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Product Details of [ 4136-97-4 ]

CAS No. :4136-97-4 MDL No. :MFCD00088091
Formula : C8H9NO3 Boiling Point : -
Linear Structure Formula :- InChI Key :QQOXBFUTRLDXDP-UHFFFAOYSA-N
M.W : 167.16 Pubchem ID :77787
Synonyms :

Calculated chemistry of [ 4136-97-4 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.12
Num. rotatable bonds : 2
Num. H-bond acceptors : 3.0
Num. H-bond donors : 2.0
Molar Refractivity : 44.15
TPSA : 72.55 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) : -6.15 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.31
Log Po/w (XLOGP3) : 1.65
Log Po/w (WLOGP) : 0.77
Log Po/w (MLOGP) : 0.74
Log Po/w (SILICOS-IT) : 0.5
Consensus Log Po/w : 0.99

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -2.15
Solubility : 1.17 mg/ml ; 0.00702 mol/l
Class : Soluble
Log S (Ali) : -2.79
Solubility : 0.273 mg/ml ; 0.00163 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.53
Solubility : 4.91 mg/ml ; 0.0294 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.31

Safety of [ 4136-97-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 4136-97-4 ]

* 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 [ 4136-97-4 ]
  • Downstream synthetic route of [ 4136-97-4 ]

[ 4136-97-4 ] Synthesis Path-Upstream   1~26

  • 1
  • [ 13684-28-1 ]
  • [ 4136-97-4 ]
YieldReaction ConditionsOperation in experiment
98% With 10% palladium on activated carbon; Degussa type; hydrogen In methanol for 1 h; Step 2:
Preparation of methyl 4-amino-2-hydroxybenzoate (83)
In a 500 ml Parr bottle, methyl 2-hydroxy-4-nitrobenzoate (1.3 g, 6.59 mmol) was added to a suspension of 10percent Pd/C (100 mg) in MeOH (40 ml).
The reaction was shaken under H2 atmosphere (30 psi) for 1 hour.
Catalyst was filtered through a pad of celite and mother liquors were evaporated under vacuum.
Methyl 4-amino-2-hydroxybenzoate was obtained as a yellow solid (1.08 g, 6.46 mmol, 98percent yield, UPLC-MS purity: 100percent, MS/ESI+ 167.9 [MH]+).
Reference: [1] ACS Catalysis, 2014, vol. 4, # 6, p. 1777 - 1782
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3597 - 3600
[3] Patent: US2014/155391, 2014, A1, . Location in patent: Paragraph 0432; 0434
[4] Journal of the Chemical Society, 1949, p. 1498,1502
[5] Proceedings - Indian Academy of Sciences, Section A, 1950, vol. <A> 32, p. 357,362
[6] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 5, p. 1749 - 1761
[7] Patent: US2004/176416, 2004, A1, . Location in patent: Page/Page column 10
[8] Catalysis Science and Technology, 2016, vol. 6, # 15, p. 6137 - 6143
  • 2
  • [ 619-19-2 ]
  • [ 4136-97-4 ]
YieldReaction ConditionsOperation in experiment
98%
Stage #1: With thionyl chloride In methanol
Stage #2: With hydrogen In ethyl acetate
2-Methoxy-4-nitrobenzoic acid (1) in CH2Cl2 (97percent) is reacted with BBr3 to provide the intermediate 2-hydroxy-4-nitro-benzoic acid, which upon treatment with SOCl2 in solvent such as MeOH (95percent), followed by hydrogenation and treatment with 10percent Pd/C in EtOAc (98percent) yields 4-amino-2-hydroxy-benzoic acid methyl ester (2).
Reference: [1] Patent: US2004/176416, 2004, A1, . Location in patent: Page/Page column 8; 9
[2] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3597 - 3600
[3] Journal of the Chemical Society, 1949, p. 1498,1502
[4] Journal of the Chemical Society, 1949, p. 1498,1502
[5] Journal of the Chemical Society, 1949, p. 1498,1502
[6] Patent: US2014/155391, 2014, A1,
  • 3
  • [ 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
  • 4
  • [ 7664-93-9 ]
  • [ 65-49-6 ]
  • [ 4136-97-4 ]
Reference: [1] Patent: US4933330, 1990, A,
  • 5
  • [ 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,
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  • [ 77-78-1 ]
  • [ 4136-97-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 6, p. 2482 - 2493
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  • [ 144-55-8 ]
  • [ 7440-44-0 ]
  • [ 65-49-6 ]
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Reference: [1] Patent: US2002/165218, 2002, A1,
  • 8
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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
  • 9
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  • [ 4136-97-4 ]
Reference: [1] Organic Process Research and Development, 2010, vol. 14, # 1, p. 92 - 98
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  • [ 2597-56-0 ]
  • [ 4136-97-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 20, p. 3597 - 3600
  • 11
  • [ 39614-82-9 ]
  • [ 4136-97-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 5, p. 1749 - 1761
  • 12
  • [ 77-78-1 ]
  • [ 4136-97-4 ]
  • [ 27492-84-8 ]
  • [ 106868-33-1 ]
Reference: [1] Journal of the Indian Chemical Society, 1994, vol. 71, # 6-8, p. 345 - 354
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  • [ 7206-70-4 ]
Reference: [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
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  • [ 18179-39-0 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2010, vol. 31, # 12, p. 3860 - 3863
  • 15
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  • [ 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
  • 16
  • [ 4136-97-4 ]
  • [ 4093-31-6 ]
Reference: [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
  • 17
  • [ 75-36-5 ]
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  • [ 4093-28-1 ]
YieldReaction ConditionsOperation in experiment
99% With sodium hydrogencarbonate In water; ethyl acetate at 0 - 20℃; for 2.25 h; A solution of Methyl 4-amino-2-hydroxy benzoate (50.7 grams, 303.6 mmol, obtained in above step) in ethyl acetate (750 mL) was added to a stirred solution of water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0 °C followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes. The reaction mixture was gradually warmed to room temperature and stirred for 2 hours. The two layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain methyl 4-acetylamino-2-hydroxy benzoate (63.5 grams).Yield: 99 percent.Ή - NMR (CDC13): δ 10.86 (bs, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.23 (s, 1H), 7.16 (bs, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.13 (bs, 1H), 3.92 (s, 3H), 2.19 (s, 3H);Mass (m/z): 208 (M-H)+.
99% With sodium hydrogencarbonate In water; ethyl acetate at 0 - 20℃; for 2 h; A solution of Methyl 4-amino-2-hydroxy benzoate (50.7 grams, 303.6 mmol, obtained in above step) in ethyl acetate (750 mL) was added to a stirred solution of water (250 mL) and sodium bicarbonate (34.9 grams, 415.5 mmol) cooled at 0° C. followed by acetyl chloride (29.7 mL, 415.5 mmol) over a period of 15 minutes.
The reaction mixture was gradually warmed to room temperature and stirred for 2 hours.
The two layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain methyl 4-acetylamino-2-hydroxy benzoate (63.5 grams).
Yield: 99percent.
1H-NMR (CDCl3): δ 10.86 (bs, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.23 (s, 1H), 7.16 (bs, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.13 (bs, 1H), 3.92 (s, 31-1), 2.19 (s, 3H); Mass (m/z): 208 (M-H)+.
87.9% With sodium hydrogencarbonate In water; ethyl acetate at 20℃; for 2 h; Compound 77.1 (2.0 g, 12.0 mmol, 1.0 eq) in EtOAc (30 mL) was added to a cooled solution of NaHCO3 (1.38 g, 16.4 mmol, 1.37 eq) in water (15 mL).
The reaction was stirred for 10 minutes.
Acetyl chloride (1.28 g, 16.4 mmol, 1.37 eq) was added to the mixture over 15 minutes and the reaction was stirred at room temperature for 2 hours.
After completion of the reaction, mixture was quenched with water and extracted with EtOAc.
Organic layers were combined, washed with satd.
NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to obtain crude material.
The crude was purified by trituration with EtOAc and n-hexane to furnish 77.2 (2.2 g, 87.9percent). MS(ES): m/z 209.20 [M+H]+.
Reference: [1] Patent: WO2013/42135, 2013, A1, . Location in patent: Page/Page column 11
[2] Patent: US2014/187581, 2014, A1, . Location in patent: Paragraph 0095-0097
[3] Organic Process Research and Development, 2010, vol. 14, # 1, p. 92 - 98
[4] Patent: US2016/251376, 2016, A1, . Location in patent: Paragraph 0955; 0956; 0957
[5] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2657 - 2662
[6] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 2079 - 2084
[7] Patent: US4857517, 1989, A,
[8] Patent: US4859683, 1989, A,
  • 18
  • [ 108-24-7 ]
  • [ 4136-97-4 ]
  • [ 4093-28-1 ]
YieldReaction ConditionsOperation in experiment
92.4% at 40℃; for 1 h; To a 2 L three-necked flask, 2 (108 g, 0.65 mol) and glacial acetic acid (540 mL) were added, the temperature was raised to 40 ° C after stirring,Acetic anhydride (79.2 g, 0.78 mol) was added dropwise and the reaction mixture was gradually clarified. Bi completed, TLC monitoring, the reaction was added water (1000mL) about 1h,Precipitation of a large amount of solid. After cooling to room temperature, suction filtration,Filter cake was washed with water and dried to give a white solid 125g, yield 92.4percent, purity 99.9percent
86% for 19 h; Cooling with ice To a solution of compound 1b (2.46 g, 15.3 mmol) in anhydrous acetone (25 ml) was added acetic anhydride (3 ml, 31.7 mmol) in an ice bath with magnetic stirring. After being stirred for 19 h, the solvent was evaporated in vacuo, and the solid residue was washed with water and filtered to provide compound 2b (2.74 g, 86percent) as white powders.Compound 2b: Mwt: 209.20; Rf: 0.50 (ethyl acetate:hexane=1:1). 1H-NMR (DMSO-d6, 300 MHz) δ (ppm): 2.06 (3H, s, CH3), 3.85 (3H, s, OCH3), 7.04 (1H, dd, J=6.6, 2.1 Hz, Ar H-5), 7.37 (1H, d, J=1.8 Hz, Ar H-3), 7.70 (1H, d, J=8.7 Hz, Ar H-6), 10.22 (1H, s, ArNH), 10.6 (1H, s, OH).
79% at 1 - 20℃; for 22.9 h; Stage 2; Methyl 4-(acetylamino)-2-hydroxybenzoate; Methyl 4-aminosalicylate (1.0 eq.) was dissolved in 9 vol dichloromethane atTOut=20°C to give a pale brown solution. The solution was cooled over 33 min. toTi=1°C. To the solution was added 1.2 eq. acetic acid anhydride in 2 vol <n="29"/>dichloromethane over 52 min. at Ti=2 to 2.10C. The solution was further stirred at Ti=2.1°C for 30 min., warmed to Ti=20°C over 32 min. and kept stirring at Ti=20°C for 3 h to give a pale brown suspension. After further stirring at Ti=20°C for 18 h the reaction was sampled to reveal 99percent conversion according to HPLC. To the suspension was added 3 vol heptane at Ti=20°C. The suspension was cooled over 49 min. to Ti=IO0C and kept stirring for 32 min. at Ti=IO0C. The suspension was filtered over a glass sinter funnel; the mother liquor was collected and washed in two portions with 2 vol water and 2 vol heptane. The filter cake was dried on the sinter funnel under N2-stream for 2.5 h. The filter cake was further dried on the rotary evaporator at Tout=40oC and 17 mbar to afford the title compound in 3.463 kg (36percent uncorr. yield; 100percent a/a HPLC). The second portion was dried on the rotary evaporator at Tout=40oC and 16 mbar to afford the title compound in 4.225 kg (43percent uncorr. yield; 100percent a/a HPLC). The overall yield was 79percent (uncorrected).
72.4% at 0 - 10℃; for 4 h; Acetic anhydride (Ac20) (66.50 mL, 0.704 mole) was added drop wise to a stirred solution of methyl 4-amino-2-hydroxy benzoate (98 grams, 0.586 mole, obtained in the above step) in DCM (980 mL) at 0 °C. Then reaction mass was slowly brought to 10 °Cand stirred for 4 hours at the same temperature, while monitoring the progress of the reaction by TLC. Reaction mass was poured into chilled water (1000 mL) and stirred for 30 minutes. The solid obtained was filtered and dissolved in ethyl acetate (EtOAc) (1000 mL). The organic phase was washed with brine solution (500 mL), dried over Na2SO4 and concentrated under vacuum to obtain the title compound.Weight: 88.8 grams (Yield: 72.4 percent).1H - NMR (δ ppm): 2.03 (3H, s), 3.82 (3H, s), 7.00 - 7.03 (1H,dd, 3 8.68, 1.60 Hz), 7.33- 7.34 (1H, d, J = 1.72 Hz), 7.66 - 7.68 (1H, d, J = 8.72 Hz), 10.18 (1H, bs), 10.57 (1H, s); Mass (m/z): 210.2 (M+H).

Reference: [1] Tetrahedron, 1986, vol. 42, # 12, p. 3259 - 3268
[2] Chemistry - An Asian Journal, 2016, vol. 11, # 9, p. 1376 - 1381
[3] Patent: CN107337658, 2017, A, . Location in patent: Paragraph 0041; 0042
[4] Patent: US2012/101157, 2012, A1, . Location in patent: Page/Page column 9
[5] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 3839 - 3847
[6] Patent: WO2007/48643, 2007, A1, . Location in patent: Page/Page column 12; 27-28
[7] Patent: WO2016/128990, 2016, A1, . Location in patent: Page/Page column 25-26
[8] Journal of the Chemical Society, 1949, p. 1498,1502
[9] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
  • 19
  • [ 127-09-3 ]
  • [ 4136-97-4 ]
  • [ 4093-28-1 ]
YieldReaction ConditionsOperation in experiment
95.2% at 35 - 40℃; for 2 h; Enzymatic reaction (136.8 g, 1.0 mol) sodium acetate trihydrate was added to the reaction solution of methyl p-amino salicylate, the pH of the reaction solution was controlled at 6.5-7.5 with 10percent sodium carbonate or 10percent acetic acid, and the temperature was controlled at 35-40°C. Then, 40.0g of acetylase was added, the temperature and pH were strictly controlled, the reaction was carried out for 2 hours and the reaction was completed. The methanol was recovered under reduced pressure, and 500 g of ethyl acetate was added to the mother liquor for extraction, then carried out liquid separation, drying and concentration, followed by crystallization under reduced pressure, suction filtration, and drying at 50° C to obtain 199.2 g of Methyl p-acetaminosalicylate. The yield was 95.2percent and the purity was 99.1percent
Reference: [1] Patent: CN107540568, 2018, A, . Location in patent: Paragraph 0022; 0024
  • 20
  • [ 4136-97-4 ]
  • [ 4093-28-1 ]
YieldReaction ConditionsOperation in experiment
82% With hydrogenchloride; acetic anhydride In water EXAMPLE 15
Synthesis of Methyl 4-acetamidosalicylate (10)
To a suspension of 4.17 g (0.025 mole) methyl 4-aminosalicylate (9) in 20 mL water, was added 3 mL (0.032 mole) acetic anhydride (Aldrich 11,004-3) while stirring.
The mixture was heated at 800 for 30 minutes and cooled to room temperature.
The precipitate was collected and added into 100 ml of 10percent hydrochloric acid.
This suspension was stirred at room temperature for 10 minutes, filtered and dried to give 4.3 g (82percent) of a crude solid, which was recrystallized from H2O/CH3OH, yielding 3 g (70percent) of 10 as white crystals, mp 153-154.
Infrared (IR) and NMR analysis gave the following results: IR (potassium bromide): 3319(NH), 1680 (C=O),1604, 1157 cm-1. 1H nmr (90 MHz, CDCI3 +DMSO-d6):δ 10.80 (1H, S, OH), 9.74 (1H, br s, NH), 7.73 (1H; d, 3JH5-H6=9 Hz; H-6), 7.37 (1H; d, 4JH5-H3=1.8 Hz; H-3),7.11 (1H; dd, 3JH6-H5=9HZ, 4JH3-H5=1.8 Hz; H-5), 3.91 (3H; s; OCH3), 2.15 (3H, s, CH3).
Reference: [1] Patent: US4933330, 1990, A,
[2] Patent: US6482982, 2002, B1,
  • 21
  • [ 4136-97-4 ]
  • [ 27475-11-2 ]
Reference: [1] Journal of medicinal chemistry, 1970, vol. 13, # 4, p. 674 - 680
  • 22
  • [ 4136-97-4 ]
  • [ 5985-89-7 ]
Reference: [1] Acta Chemica Scandinavica (1947-1973), 1948, vol. 2, p. 220,222
  • 23
  • [ 4136-97-4 ]
  • [ 24190-77-0 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 22, p. 2657 - 2662
[2] Patent: US2014/187581, 2014, A1,
[3] Patent: WO2016/128990, 2016, A1,
[4] Patent: CN107337658, 2017, A,
[5] Patent: WO2013/42135, 2013, A1,
  • 24
  • [ 4136-97-4 ]
  • [ 108282-38-8 ]
Reference: [1] Letters in Drug Design and Discovery, 2012, vol. 9, # 5, p. 489 - 493
  • 25
  • [ 4136-97-4 ]
  • [ 123654-26-2 ]
Reference: [1] Patent: CN107337658, 2017, A,
  • 26
  • [ 4136-97-4 ]
  • [ 201214-53-1 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1997, vol. 45, # 12, p. 2079 - 2084
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