* 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.
Stage #1: With sodium hydroxide; water In ethanol at 0 - 20℃; Stage #2: With hydrogenchloride In water
Example 15 (S)-1-(tert-Butoxycarbonyl)azetidine-2-carboxylic Acid (13). To a solution of (S)-2-azetidinecarboxylic acid 12 (1.0 g, 10.0 mmol) and di-tert-butyl dicarbonate (2.83 g, 12.5 mmol) in ethanol (20 mL) and water (10 mL) was added NaOH (420 mg, 10.5 mmol) at 0° C. The mixture was stirred overnight at ambient temperature. After evaporation of the ethanol, water (20 mL) was added, then acidified with diluted HCl to a pH of 3 and extracted with ethyl acetate (50 mL*3). The combined ethyl acetate was washed with water (30 mL) and saturated NaCl (30 mL), and dried over Na2 SO4. After evaporation of the ethyl acetate to afford 1.98 g (100percent) of 13 as a white solid. 1H NMR (300 MHz, CDCl3) δ 4.79 (m, 1H), 3.93 (m, 2H), 2.46 (m, 2H), 1.48 (s, 9H).
Reference：
[1] Journal of Medicinal Chemistry, 2005, vol. 48, # 24, p. 7637 - 7647
[2] Patent: US2009/68105, 2009, A1, . Location in patent: Page/Page column 11
[3] Chemical Communications, 2016, vol. 52, # 7, p. 1354 - 1357
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 1998, vol. 41, # 5, p. 451 - 463
[5] Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2251 - 2259
[6] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S251 - S253
[7] Angewandte Chemie - International Edition, 2013, vol. 52, # 30, p. 7829 - 7832[8] Angew. Chem., 2013, vol. 125, # 30, p. 7983 - 7986,4
[9] Journal of Medicinal Chemistry, 1986, vol. 29, # 10, p. 2104 - 2107
[10] Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 2090 - 2099
[11] Journal of Medicinal Chemistry, 1996, vol. 39, # 4, p. 817 - 825
[12] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 605 - 618
[13] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 23, p. 4223 - 4228
[14] Patent: US2006/183745, 2006, A1, . Location in patent: Page/Page column 55
[15] Patent: US5948793, 1999, A,
[16] Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 3020 - 3029
[17] Patent: US6685617, 2004, B1, . Location in patent: Page/Page column 144
[18] Journal of the American Chemical Society, 2017, vol. 139, # 32, p. 11300 - 11306
9
[ 2133-34-8 ]
[ 51077-14-6 ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: for 12 h;
EXAMPLE 3 Methanol (40mL) was added to the (R)-4-phthalimido-2-chlorobutyric acid (5 g) and the mixture was stirred. To the mixture 80percent hydrazine hydrate (2.3 g) was added with stirring, and the mixture was stirred at 40°C overnight. Water (30 mL) was then added to the mixture with stirring, and 47percent sulfuric acid (13 mL) was added. The mixture was stirred at room temperature for 4 hours and the precipitate was filtered out. The filtrate was concentrated under reduced pressure to recover an aqueous solution of (R)-4-amino-2-chlorobutyric acid. A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows:1H-NMR (D2O): δ 2.15-2.45 (m,2H), 3.19 (t,2H), 4.45 (t, 1H) The solution was then placed in an ice bath and an aqueous sodium hydroxide solution (400 g/L) was added to the solution in order to adjust the pH of the solution to 2.0. Water was added to the solution to obtain about 130 g of solution. The resultant solution was heated to about 90°C with stirring. Magnesium hydroxide (1.0 g) was added to the solution and the solution was stirred for 5 hours to produce an aqueous solution of (S)-azetidine-2-carboxylic acid. A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows: 1H-NMR (CD3OD): δ 2.15 (m,1H), 2.58 (m,1H), 3.90 (m,1H), 4.02 (q,1H), 4.60 (t,1H) The solution was spontaneously cooled to room temperature. Sodium carbonate (2.1 g) and DIBOC.(TM). (4.3 g) were added with stirring and the mixture was further stirred overnight. Hydrochloric acid (6N) was added to the solution in order to adjust the pH of the solution to 2.0. The resultant solution was extracted with ethyl acetate three times. The resultant organic solution was washed with a saturated brine solution and dried with sodium sulfate. The solvent in the mixture was then removed to recover (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (2.1 g) (yield 55percent, optical purity 89.3 percente.e.). A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows:1H-NMR (CDCl3): δ 1.48 (s,9H), 2.40-2.60 (bs,2H), 3.80-4.00 (bs,2H), 4.80 (t,1H)
41%
Stage #1: for 12 h;
EXAMPLE 4 Dioxane (3 mL) was added to (S)-4-phthalimido-2-hydroxybutyric acid (1.0 g) in a nitrogen atmosphere. Thionyl chloride (2.5 g) was added to the mixture with stirring, and the mixture was stirred at 40°C for one hour. Pyridine (0.06 g) was then added to the mixture and further stirred at 40°C for 15 hours to produce a solution of dioxane and (R)-4-phthalimido-2-chlorobutyryl chloride. The solution was placed in an ice bath and then water (5 mL) was added with stirring. The solution was extracted with ethyl acetate at room temperature. The resultant organic solution was washed with a brine solution and was dried with mirabilite. The resultant solution containing ethyl acetate was concentrated under reduced pressure to recover (R)-4-phthalimido-2-chlorobutyric acid. Methanol (9 mL) was added to the compound. To the mixture 80percent hydrazine hydrate (0.5 g) was added with stirring, and the mixture was stirred at 40°C overnight. Water (6 mL) was then added to the solution with stirring and 47percent sulfuric acid (3 mL) was added to the solution. The mixture was stirred at room temperature for three hours and the precipitate was filtered. The filtrate was concentrated under reduced pressure to produce an aqueous solution of (R)-4-amino-2-chlorobutyric acid. The solution was then placed in an ice bath and an aqueous sodium hydroxide solution (400 g/L) was added to the solution in order to adjust the pH of the solution to 2.0. Water was added to the solution to obtain about 30 g of solution. The resultant solution was heated to about 80°C with stirring. Magnesium hydroxide (0.20 g) was added to the solution and the solution was stirred for 10 hours to produce an aqueous solution of (S)-azetidine-2-carboxylic acid. The solution was spontaneously cooled to room temperature. Sodium carbonate (0.43 g) and DIBOC.(TM). (0.90 g) were added with stirring and the mixture was further stirred overnight. Hydrochloric acid (6N) was added to the solution in order to adjust the pH of the solution to 2.0. The resultant mixture was extracted with ethyl acetate three times. The resultant organic solution was washed with a saturated brine solution and dried with sodium sulfate. The solvent in the mixture was then removed to recover (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (0.32 g) (yield 41percent, optical purity 87.1 percente.e.).
Reference：
[1] Journal of the American Chemical Society, 1981, vol. 103, # 9, p. 2409 - 2410
13
[ 24424-99-5 ]
[ 2133-34-8 ]
[ 159749-28-7 ]
Yield
Reaction Conditions
Operation in experiment
63.1%
Stage #1: With 4-methyl-morpholine In 1,4-dioxane; water at 0 - 25℃; for 22 h; Stage #2: With hydrogenchloride In water at 0℃;
A mixture of (S)-2-azetidinecarboxyic acid (1Og, 98.9mmol), di-tert butyl dicarbonate (28.06g, 128.6mmol), N-methyl morpholine (11.5g, 113.7mmol), 1,4-dioxane (160ml) and water (160ml) was stirred at O0C for 4 hours and then at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in water, washed with DCM and the aqueous layer acidified to pH 1.0 at O0C with concentrated hydrochloric acid. The aqueous layer was extracted with DCM and the organic layer dried (Na2SO4) over anhydrous sodium sulfate to give iV-tert-butyloxycarbonylazetidin-2-yl carboxylic acid (12.61g, 63.1percent) as an oil; NMR Spectrum (CDCl3) 1.42 (s, 9H), 2.40 (m, IH), 2.59 (m, IH), 3.90 (m, 2H), 4.80 (t, IH).
Reference：
[1] Patent: WO2006/100461, 2006, A1, . Location in patent: Page/Page column 79
[2] Patent: US5409946, 1995, A,
14
[ 2133-34-8 ]
[ 104587-62-4 ]
Reference：
[1] Synlett, 1998, # 10, p. 1162 - 1164
15
[ 24424-99-5 ]
[ 2133-34-8 ]
[ 161511-85-9 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2002, vol. 45, # 5, p. 423 - 434
SYNTHETIC EXAMPLES; Example 1; Synthesis of (S)-1-[(R)-7-(3,5-Dichloro-phenyl)-5-methyl-6-oxo-5-(4-pyrimidin-5-yl-benzyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-azetidine-2-carboxylic acid; Thionyl chloride (0.144 mL) was added to a solution of (S)-(-)-2-azetidinecarboxylic acid (0.1 g, 0.99 mmol) in CH3OH (4 mL) and stirred at room temperature for 3 h. The volatiles were removed in vacuo to afford 0.180 g of the desired (s)-(-)-azetidine carboxylic acid methyl ester hydrochloride, which was used without further purification.
Example 15 (S)-1-(tert-Butoxycarbonyl)azetidine-2-carboxylic Acid (13). To a solution of (S)-2-azetidinecarboxylic acid 12 (1.0 g, 10.0 mmol) and di-tert-butyl dicarbonate (2.83 g, 12.5 mmol) in ethanol (20 mL) and water (10 mL) was added NaOH (420 mg, 10.5 mmol) at 0 C. The mixture was stirred overnight at ambient temperature. After evaporation of the ethanol, water (20 mL) was added, then acidified with diluted HCl to a pH of 3 and extracted with ethyl acetate (50 mL*3). The combined ethyl acetate was washed with water (30 mL) and saturated NaCl (30 mL), and dried over Na2 SO4. After evaporation of the ethyl acetate to afford 1.98 g (100%) of 13 as a white solid. 1H NMR (300 MHz, CDCl3) delta 4.79 (m, 1H), 3.93 (m, 2H), 2.46 (m, 2H), 1.48 (s, 9H).
With tetramethyl ammoniumhydroxide; In acetonitrile; at 25℃; for 77h;
(a) (S)-1-(tert-Butyloxycarbonyl)azetidine-2-carboxylic acid.; A mixture of <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (1.0 g, 9.9 mmol, Toronto Research), tetramethylammonium hydroxide pentahydrate (2.0 g, 11 mmol, Aldrich) and di-tert-butyl dicarbonate (3.2 g, 15 mmol, Aldrich) in acetonitrile (50 mL) was stirred for 3 d at 25 C. Additional amount of di-tert-butyl dicarbonate (1.0 g, 4.6 mmol) was added and the mixture was stirred for 5 h at 25 C. The reaction mixture was evaporated under reduced pressure and the residue was partitioned between aqueous solution of K2CO3 and 1:1 mixture of EtOAc/hexane. The aqueous phase was separated, acidified with aqueous solution of citric acid, and extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was dried under vacuo to afford the title compound as a white solid. MS (ESI, neg. ion.) m/z: 200 (M-1).
With 4-methyl-morpholine; sodium hydrogencarbonate; In 1,4-dioxane; water;
7a. 1-t-butyloxycarbonyl-2-(S)-azetidinecarboxylic acid To an ice cooled solution of 2-(S)-azetidinecarboxylic acid (10.15 g, 100.39 mmol) in 1,4 dioxane:water (300 mL, 1:1) was added di-tert-butyl dicarbonate (28.48 g, 130.51 mmol), followed by 4-methylmorpholine (11.68 g, 115.45 mmol). The reaction mixture continued to stir 18 hours, gradually warming to room temperature. The reaction mixture was then poured into a ice cooled saturated solution of sodium bicarbonate (250 mL) and washed with ethyl acetate (3*250 ml). The aqueous was then acidified with potassium hydrogen sulfate (pH=1) and the product extracted with ethyl acetate (3*300 ml). These extracts were then dried (Na2 SO4), filtered and concentrated in vacuo. The resulting semisolid was carried forward without further purification. MS (DCI/NH3) m/e 202 (M+H)+, 219 (M+NH4)+. 1 H NMR (CDCl3, 300 MHz) delta: 10.0 (br s, 1H), 4.81-4.76 (t, J=15 Hz, 1H), 3.99-3.83 (m, 2H), 2.62-2.38 (m, 2H), 1.48 (s, 9H).
To a mixture of (S)-(-)-2-azetidinecarboxylic acid (110 mg, 1.1 mmol), Boc2O (290 mg, 1.30 mmol), and DMAP (0.017 g, 0.14 mmol) in 4:1 DMF/H2O (10 mL) is added Et3N (0.30 mL, 2.2 mmol). The reaction mixture is stirred at rt for 68 h, and then is concentrated. The concentrate is diluted with EtOAc, and the EtOAc solution is washed with cold 10% KHSO4. The combined organic extracts are dried, filtered and concentrated to give the title compound as a colorless oil: TLC (750:250:1 Hexanes/acetone/HCO2H) Rf=0.26; 1H NMR (CD3OD) delta 4.97 (1H), 4.57 (1H), 3.98 (1H), 3.87 (1H), 2.57 (H), 2.13 (1H), 1.42 (9H); MS (-ESI) m/z 200.3.
To a mixture of (5)-azetidine-2-carboxylic acid (1.0 g, 9.89 mmol) in aqueous NaOH solution (2.5 mL, 10 mmol, 4M) was added aqueous sodium hydroxide solution (3.0 mL, 12 mmol, 4 M) drop-wise at 0C, followed by drop-wise addition of benzylcarbonochloridate (1.53 mL, 10.88 mmol). After the addition was complete, the reaction was stirred at room temperature overnight. The reaction mixture was then washed with diethyl ether (30 mL), and the water layer was acidified with dilute hydrochloric acid (1M). The water layer was then extracted with ethyl acetate (30 mL x 3), and the combined ethyl acetate extracts were dried over Na2SO4, filtered and concentrated to give (S)-1-((benzyloxy)carbonyl)azetidine-2-carboxylic acid (2.1 g, 90.2% yield) as a colorless oil. LC-MS: m/z = 236 [M+Hf?, ee> 99% (CHIRALPAK AS-H, 15% ethanol / hexane).
53%
To a solution of <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (101.1 mg, 1 mmol) in 2N aqueousNaOH (0.675 ml) is added benzylchloroformiate (169 ul, 204.7 mg, 1.2 eq.) and theresulting mixture is stirred at rt for 2 h. The aqueous phase is washed once with EtiO.The aqueous solution is set to pH=2 with a concentrated aqueous HCI solution and thensaturated with solid Na2SO4. It is extracted three times with AcOEt. The combinedorganic phase is dried over Na2SO4. The solvents are evaporated under a stream of airand the crude oil dried under high vacuum overnight, yielding the title compound (126mg) in 53% as a colourless oil: fa = 0.76 min (LC-3), ESI-MS (pos.): m/z 277.16[M+Naf; ^-NMR (CDC13): 5 (ppm) 2.53 (bs, 2H, C^CHaN), 4.01 (t, 2H, CJJbN),4.82 (t, 1 H, CHC02H), 5.15 (s, 2H, OCtfcPh), 7.35 (s, 5 H, Harom.).
In water; N,N-dimethyl-formamide; at 0 - 20℃;
Example 301 (S)-2-[4-(4-Cyclopropylcarbamoyl-phenyl)-thiazol-2-ylcarbamoyl]-azetidine-1-carboxylic acid benzyl ester (Compound 5301) (S)-Azetidine-1,2-dicarboxylic acid 1-benzyl ester (S)-Azetidine-2-carboxylic acid (250.4 mg, 2.5 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0 C., and DIEA (645 muL, 3.7 mmol) was added followed by benzyl chloroformate (530 muL, 3.7 mmol). The reaction was stirred at 0 C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
EXAMPLE 3 Methanol (40mL) was added to the (R)-4-phthalimido-2-chlorobutyric acid (5 g) and the mixture was stirred. To the mixture 80percent hydrazine hydrate (2.3 g) was added with stirring, and the mixture was stirred at 40°C overnight. Water (30 mL) was then added to the mixture with stirring, and 47percent sulfuric acid (13 mL) was added. The mixture was stirred at room temperature for 4 hours and the precipitate was filtered out. The filtrate was concentrated under reduced pressure to recover an aqueous solution of (R)-4-amino-2-chlorobutyric acid. A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows:1H-NMR (D2O): delta 2.15-2.45 (m,2H), 3.19 (t,2H), 4.45 (t, 1H) The solution was then placed in an ice bath and an aqueous sodium hydroxide solution (400 g/L) was added to the solution in order to adjust the pH of the solution to 2.0. Water was added to the solution to obtain about 130 g of solution. The resultant solution was heated to about 90°C with stirring. Magnesium hydroxide (1.0 g) was added to the solution and the solution was stirred for 5 hours to produce an aqueous solution of (S)-azetidine-2-carboxylic acid. A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows: 1H-NMR (CD3OD): delta 2.15 (m,1H), 2.58 (m,1H), 3.90 (m,1H), 4.02 (q,1H), 4.60 (t,1H) The solution was spontaneously cooled to room temperature. Sodium carbonate (2.1 g) and DIBOC.(TM). (4.3 g) were added with stirring and the mixture was further stirred overnight. Hydrochloric acid (6N) was added to the solution in order to adjust the pH of the solution to 2.0. The resultant solution was extracted with ethyl acetate three times. The resultant organic solution was washed with a saturated brine solution and dried with sodium sulfate. The solvent in the mixture was then removed to recover (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (2.1 g) (yield 55percent, optical purity 89.3 percente.e.). A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows:1H-NMR (CDCl3): delta 1.48 (s,9H), 2.40-2.60 (bs,2H), 3.80-4.00 (bs,2H), 4.80 (t,1H)
41%
EXAMPLE 4 Dioxane (3 mL) was added to (S)-4-phthalimido-2-hydroxybutyric acid (1.0 g) in a nitrogen atmosphere. Thionyl chloride (2.5 g) was added to the mixture with stirring, and the mixture was stirred at 40°C for one hour. Pyridine (0.06 g) was then added to the mixture and further stirred at 40°C for 15 hours to produce a solution of dioxane and (R)-4-phthalimido-2-chlorobutyryl chloride. The solution was placed in an ice bath and then water (5 mL) was added with stirring. The solution was extracted with ethyl acetate at room temperature. The resultant organic solution was washed with a brine solution and was dried with mirabilite. The resultant solution containing ethyl acetate was concentrated under reduced pressure to recover (R)-4-phthalimido-2-chlorobutyric acid. Methanol (9 mL) was added to the compound. To the mixture 80percent hydrazine hydrate (0.5 g) was added with stirring, and the mixture was stirred at 40°C overnight. Water (6 mL) was then added to the solution with stirring and 47percent sulfuric acid (3 mL) was added to the solution. The mixture was stirred at room temperature for three hours and the precipitate was filtered. The filtrate was concentrated under reduced pressure to produce an aqueous solution of (R)-4-amino-2-chlorobutyric acid. The solution was then placed in an ice bath and an aqueous sodium hydroxide solution (400 g/L) was added to the solution in order to adjust the pH of the solution to 2.0. Water was added to the solution to obtain about 30 g of solution. The resultant solution was heated to about 80°C with stirring. Magnesium hydroxide (0.20 g) was added to the solution and the solution was stirred for 10 hours to produce an aqueous solution of (S)-azetidine-2-carboxylic acid. The solution was spontaneously cooled to room temperature. Sodium carbonate (0.43 g) and DIBOC.(TM). (0.90 g) were added with stirring and the mixture was further stirred overnight. Hydrochloric acid (6N) was added to the solution in order to adjust the pH of the solution to 2.0. The resultant mixture was extracted with ethyl acetate three times. The resultant organic solution was washed with a saturated brine solution and dried with sodium sulfate. The solvent in the mixture was then removed to recover (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (0.32 g) (yield 41percent, optical purity 87.1 percente.e.).
With magnesium hydroxide; sodium hydroxide; In water; at 90℃; for 5h;
The solution was then placed in an ice bath and an aqueous sodium hydroxide solution (400 g/L) was added to the solution in order to adjust the pH of the solution to 2.0. Water was added to the solution to obtain about 130 g of solution. The resultant solution was heated to about 90C with stirring. Magnesium hydroxide (1.0 g) was added to the solution and the solution was stirred for 5 hours to produce an aqueous solution of (S)-azetidine-2-carboxylic acid. A small amount of the solution was sampled to identify the molecular structure by NMR. The analytical data was as follows: 1H-NMR (CD3OD): delta 2.15 (m,1H), 2.58 (m,1H), 3.90 (m,1H), 4.02 (q,1H), 4.60 (t,1H)
With magnesium hydroxide; sodium hydroxide; at 80℃; for 10h;pH 2.0;
EXAMPLE 4 Dioxane (3 mL) was added to (S)-4-phthalimido-2-hydroxybutyric acid (1.0 g) in a nitrogen atmosphere. Thionyl chloride (2.5 g) was added to the mixture with stirring, and the mixture was stirred at 40C for one hour. Pyridine (0.06 g) was then added to the mixture and further stirred at 40C for 15 hours to produce a solution of dioxane and (R)-4-phthalimido-2-chlorobutyryl chloride. The solution was placed in an ice bath and then water (5 mL) was added with stirring. The solution was extracted with ethyl acetate at room temperature. The resultant organic solution was washed with a brine solution and was dried with mirabilite. The resultant solution containing ethyl acetate was concentrated under reduced pressure to recover (R)-4-phthalimido-2-chlorobutyric acid. Methanol (9 mL) was added to the compound. To the mixture 80% hydrazine hydrate (0.5 g) was added with stirring, and the mixture was stirred at 40C overnight. Water (6 mL) was then added to the solution with stirring and 47% sulfuric acid (3 mL) was added to the solution. The mixture was stirred at room temperature for three hours and the precipitate was filtered. The filtrate was concentrated under reduced pressure to produce an aqueous solution of (R)-4-amino-2-chlorobutyric acid. The solution was then placed in an ice bath and an aqueous sodium hydroxide solution (400 g/L) was added to the solution in order to adjust the pH of the solution to 2.0. Water was added to the solution to obtain about 30 g of solution. The resultant solution was heated to about 80C with stirring. Magnesium hydroxide (0.20 g) was added to the solution and the solution was stirred for 10 hours to produce an aqueous solution of (S)-azetidine-2-carboxylic acid. The solution was spontaneously cooled to room temperature. Sodium carbonate (0.43 g) and DIBOC (0.90 g) were added with stirring and the mixture was further stirred overnight. Hydrochloric acid (6N) was added to the solution in order to adjust the pH of the solution to 2.0. The resultant mixture was extracted with ethyl acetate three times. The resultant organic solution was washed with a saturated brine solution and dried with sodium sulfate. The solvent in the mixture was then removed to recover (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (0.32 g) (yield 41%, optical purity 87.1 %e.e.).
Example 16 A mixture of an aqueous N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylic acid solution (74.21 g., net: 23.7 g), which had been obtained in a similar manner as described in Example 15, and 10% palladium hydroxide on carbon (dry weight: 2.08 g) was stirred under hydrogen atmosphere at 50 C. for 21 hours. Acetic acid (0.76 g) was added to the reaction mixture, kept at the same temperature for 1 hour, and filtered to remove the catalyst. Separated water layer was concentrated under reduced pressure to give a residue, which was dried under reduced pressure to give a white solid of (S)-azetidine-2-carboxylic acid (12.08 g; >99% e.e). Yield 96%.
90%
EXAMPLE 11 Synthesis of (S)-azetidine-2-carboxylic Acid STR16 A reaction flask was charged with the (S)-N-benzyloxycarbonylazetidine-2-carboxylic acid obtained in Example 8 (1.50 g, 6.38 mmol), palladium carbon (10%, 497 mg) and methanol (15 mL), and the mixture was stirred in a hydrogen gas atmosphere at 25 C. for 3 hours. The palladium carbon was filtered off and washed with water, The filtrate and washings were combined and concentrated to give white crystals (0.58 g). Based on its proton NMR spectrum (FIG. 8), this product was identified as the desired product (S)-azetidine-2-carboxylic acid (yield 90%).
Without isolating the (S)-azetidine-2-carboxylic acid formedinthereaction mixture, 2.5 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 1.13 g of sodium carbonate and 1.2 ml of di-tert-butyl dicarbonate were added to the reaction mixture and the reaction was further carried out at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 2.5 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 2.6 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 1.3 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 1.3 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 1.3 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, 1.3 ml of di-tert-butyl dicarbonate was added to the reaction mixture and the reaction was further conducted at room temperature overnight.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, the reaction mixture was adjusted to pH 7.0 with concentrated hydrochloric acid and 50.5 g of sodium carbonate and 31.6 g of di-tert-butyl dicarbonate were serially added to the reaction mixture.
Without isolating the (S)-azetidine-2-carboxylic acid formed in the reaction mixture, the reaction mixture was adjusted to pH 7.0 with concentrated hydrochloric acid and 64.9 g of sodium carbonate and 31.6 g of di-tert-butyl dicarbonate were serially added to the reaction mixture.
Without particularly isolating (S)-azetidine-2-carboxylic acid in the reaction solution, 6 N hydrochloric acid was added to the reaction solution to adjust pH to 9.6, 224.3 mg of sodium carbonate and 233.1 mg of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 10 hours.
38
[ 32315-10-9 ]
[ 2133-34-8 ]
azethidine-2-carboxylic acid N-carboxyamino acid anhydride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Synthesis of Azethidine-2-carboxylic Acid N-carboxyamino Acid Anhydride At room temperature, (S)-azethidine-2-carboxylic acid (1.0 g, 99.9% ee or higher) was suspended in 25 ml of tetrahydrofuran. Then tri-phosgene (1.0 g) was added thereto. The suspension was heated to 50 C. and stirred for 4 hours. After allowing to cool, the solvent was distilled off under reduced pressure to give a pale yellow oil (1.5 g). 1H-NMR(CDC13) delta 4.52 (dd, 1H), 3.76-3.62 (m, 2H), 2.44-2.36 (m, 1H), 2.23-2.14 (m, 1H), 13C-NMR (CDC13) delta 169.10, 152.27, 55.44, 40.37, 34.22.
With hydrogenchloride; sodium carbonate; In water;
Step A. N-(2-Thiophene-sulfonyl)-azetidine-2(S)-carboxylic Acid To a magnetically stirred mixture of azetidine-2(S)-carboxylic acid (1.0 g, 10 mmol) and Na2CO3 (2.1 g, 20 mmol) in 30 mL of water at 0 C. was added thiophene-2-sulfonyl chloride (1.8 g, 10 mmol), and the reaction was allowed to slowly warm up to room temperature overnight. The reaction was quenched by careful addition of concentrated HCl at 0 C. to pH above 2, and the product was extracted with EtOAc (3*15 mL). The extracts were dried over Na2SO4, and concentrated to dryness to provide the title compound as a white solid, which is >90% pure by 1H-NMR and used without further purification. 400 MHz 1H NMR (CD3OD): delta 2.2-2.4 (m, 2H), 3.7-3.9 (m, 2H), 4.42 (dd, 1H), 7.30 (dd, 1H), 7.75 (dd, 1H), 7.95 (dd, 1H).
With N-ethyl-N,N-diisopropylamine; sodium hydroxide; In acetone; at 20℃;
To a round bottom flask was added (,S)-azetidine-2-carboxylic acid (63, 51 1 mg, 5.05 mmol) and sodium hydroxide (7.0 mL of IN; 7.08 mmol). The reaction was cooled to 0 C and 3,5-dichlorobenzenesulfonyl chloride (65, 1.36 g, 5.56 mmol) was added followed by N,N- diisopropylethylamine (1.0 mL, 5.81 mmol) and acetone (7 mL) and the reaction was stirred overnight at room temperature. The acetone was evaporated and the aqueous layer extracted with diethyl ether (3 x 50 mL). The aqueous layer was adjusted to pH=l using cone. HC1 and then extracted with ethyl acetate (3 x 75 mL). The ethyl acetate layers were pooled, dried using sodium sulfate, filtered and concentrated in vacuo to give product (,S)-l-((3,5- dichlorophenyl)sulfonyl)azetidine-2-carboxylic acid (67, 1.6 g, 100% yield) as a white solid. LC- MS: tR=2.06 min; m/z=309.8, 31 1.9. 1 NHMR (400 MHz, DMSO-d6) delta ppm 13.08 (br. s., 1 H) 8.06 (t, J=1.83 Hz, 1 H) 7.85 (d, J=1.96 Hz, 2 H) 4.63 (dd, J=9.54, 7.58 Hz, 1 H) 3.67 - 3.88 (m, 2 H) 2.29 - 2.42 (m, 1 H) 2.13 - 2.28 (m, 1 H).
With hydrogenchloride; sodium carbonate; In water;
Step A. N-(3,5-Dichlorobenzenesulfonyl)-2(S)-azetidinecarboxylic Acid To a magnetically stirred mixture of azetidine-2(S)-carboxylic acid (1 g, 10.5 mmol) and Na2CO3 (2.76 g, 20 mmol) in 15 mL of water at 0 C. was added 3.5-dichlorobenzenesulfonyl chloride (2.94 g, 12 mmol), and the reaction was allowed to slowly warm up to room temperature overnight. The reaction was quenched by careful addition of concentrated HCl at 0 C. (pH=ca. 2), and the product was extracted with EtOAc (3*15 mL). The extracts were dried over Na2SO4, and concentrated to dryness to provide the final productproduct as a white solid, which is >90% pure by 1H NMR and was used directly. 500 MHz 1H NMR (CD3OD): delta 2.3-2.4 (m, 2H), 3.39 (m, 1H), 3.95 (q, J=9 Hz, 1H), 4.68 (t, 1H, J=8.5 Hz), 7.62 (t, 1H, J=8 Hz), 7.73-7.70 (m, 1H), 7.79 (t, J=2 Hz, 1H), 7.84 (d, J=2 Hz, 1H).
methyl N-[(RS)-methylbenzyl]azetidine-2-(RS)-carboxylate[ No CAS ]
tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate[ No CAS ]
[ 87-69-4 ]
L-tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate[ No CAS ]
[ 2133-34-8 ]
Yield
Reaction Conditions
Operation in experiment
In methanol; toluene;
Example 12 200 g of 49.2% methyl N-[(RS)-methylbenzyl]azetidine-2-(RS)-carboxylate solution in toluene was added dropwise to a solution of L-tartaric acid (6.84 g) in methanol (10.26 g) at 60 C. 0.005 g of tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate was added as seed crystals to the mixture and was maintained at the temperature for 0.5 hour. To the resulting slurry was added 30 g of 50% methyl N-[(RS)-methylbenzyl]azetidine-2-(RS)-carboxylate in toluene solution was added dropwise at 60 C. over 1 hour. The slurry was cooled to 0 C. and crystals were collected by filtration. The obtained crystals were washed with cold methanol and dried in vacuo to give L-tartaric acid salt of methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (16.5 g, yield: 15.7%, 99.7% d.e.). The obtained crystals were treated in the following Example 14, 15 or 16 to yield (S)-azetidine-2-carboxylic acid. (>99% e.e).
With sodium hydrogencarbonate; In 1,4-dioxane; water;
7a. 1-t-butyloxycarbonyl-2-(S)-azetidinecarboxylic acid To an ice cooled solution of 2-(S)-azetidinecarboxylic acid (10.15 g, 100.39 mmol) in 1, 4 dioxane:water (300 mL, 1:1) was added di-tert-butyl dicarbonate (28.48 g, 130.51 mmol), followed by 4methylmorpholine (11.68 g, 115.45 mmol). The reaction mixture continued to stir 18 hours, gradually warming to room temperature. The reaction mixture was then poured into a ice cooled saturated solution of sodium bicarbonate (250 mL) and washed with ethyl acetate (3*250 ml). The aqueous was then acidified with potassium hydrogen sulfate (pH=1) and the product extracted with ethyl acetate (3*300 ml). These extracts were then dried (Na2 SO4), filtered and concentrated in vacuo. The resulting semisolid was carried forward without further purification. MS (DCI/NH3) m/e 202 (M+H)+, 219 (M+NH4)+. 1 H NMR (CDCl3,300 MHz) delta: 10.0 (br s, 1H), 4.81-4.76 (t, J=15Hz, 1H), 3.99-3.83 (m, 2H), 2.62-2.38 (m, 2H), 1.48 (s, 9H).
Example 1 Resolution of Racemic N-Benzoylazetidine-2-carboxylic Acid Methyl Ester The ester (4.8 g, 21.9 mmol) was stirred in buffer solution (pH 7.5, 50 mM potassium phosphate, 100 mL) at room temperature. Lipase from Candida antarctica (0.48 g; Chirazyme L2; Boehringer Mannheim) was added and the mixture titrated to pH 7.5 using 1M NaOH. When base uptake showed 38% conversion after 3.5 hours, the enzyme was removed by filtration, and the pH adjusted to 8.5 with 5M NaOH. The ester was extracted with ethyl acetate (300 ml, 5 times), then the combined organic solutions washed with saturated sodium bicarbonate solution (100 ml), brine (100 ml), dried over MgSO4, then filtered and evaporated in vacuo to yield a colourless oil (7.72 g, 57% e.e., determined by chiral GC: Chirasil DEX CB column) for racemization. The acid product was recovered by acidification of the biotransformation solution to pH 1.6, followed by extraction with ethyl acetate (200 ml, 4 times). The resulting solution was dried over MgSO4, then evaporated to dryness to give a viscous oil (1.7 g, 84% e.e., determined by derivatization to the corresponding methyl ester and subsequent chiral GC analysis as above). (S)-N-Benzoylazetidine-2-carboxylic acid (1.6 g, 84% e.e.) was stirred in 4M NaOH solution (100 ml) for 18 hours at ambient temperature followed by 3.5 hours at 75 C. After cooling to 4 C. and acidification to pH 1.5, the solution was extracted with ethyl acetate (250 ml) then evaporated to dryness to give a white solid (1.11 g). This was dissolved in water (100 ml) then Amberlite IRA-67 added (4 g). The reaction was stirred at room temperature, then the resin removed by filtration, and the filtrate evaporated in vacuo to yield the free amino acid as a white solid (0.90 g). The product was crystallized to 98% e.e., by reflux in methanol for 15 minutes, followed by crystallization at 4 C., to give (S)-azetidine-2-carboxylic acid as a white solid (0.39 g, 98% e.e., determined by chiral HPLC: Chirex (D) Penicillamine column).
44
[ 24424-99-5 ]
[ 2133-34-8 ]
[ 159749-28-7 ]
Yield
Reaction Conditions
Operation in experiment
63.1%
A mixture of (S)-2-azetidinecarboxyic acid (1Og, 98.9mmol), di-tert butyl dicarbonate (28.06g, 128.6mmol), N-methyl morpholine (11.5g, 113.7mmol), 1,4-dioxane (160ml) and water (160ml) was stirred at O0C for 4 hours and then at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue was dissolved in water, washed with DCM and the aqueous layer acidified to pH 1.0 at O0C with concentrated hydrochloric acid. The aqueous layer was extracted with DCM and the organic layer dried (Na2SO4) over anhydrous sodium sulfate to give iV-tert-butyloxycarbonylazetidin-2-yl carboxylic acid (12.61g, 63.1%) as an oil; NMR Spectrum (CDCl3) 1.42 (s, 9H), 2.40 (m, IH), 2.59 (m, IH), 3.90 (m, 2H), 4.80 (t, IH).
With 4-methyl-morpholine; In 1,4-dioxane; water;
41 a. 1-(t-butyloxycarbonyl)-azetidine-2-carboxylic acid A 10.15 g (100.39 mmol) sample of (S)-azetidine-2-carboxylic acid (Fluka) was dissolved in 300 mL of 1:1 H2 O: dioxane and stirred under N2. To this solution was added 12.64 mL (115 mmol) of N-methylmorpholine (NMM), and the solution was cooled to to 0 C. To the cooled solution was slowly added 29.98 mL (130 mmol) of di-t-butyl dicarbonate, and the reaction mixture was allowed to warm to room temperature and stirred for 16 hr. An additional 10 mg of di-t-butyl dicarbonate was added and the reaction was stirred for 2 hours longer. The reaction was quenched by pouring it into 250 mL of satd aqueous Na2 CO3, and the mixture was washed with ethyl acetate. The aqueous solution was adjusted to pH 2 with 10% citric acid and 3M HCl and extracted with ethyl acetate. The extracts were dried over Na2 SO4 and the solvent was removed under vacuum to give the title product as a white solid. MS: 21 9 (m, 2(M+NH4)+, (M+H)+. 1 H NMR (CDCl3) delta: 1.48 (s, 9H), 2.4-2.6 (b, 2H), 3.88=3.98 (m, 2H), 4.80 (b, 1H).
a) 59.3 g (0.3 mol) of 5-chloro-isatoic anhydride and 30.3 g (0.3 mol) of (S)-azetidine-2-carboxylic acid were suspended in 400 ml of N,N-dimethylformamide/acetic acid 5:1 and heated to 87-90 in an oil bath under argon for 64 hrs. The solvent was removed in a vacuum and the residue was taken up in 500 ml of methanol, whereupon the mixture was stirred at room temperature for 30 min. The white, pure crystals were filtered off under suction. The solvent was removed in a vacuum and the semi-crystalline residue was recrystallized from 60 ml of methanol (hot filtration). The products were combined and dried in a vacuum. There were obtained 61.3 g (86%) of (S)-6-chloro-1,2,4,9,10,10a-hexahydro-azeto[2,1-c][1,4]benzodiazepine-4,10-dione of m.p. 229-231 (dec.).
1-(11-acetoxy-6,17-dihydroxy-1-methoxymethyl-10,13-dimethyl-3,7-dioxo-1,7,10,11,12,13,14,15,16,17-decahydro-2-oxa-cyclopenta[a]phenanthren-4-ylidenemethyl)-azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane; at 20℃; for 12h;
Example 38: Preparation of 1-(1 l-Acetoxy-6,17-dihydroxy-l -methoxymethyl- 10, 13- dimethyl-3 ,7-dioxo- 1 ,7, 10, 11 , 12, 13 , 14, 15 , 16, 17-decahydro-2-oxa-cyclopenta[a]phenanthren- 4-ylidenemethyl)-azetidine-2-carboxylic acid; To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 muL, 0.46 mmol) in 2 mL CH2Cl2 is added <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (47 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 533 (M+H).
C. To a solution of 0.50 g of (S)-2-azetidine carboxylic acid in 15 ml of 10% aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethylchloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution washed with ether. The aqueous layer was cooled to 0 C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl)azetidine-2-carboxylic acid.
C. To a solution of 0.50 g of (S)-(-)-2-azetidine carboxylic acid in 15 ml of 10 aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethyl chloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0 C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution was washed with ether. The aqueous layer was cooled to 0 C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl) azetidine-2-carboxylic acid.
Without particularly isolating (R)-4-amino-2-chlorobutyric acid in the reaction solution, the reaction solution was neutralized with a 30% sodium hydroxide aqueous solution until a pH of 11, 1.21 g of barium hydroxide octahydrate was added, and the solution was stirred with heating at 100C for 26 minutes. The reaction solution was adjusted to pH 1 by addition of 6 N hydrochloric acid. The reaction solution was passed several times through an ion exchange resin (Amberlite IR 120) column and, then, the ion exchange resin was washed with water until the pH of washings reached to 6 to 7. Thereafter, the ion exchange resin was washed with aqueous ammonia, and the washings were concentrated to give 70.8 mg of (S) -azetidine-2-carboxylic acid (yield 73.2%, optical purity 67.9% ee).
60.5%
Without particularly isolating (R)-4-amino-2-chlorobutyric acid in the reaction solution, the solution was neutralized to pH 7 with a 30% sodium hydroxide aqueous solution, 519.4 mg of barium hydroxide octahydrate was added, and the mixture was stirred with heating at 100C for 27 minutes. 6 N hydrochloric acid was added to the reaction solution to adjust pH to 1.0. This reaction solution was passed several times through an ion exchange resin (Amberlite IR 120) column and, then, the ion exchange resin was washed with water until the pH of washings reached to 6 to 7. Thereafter, the ion exchange resin was washed with aqueous ammonia, and the washings were concentrated to give 25.2 mg of (S)-azetidine-2-carboxylic acid (yield 60.5%, optical purity 87.0% ee).
50
[ 2133-34-8 ]
[ 69684-70-4 ]
Yield
Reaction Conditions
Operation in experiment
a Synthesis of methyl (S)-2-azetidine carboxylate: 900 mg of azetidine-(S)-2-carboxylic acid was treated according to the same procedure as Example 1-g) to obtain 1 g of the title compound as a colorless oil.
To MR 97 (0.3 g, 0.8 mmol) and <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (2) (0.16 g, 1.61 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.61 g, 4.02 mmol). The reaction mixture was stirred and heated at 150 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 0.057 g (16%) of BB-04 as light yellow solid. 1H NMR (DMSO-d6, 400 MHz): 9.4 (s, 1H), 8.13 (d, J=6.8 Hz, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.66 (s, 1H), 7.5-7.59 (m, 4H), 6.47 (d, J=8.0 Hz, 1H), 4.6-4.7 (m, 1H), 4.04 (s, 2H), 3.8-3.96 (m, 2H), 2.3-2.6 (m, 2H); MS (APCI+): 454.0 (M+1), LC-MS: 100%.
To MR 129 (0.28 g, 0.76 mmol) and <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (2) (0.15 g, 1.52 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.58 g, 3.8 mmol). The reaction mixture was stirred and heated at 150 C. for 15 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 0.22 g of white solid. The solid was suspended in ether (4.0 mL) was added 2M HCl in ether (1.8 mL, 3.6 mmol). The reaction mixture was stirred for 1 h at room temperature, concentrate under N2 flow, than dried under vacuum to afford 0.22 g (64%) of BB-08 as white solid. 1H NMR (DMSO-d6, 400 MHz): 8.08 (d, J=1.6 Hz, 1H), 7.94 (d, J=1.6 Hz, 1H), 7.87 (t, J=2.0 Hz, 1H), 7.82 (br s, 1H), 7.75-7.79 (m, 1H), 7.46-7.58 (m 4H), 6.76 (br s, 1H), 4.86-5.07 (m, 1H), 4.05 (s, 2H), 3.98-4.2 (m, 2H), 2.79 (s, 3H), 2.65-2.75 (m, 1H), 2.36-2.45 (m, 1H); MS (APCI+): 450.0 (M+1), LC-MS: 98.3%.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; at 160℃; for 0.333333h;
A-066 Synthesis of (S)-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 <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (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 5% methanol in dichloromethane to afford 0.042 g (17%) of A-066 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 7.98 (d, J=2.0 Hz, 1H), 7.39-7.48 (m, 3H), 7.37 (s, 1H), 7.24-7.3 (m, 2H), 6.92 (d, J=8.4 Hz, 1H), 6.4 (d, J=8.4 Hz, 1H), 4.58 (dd, J=9.2, 6.4 Hz, 1H), 3.7-3.9 (m, 2H), 3.8 (s, 2H), 3.72 (s, 3H), 2.3-2.55 (m, 2H); MS (APCI+): 427.1 (M+1), LC-MS: 100%.
1.6g (7.4 mmol) of Boc-L-allylglycine was dissolved in methanol (25 ml), followed by bubbling with ozone gas at -78 C. After bubbling until color of the solution turned blue, oxygen was bubbled until the blue color disappeared. After returning to room temperature, 752 mg (7.4 mmol) of <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> and 470 mg (7.4 mmol) of sodium cyanoborohydride were added, followed by stirring for one hour. After vacuum concentration of the reaction mixture, 2.1 g of compound (3-3) (yield 93%) was obtained by short-pass silica gel chromatography with silica gel (after removing the residue of sodium cyanoborohydride and a small amount of byproduct derived from L-allylglycine with a mobile phase: a mixture solution of ethyl acetate: methanol = 5:1 (v/v), methanol solution was passed through).
With hydrogen;palladium 10% on activated carbon; In methanol; water; for 19h;
N-methyl-L-azetidine-2-carboxilic acid To a suspension of <strong>[2133-34-8]L-azetidine-2-carboxylic acid</strong> (290 mg, 2 87 mmol, 1 equiv) in MeOH (3.6 mL), was added aqueous formaldehyde solution (37%, 235 muL, 3.15 mmol, 1. 1 equiv) and palladium on carbon (10%, 76 mg). The flask was fitted with a septum and evacuated and back-filled three times with hydrogen gas. The reaction was stirred under an atmosphere (balloon) of hydrogen gas for 19 h, and was filtered through celite to remove the palladium catalyst. The resulting solution was concentrated under reduced pressure, concentrated from toluene three times and dried under vacuum to afford N-methyl-L-azetidine-2-carboxilic acid: 1II NMR (400 MHz, CD3OD) delta 4.50 (t, J= 9.5 Hz, 1 H), 3.96 (dt, J = 4.3, 9.8 Hz, I H), 3.81 (q, J = 9.8 Hz, 1 H), 2.86 (s, 3 H), 2.71-2.60 (m, 1 H), 2.50-2.38 (m, 1 H).
1-((1R,1'R,3R,3'R,5S,5'S)-[3,9'-bi(9'-azabicyclo[3.3.1]nonan)]-3'-yl)-3-chloroquinoxalin-2(1H)-one[ No CAS ]
[ 2133-34-8 ]
[ 1442424-10-3 ]
Yield
Reaction Conditions
Operation in experiment
24%
With triethylamine; In dimethyl sulfoxide; at 25 - 100℃; for 2h;
To a solution of a compound 1D3 (0.5mmol, 213mg) and TEA (l .Ommol, 102mg, Sigma-Aldrich, St. Louis, MO) in DMSO (3mL) at temperature of about 25C was added (5)-azetidine-2-carboxylic acid (30, 1.0 mmol, 101 mg, Sigma-Aldrich). The resulting reaction mixture was heated to 100C and stirred at that temperature for 2 hours. Thereafter, the mixture was evaporated under reduced pressure to provide a product which was chromatographed on a flash column eluted with DCM/MeOH to provide Azetidine-Substituted Quinoxaline-Type Piperidine Compound B2a(ii), (S)- 1 -(4-(( 1 R,3R,5S)-9-(( li?,3r,55)-bicyclo[3.3.1 ]nonan-3-yl)-9-azabicyclo[3.3.1 ]no nan-3-yl)-3-oxo-3,4-dihydroquinoxalin-2-yl)azetidine-2-carboxylic acid (yield 24%). The identity of Azetidine-Substituted Quinoxaline-Type Piperidine Compound B2a(ii) was confirmed using NMR and MS. Azetidine-Substituted Quinoxaline-Type Piperidine Compound B2a(ii): NMR: deltaEta (ppm, CD3OD): 7.67 (d, J=8.3Hz, 1H), 7.53 (d, J=7.9Hz, 1 H), 7.32 (m, 2H), 5.36 (br, 2H), 4.36 (m, 2H), 4.20 (d, J=10.9Hz, 3H), 3.04 (m, 2H), 2.87 (br, 1 H), 2.69 (d, J= 13.1 Hz, 1 H), 2.30-2.21 (m, 9H), 1.79 (m, 13H); MS: m/e=49 A [M+ l ].
(2S)-1-[(4-fluorobenzene)sulfonyl]azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With sodium hydroxide; In tetrahydrofuran; at 0 - 20℃; for 18h;
4-Fluorobenzene-1 -sulfonyl chloride (2.14 g, 11.00 mmol, 1.00 equiv) was added into a solution of <strong>[2133-34-8](2S)-azetidine-2-carboxylic acid</strong> (1 g, 9.89 mmol, 1.10 equiv) in saturated aqueous sodium hydroxide (6 mL)/tetrahydrofuran (6 mL) at 0C. The resulting mixture was stirred for 18 h at room temperature. The mixture was extracted with ether. The pH value of the aqueous solution was adjusted to 3 with 2 M hydrogen chloride. The resulting mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (1.7 g, 60%) as a white solid.
[(η5-C5Me4CH2C6H5)Ir(L-azetidine 2-carboxylate)Cl][ No CAS ]
[(η5-C5Me4CH2C6H5)Ir(L-azetidine 2-carboxylate)Cl][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In methanol; for 0.5h;
General procedure: A round bottom flask was charged with appropriate amounts of the respective [Cp R IrCl2]2, amino acid, sodium hydrogen carbonate, and methanol with magnetic stirring. The initially orange solution changed to yellow over the course of approximately 30min. The solvent was then removed under reduced pressure. The product was extracted away from unreacted amino acid and sodium hydrogen carbonate with dichloromethane (3×10mL) and filtered. The complexes were recrystallized from dichloromethane and ether or hexanes and collected on a frit as yellow crystalline powders.
7-chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine[ No CAS ]
[ 2133-34-8 ]
(2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
11%
With potassium carbonate; In 1,4-dioxane; at 50℃; for 48h;
Example 8-10 (2S)-1-(5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidin-7-yl)azetidine-2-carboxylic acid 7-Chloro-5-methyl-2-{1-[4-(trifluoromethyl)phenyl]ethyl}pyrazolo[1,5-a]pyrimidine (200 mg, 0.589 mmol, INTERMEDIATE a8) was added to a suspension of (S)-azetidine-2-carboxylic acid (119 mg, 1.177 mmol) and potassium carbonate (244 mg, 1.766 mmol) in 1,4-dioxane (5 mL). The mixture was stirred at 50 C. for 48 hours and then concentrated under vacuum. Purification of the residue by flash chromatography on silica gel eluted with methanol/dichloromethane (gradient from 0:1 to 1:3) provided the titled compound (26.1 mg, 11%). MS(ESI+) m/z 405.1 [M+H]+; 1H NMR (400 MHz, CD3OD) delta ppm 1.70 (d, 3H), 2.38 (m, 4H), 2.89 (m, 1H), 3.37 (s, 3H), 4.33 (q, 1H), 5.69 (s, 1H), 5.98 (s, 1H), 7.54 (d, 2H), 7.60 (d, 2H).
5-fluorobenzofuran-2-ylsulfonyl chloride[ No CAS ]
[ 2133-34-8 ]
(2S)-1-(5-fluorobenzofuran-2-ylsulfonyl)azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 0.5h;
To (S)-azetidine-2-carboxylic acid (1.9 g, 19 mmol) were added saturated aqueous sodium hydroxide solution (15 mL) and a solution of A-3 (4.5 g, 19 mmol) in tetrahydrofuran (15 mL) and the mixture was stirred at room temperature for 30 min. Tetrahydrofuran was evaporated, adjusted to pH3-4 with 1 mol/L aqueous hydrochloric acid solution, and the precipitate was collected by filtration, and dried to give the title compound (4.0 g, 13 mmol, 71%). MS (ESI) m/z 300 (M+H)+ 1H NMR (300 MHz, CD3OD) delta 7.71 (dd, J=9.2, 4.1 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J=8.4, 2.7 Hz, 1H), 7.34 (ddd, J=9.3, 9.0, 2.7 Hz, 1H), 4.76 (t, J=8.4 Hz, 1H), 4.03-3.96 (m, 2H), 2.45-2.36 (m, 2H)
71%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 0.5h;
To 65 (S)-azetidine-2-carboxylic acid (1.9 g, 19 mmol) were added saturated aqueous sodium hydroxide solution (15 mL) and a solution of A-1 (4.5 g, 19 mmol) in 14 tetrahydrofuran (15 mL) and the mixture was stirred at room temperature for 30 min. Tetrahydrofuran was evaporated, adjusted to pH3 - 4 with 1 mol/L aqueous hydrochloric acid solution, and the precipitate was collected by filtration, and dried to give the 66 title compound (4.0 g, 13 mmol, 71%). MS (ESI) m/z 300 (M+H)+ 1H NMR (300 MHz, CD3OD) delta 7.71 (dd, J = 9.2, 4.1 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J = 8.4, 2.7 Hz, 1H), 7.34 (ddd, J = 9.3, 9.0, 2.7 Hz, 1H), 4.76 (t, J = 8.4 Hz, 1H), 4.03-3.96 (m, 2H), 2.45-2.36 (m, 2H).
(S)-1-(phenylsulfonyl)azetidine-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With N-ethyl-N,N-diisopropylamine; sodium hydroxide; In acetone; at 20℃;
To a round bottom flask was added (,S)-azetidine-2-carboxylic acid (63, purchased from Chem Impex International, 500 mg, 4.95 mmol) and sodium hydroxide (6.9 mL of IN; 6.92 mmol). The reaction was cooled to 0 C and benzenesulfonyl chloride (64, 0.96 g, 5.44 mmol) was added followed by N,N-diisopropylethylamine (0.97 mL, 5.69 mmol) and acetone (7 mL) and the reaction was stirred overnight at room temperature. The acetone was evaporated and the aqueous layer extracted with diethyl ether (3 x 50 mL). The aqueous layer was adjusted to pH=l using cone. HC1 and then extracted with ethyl acetate (3 x 75 mL). The ethyl acetate layers were pooled, dried using sodium sulfate, filtered and concentrated in vacuo to give product (S)-l- (phenylsulfonyl)azetidine-2-carboxylic acid (66, 1.14 g, 95% yield) as a white solid. LC-MS: tR=1.46 min; m/z=24 .9. 1H NMR (400 MHz, DMSO-d6) delta ppm 12.98 (s, 1 H) 7.80 - 7.89 (m, 2 H) 7.73 - 7.80 (m, 1 H) 7.64 - 7.72 (m, 2 H) 4.34 (t, J=8.68 Hz, 1 H) 3.69 (td, J=7.64, 5.75 Hz, 1 H) 3.60 (q, J=8.23 Hz, 1 H) 2.15 - 2.26 (m, 2 H).
To a rbf (round bottom flask) was added ester (3.77 g, 18.3 mmol) and NMP (37 mL, 0.5M) at rt. To the vessel was added potassium carbonate (5.06 g, 36.6 mmol, 2.0 equiv.) and (S)-azetidine-2-carboxylic acid (1.94 g, 19.2 mmol, 1.05 equiv.). The mixture was heated to 125 C. for 2 hours, until completed by LCMS. The vessel was cooled to rt, and DMF (37 mL), methylamine HCl (2.47 g, 36.6 mmol, 2.0 equiv.), and DIPEA (6.4 mL, 36.6 mmol, 2.0 equiv.) were added. Finally, HATU (8.35 g, 22.0 mmol, 1.2 equiv.) was added, and the mixture was stirred at rt for 15-30 minutes, until completed by LCMS. The mixture was diluted with saturated sodium bicarbonate (37 mL) and water (260 mL). The aqueous mixture was then extracted ×3 with ethyl acetate, until the aqueous layer showed to only possess minimal desired product by LCMS. The combined organics were washed ×1 with water and ×1 with brine, dried over magnesium sulfate, filtered, and partially concentrated.
(S)-2,6-dichloro-N-(2-(diethylamino)propyl)isonicotinamide[ No CAS ]
[ 2133-34-8 ]
C17H25ClN4O3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 120℃; for 0.5h;Inert atmosphere;
Synthesis of 2-chloro-N-((S)-2-(diethylamino)propyl)-6-((S)-2-(methylcarbamoyl)azetidin-1-yl)isonicotinamide (275D) Dichloroarene, K2CO3, and L-azetidine carboxylic acid were taken up in 1 mL of NMP in a microwave vial. The vial headspace was purged with argon, sealed and the vial heated to 120 C (to avoid decarboxylation) for 30 minutes. The reaction mixture was then diluted with DMF (1 mL) and the requisite as a TFA salt, DIPEA, and HATU were added sequentially. After 5 minutes, LCMS showed full conversion of carboxylic acid to desired amide product. Synthesis of Final Product 275 Product 275D was coupled with boronic ester 1D as shown in Example 1 to provide the product 275, as a TFA salt. LC/MS (M+H): 547.364; 1H NMR (400 MHz, Methanol-d4) delta 8.90 (d, J=7.4 Hz, 1H), 8.64 (s, 1H), 8.35 (d, J=1.3 Hz, 1H), 8.00-7.96 (m, 1H), 7.73 (dd, J=5.0, 1.1 Hz, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.25 (dd, J=5.1, 3.8 Hz, 1H), 6.68 (s, 1H), 4.16 (t, J=4.4 Hz, 1H), 4.08 (d, J=8.0 Hz, 1H), 3.95 (dd, J=14.2, 5.7 Hz, 1H), 3.86 (d, J=6.2 Hz, 1H), 3.53 (dt, J=13.6, 6.9 Hz, 2H), 3.38 (dd, J=7.2, 2.8 Hz, 2H), 3.22 (dd, J=13.4, 7.0 Hz, 2H), 2.82 (s, 3H), 2.73-2.63 (m, 1H), 2.59 (d, J=8.6 Hz, 1H), 1.47 (t, J=7.3 Hz, 6H), 1.41 (t, J=7.3 Hz, 3H).
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