* 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.
With sodium hydroxide In 1,4-dioxane at 20℃; for 16 h;
Preparational Example 26 Preparation of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid 200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80percent). 1H NMR (400 MHz, CDCl3) δ 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
80%
With sodium hydroxide In 1,4-dioxane at 20℃; for 16 h;
200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80percent). 1H NMR (400 MHz, CDCl3) δ 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
67%
With sodium hydroxide; water In 1,4-dioxane at 20℃; for 15 h;
α-Aminoisobutyric acid (1.0 g, 9.70 mmol) was dissolved in a mixture of dioxane (15.0 mL) and 0.5 M NaOH (15.0 mL). To this solution was added di-tert-butyl dicarbonate (2.5 g, 11.64 mmol, 1.2 equiv.) and the resulting mixture stirred at RT for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL) and 1 M HCl (30 mL). The aqueous solution was extracted with EtOAc (2*30 mL) and the combined organic phases were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (1.3 g, 67percent) as a white solid: mp 122-123° C.; 1H NMR (CDCl3+methanol-d4) δ 1.44 (s, 9H), 1.51 (s, 6H), 3.99 (br s, NH).
66%
With sodium hydroxide In 1,4-dioxane at 0 - 20℃;
To a stirred solution of 2-Amino-2-methylpropanoic acid (50 g, 484.87 mmol, 1.0 eq)in 1,4-dioxane (500 mL) at 0 oc was added 2N NaOH solution (500 mL) followed by di-tertbutyldicarbonate(158.55 g, 727.30 mmol, 1.5 eq). The reaction mixture was allowed to stir atroom temperature for overnight. After completion of the reaction (monitored by TLC), the organic phase was evaporated under reduced pressure, reaction mixture was diluted withwater (100 mL), cooled to 0 °C, pH adjusted to 5 with IN HCI and then extracted with DCM(3x500 mL). The combined organic extracts were washed with water (500 mL) and brinesolution (200 mL). The organic layer was dried over Na2S04, filtered and evaporated underreduced pressure. The residue was stirred with n-hexane (500 mL) at room temperature for about 30 minutes. The solid was filtered and dried under vacuum to obtain the title compound(65 g, yield: 66percent) as a white solid. 1H NMR (300 MHz, CDCh): 8 ppm 9.50 (brs, IH), 1.53(s, 6H), 1.44 (s, 9H); ESI-MS: m/z 226.03 (M+Nat
64.4%
With sodium hydroxide In 1,4-dioxane; water at 20℃;
Method 1 : To a stirred solution of 2-Amino-2-methylpropanoic acid (30 g, 290.92 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 °C was added 2N NaOH solution (300 ml) followed by (Boc)20 (95.13 g, 436.38 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml), cooled to 0 °C, pH adjusted to 5 with IN HC1 and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room temperature for about 30 minutes. The obtained solid was filtered and dried under vacuum to obtain the desired product (38.0 g, yield: 64.4percent) as a white solid.
61%
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 16 h; Inert atmosphere
A solution of compound 14 (10.0 grams, 97.0 mmol) in dioxane (150 ml) and NaOH (5percent, 150 ml) was cooled to 0° C., then Boc2O was added dropwised. The mixture was stirred for 16 hours at room temperature under N2 atmosphere, then added HCl (concentrated) to make PH to 3, and the mixture was extracted with EtOAc (100 ml×3), washed with brine (50 ml), dried over Na2SO4, concentrated in vacuo and purified on silica gel column (PE/EtOAc=5:1) to give the product as white solid (12.1 grams, 61percent yield).
49%
With triethylamine In methanol at 60℃; for 0.5 h;
The starting materials N1, 2-dimetliylalaninamide and 2-methylalaninamide used in Examples 95 and 97 were prepared from 2-aminoisobutyric acid (ex. Aldrich) following the procedure below: Di-tert-butlydicarbonate (6.98 g, 32.0 mmol) was added to a stirred solution of the 2- aminoisobutyric acid (3 g, 29.13 mmol) in methanol/triethylmine (10/90) (100 ml). The reaction mixture was heated at 60°C/30 minutes, cooled to room temperature and concentrated to dryness. The residue was taken up in dichloromethane (100 ml), washed with 10percent aqueous potassium hydrogensulfate, water, dried over magnesium sulfate, filtered and evaporated to dryness to give N-(tert-butoxycarbonyl)-2-methylalanine (2.87 g, 49percent) as a white solid ; 1H NMR Spectrum : (CDC13) 1.45 (s, 6H), 1.53 (s, 9H), 5.2 (br s, 1H).
45.44%
With hydrogenchloride; sodium hydroxide In tetrahydrofuran
E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid 2-Aminoisobutyric acid (140 g, 1.36 mol), 1 N NaOH (1620 mL, 1.63 mol), (Boc)2O (375 mL, 1.63 mol) and THF 420 mL were mixed together and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (700 mL) and adjusted to about pH 3.0 by adding 6 N HCl. The organic phase separated was washed with saturated NaCl solution and concentrated to approximately 1/4 of the original volume. After treatment with hexane a white solid product was isolated and collected (125.8 g, yield 45.44 percent). An additional 7.8 g of product was recovered from the mother liquor.
44%
With sodium hydroxide In tetrahydrofuran at 20℃;
Step 1To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and Tiff (30 mL) was added (Boc)20 (26 g, 0.12 rnol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2), The organic phases were combined, washed with brine, dried over Na2SC>4. concentrated to give 9 g (44percent) of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid
44%
With sodium hydroxide In tetrahydrofuran at 20℃;
Step 1. To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and THF (30 mL) was added (Boc)2O (26 g, 0.12 mol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2). The organic phases were combined, washed with brine, dried over Na2SO4, concentrated to give 9 g (44percent)of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid.
40.7%
With sodium hydroxide In tetrahydrofuran; water at 20℃;
To a solution of 2-amino-2-methylpropanoic acid (4.0 g, 39 mmol) , NaOH (1.55 g, 38.8 mmol) , water (50 mL) , and THF (20 mL) was added (Boc)2O (10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirred overnight at rt, then concentrated to dryness, and extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound as a white solid (3.21 g, 40.7yield) .
Reference：
[1] Bulletin of the Chemical Society of Japan, 1987, vol. 60, # 4, p. 1391 - 1397
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 20, p. 5679 - 5683[3] Angew. Chem., 2018, vol. 130, p. 5781 - 5785,5
[4] Patent: US2015/210635, 2015, A1, . Location in patent: Paragraph 0502-0504
[5] Patent: EP2865664, 2015, A1, . Location in patent: Paragraph 0118; 0119
[6] Journal of Molecular Structure, 2003, vol. 646, # 1-3, p. 111 - 123
[7] Chemistry - A European Journal, 2012, vol. 18, # 31, p. 9516 - 9520
[8] Patent: US7202279, 2007, B1, . Location in patent: Page/Page column 49
[9] Patent: WO2018/29604, 2018, A1, . Location in patent: Page/Page column 28; 29
[10] Patent: WO2016/178092, 2016, A2, . Location in patent: Page/Page column 39
[11] Tetrahedron, 2004, vol. 60, # 40, p. 8929 - 8936
[12] Patent: US9096645, 2015, B2, . Location in patent: Page/Page column 39; 40
[13] Polish Journal of Chemistry, 1991, vol. 65, # 7-8, p. 1427 - 1431
[14] Tetrahedron Letters, 1996, vol. 37, # 40, p. 7319 - 7322
[15] Patent: WO2005/75439, 2005, A1, . Location in patent: Page/Page column 198-199
[16] Patent: US6448263, 2002, B1,
[17] Patent: WO2012/158764, 2012, A1, . Location in patent: Page/Page column 229
[18] Patent: WO2014/22569, 2014, A1, . Location in patent: Page/Page column 108; 109
[19] Patent: WO2018/103058, 2018, A1, . Location in patent: Page/Page column 349
[20] Patent: WO2005/19174, 2005, A1, . Location in patent: Page/Page column 51-52
[21] Patent: US2012/322811, 2012, A1, . Location in patent: Page/Page column 18
[22] Patent: WO2017/100668, 2017, A1, . Location in patent: Page/Page column 349
2
[ 84758-55-4 ]
[ 30992-29-1 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With lithium hydroxide In tetrahydrofuran; methanol; water at 20℃; for 12 h; Stage #2: With hydrogenchloride In tetrahydrofuran; methanol; water
In a 50-mL flask, methyl-2-aminobutoxycarbonyl-2-methylpropanoate (327 mg, 1.50 mmol) was charged, and dissolved through addition of tetrahydrofuran (15 ml), and methanol (15 ml). Lithium hydroxide dissolved in purified water (15 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate (20mL). The organic layer was dried with magnesium sulfate, and filtered. Through vacuum distillation, the solvent was removed so as to obtain methyl-2-aminobutoxycarbonyl-2-methylpropanoic acid compound (335mg, 99 percent).[615] 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, HO-CO-, 1H), 7.05 (s, -NH-CO2-, 1H), 1.40 (s, C3H9-O-, 9H), 1.25 (s, 6H).
99%
With water; lithium hydroxide In tetrahydrofuran; methanol
In a 50-mL flask, methyl-2-aminobutoxycarbonyl-2-methylpropanoate (327 mg, 1.50 mmol) was charged, and dissolved through addition of tetrahydrofuran (15 ml), and methanol (15 ml). Lithium hydroxide dissolved in purified water (15 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate (20 mL). The organic layer was dried with magnesium sulfate, and filtered. Through vacuum distillation, the solvent was removed so as to obtain methyl-2-aminobutoxycarbonyl-2-methylpropanoic acid compound (335 mg, 99percent). [0336] 1H NMR (400 MHz, DMSO-d6) δ 12.1 (s, HO—CO—, 1H), 7.05 (s, —NH—CO2—, 1H), 1.40 (s, C3H9—O—, 9H), 1.25 (s, 6H).
With ruthenium(IV) oxide; sodium periodate In tetrachloromethane; water; acetonitrile at 20℃; for 2 h;
General procedure: To a solution of N-protected amino alcohol 4a–g (0.5 mmol) in a 2:2:3 mixture of CCl4/MeCN/H2O (7 mL) were successively added NaIO4(321 mg, 1.5 mmol) and RuO2·xH2O (3.5 mg, 0.025 mmol) at r.t. Theresulting dark mixture was vigorously stirred for 2 h at r.t. thenCH2Cl2 (10 mL) and H2O (10 mL) were added. The layers were separatedand the aqueous phase was extracted with CH2Cl2 (2 × 10 mL). Thecombined organic layers were washed with brine, dried over MgSO4,filtered and the solvent was removed in vacuo. The black residue waspurified by chromatography on silica gel (CH2Cl2–MeOH, 99:1 to95:5) to afford the N-Boc-protected amino acid 7a–g.
With sodium hydroxide In 1,4-dioxane; water at 0 - 20℃; for 12 h;
Method 2: To a stirred solution of 2-carboxypropan-2-aminium chloride (15.0 g, 145.63 mmol) in 1,4-dioxane (75 mL), added 2N NaOH solution (75 mL), (Boc)20 (47.62 g, 218.44 mmol) at 0 °C and stirred the reaction mixture for about 12 hours at room temperature. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was washed with EtOAc (200 mL) to remove the impurities, then aqueous part was acidified with IN HC1 (pH-2-3) and extracted with CH2C12 (2x200 mL). The combined organic extracts were washed with water, dried over Na2S04, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 30percent EtOAc: n-Hexane as an eluent to afford the desired product (15.0 g, yield: 50.74percent) as an off white solid. 1H NMR (300 MHz, DMSO): δ 12.18 (s, 1H), 7.05 (s, 1H), 1.36 (s, 9H), 1.29 (s, 6H); ES Mass: 226.06 [M+Na]+.
50.74%
With sodium hydroxide In 1,4-dioxane at 0 - 20℃; for 12 h;
To a stirred solution of 2-carboxypropan-2-aminium chloride (15.0 gr, 145.63 mmol) in 1,4-dioxane (75 mL), added 2N NaOH solution (75 mL), (Boc)2O (47.62 gr, 218.44 mmol) at 0°C and stirred the reaction mixture for about 12 hours at room temperature. After complete conversion of starting material, the reaction mixture was washed with EtOAc (200 mL) to remove the impurities, then aqueous part was acidified with 1N HCl (P= 2-3) and extracted with CH2Cl2 (2x200 mL). The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silicagel column chromatography by using 30percent EtOAc: n-Hexane as an eluent to afford the desired product (15.0 g, yield: 50.74percent) as an off white solid. 1H MR (300 MHz, DMSO): δ 12.18 (s, 1H), 7.05 (s, 1H), 1.36 (s, 9H), 1.29 (s, 6H); ES Mass: [M+23]+ 226.06.
Step 1To a solution of 2-amino-2-methylpropanoic acid (10.30.1 mol, 1.0 equiv) in 1 N NaOH (100 mE) and THF (30 mE) was added (l3oc)20 (26 g, 0.12 mol, 1.2 equiv) portionwiseroom temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mEx2). The aqueous phase was adjusted to PH=34, then extracted with ethyl acetate (200 mEx2). The organic phases were combined, washed with brine, dried over Na2504, concentrated to give 9 g (44percent) of the desired product 2-(tert-butoxycarbonylamino)-2-me- thylpropanoic acid as a white solid.
With sodium hydroxide In water; <i>tert</i>-butyl alcohol
A. 5.0 G of Aib (48 mmol) was dissolved in 15 ml of water containing 2.0 g of sodium hydroxide (1 eq.) and 25 ml of t-butanol. To this was added 11.5 q of t-butyldicarbonate (1.1 eq.) dropwise over 30 minutes. The reaction mixture was allowed to stir overnight. The turbid reaction mixture was diluted with 25 ml of water and extracted with hexane (3*50 ml). The aqueous layer was then acidified to pH 2-3 with solid sodium bisulfate (7.1 g) and extracted with ethyl acetate (3*50 ml). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate and evaporated to yield 4.9 g of Boc-Aib (51percent), m.p. 117°-118° (after drying in vacuum); elemental analysis: C, 53.19; H, 8.43; N, 6,89; (calculated); C, 53.30; H, 8.26; N, 7.10 (found).
Reference：
[1] Patent: US4876243, 1989, A,
[2] Synthesis (Germany), 2016, vol. 48, # 6, p. 906 - 916
7
[ 58632-95-4 ]
[ 62-57-7 ]
[ 30992-29-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 19, p. 5133 - 5140
[2] Journal of the American Chemical Society, 1981, vol. 103, # 20, p. 6127 - 6132
Stage #1: With pyridine; di-<i>tert</i>-butyl dicarbonate In acetonitrile at 20℃; for 0.333333 h; Stage #2: With ammonia In water; acetonitrile for 4.33333 h;
A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88percent) as white solid; MS (EI): m/e 225.1 [M+Na]+.
88%
Stage #1: With pyridine; di-<i>tert</i>-butyl dicarbonate In acetonitrile at 20℃; for 0.333333 h; Stage #2: With ammonia In acetonitrile for 4.3 h;
A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88percent) as white solid; MS(EI): m/e 225.1 [M+Na]+.
Reference：
[1] Patent: US2012/316147, 2012, A1, . Location in patent: Page/Page column 33-34
[2] Patent: WO2012/168350, 2012, A1, . Location in patent: Page/Page column 80
[3] Tetrahedron, 2004, vol. 60, # 40, p. 8929 - 8936
[4] Tetrahedron Letters, 2000, vol. 41, # 50, p. 9809 - 9813
[5] Tetrahedron Letters, 2003, vol. 44, # 3, p. 463 - 466
[6] Journal of Heterocyclic Chemistry, 1981, vol. 18, # 8, p. 1629 - 1633
[7] Journal of Medicinal Chemistry, 2002, vol. 45, # 25, p. 5471 - 5482
[8] Patent: WO2009/70485, 2009, A1, . Location in patent: Page/Page column 102
A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88%) as white solid; MS (EI): m/e 225.1 [M+Na]+.
88%
A mixture of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (CAN: 30992-29-1, 20 g, 98 mmol), di-tert-butyl dicarbonate (CAN 24424-99-5, 27.67 g, 147 mmol) and pyridine (4.6 mL) in acetonitrile (500 mL) was stirred at room temperature for 20 min. Ammonia (10 mL) was added dropwise for 20 min. The resulting reaction mixture was stirred for 4 h. After removal of most of the solvent under reduced pressure, the solid was filtered off and washed with acetonitrile. The solid was brought to dryness under reduced pressure to give the title compound (17.5 g, 88%) as white solid; MS(EI): m/e 225.1 [M+Na]+.
71%
With pyridine; ammonium hydroxide; di-tert-butyl dicarbonate; In acetonitrile; at 20℃; for 5h;Inert atmosphere;
Ammonium hydroxide (1 mL, 4.92 mmol) was added to a solution of commercially available 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid, 1 (1 g, 4.92 mmol), BOC-Anhydride (1.396 g, 6.40 mmol), and pyridine (0.398 mL, 4.92 mmol) in acetonitrile (25 mL) and the resulted reaction mixture was stirred at room temperature for 5h. The crude reaction mixture was diluted with water and extracted with CH2Cl2 (3*25 mL). Combined the organic layers and dried over anhydrous Na2SO4. Solvent was removed under vacuo and the solid formed was filtered off to give tert-butyl (1-amino-2-methyl-1-oxopropan-2-yl)carbamate, 2 (0.702 g, 71%) as colorless solid. 1H NMR (400 MHz, DMSO-d6): delta 7.01 (s, 1H, NH), 6.84 (s, 1H, NH2), 6.67 (s, 1H, NH2), 1.37 (s, 9H, Boc), 1.30 (s, 6H, CH3).
To a cooled (-10 C) solution of 2-tert-butoxycarbonylamino-2-methyl-propionic acid (1.00 g, 4.92 mmol) and triethylamine (686 muL, 4.92 mmol) in tetrahydrofuran (20 mL) was added ethyl chloroformate (470 muL, 4.92 mmol). The reaction mixture was stirred for 1 h. The ammonium hydroxide (1.20 mL, 19.7 mmol) was added and the solution was stirred at room temperature for 16 h. The product was then filtered through a Buchner funnel and dried in vacuo to afford 945 mg of the title compounds as a white solid, m/z 203.3 [M + I]+.
19 g
To a stirred solution of 2- ((tert-butoxycarbonyl) amino) -2-methylpropanoic acid (30 g, 174.6 mmol) in THF (300 ml), CDI (28.68 g, 177.04 mmol) was added. The resulting mixture was stirred at RT for 15 min. After the reaction was complete, NH 3 . H2O (1.53 g, 11.8 mmol) was added dropwise at 0C. The reaction was stirred 30 min. The reaction mixture was quenched with water and extracted with EA. The organic layer was washed with sat. Na2CO3, brine and dried over Na2SO4. The solution was filtered, concentrated and purified by silica gel column chromatography (MeOH: DCM= 0-10%) to give 19 g of the title product. MS (ES+) : 147 [M-56+1] +.
In a 50-mL flask, methyl-2-aminobutoxycarbonyl-2-methylpropanoate (327 mg, 1.50 mmol) was charged, and dissolved through addition of tetrahydrofuran (15 ml), and methanol (15 ml). Lithium hydroxide dissolved in purified water (15 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate (20mL). The organic layer was dried with magnesium sulfate, and filtered. Through vacuum distillation, the solvent was removed so as to obtain methyl-2-aminobutoxycarbonyl-2-methylpropanoic acid compound (335mg, 99 %).[615] 1H NMR (400 MHz, DMSO-d6) delta 12.1 (s, HO-CO-, 1H), 7.05 (s, -NH-CO2-, 1H), 1.40 (s, C3H9-O-, 9H), 1.25 (s, 6H).
99%
With water; lithium hydroxide; In tetrahydrofuran; methanol;
In a 50-mL flask, methyl-2-aminobutoxycarbonyl-2-methylpropanoate (327 mg, 1.50 mmol) was charged, and dissolved through addition of tetrahydrofuran (15 ml), and methanol (15 ml). Lithium hydroxide dissolved in purified water (15 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, neutralized with 2N-hydrochloric acid aqueous solution, and extracted with ethyl acetate (20 mL). The organic layer was dried with magnesium sulfate, and filtered. Through vacuum distillation, the solvent was removed so as to obtain methyl-2-aminobutoxycarbonyl-2-methylpropanoic acid compound (335 mg, 99%). [0336] 1H NMR (400 MHz, DMSO-d6) delta 12.1 (s, HO-CO-, 1H), 7.05 (s, -NH-CO2-, 1H), 1.40 (s, C3H9-O-, 9H), 1.25 (s, 6H).
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 16h;Cooling with ice;
General procedure: To a stirred solution of 2-(1-(aminomethyl) cyclohexyl)acetic acid 2a (2g, 11.68 mmol, 1equiv.) in 1, 4-dioxane (20 mL) atice temperature, aq. NaOH (560.57mg, 14.02 mmol, 1.2 equiv,dissolved in 10 mL water) was added followed by addition of ditert-butyl dicarbonate (5.10 gm, 23.36mmol, 2 equiv.) in 1,4-dioxane (5mL). The reaction mixture was stirred at room temperature for 16 h. The resulting suspension was concentrated in vacuo and the residuewas dissolved in water (10-15mL) and washed by ethyl acetate (15mL x 2). The resultingaqueous layer was acidified using dilute KHSO4 solution, followed by extraction withethyl acetate (30 mL x 3), dried (Na2SO4) and concentrated in vacuo to afford 3a as awhite solid, which was carried forward for the next reaction. Yield: 3.04g, 95%.
80%
With sodium hydroxide; In 1,4-dioxane; at 20℃; for 16h;
Preparational Example 26 Preparation of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid 200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80%). 1H NMR (400 MHz, CDCl3) delta 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
80%
With sodium hydroxide; In 1,4-dioxane; at 20℃; for 16h;
200 mg (1.94 mmol) of 2-amino-2-methylpropanoic acid was dissolved in 8.0 ml of 1.0 N NaOH solution and 8.0 ml of 1,4-dioxane solution, to which 846 mg (3.88 mmol) of Boc2O was added. The mixture was stirred at room temperature for 16 hours, and then 1,4-dioxane was eliminated by evaporation under reduced pressure. The residue was acidized with 1 N HCl to be pH 3, and followed by extraction with 320 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by evaporation under reduced pressure to give 315 mg of 2-(t-butoxycarbonylamino)-2-methylpropanoic acid (yield: 80%). 1H NMR (400 MHz, CDCl3) delta 5.07 (brs, 1H), 1.54 (s, 6H), 1.45 (s, 9H)
67%
With sodium hydroxide; water; In 1,4-dioxane; at 20℃; for 15h;
alpha-Aminoisobutyric acid (1.0 g, 9.70 mmol) was dissolved in a mixture of dioxane (15.0 mL) and 0.5 M NaOH (15.0 mL). To this solution was added di-tert-butyl dicarbonate (2.5 g, 11.64 mmol, 1.2 equiv.) and the resulting mixture stirred at RT for 15 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (50 mL) and 1 M HCl (30 mL). The aqueous solution was extracted with EtOAc (2*30 mL) and the combined organic phases were washed with brine (40 mL), dried over sodium sulfate, and concentrated under reduced pressure to afford the title compound (1.3 g, 67%) as a white solid: mp 122-123 C.; 1H NMR (CDCl3+methanol-d4) delta 1.44 (s, 9H), 1.51 (s, 6H), 3.99 (br s, NH).
66%
With sodium hydroxide; In 1,4-dioxane; at 0 - 20℃;
To a stirred solution of 2-Amino-2-methylpropanoic acid (50 g, 484.87 mmol, 1.0 eq)in 1,4-dioxane (500 mL) at 0 oc was added 2N NaOH solution (500 mL) followed by di-tertbutyldicarbonate(158.55 g, 727.30 mmol, 1.5 eq). The reaction mixture was allowed to stir atroom temperature for overnight. After completion of the reaction (monitored by TLC), the organic phase was evaporated under reduced pressure, reaction mixture was diluted withwater (100 mL), cooled to 0 C, pH adjusted to 5 with IN HCI and then extracted with DCM(3x500 mL). The combined organic extracts were washed with water (500 mL) and brinesolution (200 mL). The organic layer was dried over Na2S04, filtered and evaporated underreduced pressure. The residue was stirred with n-hexane (500 mL) at room temperature for about 30 minutes. The solid was filtered and dried under vacuum to obtain the title compound(65 g, yield: 66%) as a white solid. 1H NMR (300 MHz, CDCh): 8 ppm 9.50 (brs, IH), 1.53(s, 6H), 1.44 (s, 9H); ESI-MS: m/z 226.03 (M+Nat
64.4%
With sodium hydroxide; In 1,4-dioxane; water; at 20℃;
Method 1 : To a stirred solution of 2-Amino-2-methylpropanoic acid (30 g, 290.92 mmol, 1.0 eq) in 1,4-dioxane (300 ml) at 0 C was added 2N NaOH solution (300 ml) followed by (Boc)20 (95.13 g, 436.38 mmol, 1.5 eq). The reaction mixture was allowed to stir at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The organic phase was evaporated under reduced pressure, the reaction mixture was diluted with water (50 ml), cooled to 0 C, pH adjusted to 5 with IN HC1 and then extracted with DCM (3x300 ml). The combined organic extracts were washed with water (300 ml), brine (100 ml) solution, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was stirred with n-hexane (300 ml) at room temperature for about 30 minutes. The obtained solid was filtered and dried under vacuum to obtain the desired product (38.0 g, yield: 64.4%) as a white solid.
61%
With sodium hydroxide; In 1,4-dioxane; water; at 0 - 20℃; for 16h;Inert atmosphere;
A solution of compound 14 (10.0 grams, 97.0 mmol) in dioxane (150 ml) and NaOH (5%, 150 ml) was cooled to 0 C., then Boc2O was added dropwised. The mixture was stirred for 16 hours at room temperature under N2 atmosphere, then added HCl (concentrated) to make PH to 3, and the mixture was extracted with EtOAc (100 ml×3), washed with brine (50 ml), dried over Na2SO4, concentrated in vacuo and purified on silica gel column (PE/EtOAc=5:1) to give the product as white solid (12.1 grams, 61% yield).
49%
With triethylamine; In methanol; at 60℃; for 0.5h;
The starting materials N1, 2-dimetliylalaninamide and 2-methylalaninamide used in Examples 95 and 97 were prepared from 2-aminoisobutyric acid (ex. Aldrich) following the procedure below: Di-tert-butlydicarbonate (6.98 g, 32.0 mmol) was added to a stirred solution of the 2- aminoisobutyric acid (3 g, 29.13 mmol) in methanol/triethylmine (10/90) (100 ml). The reaction mixture was heated at 60C/30 minutes, cooled to room temperature and concentrated to dryness. The residue was taken up in dichloromethane (100 ml), washed with 10% aqueous potassium hydrogensulfate, water, dried over magnesium sulfate, filtered and evaporated to dryness to give N-(tert-butoxycarbonyl)-2-methylalanine (2.87 g, 49%) as a white solid ; 1H NMR Spectrum : (CDC13) 1.45 (s, 6H), 1.53 (s, 9H), 5.2 (br s, 1H).
45.44%
With hydrogenchloride; sodium hydroxide; In tetrahydrofuran;
E. 2-tert-Butoxycarbonylamino-2-methyl-propionic acid <strong>[62-57-7]2-Aminoisobutyric acid</strong> (140 g, 1.36 mol), 1 N NaOH (1620 mL, 1.63 mol), (Boc)2O (375 mL, 1.63 mol) and THF 420 mL were mixed together and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (700 mL) and adjusted to about pH 3.0 by adding 6 N HCl. The organic phase separated was washed with saturated NaCl solution and concentrated to approximately 1/4 of the original volume. After treatment with hexane a white solid product was isolated and collected (125.8 g, yield 45.44 %). An additional 7.8 g of product was recovered from the mother liquor.
44%
With sodium hydroxide; In tetrahydrofuran; at 20℃;
Step 1To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and Tiff (30 mL) was added (Boc)20 (26 g, 0.12 rnol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2), The organic phases were combined, washed with brine, dried over Na2SC>4. concentrated to give 9 g (44%) of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid
44%
With sodium hydroxide; In tetrahydrofuran; at 20℃;
Step 1. To a solution of 2-amino-2-methylpropanoic acid (10.3 g, 0.1 mol, 1.0 equiv) in 1 N NaOH (100 mL) and THF (30 mL) was added (Boc)2O (26 g, 0.12 mol, 1.2 equiv) portionwise at room temperature. This mixture was stirred overnight at room temperature. The mixture was concentrated and then extracted with ethyl acetate (100 mLx2). The aqueous phase was adjusted to PH=3~4, then extracted with ethyl acetate (200 mLx2). The organic phases were combined, washed with brine, dried over Na2SO4, concentrated to give 9 g (44%)of the desired product 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid as a white solid.
40.7%
With sodium hydroxide; In tetrahydrofuran; water; at 20℃;
To a solution of 2-amino-2-methylpropanoic acid (4.0 g, 39 mmol) , NaOH (1.55 g, 38.8 mmol) , water (50 mL) , and THF (20 mL) was added (Boc)2O (10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirred overnight at rt, then concentrated to dryness, and extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound as a white solid (3.21 g, 40.7yield) .
With sodium hydroxide; In tetrahydrofuran; water; for 4h;
To a solution of 2-aminoisobutyric acid (10 g, 97 mmol) in 1M aqueous NAOH (100ml) was added tert-butyloxycarbonyl anhydride (26 g, 120 mmol) in THF (30 ml). The reaction mixture was stirred for 4 h, diluted with ethyl acetate (250 ml), washed with 0. 5M aqueous HCl (200 ml), and finally with brine. The organic layer was dried over sodium sulfate and concentrated in vacuo yielding crude N-BOC-2-AMINOISOBUTYRIC acid (7.3 g).
With triethylamine; sodium hydroxide; In methanol; water; at 20℃;
2-Amino-2-methyl-propionic acid (50.0 g) was suspended in a mixture of methanol and triethylamine (9:1, 1.2 L) (Scheme 11). 1M aqueous NaOH (450 mL) was added with stirring until all solid was dissolved. Di-tert-butyl dicarbonate (Boc2O; 214.0 g) was added, and the mixture was stirred at ambient temperature overnight. The organic volatiles were removed in vacuo. EtOAc (500 mL) was added. The organic layer was washed with brine and dried over Na2SO4, filtered, then concentrated to afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 90 g) as a white solid which was used directly in next step directly.
With water; sodium hydroxide; In tetrahydrofuran; at 20℃;Inert atmosphere;
To a solution of 2-amino-2- methylpropanoic acid (4.0 g, 39 mmol), NaOH (1.55 g, 38.8 mmol), water (50 mL), and THF (20 mL) was added (Boc)20 (10.16 g, 46.55 mmol) portion wise at rt. The mixture was stirred overnight at rt, then concentrated to dryness, and extracted with EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1 M aqueous HCl, extracted with EtOAc, washed with brine, dried over anhydrous Na2S04, and concentrated to dryness to give the title compound as a white solid (3.21 g, 40.7% yield).
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6.0h;
Step 1: Methyl N-(tert-butoxycarbonyl)-2-methylalaninate (P1) To a solution of Boc-alpha-methylalanine in DMF (0.4 M) was added K2CO3 (1 eq) and MeI (1.2 eq). The mixture was stirred at RT for 6 h and then diluted with EtOAc, washed with water and sat. aq. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) delta: 7.20 (1H, br. s), 3.58 (3H, s), 1.40-1.27 (15H, m). MS (ES) C10H19NO4 requires: 217, found: 240 (M+Na)+.
With pyridine; ammonium bicarbonate; In 1,4-dioxane;Heating / reflux;Product distribution / selectivity;
Description 1: /^-[(i.i-DimethylethyOoxylcarbony^^-methylalaninamide (D1); lambda/M[(1 J-Dimethylethyl)oxy]carbonyl}-2-methylalanine (8.12 g) and (Boc)2O (9.603 g) was weighed into a round bottom flask and 1 ,4-dioxan (200 ml_ added). Pyridine (2.43 imL) was syringed under argon. NH4HCO3 (3.16 g) was added slowly afterwards. Reaction was left overnight over a stirrer hotplate under argon. A small amount of reaction mixture was removed of its solvent using the rotary evaporator and checked by running the NMR and also the NMR of the starting material in DMSO for comparison. The NMR showed that there was still some starting material left in the reaction mixture. Reaction was left for two more days. NMR showed that reaction has gone to completion. The solvent was removed using a rotary evaporator and product was placed in the oven to dry overnight. The title compound D1 was confirmed by NMR.NMR deltaH (CDCI3) 1.45 (9H, s), 1.51 (6H, s), 4.95 (1 H, broad s), 5.40 (1 H, broad s), 6.40 (1 H1 br s).
With pyridine; ammonium bicarbonate; In 1,4-dioxane; for 120h;Product distribution / selectivity;
Description 1 - alternative procedure: Af-(I(1, 1-Dimethylethyl)oxy]carbonyl}-2- methylalaninamide (D1); To a solution of lambda/M[(1.1-Dimethylethyl)oxy]carbonyl}-2-methylalanine (51.3 g, 0.253 mol), (BoC)2O (60.6 g, 0.278 mol) and pyridine (21.5 mL) in 1 ,4- dioxan (1.1 L) under argon was added NH4HCO3 (20.4 g, 0.258 mol). The mixture was stirred with a <n="26"/>mechanical stirrer under argon for 5 days, the mixture was filtered and the precipitate washed with 1 ,4-dioxan and the filtrate was concentrated on the rotary evaporator and the resulting solid was dried in the vacuum oven at 40 0C for 2 h to give 50.11 g of white solid (D1), with NMR data consistent with those previously obtained.
To a round bottom flask were added 2-(teri-butoxycarbonylamino)-2-methylpropanoic acid (2.0 g, 9.8 mmol), concentrated H2SO4 (0.1 mL), and MeOH (20 mL) and stirred at 60 C for 5 h. The mixture was concentrated to dryness, the residue was diluted with EtOAc, washed with saturated NaHC03 and brine, dried over anhydrous Na2S04, filtered, and concentrated to dryness to give the title compound as a white solid 1.78 g, 83.3% yield).
83.3%
With sulfuric acid; at 60℃; for 5.0h;
To a round bottom flask were added 2- (tert-butoxycarbonylamino) -2-methylpropanoic acid (2.0 g, 9.8 mmol) , concentrated H2SO4(0.1 mL) , and MeOH (20 mL) and stirred at 60 for 5 h. The mixture was concentrated to dryness, the residue was diluted with EtOAc, washed with saturated NaHCO3and brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness to give the title compound as a white solid 1.78 g, 83.3yield) .
In the 100 mL three-necked round bottom flask, 4-methylmorpholine (6.50 ml, 24.60 mmol) was added drop wise to a stirred mixture of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (5.00 g, 24.60 mmol) in tetrahydrofuran (10 ml) at -10C. Then isobutyl carbonochloridate (7.80 ml, 24.60 mmol) was added dropwise to the mixture under nitrogen. The reaction mixture was stirred at -10C for 1 hr. The solids were filtered out. The filtrate was added dropwise to thesodium borohydride (1.86 g, 49.2 mmol)in water (20 mL). The reaction was stirred for 30 mm. The reaction mixture was quenched with water/ice (20 mL), extracted with ethyl acetate (3 x 100mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1/10) to give the title compound. LCMS (ESI) calc?d for C9H,9N03 [M +H]:190,found:190. ?HNMR(400 MHz, DMSO-d6): 4.69 (t,J=5.6 Hz, 1H), 3.29 (d,J6.0 Hz, 2H), 1.37 (s, 9H), 1.16 (s, 6H).
Following the procedure of Example 3 using 2-aminodibenzthiophene (Bull. Soc. Chim. Fr. (1996), 133 (6), 597-610) and the appropriate acid the following compounds were prepared.
Step A: 2-(t-Butoxycarbonylamino)-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-propanamide Prepared from 2-(t-butoxycarbonylamino)-2-methylpropanoic acid and <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one</strong> (Example 1, Step A) by the procedure described in Example 25, Step A. 1 H NMR (200 MHz, CDCl3): 1.38 *s,12H), 1.44 (s,3H), 1.90 (m,1H), 2.5-3.0 (m,3H), 4.45 (m,1H), 5.10 (s,1H), 6.97 (m,1H), 7.20 (m,3H), 8.45 (s,1H).
1,1-dimethylethyl {2-[(3-amino-4-chlorophenyl)amino]-1,1-dimethyl-2-oxoethyl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 18h;
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (4.00 g, 7.69 mmol) was added to a mixture of 4-chloro-1 ,3-phenylenediamine (1.00 g, 7.01 mmol), N-(te/f-butoxycarbonyl)-2-aminoisobutyric acid (1.60 g, 7.87 mmol), N,N-diisopropylethylamine (3.00 mL, 17.2 mmol) and dichloromethane (7 ml_) and the mixture stirred 18 h under nitrogen. The mixture was diluted with ethyl acetate, washed with 1 M aqueous hydrochloric acid and brine, then dried (MgSO4). The solvent was removed under reduced pressure and the residue EPO <DP n="118"/>chromatographed (silica gel, 10-50percent ethyl acetate/hexane) to give the title compound (0.75 g, 33percent) as a solid. 1 H NMR (400 MHz, DMSO-c/6) delta ppm 1.36 (m, 15 H) 5.29 (s, 2 H) 6.73 (br s, 1 H) 6.88 (br s, 1 H) 7.05 (d, J=8.59 Hz, 1 H) 7.20 (s, 1 H) 9.21 (s, 1 H)
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In tetrahydrofuran; at 0℃; for 24h;
Step 1: tert-Butyl [1,1-dimethyl-2-oxo-2-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)ethyl]carbamate To a stirred suspension of BOC-2-aminoisobutyric acid (4 g, 19.7 mmol) and <strong>[38309-60-3]3H-spiro[2-benzofuran-1,4'-piperidine]</strong> (3.7 g, 19.7 mmol) and N,N,N',N'-tetramethyl-o-(benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (11.2 g, 29.5 mmol) in THF (70 mL) cooled in ice, triethylamine (8.2 mL, 59 mmol) was added slowly and stirring without cooling was continued for 24 h. The mixture was filtered, evaporated to dryness and extracted with AcOEt, 1 M citric acid, 50% NaCl, 10% Na2CO3, 50% NaCl. The resulting foam was dissolved in heptane/AcOEt 1:2 (80 mL) which led to spontaneous crystallization. One obtained 5.54 g (75%) of white crystals. MS: m/z=375 [M+H]+.
With potassium carbonate; methyl iodide; In N,N-dimethyl-formamide;
Step 1: Methyl N-(tert-butoxycarbonyl)-2-methylalaninate (P1) To a solution of Boc-alpha-methylalanine in DMF (0.4 M) was added K2CO3 (1 eq) and MeI (1.2 eq). The mixture was stirred at RT for 6 h and then diluted with EtOAc, washed with water and sat. aq. NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) delta: 7.20 (1H, br. s), 3.58 (3H, s), 1.40-1.27 (15H, m). MS (ES) C10H19NO4 requires: 217, found: 240 (M+Na)+.
Example 5.2-Cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy- 1 , 1 ,2-trimethyl- -amideStep 1In a round-bottomed flask N-Boc-aminoisobutyric acid (1.20 g, 5.90 mmol) was dissolved in dichloromethane (22 mL) and MeOH (11 mL). (Trimethylsilyl)diazomethane (2.0M in hexanes, 5.0 mL, 10.0 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was quenched with a small portion of acetic acid and concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated aqueous Na2CC"3. The aqueous layer was extracted with dichloromethane and the combined organics were dried over Na2S04 and concentrated to afford 1.3 g (99%) of N-Boc-aminoisobutryric acid methyl ester as an off- white solid.
Intermediate P: 4,4,5,5-tetramethyloxazolidin-2-oneStep 1 : Preparation of Methyl 2-(tert-butoxycarbonylamino)-2-methylpropanoate To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (10.03 g, 49.4 mmol) in MeOH/DCM (60mL/140ml_) at room temperature was added drop wise (trimethylsilyl)diazomethane (37.0 mL, 74.0 mmol). The reaction mixture was stirred for 30 minutes. Acetic acid was added drop wise to quench (trimethylsilyl)diazomethane. The reaction mixture was concentrated under reduced pressure to afford the desired product as a white solid (10.56 g). LCMS m/z 240.2 (M + Na)+, Rt 0.71 min.
In 2,2,2-trifluoroethanol; toluene; at 20℃;Microwave irradiation;
General procedure: tert-Butyl (2-aminophenyl)carbamate (1 equiv, 1.0 mmol,208 mg) and ethyl glyoxylate (1.5 equiv, 1.5 mmol, 361 muLof a 50% solution in toluene) were dissolved in TFE (5 mL).After 10 min, N-Boc-glycine (1 equiv, 1.0 mmol, 175 mg)and 6-isocyano-2,3-dihydrobenzo[b][1,4]dioxane (1 equiv,1.0 mmol, 161 mg) were added to the reaction mixture,which was stirred overnight at r.t. The reaction wasmonitored by LC-MS and TLC. Upon completion, thesolvent was removed in vacuo and the crude materialdissolved in 10% TFA-DCE (3.0 mL), with subsequentirradiation at 120 C for 10 min. After the vial was cooled tor.t., the mixture was diluted with EtOAc (50 mL), and theorganic layer was washed with sat. NaHCO3 (20 × 2 mL) andbrine. The organic phase was dried over MgSO4, evaporatedin vacuo, and the crude material was purified by flashchromatography (MeOH-EtOAc 0-10%) using an ISCOpurification system to afford N-{2,3-dihydrobenzo-[b][1,4]dioxan-6-yl}-3-oxo-1,2,3,4-tetrahydrobenzo-[4,5]imidazo[1,2-a]pyrazine-4-carboxamide (1c) as a whitesolid (197 mg, 54% yield).
In 2,2,2-trifluoroethanol; toluene; at 20℃;Microwave irradiation;
General procedure: tert-Butyl (2-aminophenyl)carbamate (1 equiv, 1.0 mmol,208 mg) and ethyl glyoxylate (1.5 equiv, 1.5 mmol, 361 muLof a 50% solution in toluene) were dissolved in TFE (5 mL).After 10 min, N-Boc-glycine (1 equiv, 1.0 mmol, 175 mg)and 6-isocyano-2,3-dihydrobenzo[b][1,4]dioxane (1 equiv,1.0 mmol, 161 mg) were added to the reaction mixture,which was stirred overnight at r.t. The reaction wasmonitored by LC-MS and TLC. Upon completion, thesolvent was removed in vacuo and the crude materialdissolved in 10% TFA-DCE (3.0 mL), with subsequentirradiation at 120 C for 10 min. After the vial was cooled tor.t., the mixture was diluted with EtOAc (50 mL), and theorganic layer was washed with sat. NaHCO3 (20 × 2 mL) andbrine. The organic phase was dried over MgSO4, evaporatedin vacuo, and the crude material was purified by flashchromatography (MeOH-EtOAc 0-10%) using an ISCOpurification system to afford N-{2,3-dihydrobenzo-[b][1,4]dioxan-6-yl}-3-oxo-1,2,3,4-tetrahydrobenzo-[4,5]imidazo[1,2-a]pyrazine-4-carboxamide (1c) as a whitesolid (197 mg, 54% yield).
In 2,2,2-trifluoroethanol; toluene; at 20.0℃;Microwave irradiation;
General procedure: tert-Butyl (2-aminophenyl)carbamate (1 equiv, 1.0 mmol,208 mg) and ethyl glyoxylate (1.5 equiv, 1.5 mmol, 361 muLof a 50% solution in toluene) were dissolved in TFE (5 mL).After 10 min, N-Boc-glycine (1 equiv, 1.0 mmol, 175 mg)and 6-isocyano-2,3-dihydrobenzo[b][1,4]dioxane (1 equiv,1.0 mmol, 161 mg) were added to the reaction mixture,which was stirred overnight at r.t. The reaction wasmonitored by LC-MS and TLC. Upon completion, thesolvent was removed in vacuo and the crude materialdissolved in 10% TFA-DCE (3.0 mL), with subsequentirradiation at 120 C for 10 min. After the vial was cooled tor.t., the mixture was diluted with EtOAc (50 mL), and theorganic layer was washed with sat. NaHCO3 (20 × 2 mL) andbrine. The organic phase was dried over MgSO4, evaporatedin vacuo, and the crude material was purified by flashchromatography (MeOH-EtOAc 0-10%) using an ISCOpurification system to afford N-{2,3-dihydrobenzo-[b][1,4]dioxan-6-yl}-3-oxo-1,2,3,4-tetrahydrobenzo-[4,5]imidazo[1,2-a]pyrazine-4-carboxamide (1c) as a whitesolid (197 mg, 54% yield).
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In dichloromethane for 1h;
20g
General procedure: C-(4-Trifluoromethyl-pyridin-2-yl)-methylamine dihydrochloride (0.5 g, 2.01 mmol), 2- tert-butoxycarbonylamino-2-methylpropionic acid (0.45 g, 2.21 mmol), TBTU (0.71 g, 2.21 mmol) and triethylamine (1.15 mL, 8.23 mmol) are combined in dichioromethane (10 mL) and the mixture stirred for 1 hour. The mixture is washed with 0.2M aqueous NaOH, dried over sodium sulphate and the solvent removed under vacuum. The residue is purified by flash chromatography (eluent 0-100% ethyl acetate in cyclohexane) to give the title compound (703 mg, 97%).U PLC-MS (Method 2): R = 1 .00 mmMS (ESI pos): mlz = 362 (M+H)
11193]Example 1111194] TEA (6 mE, 44.985 mmol) followed by T1311J (5.3 g, 16.511 mmol) are added to 4-chloro-o-phenylenediamine (2.1 g, 15.001 mmol) and a-(l3oc-amino)isobutyric acid, l3oc-a-methylalanine (3.3 g, 16.247 mmol) in THF (50 mE). After stirring for 3d at rt, volatiles are evaporated under reduced pressure, the residue taken up in EtOAc, washed with 5% citric acid, 2M NaOH, dried over Na2504, filtered andevaporate under reduce pressure to give a residue that is purified by flash chromatography (eluent 50% EtOAc/cyclohexane) to thrnish a mixture of adducts (4.2 g, 85%). Such mixture is heated at 60 C. overnight in acetic acid (35 mE). Volatiles are evaporated under reduced pressure to give a residue that is taken up in EtOAc, washed with 2M NaOH, dried over MgSO4, filtered and evaporate under reduce pressure to give a residue. Such residue is suspended in DCM (25 mE) and treated with TFA (10 mE). Stirring is continued for 2 h. Volatiles are evaporated under reduced pressure and the resulting residue taken up with methyl tert-butyl ether, washed with 0.5 M HC1 and evaporated under reduced pressure. The resulting mixture is taken up and evaporated twice with EtOR to give a residue (3.4 g). 57mg of suchresidue (0.2 mmol) and DIPEA (65 jii, 0.4 mmol) in DMF (1 mE) are added to HATU (84 mg, 0.220 mmol), meso-(1R,55,6r)-3- (tert-butoxycarbonyl)-3-azabicyclo[3.1 .0]hexane-6-car- boxylic acid (45 mg, 0.200 mmol) and DIPEA (113 pi, 0.700mmol) in DMF (2 mE) and stirring is continued overnight at rt and the reaction mixture purified by preparative HPEC (stationary phase: Xl3ridge C18 5 tm 19x100 mm. Mobile phase: ACN/H20+NH4COOH 5 mM). Fractions containing the title compound are combined and lyophilised. The residue in MeOH (3 mE) is treated with HC1 in ethyl ether (2M, 1.2 mE, 25.6 10 mmol). Afier stirring for 3 h, volatiles are evaporated under reduced pressure and the resulting residue redissolved in ACN/H20 1:1 and lyophilised to thrnish the title compound (86 mg, 100%)11195] UPEC-MS (Method 4): R=0.83 mm11196] MS (ESI pos): mlz=319 (M+H)
1-[(tert-butoxy)carbonyl]amino}-3,6,9,12,15,18-hexaoxahenicosan-21-oic acid[ No CAS ]
[ 13836-37-8 ]
C100H145ClN19O23PolS[ No CAS ]
[ 73821-95-1 ]
[ 18942-49-9 ]
[ 73821-97-3 ]
[ 6404-28-0 ]
[ 55260-24-7 ]
[ 25024-53-7 ]
cyclo(30−33)[D-Phe12, Nle21,38,Aib27,32,40,Glu30,Lys33]-(21-amino-4,7,10,13,16,19-hexaoxaheneicosanoyl)-{human/rat corticotropin releasing factor}(9−41)[ No CAS ]
With ruthenium(IV) oxide; sodium periodate; In tetrachloromethane; water; acetonitrile; at 20℃; for 2h;
General procedure: To a solution of N-protected amino alcohol 4a-g (0.5 mmol) in a 2:2:3 mixture of CCl4/MeCN/H2O (7 mL) were successively added NaIO4(321 mg, 1.5 mmol) and RuO2·xH2O (3.5 mg, 0.025 mmol) at r.t. Theresulting dark mixture was vigorously stirred for 2 h at r.t. thenCH2Cl2 (10 mL) and H2O (10 mL) were added. The layers were separatedand the aqueous phase was extracted with CH2Cl2 (2 × 10 mL). Thecombined organic layers were washed with brine, dried over MgSO4,filtered and the solvent was removed in vacuo. The black residue waspurified by chromatography on silica gel (CH2Cl2-MeOH, 99:1 to95:5) to afford the N-Boc-protected amino acid 7a-g.
ethyl (2E)-2-(2-[[(tert-butoxy)carbonyl]amino]-2-methylpropanamido)-2-(hydroxyimino)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;
Ethyl (2E)-2-(2-[[(tert-butoxy)carbonyl]amino]-2-methylpropanamido)-2-(hydroxyimino)acetate In a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, <strong>[10489-74-4]ethyl [(Z)-N-hydroxycarbamimidoyl]formate</strong> (820 mg, 6.21 mmol, 1.00 equiv) was dissolved in N,N-dimethylformamide (10 mL), to which were added HATU (3.54 g, 9.31 mmol, 1.50 equiv), DIEA (2.4 g, 18.57 mmol, 2.99 equiv) and 2-[[(tert-butoxy)carbonyl]amino]-2-methyl propanoic acid (1.26 g, 6.20 mmol, 1.00 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. When the reaction was done, it was quenched by the addition of 10 mL water and the resulting mixture was extracted with dichloromethane (3*15 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (10% to 50% gradient) to afford ethyl (2E)-2-(2-[[(tert-butoxy)carbonyl]amino]-2-methylpropanamido)-2-(hydroxyimino)acetate (300 mg, 15%) as light yellow solid.
(2-methyl-1-(((3-methylpyridin-2-yl)methyl)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In tetrahydrofuran; at 20℃;
3-methyl-2-(aminomethyl)pyhdine (13.5 g, 1 10 mmol), is suspended in dry THF and 2-tert-butoxycarbonylamino-2-methylpropionic acid (22.4 g, 1 10 mmol) is added followed by TEA (46.1 mL, 331 mmol) and TBTU (35.4 g, 1 10 mmol). The mixture is stirred overnight at room temperature then the solvent is evaporated, the residue is diluted with dichloromethane and washed with 1 N NaOH solution and brine. The organic layer is dried, filtered and evaporated under reduced pressure to give a residue that is purified by flash chromatography (eluent 50-100% EtOAc/cyclohexane) to furnish the title compound (28.5 g, 84%). UPLC-MS (Method 2): Rt = 0.98 min MS (ESI+): m/z = 308 (M+H)+
84%
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In tetrahydrofuran; at 20℃;
3-methyl-2-(aminomethyl)pyhdine (13.5 g, 1 10 mmol), is suspended in dry THF and 2-tert-butoxycarbonylamino-2-methylpropionic acid (22.4 g, 1 10 mmol) is added followed by TEA (46.1 mL, 331 mmol) and TBTU (35.4 g, 1 10 mmol). The mixture is stirred overnight at room temperature then the solvent is evaporated, the residue is diluted with dichloromethane and washed with 1 N NaOH solution and brine. The organic layer is dried, filtered and evaporated under reduced pressure to give a residue that is purified by flash chromatography (eluent 50-100% EtOAc/cyclohexane) to furnish the title compound (28.5 g, 84%). UPLC-MS (Method 2): Rt = 0.98 min MS (ESI+): m/z = 308 (M+H)+
2-(4-chlorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)-2-methyl propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.2%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;
1 Step 1: Synthesis of 2-(4-chlorophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)amino)-2-methyl propanoate
To a stirred solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (11.0 g, 54.18 mmol, 1.0 eq) in DCM (250 ml) at 0° C. was added DIPEA (48 ml, 270.93 mmol, 5.0 eq) and 2-bromo-1-(4-chlorophenyl)ethan-1-one (15.2 g, 65.01 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for overnight. TLC indicated starting material was consumed and the desired product was observed. The reaction mixture was diluted with water (200 ml) and extracted with DCM (3*150 ml). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silicagel column chromatography by using DCM as an eluent to obtain the desired product (18.5 g, yield: 96.2%) as a yellow solid. 1H NMR (300 MHz, CDCl3): δ ppm 7.85 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 5.34 (s, 2H), 1.61 (s, 6H), 1.44 (s, 9H); ESI-MS: m/z 378.0 (M+Na)+.
With potassium <i>tert</i>-butylate In tetrahydrofuran; N,N-dimethyl-formamide at 30℃;
tert-butyl {1-[(3-bromobenzyl)(methyl)amino]-2-methyl-1-oxopropan-2-yl}carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;
To a mixture of 6 (500 mg, 2.50 mmol) in CH2Cl2 (5.0 mL) were added N-(tert-butoxycarbonyl)-2-methylalanine (533 mg, 2.62 mmol), WSCD*HCl (527 mg, 2.75 mmol), and HOBt (371 mg, 2.75 mmol). After being stirred at room temperature for 3 h, the mixture was diluted with water and extracted with CHCl3. The organic layer was washed with HCl aqueous solution and saturated NaHCO3 aqueous solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH = 98:2) to afford tert-butyl {1-[(3-bromobenzyl)(methyl)amino]-2-methyl-1-oxopropan-2-yl}carbamate (23) (915 mg, 95percent) as a colorless oil. To a mixture of 23 (286 mg, 0.74 mmol) in DME (2.9 mL)/water (1.4 mL) were added 15 (225 mg, 0.78 mmol), Na2CO3 (236 mg, 2.23 mmol), and Pd(PPh3)4 (26 mg, 0.022 mmol). The mixture was stirred at 90 °C for 36 h. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with water and extracted with CHCl3. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH = 98:2) to afford tert-butyl [2-methyl-1-(methyl[4'-(morpholin-4-yl)biphenyl-3-yl]methyl}amino)-1-oxopropan-2-yl]carbamate (290 mg, 84percent) as a colorless oil. To a solution of tert-butyl [2-methyl-1-(methyl[4'-(-morpholin-4-yl)biphenyl-3-yl]methyl}amino)-1-oxopropan-2-yl]carbamate (290 mg, 0.62 mmol) in MeOH was added 4 M HCl/EtOAc. After being stirred at room temperature for 4 h, the mixture was concentrated in vacuo. The residue was diluted with saturated NaHCO3 aqueous solution, and the mixture was extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated in vacuo. To a solution of the residue in EtOH was added (2R,3R)-tartaric acid (93 mg, 0.62 mmol). The resulting precipitate was filtered to give the product (160 mg, 50percent) as a colorless solid.
(S)-2-(4-(5-chloro-2-(isopropylamino)pyridin-4-yl)-1H-pyrrole-2-carboxamido)-2-(3-chlorophenyl)ethyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With dmap; 1,2-dichloro-ethane; In dichloromethane; at 20℃;
To a mixture of (i(3- chioropheny 1)24iydroxyethyi)- 1H-pyrroie--2-carboxami de (44 ing, 0,1 mmoi) and 2((tert.- butoxycarbonyl)amino).-2.methylpropanoic acid (23 mg, 0.11 mmol) in dry CH2C12 (4.5 mL) was added EDC (21 mg, 0.11 mmol) and DMAP (14 mg, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with aqueous NH4CI solution. The organic layer was dried over Na2SO4 and concentrated in vacuum. The crude residue was purified by ISCO using DCM/MeOEI (0-J0%) as eluent to afford 59 mg (96%) of product. ESMS calculated (C30H37C12N505): 618.55; found: 619 (M+H).
benzyl 4-(2-((tert-butoxycarbonyl)amino)- 2-methylpropanamido)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃;
To a solution of 2-((tert-butoxycarb - - acid (300 mg, 1.47 mmol) in N,N-dimethylformamide (5 mL) was added benzyl 4-aminopiperidine-1- carboxylate (346 mg, 1.47 mmol), HATU (842 mg, 2.21 mmol) and DIPEA (0.773 mL, 4.43 mmol). The resulting mixture was stirred overnight at 80 C then concentrated under reduced pressure to give the crude product. The crude product was added to a silica gel column and was eluted with dichloromethane/methanol to give benzyl 4-(2-((tert- butoxycarbonyl)amino)-2-methylpropanamido)piperidine-1-carboxylate (500 mg, 1.192 mmol, 81% yield) as a white solid. LCMS m/z = 442.1 [M+Na]+.
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 30℃; for 16h;
2-(5-(tert-Butyl)-1H-benzo[d]imidazol-2-yl)propan-2-amine wasprepared in parallel format using the following protocol: A solution of2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid in DMA (100umol, 1.0 eq) was dispensed into 8 vials, followed by a solution ofPyBOP (55 mg, 110 umol, 1.1 eq). The vials were diluted with DMA(800 muL), capped and shaken at 30 °C for 30 min. A solution of the intermediates,including <strong>[68176-57-8]4-(tert-butyl)benzene-1,2-diamine</strong> (100 umol,1.0 eq), in DMA (400 ul) was dispensed to the vials. DIEA (75 muL, 300umol, 1.0 eq) was added to the vials, which were capped and shaken at30 °C for 16 hrs. The solvent was removed by a Speedvac to give thecrude intermediate tert-butyl (1-((2-amino-4-(tert-butyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl) carbamate which was used for next stepwithout further purification. The intermediates, including tert-butyl (1-((2-amino-4-(tert-butyl)phenyl)amino)-2-methyl-1-oxopropan-2-yl)carbamate(75 mumol, 1.0 eq) in acetic acid (400 muL) were dispensed into in8 mL vials followed by addition of 6 N HCl (150 muL) to each vial. Thevials were capped and shaken at 100 °C for 2 hrs. The solvent was removedby a Speedvac and the residue was purified by preparative HPLCto give pure 2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)propan-2-amine. HRMS for C14H22N3 MS m/z [M+H]+: Calc?d: 232.1808,Found: 232.1808.
To a 1 L three-necked flask was added Compound I (50.0 g, 0.267 mol) and the compound N-tert-butoxycarbonyl-2-methylalanine (60.1 g, 0.295 mol) under a nitrogen atmosphere.Add 150 mL of anhydrous THF and stir at room temperature until the solid is completely dissolved. Add DIPEA (38.2 g, 0.295 mol) and control the reaction temperature at 10-30 C, then add 50 mL of anhydrous THF, stir at room temperature for 10-15 min.CDI (52.3 g, 0.322 mol) was added in portions, and the internal temperature was raised to 50-60 C and stirred for 30 min.DBU (61.3 g, 0.403 mol) was added and reacted at 55-65 C for 3-4 h to stop the reaction.Add 150 mL of citric acid aqueous solution at 60 C and stir for 30 min.Liquid separation, organic phase concentration, solvent replacement with ethanol, ethanol recrystallization, suction filtration,The white solid was dried to 45.8 g, and the yield was 49.5%.
9‐(carboxymethylthio)‐1,7‐dicarba‐closododecaborane(12)[ No CAS ]
[ 86123-10-6 ]
[ 150629-67-7 ]
[ 32926-43-5 ]
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine[ No CAS ]
Aib‐H‐(D‐2‐Nal)‐fK(9‐(carboxymethylthio)‐1,7‐dicarba‐closododecaborane(12))‐NH2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2 mg
General procedure: The first four amino acids (from the C-terminus) of peptide 13 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used: The remaining two amino acids of peptide 13 were coupled manually using a 5-fold molar excess of amino acid, FIOBt and DIC (75 pmol each) in DMF as solvent. In addition, the whole sequence of peptide 15 was prepared by manual synthesis on a Rink amide AM resin using the same reagent conditions. Following coupling scheme was applied: In case of peptide 15, the resin was treated with a capping solution of 10 % DIPEA and 10 % acetic anhydride in DCM (15 min, 500 pi) after loading with the first C-terminal amino acid. Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). Peptides 14 and 16 were entirely prepared by automated peptide synthesis as described in the general section. The coupling scheme was as follows: The first two C-terminal amino acids of peptide 17 and 18 were coupled by automated peptide synthesis as described in the general section. Following coupling scheme was used:The remaining three amino acids of peptide 17 and 18 were coupled manually using a 3-fold or 5- fold molar excess of the amino acid and a 5-fold molar excess of FIOBt and DIC (75 pmol each) in DMF as solvent. The coupling scheme was as follows: Removal of Fmoc protecting groups after each manual coupling step was accomplished by using 20 % piperidine in DMF (2 x 10 min, 500 pi each). For the removal of the Mmt protecting group in peptide 13, the resin was treated with a cleavage mixture consisting of 2 % TFA, 5 % TIS in DCM (8 x 2 min, 1 ml each). After each deprotection step, the resin was washed with DCM. Finally, the resin was incubated with 5 % DIPEA in DCM (2 x 10 min, 1 ml each). For the cleavage of the Dde protecting group in all other peptides (14-18), the resin was treated with 2 % hydrazine in DMF (10 x 10 min, 1 ml each). In case of peptide 14, the building block Fmoc-L-Dap(Mtt)-OFI was coupled manually in 3-fold molar excess with a 5-fold molar excess of FIOBt and DIC (75 pmol each) to the e-amino group of the C- terminal lysine. DMF was used as solvent and the coupling time was approximately 16 h. For peptide 16, the building block Fmoc-L-Dap(Fmoc)-OFI was coupled manually in 5-fold molar excess with FIOBt and DIC (75 pmol each) in DMF to the C-terminal lysine side-chain. The coupling time was 4 h. Subsequently, removal of the Fmoc protecting groups was achieved by using 20 % piperidine in DMF (2 x 10 min, 500 mI each). 6-TAMRA was coupled manually to peptide 16 using a 2-fold molar excess of the fluorophore, FIATU and DIPEA (30 pmol each) in DMF as solvent for 5 h. Afterwards, removal of the Mtt protecting group in peptide 16 was performed as described for the Mmt deprotection above.The carbaboranes were coupled manually in 3-fold molar excess per free lysine or Dap amino group, except for mlJ9b, which was coupled in 1.5-fold molar excess per free amino group. Coupling reactions were prepared as follows: Peptides 13, 14 and 17: 3 eq. m9b, 5 eq. FIOBt and 5 eq. DIC in DMF as solvent. Peptide 15: 3 eq. bm9x, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 16: 3 eq. mlJ9b, 4 eq. FIOBt and 4 eq. DIC in DMF. Peptide 18: 1.5 eq. mlJ9b, 2 eq. FIOBt and 2 eq. DIC in DMF. All coupling reactions were performed overnight for approximately 16 h. Cleavage of conjugates 13-15 and 17 from the resin and simultaneous side chain deprotection was accomplished using a mixture of TFA/TA/EDT (90:7:3, 1 ml) for 3 h. Cleavage of conjugates 16 and 18 from the resin was achieved using a mixture of TFA/FhO (95:5, 1 ml) for 3 h. The crude conjugates were precipitated and washed with an ice-cold mixture of hexane/diethyl ether (3:1, v/v), dissolved in ACN/FI2O and subsequently lyophilized. The first purification of the crude conjugate 13 was performed by preparative RP-HPLC using a C18- column (Phenomenex Jupiter 5u 300 A: 250 mm c 21.2 mm, 5 pm, 300 A) with a flow rate of 10 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. Conjugate 13 had to be purified a second time using a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 50 % to 80 % eluent B in A over 30 min. For purification of conjugate 14, a XBridge C18-column (Waters XBridge Peptide BEH C18 OBD: 250 mm c 19 mm, 10 pm, 130 A) with a flow rate of 15 ml/min and a linear gradient of 30 % to 60 % eluent B in A over 30 min was applied. Purification of the conjugates 15-17 was achieved using a Kinetex C18-column (Phenomenex Kinetex 5u XB-C18: 250 mm c 21.2 mm, 5 pm, 100 A) with a flow rate of 15 ml/min. For conjugate 15 and 16, a linear gradient of 40 % to 70 % eluent B in A over 30 min was used, whereas for conjugate 17 a gradient of 50 % to 80 % eluent B in A over 30 min was applied. Purification of the...
Under a nitrogen atmosphere, a compound I (50.0 g, 0.267 mol) and a compound N-tert-butoxycarbonyl-2-methylalanine (60.1 g, 0.295 mol) were added to a 1 L three-necked flask, and 150 mL of anhydrous THF was added at room temperature. Stir until the solid is completely dissolved, add DIPEA (38.2 g, 0.295 mol) and control the reaction temperature at 10-30 C, then add 50 mL of anhydrous THF, stir at room temperature for 10-15 min, add CDI (52.3 g, 0.322 mol) in portions. The internal temperature was raised to 50-60 C and stirred for 30 min. DBU (61.3 g, 0.403 mol) was added and reacted at 55-65 C for 3-4 h to stop the reaction. Add 60 mL of citric acid aqueous solution at 60 C and stir for 30 min, separate the liquid, concentrate the organic phase to 50-100 mL, add 250 mL of isopropanol, concentrate again to 50-100 mL, replace the solvent with isopropyl alcohol three times, then concentrate to 50 mL, test System KF value, KF=0.03%, adding 4 mL of HCl isopropanol solution 250 mL, heating to 55-65 C for 2 h, stop the reaction, concentrate to 100 mL, add 100 mL of isopropanol, concentrate again to 100 mL, add 400 mL N-heptane, precipitated solid, suction filtration, 50 mL of n-heptane washed filter cake,Drying under vacuum at 60 C gave a white solid compound (IV) hydrochloride, 71.6 g,The yield in two steps was 86.7%.
Under a nitrogen atmosphere, a compound I (10.0 g, 0.053 mol) and a compound N-tert-butoxycarbonyl-2-methylalanine (12.0 g, 0.295 mol) were added to a 1 L three-necked flask, and 30 mL of anhydrous THF was added at room temperature. Stir until the solid is completely dissolved, add DIPEA (7.7 g, 0.060 mol) and control the reaction temperature at 10-30 C, then add 10 mL of anhydrous THF, stir at room temperature for 10-15 min, add CDI (10.5 g, 0.064 mol) in portions. The internal temperature was raised to 50-60 C and stirred for 30 min. DBU (12.3 g, 0.081 mol) was added and reacted at 55-65 C for 3-4 h to stop the reaction. Add 30 mL of citric acid aqueous solution at 60 C and stir for 30 min, separate the liquid, concentrate the organic phase to 10-20 mL, add 50 mL of isopropanol, concentrate again to 10-20 mL, replace the solvent with isopropyl alcohol three times, then concentrate to 10 mL, test The system KF value, KF=0.03%, adding trifluoroacetic acid (18.3g, 0.162mol), heating to 30-65 C for 4h, stop the reaction, concentrated to 25mL under reduced pressure, add n-heptane 200mL and beat white solid,10.1 g of trifluoroacetic acid salt of formula IV in a two step yield of 49.0%.
(7R,8R,9S,13S,14S,17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.18 g
Stage #1: fulvestrant With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; for 0.5h;
Stage #2: Boc-Aib-OH In dichloromethane at 0 - 27℃; for 16h;
34.1 Step: l Preparation of 7R,8R,9S, l3S, l4S, l7S)-l7-hydroxy-l3-methyl-7-(9-((4,4,5,5,5- pentafluoropentyl)sulfmyl)nonyl)-7,8,9, 11 , 12, 13, 14, 15 , 16, 17-decahydro-6i7- cyclopenta[a]phenanthren-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate
To a stirred solution of fulvestrant (0.300 g) in dichloromethane (6 ml) was added DMAP (0.012 g) followed by DCC (0.153 g) at 0° C and stirred for 30 min. A solution of 2-(tert- butoxycarbonylamino)-2-methylpropionic acid (0.100 g) in dichloromethane (2 ml) was added to the reaction mixture at 0° C and stirred at 25-27° C for 16 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was evaporated under reduced pressure to provide crude material which was purified by column chromatography to afford 7R,8R,9S, l3S, l4S,l7S)-l7-hydroxy-l3-methyl-7-(9-((4,4,5,5,5- pentafluoropentyl)sulfmyl)nonyl)-7,8,9, 11 , 12, 13, 14, 15 , 16, 17-decahydro-6i7- cyclopenta[a]phenanthren-3-yl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (0.180 g) as a sticky solid.
With (1,2-dimethoxyethane)dichloronickel(II); (4s,6s)-2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile; caesium carbonate; 4,4'-di-tert-butyl-2,2'-bipyridine In N,N-dimethyl acetamide at 25 - 30℃; for 48h; Sealed tube; Irradiation;
tert-butyl N-[1-[3-(3-fluorophenyl)-1,2,4-oxadiazol-5-yl]-1-methylethyl]carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
140 mg
Stage #1: Boc-Aib-OH With 1,1'-carbonyldiimidazole In N,N-dimethyl-formamide for 1h;
Stage #2: 3-fluoro-N'-hydroxybenzenecarboximidamide In N,N-dimethyl-formamide at 100℃; for 2h;
32 A-51:
A mixture of 2-(tert-butoxycarbonylamino)-2-methyl -propanoic acid (580.16 mg, 2.85 mmol) and CDI (462.86 mg, 2.85 mmol) in DMF (6 mL) was stirred at 15 °C for 1 hour and then 3-fluoro-N-hydroxy-benzamidine (400 mg, 2.6 mmol) was added. The reaction mixture was then stirred at 100 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 2). The combined organic phase was washed with brine (20 mL), dried over INfeSCL, filtered and concentrated to give the crude product. The crude product was purified by flash chromatography on silica gel (EtOAc in PE = 0% to 30% to 60%) to give the product (140 mg, 344.1 pmol, 13% yield) as a solid. LCMS Rt = 0.91 min in 1.5 min chromatography, 5- 95AB, MS ESI calcd. for C12H13FN3O3 [M+H-t-Bu]+ 266.1, found 266.0.
cycloheptylmethyl 2-(chloro-15-azanyl)-2-methylpropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: cycloheptylmethanol; Boc-Aib-OH With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17h;
Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane for 18h;
89 Synthesis of cycloheptylmethyl 2-(chloro-l5-azanyl)-2-methylpropanoate (89a)
2-(tert-Butoxycarbonylamino)-2-methyl-propanoic acid (2.5 g, 12.3 mmol), cycloheptylmethanol (2.18 g, 17.1 mmol), 4-dimethylaminopyridine (4.5 g, 36.9 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (7.07 g, 36.9 mmol) were dissolved in dichloromethane (30 ml) and stirred at room temperature. After 17 h the reaction was diluted with DCM (10 ml). The solution was washed with water (2 x 50 ml), saturated ammonium chloride (50 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-50 % ethyl acetate / hexanes with ELSD). The fractions containing product were combined and the solvent was removed under reduced pressure. A solution of hydrogen chloride in 1,4-dioxane (4N, 10 ml, 24.6 mmol) was added to a solution of the residue in dichloromethane (10 ml). After 18 h the solvent was removed under reduced pressure. The residue was co-evaporated with dichloromethane (40 ml). The residue was subjected to high vacuum for 5 hours, to afford intermediate 89a.1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 3H), 3.98 (d, J = 6.5 Hz, 2H), 1.887-1.78 (m, 1H), 1.74-1.60 (m, 3H), 1.58 - 1.50 (m, 2H), 1.49 (s, 6H), 1.46 - 1.12 (m, 6H).
Stage #1: cycloheptylmethanol; Boc-Aib-OH With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 17h;
Stage #2: With hydrogenchloride In 1,4-dioxane; dichloromethane for 18h;
89 Synthesis of cycloheptylmethyl 2-(chloro-l5-azanyl)-2-methylpropanoate (89a)
2-(tert-Butoxycarbonylamino)-2-methyl-propanoic acid (2.5 g, 12.3 mmol), cycloheptylmethanol (2.18 g, 17.1 mmol), 4-dimethylaminopyridine (4.5 g, 36.9 mmol) and 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (7.07 g, 36.9 mmol) were dissolved in dichloromethane (30 ml) and stirred at room temperature. After 17 h the reaction was diluted with DCM (10 ml). The solution was washed with water (2 x 50 ml), saturated ammonium chloride (50 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-50 % ethyl acetate / hexanes with ELSD). The fractions containing product were combined and the solvent was removed under reduced pressure. A solution of hydrogen chloride in 1,4-dioxane (4N, 10 ml, 24.6 mmol) was added to a solution of the residue in dichloromethane (10 ml). After 18 h the solvent was removed under reduced pressure. The residue was co-evaporated with dichloromethane (40 ml). The residue was subjected to high vacuum for 5 hours, to afford intermediate 89a.1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 3H), 3.98 (d, J = 6.5 Hz, 2H), 1.887-1.78 (m, 1H), 1.74-1.60 (m, 3H), 1.58 - 1.50 (m, 2H), 1.49 (s, 6H), 1.46 - 1.12 (m, 6H).
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