[ CAS No. 2517-04-6 ] {[proInfo.proName]}

Name: 2517-04-6|Azetidine-2-carboxylic acid|98%
Brand: Ambeed
SKU: A217569
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Quality Control of [ 2517-04-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 2517-04-6 ]

Product Details of [ 2517-04-6 ]

CAS No. :	2517-04-6	MDL No. :	MFCD00066660
Formula :	C₄H₇NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	101.10	Pubchem ID :	-
Synonyms :		Chemical Name :	Azetidine-2-carboxylic acid

Calculated chemistry of [ 2517-04-6 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.75
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	27.72
TPSA :	49.33 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) :	-8.93 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.86
Log Po/w (XLOGP3) :	-2.84
Log Po/w (WLOGP) :	-0.95
Log Po/w (MLOGP) :	-3.0
Log Po/w (SILICOS-IT) :	-0.02
Consensus Log Po/w :	-1.19

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	3.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	1.39
Solubility :	2470.0 mg/ml ; 24.5 mol/l
Class :	Highly soluble
Log S (Ali) :	2.36
Solubility :	23200.0 mg/ml ; 229.0 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	0.17
Solubility :	150.0 mg/ml ; 1.49 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.37

Safety of [ 2517-04-6 ]

Signal Word:	Danger	Class:	N/A
Precautionary Statements:	P264-P270-P280-P301+P312+P330-P305+P351+P338+P310-P501	UN#:	N/A
Hazard Statements:	H302-H318	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 2517-04-6 ]

* 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 [ 2517-04-6 ]
Downstream synthetic route of [ 2517-04-6 ]

[ 2517-04-6 ] Synthesis Path-Upstream 1~8

1
[ 39897-13-7 ]
[ 2517-04-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1996, vol. 39, # 4, p. 817 - 825

2
[ 22742-42-3 ]
[ 2517-04-6 ]

Reference： [1] Tetrahedron Asymmetry, 1992, vol. 3, # 7, p. 859 - 862

3
[ 56-12-2 ]
[ 2517-04-6 ]

Reference： [1] Biochemical Journal, 1956, vol. 64, p. 323,330

4
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 51077-14-6 ]

Reference： [1] Patent: US4902684, 1990, A,

5
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 159749-28-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3703 - 3726
[2] Patent: US5612360, 1997, A,
[3] Patent: US5646165, 1997, A,
[4] Patent: US5681844, 1997, A,
[5] Patent: US5739104, 1998, A,
[6] Patent: WO2012/162635, 2012, A1, . Location in patent: Page/Page column 118
[7] Patent: EP2697246, 2018, B1, . Location in patent: Paragraph 0284
[8] Patent: US5556981, 1996, A,
[9] Patent: US5658939, 1997, A,

6
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 161511-85-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With hydrogenchloride; borane In tetrahydrofuran; sodium carbonate	N-t-Butoxycarbonyl-2(S)-hydroxymethylazetidine Azetidine-2-carboxylic acid (1.25 g, 12.4 mmol) was dissolved in 10 mL of 2M aqueous sodium carbonate and a solution of di-tert-butyldicarbonate in 10 mL of THF was added and the mixture was stirred overnight. The mixture was diluted with water and ether and the layers were separated. The ether layer was washed with water and pH of the combined aqueous phases adjusted to ~2 with phosphoric acid. The mixture was extracted with 4 portions of 20percent isopropanot/chloroform and the combined organic phases were dried, filtered and concentrated. The residue was dissolved in 15 mL of THF and cooled in an ice bath. The solution was treated with 25 mL of borane in THF (1M, 25 mmol) and stirring was continued for 1 hour. The ice bath was removed and the solution stirred for 2 hours and then quenched by the careful addition of 25 mL of 4:1 THF/water. The mixture was stirred for 15 minutes, carefully treated with 25 mL of 1N aqueous HCl, and diluted with ethyl acetate. The layers wre separated and the aqueous layer extracted with 2 additional portions of ethyl acetate. The combined organic fractions were washed with 2M aqueous sodium carbonate, water, brine, and dried, filtered and concentrated to provide 2.18 g (94percent) of the title compound. MS (DCI, NH₃): 188 (MH⁺).

Reference： [1] Patent: US6221865, 2001, B1,

7
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 228857-58-7 ]

Reference： [1] Patent: WO2004/7444, 2004, A2, . Location in patent: Page 79

8
[ 67-56-1 ]
[ 2517-04-6 ]
[ 647854-63-5 ]

Reference： [1] Patent: WO2004/7444, 2004, A2, . Location in patent: Page 60-61

[ 2517-04-6 ] Synthesis Path-Downstream 1~48

1
[ 56-12-2 ]
[ 2517-04-6 ]

Reference： [1]Biochemical Journal,1956,vol. 64,p. 323,330

2
[ 930-88-1 ]
[ 100-52-7 ]
[ 2517-04-6 ]
[ 119751-76-7 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 2703 - 2714

3
[ 67-56-1 ]
[ 2517-04-6 ]
[ 134419-57-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1992,p. 2615 - 2624
[2]Journal of the Chemical Society. Perkin transactions I,1996,p. 1819 - 1824

4
[ 107-97-1 ]
[ 2517-04-6 ]
1-(2-Benzoyloxy-acetyl)-azetidine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1988,vol. 77,p. 285 - 298

5
[ 1217-89-6 ]
[ 4835-96-5 ]
[ 2517-04-6 ]
[ 137441-55-5 ]

Reference： [1]Tetrahedron Letters,1991,vol. 32,p. 5417 - 5420

6
[ 4835-96-5 ]
[ 91-56-5 ]
[ 2517-04-6 ]
[ 137441-51-1 ]

Reference： [1]Tetrahedron Letters,1991,vol. 32,p. 5417 - 5420

7
[ 108-98-5 ]
[ 2517-04-6 ]
[ 52162-05-7 ]
[ 114502-03-3 ]

Reference： [1]Tetrahedron,1987,vol. 43,p. 3881 - 3888

8
[ 501-53-1 ]
[ 2517-04-6 ]
[ 174740-81-9 ]

Reference： [1]Tetrahedron Asymmetry,1992,vol. 3,p. 859 - 862

9
[ 13551-90-1 ]
[ 2517-04-6 ]
[ 134419-51-5 ]

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 2484 - 2488

10
[ 22742-42-3 ]
[ 2517-04-6 ]

Reference： [1]Tetrahedron Asymmetry,1992,vol. 3,p. 859 - 862

11
[ 30562-34-6 ]
[ 2517-04-6 ]
1-((4E,6Z,10E)-(8S,9S,12S,13R,14S,16R)-9-Carbamoyloxy-13-hydroxy-8,14-dimethoxy-4,10,12,16-tetramethyl-3,20,22-trioxo-2-aza-bicyclo[16.3.1]docosa-1⁽²¹⁾,4,6,10,18-pentaen-19-yl)-azetidine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 3806 - 3812

12
[ 13139-17-8 ]
[ 2517-04-6 ]
[ 174740-81-9 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 817 - 825

13
[ 39897-13-7 ]
[ 2517-04-6 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 817 - 825

Yield	Reaction Conditions	Operation in experiment
		, characterized in that Z is selected from the following compounds: 4-aminopyrrolidine-2-carboxylic acid azetidine-2-carboxylic acid 2-carboxymorpholine acid 1,3-dihydro-2H-isoindolecarboxylic acid 4-hydroxypyrrolidine-2-carboxylic acid indoline-2-carboxylic acid isonipecotic acid pyroglutamic acid pipecolic-2-carboxylic acid ...

16
[ 2517-04-6 ]
[ 166814-78-4 ]
[ 273928-41-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 531 - 534

17
[4-((2-acetylamino-4-oxo-butyryloxy)-diphenyl-methyl)phenoxy]-poly(styrene-co-divinylbenzene), copolymer 99:1, trityl loading: 1.47 mmol/g [ No CAS ]
[ 2517-04-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2003,vol. 345,p. 1229 - 1236

18
[ 383-63-1 ]
[ 2517-04-6 ]
1-(2,2,2-Trifluoro-acetyl)-azetidine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2006,vol. 128,p. 4230 - 4231

19
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 228857-58-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0℃; for 3.16667h;	To a stirred suspension of azetidine-2R-caboxylic acid [(5G,] 49.5 mmol) in DCM (100 mL) at [0 C] was added Et3N (8.3 mL) followed by a solution [BOC2O] (12.5 mL) in DCM (10 mL) over the period of 10 min. The resulting reaction mixture was continued stirring for 3 h at 0 [C] and then treated with saturated aqueous citric acid solution (25 mL). The organic layer was separated, washed with brine (50 mL), water (50 mL), brine (50 mL), dried over [MGS04,] and concentrated to give desired product (10.4 g).

Reference： [1]Patent: WO2004/7444,2004,A2 .Location in patent: Page 79

20
[ 67-56-1 ]
[ 2517-04-6 ]
[ 647854-63-5 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 0 - 23℃; for 17.83h;	To a stirred suspension of azetidine-2R-carboxylic acid (504 mg, 4.99 mmol) in [MEOH] (20 mL) at 0 [C] thionyl chloride (0.90 mL) was added over the course of I min. After 50 min the reaction was warmed to [23 C,] stirred for a further 17 h, then concentrated in vacuo to give azetidine-2R-carboxylic acid methyl ester as hydrochloride salt [(HYGROSCOPIC).]

Reference： [1]Patent: WO2004/7444,2004,A2 .Location in patent: Page 60-61

21
[ 705-21-5 ]
[ 2517-04-6 ]
N-(3,5-Dichlorophenylsulfonyl)-azetidine-2(S)-carboxylic Acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium carbonate; In water;	Step A N-(3,5-Dichlorophenylsulfonyl)-azetidine-2(S)-carboxylic Acid To a solution of 2.0 g (19.8 mmol) of (L)-azetidine-2-carboxylic acid and 4.6 g (43.6 mmol) of Na2CO3 in 100 mL of H2O at 0 C. was added 5.8 g (23.8 mmol) of 3,5-dichlorophenylsulfonylchloride. The reaction was allowed to come to room temperature overnight and was then diluted with Et2O and H2O. The layers were separated and the organic phase was discarded. The aqueous phase was acidified to pH~4 with 1M HCl and extracted with EtOAc (4*50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give N-(3,5-dichlorophenylsulfonyl)-azetidine-2-carboxylic acid (6.0 g, 100%) as a white solid. 500 MHz 1H NMR (D4-MeOH): delta 7.83 (s, 2H), 7.80 (s, 1H), 4.63 (t, 1H), 3.95 (q, 1H), 3.80 (m, 1H), 2.40 (m, 2H).

Reference： [1]Patent: US2003/92746,2003,A1

22
[ 174346-82-8 ]
2-(2,5-dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine [ No CAS ]
[ 2517-04-6 ]
[ 310431-87-9 ]

Yield	Reaction Conditions	Operation in experiment
45%		EXAMPLE 71 6-[4-(Azetidin-2-ylmethoxy)-naphthalen-1-yl]-pyridin-2-ylamine Prepared as in Example 24 using L-azetidine-2-carboxylic acid as the precursor to N-t-BOC-azetidine-2-methanol as the reagent to add to 2-(2,5-dimethylpyrrolyl)-6-(4-fluoro-naphth-1-yl)pyridine, followed by removal of blocking groups to afford 45% yield of a solid, mp 135-150 C. 1H-NMR (delta, CDCl3): 2.33 (m, 1H), 2.43 (m, 1H), 3.4 (bs, 1H), 3.54 (m, 1H), 3.67 (m, 1H), 4.20 (m, 2H), 4.37 (m, 1H), 4.625 (bs, 2H), 6.45 (d, J=8, 1H), 6.84 (m, 2H), 7.45 (m, 4H), 8.10 (m, 1H), 8.31 (m, 1H). 13C-NMR (delta, CDCl3): 23.93, 44.25, 57.45, 72.10, 104.39, 106.54, 115.15, 122.00, 125.04, 125.63, 125.73, 126.63, 127.15, 131.50, 132.06, 137.95, 154.59, 157.62, 158.03. MS (%): 306 (parent+1, 100). Anal. Calc'd. for C19H19N3O.2HCl.3/2H2O.1/2(C4H8O): C 56.13, H 6.28, N 9.35. Found: C 56.24, H 6.52, N 9.05.

Reference： [1]Patent: US2001/49379,2001,A1

Yield	Reaction Conditions	Operation in experiment
8.05 g (64%)		EXAMPLE 6 Azetidine-2-carboxylic acid Hydrogenation was carried out on the resultant pure title compound of Example 2 above (70.35 g; 250 mmol) in acetic acid (700 mL), using palladium on carbon catalyst. After hydrogenation was complete, the catalyst was filtered off, and the filtrates were concentrated resulting in a mixture containing a theoretical amount of 25.25 g D,L-AzeOH. Acetic acid was added to the residue, resulting in a 13.5% w/w solution of D,L-AzeOH in acetic acid. A D-tartaric acid resolution was carried out on 5.05 g (50 mmol) of D,L-AzeOH, in analogous fashion to procedures described in international patent application WO 97/41084, yielding 8.05 g (64%) of crude L-AzeOH-D-tartrate with a diastereomeric excess of 95.8%. The crude salt was recrystallized from aqueous ethanol, yielding 6.28 g of pure L-AzeOH-D-tartrate as white crystals. HPLC indicated a diastereomeric excess of 100%.

Yield	Reaction Conditions	Operation in experiment
		Preparation of L-Azetidine-2-carboxylic acid (L-AzeOH) EXAMPLE 9 L-AzeOH-D-tartrate (7.2 g; 28 mmol; e.e. of 99%) was dissolved in hot water (16 mL). At about 45 C. aqueous potassium hydroxide (6 mL; 6 M; 24 mmol) was added over 15 minutes. The solution was cooled to 5 C. at which temperature potassium hydrogen tartrate was formed, which was filtered and washed with cold water (3 mL). The combined filtrate was concentrated under vacuum to give a crude product which was stirred for 1 hour at 60 C. with water (1 mL) and acetone (30 mL). The product was filtered off and dried to yield 2.5 g (89%) of L-AzeOH with an e.e. of 96%.

25
[ 78756-28-2 ]
[ 2517-04-6 ]
(S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5AH)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In N-methyl-acetamide;	a) A solution of 26.9 g (0.171 mol) of 2H-thieno-[3,2-d][1,3]-oxazine-2,4(1H)-dione and 16.1 g (0.171 mol) of L-azetidine-2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid was stirred at 120 for 3 hrs. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione as colorless crystals; m.p. 274.
	With acetic acid; In N-methyl-acetamide;	a) A solution of 26.9 g (171mmol) of 2H-thieno[3,2-d][1,3]oxazine-2,4(1H)-dione (EP 27214) and 16.1 g (171 mmol) of L-azetidine-2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid was stirred at 120 for 3 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione as a colourless crystallizate of m.p. 274.

Reference： [1]Patent: US5885986,1999,A
[2]Patent: US5665718,1997,A

26
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 159749-28-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In sodium hydroxide;	EXAMPLE 43 1-[1-Oxo-2-[5-[2-(2H-tetrazol-5-yl]phenyl]-1H-benzimidazol-1-yl]octyl-2-azetidinecarboxylic Acid 2-Azetidinecarboxylic acid (39.6 moles, 4.0 g) was dissolved in sodium hydroxide 44 ml, 1N and 30 t-butanol. Di-t-butyldicarbonate (39.6 mmoles, 8.83 g) was added over 1 hour. The reaction was stirred at room temperature overnight, washed with 50 ml hexane, and acidified to pH 1.5 using 2 N HCl. The product was extracted with ether. The ether solution was dried and concentrated to yield 6.15 g of N-t-Boc-azetidine-carboxylic acid.
	With sodium hydrogencarbonate; In 1,4-dioxane; water; ethyl acetate;	Example 78 Preparation of N-Boc-L-2-azetidinecarboxylic acid STR130 L-2-azetidinecarboxylic acid (34.5 g, 341.7 mmole) and sodium bicarbonate (33.96 g, 404 mmole) are suspended in 600 mL of deionized water. A solution of di-t-butyl dicarbonate (80.88 g, 370 mmole) in 350 mL of dioxane is added and the slurry is stirred for 18 hours. The slurry is extracted with diethyl ether (2100 mL). The slurry is layered with ethyl acetate (200 mL) and acidified with 1N hydrochloric acid to pH 2 (pH papers). The resulting organic layer is saved and the remaining aqueous layer is further extracted with ethyl acetate (2200 mL). The organic extracts are combined, washed with brine, dried with MgSO4 and the solvent evaporated under vacuum to give the title compound.
	In methanol; dichloromethane; water;	EXAMPLE 21 STR56 Preparation of L-N-BOC-Azetidine-2-Carboxylic Acid L-azetidine-2-carboxylic acid (5 gm, 0.00495 mole) was suspended in 50 ml of 50% MeOH/H2 O. The pH was adjusted to 8 with 4N NaOH. The reaction mixture was cooled to 10 C. and di-t-butyldicarbonate (11.33 gm., 0.00519 mole) was added. The pH was maintained at 9-9.5 with NaOH. After about 0.5 hour, the cooling bath was removed. The reaction mixture was stirred at room temperature for 3-4 hours. TLC was taken in 5% MeOH/CH2 Cl2. When the reaction was complete, the reaction mixture was acidified to pH 3 with 10% citric acid, and extracted with 3*150 ml of EtOAc, dried over MgSO4, filtered and evaporated to give a semi-crystalline compound (9.9 gm.) FAB m/z 292 (M+H)+.

		Example 16.6a. Synthesis of l-(ferZ-butoxycarbonyl)azetidine-2-carboxylic acid A solution of azetidine-2-carboxylic acid (2.0g, 19.8 mmol, 1 equiv), (Boc)20 (8.6 g, 39.6 mmol, 2 equiv) and NaOH (1.6 g, 39.6 mmol, 2 equiv) in water was stirred at rt overnight. The mixture was then adjusted to pH 2 with 0.1 N HCI and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure to give the crude product, which was directly used for the next step without further purification.
	With sodium hydroxide; In ethanol; water; at 0 - 20℃; for 18.0h;	Same condition as to get Pro-OAllyl TFA salt, starting from Boc-Azetidine-2-carboxylic acid). Boc-Azetidine-2-carboxylic acid was obtained from Azetidine-2-carboxylic (7.02 mmol) in the presence of Boc anhydride (1.25 eq); NaOH (1.05 eq); EtOH/water (14/7ml) from 0C to Rt over 18 h.
	With hydrogenchloride; In sodium hydroxide;	EXAMPLE 43 1-[1-Oxo-2-[5-[2-(2H-tetrazol-5-yl]phenyl]-1H-bezimidazol-1-yl]octyl-2-azetidinecarboxylic acid 2-Azetidinecarboxylic acid (39.6 moles, 4.0 g) was dissolved in sodium hydroxide 44 ml, 1N and 30 t-butanol. Di-t-butyldicarbonate (39.6 mmoles, 8.83 g) was added over 1 hour. The reaction was stirred at room temperature overnight, washed with 50 ml hexane, and acidified to pH 1.5 using 2N HCl. The product was extracted with ether. The ether solution was dried and concentrated to yield 6.15 g of N-t-Boc-azetidine-carboxylic acid.
	With sodium hydrogencarbonate; In 1,4-dioxane; water; ethyl acetate;	Example 78 Preparation of N-Boc-L-2-azetidinecarboxylic acid STR131 L-2-azetidinecarboxylic acid (34.5 g, 341.7 mmole) and sodium bicarbonate (33.96 g, 404 mmole) are suspended in 600 mL of deionized water. A solution of di-t-butyl dicarbonate (80.88 g, 370 mmole) in 350 mL of dioxane is added and the slurry is stirred for 18 hours. The slurry is extracted with diethyl ether (2100 mL). The slurry is layered with ethyl acetate (200 mL) and acidified with 1N hydrochloric acid to pH 2 (pH papers). The resulting organic layer is saved and the remaining aqueous layer is further extracted with ethyl acetate (2200 mL). The organic extracts are combined, washed with brine, dried with MgSO4 and the solvent evaporated under vacuum to give the title compound.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3703 - 3726
[2]Patent: US5612360,1997,A
[3]Patent: US5646165,1997,A
[4]Patent: US5739104,1998,A
[5]Patent: WO2012/162635,2012,A1 .Location in patent: Page/Page column 118
[6]Patent: EP2697246,2018,B1 .Location in patent: Paragraph 0284
[7]Patent: US5556981,1996,A
[8]Patent: US5658939,1997,A

27
[ 172411-18-6 ]
[ 2517-04-6 ]
[ 172409-70-0 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In N-methyl-acetamide;	c) A solution of 19.6 g (98.4 mmol) of 5,6-difluoro-2,4-dihydro-1H-3,1-benzoxazine-2,4-dione and 9.95 g (98.4 mmol) of L-azetidine-2-carboxylic acid in 125 ml of dimethylformamide and 25 ml of acetic acid was stirred at 120 for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 16 g (68%) of (S)-5,6-difluoro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione as colourless needles of m.p. >250.

Reference： [1]Patent: US5665718,1997,A

28
[ 78755-94-9 ]
[ 2517-04-6 ]
[ 172410-40-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In N-methyl-acetamide;	a) A solution of 10 g (55.2 mmol) of 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione and 5.66 g (55.2 mmol) of L-azetidine-2-carboxylic acid in 75 ml of dimethylformamide and 15 ml of acetic acid was stirred at 120 for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 6 g (42%) of (S)-5-fluoro-1,2,4,9,10,10a-hexahydroazeto[2,1-c][1,4]benzodiazepine-4,10-dione as beige needles of m.p. 232-233.5.

Reference： [1]Patent: US5665718,1997,A

29
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 51077-14-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In water; acetone;	A. S-1-[(1,1-Dimethylethoxy)carbonyl]azetidine-2-carboxylic acid Di-t-butyl dicarbonate (2.18 g, 9.9 mmol) was added in one portion to a stirred mixture of (L)-azetidine-2-carboxylic acid (1.0 g; 9.9 mmol), triethylamine (2.12 ml; 15.0 mmol), 10 ml of acetone and 10 ml of water. The resulting reaction mixture was stirred 4 hours at room temperature at which time the mixture was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was acidified to pH 3 with 10percent citric acid solution. The resulting acidic mixture was extracted with 2*200 ml ethyl acetate and the combined organic extracts dried (magnesium sulfate) and concentrated to afford the title A compound (2.0 g) as a colorless oil.

Reference： [1]Patent: US4902684,1990,A

30
[ 24424-99-5 ]
[ 100-39-0 ]
[ 2517-04-6 ]
1-[(1,1-dimethylethoxy)carbonyl]-L-azetidine-2-carboxylic acid, phenylmethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; triethylamine; In N-methyl-acetamide; hexane; water; ethyl acetate; acetone;	(A) L-<strong>[2517-04-6]Azetidine-2-carboxylic acid</strong>, phenylmethyl ester L-<strong>[2517-04-6]Azetidine-2-carboxylic acid</strong> (0.88 g, 8.7 mmole) in 30 ml of 1:1 acetone:water was treated with 1.32 g (13.1 mmole) of triethylamine followed by 2.22 g (10.1 mmole) of 1,1-dimethylethoxycarboxylic anhydride. After 24 hours at 25 C., acetone was evaporated in vacuo, 1.0 g of sodium bicarbonate and 50 ml water were added, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified (10% potassium bisulfate) and extracted with ethyl acetate. Drying (sodium sulfate) and evaporation gave 1.8 g of a low melting solid. This was dissolved in 6 ml of dimethylformamide and treated with 1.5 g of sodium bicarbonate and 6 g of benzyl bromide. Stirring at 25 C. for 14 hours caused complete reaction. Water and ethyl acetate were added, layers separated, and organics washed (water), dried (sodium sulfate) and evaporated to an oil. Chromatography on silica in hexane:ethyl acetate (1:1) gave 1-[(1,1-dimethylethoxy)carbonyl] -L-azetidine-2-carboxylic acid, phenylmethyl ester (1.8 g) as a colorless oil.

Reference： [1]Patent: US4576749,1986,A

31
[ 2517-04-6 ]
[ 128740-03-4 ]
ethyl 1,4-diazatricyclo[6.2.0.02,6 ]decane-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; toluene;	a) Ethyl 1,4-diazatricyclo[6.2.0.02,6 ]decane-4-carboxylate STR48 17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight in a water separator with 10 g (0.1 mol) of azetidine-2-carboxylic acid in 200 ml of toluene. Unreacted amino acid is filtered off with suction, the filtrate is concentrated and the residue is distilled. Yield: 13.8 g (65.6% of theory). Boiling point: 108 C./0.35 mbar.

Reference： [1]Patent: US5071999,1991,A

32
5-fluoro-isatoic acid anhydride [ No CAS ]
[ 67-68-5 ]
[ 2517-04-6 ]
(S)-6-fluoro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(a) A mixture of 23.7 g (0.131 mol) of 5-fluoro-isatoic acid anhydride, 13.23 g (0.131 mol) of L-azetidine-2-carboxylic acid and 150 ml of dimethyl sulphoxide is heated to 90 for 3 hours, subsequently evaporated in a high vacuum and the residue is heated in a high vacuum for 17 hours. By recrystallization from methanol there is obtained (S)-6-fluoro-1,10a-dihydroazeto[2,1-c][1,4]benzodiazepine-4,10(2H,9H)-dione of melting point 216-217.

Reference： [1]Patent: US4489003,1984,A

33
[ 24424-99-5 ]
[ 2517-04-6 ]
[ 161511-85-9 ]

Yield	Reaction Conditions	Operation in experiment
2.18 g (94%)	With hydrogenchloride; borane; In tetrahydrofuran; sodium carbonate;	N-t-Butoxycarbonyl-2(S)-hydroxymethylazetidine <strong>[2517-04-6]Azetidine-2-carboxylic acid</strong> (1.25 g, 12.4 mmol) was dissolved in 10 mL of 2M aqueous sodium carbonate and a solution of di-tert-butyldicarbonate in 10 mL of THF was added and the mixture was stirred overnight. The mixture was diluted with water and ether and the layers were separated. The ether layer was washed with water and pH of the combined aqueous phases adjusted to ~2 with phosphoric acid. The mixture was extracted with 4 portions of 20% isopropanot/chloroform and the combined organic phases were dried, filtered and concentrated. The residue was dissolved in 15 mL of THF and cooled in an ice bath. The solution was treated with 25 mL of borane in THF (1M, 25 mmol) and stirring was continued for 1 hour. The ice bath was removed and the solution stirred for 2 hours and then quenched by the careful addition of 25 mL of 4:1 THF/water. The mixture was stirred for 15 minutes, carefully treated with 25 mL of 1N aqueous HCl, and diluted with ethyl acetate. The layers wre separated and the aqueous layer extracted with 2 additional portions of ethyl acetate. The combined organic fractions were washed with 2M aqueous sodium carbonate, water, brine, and dried, filtered and concentrated to provide 2.18 g (94%) of the title compound. MS (DCI, NH3): 188 (MH+).

Reference： [1]Patent: US6221865,2001,B1

34
[ 1155287-93-6 ]
[ 2517-04-6 ]
[ 1155286-71-7 ]

Yield	Reaction Conditions	Operation in experiment
23%		To MR 97 (0.07 g, 0.19 mmol) and D,L-azetidine-2-carboxylic acid (2) (0.06 g, 0.56 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.14 g, 0.94 mmol). The reaction mixture was stirred and heated at 160 C. for 20 min. Cooled to room temperature, diluted with dichloromethane (6 mL), washed with 0.5 N HCl (2×2 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 0.022 g (23%) of BB-01 as light yellow solid. 1H NMR (DMSO-d6, 400 MHz): 9.35 (s, 1H), 8.12 (d, J=7.2 Hz, 1H), 8.05 (s, 1H), 7.66 (s, 1H), 7.45-7.59 (m, 4H), 6.41 (d, J=8.4 Hz, 1H), 4.58 (dd, J=8, 6.8 Hz, 1H), 4.03 (s, 2H), 3.72-3.8 (m, 2H), 2.3-2.41 (m, 2H); MS (APCI+): 454.1 (M+1), LC-MS: 99%.

Reference： [1]Patent: US2009/130076,2009,A1 .Location in patent: Page/Page column 47

35
[ 1155877-95-4 ]
[ 2517-04-6 ]
[ 1155877-05-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 160℃; for 0.333333h;	A-055 Synthesis of 1-[5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-azetidine-2-carboxylic acid To 5-(3'-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (Int-32) (0.2 g, 0.58 mmol) and azetidine-2-carboxylic acid (2) (0.18 g, 1.74 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.44 g, 2.89 mmol). The reaction mixture was stirred and heated at 160 C. for 20 min. Cooled to room temperature, diluted with dichloromethane (8 mL), washed with 0.5 N HCl (2*4 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 3% methanol in dichloromethane to afford 0.19 g (77%) of A-055 as off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.87 (d, J=2.0 Hz, 1H), 7.4-7.47 (m, 2H), 7.37 (s, 1H), 7.2-7.3 (m, 3H), 6.91 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.8 Hz, 1H), 4.08 (dd, J=9.0, 6.8 Hz, 1H), 3.62-3.74 (m, 2H), 3.74 (s, 2H), 3.71 (s, 3H), 2.18-2.3 (m, 2H); MS (APCI+): 427.1 (M+1), LC-MS: 97.1%; HPLC 95.2%

Reference： [1]Patent: US2009/136473,2009,A1 .Location in patent: Page/Page column 39-40

36
[ 1158238-02-8 ]
[ 2517-04-6 ]
[ 1155877-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 160℃; for 0.5h;	To 5-(3'-chloro-6-methoxy-biphenyl-3-ylmethyl)-2-fluoro-pyridine (Int-41, prepared in a similar manner as Int-32) (0.27 g, 0.82 mmol) and azetidine-2-carboxylic acid (0.12 g, 1.24 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.63 g, 4.12 mmol). The reaction mixture was stirred and heated at 160 C. for 30 min. Cooled to room temperature, diluted with dichloromethane (8 mL), washed with 0.5 N HCl (2×4 mL), dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane to afford 0.1 g off-white solid. The solid was dissolved in acetic acid (5 mL), lyophilized to afford 0.102 g (30%) of A-067 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 8.02 (d, J=2.0 Hz, 1H), 7.36-7.5 (m, 5H), 7.14-7.22 (m, 2H), 7.04 (d, J=8.4 Hz, 1H), 6.38 (d, J=8.4 Hz, 1H), 4.58 (dd, J=8.8, 6.8 Hz, 1H), 3.7-3.9 (m, 2H), 3.79 (s, 2H), 3.73 (s, 3H), 2.3-2.55 (m, 2H), 1.91 (s, 3H); MS (APCI+): 409.1 (M+1), LC-MS: 100%.

Reference： [1]Patent: US2009/136473,2009,A1 .Location in patent: Page/Page column 45

37
[ 1155877-93-2 ]
[ 2517-04-6 ]
[ 1155877-43-2 ]

Yield	Reaction Conditions	Operation in experiment
58%		Synthesis of 1-[5-(3'-Chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyrimidin-2-yl]-azetidine-2-carboxylic acid A mixture of azetidine-2-carboxylic acid (56 mg, 0.56 mmol) and sodium hydride (60% weight dispersion, 33 mg, 0.84 mmol) in dimethylformamide (1 mL) was stirred under gas evolution ceased. After 2 min of stirring Int-29 (102 mg, 0.28 mmol) was added, and the reaction heated at 120 C. overnight. The reaction was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (3*5 mL). The combined extracts were dried over sodium sulfate, filtered, and the solvent removed under vacuum. The residue was purified by silica gel column chromatography (9:1 dichloromethane/methanol) to give A-049 (65.3 mg, 58% yield) as a cream solid. 1H NMR (400 MHz, DMSO-d6) delta 2.17-2.28 (m, 1H) 2.55-2.67 (m, 1H) 3.72 (s, 3H) 3.78 (s, 2H) 3.87-4.05 (m, 2H) 4.63 (dd, J=9.12, 5.77 Hz, 1H) 6.93 (d, J=8.59 Hz, 1H) 7.25-7.36 (m, 2H) 7.38 (s, 1H) 7.41-7.47 (m, 2H) 8.25 (s, 2H) 12.64 (br. s., 1H). LCMS=95.0%

Reference： [1]Patent: US2009/136473,2009,A1 .Location in patent: Page/Page column 57

38
[ 1227243-19-7 ]
[ 2517-04-6 ]
[ 1227243-20-0 ]

Yield	Reaction Conditions	Operation in experiment
48%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 150℃; for 1.0h;	A mixture of compound D-24 (65 mg, 0.17 mmol), D,L-<strong>[2517-04-6]Azetidine-2-carboxylic acid</strong> (34 mg, 0.34 mmole) and DBU (304 mg, 2 mmole) was stirred at 150 0C for 1 hr. and cooled to r.t.,. A saturated NH4CI aq. was added and the aqueous portion was extracted with DCM (5 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 35 mg of D-26 in 48 % yield. To a solution of D-26 (35 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.15 ml), solid was washed with ether to give 35 mg of D-26 HCl salt as solid. 1H- NMR (400 MHz, DMSO-d6): 2.40 (IH, m), 2.46 (3H, s), 2.77 (IH, m), 4.08 (2H, s), 4.12 (IH, m), 4.21 (IH, m), 5.10 (IH, m), 6.90 (IH, br), 7.65 (3H, m), 7.78 (IH, s), 7.94 (IH, s), 7.96 (IH, m), 8.11 (IH, m), 8.17 (IH, s), 8.85 (IH, s). MS(APCI+): 433.1 (M+ 1). LC-MS: 97 %.
48%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 150℃; for 1.0h;	Synthesis of l-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-azetidine-2-carboxylic acid (D-26): A mixture of compound D-24 (65 mg, 0.17 mmol), D,L-<strong>[2517-04-6]Azetidine-2-carboxylic acid</strong> (34 mg, 0.34 mmole) and DBU (304 mg, 2 mmole) was stirred at 150 oC for 1 hr. and cooled to r.t.,. A saturated NH4C1 aq. was added and the aqueous portion was extracted with DCM (5 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 35 mg of D-26 in 48 % yield. To a solution of D-26 (35 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.15 ml), solid was washed with ether to give 35 mg of D-26 HCl salt as solid. 1H- NMR (400 MHz, DMSO-d6): 2.40 (IH, m), 2.46 (3H, s), 2.77 (IH, m), 4.08 (2H, s), 4.12 (IH, m), 4.21 (IH, m), 5.10 (IH, m), 6.90 (IH, br), 7.65 (3H, m), 7.78 (IH, s), 7.94 (IH, s), 7.96 (IH, m), 8.11 (IH, m), 8.17 (IH, s), 8.85 (IH, s). MS(APCI+): 433.1 (M+l). LC-MS: 97 %.

Reference： [1]Patent: WO2010/59838,2010,A2 .Location in patent: Page/Page column 117-118
[2]Patent: WO2010/59836,2010,A1 .Location in patent: Page/Page column 59

39
C₂₂H₁₉Cl₂FN₄O₃ [ No CAS ]
[ 2517-04-6 ]
C₂₆H₂₅ClFN₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 120℃; for 4.0h;	Step 3: Intermediate 3011 B (50 mg, 0.1 1 mmol) is charged in a vial and dissolved in NMP (0.5 ml_). Diisopropylethylamine (55 muIota_, 0.31 mmol, 3.0 eq) is added followed by azetidine-2- carboxylic acid (Toronto) (21 mg, 0.21 mmol, 2.0 eq) and the solution is stirred at 120 C for 4 h. Following completion of the reaction, the solution is filtered and purified by preparative HPLC to provide compound 3011 (tR: 1 .71 , (M+H)+: 542.3/544.3).

Reference： [1]Patent: WO2013/152063,2013,A1 .Location in patent: Page/Page column 50-51

40
[ 75454-03-4 ]
[ 2517-04-6 ]
C₁₃H₁₈N₂O₄S [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 82 - 85

41
[ 2517-04-6 ]
[ 766483-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; sodium hydrogencarbonate; In ethanol;	Step 1. Synthesis of azetidine-2-carboxylic acid ethyl ester (#F1). Thionyl chloride (5.5 mL, 74.3 mmol) was added to a solution of azetidine-2-carboxylic acid (5.0 g, 49.5 mmol) in ethanol at 0 C. The reaction mixture was stirred at room temperature for 2 h. After the depletion of the starting material, the reaction was cooled to 0 C. and treated with solid NaHCO3. The slurry was filtered through a Celite pad and washed with (100 mL) of ethanol. The filtrate was stripped under reduced pressure to give a residue then dissolved in DCM and washed with water, brine, dried and concentrated to give #F1 (6.3 g, 100% crude). The residue was used for the next step without any further purification. Rf: 0.6 (10% MeOH in DCM). GCMS m/z=129.2; 1H NMR (300 MHz, D2O): delta 1.33 (t, J=6.9 Hz, 3H), 2.70-2.92 (m, 2H), 3.95-4.08 (m, 1H), 4.16-4.25 (m, 1H), 4.37 (q, J=6.9 Hz, 2H), 5.21 (t, J=9.9 Hz, 1H).

Reference： [1]Patent: US2014/155390,2014,A1 .Location in patent: Page/Page column

42
[ 1346447-80-0 ]
[ 2517-04-6 ]
N-(3-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)azetidine-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 197 - 211

43
[ 64-17-5 ]
[ 2517-04-6 ]
[ 766483-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 0 - 20℃; for 2.0h;	Thionyl chloride (5.5 mL, 74.3 mmol) was added to a solution of azetidine-2-carboxylic acid (5.0 g, 49.5 mmol) in ethanol at 0 C. The reaction mixture was stirred at room temperature for 2 h. After the depletion of the starting material, the reaction was cooled to 0 C and treated with solid NaHC03. The slurry was filtered through a Celite pad and washed with (100 mL) of ethanol. The filtrate was stripped under reduced pressure to give a residue then dissolved in DCM and washed with water, brine, dried and concentrated to give F1 (6.3 g, 100% crude). The residue was used for the next step without any further purification. Rf: 0.6 (10% MeOH in DCM). GCMS m/z = 129.2; 1 H NMR (300 MHz, D20): delta 1.33 (t, J = 6.9 Hz, 3H), 2.70 - 2.92 (m, 2H), 3.95 - 4.08 (m, 1 H), 4.16 - 4.25 (m, 1 H), 4.37 (q, J = 6.9 Hz, 2H), 5.21 (t, J = 9.9 Hz, 1 H).

Reference： [1]Patent: WO2015/181676,2015,A1 .Location in patent: Page/Page column 150-151

44
[ 10342-83-3 ]
[ 2517-04-6 ]
N-[4-(1-oxopropyl)phenyl]-DL-azetidine-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 3703 - 3726

45
1-((2-(trimethylsilyl)ethyl)sulfonyl)azetidine-2-carboxylic acid [ No CAS ]
[ 2517-04-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With cesium fluoride; In N,N-dimethyl-formamide; at 95℃; for 48.0h;	To a stirred solution of 3z (30 mg, 0.113 mmol) in dry DMF (2 mL) was added cesium fluoride (0.34 mmol). The mixture was stirred at 95 C for 48 h. The solvent was removed in vacuo. The solid residue was extracted with CHCl3 (3 * 1 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography (MeOH/EtOAc 20-50%) to afford (±)-AZE (6 mg) in 52% yield. 1H NMR (CDCl3, 300 MHz): delta = 4.90 (dd, J = 9.3, 5.7 Hz, 1 H), 1.49-1.43 (m, 2 H), 2.60-2.72 (m, 1 H), 2.49-2.33 (m, 1 H).

Reference： [1]Tetrahedron,2017,vol. 73,p. 5096 - 5106

46
[ 98-59-9 ]
[ 2517-04-6 ]
[ 39897-13-7 ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 652 - 656

47
acetyl coenzyme A sodium salt [ No CAS ]
[ 2517-04-6 ]
[ 37712-76-8 ]

Reference： [1]Green Chemistry,2018,vol. 20,p. 3426 - 3431

48
[ 814-68-6 ]
[ 2517-04-6 ]
1-acryloylazetidine-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With potassium hydroxide; at 0℃; for 1.0h;	A solution of tert-butyl 4-(2-bromoacetyl)-1 H-pyrrolo[2,3-b]pyridine-1 -carboxylate (which can be prepared according to J. Med. Chem., 2008, 51(3), 487) (0.051 g, 0.15 mmol), 2- aminopyrimidine (0.018g, 0.188 mmol) and sodium bicarbonate (0.025g, 0.03 mmol) in isopropanol (1 ml_) was stirred and heated at 80C for 2h. After cooling, the mixture was concentrated in vacuo and the residue was suspended in water and extracted with DCM. The organic phase was filtered through a phase separator and the filtrate was concentrated in vacuo. The residue was purified by FCC eluting with 0-4% methanol in DCM to give the title compound (0.017g) as a yellow gum. LCMS (Method 3) Rt 1.14 min m/z 280 (MH+-t-Bu]

Reference： [1]Patent: WO2019/58132,2019,A1 .Location in patent: Page/Page column 78

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P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 2517-04-6 ] {[proInfo.proName]}

Quality Control of [ 2517-04-6 ]

Related Doc. of [ 2517-04-6 ]

Product Details of [ 2517-04-6 ]

Calculated chemistry of [ 2517-04-6 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 2517-04-6 ]

Application In Synthesis of [ 2517-04-6 ]

[ 2517-04-6 ] Synthesis Path-Upstream 1~8

[ 2517-04-6 ] Synthesis Path-Downstream 1~48

Related Functional Groups of [ 2517-04-6 ]

Carboxylic Acids

Related Parent Nucleus of [ 2517-04-6 ]

Aliphatic Heterocycles

Azetidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 2517-04-6 ]

Related Parent Nucleus of
[ 2517-04-6 ]