Home Cart 0 Sign in  

[ CAS No. 65-49-6 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 65-49-6
Chemical Structure| 65-49-6
Structure of 65-49-6 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 65-49-6 ]

Related Doc. of [ 65-49-6 ]

Alternatived Products of [ 65-49-6 ]

Product Details of [ 65-49-6 ]

CAS No. :65-49-6 MDL No. :
Formula : C7H7NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :WUBBRNOQWQTFEX-UHFFFAOYSA-N
M.W : 153.14 Pubchem ID :4649
Synonyms :
4-ASA;4-aminosalicylate;Sanipirol-4;PAS;NSC 211698;NSC 2083;p-Aminosalicylic Acid;Aminosalicylic acid;Para-aminosalicylic acid

Calculated chemistry of [ 65-49-6 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 3.0
Molar Refractivity : 39.83
TPSA : 83.55 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.3 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.84
Log Po/w (XLOGP3) : 1.32
Log Po/w (WLOGP) : 0.68
Log Po/w (MLOGP) : -0.7
Log Po/w (SILICOS-IT) : 0.02
Consensus Log Po/w : 0.43

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -1.96
Solubility : 1.68 mg/ml ; 0.011 mol/l
Class : Very soluble
Log S (Ali) : -2.68
Solubility : 0.323 mg/ml ; 0.00211 mol/l
Class : Soluble
Log S (SILICOS-IT) : -0.82
Solubility : 23.1 mg/ml ; 0.151 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.04

Safety of [ 65-49-6 ]

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

Application In Synthesis of [ 65-49-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Upstream synthesis route of [ 65-49-6 ]
  • Downstream synthetic route of [ 65-49-6 ]

[ 65-49-6 ] Synthesis Path-Upstream   1~43

  • 1
  • [ 619-19-2 ]
  • [ 65-49-6 ]
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
  • 3
  • [ 17980-39-1 ]
  • [ 65-49-6 ]
Reference: [1] Patent: US2013/96249, 2013, A1, . Location in patent: Page/Page column
[2] Patent: US2013/96249, 2013, A1, . Location in patent: Page/Page column
[3] Patent: US2013/96249, 2013, A1, . Location in patent: Page/Page column
  • 4
  • [ 6018-19-5 ]
  • [ 65-49-6 ]
Reference: [1] Patent: CN104402749, 2017, B, . Location in patent: Paragraph 0057-0059
  • 5
  • [ 108-46-3 ]
  • [ 65-49-6 ]
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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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,
  • 26
  • [ 65-49-6 ]
  • [ 18107-18-1 ]
  • [ 18179-39-0 ]
Reference: [1] Patent: WO2007/37187, 2007, A1, . Location in patent: Page/Page column 132
  • 27
  • [ 65-49-6 ]
  • [ 18179-39-0 ]
Reference: [1] Patent: US2014/81044, 2014, A1,
[2] Patent: WO2014/45135, 2014, A1,
[3] Patent: US2016/2269, 2016, A1,
  • 28
  • [ 65-49-6 ]
  • [ 345-29-9 ]
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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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] Patent: US6525042, 2003, B1,
[2] Patent: EP1104754, 2001, A1,
  • 31
  • [ 65-49-6 ]
  • [ 4093-29-2 ]
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,
  • 34
  • [ 65-49-6 ]
  • [ 22717-56-2 ]
Reference: [1] Patent: EP1424336, 2004, A1,
  • 35
  • [ 65-49-6 ]
  • [ 71675-87-1 ]
Reference: [1] Patent: WO2011/158084, 2011, A1,
[2] Patent: WO2011/158084, 2011, A1,
  • 36
  • [ 65-49-6 ]
  • [ 57-13-6 ]
  • [ 5985-89-7 ]
Reference: [1] Patent: DE930031, 1953, ,
  • 37
  • [ 65-49-6 ]
  • [ 24190-77-0 ]
Reference: [1] Patent: US2014/187581, 2014, A1,
[2] Patent: WO2016/128990, 2016, A1,
[3] Patent: CN107337658, 2017, A,
[4] Patent: WO2013/42135, 2013, A1,
  • 38
  • [ 65-49-6 ]
  • [ 108282-38-8 ]
Reference: [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
  • 39
  • [ 65-49-6 ]
  • [ 71675-85-9 ]
Reference: [1] Patent: WO2011/158084, 2011, A1,
[2] Patent: WO2011/158084, 2011, A1,
  • 40
  • [ 65-49-6 ]
  • [ 123654-26-2 ]
Reference: [1] Patent: CN107337658, 2017, A,
  • 41
  • [ 65-49-6 ]
  • [ 417721-36-9 ]
Reference: [1] Patent: CN107629001, 2018, A,
  • 42
  • [ 65-49-6 ]
  • [ 205448-66-4 ]
Reference: [1] Patent: CN107629001, 2018, A,
  • 43
  • [ 65-49-6 ]
  • [ 1334493-07-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5605 - 5609
[2] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 11, p. 1102 - 1107
Same Skeleton Products
Historical Records