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Chemical Structure| 36476-78-5
Chemical Structure| 36476-78-5
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Product Details of [ 36476-78-5 ]

CAS No. :36476-78-5 MDL No. :MFCD00191763
Formula : C4H7NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :GFZWHAAOIVMHOI-UHFFFAOYSA-N
M.W : 101.10 Pubchem ID :93192
Synonyms :
Chemical Name :Azetidine-3-carboxylic acid

Calculated chemistry of [ 36476-78-5 ]      Expand+

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 Ų

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) : -9.17 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.76
Log Po/w (XLOGP3) : -3.18
Log Po/w (WLOGP) : -1.09
Log Po/w (MLOGP) : -0.79
Log Po/w (SILICOS-IT) : -0.02
Consensus Log Po/w : -0.86

Druglikeness

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

Water Solubility

Log S (ESOL) : 1.6
Solubility : 4050.0 mg/ml ; 40.0 mol/l
Class : Highly soluble
Log S (Ali) : 2.71
Solubility : 52200.0 mg/ml ; 516.0 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 : 1.0

Safety of [ 36476-78-5 ]

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

Application In Synthesis of [ 36476-78-5 ]

* 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 [ 36476-78-5 ]
  • Downstream synthetic route of [ 36476-78-5 ]

[ 36476-78-5 ] Synthesis Path-Upstream   1~11

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Reference: [1] Patent: US4639334, 1987, A,
[2] Synthetic Communications, 2003, vol. 33, # 19, p. 3347 - 3353
[3] Patent: US4560507, 1985, A,
[4] Patent: US4812581, 1989, A,
[5] Patent: US4812581, 1989, A,
[6] Patent: US4812581, 1989, A,
[7] Patent: US4812581, 1989, A,
[8] Patent: US4812581, 1989, A,
[9] Patent: EP221579, 1987, A1,
[10] Patent: EP221579, 1987, A1,
[11] Patent: WO2004/35538, 2004, A1, . Location in patent: Page 26
  • 2
  • [ 26096-30-0 ]
  • [ 87-69-4 ]
  • [ 94985-27-0 ]
  • [ 36476-78-5 ]
Reference: [1] Patent: US4812581, 1989, A,
  • 3
  • [ 24424-99-5 ]
  • [ 36476-78-5 ]
  • [ 142253-55-2 ]
YieldReaction ConditionsOperation in experiment
100% With triethylamine In methanol at 20℃; for 18 h; Example 4Ethyl 6-(3-[(benzylsuIfonyl)amino]carbonyl}azetidin-l-yl)-5-cyano-2- 30 (difluoromethyl)nicotinate(a) l-(tert-Butoxycarbonyl)azetidine-3-carboxylic acid <n="92"/>91(BoC)2O (25.535 g, 117 mmol) dissolved in MeOH (70 mL) was added dropwise during 20 minutes to a stirred slurry of azetidine-3-carboxylic acid (10.11 g, 100 mmol) and Et3N (27.8 mL, 200 mmol) in MeOH (105 mL) at r.t (mildly exotermic reaction) and the mixture 5 was stirred over night (18 hours). The reaction was evaporated to dryness and THF (120 mL) was added and evapoprated to give crude l-(tert-butoxycarbonyl)azetidine-3- carboxylic acid which was used without further purification in the next step. Yield: 25.89 g (128 percent) 1H NMR (400 MHz, CDCl5) δ 1.43 (9H, s), 3.21-3.34 (IH, m), 4.00-4.13 (4H, m).10
100% With triethylamine In methanol at 20℃; for 18 h; (a)
1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid
(Boc)2O (25.535 g, 117 mmol) dissolved in MeOH (70 mL) was added dropwise during 20 minutes to a stirred slurry of azetidine-3-carboxylic acid (10.11 g, 100 mmol) and Et3N (27.8 mL, 200 mmol) in MeOH (105 mL) at r.t (mildly exotermic reaction) and the mixture was stirred over night (18 hours).
The reaction was evaporated to dryness and THF (120 mL) was added and evapoprated to give crude 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid which was used without further purification in the next step. Yield: 25.89 g (128percent)
1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 3.21-3.34 (1H, m), 4.00-4.13 (4H, m).
95% With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24 h; Example 90 Ethyl 6-{3-[(benzyIsulfonyl)carbamoyl]azetidin-l-yl}-5-cyano-2-[(2-oxopyrrolidin-l- yl)methyl]nicotinate(a) l-(toer^Butoxycarbonyl)azetidine-3-carboxylic acidDi-tert-buyldicarbonate (18 g, 83 mmol) was added to a solution of 3-azetidinecarboxylic acid (7.6 g, 75 mmol) in THF (150 mL), water (75 mL) and IM NaOH (75 mL), the reaction mixture was stirred at rt for 24 h. The organic solvent was concentrated in vacuo and the water was made acidic by addition of 4 M HCl (pH 1). The water phase was extracted with EtOAc and the combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo to give l-(te7t-butoxycarbonyl)azetidine-3-carboxylic acid as a white solid. Yield: 14.4 g (95percent). <n="177"/>1H-NMR (400 MHz, DMSO-J6) δ 1.36 (9H, s), 3.27-3.36 (IH, m), 3.80-3.87 (2H, m), 3.93-4.02 (2H, m), 12.64 (IH, s).
90% With triethylamine In 1,4-dioxane; water at 4 - 20℃; for 24 h; A mixture of 297 (1 g, 10 mmol) in 1 :1 water-dioxane (50 mL) was treated with Et3N (4 mL, 13 mmol) and BOC2O (2.8 g, 13 mmol) at 4°C and allowed to warm to 20°C for one day. The solvent was then removed in vacuo. The residue was taken up in 1 :1 water-ethyl acetate and the organic layer was discarded. The aqueous layer was acidified with 1 N aqueous HCl and extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried (Na2SO4), and concentrated to give 298 as a white solid (1.8 g, 90percent).
80% With triethylamine In tetrahydrofuran; water at 0 - 20℃; for 17.5 h; At a temperature of 0 °C, di-ferf-butyl dicarbonate (24.0 g, 110 mmol) was added portionwise to a solution of azetidine-3-carboxylic acid (9.4 g, 93 mol) and triethylamine (28 ml, 200 mmol) in THF (200 ml) and water (200 ml). After completed addition (30 min), the reaction mixture was stirred for 17 h at room temperature. The yellow solution was diluted with ethyl acetate (200 ml) and a pH value of 5 was adjusted by addition of 6 N hydrochloric acid. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 ml). The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was dried in vacuo and the title compound was obtained in 85 percent purity (18 g of a colourless solid, 80 percent yield).
73% With sodium hydroxide In tetrahydrofuran; water at 20℃; for 24 h; 60 mL of THF and 60 mL of 0.5 M NaOH aqueous solution were added to azetidin-3-carboxylic acid (3 g, 30mmol). Di-tert-butyl dicarbonate (6.8 g, 31.1 mmol) was slowly added thereto, and the mixture was stirred at roomtemperature for 24 hours. The reaction solution was concentrated under reduced pressure. The reaction solution wasadjusted to pH 4 by the addition of water and HCl aqueous solution, and extracted with EtOAc. The organic layer wasdried with MgSO4 to obtain the title compound (4.5 g, 73 percent).1H-NMR (CDCl3) δ 4.12 (4H, m), 3.38 (1H, m), 1.44 (9H, s)
70% With potassium hydroxide In tetrahydrofuran; water at 20℃; for 16 h; Step 1: Azetidine-l,3-dicarboxylic acid mono-tert-butyl esterDi-tert-buyldicarbonate (2.5 g, 11.88 mmol) was added to a stirred solution of 3- azetidinecarboxylic acid (1.0 g, 9.9 mmol) in a mixture of THF / water (12 mL : 2 mL) and 1 M KOH (1 mL) at room temperature. The reaction mixture was stirred for 16 hours and then concentrated to dryness. The crude was partitioned between an aqueous solution of IN NaOH (10 mL) and diethyl ether (50 mL). The ether layer was discarded and the aqueous layer was acidified with a 3M aqueous solution of KHS04 untill pH = 2 and extracted with diethyl ether (3 x 100 ml). The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white solid (1.4 g, 70percent).*H NMR (400 MHz, DMSO-d6) δ (ppm) : 12.64 (s, 1 H), 4.02-3.93 (m, 2H), 3.87-3.80 (m, 2H), 3.36-3.27 (m, 1 H), 1.36 (s, 9H).
100% With triethylamine In tetrahydrofuran; water; ethyl acetate EXAMPLE 37
N-Boc-3-Azetidinecarboxylic Acid 46
A solution of 3-Azetidinecarboxylic acid (45) (250 mg, 2.47 mmol) in 5 mL of THF and 5 mL of H2O was cooled in an ice-water bath and NEt3 (689 μL) was added with stirring.
Stirring and cooling were continued while di-tert-butyl dicarbonate (570 mg, 1.05 eq.) was introduced.
The mixture was warmed to room temperature and stirred overnight.
20 mL of Ethyl acetate and 10 mL of H2O were added to mixture.
The aqueous layer was extracted with ethyl acetate (2*20 mL).
The extracts were combined and washed with aqueous potassium carbonate (sat., 2*10 mL), aqueous HCl (5percent, 2*10 mL), brine (10 mL), and dried over anhydrous sodium sulfate, and filtered.
Removal of solvents gave 46 as a white solid 0.50 g (100percent).
100% With triethylamine In tetrahydrofuran; water; ethyl acetate EXAMPLE 37
N-Boc-3-Azetidinecarboxylic acid 46
A solution of 3-Azetidinecarboxylic acid (45) (250 mg, 2.47 mmol) in 5 mL of THF and 5 mL of H2O was cooled in an ice-water bath and NEt3 (689 μL) was added with stirring.
Stirring and cooling were continued while di-tert-butyl dicarbonate (570 mg, 1.05 eq.) was introduced.
The mixture was warmed to room temperature and stirred overnight.
20 mL of Ethyl acetate and 10 mL of H2O were added to mixture.
The aqueous layer was extracted with ethyl acetate (2*20 mL).
The extracts were combined and washed with aqueous potassium carbonate (sat., 2*10 mL), aqueous HCl (5percent, 2*10 mL), brine (10 mL), and dried over anhydrous sodium sulfate, and filtered.
Removal of solvents gave 46 as a white solid 0.50 g (100percent)
9.9 g With triethylamine In tetrahydrofuran; water at 20℃; for 17 h; The title compound (D25) (9.9 g) was prepared according to the experimental procedure described in Description 18 starting from 3-azetidine carboxylic acid (5 g, 49.45 mmol, available from Aldrich 391131) (1.5 g, 4.72 mmol). Reaction time: 17 h

Reference: [1] Patent: WO2008/4946, 2008, A1, . Location in patent: Page/Page column 90-91
[2] Patent: US2008/171732, 2008, A1, . Location in patent: Page/Page column 36
[3] Patent: WO2008/85119, 2008, A1, . Location in patent: Page/Page column 175-176
[4] Patent: WO2008/108957, 2008, A2, . Location in patent: Page/Page column 98
[5] Patent: WO2008/95912, 2008, A2, . Location in patent: Page/Page column 77
[6] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0291
[7] Patent: WO2011/61214, 2011, A1, . Location in patent: Page/Page column 146-147
[8] European Journal of Medicinal Chemistry, 1999, vol. 34, # 5, p. 363 - 380
[9] Patent: US6645980, 2003, B1,
[10] Patent: US2002/16337, 2002, A1,
[11] Patent: US6635661, 2003, B2,
[12] Patent: US6020368, 2000, A,
[13] Patent: US2007/105866, 2007, A1, . Location in patent: Page/Page column 63
[14] Patent: WO2008/85119, 2008, A1, . Location in patent: Page/Page column 113-114
[15] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 20, p. 5581 - 5585
[16] Journal of Medicinal Chemistry, 2010, vol. 53, # 9, p. 3645 - 3674
[17] Patent: EP2277861, 2011, A1, . Location in patent: Page/Page column 19
[18] Patent: EP2287173, 2011, A1, . Location in patent: Page/Page column 50
[19] Patent: US2012/28937, 2012, A1, . Location in patent: Page/Page column 15
[20] Patent: US2013/261100, 2013, A1, . Location in patent: Paragraph 0336-0337
[21] Patent: WO2016/44770, 2016, A1, . Location in patent: Page/Page column 553
[22] Patent: WO2018/152405, 2018, A1, . Location in patent: Paragraph 00186
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Reference: [1] Patent: US5977178, 1999, A,
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  • [ 501-53-1 ]
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YieldReaction ConditionsOperation in experiment
100%
Stage #1: With sodium hydroxide In water at 0℃; for 16 h;
Stage #2: With hydrogenchloride In water
3-AZETIDINECARBOXYLIC acid (4. uG, 39. 6 mmol) was dissolved in IN sodium hydroxide solution (4uML) and cooled to 0°C. Benzyl CHLOROFORMATE (5. 9mL, 41mmol) was added followed by further IN sodium hydroxide solution (41mL) dropwise. The mixture was stirred vigorously for 16hrs then made acidic with 2N hydrochloric acid. This suspension was extracted with dichloromethane (2XLOOML) and the extracts dried over MGS04. CONCENTRATION yielded the title compound (9.3g, 39.6mmol, 100percent). 1H NMR (400MHZ, CDC13) : 8 7.37-7. 29 (5H, m), 5.10 (2H, s), 4.21 (4H, d, J 7. 5HZ), 3.43 (1H, quintet, J 7. 5Hz).
83%
Stage #1: With potassium carbonate In 1,4-dioxane; water at 20℃; for 6 h;
Stage #2: With piperazine In 1,4-dioxane; water for 0.5 h;
EXAMPLE 27; 2-(3-methylazetidin-3-yl)-1H-benzimidazole-4-carboxamide; EXAMPLE 27A; 1-[(benzyloxy)carbonyl]azetidine-3-carboxylic acid A suspension of azetidine-3-carboxylic acid (2.5 g, 24.75 mmol) and potassium carbonate (4.0 g) in a mixture of 1,4dioxane (25 ml) and water (50 ml) was treated with benzyl chloroformate (4.0 ml, 27.23 mmol) at room temperature for 6 hours. Piperazine (5 drops) was added and the mixture was stirred for additional 0.5 hour. The organic volatiles were removed and the residue was partitioned between ethyl acetate and 2 N HCl solution. The organic layer was washed with brine, dried over MgSO4 and concentrated to give Example 27A (4.8 g, Yield: 83percent). MS (DCI/NH3) m/z 236 (M+H)+.
73%
Stage #1: With sodium hydroxide In 1,4-dioxane; water for 18 h;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in dioxane (325 ml) were added IN sodium hydroxide (124 ml, 124 mmol) and benzyl chloroformate (8.44 ml, 59.3 mmol). The reaction was allowed to stir for 18 h. The reaction was diluted with 3N HCl until pH 2 was obtained. The product was extracted with EtOAc (2x), washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via flash chromatography (silica, 0-70percent methanol(0.5percent acetic acid)/dichloromethane) to yield 1- [(benzyloxy)carbonyl]azetidine-3-carboxylic acid as a yellow oil (73percent). 1H NMR (400 MHz, CD3OD) δ 7.37-7.26 (m, 5H), 5.08 (s, 2H), 4.18 (m, 2H), 4.1 1 (br s, 2H), 3.44 (m, IH).
65%
Stage #1: With potassium carbonate In 1,4-dioxane; water at 0 - 20℃;
Stage #2: With hydrogenchloride In 1,4-dioxane; water
To a 0 0C stirred solution of 3-azetidine carboxylic acid (500 mg, 4.95 mmol) in 2 M K2CO3 aqueous (5 ml) and dioxane (5 ml), benzyl chlorocarbonate (929 mg / 0.78 ml, 5.45 mmol) was added dropwise. The reaction mixture was allowed to warm to RT and stirred for 15 hours. The reaction was monitored by TLC. Upon completion the reaction mixture was quenched with piperazine (42 mg, 0.50 mmol), concentrated at reduced pressure and treated with 2 M aqueous HCl (10 ml). The aqueous layer was extracted with EtOAc (5 x 10 ml), the phases separated, dried (MgSO4), filtered and concentrated at reduced pressure. The crude orange oil was purified by silica FCC to give the title compound (760 mg, 65percent yield) as a white solid.LCMS data (reaction IPC): Calculated MH+ (236); Found 7percent (MH+) m/z 236, Rt = 1.09 min. NMR data: 1H NMR (500 MHz, Chloroform-J) δ ppm 8.49 (1 H, br. s.), 7.30 - 7.42 (5 H, m), 5.10 - 5.15 (2 H, m), 4.18 - 4.27 (4 H, m), 3.43 (1 H, m).
47.8% With potassium carbonate In 1,4-dioxane; water at 0 - 35℃; for 12 h; To an ice cold solution of 3-azetidine carboxylic acid (2 g, 19.8 mmol) in 5:1 dioxane-water (15 mL) was added successively K2CO3 (4 g, 29.7 mmol) and CBz-Cl (4 g, 23.7 mmol). The reaction mixture was treated at a temperature in the range of 20 0C to 35 0C over a period of 12 h. The volatiles were evaporated under reduced pressure and the residue was worked up with chloroform. The crude product obtained was further purified by column chromatography to afford azetidine-l,3-dicarboxylic acid monobenzyl ester (2.2 g, 47.8percent).1H NMR (CDC13, 200MHz): d 7.35 (bs, 5H), 5.10 (s, 2H), 4.2 l(d, J=7.2 Hz, 4H),3.50-3.39 (m, IH).

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[8] Patent: WO2010/60952, 2010, A1, . Location in patent: Page/Page column 84-85
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
Stage #2: With hydrogenchloride In water
Preparation of Intermediate 1 (Int. l); (Z)-tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int.1-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid [00103] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 = 236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran at 20℃;
Stage #2: With hydrogenchloride In water
Preparation of Intermediate 1 (Int. l); tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int.1-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid; [00109] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 = 236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
Stage #2: With hydrogenchloride In water; ethyl acetate
Preparation 25A: l-(Benzyloxycarbonyl)azetidine-3 -carboxylic acidCbZlM^-CO2Hv (25A) [00262] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate.Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3- carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 = 236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).
99% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; INTERMEDIATE 6tert-Butyl azetidine-3 -carboxylate acetic acid saltStep A: l-(Benzyloxycarbonyl)azetidine-3-carboxylic acidCbzN-C°2H (I-6A)[00202] To a solution of azetidine-3 -carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in THF (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous hydrochloric acid solution and was then extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, followed by brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3 -carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min (condition B); LC/MS M+1 = 236.15. XH NMR (400 MHz, CDC13) δ ppm 3.39 - 3.49 (m, 1H), 4.22 (d, J=7.28 Hz, 4H), 5.1 1 (s, 2H), and 7.29-7.39 (m, 5H).
99% With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃; 1-A: l-(Benzyloxycarbonyl)azetidine-3 -carboxylic acid[0119] To a solution of azetidine-3 -carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded l-(benzyloxycarbonyl) azetidine-3 -carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: Column: YMC Combiscreen ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H20, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H20, 0.1percent TFA. LC/MS M+1 = 236.15. XH-NMR (400 MHz, CDC13) δ ppm 3.39-3.49 (m, 1H), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29-7.39 (m, 5H).
99%
Stage #1: With sodium hydrogencarbonate In tetrahydrofuran; water at 20℃;
Stage #2: With hydrogenchloride In water
Preparation of Intermediate 1 (Int. l); tert-Butyl 1 -(4-(N'-hydroxycarbamimidoyl)-benzyl)azetidine-3 -carboxylate; Int. l-A. l-(Benzyloxycarbonyl)azetidine-3-carboxylic acid; [00101] To a solution of azetidine-3-carboxylic acid (88 g, 0.871 mol) and sodium bicarbonate (161 g, 1.92 mol) in water (1.75 L) at room temperature was added a solution of benzyl 2,5-dioxopyrrolidin-l-ylcarbonate (239 g, 0.959 mol) in tetrahydrofuran (3.5 L). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate (2 x 500 mL). The aqueous layer was acidified with a 1.0 N aqueous solution of hydrochloric acid and extracted with ethyl acetate (3 x 750 mL). The organic layer was washed with water, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 1- (benzyloxycarbonyl) azetidine-3-carboxylic acid as colorless oil (202 g, 99percent yield). The compound had an HPLC retention time = 2.27 min. - Column: YMC COMBISCREEN.(R). ODS-A 4.6 x 50 mm (4 min.); Solvent A = 10percent MeOH, 90percent H2O, 0.1percent TFA; Solvent B = 90percent MeOH, 10percent H2O, 0.1percent TFA. LC/MS M+1 =236.15. 1H NMR (400 MHz, CDCl3) δ ppm 3.39 - 3.49 (m, IH), 4.22 (d, J=7.28 Hz, 4H), 5.11 (s, 2H), and 7.29 - 7.39 (m, 5H).

Reference: [1] Patent: WO2010/85584, 2010, A1, . Location in patent: Page/Page column 38-39
[2] Patent: WO2010/85581, 2010, A1, . Location in patent: Page/Page column 42-43
[3] Patent: WO2011/17578, 2011, A1, . Location in patent: Page/Page column 125-126
[4] Patent: WO2011/59784, 2011, A1, . Location in patent: Page/Page column 86-87
[5] Patent: WO2012/12477, 2012, A1, . Location in patent: Page/Page column 44-45
[6] Patent: WO2010/85582, 2010, A1, . Location in patent: Page/Page column 38
[7] Patent: WO2011/95556, 2011, A1, . Location in patent: Page/Page column 69
[8] Journal of Medicinal Chemistry, 2016, vol. 59, # 6, p. 2820 - 2840
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YieldReaction ConditionsOperation in experiment
94% With hydrogen In methanol; water EXAMPLE IX
1-methyl-azetidine-3-carboxylic acid
200 mg azetidine-3-carboxylic acid are dissolved in 10 ml of methanol, combined with 165 μl of a 37percent solution of formaldehyde in water as well as 20 mg 10percent palladium on charcoal and hydrogenated at 4 bar until the hydrogen uptake has ended.
Then the catalyst is eliminated by suction filtering, the solvent is eliminated in vacuo, the residue is taken up in methanol and toluene and the solvents are again eliminated in vacuo.
Yield: 214 mg (94percent of theory)
Mass spectrum (ESI+): m/z=116 [M+H]+
Reference: [1] Patent: US2011/269737, 2011, A1, . Location in patent: Page/Page column 44
  • 8
  • [ 67-56-1 ]
  • [ 36476-78-5 ]
  • [ 100202-39-9 ]
YieldReaction ConditionsOperation in experiment
100% With thionyl chloride In acetonitrile at 0 - 20℃; for 2.33333 h; To a stirring suspension of 3-azetidine carboxylic acid in MeOH at O0C3 was added SOCl2 dropwise. After 20 minutes, the ice bath was removed, the solution was warmed to rt and was stirred for 2 hours. The solvent was removed in vaccuo to afford the title compound as its HCl salt (1.5g, 100percent). 1H NMR (400 MHz, CD3OD) δ 3.71 - 3.77 (m, 1 H) 3.77 (s, 3 H) 4.18 - 4.31 (m, 4 H).
100% at 0 - 25℃; for 2.25 h; Step 1 : Preparation of C34. A suspension of C33 (1.0 g, 9.89 mmol) in methanol (50 mL) was cooled to 0 °C. Thionyl chloride (1.49 mL, 20.3 mmol) was slowly added dropwise over one minute. The reaction was stirred at 0 °C for 15 minutes. The cooling bath was removed and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The residue was diluted with toluene, and then re-concentrated to dryness. The residue was dried under vacuum to afford the hydrochloride salt of C34 as a sticky yellow solid. Yield: 1.52 g, 10.0 mmol, quantitative. 1H NMR (400 MHz, DMSO-d6) δ 9.56 (br s, 1 H), 9.24 (br s, 1 H), 3.98-4.13 (m, 4H), 3.68 (s, 3H), 3.66-3.76 (m, 1 H).
100% at 5 - 65℃; A stirred suspension of azetidine-3-carboxylic acid (2 g, 19.8 mmol) in MeOH (8 ml) was cooled to 5 0C in an ice-water bath. Thionyl chloride (4.3 ml, 59 mmol) was added dropwise at such a rate as to maintain reaction temperature below 30 0C. A further portion of MeOH (8 ml) was added carefully and the mixture heated at 650C overnight. Evaporation of the solvent and co-evaporation with MeOH (2 x 20 ml) at reduced pressure provided the title compound as viscous brown oil that crystallized on standing (3.17 g, 100percent). The material was used without purification.LCMS data: Calculated MH+ (116); Found 100percent (MH+) m/z 116, Rt = 0.18 min.NMR data: 1H NMR (250 MHz, DMSO) δ ppm 9.60-8.90 (2H, br m), 4.05 (4H, br s), 3.65(3H, s)
90% at 20℃; Cooling with ice Synthesis of 192-A. To a solution of azetidine-3-carboxylic acid (5.00 g, 49.5 mmol) in MeOH (100 mL) was added SOCl2 (11.8 g, 99.0 mmol) dropwise at ice bath. The solution was stirred at room temperature overnight. The reaction mixture concentrated to dryness to give 192-A (6.8 g, 90percent) as a white solid.

Reference: [1] Patent: WO2006/33633, 2006, A1, . Location in patent: Page/Page column 68
[2] Patent: WO2012/73138, 2012, A1, . Location in patent: Page/Page column 55-56
[3] Patent: WO2009/135842, 2009, A1, . Location in patent: Page/Page column 150
[4] European Journal of Medicinal Chemistry, 2010, vol. 45, # 6, p. 2453 - 2466
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9508 - 9530
[6] Patent: WO2017/7756, 2017, A1, . Location in patent: Paragraph 466
[7] Patent: WO2006/64757, 2006, A1, . Location in patent: Page/Page column 126
[8] Patent: WO2009/16084, 2009, A1, . Location in patent: Page/Page column 50
[9] Patent: WO2005/103001, 2005, A1, . Location in patent: Page/Page column 35-36
[10] Patent: WO2010/85584, 2010, A1, . Location in patent: Page/Page column 43-44
[11] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 1, p. 144 - 148
[12] Patent: WO2018/108954, 2018, A1, . Location in patent: Page/Page column 19
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YieldReaction ConditionsOperation in experiment
100% With chloro-trimethyl-silane In methanol Preparation 41
Azetidine-3-carboxylic acid methyl ester hydrochloride .
A mixture of azetidine-3-carboxylic acid (1.26 g) and chlorotrimethylsilane (7.1 mL) in methanol (10 mL) was heated at reflux for 5 h and concentrated leaving a solid (1.88 g, 100percent).
1H NMR (300 mHz, D2O) d 4.31 (m, 4H), 3.81 (m, 1H), 3.78 (s, 3H).
Reference: [1] Patent: EP978279, 2000, A1,
[2] Patent: US4534787, 1985, A,
  • 10
  • [ 1230487-01-0 ]
  • [ 36476-78-5 ]
  • [ 1230487-00-9 ]
YieldReaction ConditionsOperation in experiment
20%
Stage #1: With acetic acid In methanol at 20℃; for 0.333333 h;
Stage #2: With sodium cyanoborohydride In methanol at 20℃;
Step 12 (0282) (0283) [00262] 1-([4-[(1E)-1-([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2- ethylphenyl]methyl)azetidine-3-carboxylic acid: To a solution of 4-[(1E)-1-([[4-cyclohexyl- 3-(trifluoromethyl) phenyl]methoxy]imino) ethyl]-2-ethylbenzaldehyde (500 mg, 1.16 mmol, 1.00 equiv.) in methanol (10 mL), azetidine-3-carboxylic acid (234.3 mg, 2.32 mmol, 2.00 equiv.) and acetic acid (0.6 mL) was added. The resulting solution was stirred for 20 min at room temperature. Then NaBH3CN (36.41 mg, 0.58 mmol, 0.50 equiv) was added in portions. The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with water (10 mL). The mixture was extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Shield RP18 OBD Column, 5um, 19*150mm; mobile phase, Water (0.1percentFA) and ACN (35.0percent ACN up to 55.0percent in 7 min); Detector, UV 254 nm to afford 120 mg (20percent) of 1-([4-[(1E)-1- ([[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]imino)ethyl]-2- ethylphenyl]methyl)azetidine-3-carboxylic acid as a white solid. 1H NMR (300 MHz, CD3OD) δ: 7.75-7.48 (m, 5H), 7.40-7.38 (m, 1H), 5.21 (s, 2H), 4.44 (s, 2H), 4.22-4.19 (m, 4H), 3.46-3.41 (m, 1H), 2.99-2.88 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.24 (s, 3H), 1.92-1.71 (m, 5H), 1.64-1.30 (m, 5H), 1.23 (t, J = 7.5 Hz, 3H). LC-MS: m/z = 517 [M+H]+.
Reference: [1] Patent: WO2017/120124, 2017, A1, . Location in patent: Paragraph 00261-00262
[2] Patent: WO2010/71794, 2010, A1, . Location in patent: Page/Page column 22
[3] Patent: WO2013/113915, 2013, A1, . Location in patent: Page/Page column 32
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  • [ 1418144-66-7 ]
  • [ 36476-78-5 ]
  • [ 1230487-00-9 ]
Reference: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 333 - 337
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