* 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
2
[ 207791-17-1 ]
[ 24424-99-5 ]
[ 51077-14-6 ]
Yield
Reaction Conditions
Operation in experiment
61.1%
With hydrogenchloride; sodium methylate; triethylamine In methanol; 1,2-dimethoxyethane; water; ethyl acetate
Example 7 Removal of Nitrobenzenesulfonyl Group and Synthesis of (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic Acid A 28percent sodium methoxide/methanol solution (0.77 ml; 2.50 molar equivalents) was added to a solution of (S)-N-(2-nitrobenzenesulfonyl)azetidine-2-carboxylic acid (429.4 mg; 46.4percent ee) in dry dimethoxyethane (5 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 3 hours at room temperature. One normal hydrochloric acid (2.25 ml), successively triethylamine (0.33 ml; 1.58 molar equivalents) and a dimethoxyethane solution (1.5 ml) containing di-tert-butyl dicarbonate (387.6 mg; 1.17 molar equivalents) were added to the reaction mixture, followed by stirring for 17 hours at room temperature. The reaction solvents were removed by evaporation under reduced pressure, and water (3 ml), ethyl acetate (15 ml) and 1 N hydrochloric acid (4 ml) were added to the resulting concentrate under ice cooling, followed by extraction and solution separation. The aqueous layer was extracted twice with ethyl acetate (15 ml and 10 ml). The resulting organic layer was dried over sodium sulfate, filtered and concentrated to obtain an oily product. This oily product was purified by silica gel column chromatography (developing solution: methylene chloride/hexane=1/1 to 2/1-->ethyl acetate/hexane=1/10 to 1/2) to obtain (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (184.6 mg; overall yield: 61.1percent). HPLC analysis conducted under the same conditions as in Reference Example 4 resulted in 38.8percent ee. 1H-NMR (CDCl3) δ1.48 (s, 9H), 2.40-2.60 (br s, 2H), 3.80-4.00 (br s, 2H), 4.80 (t, 1H)
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.).
Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; for 48 h; Stage #2: With water In tetrahydrofuran at 0℃;
Example 16 (S)-tert-Butyl 2-(Hydroxymethyl)azetidine-1-carboxylate (14).17 To a solution of 13 (0.94 g, 4.7 mmol) in THF (10 mL) was added slowly a 1 M BH3 in THF (21.0 mL) at 0° C. The mixture was stirred 2 days at ambient temperature, then cold water (20 mL) was added at 0° C. After evaporation of the THF in vacuo, an 10percent aqueous solution of citric acid (15 mL) was added and extracted with ethyl acetate (50 mL*2). The combined ethyl acetate was washed with saturated NaHCO3 (30 mL) and NaCl (30 mL), and dried over Na2SO4. Evaporation of the ethyl acetate in vacuo afforded 0.86 g (100percent) of 14 as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.40 (m, 1), 3.85-3.70 (m, 3H), 2.13 (m, 1H), 1.90 (m, 1H), 1.42 (s, 9H).
87%
With boron dimethyl-trifluoro sulphide In tetrahydrofuran at 0℃; for 2 h; Heating / reflux
(S)-1-(tert-butoxycarbonyl)-2-azetidinecarboxylic acid (10.42 g, 49.4mmol) was introduced into a 500-mLpear-shaped flask, and tetrahydrofuran (200 mL) was added to dissolve the compound. Then, a tetrahydrofuran solution of 10 M borane-dimethyl sulfide complex salt (9.87 mL, 98.7 mmol) was slowly added at 0°C, and the mixture was heated to reflux for 2 hours while stirring. The reaction solution was left to cool, and then was concentrated under reduced pressure. Ice water (100 mL) was poured thereto, and the mixture was extracted with ethyl acetate (200 mLx2). The extract was washed with saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After filtering the extract, the filtrate was concentrated under reduced pressure to obtain the title compound (8.03 g, 42.9mmol, 87percent) as an oily matter. NMR(CDCl3)δ:1.45(9H,s),1.93(1H,brs),2.13-2.22(1H,m),3.67-3.81(3H,m),3.87(1H,q,J=8.8Hz),4.21(1H,br s),4.44(1H,br s). MS(ESI)m/z:188(M++1).
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] Journal of Medicinal Chemistry, 1996, vol. 39, # 4, p. 817 - 825
[4] Angewandte Chemie - International Edition, 2013, vol. 52, # 30, p. 7829 - 7832[5] Angew. Chem., 2013, vol. 125, # 30, p. 7983 - 7986,4
[6] Chemical Communications, 2016, vol. 52, # 7, p. 1354 - 1357
[7] Journal of Labelled Compounds and Radiopharmaceuticals, 1998, vol. 41, # 5, p. 451 - 463
[8] Journal of Medicinal Chemistry, 1999, vol. 42, # 12, p. 2251 - 2259
[9] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S251 - S253
[10] Patent: EP1961750, 2008, A1, . Location in patent: Page/Page column 53; 88
[11] Bioorg. Med. Chem. Lett., 1996, vol. 6, # 19, p. 2283 - 2288
[12] Tetrahedron Asymmetry, 2001, vol. 12, # 4, p. 605 - 618
[13] Patent: WO2010/60952, 2010, A1, . Location in patent: Page/Page column 75
[14] Journal of Medicinal Chemistry, 2017, vol. 60, # 4, p. 1417 - 1431
14
[ 51077-14-6 ]
[ 105443-94-5 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With chloroformic acid ethyl ester; triethylamine In tetrahydrofuran at -10℃; for 0.333333 h; Stage #2: With ammonium hydroxide In tetrahydrofuran; water
Boc-L-2-azetidinecarboxylic acid compound 8a (2.91 g, 14.45 mmol) and Et3N (2.01 mL, 14.45 mmol) were dissolved in THF (33 mL) and cooled to -1O0C. Ice-cooled ethyl chloroformate was added dropwise followed by continued stirring for twenty minutes at the same temperature. A solution of 28percent NH4OH (3.21 mL) was added, and the reaction gradually warmed to ambient temperature. The THF solvent was removed under reduced pressure, and the residue partitioned between EtOAc and water. The organic phase was separated, dried (MgSO4), and the solvent removed to give compound 9a as a white crystalline solid (2.36 g, 82percent). 1H NMR (400MHz, DMSO-d6): δ 1.34 (s, 9H), 1.96-1.98 (m, 1 H), 2.30-2.39 (m, 1H), 3.75-3.80 (m, 2H), 4.37 (dd, J = 9.1 , 5.5 Hz), 7.11 (s, 1 H), 7.34 (s, 1H).
Reference：
[1] Patent: WO2007/23382, 2007, A2, . Location in patent: Page/Page column 70
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 3037 - 3040
[3] Patent: WO2014/141065, 2014, A1, . Location in patent: Page/Page column 50
2-{2-[7-chloro-3-(3,5-dimethyl-phenyl)-6-nitro-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-azetidine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
(R)-4-N-(tert-butoxycarbonyl)amino-2-chlorobutyric acid[ No CAS ]
[ 51077-14-6 ]
Yield
Reaction Conditions
Operation in experiment
54.8%
With hydrogenchloride; acetic acid; In tetrahydrofuran; water; ethyl acetate;
Example 5 Under argon gas at room temperature, 333.8 mg of the (R)-4-N-(tert-butoxycarbonyl)amino-2-chlorobutyric acid obtained in Example 4and dissolved in 8 ml of dry tetrahydrofuran was added dropwise to a suspension of 136.4 mg of 60percent sodium hydride/oil in 2 ml of dry tetrahydrofuran under stirring and the reaction was conducted at room temperature for 23 hours and at 50° C. for 5 hours. To this reaction mixture under water cooling was added 0.2 ml of acetic acid and the solvent was distilled off. To the residue were added 15 ml of ethyl acetate, 15 ml of water, and 1.5 ml of 3N hydrochloric acid, and after phase separation, the aqueous layer was further extracted twice with the same amount of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was sampled and analyzed by HPLC to confirm the formation of (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid. The yield was 54.8percent. The optical purity of the product as determined by high performance liquid chromatography with a chiral column (Chiralcel OD-R (Daicel)) was 89.5percent ee and the optical yield over amino protection reaction through cyclization reaction was 100percent. In addition, a sample of the product was purified by silica gel column chromatography and subjected to NMR analysis for the structural confirmation. 1H-NMR (CDCl3) delta: 1.48 (s, 9H), 2.40~2.60 (bs, 2H), 3.80~4.00 (bs, 2H), 4.80 (t, 1H)
5-(aminomethyl)pyridine-2-carbonitrile dihydrochloride[ No CAS ]
[ 51077-14-6 ]
[ 433939-63-0 ]
Yield
Reaction Conditions
Operation in experiment
73%
With dmap; 1-[bis(dimethylamino)methylen]-1-H-benzotriazolim-tetrafluoroborate-3-oxide; In DMF (N,N-dimethyl-formamide);
To a mixture of 5-(aminomethyl)pyridine-2-carbonitrile*2 HCl (0.175 g, 0.85 mmol; see step (v) above), Boc-Aze-OH (0.201 g, 1.00 mmol) and TBTU (0.321 g, 1.00 mmol) in 5 mL of DMF was added dimethylaminopyridine (0.367 g, 3.00 mmol). The mixture was stirred overnight and subsequently poured into water and extracted three times with EtOAc. The combined organic phase was washed with aqueous sodium bicarbonate, dried (Na2SO4) and evaporated. The crude product started to crystallise and was used as such in the next step. Yield: 0.23 g (73percent). 1H NMR (500 MHz, CDCl3) delta8.66 (s, 1H), 8.2-7.8 (broad, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 4.73 (m, 1H), 4.65-4.5 (m, 2H), 3.94 (m, 1H), 3.81 (m, 1H), 2.6.2.35 (m, 2H), 1.8 (broad, 1H), 1.45 (s, 9H)
73%
With dmap; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In DMF (N,N-dimethyl-formamide);
To a mixture [OF 5- (AMINOMETHYL)] pyridine-2-carbonitrile x 2 HCI (0.175 g, 0.85 mmol; see step (v) above), Boc-Aze-OH (0.201 g, 1.00 mmol) and TBTU (0.321 g, 1.00 mmol) in 5 mL of DMF was added dimethylaminopyridine (0.367 g, 3.00 mmol). The mixture was stirred overnight and subsequently poured into water and extracted three times with EtOAc. The combined organic phase was washed with aqueous sodium bicarbonate, dried [(NA2SO4)] and evaporated. The crude product started to crystallise and was used as such in the next step. Yield: 0.23 g (73percent).
With dmap; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In DMF (N,N-dimethyl-formamide);
To a solution of [H2N-CH2-(2-(AMINO (TRIMETHYLSILYLETHYLIMINO) METHYL)-5-PYRIDINYL)] x 2 HCI (0.21 g, 0.57 mmol; see step (iv) above), Boc-Aze-OH (0.127 g, 0.631 mmol), and TBTU (233 mg, 0.726 mmol) in 5 mL of DMF was added dimethylaminopyridine (269 mg, 2.20 mmol). The mixture was stirred overnight, poured into 100 mL of water and extracted with EtOAc three times. The combined organic phase was washed with aqueous sodium bicarbonate and water, dried [(NA2S04)] and evaporated. The crude product was flash chromatographed on silica gel with EtOAc to give 170 mg (56percent) of the desired product. 'H NMR (500 MHz, [CDC13)] [8] 9.33 (broad, 1H), 8.54 (s, 1H), 8.41 (d, 1H), 8.36 (broad, [1H),] 7.75 (m, [1H),] 4.72 (m, [IH),] 4.56 (m, 2H), 4.26 (m, 2H), 3.93 (m, 1H), 3.80 (m, [1H),] 2.6-2. 4 (m, 2H), 1.42 (s, 9H), 1.14 (m, 2H), 0.07 (s, 9H)
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide);
To a stirred solution of Boc-Aze-OH (0.189 g, 0.94 mmol), H-Pab (2,5-diF) (Teoc) x 2 HCI (0.36 g, 0.89 mmol; see step (xi) above) and [PYBOP] (0.54 g, 1.03 mmol) in 5 mL [OF DMF] was added diisopropylethyl amine (0.49 g, 3.8 mmol) and the mixture was allowed to react overnight. The resultant was then poured into aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic phase was washed with water, dried [(NA2SO4)] and evaporated. Flash chromatography on silica gel with heptane: EtOAc (3: 7) gave a sufficiently pure compound. Yield: 0.25 g (48percent). [APOS;H NMR (500 MHZ, CDC13) 6] 7.98 (dd, [IH),] 7.13 (dd, [1H),] 4.69 (m, [1H),] 4. [53] (m, 2H), 4.22 (m, 2H), 3.92 (m, [1H),] 3.79 (m, [1H),] 2.55-2. 35 (m, 2H), 1.44 (s, 9H), 1.11 (m, 2H), 0.06 (s, 9H)
2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide hydrochloride[ No CAS ]
[ 51077-14-6 ]
2-[2-[2-ethyl-4-(1-methyl-carbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl-(4-fluorobenzyl)-2-oxo-ethylcarbamoyl]-azetidine]-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 0℃; for 4h;
2- {4- [2-Amino- 3- (4-fluorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propioamide, 41, (0.78g, 0.83 mmol) and Boc-L-azetidine-2-carboxylic acid (0.17 g, 0.83 mmol), 1- (3- dimethylamino-propyl)-3-ethylcarbodiimide (0.19 g, 1.0 mmol) and 1-hydroxybenzotriazole (0.22 g, 1.66 mmol) are dissolved in anhydrous DMF (2 mL). The reaction mixture is cooled to 0 C, then N-methylmorpholine (0.6 mL, 5.46 mmol) is added. The reaction mixture is stirred for 4 hrs. EtOAc (30 mL) and water (100 mL) are added, and the organic layer is separated. The aqueous layer is extracted with EtOAc (3x30 mL). All organic layers are combined and washed with water (2x50 mL), and dried over Na2SO4. The solution is concentrated in vacuo to afford the desired product which is used without further purification. 2- [2- [2-ethyl-4- (1-methyl-carbamoyl-2-naphthalen-2-ylethyl)-piperazin-1-yl- (4- fluorobenzyl)-2-oxo-ethylcarbamoyl]-azetidine-1-carboxylic acid tert-butyl ester is dissolved in DCM/TFA/H20 (2/1/0. 1) (10 mL) and stirred at room temperature for 1 hour. 1, 2- dichloroethane (10 mL) is added. The organic layers are combined, washed with water (2 x 50 mL), dried over Na2SO4, then concentrated in vacuo to provide a crude product which is purified by preparative HPLC to afford 32 mg of the desired product. (HCS3621-118).'H NMR (CDC13, 300 MHz, ) : 7.90-7. 84 (m, 3H), 7.75 (s, 1H), 7.54-7. 51 (m, 2H), 7.43-7. 34 (m, 3H), 7.18-7. 08 (m, 2H), 5.30-5. 25 (m, 1 H), 5.06-5. 00 (m, 1.5H), 4.59 (bs s, 0.5H), 4.43 (d, J = 14.2 Hz, 0. 5H), 4.21- 4.11 (m, 1.5H), 4.00-3. 91 (m, 1 H), 3.80-3. 69 (m, 1 H), 3.55 (t, J = 7.5 Hz, 0.5H), 3.40-3. 38 (m, 3H), 3.32-3. 20 (m, 4H), 3.17-2. 75 (m, 6H), 2.73-2. 67 (m, 1.5H), 2.51-2. 24 (m, 1. 5H), 2.02-1. 54 (m, 2.5H), 0.88-0. 77 (m, 3H) ; 13C NMR, (CDCI3, 75 MHz) 8 172.0, 169.0, 165.4, 162.3, 136.8, 136.1, 135.4, 134.2, 133.9, 133.0, 132.8, 132.7, 129.5, 129.4, 129.0, 128.9, 127.6, 127.1, 127.0, 117.1, 116.8, 116.5, 71.3, 60.2, 57.1, 54.2, 52.4, 52.0, 51.9, 50.5, 50.0, 49.9, 49.7, 49.1, 45.5, 42.2, 39.7, 38.5, 35.9, 35.7, 26.3, 25.3, 24.0, 23.4, 11.1 ; HRFAB (positive) m/e 574.319344 calculated for C33H40FN5O3 (M+H) +, Found 574.320780.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;
[BOC- (S)] Aze-OH (1.14 g, 5.6 mmol) was dissolved in 45 [ML] of DMF. 4- Aminomethyl-2,6-difluorobenzonitrile (1.00 g, 5.95 mol, see Example [L] (xiv) above), [PYBOP] (3.10 g, 5.95 mmol) and DIPEA (3.95 mL, 22.7 mmol) were added and the solution was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between H20 and EtOAc (75 [ML] each). The aqueous phase was extracted with 2 x 50 mL EtOAc and the combined organic phase was washed with brine and dried over [NA2S04.] Flash chromatography (Si02, EtOAc/heptane (3/1) ) yielded the sub-title compound (1.52 g, 77percent) as an oil which crystallized in the refrigerator. 'H-NMR (400 MHz; CD30D) : [8] 7.19 (m, 2H), 4.65-4. 5 (m, 3H), 3.86 (m, 1H), 3.73 (m, 1H), 2. [45-2.] 3 (m, 2H), 1.39 (s, 9H)
77%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;
[BOC- (S)] Aze-OH (1.14 g, 5.6 mmol) was dissolved in 45 [ML] of DMF. 4- [AMINOMETHYL-2, 6-DIFLUOROBENZONITRILE] (1.00 g, 5.95 mol, see Example [1] (xiv) above), [PYBOP] (3.10 g, 5.95 mmol) and DIPEA (3.95 mL, 22.7 mmol) were added and the solution was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between H20 and EtOAc (75 [ML] each). The aqueous phase was extracted with 2 x 50 mL EtOAc and the combined organic phase was washed with brine and dried over [NA2SO4.] Flash chromatography [(SI02,] EtOAc/heptane (3/1) ) yielded the sub-title compound (1.52 g, 77percent) as an oil which crystallized in the refrigerator. 'H-NMR (400 MHz; CD30D): 8 7.19 (m, 2H), 4.65-4. 5 (m, 3H), 3.86 (m, 1H), 3.73 (m, 1H), 2.45-2. 3 (m, 2H), 1.39 (s, 9H)
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 0℃; for 2h;
Boc-Pab (2,6-diF) (Teoc) (1.009 g, 2.35 mmol; see step (x) above) was dissolved in 50 mL of EtOAc saturated with HCl (g). The mixture was left for 10 min., evaporated and dissolved in 18 mL of DMF, and then cooled on an ice bath. Boc- Aze-OH (0.450 g, 2.24 [MMOL), PYBOP] (1.24 g, 2.35 mmol) and lastly diisopropylethyl amine (1.158 g, 8.96 mmol) were added. The reaction mixture was stirred for 2 h and then poured into 350 mL of water and extracted three times with EtOAc. The combined organic phase was washed with brine, dried [(NA2S04)] and evaporated. Flash chromatography on silica gel with heptane: EtOAc (1: 3) gave 1.097 g [(96percent)] of the desired compound. 'H NMR (500 MHz, [CDC13)] [8] 7.46 (m, 2H), 4.65-4. 5 (m, 3H), 4.23 (m, 2H), 3.87 (m, [1H),] 3.74 (m, [1H),] 2.45-2. 3 (m, 2H), 1.40 (s, 9H), 1.10 (m, 2H), 0.05 (s, 9H)
96%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 0℃; for 2h;
Boc-Pab (2,6-diF) (Teoc) (1.009 g, 2.35 mmol; see step (x) above) was dissolved in 50 mL of EtOAc saturated with HCI (g). The mixture was left for 10 min., evaporated and dissolved in 18 mL of DMF, and then cooled on an ice bath. Boc- Aze-OH (0.450 g, 2.24 mmol), [PYBOP] (1.24 g, 2.35 mmol) and lastly diisopropylethyl amine (1.158 g, 8.96 mmol) were added. The reaction mixture was stirred for 2 h and then poured into 350 [ML] of water and extracted three times with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4) and evaporated. Flash chromatography on silica gel with heptane : EtOAc (1: 3) gave 1.097 g (96percent) of the desired compound. 'H NMR (500 MHz, [CDC13)] 8 7.46 (m, 2H), 4.65-4. 5 (m, 3H), 4.23 (m, 2H), 3.87 (m, [1H),] 3.74 (m, [1H),] 2.45-2. 3 (m, 2H), [1.] 40 (s, 9H), 1.10 (m, 2H), 0.05 (s, 9H)
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide);
To a stirred solution of Boc-Aze-OH (0.189 g, 0.94 mmol), H-Pab(2,5-diF)(Teoc).x.2 HCl (0.36 g, 0.89 mmol; see step (xi) above) and PyBOP (0.54 g, 1.03 mmol) in 5 mL of DMF was added diisopropylethyl amine (0.49 g, 3.8 mmol) and the mixture was allowed to react overnight. The resultant was then poured into aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organic phase was washed with water, dried (Na2SO4) and evaporated. Flash chromatography on silica gel with heptane:EtOAc (3:7) gave a sufficiently pure compound. Yield: 0.25 g (48percent). [1077] 1H NMR (500 MHz, CDCl3) delta7.98 (dd, 1H), 7.13 (dd, 1H), 4.69 (m, 1H), 4.53 (m, 2H), 4.22 (m, 2H), 3.92 (m, 1H), 3.79 (m, 1H), 2.55-2.35 (m, 2H), 1.44 (s, 9H), 1.11 (m, 2H), 0.06 (s, 9H)
H2N-CH2-(2-(amino(trimethylsilylethylimino)methyl)-5-pyridinyl) dihydrochloride[ No CAS ]
[ 51077-14-6 ]
Boc-Aze-NH-CH2-(2-(amino trimethylsilylethyimino)methyl)-5-pyridinyl[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With dmap; 1-[bis(dimethylamino)methylen]-1-H-benzotriazolim-tetrafluoroborate-3-oxide; In DMF (N,N-dimethyl-formamide);
To a solution of H2N-CH2-(2-(amino(trimethylsilylethylimino)methyl)-5-pyridinyl).x.2 HCl (0.21 g, 0.57 mmol; see step (iv) above), Boc-Aze-OH (0.127 g, 0.631 mmol), and TBTU (233 mg, 0.726 mmol) in 5 mL of DMF was added dimethylaminopyridine (269 mg, 2.20 mmol). The mixture was stirred overnight, poured into 100 mL of water and extracted with EtOAc three times. The combined organic phase was washed with aqueous sodium bicarbonate and water, dried (Na2SO4) and evaporated. The crude product was flash chromatographed on silica gel with EtOAc to give 170 mg (56percent) of the desired product. [0905] 1H NMR (500 MHz, CDCl3) delta9.33 (broad, 1H), 8.54 (s, 1H), 8.41 (d, 1H), 8.36 (broad, 1H), 7.75 (m, 1H), 4.72 (m, 1H), 4.56 (m, 2H), 4.26 (m, 2H), 3.93 (m, 1H), 3.80 (m, 1H), 2.6-2.4 (m, 2H), 1.42 (s, 9H), 1.14 (m, 2H), 0.07 (s, 9H)
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;
Standard EDC coupling was performed using amine b (100 mg, 0.2 mmol), the carboxylic acid a, (58 mg, 0.29 mmol) and EDC (56 mg, 0.29 mmol). BOC-protected final product was purified by chromatography ISCO CombiFlash 12 g column with a solvent gradient of 0-65percent ethyl acetate-dichloromethane over 15 min. Standard BOC-deprotection was performed using 2:1 DCM : TFA with few drops of water. Final product c was purified by reverse- phase HPLC Ci8 column with a solvent gradient of 5-50percent acetonitrile-water over 18 min. Yield of product c was 132 mg.
(2S)-tert-butyl 2-((2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro-N,N,N',N'-bis(tetramethylene)formamidinium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 250℃; for 96h;
(b) (2S)-tert-Butyl 2-((2-(6-(2-acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)carbamoyl)azetidine-1-carboxylate;. To a solution of N-(4-(6-(2-amino-4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)-benzo[d]thiazol-2-yl)acetamide (1.5 g, 3.3 mmol, prepared as described in WO04014871) and (S)-1-(tert-butyloxycarbonyl)azetidine-2-carboxylic acid from step (a) above (1.0 g, 5.0 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropylethylamine (0.87 mL, 5.0 mmol, Aldrich) and chloro-dipyrrolidinocarbenium hexafluorophosphate (1.7 g, 5.0 mmol, Fluka). The mixture was stirred for 4 d at 250C and diluted with EtOAc. The mixture was washed with aqueous solution of NaHCO3, H2O and brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (gradient: 5-55percent EtOAc/hexane) to give the title compound as a yellow solid. MS (ESI, pos. ion.) m/z: 629 (M+1).
With hydrogenchloride; sodium methylate; triethylamine; In methanol; 1,2-dimethoxyethane; water; ethyl acetate;
Example 7 Removal of Nitrobenzenesulfonyl Group and Synthesis of (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic Acid A 28percent sodium methoxide/methanol solution (0.77 ml; 2.50 molar equivalents) was added to a solution of (S)-N-(2-nitrobenzenesulfonyl)azetidine-2-carboxylic acid (429.4 mg; 46.4percent ee) in dry dimethoxyethane (5 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 3 hours at room temperature. One normal hydrochloric acid (2.25 ml), successively triethylamine (0.33 ml; 1.58 molar equivalents) and a dimethoxyethane solution (1.5 ml) containing di-tert-butyl dicarbonate (387.6 mg; 1.17 molar equivalents) were added to the reaction mixture, followed by stirring for 17 hours at room temperature. The reaction solvents were removed by evaporation under reduced pressure, and water (3 ml), ethyl acetate (15 ml) and 1 N hydrochloric acid (4 ml) were added to the resulting concentrate under ice cooling, followed by extraction and solution separation. The aqueous layer was extracted twice with ethyl acetate (15 ml and 10 ml). The resulting organic layer was dried over sodium sulfate, filtered and concentrated to obtain an oily product. This oily product was purified by silica gel column chromatography (developing solution: methylene chloride/hexane=1/1 to 2/1-->ethyl acetate/hexane=1/10 to 1/2) to obtain (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (184.6 mg; overall yield: 61.1percent). HPLC analysis conducted under the same conditions as in Reference Example 4 resulted in 38.8percent ee. 1H-NMR (CDCl3) delta1.48 (s, 9H), 2.40-2.60 (br s, 2H), 3.80-4.00 (br s, 2H), 4.80 (t, 1H)
With hydrogenchloride; lithium methanolate; triethylamine; In methanol; 1,2-dimethoxyethane; water; ethyl acetate;
Example 8 Removal of Nitrobenzenesulfonyl Group and Synthesis of (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic Acid A 1 M lithium methoxide/methanol solution (3.75 ml; 2.50 molar equivalents) was added to a solution of (S)-N-(2-nitrobenzenesulfonyl)azetidine-2-carboxylic acid (429.4 mg; 46.4percent ee) in dry dimethoxyethane (5 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 94 hours at room temperature. One normal hydrochloric acid (2.25 ml), successively triethylamine (0.33 ml; 1.58 molar equivalents) and a dimethoxyethane solution (1.5 ml) containing di-tert-butyl dicarbonate (397.7 mg; 1.20 molar equivalents) were added to the reaction mixture, followed by stirring for 24 hours at room temperature. On the way, water (6 ml) was further added for decreasing insoluble matter. The reaction solvents were removed by evaporation under reduced pressure, and ethyl acetate (15 ml) and 1 N hydrochloric acid (8 ml) were added to the resulting concentrate under ice cooling, followed by extraction and solution separation. The aqueous layer was extracted three times with ethyl acetate (15 ml). The resulting organic layer was dried over sodium sulfate, filtered and concentrated to obtain an oily product.
With hydrogenchloride; sulfuric acid; sodium carbonate; In tetrahydrofuran; water; ethyl acetate;
A mixed solution of tetrahydrofuran (70 ml)/water (60 ml) containing (S)-N-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (20.51 g; also containing (R)-isomer) and sulfuric acid (10.03 g) was stirred for 1 hour under ice cooling, 1.5 hours at room temperature, and for 28 hours under heating at 45 to 48° C. On the way, 6 N hydrochloric acid (20 ml) was further added after about 20 hours. The reaction mixture was cooled with ice, and sodium carbonate (38.92 g), 2-nitrobenzenesulfonyl chloride (29.42 g), tetrahydrofuran (50 ml) and water (60 ml) were added in turn thereto, followed by stirring for 70 minutes under ice cooling and for 37 hours at room temperature. On the way, sodium carbonate (5.45 g) was further added after 30 minutes. Water (140 ml) was added to the reaction mixture, and the organic solvent was removed by evaporation under reduced pressure. Then, water (40 ml) and ethyl acetate (140 ml) were added, followed by extraction and solution separation, and the organic layer was extracted again with water (100 ml). Ethyl acetate (30 ml) and concentrated hydrochloric acid (40 ml) were added to the resulting aqueous layer, and ethyl acetate (100 ml) was further added, followed by extraction and solution separation. The aqueous layer was extracted again with ethyl acetate (120 ml). The resulting organic layer was dried over sodium sulfate, filtered, concentrated and dried under vacuum to obtain (S)-N-(2-nitrobenzenesulfonyl)azetidine-2-carboxylic acid (26.2 g; yield: 89.8percent). Analysis according to high performance liquid chromatography (HPLC) resulted in 46.4percent ee.
Example 1 Under an argon atmosphere, 1.00 g (4.97 mmol) of (S)-N-t-butoxycarbonyl-2-azetidinecarboxylic acid was dissolved in 15 ml of tetrahydrofuran and 502 mg (4.97 mmol) of triethylamine was added thereto. While stirring the reaction mixture at 0° C., 539 mg (4.97 mmol) of ethyl chlorocarbonate was added gradually and dropwise. After the dropping was completed, the mixture was stirred at 0° C. for 30 minutes, and then 463 mg (4.97 mmol) of aniline was added. After stirring at 0° C. for 1 hour, the stirring was continued at room temperature for 16 hours. The reaction mixture was stirred under heating to reflux for further 3 hours, and then cooled to room temperature. Solid was filtered and washed with ethyl acetate. Then the organic layer was concentrated and the residue was purified by column chromatography to give the desired product, i.e., optically active 1.27 g (yield: 93percent) of (S)-1-t-butoxycarbonyl-N-phenyl-2-azetidinecarboxamide in the form of a white solid.
N-(tert-Butoxycarbonyl)-(S)-(-)-2-azetidinecarboxylic acid n-decyl amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; ethyl acetate;
Example 2 N-(tert-Butoxycarbonyl)-(S)-(-)-2-azetidinecarboxylic Acid n-decyl Amide (285) N-(tert-Butoxycarbonyl)-(S)-(-)-2-azetidinecarboxylic acid (1) (90 mg; 0.447 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (72 mg; 0.470 mmol), N,N-diisopropylethylamine (116 mg; 0.895 mmol) and PyBOP (244 mg; 0.470 mmol) are added sequentially. The reaction is stirred for 4 days at room temperature, then concentrated under reduced pressure. The crude product is purified via silica gel chromatography using a gradient elution (10percent-->60percent ethyl acetate in hexanes) affording the desired product (285). ISMS: MH+341.4 Compounds 283, 284 and 286 are prepared in a similar manner using n-hexylamine, n-octylamine and n-dodecylamine, respectively, in place of n-decylamine.
Example 2 5.00 g of (S)-N-t-butyloxycarbonyl-azetidine-2-carboxylic acid (99.6percent e.e.) obtained in a similar manner as in Example 1 was added to 53 g of a 17percent solution of hydrogen chloride in ethyl acetate and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to give 3.45 g of (S)-azetidine-2-carboxylic acid hydrochloride. The yield was 100percent, and an HPLC analysis of the salt on a chiral column showed 99.6percent e.e.
46
[ 161511-85-9 ]
[ 51077-14-6 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hypochlorite; sodium bicarbonate; sulfuric acid; cyfluthrin; sodium thiosulfate; sodium bromide; In water; ethyl acetate;
EXAMPLE 10 Synthesis of (S)-N-t-butoxycarbonylazetidine-2-carboxylic Acid STR15 A reaction flask was charged with the (S)-N-t-butoxycarbonylazetidine-2-methanol (2.97 g, 15.9 mmol) obtained in Example 5, TEMPO (25.0 mg, 0.159 mmol), NaBr (4.94 g, 47.7 mmol), ethyl acetate (35 mL) and water (7 mL). Thereto was added, at 5 to 10° C., a mixture of an aqueous solution of sodium hypochlorite (Nakalai Tesque, 80 mL) and sodium hydrogen carbonate (4.68 g, 55.7 mmol). Stirring was further continued for 3 hours. Sodium thiosulfate (0.79 g, 5.06 mmol) was added to the reaction mixture, and the mixture was stirred for 5 minutes. Then, the reaction mixture was adjusted to pH 2 by adding 10percent sulfuric acid and extracted with ethyl acetate (50 mL*2), the organic layer was washed with water (50 mL*2), dried over magnesium sulfate and filtered, and the filtrate was concentrated to give white crystals (3.18 g).
B. S-1-[(1,1-Dimethylethoxy)carbonyl]azetidine-2-carboxylic acid methyl ester A mixture of (S)-1-[(1,1-Dimethylethoxy)carbonyl]-azetidine-2-carboxylic acid (2.0 g; 9.9 mmol), potassium carbonate (6.9 g; 50.0 mmol), and methyliodide (6.25 ml; 100.0 mmol) in 20 ml of dimethylformamide was stirred under argon at room temperature for 1 d. The excess methyliodide was pumped into a dry ice cooled trap and the remaining mixture poured into water and extracted with 300 ml of ethyl ether. The organic extract was washed with 2*150 ml of brine, dried (magnesium sulfate) and concentrated to afford 1.85 g of the title B as a colorless liquid. [alpha]D =-114.8° (c =2.5, chloroform).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; acetic acid; In methanol; N,N-dimethyl-formamide;
110b. N-(1-Amino-isoquinolin-6-ylmethyl)-1-tert.butoxycarbonyl-azetidin-2(S)-carboxamide 2.00 g 1-Tert.butoxycarbonyl-azetidin-2(S)-carboxylic acid, 1.70 g 1-amino-6-aminomethyl-isoquinolin, 3.50 g TBTU were dissolved in 40 mL DMF. 3.55 mL N-methylmorpholin was added slowly with stirring. The solution was applied to a reversed-phase chromatography column (lenght 100 mm, diameter 14 mm; Merck Lichroprep RP-18, 15-25 u). Elution was started with 25 mL of methanol/water containing 0.3percent acetic acid (10: 90), then a linear gradient to pure methanol over a period of 75 mL was applied followed by 50 mL of pure methanol. Fraktions of 5 mL each were sampled. The solvent was evaporated to give 3.4 g of the tile compound. MS: 357
In methanol; diethyl ether; dichloromethane; at 0℃;
A solution of trimethylsilyldiazomethane in ether (2M, 9 mL) was added dropwise to a stirred, ice-bath cooled, mixture of l-Boc-L-azetidine-2-carboxylic acid (3 g, 15 mmol), dichloromethane (20 mL) and methanol (5 mL) until yellow colour persisted. The mixture was concentrated in vacuo. The residue was treated with THF (30 mL) and N,O-dimethylhydroxylamine hydrochloride (2.04 g; 20.9 mmol) and cooled to O0C. /-Propylmagnesium chloride in THF (2 M, 22.4 ml, 44.7 mmol) was added dropwise to the mixture and it was stirred for 30 min. After quenching with saturated aqueous NH4Cl (25 ml) and concentrated NH3 (25 ml), the mixture was extracted into ethyl acetate (150 mL). The organic extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel (hexanes-ethyl acetate 0-100percent) to give the title product (2.73 g, 75percent). 1H NMR (500 MHz, CDCl3): delta 5.03 (IH, m), 4.05 (IH, m), 3.87 (IH, m), 3.71 (3H, s), 3.22 (3H, s), 2.46 (IH, m), 2.13 (IH, m), 1.43 (9H, s).
(S)-2-(4'-ethoxycarbonyl-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl)-azetidine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 4-methyl-morpholine; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 18h;
(S)-2-(4'-Ethoxycarbonyl-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl)-azetidine-l- carboxylic acid tert-butyl ester; A mixture of 5'-amino-2'-trifluoromethoxy-birhohenyl-4-carboxylic acid (150mg), (S)- azetidine-l,2-dicarboxylic acid 1 -tert-butyl ester (93mg), HBTU (262mg) and N-methyl morpholine (0.14ml) in dry DMF (3ml) was stirred at room temp for 18h. The mixture was then partitioned between water and DCM. The dried organic layer was evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1 : 1 gave a pale orange oil (188mg).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;
Boc-L-2-azetidine carboxylic acid compound 8a (2.01 g, 10.0 mmol) was dissolved in CH2CI2 (50.0 mL) and cooled to 00C. To this was added in succession HOBt (1.62 g, 11.99 mmol), methylamine hydrochloride (2.02 g, 30.0 mmol), N-methylmorpholine (4.39 mL, 40.0 mmol), and EDC (2.10 g, 10.99 mmol). The reaction was stirred at O0C for one hour, then warmed to room temperature and stirred overnight. The reaction was diluted' with EtOAc. The organic layer was separated, washed successively with 1 N HCI, saturated NaHCO3, and brine. After drying (MgSO4) the solvent was removed to give 1.84 g (86percent) compound 8b as oil which solidified upon standing. 1H NMR (400MHz, DMSO-d6): delta 1.34 (s, 9H), 1.90-1.98 (m, 1H), 2.29-2.38 (m, 1 H), 2.61 (d, J = 4.5 Hz, 3H)1, 3.75-3.80 (m, 2H), 4.37 (dd, J = 9.1 , 5.6 Hz), 7.87 (br, 1H).
Boc-NH-CH2-(5-cyano)-2-pyrimidine (1.14 g, 4.87 mmol; see step (iii) above) was dissolved in 50 mL of EtOAc saturated with HCl(g) and allowed to react for 1 h and concentrated. The residue was dissolved in 20 mL of DMF and cooled in an ice bath. Diisopropylethyl amine (3.5 mL, 0.020 mol), Boc-Aze-OH (1.08 g, 5.37 mmol) and HATU (2.80 g, 5.38 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (40:60). The acetonitrile was evaporated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was dried (MgSO4) and evaporated. [0936] Yield: 1.12 g (72percent). [0937] 1H NMR (400 MHz, CDCl3) delta8.95 (s, 2H), 4.82 (d, 2H), 4.74 (m, 1H), 3.95 (m, 1H), 3.84 (m, 1H), 2.6-2.4 (m, 2H), 1.47 (s, 9H)
72%
[BOC-NH-CH2- (5-CYANO)-2-PYRIMIDINE] (1.14 g, 4.87 mmol; see step (iii) above) was dissolved in 50 mL of EtOAc saturated with [HCL (G)] and allowed to react for 1 h and concentrated. The residue was dissolved in 20 mL of DMF and cooled in an ice bath. [DIISOPROPYLETHYL] amine (3.5 mL, 0.020 mol), Boc-Aze-OH (1.08 g, 5.37 mmol) and HATU (2.80 g, 5.38 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN: 0. IM NH40Ac (40: 60). The acetonitrile was evaporated and the aqueous layer was extracted three times with EtOAc. The combined organic layer was dried (MgS04) and evaporated. Yield: 1.12 g (72percent). 'H NMR (400 MHz, [CDC13)] 8 8.95 (s, 2H), 4.82 (d, 2H), 4.74 (m, 1H), 3.95 (m, 1H), 3.84 (m, 1H), 2.6-2. 4 (m, 2H), 1.47 (s, 9H)
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (y) above) and diiisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74percent) of the desired sub-title compound. [0979] 1H NMR (300 MHz, CD3OD) delta7.70 (m, 1H), 7.35-7.25 (m, 2H), 4.65-4.35 (m, 3H), 4.0-3.85 (m, 2H), 2.51 (m, 1H), 2.19 (m, 1H), 1.40 (s, 9H).
74%
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4- aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (v) above) and diiisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN: 0. IM NH40Ac (50: 50). Freeze- drying gave 0.237 g (74percent) of the desired sub-title compound. 'H NMR (300 MHz, CD30D) 8 7.70 (m, [1H),] 7.35-7. 25 (m, 2H), 4.65-4. 35 (m, 3H), 4.0- 3.85 (m, 2H), 2.51 (m, [1H),] 2.19 (m, [1H),] 1.40 (s, 9H)
Boc-Pab (2,6-diF) (Teoc) (1.009 g, 2.35 mmol; see step (x) above) was dissolved in 50 mL of EtOAc saturated with [HCL] (g). The mixture was left for 10 [MIN.,] evaporated and dissolved in 18 mL of DMF, and then cooled on an ice bath. Boc-Aze-OH (0.450 g, 2.24 mmol), [PYBOP] (1.24 g, 2.35 mmol) and lastly diisopropylethyl amine [(1.] 158 g, 8.96 mmol) were added. The reaction mixture was stirred for 2 h and then poured into 350 mL of water and extracted three times with EtOAc. The combined organic phase was washed with brine, dried [(NA2SO4)] and evaporated. Flash chromatography on silica gel with heptane: EtOAc (1: 3) gave 1.097 g (96percent) of the desired compound. 'H NMR (500 MHz, [CDC13)] [5] 7.46 (m, 2H), 4.65-4. 5 (m, 3H), 4.23 (m, 2H), 3.87 (m, 1H), 3.74 (m, [1H),] 2.45-2. 3 (m, 2H), 1.40 (s, 9H), 1.10 (m, 2H), 0.05 (s, 9H)
Boc-Pab (2,6-diF) (Teoc) (1.009 g, 2.35 mmol; see step (x) above) was dissolved in 50 mL of EtOAc saturated with HCl (g). The mixture was left for 10 min., evaporated and dissolved in 18 [ML] of DMF, and then cooled on an ice bath. Boc- Aze-OH (0.450 g, 2.24 mmol), [PYBOP] (1.24 g, 2.35 mmol) and lastly diisopropylethyl amine (1.158 g, 8.96 mmol) were added. The reaction mixture was stirred for 2 h and then poured into 350 [ML] of water and extracted three times with EtOAc. The combined organic phase was washed with brine, dried [(NA2S04)] and evaporated. Flash chromatography on silica gel with heptane: EtOAc (1: 3) gave 1.097 g (96percent) of the desired compound. 'H NMR (500 MHz, [CDC13)] [8] 7.46 (m, 2H), 4.65-4. 5 (m, 3H), 4.23 (m, 2H), 3.87 (m, 1H), 3.74 (m, [1H),] 2.45-2. 3 (m, [2H),] 1.40 (s, 9H), 1.10 (m, 2H), 0.05 (s, 9H)
To a mixture of acid N-2 (Scheme N, where n is 2, m is 0, X is N, Y is -CO2-, R3 is (1,1-dimethyl)ethyl, and the stereochemistry is (S)) (1.04 g; 5.17 mmol) and HOBt.H2O (0.71 g, 5.3 mmol) in CH2Cl2 (10 mL) at 0° C. is added a mixture of EDCHCl (1.00 g, 5.22 mmol) in CH2Cl2 (20 mL). The reaction mixture is stirred at 0° C. for 30 min, and then N-3 (Scheme N where R5 is 4-[(2,6-dichlorobenzoyl)amino]phenyl and stereochemistry is (S)) (2.10 g, 5.20 mmol) and N-methylmorpholine (0.60 mL, 5.46 mmol) are added. The reaction mixture is stirred at 0° C. for 30 min and at rt for 3 h. The reaction mixture is partitioned between 10percent KHSO4 and CH2Cl2. The aqueous phase is extracted twice more with CH2Cl2. The combined organic extracts are washed with saturated NaHCO3 and brine, and then are dried, filtered and concentrated to a yellow oil (2.54 g) that is purified by silica flash chromatography to give the title compound as a white foam: mp 106-108° C.; TLC (1:1Hexanes/EtOAc); Rf=0.21; [alpha]25D -38 (c 1.01, MeOH); 13C NMR (CD3OD) delta 172.37, 171.58, 163.64, 156.68, 136.98, 136.22, 133.11, 131.87, 130.90, 129.49, 127.91, 120.00, 80.42, 61.87, 53.31, 51.45, 36.40, 27.16, 20.08; MS (EI) m/z 551, 549, 478, 476, 451, 449, 396, 394, 351, 349, 280, 278, 175, 173; Anal. C, 56.33; H, 5.48; N, 7.23; Cl, 12.43; (calcd for 0.52percent H2O: C, 56.44; H, 5.34; N, 7.59; Cl, 12.82).
Boc-Pab(2,6-diF)(Teoc) (1.009 g, 2.35 mmol; see step (x) above) was dissolved in 50 mL of EtOAc saturated with HCl(g). The mixture was left for 10 min., evaporated and dissolved in 18 mL of DMF, and then cooled on an ice bath. Boc-Aze-OH (0.450 g, 2.24 mmol), PyBOP (1.24 g, 2.35 mmol) and lastly diisopropylethyl amine (1.158 g, 8.96 mmol) were added. The reaction mixture was stirred for 2 h and then poured into 350 mL of water and extracted three times with EtOAc. The combined organic phase was washed with brine, dried (Na2SO4) and evaporated. Flash chromatography on silica gel with heptane:EtOAc (1:3) gave 1.097 g (96percent) of the desired compound. [1021] 1H NMR (500 MHz, CDCl3) delta7.46 (m, 2H), 4.65-4.5 (m, 3H), 4.23 (m, 2H), 3.87 (m, 1H), 3.74 (m, 1H), 2.45-2.3 (m, 2H), 1.40 (s, 9H), 1.10 (m, 2H), 0.05 (s, 9H)
A mixture of 1-Boc-L-azetidine-2-carboxylic acid (10 g), conc. H2SO4 (1 mL) in dry MeOH (200 mL) was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo, the residue was diluted with EA, basified with sat. NaHCO3 solution. The organic extract was washed with water, dried (MgSO4), filtered and concentrated to yield the crude methyl ester as a yellow oil (11 g, 102percent). This crude ester was dissolved in dry MeOH (200 mL) and treated with 7M ammonia solution in MeOH (100 mL). The resulting white suspension was stirred at RT for 72 h and filtered off. The filtrate was concentrated in vacuo to give the title compound as a white solid (8.5 g, 92percent).1H-NMR (CDCl3): delta=1.44 (s, 9H); 2.46 (m, 2H); 3.88 (m, 2H); 4.63 (m, 1H).
With N-ethyl-N,N-diisopropylamine; HATU; In ISOPROPYLAMIDE; at 20℃; for 18h;
0-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added in one portion to 8-(8-aminodibenzo[b,d]thiophen-4-yl)-2-morpholino- 4H-chromen-4-one (A8\\ 100 mg, 0.23 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2- carboxylic acid (51.7 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.102 ml_, 0.58 mmol) in DMA (1.5 mL) at ambient temperature. The resulting solution was stirred at ambient temperature for 18 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. This was purified by flash silica chromatography, elution gradient 0 to 5percent 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford (2S)-tert-butyl 2-(6-(2-morpholino-4-oxo-4H-chromen-8- yl)dibenzo[b,d]thiophen-2-ylcarbamoyl)azetidine-1-carboxylate (36.5 mg, 26 percent) as a white solid; 1H NMR (400 MHz, CDCI3) delta 1.53 (9H, s), 2.51 (1 H, br s), 2.69 (1H, br s), 3.08 (4H, t), 3.50 (4H, t), 3.85 - 3.91 (1 H, m), 4.00 (1 H, q), 4.91 (1 H, t), 5.51 (1 H, s), 7.44 - 7.52 (3H, m), 7.57 (1 H, t), 7.72 (1 H, d), 7.75 - 7.77 (1 H, m), 8.23 (1 H, s), 8.27 - 8.29 (1 H, m), 8.71 (1 H, d), 9.80 (1 H, br s); m/z: 612.07 (MH+).
With N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; In toluene; at 20℃; for 18h;Product distribution / selectivity;
2-Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (368.5mg; 1.49mmol) is added to a mixture of boc-L-azetidine^-carboxylic acid (200mg; 0.994mmol) and 3-amino-5-t-butylisoxazole (139mg; 0.994mmol) in toluene (5mL) at room temperature and the mixture is stirred for 18 hours. After this time, the reaction mixture is quenched with water and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 324 [M+H+] .
trans-N-1-(6-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,4-diamine[ No CAS ]
[ 51077-14-6 ]
(S)-tert-butyl 2-(4-(6-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)cyclohexylcarbamoyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
Example 106a(S)-tert-butyl 2-((1r,4S)-4-(6-chloro-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)cyclohexylcarbamoyl)azetidine-1-carboxylate; To a solution of Example 61b (0.125, 0.37 mmol) in 4 mL DMF was added EDC (0.14 g, 0.73 mmol), HOBT (0.11 g, 0.73 mmol), diisopropylethylamine (0.142 g, 1.09 mmol) and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (0.088 g, 0.44 mmol). The reaction was allowed to stir at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed with water (2.x.), brine, dried over magnesium sulfate, filtered, and concentrated. Flash chromatography performed with an Analogix280 using an SF 12-24 column (0percent to 6percent ethyl acetate/hexanes gradient over 30 minutes) to give 80 mg of the title compound as a solid. MS (ESI+) m/z 525.1 (M+H)+.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 0 - 20℃; for 7.33333h;
To a solution of 4-[(35)-3-amino-l-pyrrolidinyl]-4'-fluoro-3-biphenylcarbonitrile hydrochloride (150 mg, 0.472 mmol), (25)-l-[(l,l-dimethylethyl)oxy]carbonyl}-2- azetidinecarboxylic acid (95 mg, 0.472 mmol), and Et3N (0.197 mL, 1.416 mmol) in CH2Cl2 (2.0 mL) at 0 0C was added 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (50 wt. percent solution in EtOAc, 0.365 mL, 0.614 mmol). The reaction mixture was stirred at 0 0C for 3 h followed by RT for 4 h 20 min. CH2Cl2 (2 mL) was added and the solution was washed with saturated aq. NaHCO3 (2 x 1 mL) and 10percent aq. citric acid (2 x 1 mL). The organic solution was dried over Na2SO4, filtered, and concentrated under a stream of nitrogen at 50 0C onto Isolute.(R).. Purification via flash column chromatography (20-70percent EtOAc/hexanes) afforded the title compound (114 mg, 87percent). LC-MS m/z 465 (M+H)+, 1.20 min (ret time).
Intermediate 52(S)-tert-Butyl 2-(2-diazoacetyl)azetidine-l -carboxylate[0325][Chemical Formula 83]A solution of (S)-l-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1.80 g, 8.95 mmol) in tetrahydrofuran (90.0 mL) was cooled to 0°C, and isobutyl chloroformate (1.30 mL, 9.85 mmol) and triethylamine (1.50 mL, 10.7 mmol) were added. After stirring for 1 hour at room temperature, ammonium salt was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in acetonitrile (90.0 mL), and trimethylsilyldiazomethane (13.5 mL, 26.8 mmol) was added. After stirring for 7 hours at room temperature, to the mixture were added saturated sodium bicarbonate water and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with silica gel column (hexane/ethyl acetate = 90/10 to 75/25) to give the title compound (1.40 g, 6.22 mmol, 69percent).MS (ESI+) 226 (M++1, 100percent)
To a solution of (S)-1-Qert-butoxycarbonyl)azetidine-2-carboxylic acid (0.57 g, 2.8 mmol) and triethylamine (0.48 mL, 3.4 mmol) in tetrahydrofuran (3 mL) at 0 °C, isobutyl chioroformate (0.41 mL, 3.1 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then filtered through a pad of diatomaceous earth, rinsing with small amounts of acetonitrile (3 x 5mL). The filtrate was concentrated in vacuo and the re-dissolved in acetonitrile (3 mL) and trimethylsilyldiazomethane (1.34 mL, 8.47 mmol) was added under nitrogen. The reaction mixture was stirred at ambient temperature for 16 hours and quenched by addition of a saturated aqueous solution of sodium bicarbonate (10 mL). The mixture was extracted with ethyl acetate (2 x 15 mL), washed with brine (20 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate wasconcentrated in vacuo to afford the title compound which was used directly into the next step.
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 18h;
Example 68Atert-butyl (2S)-2-[9-(4-fluorobenzyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-5(6H)-yl]carbonyl}azetidine-1-carboxylateO-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (94 mg, 0.465 mmol, prepared as described in J. Med. Chem. 2005, 48, 7637-7647) in CH2Cl2 (2.0 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was applied directly to a column of silica gel and eluted with 5percent methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 45℃; for 12h;
The compound (300mg, 0.891 mmol) obtained in <Step 6> of Example 1, 1- Boc-L-azetidine-2-carboxylic acid (269mg, 1.336 mmol) and HATU (677mg, 1.782 mmol) were dissolved in N,N-dimethylformamide (4 mL). Then, DIPEA (0.63 mL,3.564 mmol) was added thereto, and the mixture was stirred at 45°C for 12 hours.The mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and distilled under reduced pressure, and purified by column chromatography to obtain the title compound as a transparent solid (300mg, 65percent).1H NMR(300 MHz, CDC13):
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
To a solution of (2S) -1- (tert-butoxycarbonyl) azetidine-2- carboxylic acid (10.9 g) and dimethylamine hydrochloride (8.8 g) and N-ethyl-N- (l-methylethyl)propan-2-amine (21.0 g) in DMF (200 mL) was added 0- (7-azabenzotriazol-l-yl) -Nu,Nu,Nu' ,Nu' - tetramethyluronium hexafluorophosphate (24.7 g) at roomtemperature. The reaction mixture was stirred at roomtemperature overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude product (9.5 g) containing the title compound.¾ NMR (400 MHz, CDC13) delta 1.43 (9H, s) , 2.16-2.22 (1H, m) ,2.38-2.47 (1H, m) , 2.96-3.00 (6H, m) , 3.83-3.89 (1H, m) , 4.02- 4.06 (1H, m) , 4.94-4.97 (1H, m) .
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h;
To a DCM solution of amine (30 mg, 0.13 mmol) and DIPEA (0.047 mL, 0.27 mmol) was added HOBT (6.1 mg, 0.040 mmol), acid (30 mg, 0.15 mmol), and EDC (39 mg, 0.20 mmol) in single portions. After 16 h, TLC and LC/MS indicated good conversion to the desired material. The reaction was concentrated and the residue purified by HPLC (0 to 100percent> EtO Ac/Hex gradient) to give a clear oil 1-6. LCMS: m/z 429.15 (M+Na)+
(S)-tert-butyl 2-((benzimidamidooxy)carbonyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Step A: PyBOP (2.53 g, 4.85 mmol) was added to a 000 solution of Boc-L-azetidine-2- carboxylic acid (650 mg, 3.23 mmol) and DIPEA (1.66 mL, 9.69 mmol) in DCM (14 mL) and the rxn mixture was stirred at rt for 20 mm, before N?-hydroxybenzimidamide (440 mg, 3.23 mmol)was added and stirring continued at rt for 2h. To the rxn mixture was added H20 and the mixture extracted with DCM (2x). The combined org. extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield (S)-tert-butyl 2- ((benzimidam idooxy)carbonyl)azetidine- 1 -carboxylate B-I-I which was used further without purification.
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