* 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.
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 1, p. 297 - 301
[2] Synthetic Communications, 2005, vol. 35, # 2, p. 223 - 230
[3] Australian Journal of Chemistry, 2005, vol. 58, # 2, p. 149 - 151
[4] Farmaco (1946-1952), 1948, vol. 3, p. 652,655
[5] Pr. Montana Acad., 1949, vol. 9, p. 25
[6] Yakugaku Zasshi, 1958, vol. 78, p. 129[7] Chem.Abstr., 1958, p. 8794
[8] J. elektroch. Soc. Japan, 1952, vol. 20, p. 15[9] Chem.Abstr., 1952, p. 4930
[10] Farmaco (1946-1952), 1948, vol. 3, p. 509,523
[11] Farmaco (1946-1952), 1948, vol. 3, p. 183
[12] Proceedings - Indian Academy of Sciences, Section A, 1949, vol. <A> 29, p. 196,200
[13] Farmaco (1946-1952), 1948, vol. 3, p. 509,523
[14] Journal of the Chemical Society, 1949, p. 1498,1502
[15] Journal of the Society of Chemical Industry, London, 1949, vol. 68, p. 329
[16] Journal of the Chemical Society, 1949, p. 1498,1502
[17] Latvijas PSR Zinatnu Akademijas Vestis, 1950, # 3, p. 7,24[18] Chem.Abstr., 1954, p. 9964
[19] Chemische Berichte, 1901, vol. 34, p. 4352[20] Monatshefte fuer Chemie, 1902, vol. 23, p. 432
[21] Journal of the Chemical Society, 1949, p. 1498,1502
2
[ 591-27-5 ]
[ 65-49-6 ]
Reference：
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 1422
[2] DRP/DRBP Org.Chem.,
[3] DRP/DRBP Org.Chem.,
[4] Monatshefte fuer Chemie, 1949, vol. 80, p. 197,199
[5] Organic Letters, 2012, vol. 14, # 8, p. 1974 - 1977
Reference：
[1] Zesz. Politech. Gdansk., 1957, # 2, p. 3,5[2] Chem.Abstr., 1958, p. 20025
[3] Patent: US2640854, 1950, ,
6
[ 591-27-5 ]
[ 15540-79-1 ]
[ 65-49-6 ]
Reference：
[1] Gazzetta Chimica Italiana, 1951, vol. 81, p. 609,612
[2] Recueil des Travaux Chimiques des Pays-Bas, 1950, vol. 69, p. 1021,1024
[3] Kagaku Kenkyusho Hokoku, 1952, vol. 28, p. 377[4] Chem.Abstr., 1954, p. 5831
[5] Journal of Organic Chemistry, 1958, vol. 23, p. 1422
[6] Pharmaceutisch Weekblad, 1950, vol. 85, p. 474
7
[ 124-38-9 ]
[ 65-49-6 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 11, p. 2191 - 2195
8
[ 124-38-9 ]
[ 65-49-6 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 11, p. 2191 - 2195
9
[ 298-14-6 ]
[ 591-27-5 ]
[ 65-49-6 ]
Reference：
[1] Chemistry Letters, 2011, vol. 40, # 2, p. 206 - 208
[2] Biochemical and Biophysical Research Communications, 2010, vol. 394, # 2, p. 279 - 284
[3] Bulletin of the Chemical Society of Japan, 2013, vol. 86, # 5, p. 628 - 634
[4] RSC Advances, 2014, vol. 4, # 19, p. 9673 - 9679
10
[ 124-38-9 ]
[ 65-49-6 ]
[ 38160-63-3 ]
Reference：
[1] Bulletin of the Chemical Society of Japan, 2003, vol. 76, # 11, p. 2191 - 2195
11
[ 39835-14-8 ]
[ 65-49-6 ]
Reference：
[1] Journal of the Society of Chemical Industry, London, 1949, vol. 68, p. 329
[2] Farmaco (1946-1952), 1948, vol. 3, p. 509,523
12
[ 43134-76-5 ]
[ 65-49-6 ]
Reference：
[1] Ricerca Scientifica, 1948, vol. 18, p. 1057
13
[ 6018-18-4 ]
[ 65944-71-0 ]
[ 65-49-6 ]
Reference：
[1] Crystal Growth and Design, 2013, vol. 13, # 4, p. 1551 - 1557
14
[ 1122102-49-1 ]
[ 65-49-6 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2009, vol. 44, # 1, p. 131 - 142
15
[ 65-49-6 ]
[ 77-78-1 ]
[ 27559-59-7 ]
[ 99-07-0 ]
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1951, vol. 284, p. 341,346
16
[ 67-56-1 ]
[ 65-49-6 ]
[ 4136-97-4 ]
Yield
Reaction Conditions
Operation in experiment
93%
at 0 - 20℃; for 6 h; Reflux
To a stirred solution of 4-aminosalicylic acid (50 grams, 326.7 mmol) in methanol (375 mL) at 0 °C was added concentrated sulfuric acid (99.7 mL, 1.87 mmol) maintaining temperature of the reaction below 20 °C. The reaction mixture was gradually heated to reflux and upon completion of the reaction after 6 hours it was cooled to ice bath temperature and basified with aqueous sodium hydroxide solution (10.0 N, 214.5 mL). The white precipitate that formed was filtered, washed with water, ether and dried under vacuum to obtain Methyl 4-amino-2-hydroxy benzoate (50.70 grams). Yield: 93percent.Ή - NMR (DMSO-d6): δ 10.76 (bs, 1H), 7.43 (d, J = 8.6 Hz, 1H), 6.13 (bs, 2H), 6.10 (dd, J = 8.6, 2.0 Hz, 1H), 5.99 (d, J = 2.0 Hz, 1H), 3.79 (s, 3H);Mass (m/z): 168 (M+H)+.
93%
at 0℃; for 6 h; Reflux
To a stirred solution of 4-aminosalicylic acid (50 grams, 326.7 mmol) in methanol (375 mL) at 0° C. was added concentrated sulfuric acid (99.7 mL, 1.87 mmol) maintaining temperature of the reaction below 20° C. The reaction mixture was gradually heated to reflux and upon completion of the reaction after 6 hours it was cooled to ice bath temperature and basified with aqueous sodium hydroxide solution (10.0 N, 214.5 mL). The white precipitate that formed was filtered, washed with water, ether and dried under vacuum to obtain Methyl 4-amino-2-hydroxy benzoate (50.70 grams). Yield: 93percent. 1H-NMR (DMSO-d6): δ 10.76 (bs, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.13 (bs, 2H), 6.10 (dd, J=8.6, 2.0 Hz, 1H), 5.99 (d, J=2.0 Hz, 1H), 3.79 (s, 3H); Mass (m/z): 168 (M+H)+.
92%
at 80℃; for 22 h; Inert atmosphere
In an oven-dried 500 mL roundbottom flask, 4-aminosalicylic acid (16) (5.00 g, 32.6 mmol) was dissolved in methanol (100 mL) under nitrogen atmosphere. c-H2SO4 (7mL) was added dropwise and the reaction mixture was stirred at 80 oC. After 22 h, it was cooled to room temperature and neutralized with NaHCO3 until no further gas evolution was observed. Then, the solid was filtered and washed with MeOH (100 mL). The filtrate was evaporated under reduced pressure. The crude residue was diluted with ethyl acetate (200 mL) and H2O (200 mL), and aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, and filtered. Evaporation under reduced pressure afforded methyl ester 17 (4.99 g, 92percent) as a grey solid.TLC: Rf 0.32 (3:1 hexane/EtOAc). 1H-NMR (400 MHz, CDCl3): d 10.93 (s, 1H), 7.61 (dd, 1H, J = 8.0 Hz, 0.8 Hz), 6.16-6.13 (m, 2H), 4.09 (brs, 2H), 3.88 (s, 3H). 13C-NMR (100 MHz, CDCl3): d 170.7, 163.8, 153.6, 131.8, 107.0, 103.3, 101.0, 51.9.
92.1%
at 0 - 80℃; for 6 h;
Para-aminosalicylic acid (50 g, 0.327 mol) and methanol (300 mL) were added to a 1 L three-necked flask, and the mixture was stirred well and concentrated sulfuric acid (100 mL)To ensure that the temperature control between 0 ~ 5 ° C , after the addition is complete,Transferred to an oil bath and heated to 80 ° C reflux 6h.The reaction was monitored by TLC, cooled to room temperature,Add 10mol / L sodium hydroxide solution (about 200mL) adjusted to pH 4 ~ 5, precipitated a large amount of solid, filtration, washing, drying,Obtained product 50.3g, yield 92.1percent, purity of 99.6percent
90%
With sulfuric acid In water for 16 h; Reflux
To a stirred solution of 4-amino-2-hydroxybenzoic acid (2.0g, 13.1mmol, 1.0 eq.) in MeOH (40mL) was added dropwise concentrated aqueous solution of H2SO4 (2.8mL) and the resulting mixture was refluxed for 16h. After cooling to room temperature, it was neutralized with saturated aqueous NaHCO3 solution until no further gas evolution was observed and the mixture was concentrated in vacuo. The residue was dissolved in water and extracted several times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to afford (9), as a brown solid (1.97g, 90percent yield); mp 113°C (litt.: 115°C [30]); 1H NMR (CDCl3, 400MHz) δ 10.95 (br s, 1H, OH), 7.60 (d, 3J=8.9Hz, 1H), 6.14 (m, 2H), 4.15 (br s, 2H, NH2), 3.86 (s, 3H); 13C NMR (CDCl3, 100MHz) δ 170.6, 163.6, 153.5, 131.7, 106.9, 103.0, 100.7, 51.8; IR (neat, cm−1) ν 3475, 3381, 3249, 3025, 2952, 2851, 1642, 1437, 1356, 1283, 780; MS m/z [M+H]+ 168.17.
90%
at 0 - 80℃; for 6 h;
Sulfuric acid (H2S04) (200 mL) was added drop wise to a stirred solution of 4- amino-2-hydroxy benzoic acid (100 grams, 0.653 mole) in methanol (MeOH) (1500 mL) at 0 °C. Then reaction mass was slowly heated with stirring to 80 °C and stirred for 6 hours at the same temperature, while monitoring the progress of the reaction by thin layer chromatography (TLC). The reaction mass was cooled to room temperature (RT) and MeOH was evaporated. The residue was dissolved in water and the pH was adjusted to ~ 7 by using sodium hydroxide (NaOH) solution. The solid obtained was filtered. The solid mass was dissolved in dichloromethane (DCM) (2000 mL) and washed with brine solution (500 mL). The organic phase was dried over sodium sulfate (Na2S04) and concentrated under vacuum to obtain the title compound. (0277) Weight: 98.3 grams (Yield: 90 percent). 1H-NMR (δ ppm): 3.76 (3H, s), 5.97 - 5.98 (1H, d, J = 1.88 Hz), 6.08 - 6.12 (3H, m), 7.42 - 7.44 (1H, d, J = 8.72 Hz), 10.75 (1H, s); (0279) Mass (m/z): 168.1 (M+H)+.
88%
at 1 - 55℃; for 24.0833 h;
Example 4a; 4-Amino-5-chloro-λ/-[1-(tetrahydro-2H-pyran-4-ylmethyl)-4- piperidinyl]methyl}-1 -benzofuran-7-carboxamide hydrochloride (E4a); The compound of the invention was also prepared according to Scheme 3 as follows: <n="28"/>Stage 1Methyl 4-aminosalicylate4-Amino-2-hydroxybenzoic acid (1.0 eq.) was suspended in 10 vol MeOH (pale brown suspension) at Tout=20oC. The suspension was cooled over 60 min to Ti=1°C. To the suspension was added 2.5 eq. borontrifluoride etherate over 65 min. at Ti=1 to 4°C giving a pale brown solution. The solution was heated to reflux over 3.5 h and kept refluxing for further 19.5 h at Ti=55°C. The reaction mixture was cooled over 2 h to Ti=20°C and stored in an inliner barrel (high density polyethylene coated drum).The work-up procedure was done in two portions as outlined for one portion.To the 160 L reactor was added 10 vol sat. NaHCO3-solution at Tout=20oC. Half of the reaction mixture was charged to the feeding tank from where the solution was added over 50 min. to a sat. NaHCO3-solution to afford a pale brown suspension. The pH was determined via pH-electrode (pH=8.0). The suspension was cooled over 66 min. to Ti=14°C and filtered over a 50 L glass sinter funnel. The mother liquor was collected. The filter cake was washed in two portions with 1.5 vol water and in three portions with 1.5 vol heptane. The filter cake was dried for 18 h under an N2-stream. The filter cake was further dried on the rotary evaporator at Tout=40°C and 16 mbar to afford the title compound in 3.885 kg (42percent uncorr. yield; 99.4percent a/a HPLC).The second batch was worked-up in the same manner to give the title compound in 4.239 kg (46percent uncorr. yield; 100percent a/a HPLC). The overall yield was 88percent (uncorrected).
86%
Stage #1: for 48 h; Cooling with ice; Reflux Stage #2: at 20℃;
To a solution of p-aminosalicyclic acid (15.3 g, 100.1 mmol) in anhydrous methanol (230 ml) was added concentrated H2SO4 (15 ml) slowly in an ice bath with magnetic stirring. The reaction mixture was refluxed for 48 h. After cooling to room temperature, the solvent was evaporated in vacuo. The resulting residue was basified with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was then acidified with dilute HCl and extracted with water. The organic layer was dried over Na2SO4, filtered and concentrated to provide compound 1 (13.8 g, 86percent) as brown powders.Compound 1: Mwt: 167.16; Rf: 0.47 (ethyl acetate:hexane=1:2); 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 3.77 (3H, s, OCH3), 5.98 (1H, d, J=2.1 Hz, Ar H-3), 6.10 (1H, dd, J=6.6, 2.1 Hz, Ar H-5), 6.14 (2H, s, NH2), 7.43 (1H, d, J=8.7 Hz, Ar H-6), 10.76 (1H, s, OH).
81.4%
for 24 h; Reflux
Concentrated sulfuric acid (10 mL) was added to a solution of 4-aminosalicylic acid (30.6 g, 0.2 mol) in methanol (500ml). The reaction mixture was then heated to reflux for 24 h, after which the solvent was removed. The residue was partitioned between EtOAc (1 L) and water (1 L). The organic phase was dried over Na2S04 and evaporated to provide pale solid 202 (27.7 g, 81.4percent). LC-MS (ESI): 168.0 (M+H)+; Purity: >95percent (UV, λ = 254 nm).
77%
Stage #1: at 20℃; for 1 h; Cooling with ice Stage #2: at 60 - 70℃; for 6 h;
Concentrated sulfuric acid (1.25 ml) was added dropwise tomethanol (6 ml) with cooling on a cryostatic bath. The mixture wasstirred for 1 h at room temperature, and 4-ASA (1.53 g, 10 mmol)was added to it. After refluxing at 60e70 C for 6 h, the mixture wasadjusted to pH 7e8 with 10percent Na2CO3 solution in ice-bath. Themixture was filtered to afford crude solid product. The crudeproduct was recrystallized from hot methanol, followed by coolingto 0 C. White crystals were collected and dried under high vacuumto give compound 2 (1.29 g, yield: 77percent). mp: 119e121 C; Rf 0.73in petroleum ether/diethyl ether/ethyl acetate/acetic acid (4/3/3/0.02); IR (KBr): 3260 cm1 phenolic OeH stretching vibration,3474 cm1 and 3380 cm1 NeH stretching bimodal vibration,1638 cm1 NeH bending vibration; 1662 cm1 C]O stretchingvibration, 1284 cm1 CeOeC stretching vibration; 1H NMR (DMSOd6, d ppm): 3.79 (s, 3H, -COOCH3), 6.00 (d,1H, J 2.1 Hz, HeC3), 6.13(dd, 1H, J 8.7 Hz, 2.2 Hz, HeC5), 6.14 (s, 2H, Ph-NH2), 7.46 (d, 1H,J 8.7 Hz, HeC6), 10.77 (s, 1H, Ph-OH); HRMS (ESI): Calcd forC8H9NO3, [M H], 168.0655; Found, 168.0655.
65.7%
for 4 h; Reflux
4-Aminosalicylic acid (10.0 g, 65 mmol) was dissolved in MeOH (200 mL) and was refluxed in the presence of 10 mL concentrated sulfuric acid for 4 h. After the reaction, the solution was concentrated to approximately 20 mL and was neutralized by adding a 10percent NaHCO3 aqueous solution. The crude crystal was filtered and recrystallized from MeOH/H2O (1/1) to obtain methyl 4-aminosalicylate (yield 65.7percent).
Reference：
[1] Patent: WO2013/42135, 2013, A1, . Location in patent: Page/Page column 10; 11
[2] Patent: US2014/187581, 2014, A1, . Location in patent: Paragraph 0091-0094
[3] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 1953 - 1957
[4] Patent: CN107337658, 2017, A, . Location in patent: Paragraph 0039; 0040
[5] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 12, p. 3860 - 3863
[6] European Journal of Medicinal Chemistry, 2016, vol. 116, p. 90 - 101
[7] Patent: WO2016/128990, 2016, A1, . Location in patent: Page/Page column 25
[8] Tetrahedron, 1986, vol. 42, # 12, p. 3259 - 3268
[9] Patent: WO2007/48643, 2007, A1, . Location in patent: Page/Page column 12; 26-27
[10] Tetrahedron, 2003, vol. 59, # 28, p. 5317 - 5322
[11] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 3839 - 3847
[12] Chemistry - An Asian Journal, 2016, vol. 11, # 9, p. 1376 - 1381
[13] Patent: US2012/101157, 2012, A1, . Location in patent: Page/Page column 9
[14] Organic and Biomolecular Chemistry, 2012, vol. 10, # 37, p. 7584 - 7593
[15] Patent: WO2012/149048, 2012, A1, . Location in patent: Page/Page column 88; 89; 97
[16] ChemMedChem, 2013, vol. 8, # 6, p. 904 - 908
[17] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 486 - 494
[18] Tetrahedron Letters, 2007, vol. 48, # 13, p. 2353 - 2356
[19] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2012, vol. 90, p. 72 - 77
[20] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 6, p. 1784 - 1789
[21] Journal of Medicinal Chemistry, 2009, vol. 52, # 9, p. 3112 - 3115
[22] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2657 - 2662
[23] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 2079 - 2084
[24] ChemMedChem, 2018, vol. 13, # 2, p. 186 - 198
[25] Journal of the American Chemical Society, 1949, vol. 71, p. 3564
[26] Journal of the Chemical Society, 1949, p. 1498,1502
[27] Journal of the American Chemical Society, 1949, vol. 71, p. 3564
[28] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
[29] Patent: US2015/266828, 2015, A1, . Location in patent: Paragraph 1017
[30] Patent: WO2017/11323, 2017, A1, . Location in patent: Paragraph 00364-00365
[31] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 188 - 196
[32] Patent: CN107540568, 2018, A, . Location in patent: Paragraph 0022; 0023
17
[ 7664-93-9 ]
[ 65-49-6 ]
[ 4136-97-4 ]
Reference：
[1] Patent: US4933330, 1990, A,
18
[ 1336-21-6 ]
[ 65-49-6 ]
[ 4136-97-4 ]
Yield
Reaction Conditions
Operation in experiment
60%
With sulfuric acid In methanol
EXAMPLE 14 Synthesis of Methyl 4-aminosalicylate (9) To a suspension of 9.18 g (0.06 mole) 4-aminosalicylic acid (7) (Aldrich A7,960-4) in 40 mL of dry methanol was added 8 mL of concentrated sulfuric acid slowly. The mixture was heated under reflux at 70 ° C. for 1.5 hours and then it was cooled in an ice-water bath. Enough concentrated ammonium hydroxide solution was added to adjust the pH to 9 and the precipitate was filtered, rinsed with water and dried to give 6.01 g (60percent) of 9 as a solid, mp 118-120° (ref. 120-121°). Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3473 and 3379 (NH2), 1643 (C=O),1284, cm-1. 1H nmr (90 MHz, CDCI3):δ 10.96 (1H, s, OH), 7.6 (1H; d, 3JH5-H6=9 Hz; H-6), 6.20-6.08 (2H, cm, H-3 and H-5), 4.2 (2H; br s; NH2), 3.87 (3H, s, CH3).
Reference：
[1] Patent: US6482982, 2002, B1,
19
[ 65-49-6 ]
[ 77-78-1 ]
[ 4136-97-4 ]
Reference：
[1] Journal of Medicinal Chemistry, 2010, vol. 53, # 6, p. 2482 - 2493
20
[ 144-55-8 ]
[ 7440-44-0 ]
[ 65-49-6 ]
[ 4136-97-4 ]
Reference：
[1] Patent: US2002/165218, 2002, A1,
21
[ 186581-53-3 ]
[ 65-49-6 ]
[ 4136-97-4 ]
Reference：
[1] Journal of the Indian Chemical Society, 1994, vol. 71, # 6-8, p. 345 - 354
[2] Journal of the Chemical Society, 1949, p. 1498,1502
22
[ 65-49-6 ]
[ 4136-97-4 ]
Reference：
[1] Organic Process Research and Development, 2010, vol. 14, # 1, p. 92 - 98
23
[ 65-49-6 ]
[ 77-78-1 ]
[ 27492-84-8 ]
Yield
Reaction Conditions
Operation in experiment
92.1%
With potassium hydroxide In acetone at 25℃; for 5.5 h; Large scale
(1) the bottle in the four port by adding 2 kg (13.06mol) P-amino-salicylic acid and 2.3 kg (40.10mol) grind garrulous potassium hydroxide, then adding 6 liter acetone solution, and strongly stirring. The temperature dropped to 25 °C, began to gradually dropwise 3 + (31.68mol) of sulfuric acid dimethyl ester. After dropping, to continue reaction 5.5 hours. Reaction-end splines, in addition to evaporating the solvent, and by adding 8 liters of water to dissolve, then using 25 liter of ethyl acetate extracted three times, the final combined ethyl acetate, drying the spin vaporization 2.18 kg of 4-amino-2-methoxy-benzoic acid methyl ester, in the yield of 92.1percent.
92.82%
With sodium hydroxide In acetone at 20℃; for 6 h;
1.1) After adding acetone (118.2 g, 20.37 mol) to a 500 mL three-necked flask,Further adding p-aminosalicylic acid (15.3 g, 0.1 mol) and sodium hydroxide (15.12 g, 0.27 mol), and stirring uniformly to obtain a mixture A;1.2) dimethyl sulfate (32.35g, 0.257mol) was added dropwise to the mixture A obtained in the step 1.1), after the completion of the dropwise addition, the mixture B was obtained;1.3) The mixture B is placed under room temperature conditions, after 6h to obtain a mixture C;1.4) The mixture C obtained in step 1.3) is filtered, the solid obtained after filtration is washed and dried to obtain compound II (yield 92.82percent);The washing process is: first washing with a 5percent sodium hydrogen carbonate solution,Use water again for washing
72%
With tetrabutylammomium bromide; potassium hydroxide In acetone at 25 - 35℃; for 1 h; Industry scale
4-Amino salicylic acid (VI) (2 kg) was added in acetone (12 lit) under stirring. Tetrabutyl ammonium bromide (2.09 kg) was added followed by addition of potassium hydroxide (2.18 kg) and the reaction mass was stirred. To the reaction mass dimethyl sulphate (3.89 kg) was added dropwise at 25-35°C. Stirring was continued at 25-35°C for 60 min. Reaction mass was quenched in prechilled water (30 Lit) at 0-5°C. Reaction mass was stirred and solid obtained by filtration under suction. Solid was washed with water and dried under suction. The wet solid was leached with methanol (2 Lit) at 60-65°C. The reaction mass was cooled to 0-5°C and solid was obtained by filtration, dried under vacuum.Yield : 72percentPurity: 98percent
63.4%
With potassium hydroxide In acetone at 20℃;
[0541| To a stirred solution of 269-1 (20.0 g, 130.68 mmol) in acetone (400 mL) was added KOH (18.4 g, 15 mmol) and (CH3)2S04 (29.4 mL, 318.9 mmol). The mixture was stirred at r.t. overnight. The solvent was evaporated at low pressure, and the residue was dissolved in hot water. The pH was adjusted to 9 with 1 N NaOH solution. After cooling to r.t., the precipitate was filtered off and thoroughly washed with cold EtOAc to give 269-2 as a light yellow powder (23.66 g, 63.4percent). +ESl-MS:m/z 181.8 [M+H]+.
Reference：
[1] Patent: CN105237422, 2016, A, . Location in patent: Paragraph 0018; 0019; 0020
[2] Patent: CN107629001, 2018, A, . Location in patent: Paragraph 0112; 0114-0118; 0148-0154; 0185-0190; 0221-0226
[3] Heterocycles, 2003, vol. 60, # 7, p. 1653 - 1672
[4] Patent: WO2011/158084, 2011, A1, . Location in patent: Page/Page column 10
[5] Patent: WO2015/26792, 2015, A1, . Location in patent: Paragraph 0541
[6] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 2079 - 2084
[7] Archiv der Pharmazie, 1995, vol. 328, # 7-8, p. 585 - 594
[8] Journal of Labelled Compounds and Radiopharmaceuticals, 2001, vol. 44, p. S225 - S227
24
[ 65-49-6 ]
[ 27492-84-8 ]
Reference：
[1] Journal of the Indian Chemical Society, 1994, vol. 71, # 6-8, p. 345 - 354
[2] Chemistry - A European Journal, 2012, vol. 18, # 24, p. 7377 - 7381
25
[ 65-49-6 ]
[ 7206-70-4 ]
Reference：
[1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
[2] Patent: CN105237422, 2016, A,
Reference：
[1] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1960, vol. 8, p. 591 - 597
29
[ 65-49-6 ]
[ 1666-28-0 ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: With hydrogen bromide In water Stage #2: With sodium nitrite In water at 0℃; for 0.5 h; Stage #3: at 0℃; for 1 h;
Reference Example 51 4-Bromosalicylic acid 4-Aminosalicylic acid (15.0 g, 98 mmol) and hydrobromic acid (47 percent, 100 ml) were mixed with water (100 ml).. A solution of sodium nitrite (6.8 g, 98 mmol) in water (50 ml) was added dropwise to the mixture at 0 °C, and the mixture was stirred at the same temperature for 30 minutes.. A mixture of cuprous bromide (16.9 g, 117 mmol) and hydrobromic acid (47percent, 45 ml) was added dropwise to the mixture at 0 °C, and the mixture was stirred at the same temperature for 1 hr.. The reaction mixture was combined with ethyl acetate and extracted.. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated to give the titled compound (15.5 g, 73 percent) as a gray solid.1H-NMR (DMSO-d6) δ: 7.09 (1H, dd, J = 0.9, 8.4 Hz), 7.19 (1H, d, J = 0.9 Hz), 7.69 (1H, d, J = 8.4 Hz), 10.33 (1H, br s).
35%
With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 0℃; for 2.5 h;
t-Butyl nitrite (5.10 g, 49.5 mmol) was added to a suspension of copper(II) bromide (8.80 g, 39.4 mmol) in CH3CN (50 mL), and the reaction mixture was cooled to 0°C in an ice bath. 4- Aminosalicylic acid (5.00 g, 32.7 mmol) was added in small portions over 30 min. Additional CH3CN (20 mL) was added, and the reaction mixture was allowed to stir at 00C for 2 h. The reaction mixture was poured into 20percent HCl (200 mL) and extracted with Et2O (2 x 200 mL). The combined organic phases were washed with 20percent HCl (2 x 100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in Et2O (300 mL) and extracted with 15percent NaOH (2 x 150 mL). The combined aqueous layers were washed with Et2O (100 mL), brought to pH ~1 with 20percent HCl, and extracted with Et2O (3 x 200 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with CHCl3 and collected by filtration, yielding 2.5 g (35percent) of the title compound as a crystalline solid. The material was used without further characterization or purification.
Reference：
[1] Patent: EP1424336, 2004, A1, . Location in patent: Page 136
[2] Patent: WO2006/44775, 2006, A2, . Location in patent: Page/Page column 16
[3] Nippon Kagaku Zasshi, 1957, vol. 78, p. 1608,1612[4] Chem.Abstr., 1959, p. 21342
[5] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 734 - 740
[6] Journal of Chemical Research, Miniprint, 1989, # 12, p. 2826 - 2851
[7] Organic Letters, 2009, vol. 11, # 14, p. 2972 - 2975
[8] Patent: EP1445249, 2004, A1, . Location in patent: Page 128
[9] Patent: EP1577302, 2005, A1, . Location in patent: Page/Page column 113
30
[ 65-49-6 ]
[ 222986-83-6 ]
[ 1666-28-0 ]
Yield
Reaction Conditions
Operation in experiment
21%
With hydrogen bromide; copper(I) bromide; sodium nitrite In water; ethyl acetate
Referential Example 38 2-Hydroxy-4-(4-pyridyl)benzoic acid In water (22.5 ml) and a 47percent aqueous solution of hydrobromic acid (22.5 ml), 4-amino-2-hydroxybenzoic acid (5.04 g) was dissolved. While the resulting solution mixture was maintained at 5° C. or lower, an aqueous solution (water: 15.0 ml) of sodium nitrite (2.26 g) was added dropwise thereto, followed by stirring for 30 minutes under ice cooling. The reaction mixture was added, in portions, to a solution of cuprous bromide (5.63 g) dissolved in a 47percent aqueous solution of hydrobromic acid (15 ml) under ice cooling. The resulting mixture was stirred at room temperature for 150 minutes. Ethyl acetate was added to the reaction mixture for extraction. The organic layer so obtained was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane~10percent methanol-dichloromethane), whereby 4-bromo-2-hydroxybenzoic acid (5.51 g) was obtained as a crudely purified product. The crudely purified product (298 mg) was reacted as in Referential Example 6, whereby the title compound (70 mg, 21percent) was obtained. 1H-NMR (DMSO-d6) δ: 7.30-7.40(2H,m), 7.78(2H,d,J=4.4 Hz), 7.92(1H,d,J=6.3 Hz), 8.69(2H,d,J=5.9 Hz). MS (FAB) m/z: 216 (M+H)+.
21%
With hydrogen bromide; copper(I) bromide; sodium nitrite In water; ethyl acetate
[Referential Example 38] 2-Hydroxy-4-(4-pyridyl)benzoic acid In water (22.5 ml) and a 47percent aqueous solution of hydrobromic acid (22.5 ml), 4-amino-2-hydroxybenzoic acid (5.04 g) was dissolved. While the resulting solution mixture was maintained at 5°C or lower, an aqueous solution (water: 15.0 ml) of sodium nitrite (2.26 g) was added dropwise thereto, followed by stirring for 30 minutes under ice cooling. The reaction mixture was added, in portions, to a solution of cuprous bromide (5.63 g) dissolved in a 47percent aqueous solution of hydrobromic acid (15 ml) under ice cooling. The resulting mixture was stirred at room temperaturefor 150 minutes. Ethyl acetate was added to the reaction mixture for extraction. The organic layer so obtained was washed with water and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane ~ 10percent methanol - dichloromethane), whereby 4-bromo-2-hydroxybenzoic acid (5.51 g) was obtained as a crudely purified product. The crudely purified product (298 mg) was reacted as in Referential Example 6, whereby the title compound (70 mg, 21percent) was obtained. 1H-NMR (DMSO-d6) δ: 7.30-7.40(2H,m), 7.78(2H,d,J=4.4Hz), 7.92(1H,d,J=6.3Hz), 8.69(2H,d,J=5.9Hz). MS (FAB) m/z: 216 (M+H)+.
Reference：
[1] Tetrahedron, 1986, vol. 42, # 12, p. 3259 - 3268
[2] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
[3] Patent: WO2015/26792, 2015, A1,
32
[ 65-49-6 ]
[ 4093-31-6 ]
Reference：
[1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
33
[ 65-49-6 ]
[ 4093-28-1 ]
Reference：
[1] Tetrahedron, 1986, vol. 42, # 12, p. 3259 - 3268
[2] Journal of the Chemical Society, 1949, p. 1498,1502
[3] Journal of the Chemical Society, 1949, p. 1498,1502
[4] Journal of the Chemical Society, 1949, p. 1498,1502
[5] Patent: US2012/101157, 2012, A1,
[6] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
[7] Patent: US2014/187581, 2014, A1,
[8] Chemistry - An Asian Journal, 2016, vol. 11, # 9, p. 1376 - 1381
[9] Patent: WO2016/128990, 2016, A1,
[10] Patent: CN107337658, 2017, A,
[11] Patent: CN107540568, 2018, A,
Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) was suspended in H2SO4 (26 mL, 2.7M) at -50C. Sodium nitrite (1.8 g, 26.1 mmol) in H2O (6.5 mL) was cooled to ice bath temperature and was added dropwise to the aminosalicylic acid mixture over 5 minutes. The resulting suspension was stirred at -5 C for 15 minutes. A solution of KI (6.8 g, 41 mmol) in H2SO4 (13 mL, IM) was added dropwise to the diazonium salt, with considerable evolution of N2. The reaction mixture was heated at 7O0C for 20 minutes. The reaction mixture was then partitioned between H2O and EtOAc. The organic layer was dried and concentrated. Purification by silica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yielded 4-iodosalicylic acid (5.33g, 85-90% pure).
39.8%
In a 0.5 L 3 necked flask, 4-aminosalicylic acid 45 (15.3 g, 100 mmol) was mixed with H2O (100 ml), Conc. H2SO4 (14 ml, 25.8 g, 263 mmol). The mixture was stirred and cooled to 3-5 C. and diazotated by gradual addition of cold solution of NaNO2 (6.9 g, 100 mmol) in 20 ml water with control with iodine:starch paper of excess NaNO2. Dark solution was obtained. The diazotated solution was added to cold solution of KI (26 g, 156.6 mmol) in 25 ml 1N H2SO4. After 1 min, strong and rapid evolution of nitrogen was observed without heating. Ether (10-20 ml) was added to destroy the foam. The beaker with reaction mixture was heated at 75-80 C. for 10 min. The precipitate was filtered and washed with water and dried in air to obtain 17 g of raw product, which was purified by column chromatography: 340 g SiO2, 2% MeOH in CHCl3. 10.5 g, Yield: 39.8%.
35%.
With potassium iodide; sodium nitrite;copper(I) iodide; In sulfuric acid; water;
(b) Preparation of 2-hydroxy-4-iodobenzoic acid: To 20% sulfuric acid solution (650 ml) were added 4-amino-2-hydroxybenzoic acid and 200 ml of 20% sulfuric acid solution. The solution was cooled to -10 C. and a solution of sodium nitrite (47 g, 0.34 mol) in water (100 ml) was added over 5 hours. The solution obtained was added dropwise to a suspension of potassium iodide (69.5 g, 0.42 mol) and copper(I) iodide (69.5 g, 0.36 mol) in 370 ml of 20% sulfuric acid. The mixture was stirred for 36 hours at room temperature and was then filtered. The filtrate was extracted with ethyl acetate, washed twice with saturated sodium sulfite solution and twice with water. The organic phase was concentrated on a rotary evaporator under vacuum at 40 C. The properties of the final product were as follows: White solid. Mass: 24.25 g. Yield: 35%. m.p.: 192 C. 1 H NMR (DMSO, 250 MHz): 7.17 (1H, Ar, d, J=8.25 Hz), 7.25 (1H, Ar, s), 7.42 (1H, Ar, d, J=8.25 Hz).
A suspension of 4-aminosalicylic acid (60.6 g) , water (240 mL), C-H2SO4 (90 mL) and acetic acid (240 mL) was cooled with an ice-bath. A solution of sodium nitrite (30.0 g) in water (60 mL) was added dropwise to the suspension over 30 min and the mixture was stirred at 00C for 1 hr. Then a solution of potassium iodide (200 g) in water (160 mL) was added dropwise over 30 min and the cooling-bath was removed. The mixture was stirred at room temperature for 20 hr, diluted with water and extracted with ethyl acetate (three times) . The extracts were combined, washed with 5% Na2S2Oa solution and brine, dried over MgSO4 and concentrated. The residue was suspended in acetonitrile and collected by filtration to give the title compound as a powder (35.0 g) .1H-NMR (300 MHz, DMSO-d6) delta: 7.30 (dd, J = 8.1, 1.8 Hz, IH), 7.38 (d, J = 1.8 Hz, IH), 7.51 (d, J = 8.1 Hz, IH).
A sample of 4-amino-2-hydroxysalicylic acid (10 g, 65.3 mmol) is charged to a 2 liter Erlenmeyer flask equipped with a large stir bar, cooled in an ice/water bath and treated with concentrated sulfuric acid (20 mL) and enough water to make a free flowing suspension (50 mL). After stirring for 20 minutes, the reaction is treated with a solution of sodium nitrite (4.55 g, 66.0 mmol) in water (20 mL) over the course of 10 minutes. After stirring an additional 3 minutes, the reaction is treated with a solution of potassium iodide (16.9 g, 101 mmol) in water (30 mL) over the course of 15 minutes. The cooling bath is removed and the reaction is carefully monitored and stirred as it generates a significant amount of nitrogen gas. After the reaction subsides, it is briefly heated to 70 C. after which it is allowed to cool to room temperature and sit overnight. The resulting solid is collected by filtration, washed with water and dried to give crude 2-hydroxy-4-iodo-benzoic acid that is used in the next reaction without further purification: ESMS m/z 265.0 (M+H+).
Example 1 Synthesis of 4-[2-(4-carboxy-3-hydroxy-phenyl)ethynyl]-2-hydroxy-benzoic acid (I) Synthesis of Compound 2 11.0 g (72.0 mmol) of 4-aminosalicylic acid (1) was taken in 110.0 ml 50% H2SO4 and cooled to -5 C. and stirred for 20 minutes. To this NaNO2 solution (5.5 g, 80 mmol of NaNO2 in 6.5 ml deionized water) was added drop wise maintaining temperature below 0 C. and stirred for 20 minutes. This diazonium salt solution was added drop wise to the freshly prepared CuI solution* at -5 C. After addition, temperature of the reaction mixture was raised to room temperature and then heated to 90 C. for 1 h. After completion of reaction, the reaction mixture was cooled to room temperature and filtered to obtain yellow solid which was washed with water and dried. This solid was dissolved in hot ethanol and filtered. The inorganic residue remained was washed with ethanol and the filtrate was evaporated to dryness under vacuum to obtain 16.0 g of crude Compound 2 as a brown solid. *(CuI solution: 17.95 g (72.0 mmol) CuSO4.5H2O, 5.5 g (86.0 mmol) Cu-powder and 55.0 g (332.0 mmol) KI were taken in 100.0 ml deionized water. To this 100.0 ml 20% H2SO4 was added with constant stirring. Reaction mixture was allowed to stirred at room temperature for 1 h and then it was cooled to -5 C. CuI gets precipitated out as off-white solid. The above solution of CuI is directly used for the preparation of Compound 2. Yield: 84.6% Analysis: 1H NMR (300 MHz, MeOD): delta 7.48 (d, 1H); 7.24 (d, 1H); 7.19 (dd, 1H). MS (m/z): 263 (M+-H)
Example 1 Synthesis of 4-[2-(4-carboxy-3-hydroxy-phenyl)ethynyl]-2-hydroxy-benzoic acid (I) Synthesis of Compound 2 11.0 g (72.0 mmol) of 4-aminosalicylic acid (1) was taken in 110.0 ml 50% H2SO4 and cooled to -5 C. and stirred for 20 minutes. To this NaNO2 solution (5.5 g, 80 mmol of NaNO2 in 6.5 ml deionized water) was added drop wise maintaining temperature below 0 C. and stirred for 20 minutes. This diazonium salt solution was added drop wise to the freshly prepared CuI solution* at -5 C. After addition, temperature of the reaction mixture was raised to room temperature and then heated to 90 C. for 1 h. After completion of reaction, the reaction mixture was cooled to room temperature and filtered to obtain yellow solid which was washed with water and dried. This solid was dissolved in hot ethanol and filtered. The inorganic residue remained was washed with ethanol and the filtrate was evaporated to dryness under vacuum to obtain 16.0 g of crude Compound 2 as a brown solid. *(CuI solution: 17.95 g (72.0 mmol) CuSO4.5H2O, 5.5 g (86.0 mmol) Cu-powder and 55.0 g (332.0 mmol) KI were taken in 100.0 ml deionized water. To this 100.0 ml 20% H2SO4 was added with constant stirring. Reaction mixture was allowed to stirred at room temperature for 1 h and then it was cooled to -5 C. CuI gets precipitated out as off-white solid. The above solution of CuI is directly used for the preparation of Compound 2. Yield: 84.6% Analysis: 1H NMR (300 MHz, MeOD): delta 7.48 (d, 1H); 7.24 (d, 1H); 7.19 (dd, 1H). MS (m/z): 263 (M+-H)
Stage #1: 4-Aminosalicylic acid With potassium iodide; sodium nitrite In sulfuric acid; water at 5 - 90℃; for 0.666667h;
Stage #2: diazomethyl-trimethyl-silane In tetrahydrofuran; methanol; hexane for 2h;
With pyridine; In dichloromethane; at 60℃; for 4h;
Example 1, General procedure 14- [(biphenyl-3-ylsulfonyl)amino] -2-hydroxybenzoic acidA mixture of <strong>[65685-01-0]3-phenylbenzenesulfonyl chloride</strong> (15 mg, 0.060 mmol) and 4-amino-salicylic acid (8.3 mg, 0.054 mmol) in CH2C12 (200 mu) and pyridine (13 mu, 3 equivs) was stirred at 60 C for 4 h. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (ACE C8, 5u 21x50mm, flow 25ml/min, 50 mM NH4Ac in H20/ MeCN) to give 14.8 mg (74%) of the title compound. MS (ESI+) calcd for Ci9Hi5N05S 369.0671 , found 369.0668 .
5-amino-2-(2'-hydroxy-4'-aminophenyl)benzoxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With phosphoric acid; at 150℃; for 12.0h;
<strong>[137-09-7]2,4-Diaminophenol dihydrochloride</strong> (6.43 g, 32.7 mmol) and 4-amino-2-hydroxybenzoic acid (5.01 g, 32.7 mmol) were mixed in PPA (150 mL) in a 1 L round-bottomed flask. The reaction mixture was heated to 150 C and was stirred for 12 h. The resulting mixture was cooled to room temperature and poured into ice-water with vigorous stirring. The solution was neutralized by adding sodium bicarbonate. The crude product was collected by filtration and was recrystallized in ethanol. Further purification was carried out with column chromatography using an ethyl acetate-toluene mixture as a mobile phase. After evaporation, the product was dried in vacuo (yield: 4.53 g, 37%); 1H NMR (300 MHz, CDCl3-d6): delta = 11.48 (s, OH, 1H), 7.86 (d, Ar-H, 1H), 7.46 (d, Ar-H, 1H), 6.98 (d, Ar-H, 1H), 6.93 (s, Ar-H, 1H), 6.81 (d, Ar-H, 1H), 6.71 (d, Ar-H, 1H), 3.76 (s, NH, 2H), 1.65 (s, NH, 2H).
General Procedure b (Di-benzylation of the salicylic acid). To a stirred solution of 4- aminosalicyclic acid (6.00 g, 39.2 mmol) in DMF (0.1 M) at 0 C, was added KOtBu (4.84 g, 43.2 mmol). After 15 mins, benzyl bromide (5.14 mL, 43.2 mmol) was added drop-wise. The suspension was allowed to stir at R.T. for a further 4 hrs before the reaction vessel was againcooled to 0C. A further 1.1 eqs of K1OBu (2.84g, 43.2 mmol) were added prior to the drop- wise addition of benzyl bromide (5.14 mL, 43.2 mmol). The reaction was then stirred overnight before quenching with 1120. The solution was then repeatedly extracted with ethyl acetate and the organics combined. The organics were then washed with 1120 and brine then concentrated, dried over Na2SO4 and concentrated in vacuo. The resulting residue waspurified using the Biotage Isolera automated column chromotographer in a gradient of EtOAc and Hexane and then dried under reduced pressure.Example 7 - Compound 3c benzyl 4-aminobenzoate Chemical Formula: C 4H13N02 Molecular Weight: 227.26 Compound 3c was synthesized according to general procedure b, yielding the final product 3c as a white solid (82%) .<5H (400 MHz, d-COCh) 4.25 (brs, 2H, NH2), 5.38 (s, 2H, CH), 6.63 (d, J = 8.2 Hz, 2H, CH), 7.33-7.51 (m, 5H, CH), 7.96 (d, J = 8.2 Hz, 2H,CH) ; Sc (100 MHz, d-COC ) 66.1 , 1 13.7, 1 18.9, 127.9, 128.0, 128.7, 131.7, 136.6, 151.5, 166.6; LRMS (ES+) Calcd for [Ci4HBN02 + Na] 250.08 found 250.07.
Intermediate 9 4-[(5-Bromothiophen-2-yl)sulfonyl]amino}-2-hydroxybenzoic acid A mixture of 4-aminosalicylic acid (1.16 g, 7.6 mmol) and 5-bromothiophene-2-sulfonyl chloride (1.0 g, 3.8 mmol) in aqueous dioxane (95 mL dioxane, 5 mL water) was stirred at room temperature for 7 weeks. EtOAc (100 mL) was added. The organic phase was washed with 1 M HCl (3*50 mL), water and brine and then dried over MgSO4, filtered and concentrated. The brown residue was crystallized from water/MeOH at 60 C. The precipitate was collected by filtration and dried in vacuum giving the title compound as a light brown solid (0.64 g, 45%). 1H NMR (500 MHz, DMSO-d6) delta ppm 6.70 (d, J=1.95 Hz, 1H) 6.72 (dd, J=8.55, 2.20 Hz, 1H) 7.33 (d, J=4.15 Hz, 1H) 7.52 (d, J=4.15 Hz, 1H) 7.70 (d, J=8.79 Hz, 1H) 11.11 (s, 1H). MS (ESI+) m/z 378 [M+H]+.
zinc 4-(1,3-dioxooctahydroisoindol-2-yl)-2-hydroxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
This example demonstrates the production of 4-(1 ,3-Dioxo-octahydro- isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a 500 mL four-neck round bottom flask equipped with temperature probe, heating mantle, agitator, and condenser, 21 .20 g of hexahydrophthalic anhydride and 50 mL of acetic acid were charged. At 70 00, the mixture was stirred until uniform and then 21 .7 g of 4-aminosalicylic acid and 100 mL of acetic acid were charged. After heating to reflux for 6 hours, the contents were poured into ice cold Dl H20 and vacuum filtered to collect the solid. After washing with Dl H20 and drying, 33.07 g of product were obtained. This example demonstrates the production of the zinc salt of 4-(1 ,3- dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a beaker, 4-(1 ,3-dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid is suspended in about 100-150 mL of water with a magnetic stirrer. Then, a 25% solution of sodium hydroxide was slowly added until the pH stabilized at 12.5 and the solution became clear. Then, one equivalent of zinc chloride was added (used 1 eq instead of 0.5 because metal ions can coordinate with the meta hydroxy group as well). The products precipitated out, and the mixture was filtered to collect the product.
This example demonstrates the production of 4-(1 ,3-Dioxo-octahydro- isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a 500 mL four-neck round bottom flask equipped with temperature probe, heating mantle, agitator, and condenser, 21 .20 g of hexahydrophthalic anhydride and 50 mL of acetic acid were charged. At 70 00, the mixture was stirred until uniform and then 21 .7 g of 4-aminosalicylic acid and 100 mL of acetic acid were charged. After heating to reflux for 6 hours, the contents were poured into ice cold Dl H20 and vacuum filtered to collect the solid. After washing with Dl H20 and drying, 33.07 g of product were obtained. This example demonstrates the production of the zinc salt of 4-(1 ,3- dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid having the following structure. In a beaker, 4-(1 ,3-dioxo-octahydro-isoindol-2-yl)-2-hydroxy-benzoic acid is suspended in about 100-150 mL of water with a magnetic stirrer. Then, a 25% solution of sodium hydroxide was slowly added until the pH stabilized at 12.5 and the solution became clear. Then, one equivalent of zinc chloride was added (used 1 eq instead of 0.5 because metal ions can coordinate with the meta hydroxy group as well). The products precipitated out, and the mixture was filtered to collect the product.
4-amino-2-hydroxy-N-(prop-2-yn-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N,N-diisopropylcarbodiimide; benzotriazol-1-ol; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h;
General procedure: A mixture of carboxylic acid (3 mmol) and N-hydroxybenzotriazole(1.5 mmol) was dissolved in DMF (8 mL). Propargylaminehydrochloride (3.1 mmol) and triethylamine (3 mmol) were added.The mixture was stirred at room temperature for 5 min, then N,NdiisopropylcarbodiimideHCl (DIC, 3.7 mmol)was added. After 18 hstirring, water (30 ml) was added to stop the reaction. The aqueoussolution was extracted with methylene chloride (4 8 ml) thecombined extract was placed in the refrigerator. After 12 h theformed precipitate was filtrated of, and the solvent was removed.The obtained alkyne was crystallized from ether or used withoutfurther purification.
The present invention uses commercially available <strong>[6018-19-5]sodium aminosalicylate dihydrate</strong> as raw material,After sulfuric acid neutralization of p-aminosalicylic acid.The obtained p-aminosalicylic acid is purified by solvent to obtain a new crystal form of aminosalicylic acid named Form A.
1-(4-fluorophenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)butan-1-one 4-aminosalicylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; dibutyl ether;
A 4-aminosalicylate salt is obtained in screening in a precipitation experiment using methanol. This experiment is repeated at a gram scale. The JTJ-007 free base and 4-aminosalicylic acid (ratio 1:1) are dissolved in methanol (5 mL) and then dibutylether is added as an anti-solvent (lOmL). The mixture is shaken at room temperature and a yellow solid is precipitated. The yellow solid is filtered, dried and analyzed by XRPD. XRPD analysis shows the 4-aminosalicilate salt to be crystalline.
2-hydroxy-4-(2-chloro-4-nitroanilino)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With diacetoxy-platinum; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 110℃;
The 4 - amino salicylic acid 459.42 mg dissolved in 60 ml 1, 4 - dioxane, Xantphos 52.13 mg are added under stirring, CsCO31857 Mg and Pt (OAc)213. 47 Mg, finally adding 2 - chloro -4 - nitro-bromophenylacetic 704.7 mg, in 110 C lower reaction to the full. The solvent is removed under reduced pressure, column chromatography separation obtained after the processing of the yellow solid.
With pyridine; In N,N-dimethyl-formamide; at 30℃; for 24h;Inert atmosphere;
The 4-[2-(2,6-dioxomorpholin-4-yl) ethyl] morpholine-2,6-dione (EDTA-DA) (2.56 g (0.01 mol)), and 4-ASA (3.06 g (0.02 mol)) were combined in 20 mL DMF under nitrogen atmosphere. 8 mL of pyridine (Py) was sequentially added dropwise to the mixed solution. The solid was completely dissolved for 15 min, and the reaction was stirred at 30 C for 24 h. After the reaction was completed, the reaction mixture was poured into CHCl3 to give a white precipitate. The obtained product was collected by filtration under vacuum and washed with anhydrous ethanol. After vacuum drying at 60 C for 5 h, a white powder was obtained. This white powder was dissolved in an appropriate amount of NaOH and then was followed by acidification by adding 0.1 M HCl dropwise. The pure white precipitate of EDTA-ASA was finally obtained by vacuum filtration in a yield of 92%.
General procedure: The title salts were synthesized by the reaction of 1:1 stoichiometricmixtures of 2-amino-4-methoxy-6-methylpyrimidine(34.79 mg, 0.25 mmol) with 4-aminosalicylic acid (38.28 mg,0.25 mmol) or 5-chlorosalicylic acid (43.14 mg, 0.25 mmol) inhot methanol solution (20 ml), after warming over a water bathfor 30 min. The solutions were cooled and kept at roomtemperature.Within a few days, block-shaped brown crystals ofsalt I and colourless needle-shaped crystals of salt II wereobtained by slow evaporation at room temperature. Bothcrystals were suitable for single-crystal X-ray structure analysis
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
