford a second batch of title compound (D23) (3.7 g). 1 H NMR (400MHz , CHCI3-d) δ (ppm): 6.58 (br. s., 1 H), 4.29 - 4.17 (m, 3 H), 2.53 - 2.29 (m, 3 H), 2.28 - 2.17 (m, 1 H), 1 .35 - 1 .22 (m, 3 H).
3.7 g	at 20℃; for 3 h;	To a solution of (R)-5-oxopyrrolidine-2-carboxylic acid (10 g, 69.84 mmol; available from Aldrich422614) in EtOH (100 ml) cooled at −5° C., thionyl chloride (10 ml, 139.68 mmol) was added and the resulting mixture was stirred at RT for 3 hrs. Solvents were evaporated in vacuo and the resulting residue was taken up with EtOAc (350 ml), washed with water/TEA (40/12 ml), then with water (40 ml). Collected organics were dried over Na₂SO₄and evaporated to afford a residue that was loaded on a SNAP-Si cartridge (50 g) and eluted with a mixture DCM/EtOAc from 90/10 to 50/50. Collected fractions after solvent evaporation afforded a first batch of title compound (D23) (6.4 g). The aqueous were saturated with NaCl and extracted with EtOAc (400 ml). The organic was washed with water (20 ml) dried over Na₂SO₄and evaporated in vacuo to afford a second batch of title compound (D23) (3.7 g).¹H NMR (400 MHz, CHCl3-d) δ (ppm): 6.58 (br. s., 1H), 4.29-4.17 (m, 3H), 2.53-2.29 (m, 3H), 2.28-2.17 (m, 1H), 1.35-1.22 (m, 3H).

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 3, p. 1368 - 1381
[2] Journal of Medicinal Chemistry, 1985, vol. 28, # 12, p. 1760 - 1765
[3] Patent: WO2011/79114, 2011, A1, . Location in patent: Page/Page column 81
[4] Patent: WO2013/4290, 2013, A1, . Location in patent: Page/Page column 51; 52
[5] Patent: US2014/58117, 2014, A1, . Location in patent: Paragraph 0049-0050
[6] Patent: WO2014/31581, 2014, A1, . Location in patent: Page/Page column 11
[7] Patent: US2015/87626, 2015, A1, . Location in patent: Paragraph 0410; 0411; 0412
[8] Organic and Biomolecular Chemistry, 2017, vol. 15, # 19, p. 4241 - 4245

3
[ 64-17-5 ]
[ 6893-26-1 ]
[ 68766-96-1 ]

Reference： [1] Journal of the American Chemical Society, 1992, vol. 114, # 4, p. 1495 - 1496
[2] Journal of Organic Chemistry, 2011, vol. 76, # 14, p. 5574 - 5583

4
[ 13107-55-6 ]
[ 68766-96-1 ]

Reference： [1] Tetrahedron, 1991, vol. 47, # 40, p. 8635 - 8652
[2] Patent: EP1847536, 2007, A1, . Location in patent: Page/Page column 28

5
[ 6893-26-1 ]
[ 68766-96-1 ]

Reference： [1] Tetrahedron, 1991, vol. 47, # 40, p. 8635 - 8652

6
[ 16450-41-2 ]
[ 68766-96-1 ]

Reference： [1] Sexagint, Festschrift <Kyoto 1927>, S. 30,

7
[ 68766-96-1 ]
[ 66673-40-3 ]

Reference： [1] Journal of Medicinal Chemistry, 1985, vol. 28, # 12, p. 1760 - 1765
[2] Journal of Organic Chemistry, 1992, vol. 57, # 7, p. 2158 - 2160
[3] Tetrahedron, 1991, vol. 47, # 40, p. 8635 - 8652
[4] Journal of the American Chemical Society, 1992, vol. 114, # 4, p. 1495 - 1496
[5] Patent: US2009/247500, 2009, A1, . Location in patent: Page/Page column 23
[6] Journal of Organic Chemistry, 2011, vol. 76, # 14, p. 5574 - 5583

[ 68766-96-1 ] Synthesis Path-Downstream 1~88

1
[ 16450-41-2 ]
[ 68766-96-1 ]

Reference： [1]Sexagint, Festschrift <Kyoto 1927>, S. 30,

2
[ 64-17-5 ]
[ 6893-26-1 ]
[ 68766-96-1 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496
[2]Journal of Organic Chemistry,2011,vol. 76,p. 5574 - 5583

3
[ 13107-55-6 ]
[ 68766-96-1 ]

Yield	Reaction Conditions	Operation in experiment
	at 90 - 150℃; under 2.32523 - 3.90039 Torr; for 4h;	A 10 L reactor was charged with D-glutamic acid 1 (1 kg, 6.80 mol) in absolute ethanol (5.0 L), cooled to -10C and through a dropping-funnel, thionyl chloride (2.0 kg, 14.9 mol) was added slowly over 2 h. After the addition was complete, the mixture was stirred at room temperature for 1 h and then heated to 80C for one more hour. The resulting solution was concentrated to dryness (CARE: HCl and SO2 vapours evolved). The residue was diluted with ethanol (2.5 L) and neutralized to pH=7 with addition of a solution of potassium hydroxide in ethanol (10% wt, ca. 2.0 L). The formed solid was removed by filtration and the solution concentrated to give the diethyl ester of 1 as a waxy solid. The residue was then distilled in vacuo (90C, 3.1 mbar) for 2 h and the remainder was further heated to 150C at 5.2 mbar for 2 h. At room temperature, the residue solidified. Recrystallisation from MTBE/hexane (2:1) gave the desired product 2 as a brownish solid (960 g, 90%). m.p. 49-51C. 1H-NMR (CDCl3, 300 MHz): 6.82 (bs, 1H); 4.29-4.23 (m, 1H); 4.21 (q, 2H, J=7.3Hz); 2.48-2.17 (m, 4H); 1.28 (t, 3H, J=7.3Hz) ppm.

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652
[2]Patent: EP1847536,2007,A1 .Location in patent: Page/Page column 28

4
[ 75-03-6 ]
[ 68766-96-1 ]
[ 113427-25-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 0 - 20℃;	(i) D-pyroglutamic acid ethyl ester (4.17 g, 26.53 mmol) was dissolved in tetrahydrofuran (30 ml) and ethyl iodide (2.23 ml, 27.86 mmol) was added to give a pale yellow solution. This was cooled to 0 C. and sodium hydride (60% in oil, 1.11 g, 27.86 mmol) was added portionwise. After addition of all the sodium hydride the mixture was stirred at 0 C. for a further 20 minutes until most of the bubbling had stopped. The mixture was then warmed to room temperature and stirred overnight under argon. The mixture was then treated with saturated aqueous ammonium chloride solution (~5 ml). The organic layer was separated and the aqueous layer was extracted with more dichloromethane (3*20 ml). The combined organic layers were dried by passing through a phase separator and then concentrated to a green/brown oil (3.2 g). This was purified by automated flash silica column chromatography (Biotage SP4), eluding with a 0-100% gradient of ethyl acetate in hexane, to give ethyl 1-ethyl-5-oxoprolinate as a yellow oil (1.33 g) which was used in the next step without further purification.

Reference： [1]Patent: US2008/9541,2008,A1 .Location in patent: Page/Page column 34

5
[ 68766-96-1 ]
[ 74-88-4 ]
[ 108645-70-1 ]

Yield	Reaction Conditions	Operation in experiment
		(i) D-pyroglutamic acid ethyl ester (4.0 g, 25.5 mmol) was dissolved in tetrahydrofuran (25 ml) and cooled to 0 C. Methyl iodide (1.66 ml, 26.7 mmol) was added and stirring continued for 10 minutes under argon at 0 C. Sodium hydride (60% in oil, 1.6 g, 26.7 mmol) was then added portionwise (allowing each portion to react). After addition of all the sodium hydride the mixture was allowed to warm to room temperature and stirred overnight under argon. The mixture was then treated with saturated aqueous ammonium chloride solution (~15 ml) and stirred for 4 hrs. The organic layer was separated and the aqueous layer was extracted with more dichloromethane. The combined organic layers were dried over magnesium sulphate and then concentrated to a dark oil. This was purified by flash silica column chromatography, eluding with a 0-75% gradient of ethyl acetate in hexane, to give ethyl 1-methyl-5-oxoprolinate as a colourless oil (0.27 g) which was used in the next step without further purification.

Reference： [1]Patent: US2008/9541,2008,A1 .Location in patent: Page/Page column 36-37

6
[ 108-86-1 ]
[ 68766-96-1 ]
[ 146500-35-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Heating / reflux;Product distribution / selectivity;	(i) D-pyroglutamic acid ethyl ester (0.200 g, 1.27 mmol) was dissolved in dioxane (5 ml) and treated with tris(dibenzylideneacetone)dipalladium (0) (0.058 g, 0.06 mmol), bromobenzene (0.351 ml, 1.53 mmol), cesium carbonate (0.621 g, 1.91 mmol) and Xantphos (0.110 g, 0.19 mmol). The resulting mixture was heated at reflux overnight and then allowed to cool to room temperature. The mixture was diluted with methanol and filtered. The filtrate was evaporated in vacuo and then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The aqueous layer was extracted with more dichloromethane (3 aliquots) and then the combined organic layers were washed with brine and dried over magnesium sulphate. Evaporation of the solvent gave a bright yellow residue which was purified by flash silica column chromatography, eluding with a gradient of 0-50% ethyl acetate in hexane, to give methyl 5-oxo-1-phenylprolinate (0.078 g) as a yellow oil. This was used in the next step without further purification.

Reference： [1]Patent: US2008/9541,2008,A1 .Location in patent: Page/Page column 38-39

7
[ 6893-26-1 ]
[ 68766-96-1 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

8
[ 68766-96-1 ]
[ 128811-47-2 ]

Reference： [1]Journal of Organic Chemistry,1992,vol. 57,p. 2158 - 2160

9
[ 68766-96-1 ]
[ 77674-99-8 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

10
[ 68766-96-1 ]
[ 118918-76-6 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652
[2]Journal of Organic Chemistry,2011,vol. 76,p. 5574 - 5583

11
[ 68766-96-1 ]
[ 118867-99-5 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

12
[ 68766-96-1 ]
[ 118868-02-3 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

13
[ 68766-96-1 ]
[ 118868-03-4 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

14
[ 68766-96-1 ]
[ 134037-90-4 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

15
[ 68766-96-1 ]
[ 118868-04-5 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

16
[ 68766-96-1 ]
[ 118868-01-2 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

17
[ 68766-96-1 ]
[ 118868-05-6 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

18
[ 68766-96-1 ]
[ 118868-06-7 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

19
[ 68766-96-1 ]
[ 138541-53-4 ]

Reference： [1]Journal of Organic Chemistry,1992,vol. 57,p. 2158 - 2160

20
[ 68766-96-1 ]
[ 118868-00-1 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

21
[ 68766-96-1 ]
[ 118868-00-1 ]

Reference： [1]Tetrahedron,1991,vol. 47,p. 8635 - 8652

22
[ 68766-96-1 ]
[ 138541-55-6 ]

Reference： [1]Journal of Organic Chemistry,1992,vol. 57,p. 2158 - 2160

23
[ 68766-96-1 ]
[ 138661-27-5 ]

Reference： [1]Journal of Organic Chemistry,1992,vol. 57,p. 2158 - 2160

24
[ 68766-96-1 ]
[ 138629-31-9 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

25
[ 68766-96-1 ]
[ 138629-37-5 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

26
[ 68766-96-1 ]
[ 138629-48-8 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

27
[ 68766-96-1 ]
[ 138629-49-9 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

28
[ 68766-96-1 ]
[ 138629-36-4 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

29
[ 68766-96-1 ]
[ 138629-32-0 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

30
[ 68766-96-1 ]
[ 138629-35-3 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

31
[ 68766-96-1 ]
(S)-4-[(R)-4-((S)-4-Benzyl-2-oxo-oxazolidin-3-yl)-1-formyl-4-oxo-butylcarbamoyl]-2-tert-butoxycarbonylamino-butyric acid benzyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

32
[ 68766-96-1 ]
[ 138629-45-5 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

33
[ 68766-96-1 ]
[ 138629-47-7 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

34
[ 68766-96-1 ]
[ 138629-34-2 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

35
[ 68766-96-1 ]
(S)-4-[(R)-1-[(E)-Benzylimino-methyl]-4-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-4-oxo-butylcarbamoyl]-2-tert-butoxycarbonylamino-butyric acid benzyl ester [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

36
[ 68766-96-1 ]
[ 138629-33-1 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

37
[ 68766-96-1 ]
[ 138629-44-4 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

38
[ 68766-96-1 ]
[ 138629-30-8 ]

Reference： [1]Journal of the American Chemical Society,1992,vol. 114,p. 1495 - 1496

39
[ 24424-99-5 ]
[ 68766-96-1 ]
[ 144978-12-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; triethylamine; In dichloromethane; at 20℃; for 1.5h;	A solution of D-Pyr-OEt (5.1g, 32.6 mmol) in dichloromethane (70 ml) is treated with triethylamine (4.55 ml, 32.6 mmol), di-tert~butyl-dicarbonate (14.2 g, 65.2 mmol) and 4-(dimethylamino)-pyridine(3.98 g, 32.6 mmol) and the resulting yellow solution stirred at room temperature. After 1.5 h, TLC analysis showed complete conversion. The solution is washed with water twice, then brine, dried over sodium sulphate, filtered and evaporated. The residue is purified by column chromatography(1:1 ethyl acetate / petroleum ether) affording Boc-D-Pyr-OEt as a viscous light yellow oil (7.98 g, 95 % yield) which solidifies on standing.
54%	With dmap; triethylamine; In dichloromethane; for 2h;	1.2 Synthesis of 3: 2R-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tertbutyl ester 2-ethyl ester To a stirred solution of ethyl pyroglutamate 2 (900 g, 5.73 mol) in dichloromethane (8.0 L) in a reactor, di-tert-butyldicarbonate (2.5 kg, 11.5 mol), triethylamine (800 mL, 5.73 mol) and DMAP (700 g, 5.73 mol) were added, and the reaction stirred for 2 h. The red-brown solution was concentrated to dryness, diluted in ethyl acetate (10.0 L) and washed with aq. HCl 3N (4x2.5 L). The combined organic layers were washed with water (6x2.5 L) and brine (1.0 L), and dried over sodium sulphate. The reaction mixture was concentrated to dryness, cooled in ice and triturated with MTBE and hexane (1:1) to give a brown solid (390 g). Concentration of mother liquors gave an oil (600 g) which, after chromatography (SiO2, hexane/ethyl acetate 3:1) gave a colourless solid (386 g) 3. Total yield (776g, 54%). m.p. 48-49C. 1H-NMR (CDCl3, 300 MHz): 4.57 (dd, 1H, J=9.5Hz, J=3.3Hz); 4.20 (q, 2H, J=7.3Hz); 2.72-1.77 (m, 4H); 1.46 (s, 9H); 1.26 (t, 3H, J=7.3Hz) ppm.
		Synthesis of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester To a tetrahydrofuran (200 mL) solution containing D-pyroglutamic acid ethyl ester (20g), triethylamine (35.2 mL) and di-t-butyldicarbonate (30.5 g) was added 4-dimethylaminopyridine (1.55 g), and the resultant solution was stirred for 5 hours at room temperature. To the solution was then added imidazole (1.3 g), and the reaction mixture was stirred for 30 minutes at room temperature. Solvent was removed by distillation under reduced pressure, and the resulting product was diluted with ethyl acetate. The ethyl acetate solution was successively washed 3 times with 0.2 N hydrochloric acid, and then washed with brine. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, to thereby obtain the titled compound (31.08 g). The physical properties of the compound were as follows. 1H-NMR (CDCl3) delta (ppm): 1.30 (t, J=7.2 Hz, 3H), 1.49 (s, 9H), 1.99-2.06 (m, 1H), 2.26-2.37 (m, 1H), 2.44-2.52 (m, 1H), 2.58-2.68 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.59 (dd, J=9.6, 3.2 Hz, 1H).

	dmap; In acetonitrile; at 20℃; for 18h;Cooling with ice;	Ethyl 5-oxo-D-prolinate (25.0 g), 4-dimethylaminopyridine (1.94 mL) and di-tert-butyl bicarbonate (38.13 g) were mixed in acetonitrile (225 mL) under ice-cooling, and the mixture was allowed to warm to room temperature, and stirred for 18 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=9/91?80/20) to give the title compound (41.72 g) as a pale-yellow oil.1H NMR (CDCl3, 300 MHz): delta 1.29 (3H, t, J=7.1 Hz), 1.50 (9H, s), 1.94-2.11 (1H, m), 2.21-2.42 (1H, m), 2.41-2.73 (2H, m), 4.24 (2H, q, J=7.1 Hz), 4.60 (1H, dd, J=9.4, 2.9 Hz).
	dmap; In acetonitrile; at 20℃;Cooling with ice;	To a solution of compound II-AA in 400 mL of acetonitrile cooled in an ice-bath, DMAP (2.65 g) and (Boc)20 (51.8 g, 1.5 eq) were added. The mixture was stirred at rt overnight. Solvent was removed under reduced pressure and the resulting yellow oil was purified by MPLC to give 31 g of (R)-l-tert-butyl 2-ethyl 5- oxopyrrolidine-l,2-dicarboxylate (compound III-AA).
13.7 g	With dmap; In toluene; at 20℃;	To a solution of (f?)-ethyl 5-oxopyrrolidine-2-carboxylate (D23) (10 g, 63.62 mmol) in toluene (50 ml), DMAP (390 mg, 3.2 mmol) was added before addition, after 10 min, of a solution of Boc2O (13.9 g, 63.62 mmol) in toluene (50 ml). The reaction mixture was stirred at RT overnight then diluted with EtOAc (200 ml), charged with half-saturated NaHCO3 solution (60ml) and stirred for 10 min. Phases were separated and the organics washed with water (40 ml), dried over Na2SO4 and evaporated in vacuo to afford a residue which was triturated in heptane. After filtration and drying under reduced pressure, 13.7 g of title compound (D24) were isolated. MS: (ES/+) m/z: 280 [MH+ Na+] C12H19NO5 requires 257.13 1 H NMR (400MHz , CHCI3-d) delta (ppm): 4.68 - 4.57 (m, 1 H), 4.26 (q, J = 1.3 Hz, 2 H), 2.72 - 2.58 (m, 1 H), 2.57 - 2.43 (m, 1 H), 2.42 - 2.26 (m, 1 H), 2.12 - 1 .99 (m, 1 H), 1 .52 (s, 9 H), 1 .32 (t, J = 7.1 Hz, 3 H).
13.7 g		To a solution of (R)-ethyl 5-oxopyrrolidine-2-carboxylate (D23) (10 g, 63.62 mmol) in toluene (50 ml), DMAP (390 mg, 3.2 mmol) was added before addition, after 10 min, of a solution of Boc2O (13.9 g, 63.62 mmol) in toluene (50 ml). The reaction mixture was stirred at RT overnight then diluted with EtOAc (200 ml), charged with half-saturated NaHCO3 solution (60 ml) and stirred for 10 min. Phases were separated and the organics washed with water (40 ml), dried over Na2SO4 and evaporated in vacuo to afford a residue which was triturated in heptane. After filtration and drying under reduced pressure, 13.7 g of title compound (D24) were isolatedMS: (ES/+) m/z: 280 [MH+Na+] C12H19NO5 requires 257.131H NMR (400 MHz, CHCl3-d) delta (ppm): 4.68-4.57 (m, 1H), 4.26 (q, J=7.3 Hz, 2H), 2.72-2.58 (m, 1H), 2.57-2.43 (m, 1H), 2.42-2.26 (m, 1H), 2.12-1.99 (m, 1H), 1.52 (s, 9H), 1.32 (t, J=7.1 Hz, 3H).
		4-dimethylaminopyridine (1.55 g) was added to a tetrahydrofuran (200 mL) solution containing D-pyroglutamic acid ethyl ester (20 g), triethylamine (35.2 mL) and di-t-butyl dicarbonate (30.5 g). Stirring was continued for 5 hours at room temperature. Imidazole (1.3 g) was added, and stirring was continued for 30 minutes at room temperature. The solvent was removed under a vacuum. The resultant was diluted with ethyl acetate, and the resultant was washed with 0.2 N hydrochloric acid three times and with brine, in sequence. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under a vacuum, and the title compound (31.08 g) was obtained. The physical property values are as follows. 1H-NMR (CDCl3) delta (ppm): 1.30 (t, J=7.2 Hz, 3H), 1.49 (s, 9H), 1.99-2.06 (m, 1H), 2.26-2.37 (m, 1H), 2.44-2.52 (m, 1H), 2.58-2.68 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.59 (dd, J=9.6, 3.2 Hz, 1H).

Reference： [1]Patent: WO2007/36730,2007,A1 .Location in patent: Page/Page column 120
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1383 - 1393
[3]Patent: EP1847536,2007,A1 .Location in patent: Page/Page column 28
[4]Patent: US2009/48213,2009,A1 .Location in patent: Page/Page column 70-71
[5]Patent: US2011/34469,2011,A1 .Location in patent: Page/Page column 124
[6]Patent: WO2011/79114,2011,A1 .Location in patent: Page/Page column 81
[7]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381
[8]Patent: WO2013/4290,2013,A1 .Location in patent: Page/Page column 52
[9]Patent: US2015/87626,2015,A1 .Location in patent: Paragraph 0413; 0414; 0415; 0416
[10]Patent: US2008/207900,2008,A1 .Location in patent: Page/Page column 25

40
[ 1538-75-6 ]
[ 68766-96-1 ]
[ 144978-12-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4072 - 4074

41
[ 501-53-1 ]
[ 68766-96-1 ]
[ 924907-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium hexamethyldisilazane; In tetrahydrofuran;	9.1 Reaction of 1.0 g of ethyl (R)-5-oxopyrrolidine-2-carboxylate, 949.8 mul of benzyl chloroformate, 6.9 ml of bis(trimethylsilyl)lithium amide (in THF) in 25 ml of THF under standard conditions and work-up gives 730 mg of ethyl (R)-5-oxo-N-benzyloxycarbonylpyrrolidine-2-carboxylate (?17?).

Reference： [1]Patent: US2010/160352,2010,A1 .Location in patent: Page/Page column 18
[2]Organic and Biomolecular Chemistry,2017,vol. 15,p. 4241 - 4245

42
[ 395-44-8 ]
[ 68766-96-1 ]
[ 1254699-85-8 ]

Yield	Reaction Conditions	Operation in experiment
12%	With 18-crown-6 ether; potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 80℃; for 6h;	Example R:; (R)-5-Oxo-l-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid; To the solution of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (D-pyroglutamic acid ethyl ester; 99% pure; 1403 mg, 8.84 mmol) in 20 ml of DMF l-(bromomethyl)-2- (trifluoromethyl)benzene (96% pure; 2200 mg, 8.84 mmol), K2CO3 (3660 mg, 26.5 mmol) and a small amount of each KI and 18-crown-6 were added, and the mixture was heated at 800C for 6h. Subsequently the mixture was poured into water and extracted three times with MTBE. The organic layer was washed with brine, dried over MgSO4 and the solvent removed under reduced pressure. Chromatography on silica gel using dichloromethane and dichloromethane/MeOH (99: 1) resulted in (R)-5- oxo-l-(2-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid ethyl ester (410 mg, ESI-MS [M+H]+ = 316.1; yield: 12 %), which was hydrolyzed to the corresponding carboxylate by stirring overnight at room temperature in a solution of 15 ml ethanol and 1,56 mL 2N NaOH (aq). Evaporation of the solvent, followed by addition of water to the residue, extraction with ethyl acetate, subsequent acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane, drying of the combined organic layers with MgSO4 and removal of the solvent under reduced pressure led to the desired product as a white foam. ESI-MS [M+H]+ = 288.1.

Reference： [1]Patent: WO2010/128102,2010,A1 .Location in patent: Page/Page column 147

43
[ 108-86-1 ]
[ 68766-96-1 ]
[ 1254699-87-0 ]

Yield	Reaction Conditions	Operation in experiment
17%	With caesium carbonate;4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; bis(dibenzylideneacetone)-palladium(0); In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere;	Example T:; (R)-5-Oxo-l-phenyl-pyrrolidine-2-carboxylic acid; A mixture of (R)-ethyl 5-oxo-pyrrolidine-2-carboxylate (2760 mg, 17.56 mmol), bromobenzene (2.034 ml, 3030 mg, 19.32 mmol), Pd2(dba)3 (402 mg, 0.439 mmol), Cs2CO3 (8580 mg, 26.3 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 254 mg, 0.439 mmol) in 70 ml of dioxane was stirred at 1000C for 6h under nitrogen atmosphere. Due to only partial reaction after this time additional Pd2(dba)3 (402 mg, 0.439 mmol), Cs2CO3 (2860mg, 8.77 mmol) and Xantphos (254 mg, 0.439 mmol) were added and stirring at 1000C was continued for additional 6h. The reaction mixture was then filtered via a short celite column, the solvent was removed under reduced pressure, and the remaining residue was taken up in ethyl acetate, washed successively with an aq. sat. NaHCO3 solution and an aq. citric acid solution (each 3x), then with water and brine. The organic layer was dried over Na2SO4, the solvent evaporated under reduced pressure, and the obtained residue purified by column chromatography on silica gel using dichloromethane to give (R)-ethyl 5-oxo-l-phenylpyrrolidine-2-carboxylate as a brown oil (715 mg,3.07 mmol; yield: 17%; ESI-MS [M+H]+ = 234.1). Saponification to the corresponding carboxylate was achieved by stirring at room temperature overnight in a solution of 4 ml ethanol and 1,84 ml 2N NaOH (aq). Subsequent evaporation of the solvent followed by addition of water, extraction with MTBE (3x), acidification of the aqueous layer to pH 3 using concentrated HCl, extraction with dichloromethane (3x), washing the combined organic layers with brine, drying over MgSO4 and removing the solvent under reduced pressure yielded the title compound as a pale brown powder (0.5 g; yield: 79%). ESI-MS [M+H]+ = 206.1.

Reference： [1]Patent: WO2010/128102,2010,A1 .Location in patent: Page/Page column 147-148

44
[ 68766-96-1 ]
[ 1313517-63-3 ]

Reference： [1]Patent: WO2011/79114,2011,A1

45
[ 68766-96-1 ]
[ 1091626-35-5 ]

Reference： [1]Patent: WO2011/79114,2011,A1
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1383 - 1393
[3]Patent: US2015/87626,2015,A1
[4]Patent: WO2013/4290,2013,A1

46
[ 68766-96-1 ]
[ 1313517-64-4 ]

Reference： [1]Patent: WO2011/79114,2011,A1

47
[ 68766-96-1 ]
[ 1313517-66-6 ]

Reference： [1]Patent: WO2011/79114,2011,A1

48
[ 68766-96-1 ]
[ 1311406-94-6 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 5574 - 5583

49
[ 68766-96-1 ]
[ 1311406-95-7 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 5574 - 5583

50
[ 68766-96-1 ]
[ 1311406-96-8 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 5574 - 5583

51
[ 68766-96-1 ]
[ 1311406-97-9 ]

Reference： [1]Journal of Organic Chemistry,2011,vol. 76,p. 5574 - 5583

52
[ 60-23-1 ]
[ 68766-96-1 ]
ethyl (R)-2-amino-4-(4,5-dihydrothiazol-2-yl)butanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: (a) Pyrrolidone (85 mg, 1 mmol), DCM (10 ml) and pyridine (235 mul, 3.0 mmol) are mixed in a dry 25 ml double necked R.B flask under nitrogen atmosphere. The resulting solution is cooled to -65 C and then neat triflic anhydride (229 mul, 1.3 mmol) is added slowly to the solution. After completion of the addition of Tf2O, the reaction mixture is allowed to warm up to -40 C (approx.1.5 h) then gradually cooled to -60 C and added 2-amino ethanethiol (130 mg, 1.7 mmol) followed by addition of another 235 mul (3.0 mmol) of pyridine and warmed the reaction mixture to -30 C and is allowed to stir for another hour at the same temperature and then allowed to stir for 1.5 h at room temperature. After the optimum completion of the reaction (as per TLC), the reaction mixture is then filtered through silica bed (60-120 mesh) and eluted with diethyl ether. The ethereal filtrate is concentrated and purified using Flash chromatography to obtain thiazolinized product (10a') as yellow colored oil. (In a general observation these products are sensitive to aqueous acid and are not stable enough at room temperature therefore protection of free amino terminal as carbamate is performed.)(b) The ethereal filtrate was taken in a 25 ml R.B. flask and added TEA (187 mul, 1.3 mmol) at 0 C, followed by the addition of benzyl chloroformate (186 mul, 1.5 mmol) or di-tert-butyl carbonate (344 mul, 1.5 mmol) and then allowed the reaction mixture to stir at room temperature for 10-14 h. After the completion of reaction in vacuo distillation is carried out a deep yellow colored crude product was obtained. The desired Cbz or Boc protected thiazolinized product was purified with flash chromatography on silica gel as light yellow colored oil in quantitative yield. (10a).

Reference： [1]Tetrahedron,2012,vol. 68,p. 1272 - 1279

53
[ 68766-96-1 ]
(R)-ethyl 2-(benzyloxycarbonylamino)-4-(4,5-dihydrothiazol-2-yl)butanoate [ No CAS ]

Reference： [1]Tetrahedron,2012,vol. 68,p. 1272 - 1279

54
[ 68766-96-1 ]
[ 1229439-70-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381

55
[ 68766-96-1 ]
C₁₉H₂₆FNO₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381

56
[ 68766-96-1 ]
C₂₉H₃₀F₂N₂O₄ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381

57
[ 68766-96-1 ]
C₂₄H₂₂F₂N₂O₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381

58
[ 68766-96-1 ]
[ 1356351-76-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381

59
[ 68766-96-1 ]
[ 1143524-77-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 1368 - 1381

60
[ 68766-96-1 ]
[ 932040-48-7 ]

Reference： [1]Patent: WO2013/4290,2013,A1
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1383 - 1393

61
[ 68766-96-1 ]
[ 871727-37-6 ]
[ 871727-40-1 ]

Reference： [1]Patent: WO2013/4290,2013,A1

62
[ 68766-96-1 ]
[ 1510832-47-9 ]

Reference： [1]Patent: WO2013/185082,2013,A2

63
[ 68766-96-1 ]
(2R)-ethyl 1-(3-chloro-5-(trifluoromethyl)phenyl)-5-hydroxypyrrolidine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2013/185082,2013,A2

64
[ 68766-96-1 ]
[ 1510832-31-1 ]

Reference： [1]Patent: WO2013/185082,2013,A2

65
[ 68766-96-1 ]
[ 1510832-33-3 ]

Reference： [1]Patent: WO2013/185082,2013,A2

66
[ 68766-96-1 ]
[ 1510832-36-6 ]

Reference： [1]Patent: WO2013/185082,2013,A2
[2]Patent: WO2013/185082,2013,A2

67
[ 68766-96-1 ]
[ 1510832-70-8 ]

Reference： [1]Patent: WO2013/185082,2013,A2

68
[ 1189352-83-7 ]
[ 68766-96-1 ]
[ 1510829-97-6 ]