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Stage #1: With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h; Stage #2: With hydrogenchloride In water
To a solution of compound 13-2 (5.83 g, 23.58 mmol) in THF (30 mL) at 0 °C was added LiOH aqueous solution (1.98 g, 30 mL), and the mixture was stirred at rt for 2 hrs and adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo, and the aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over Na2S04 and concentrated in vacuo to give the title compound as a white solid (5.3 g, 96percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) m/z: 234.24 [M+H] +; NMR (400 MHz, CDC13) δ (ppm): 8.76 (brs, 1 H), 5.28-5.12 (m, 1 H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H). 2.77-2.01 (m. 2H), 1.48-1.44 (d, 9H, J = 16 Hz).
96%
With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h; Inert atmosphere; Sealed tube
To a solution of compound 9-2 (5.83 g, 23.58 mmol) in THF (30 mL) was added LiOH aqueous solution (1.98 g, 30 mL) at 0 °C. At the end of the addition, the mixture was stirred at rt for 2.0 hrs. After the reaction was completed, the mixture was adjusted to pH 5 with diluted hydrochloric acid (1 M) and the THF solvent was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo to give the title compound as a white solid (5.28 g, 96percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 234.2 [M+H]+; and 'H NMR (400 MHz, CDC13) δ (ppm): 8.76 (brs, 1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J= 16 Hz).
96%
With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h;
To a solution of compound 9-2 (5.83 g.23.58 mmol) in THF (30.0 mL) was added LiOH aqueous solution (1.98 g, 30.0 mL) at 0 °C. and the mi.xture was stirred at rt for 2.0 hrs and then adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo. The aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over and concentrated in vacuo to give the title compound as a white solid (5.3 g.96percent). The compound was characterized by the following spectroscopic data: MS (ESI. pos.ion) mlz: 234.2 [M+H] : and NMR (400 MHz. CDCL) δ (ppm): 8.76 (brs.1H), 5.28-5.12 (m.1H), 4.56-4.44 (m.1H).3.86-3.58 (m. 2H), 2.77-2.01 (m.2H).1.48-1.44 (d.9H../= 16 Hz).
96%
With lithium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 2 h;
To a solution of compound 11-1 (5.83 g, 23.58 mmol) in THF (30 mL) at 0 °C was added an aqueous solution of lithium hydroxide (1.98 g, 30 mL) dropwise. At the end of the addition, the mixture was stirred at rt for 2 hours. After the reaction was completed, the mixture was acidified with aqueous HC1 (1M) till pH = 5, and then the THF was removed in vacuo. The aqueous layers were acidified with aqueous HC1 (1M) till pH = 2 and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to give the title compound as a white solid (5.27 g, 96percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 234.3 [M+H]+; and lU NMR (400 MHz, CDC13): δ 8.76 (brs, 1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m, 2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J= 16 Hz) ppm.
96%
With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h;
11067] To a solution of compound 13-2 (5.83 g, 23.58 mmol) in THF (30 mE) at 0° C. was added EiOH aqueous solution (1.98 g, 30 mE), and the mixture was stirred at it for 2 hrs and adjusted to pH 5 with diluted hydrochloric acid (1 M). The solvent THF was removed in vacuo, and the aqueous layer was adjusted to pH 2 with diluted hydrochloric acid (1 M) and extracted with EtOAc (80 mEx3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give the title compound as a white solid (5.3 g, 96percent). The compound was characterized by the following spectroscopic data:11068] MS (ESI, pos.ion) mlz: 234.24 [M+H]11069] ‘H NMR (400 MHz, CDC13) ö (ppm): 8.76 (brs,1H), 5.28-5.12 (m, 1H), 4.56-4.44 (m, 1H), 3.86-3.58 (m,2H), 2.77-2.01 (m, 2H), 1.48-1.44 (d, 9H, J=16 Hz).
96%
With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; for 2 h;
Compound 9-2 (5.83 g, 23.6 mmol) was dissolved in THF (30 mL) and an aqueoussolution of lithium hydroxide (1.98 g, 30 mL) was slowly added dropwise thereto at 0 °C. After the addition was completed, the mixture was stirred at rt for 2.0 hours. Afterthe reaction was completed, the pH of the reaction mixture was adjusted to 5 with dilutehydrochloric acid (1M). After removing the THF, the aqueous layer was adjusted to pH 2with dilute hydrochloric acid (1 M), extracted with EtOAc (80 mL x 3) Wash withsaturated brine, anhydrous Na 2SO 4Drying and concentration gave 5.27 g of white solid,yield: 96percent.
95%
With lithium hydroxide monohydrate In 1,4-dioxane; water at 20℃; for 3 h;
A solution of compound 10 (2.46 g, 9.96 mmol) in dioxane (20 mL), was added 10 mL of H2O followed by lithium hydroxide hydrate (2.09 g, 49.8 mmol) at room temperature, the reaction was stirred for 3 h (monitored by TLC). Then the solution was filtered removing the excess lithium hydroxide, the filtrate was removed the solvent in vacuo, the residue was added 10 mL of H2O and acidified with concentrated HCl to pH 3-4, the product began to precipitate, filtered and dried to afford 11 (2.2 g, 95percent) as a white solid. 1H NMR (300 MHz, CD3OD) δ 5.12-5.30 (m, 1H), 4.40 (m, 1H), 3.59-3.72 (m, 2H), 2.39-2.46 (m, 2H), 1.47 (s, 9H). MS (ESI) m/z 232 [M-H]-.
95%
With lithium hydroxide monohydrate In 1,4-dioxane; water at 20℃; for 3 h;
A solution of compound 16 (2.46 g, 9.96mmol) in dioxane (20 mL), was added 10 mL of H2O followed by lithiumhydroxide hydrate (2.09 g, 49.8mmol) at room temperature, the reaction was stirred for 3 h (monitored by TLC).Then the solution was filtered removing the excess lithium hydroxide, thefiltrate was removed the solvent in vacuo,the residue was added 10 mL of H2O and acidified with concentratedHCl to pH 3-4, the product began to precipitate , filtered and dried to afford 17 (2.2 g, 95percent) as a white solid. 1H NMR (CD3OD, 300 MHz): δ 5.12-5.30 (m, 1H), 4.40 (m, 1H), 3.59-3.72 (m, 2H), 2.39-2.46 (m, 2H),1.47 (s, 9H). MS (ESI) m/z232 [M-H]-.
95%
With lithium hydroxide monohydrate; water In 1,4-dioxane at 20℃; for 3 h;
A solution of compound 12 (2.46g, 9.96mmol) in dioxane (20mL), was added 10mL of H2O followed by lithium hydroxide hydrate (2.09g, 49.8mmol) at room temperature, the reaction was stirred for 3h (monitored by TLC). Then the solution was filtered removing the insoluble substance, and the filtrate was removed the solvent in vacuo, then the residue was added 10mL of H2O and acidified with concentrated HCl to pH 3–4, the product began to precipitate, filtered and dried to afford 13 (2.2g, 95percent) as a white solid. 1H NMR (CD3OD, 300MHz): δ 5.12–5.30 (m, 1H), 4.38–4.42 (m, 1H), 3.59–3.72 (m, 2H), 2.39–2.46 (m, 2H), 1.47 (s, 9H). MS (ESI) m/z 232 [M−H]−.
90%
With lithium hydroxide In tetrahydrofuran; water at 0 - 20℃; for 12.5 h;
To the stirred solution of l-tert-butyl-2-methyl (2iSr,4,S)-4-fluoroρyrrolidme-l,2- dicarboxylate (24.7 g, 0.1 mol) obtained in step III in THF (200 mL) cooled to 0°C was added a solution of LiOH (3.6 g, 0.15 mol) in water (200 mL) over a period of 30 min. The reaction mixture was warmed to room temperature and stirred for 12 h until the TLC reveals completion of the reaction. The reaction mixture was diluted with water, ether, and two layers were separated. The aqueous layer was acidified with cone. HCl and extracted with EtOAc. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure to obtain (2S, 45)-l-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid as an off white solid (21 g) in 90percent yield. [α]D, -65.7 (c, 1.0, CHCl3); m/z (M-I) 232; 1H NMR (CDCl3) 300 MHz δ 5.22 (ddd, J = 3.8, 3.8, 52.3 Hz, IH), 4.60-4.40 (m, IH), 3.95-3.50 (m, 2H), 2.78-2.15 (m, 2H), 1.6-1.35 (m, 9H).
70%
Stage #1: With lithium hydroxide; water In tetrahydrofuran at 20℃; for 15 h; Stage #2: With hydrogenchloride In water; ethyl acetate
[482] 500 mg (2.02 mmol) of 1-t-butyl 2-methyl(2S,4S)-4-fluoropyrrolidine-l,2-dicarboxylate obtained by referring to WO 03/002553 was dissolved in 16 mL of tetrahydrofuran and 4 mL of distilled water. Thereafter, 250 mg (6.06 mmol) of lithium hydroxide was added thereto, then stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and ethylacetoacetate was added thereto. The resulting solution was neutralized with IN hydrochloric acid, then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 330 mg of the title compound (yield: 70percent).[483] Mass (m/e) 234 (M+ 1)
Reference：
[1] Patent: WO2014/19344, 2014, A1, . Location in patent: Paragraph 00435
[2] Patent: WO2014/82380, 2014, A1, . Location in patent: Paragraph 00403; 00405
[3] Patent: WO2014/82379, 2014, A1, . Location in patent: Page/Page column 144; 145
[4] Patent: WO2014/131315, 2014, A1, . Location in patent: Page/Page column 144
[5] Patent: US2015/79028, 2015, A1, . Location in patent: Paragraph 1061; 1066; 1067; 1068; 1069
[6] Patent: CN103880823, 2017, B, . Location in patent: Paragraph 1003; 1008; 1009
[7] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[8] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
[9] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 242 - 256
[10] Chemical Communications, 2018, vol. 54, # 70, p. 9749 - 9752
[11] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[12] Patent: WO2007/113634, 2007, A1, . Location in patent: Page/Page column 61
[13] Patent: WO2005/121135, 2005, A1, . Location in patent: Page/Page column 69
[14] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746
[15] Patent: WO2008/93960, 2008, A1, . Location in patent: Page/Page column 41
[16] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4167 - 4172
[17] Patent: WO2005/42533, 2005, A2, . Location in patent: Page/Page column 55-56
[18] Patent: EP1659121, 2006, A1, . Location in patent: Page/Page column 18
[19] Patent: EP1657237, 2006, A1, . Location in patent: Page/Page column 7
[20] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 23, p. 5257 - 5261
[21] Patent: US2008/318923, 2008, A1, . Location in patent: Page/Page column 59
[22] Patent: WO2004/99185, 2004, A1, . Location in patent: Page 24
[23] Patent: WO2012/54510, 2012, A1, . Location in patent: Page/Page column 94
3
[ 587888-04-8 ]
[ 203866-13-1 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 31, p. 9262 - 9263
[2] Journal of Fluorine Chemistry, 2008, vol. 129, # 4, p. 286 - 293
4
[ 89813-47-8 ]
[ 203866-13-1 ]
Reference：
[1] Journal of the American Chemical Society, 2003, vol. 125, # 31, p. 9262 - 9263
5
[ 74844-91-0 ]
[ 203866-13-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4167 - 4172
[2] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 8, p. 2725 - 2746
[3] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[4] Patent: WO2012/54510, 2012, A1,
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[6] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
[7] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 242 - 256
[8] Patent: WO2014/131315, 2014, A1,
6
[ 24424-99-5 ]
[ 203866-13-1 ]
Reference：
[1] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
[4] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 242 - 256
7
[ 40216-83-9 ]
[ 203866-13-1 ]
Reference：
[1] Tetrahedron Letters, 1998, vol. 39, # 10, p. 1169 - 1172
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 23, p. 7418 - 7429
[3] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 111 - 122
[4] European Journal of Medicinal Chemistry, 2014, vol. 86, p. 242 - 256
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 72h;
Example 15 (4-Chloro-phenyl)-ethyl-((2S,4S)-4-fluoro-pyrrolidin-2-ylmethyl)-amine To a solution of N-ethyl-4-chloro-aniline (0.31 g, 2.0 mmol) in dichloromethane (8 ml) were added (2S,4S)-tert-butyloxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid (0.47 g, 2.0 mmol), bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.76 g, 3.0 mmol) and diisopropylethylamine (0.39 g, 3.0 mmol). The mixture was stirred for 3 days at room temperature. Aqueous sodium bicarbonate solution (20 ml) was added and the mixture was extracted with dichloromethane (3*20 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=2:1) to yield a light yellow oil (0.55 g), that was dissolved in tetrahydrofurane (15 ml). Borane-tetrahydrofurane-complex (7.4 ml, 1M, 7.4 mmol) was added and the mixture was heated at 60 C. overnight. After cooling 5 drops of aqueous hydrochloric acid (4N) were added and the solvent was evaporated. The white residue was dissolved in aqueous hydrochloric acid (4N, 10 ml) and heated at 60 C. for 1 hour. After cooling aqueous sodium hydroxide solution was added until basic pH and the mixture was extracted with dichloromethane (2*30 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute Flash-NH2 from Separtis; eluent: ethyl acetate/heptane 1:1) to yield a light yellow oil, (0.137 g, 27%); MS (ISP): 257.1 ((M+H)+.).
(2S,4S)-tert-butyl 2-((2-amino-4-chloro-3-methylphenyl)carbamoyl)-4-fluoropyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; N,N-dimethyl-formamide; at 20.0℃; for 15.0h;
(2S,4S)-1 -(tert-Butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (7; 144.27 mg, 0.6 mmol) is dissolved in a 1/1 mixture of DMF / DCM (1.2 ml) followed by the addition of DIPEA (0.44 ml, 2.52 mmol) and 4-chloro-3-methylbenzene-1 ,2-diamine (8; 121.95 mg, 0.6 mmol) dissolved in a 1/1 mixture of DMF / DCM (1.2 ml) and finally by the addition of HATU (240 mg, 0.63 mmol) dissolved in DMF (1 ml). The reaction mixture is stirred at RT for 15 h then passed through PL-HC03 packed filter syringe (1 g) with a 1/1 -mixture of DMF / DCM (4 ml). The solvent is removed under reduced pressure to give (2S,4S)-tert-butyl 2-((2-amino-4- chloro-3-methylphenyl)carbamoyl)-4-fluoropyrrolidine-1 -carboxylate (9) which is used in the next step without further purification. LC-MS: tR = 0.79 min; [M+H]+ = 372.26.
tert-butyl (2S,4S)-2-[(3,4-difluorophenyl)ethylcarbamoyl]-4-fluoropyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In ethyl acetate at 0 - 20℃; for 72h;
37.a (2S,4S)-1-(3-Cyano-4,6-dimethylpyridin-2-yl)-N-(3,4-difluorophenyl)-N-ethyl-4- fluoropyrrolidine-2-carboxamide
Step a. A solution of N-ethyl-3,4-difluoroaniline (0.07 ml_, 0.44 mmol), (2S,4S)-1-(tert- butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (CAS Number 203866-13-1; 0.25 g,1.07 mmol) and pyridine (0.35 ml_, 4.29 mmol) in EtOAc (1 ml_) was treated with T3P (1.28 ml_, 2.14 mmol, 50 wt.% in EtOAc) at 0°C. The mixture was stirred for 3 days at rt. The reaction mixture was quenched with 0.5 M aq. HCI and extracted into EtOAc. The organic extract was washed with brine, dried and evaporated. The residue was purified by column chromatography (10-50% EtOAc in cyclohexane) to provide tert-butyl (2S,4S)-2-[(3,4- difluorophenyl)-ethyl-carbamoyl]-4-fluoro-pyrrolidine-1-carboxylate, (0.170 g, 42%) as a clear gum. m/z ES+ [M+H]+373
33.1 Step 1
Add (2S, 4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidine-2-carboxylic acid (5.0g, 21.46mmol) to the dioxane hydrochloride solution (3M, 30mL) Then add concentrated hydrochloric acid (12M, 6mL) and heat to 75°C and stir for 4 hours. After concentrating the reaction solution, an oily crude product (2S, 4S)-4-fluoropyrrolidine-2-carboxylic acid hydrochloride (6.1 g) was obtained.
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