509074-26-4|4-(5-Methyl-3-phenylisoxazol-4-yl)benzene-1-sulfonyl chloride| Ambeed

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Quality Control of [ 509074-26-4 ] Purity: 97% SDS Specification

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Product Details of [ 509074-26-4 ]

CAS No. :	509074-26-4
Formula :	C₁₆H₁₂ClNO₃S
M.W :	333.79
SMILES Code :	O=S(C1=CC=C(C2=C(C)ON=C2C3=CC=CC=C3)C=C1)(Cl)=O
MDL No. :	MFCD26385552
InChI Key :	NVKQPOHDVWNXRP-UHFFFAOYSA-N
Pubchem ID :	9880756

Safety of [ 509074-26-4 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H314
Precautionary Statements:	P260-P280-P303+P361+P353-P301+P330+P331-P304+P340+P310-P305+P351+P338+P310
Class:	8
UN#:	3261
Packing Group:	Ⅲ

Computational Chemistry of [ 509074-26-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	22
Num. arom. heavy atoms	17
Fraction Csp3	0.06
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	85.42
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	68.55 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.81
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	4.08
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	5.33
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.59
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.85
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.73

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.85
Solubility	0.00467 mg/ml ; 0.000014 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-5.22
Solubility	0.00199 mg/ml ; 0.00000596 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-7.17
Solubility	0.0000225 mg/ml ; 0.0000000673 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	No
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.44 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	3.15

Application In Synthesis of [ 509074-26-4 ]

* 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.

Downstream synthetic route of [ 509074-26-4 ]

[ 509074-26-4 ] Synthesis Path-Downstream 1~35

1
[ 181696-73-1 ]
[ 509074-26-4 ]

Yield	Reaction Conditions	Operation in experiment
13.6 g (79.4 wt%)	With chlorosulfonic acid; trifluoroacetic acid; In n-heptane; water; toluene;	EXAMPLE 5 Preparation of 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonyl chloride, 6. 4,5-dihydro-5-methyl-3,4-diphenyl-5-isoxazolol (13.0 grams, 0.0513 mol) was charged to a 200 mL jacketed flask which was cooled with 0.2 C. jacket fluid. Trifluoroacetic acid (9.1 mL, 0.118 mol) was charged to the solids to provide a solution at 38.6 C. The solution was cooled to 2.1 C. and chlorosulfonic acid (34.7 mL, 0.522 mol) was added slowly while maintaining the temperature below 14 C. The solution was heated to 60 C., held for 2.5 hours, cooled to 20 C., and transferred to a 125 mL addition funnel. Toluene (52 mL) and water (52 mL) were charged to the 200 mL jacketed reactor, and cooled to 4 C. The reaction solution was then added slowly to the 200 mL jacketed reactor while maintaining the temperature below 20 C. The multi-phase mixture was warmed to 20 C., and transferred to a 250 mL separatory funnel. Toluene (50 mL) and water (10 mL) were added and the mixture was shaken. Settling of the mixture resulted in two cloudy phases. The toluene phase was washed twice with 15 mL of water, transferred to a 250 mL flask with a 20 mL toluene rinse, and vacuum distilled to 17.4 g of an oil. After initiating crystallization with a glass rod and cooling, heptane (20 mL) was added to the crystalline mass which was broken up to form a powder. The off white powder was collected by filtration. Portions of 50 mL of heptane were used to aid the transfer of solids to the filter. The cake was dried in a vacuum oven (35 C.) to provide 13.6 g (79.4 wt %) of the sulfonyl chloride as an 85:15 mixture of the para and meta isomers. HRMS Calculated for (M+1) C16H13NO3Cl: 334.0305; Found (M+1): 334.0309.

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 775 - 777.
[2]Patent: US2003/105334,2003,A1 .
[3]Patent: EP1223167,2002,A2 .Location in patent: Page 23.

2
[ 509074-26-4 ]
[ 181695-72-7 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With ammonia; In ethyl acetate; at 20 - 25℃; for 2h;	Add 80mL of dichloromethane to the reaction bottle, add compound I11.76g, add formic acid 4.60g, add chlorosulfonic acid 58.26g dropwise at a temperature control of 10-20 C, dropwise finish after 15min, then stir for 15min, add potassium carbonate 27.64g, add Sodium iodide 1.18g, heated to 35-45 C, and the reaction was completed after 1h by TLC (developing agent n-heptane: ethyl acetate = 4: 1, compound I Rf = 0.9, compound II Rf = 0.7). Add the reaction dropwise to the purified water at 0 5 , and control the temperature to be below 20 during the dropwise addition. After the dropwise addition, add 60mL of ethyl acetate and stir for 10min, let stand for 30min, separate the liquid, and wash the organic phase once with purified water. A solution of compound II in ethyl acetate was obtained, and 32.93 g of 25% -28% concentrated ammonia solution was added. The temperature was controlled at 20-25 C and stirred for 2 h. The reaction was monitored by TLC (developing agent n-heptane: ethyl acetate = 2: 1, (Rf of compound II = 0.9, Rf of compound III = 0.4), stand for 30 minutes, separate the layers, wash the organic phase twice with purified water, evaporate the solvent under reduced pressure at 50 C, and add 80 mL of absolute ethanol-methanol (10 : 1), heated to 60 , stirred until dissolved, slowly cooled to 0 ~ 5 , stirred and crystallized for 1h, suction filtered, vacuum dried at 55-60 for 8h, to obtain 14.59g compound III, yield 92.8% , HPLC detection purity 99.8%, the largest single impurity 0.08%.
88.9%	With ammonia; In dichloromethane; at 5 - 30℃; for 1h;	Add Intermediate III (33.4g/0.1mol) and dichloromethane (100g) into the reaction flask, lower the temperature to 5-10, add 25% ammonia (70g/0.5mol) dropwise, control the temperature not to exceed 20, dropwise After the addition is complete, the temperature is raised to 20-30C and stirred for 1 hour; the temperature is lowered to 0-5C, and after stirring for 2 hours, suction filtration is carried out, and the filter cake is rinsed with 20 g of dichloromethane and 20 g of water respectively.The filter cake was dried by blowing at 70C for 16 hours to obtain Intermediate IV (27.9g) with a yield of 88.9%.
80%		Charged 120 lit. of methylene chloride 20 kg of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride into reactor and stirred the reaction mass for 5 to 10 minutes till the dissolution. 1 kg of carbon was charged into above solution, stirred for 30-45 minutes, filtered, and washed with 40ml of methylene chloride. The combined filtrate was charged into reactor and 90 lit. of ammonia solutions were added into the filtrate at 20-30C for 60-90 minutes. Distilled methylene chloride at atmospheric pressure below 40C upto 300 to 340 lit. volume left in the reactor. The reaction mass was cooled to 5-10C and stirred for 30-45 minutes and filtered and washed with 20 lit. methylene chloride. The resultant wet cake was pressed under Nitrogen for 30-45 minutes. The wet material was charged into reactor and 100 lit. of water were added into reactor and stirred for 45-60 minutes and filtered, pressed the wet cake under nitrogen for 15-20 minutes followed by washing with 20 lit. of water. Again wet cake was pressed under nitrogen for 30-45 minutes. The resultant compound was dried under vacuum for one hours at 25-35 C and further dried at 80-85 C for 1 hours to afford the title compound.(Yield 15kg,80%).

77%	With ammonium hydroxide; In dichloromethane; at 10 - 50℃;Cooling with ice;	The system was added dropwise to 1200 ml of ice water.Temperature control is about 10 degrees,Liquid separation extraction,The organic phase is washed twice with water.The organic phase is stirred with ammonia (700 ml) at room temperature.The dot plate shows that the reaction is complete,(PE: EA=4:1),The organic phase is removed by a 50 C rotary steaming system.The remaining system was added with 2 L of ethyl acetate.1L of water is stirred until it is dissolved.Liquid separation extraction,The aqueous phase was back extracted with ethyl acetate.Combine the organic phase,Wash with purified water,The organic phase was removed by rotary evaporation to give a crude material.Add 1L of ethanol,Heat to dissolve,Recrystallization,Filtered to give a crude product (350g).The final product 310 g (986.13 mmol) was obtained (HPLC > 99.5%).White solid, yield 77%.
	With ammonia; In water monomer; at 20 - 60℃;Product distribution / selectivity;	EXAMPLE 2 25 ml of 19.5% w/v aqueous ammonia solution were added slowly to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride (5 grams) in water (25 ml) at 25-35 C. The reaction mass was heated to 55-60 C. and stirred at this temperature until completion of the reaction. The reaction mass was cooled to about 20-30 C. The solid was filtered and washed with water (30 ml). The compound was suction dried under reduced pressure followed by drying at 25-35 C. under reduced pressure to obtain the desired crystalline Form A of valdecoxib. The yield of the compound was 4.2 grams.
	With ammonia; In dichloromethane; water monomer; at 25 - 30℃; for 0.583333 - 0.75h;Product distribution / selectivity;	EXAMPLE 1; 25 ml of 19.5% w/v aqueous ammonia solution were added slowly to a solution of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride (5 grams) in dichloromethane (50 ml) at 25-30 C. 0.5 grams of crystalline Form A of valdecoxib (as seeding material) was charged to the reaction mass at 25-30 C. and the reaction mass was stirred for 35-45 minutes. The separated solid was filtered and washed with dichloromethane (5 ml). The compound was suction dried under reduced pressure followed by drying at 35-40 C. under reduced pressure to obtain the desired crystalline Form A of valdecoxib. The yield of the compound was 4 grams and the X-ray diffraction pattern for the product is shown in FIG. 1.
	With ammonia; In water monomer; at 0℃; for 1h;Product distribution / selectivity;	Example 16: 4-f3-Methyl-5-phenyl-4-isoxazolyllbenzenesulfonamide (valdecoxib, 19).; A solution of 5-methyl-3,4-diphenyl isoxazole 18 (250 mg, 1.1 mmol) in chlorosulfonic acid (1 ml) was stirred at 0C for 3 hours. The reaction was cautiously added to concentrated ammonium hydroxide (6 ml) in the cold (0C). The resultant reaction mixture was stirred at 0C for 1 hour. The reaction was cautiously diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo to give the crude product. This material was chromatographed on silica gel using 25% ethyl acetate in toluene as the eluent to give the desired sulfonamide as a crystalline solid (110 mg, 40% yield of 19) : mp 85 - 87C. Anal. Calc'd. for C16H14N2O3 S: C, 61.13; H, 4.49; N, 8.91; S, 10.20. Found: C, 60.88; H, 4.61; N, 8.55; S, 10.40.
	With ammonia; In dichloromethane; at 0℃; for 1h;	EXAMPLE 4 4- (5-Methyl-3-phenyl-4-isoxazolyl) benzenesulfonamide (step 3) Charged 400 ml of dichloromethane in a dry 1L four neck round bottom flask, into this 7.8 g of sulfonyl chloride from example 3 (0.02296 mol) was added at room temperature and stirred well. Reaction mass cooled to 0C and ammonia gas was purged for an hour, during this white solid was formed in the reaction mass. After one hour analysed by HPLC showed completion of reaction. Reaction mass allowed to come to room temperature and dichloromethane layer is washed thrice with water (3 x 100 ml). Dried over anhydrous sodium sulfate and filtered. Dichloromethane is distilled to obtain a one fourth of the initial volume and then cooled to 0 to 5C to get the product crystallised. The product is then filtered and washed with pre-cooled dichloromethane (2 x 10 ml) and the product dried under vacuum at 60 to 70C to obtain a crystalline product (5.6 g, HPLC purity = 99. 7%).
	With ammonium hydroxide; In dichloromethane; at 20 - 30℃;Large scale;	The 3.0 kg 5 - methyl - 3, 4 - diphenyl isoxazole added to the 30 L glass reaction flask, then adding 9.9 kg methylene chloride, stirring to dissolve, cooling the solution to - 5 - 0 C, to the reaction solution slowly dropping 15.0 kg chloro sulfonic acid and temperature control ≤ 20 C, after dropping, water bath heating to 35 C insulation reaction 4 - 5 of H, then the reaction liquid cooling to 0 - 5 C.The 15.9 kg methylene chloride and 12.0 kg purified water by adding another 50 L in the reaction bottle, cooling to 0 - 5 C, slowly dropping has cooling of the reaction fluid and temperature control ≤ 20 C, after dropping stirring 0.5 h; layered, for methylene chloride level (the upper layer) 12.0 kg (25% w/w) saturated sodium chloride solution agitation washing, the delaminated, taking methylene chloride level (lower) spare; to the 50 L reaction flask add 5.4 kg concentrated ammonia water, then slowly adding the dichloromethane layer solution, at room temperature (20 - 30 C) stirring the reaction 2 - 3 H of the; added to the reaction solution after 11.7 kg isopropanol, 35 C thermal insulation to continue stirring 1.5 h, then cooled to 15 - 20 C, stirring crystallization 6 h, then adding, for material 2.4 kg of cold isopropanol washing, 60 C drying under atmospheric pressure 5 - 10 the H, get-cutting to past cloth thick 3.1 kg; will-cutting to past cloth thick 3.1 kg and 7.36 kg methanol by adding 30 L glass reaction flask, stirring under heating to 60 - 70 C reflux, filtered to remove insoluble matter, then adding 3.1 kg purified water, the temperature slowly drops to 15 - 20 C, stirring crystallization 6 h, filtered, in order to 3.1 kg cold methanol/water (V/V=3:1, W/W=2.37: 1) in the solution, 60 C drying under atmospheric pressure 5 - 10 the H, get-cutting to [...] 2.2 kg.
5.73 kg	With ammonium hydroxide; In dichloromethane; at 0 - 30℃; for 1h;	20kg of ammonia water was added to the reactor, and the dichloromethane solution of 6.0kg of Intermediate I (prepared by Example 2) was added dropwise at 0-15C for temperature control (6.0kg of Intermediate I was dissolved in 9.1kg of dichloromethane). After dropping, the temperature was raised to 25-30C for 1 hour. 28kg of purified water was added, and stirring was continued for 1 hour at 25-30C. Centrifuge, wash with purified water, and dry to obtain 6kg of crude product. Add 30kg of ethanol with a water content of 5%, be warming up to 70-80C to dissolve, cool to 20-25C for crystallization for 1 hour, centrifuge, rinse with 1.2kg of absolute ethanol, and dry to obtain 5.73kg of white solids, namely for valdecoxib. The purity is 99.6% (see Figure 2 for details).

References: [1]Patent: CN111100084,2020,A .Location in patent: Paragraph 0038-0045.
[2]Patent: CN112661713,2021,A .Location in patent: Paragraph 0025; 0030; 0033; 0038; 0041; 0046.
[3]Patent: EP1550658,2005,A1 .Location in patent: Page/Page column 7.
[4]Synthetic Communications,2012,vol. 42,p. 639 - 649.
[5]Patent: CN105726496,2019,B .Location in patent: Paragraph 0054; 0055; 0056.
[6]Patent: EP1223167,2002,A2 .Location in patent: Page 23.
[7]Journal of Medicinal Chemistry,2000,vol. 43,p. 775 - 777.
[8]Patent: US2005/272787,2005,A1 .Location in patent: Page/Page column 2.
[9]Patent: US2005/272787,2005,A1 .Location in patent: Page/Page column 2.
[10]Patent: WO2005/123701,2005,A1 .Location in patent: Page/Page column 38-39.
[11]Patent: WO2005/85218,2005,A1 .Location in patent: Page/Page column 10.
[12]Patent: CN107137361,2017,A .Location in patent: Paragraph 0031-0033.
[13]Green Chemistry,2022,vol. 24,p. 1983 - 1988.
[14]Patent: CN113845488,2021,A .Location in patent: Paragraph 0047; 0082-0083.

3
[ 952-06-7 ]
[ 509074-26-4 ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 775 - 777.
[2]Patent: EP1223167,2002,A2 .

4
[ 23356-96-9 ]
[ 509074-26-4 ]
((2S)-1-[4-(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl}pyrrolidin-2-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	In tetrahydrofuran; at -78 - 20℃; for 6h;	4-(5-Methyl-3-phenylisoxazol-4-yl) benzenesulfonyl chloride (200 mg, 0.60 mmol) was dissolved in THF (3 ml) and the solution was cooled to-78C. After S- (-)-prolinol (182 mg, 1.80 mmol) was added to the solution, the mixture was gradually warmed to room temperature and stirred at room temperature for 6 hours. Ethyl acetate (8 ml) was added thereto, and the mixture was washed with water (3 ml) and subsequently with brine (2 ml), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-> 1: 1) to give ((2S)-1-[4- (5-methyl-3-phenylisoxazol-4-yl)- phenyl] sulfonyl} pyrrolidin-2-yl) methanol (232 mg, 97%) as a liquid. MS: 399 [M+H] +, APCI (MeOH)

References: [1]Patent: WO2005/37271,2005,A2 .Location in patent: Page/Page column 115-116.

5
[ 7790-94-5 ]
[ 37928-17-9 ]
[ 509074-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃; for 12h;Heating / reflux;	Example 5 Preparation of 3-PHENVL-4- (4-CHLOROSULFONYL-PHENVL)-5-METHYL-ISOXAZOLE (II) 6.65 g (0.1 mol) CHLOROSULFONIC acid was dissolved in 50 mi of anhydrous dichloro methane. The solution was cooled to 0 C'and solution of 4.7 g (0.02 mol) 3,4- diphenyl-5-methyl-isoxazole in 20 ml of anhydrous dichloro methane was added. The reaction mixture was stirred for 2 hours at room temperature and for another 10 hours at boiling point. The solvent was evaporated and the residue was poured onto 50 g of ice. This suspension was extracted twice with 40 ml of ethyl acetate. The combined organic phase was extracted 50 ml of water, dried over anhydrous MAGNESIUMSULFATE. After filtration and evaporation the residue was dissolved in hot cyclohexane and cooled to +15 C FOR crystallization. The precipitated product (4g) was filtered and RECRYSTALLIZED from 50 ml of cyclohexane to afford the title compound (II) (3.7 g; mp.: 106-107 C).

References: [1]Patent: WO2005/7620,2005,A2 .Location in patent: Page/Page column 15-16.

6
[ 509074-26-4 ]
N-hydroxy-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamidee monohydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With hydroxylamine hydrochloride; In 1,4-dioxane; water; at 10℃; for 3h;Product distribution / selectivity;	Example 1 N-HYDROXI-4 (3-PHENVL-5-METHVL-ISOXAZOLE-4-VLL-BENZENESULFONAMIDE monohydrate A. 6.88 g (0.099 mol) hydroxylamine-hidrochloride was suspended in 50 mi dioxane, cooled to +10 C AND was added solution of 8.1 g (0.099 mole) sodium acetate in 25 ml water. Solution of 11 g (0.033 mole) 3-phenyl-4- (4-chloro-sulfonyl-phenyl)- 5-methyl-isoxazole in 50 mi dioxane was added during 30 minutes. The mixture was stirred for 30 minutes and was added to 500 ml of water and the suspension was shaken for 2 hours. The crude product was dissolved in ethyl acetate (200 ml) and the solution was extracted with 5 % aqueous solution of ETHYLENEDIAMINETETRAACETIC acid disodium salt (40 ML), then with water (40 ML) and finally with brine (20 ML). The solution was evaporated in vacuo. The residue was dissolved in ethanol (90 ML), DECOLORIZED by activated carbon (1 g), filtered and water (270 ML) containing ascorbic acid (3 g) was added to the solution at 60 C. The solution was cooled (+ 5 C) and the precipitated product was filtered, washed with water and dried to afford the title compound (7.8 g; 68 %; mp: 95- 110 C) H NMR (DMSd6, 30 C, 6TMS : 0. 00 ppm): 2.49 s (3H); 7.33-7. 52 m (7H) ; 8.82-7. 88 m (2H); 9.67 s (2H). The purity was 99.9 % by HPLC.
54%	With hydroxylamine;tetra(n-butyl)ammonium hydrogensulfate; In water; ethyl acetate; at 20℃; for 8 - 20h;Product distribution / selectivity;	B. 5.4 g (0.016 mol) of 3-PHENYL-4- (4-CHLOROSULFONYI-PHENYL)-5-METHYL-ISOXAZOLE was dissolved in 65 ml of ethyl acetate. 2.3 ml (0,035 mol) of 50 % aqueous solution of hydroxylamine and 0.3 g of TETRABUTYLAMMONIUM HYDROGENSULFATE in water (65 ML). The reaction mixture was stirred at room temperature for 8-20 hours. Ethyl acetate (150 ML) and water (150 ml) were added to the reaction mixture. The organic phase was separated and dried over sodium sulfate, then the solution was evaporated under reduced pressure. The residue (4.9 g) was dissolved in 70 ml of ethanol and after decolorization by activated carbon the solution was filtered. Water (210 ml) was added to the solution and the crystalline product was filtered, washed with water and dried. Yield 3.0 g (54 %).

References: [1]Patent: WO2005/7620,2005,A2 .Location in patent: Page/Page column 13-14.
[2]Patent: WO2005/7620,2005,A2 .Location in patent: Page/Page column 14.

7
[ 37928-17-9 ]
[ 509074-26-4 ]

Yield	Reaction Conditions	Operation in experiment
59.15%	With sulfonic chloride acid; In dichloromethane; at 0 - 10℃; for 9 - 11h;Heating / reflux;	75 lit. of methylene chloride was added into reactor and cooled to 10-15C and added slowly 98.00 kg of chlorosulfonic acid. To this, solution of 3, 4 - Diphenyl-5- methyl isoxazole in 50 lit. of methylene chloride was added slowly to the reaction mass at 0-10Cand heated to reflux for 9-11 hours. The reaction mass was cooled to 25-35C. The resultant reaction mass was added slowly to the chilled water (175 lit.) at 0-10C, and temperature of reaction mass was raised to 25-35 C. Aqueous and organic layer were separated, and aqueous layer was extracted with 125 lit of methylene chloride in two lots. The combined organic layer was washed with 575 lit water in three lots. The combined organic layer was charged into a reactor and distilled of methylene chloride below 60C. The resultant crude solid was dissolved in 250 lit. of cyclohexane and heated to reflux for 30-45 minutes. 75 lit. of water was added to the reaction mass and again heated to reflux for 15-30 minutes. The reaction mass was settled. Organic and bottom aqueous layer were separated. Organic layer was cooled to 25-35C and maintain at 25-35C for 45-60C and filtered and washed with cyclohexane. This step was repeated twice. Finally the wet compound was dried at 50-55 C to afford the title compound.(Yield 21.3kg, 59.15%).
	With sulfonic chloride acid; at 0℃; for 3h;Product distribution / selectivity;	Example 16: 4-f3-Methyl-5-phenyl-4-isoxazolyllbenzenesulfonamide (valdecoxib, 19).; A solution of 5-methyl-3,4-diphenyl isoxazole 18 (250 mg, 1.1 mmol) in chlorosulfonic acid (1 ml) was stirred at 0C for 3 hours. The reaction was cautiously added to concentrated ammonium hydroxide (6 ml) in the cold (0C). The resultant reaction mixture was stirred at 0C for 1 hour. The reaction was cautiously diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo to give the crude product. This material was chromatographed on silica gel using 25% ethyl acetate in toluene as the eluent to give the desired sulfonamide as a crystalline solid (110 mg, 40% yield of 19) : mp 85 - 87C. Anal. Calc'd. for C16H14N2O3 S: C, 61.13; H, 4.49; N, 8.91; S, 10.20. Found: C, 60.88; H, 4.61; N, 8.55; S, 10.40.
7.07 g (100 wt%)	With sulfonic chloride acid; trifluoroacetic acid; In n-heptane; water monomer; toluene;	EXAMPLE 6 Preparation of 4-(5-methyl-3-phenyl-4-isoxazolyl)benzenesulfonyl chloride, 6. 5-methyl-3,4-diphenyl isoxazole (5.0 g, 0.0213 mol) was charged to a 100 mL jacketed reactor which was cooled with 0.2 C. jacket fluid. Trifluoroacetic acid (3.5 mL, 0.045 mol) was charged to the solids to provide a solution at 3 C. Chlorosulfonic acid (13.3 mL, 0.201 mol) was added slowly while maintaining the reaction temperature below 20 C. The solution was heated to 60 C. and held for 2.2 hours. The solution was then cooled to 6 C. and transferred to a 60 mL addition funnel. Toluene (20 mL) and water (20 mL) were charged to the 100 mL jacketed reactor and cooled to 6 C. The reaction solution was then added slowly to the 100 mL jacketed reactor while maintaining the temperature below 16 C. The multi-phase mixture was transferred to 125 mL separatory funnel. Toluene (20 mL) and water (5 mL) were added and the mixture was shaken. Settling of the mixture resulted in two cloudy phases. The toluene phase was washed twice with 5 mL of water, transferred to a 125 mL flask with a 17 mL toluene rinse, and vacuum distilled to a semi-crystalline concentrate. The concentrate was dissolved in 100 mL of toluene and vacuum distilled to an oil. After initiating crystallization with a glass rod, heptane (11 mL) was added, and the mass broken up to produce an off white powder. The solids were collected by filtration. Portions of 25 mL of heptane were used to aid the transfer of solids to the filter. The cake was dried to provide 7.07 g (100 wt %) of the sulfonyl chloride as an 85:15 mixture of the para and meta isomers. HRMS Calculated for (M+1) C16H13NO3Cl: 334.0305; Found: (M+1): 334.0299.

	With sulfonic chloride acid; In dichloromethane; at -5 - 35℃; for 10h;	To the reaction flask, 8.0 g of 5-methyl-3,4-diphenylisoxazole and 40 g of methylene chloride were added and the temperature was lowered to -5 C in an ice bath. 32 g of chlorosulfonic acid was added dropwise, and the temperature of the reaction solution was controlled to <5 Lt; 0 & gt; C. After the dropwise addition of chlorosulfonic acid, the temperature was slowly raised to 35 C and the reaction was allowed to proceed for 10 h. The reaction mixture was stopped by monitoring the reaction mixture to 5-methyl-3,4-diphenylisoxazole (the developing solvent was ethyl acetate: petroleum ether = 1: 6, v: v). 100g of crushed ice was added to the reaction flask, stirred for 1h, poured into a separatory funnel and allowed to stand for separation, and the lower aqueous phase was separated. The upper organic phase by adding 5g anhydrous sodium sulfate drying 2h, filtered to get a clear liquid. The organic phase was concentrated in vacuo. The concentration was 45 C and the vacuum was -0.08 MPa. And concentrated to dryness to give a pale yellow solid as the main component,The reaction mixture was heated to 75 C for 6 hours, and the reaction was monitored by TLC until the spots disappeared in the intermediate I (developing solvent: ethyl acetate: petroleum ether = 1: 1) and the mixture was stirred for 1 hour. 1: 8, v: v) to stop the reaction. Hot vacuum concentrated ethanol about 25ml, cooling, stirring crystallization at -5 above 6h. Filtration, crude products were 13.5g tide.13.5 g of the above crude product was added to 100 ml of water, stirred at a temperature of 25 C for 2 hours, and then filtered. Filtration products directly after the addition of ethanol 30ml, heated to 75 reflux to the total solution, the cooling, stirring crystallization at -5 above 6h. Filtration, in refined products tide goods. Dried at 45 C for 8 h. The final product, ethyl 4- (5-methyl-3-phenyl-isoxazolyl) benzenesulfonate, was obtained in a yield of 61.7%
	With sulfonic chloride acid; In dichloromethane; at -5 - 35℃;Large scale;	The 3.0 kg 5 - methyl - 3, 4 - diphenyl isoxazole added to the 30 L glass reaction flask, then adding 9.9 kg methylene chloride, stirring to dissolve, cooling the solution to - 5 - 0 C, to the reaction solution slowly dropping 15.0 kg chloro sulfonic acid and temperature control ≤ 20 C, after dropping, water bath heating to 35 C insulation reaction 4 - 5 of H, then the reaction liquid cooling to 0 - 5 C.The 15.9 kg methylene chloride and 12.0 kg purified water by adding another 50 L in the reaction bottle, cooling to 0 - 5 C, slowly dropping has cooling of the reaction fluid and temperature control ≤ 20 C, after dropping stirring 0.5 h; layered, for methylene chloride level (the upper layer) 12.0 kg (25% w/w) saturated sodium chloride solution agitation washing, the delaminated, taking methylene chloride level (lower) spare; to the 50 L reaction flask add 5.4 kg concentrated ammonia water, then slowly adding the dichloromethane layer solution, at room temperature (20 - 30 C) stirring the reaction 2 - 3 H of the; added to the reaction solution after 11.7 kg isopropanol, 35 C thermal insulation to continue stirring 1.5 h, then cooled to 15 - 20 C, stirring crystallization 6 h, then adding, for material 2.4 kg of cold isopropanol washing, 60 C drying under atmospheric pressure 5 - 10 the H, get-cutting to past cloth thick 3.1 kg; will-cutting to past cloth thick 3.1 kg and 7.36 kg methanol by adding 30 L glass reaction flask, stirring under heating to 60 - 70 C reflux, filtered to remove insoluble matter, then adding 3.1 kg purified water, the temperature slowly drops to 15 - 20 C, stirring crystallization 6 h, filtered, in order to 3.1 kg cold methanol/water (V/V=3:1, W/W=2.37: 1) in the solution, 60 C drying under atmospheric pressure 5 - 10 the H, get-cutting to [...] 2.2 kg.
30 g	With sulfonic chloride acid; In dichloromethane; at 40℃;	1) Chlorosulfonic acid (100g),The compound of formula 1-1 (50 g) was added sequentially to 50 mL of dichloromethane.The reaction was carried out at 40 C overnight.2) The reaction solution was monitored by TLC (thin layer chromatography), and a trace amount of raw material remained.3) After cooling to room temperature, the reaction was dropped into ice (about 500 g) and extracted with ethyl acetate (500 mL) to obtain organicphase. The organic phase was concentrated to dryness to give an oil. Add 100 mL of ethyl acetate to the oil, add 600 mL of petroleum ether, and stir.2h, a solid precipitated. The filter cake was washed by filtration with a mixed solvent of petroleum ether / ethyl acetate (6:1). Vacuum drying the filter cakeThe compound of formula 1-3 (30 g) was obtained.
	With sulfonic chloride acid; In dichloromethane; at 0 - 60℃; for 5h;	SM (300 g, 1275 mmol) was added to a 5 L three-necked flask.Mix well in dichloromethane (300 ml ice bath).Temperature control is around 0-5 degrees,Dichloromethanesulfonic acid in dichloromethane (1486 g, 12750 mmol,Methylene chloride (700ml),After 2 hours, the addition is completed.Warm up to 60 degrees and stir for 3 hours.The TLC dot plate showed complete reaction (PE: EA = 4:1).The system was added dropwise to 1200 ml of ice water.Temperature control is about 10 degrees,Liquid separation extraction,The organic phase is washed twice with water.The organic phase is stirred with ammonia (700 ml) at room temperature.The dot plate shows that the reaction is complete,(PE: EA=4:1),The organic phase is removed by a 50 C rotary steaming system.The remaining system was added with 2 L of ethyl acetate.1L of water is stirred until it is dissolved.Liquid separation extraction,The aqueous phase was back extracted with ethyl acetate.Combine the organic phase,Wash with purified water,The organic phase was removed by rotary evaporation to give a crude material.Add 1L of ethanol,Heat to dissolve,Recrystallization,Filtered to give a crude product (350g).The final product 310 g (986.13 mmol) was obtained (HPLC > 99.5%).White solid, yield 77%.
	With sulfonic chloride acid; In dichloromethane; at -2 - 35℃; for 0.5h;	Add 50g of dichloromethane and 5g of starting material 5-methyl-3,4-diphenylisoxazole to a 100mL three-neck reaction flask, stir and cool to -2 C, connect the tail gas adsorption device at a rate of 2mL / min , Slowly add 16.5g of chlorosulfonic acid to control the reaction temperature up to 25 .After the dropwise addition, it was stirred for 0.5 hours, and then heated to 35 C.The reaction progress was monitored by HPLC, calculated by the area normalization method, until the starting material 5-methyl-3,4-diphenylisoxazole≤1.0%, meta-chlorosulfonate isomer≤1.0%, the reaction was stopped , Get the reaction solution.Slowly drop the reaction solution into ice water, cool it, control the maximum temperature not to exceed 15 C, and stir for 0.5 hours after the dropwise addition.The solution was separated by standing, extracted with fresh dichloromethane, and then the organic phases were combined, washed with aqueous sodium chloride solution and separated, and dried over anhydrous sodium sulfate.Suction filtration to obtain a solution of para-chlorosulfonate intermediate in dichloromethane for use.
		Add 80mL of dichloromethane to the reaction bottle, add compound I11.76g, add formic acid 4.60g, add chlorosulfonic acid 58.26g dropwise at a temperature control of 10-20 C, dropwise finish after 15min, then stir for 15min, add potassium carbonate 27.64g, add Sodium iodide 1.18g, heated to 35-45 C, and the reaction was completed after 1h by TLC (developing agent n-heptane: ethyl acetate = 4: 1, compound I Rf = 0.9, compound II Rf = 0.7). Add the reaction dropwise to the purified water at 0 5 , and control the temperature to be below 20 during the dropwise addition. After the dropwise addition, add 60mL of ethyl acetate and stir for 10min, let stand for 30min, separate the liquid, and wash the organic phase once with purified water. A solution of compound II in ethyl acetate was obtained, and 32.93 g of 25% -28% concentrated ammonia solution was added. The temperature was controlled at 20-25 C and stirred for 2 h. The reaction was monitored by TLC (developing agent n-heptane: ethyl acetate = 2: 1, (Rf of compound II = 0.9, Rf of compound III = 0.4), stand for 30 minutes, separate the layers, wash the organic phase twice with purified water, evaporate the solvent under reduced pressure at 50 C, and add 80 mL of absolute ethanol-methanol (10 : 1), heated to 60 , stirred until dissolved, slowly cooled to 0 ~ 5 , stirred and crystallized for 1h, suction filtered, vacuum dried at 55-60 for 8h, to obtain 14.59g compound III, yield 92.8% , HPLC detection purity 99.8%, the largest single impurity 0.08%.
	With sulfonic chloride acid; In dichloromethane; at 40℃; for 5h;	Add 50g of 5-methyl-3,4-diphenylisoxazole, 250ml of dichloromethane and 198g of chlorosulfonic acid into a reaction flask, and react under reflux at 40C for 5 hours.After the reaction is completed, the temperature is lowered to 05C, and it is added dropwise to 800g ice water and stirred for 30 minutes.Static stratification, liquid separation, 400ml dichloride phase washed once with water, directly cast to the next step.
7.12 kg	With sulfonic chloride acid; In dichloromethane; at 0℃; for 4h;Reflux; Large scale;	15.6kg of dichloromethane and 6.0kg of SM1 were added to the reaction kettle, and the temperature was lowered to 0-15C with stirring.Slowly add 26.64kg of chlorosulfonic acid dropwise, and control the internal temperature to 0-15C. dripping,The reaction was heated to 40-45C and refluxed for 4 hours. Cool down to 0-15C,The reaction solution was slowly added dropwise to 72 kg of purified water, and the internal temperature was controlled to 0-30C. static layering,The organic phase was separated, and the aqueous phase was extracted with 18 kg of ethyl acetate (no emulsification, no need to stand),The organic phase was separated and washed with 5.0 kg of purified water. After concentrating the organic phase of dichloromethane, add the organic phase of ethyl acetate and concentrate again until the remaining mass of the system is 15kg±1kg.The temperature was controlled at 30-40C, and 33kg of n-hexane was added dropwise, and the temperature was slowly lowered to 10-20C, stirred and crystallized for 1 hour, centrifuged, rinsed with 6kg of n-hexane, and dried under vacuum at 60-65C to obtain 7.12kg of white solid.The purity is 99.36% (see Figure 1 for details).

References: [1]Synthetic Communications,2012,vol. 42,p. 639 - 649.
[2]Patent: EP1550658,2005,A1 .Location in patent: Page/Page column 7.
[3]Patent: WO2005/123701,2005,A1 .Location in patent: Page/Page column 38-39.
[4]Patent: US2003/105334,2003,A1 .
[5]Patent: CN105367508,2016,A .Location in patent: Paragraph 0038; 0045.
[6]Patent: CN107137361,2017,A .Location in patent: Paragraph 0031-0033.
[7]Patent: CN109734681,2019,A .Location in patent: Paragraph 0027; 0028; 0029; 0030.
[8]Patent: CN105726496,2019,B .Location in patent: Paragraph 0054; 0055; 0056.
[9]Patent: CN110938043,2020,A .Location in patent: Paragraph 0052; 0074-0077; 0095-0098; 0110-0113; 0125-0140.
[10]Patent: CN111100084,2020,A .Location in patent: Paragraph 0038-0045.
[11]Patent: CN111848538,2020,A .Location in patent: Paragraph 0008; 0022.
[12]Green Chemistry,2022,vol. 24,p. 1983 - 1988.
[13]Patent: CN113845488,2021,A .Location in patent: Paragraph 0047; 0074-0077.

Yield	Reaction Conditions	Operation in experiment
	In cyclohexane; ethyl acetate; at 25 - 60℃; for 1.25 - 1.5h;Purification / work up;	EXAMPLE 3; PROCESS FOR PURIFICATION OF 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL) BENZENE SULFONYL CHLORIDE; 5.0 grams of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride were added to 5 ml of ethyl acetate and heated to 55-60 C. Charged 45 ml of cyclohexane and stirred at 55-60 C. for about 45 minutes. Cooled the reaction mass to 25-30 C. accompanied by stirring for 30-45 minutes. Filtered the solid and washed with 5 ml of cyclohexane. Dried the compound at 50 C. to get about 3.4 grams of the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride.
	In dichloromethane; cyclohexane; at 25 - 45℃; for 1 - 1.25h;Purification / work up;	EXAMPLE 4; PROCESS FOR PURIFICATION OF 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL) BENZENE SULFONYL CHLORIDE; 5.0 grams of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride were added to 5 ml of dichloromethane and heated to 35-45 C. and stirred for 30 minutes. 45 ml of cyclohexane was charged and the reaction mass was cooled to 25-30 C. accompanied by stirring for 30-45 minutes. The solid was filtered and washed with 5 ml of cyclohexane. The compound was dried at 50 C. to get the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride. (Yield 3.9 grams).
	In cyclohexane; at 25 - 30℃; for 1.25 - 1.5h;Heating / reflux;Purification / work up;	EXAMPLE 5; PROCESS FOR PURIFICATION OF 4-(5-METHYL-3-PHENYL-4-ISOXAZOLYL) BENZENE SULFONYL CHLORIDE; 5.0 grams of 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride were added to 50 ml of cyclohexane and heated to reflux temperature and stirred for 30 minutes. The reaction mass was cooled to 25-30 C. accompanied by stirring for 45-60 minutes. The solid was filtered and washed with 5 ml of cyclohexane. The resultant compound was dried at 50 C. to get the pure 4-(5-methyl-3-phenyl-4-isoxazolyl) benzene sulfonyl chloride. (Yield 3.9 grams).

9
[ 181696-73-1 ]
[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl chloride [ No CAS ]
[ 509074-26-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 15: Preparation of 4-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulfonyl chloride (28).; 4,5-Dihydro-5-methyl-3,4-diphenyl-5-isoxazolol 17 (13.0 grams, 0.0513 mol) was charged to a 200 mL jacketed flask which was cooled with 0.2C jacket fluid. Trifluoroacetic acid (9.1 mL, 0.118 mol) was charged to the solids to provide a solution at 38.6C. The solution was cooled to 2.1 C and chlorosulfonic acid (34.7 mL, 0.522 mol) was added slowly while maintaining the temperature below 14C. The solution was heated to 60C, held for 2.5 hours, cooled to 20C, and transferred to a 125 mL addition funnel. Toluene (52 mL) and water (52 mL) were charged to the 200,mL jacketed reactor, and cooled to 4C. The reaction solution was then added slowly to the 200 mL jacketed reactor while maintaining the temperature below 20C. The multi-phase mixture was warmed to 20C, and transferred to a 250 mL separatory funnel. Toluene (50 mL) and water (10 mL) were added and the mixture was shaken. Settling of the mixture resulted in two cloudy phases. The toluene phase was washed twice with 15 mL of water, transferred to a 250 mL flask with a 20 mL toluene rinse, and vacuum distilled to 17.4 g of an oil. After initiating crystallization with a glass rod and cooling, heptane (20 mL) was added to the crystalline mass which was broken up to form a powder. The off white powder was collected by filtration. Portions of 50 mL of heptane were used to aid the transfer of solids to the filter. The cake was dried in a vacuum oven (35C) to provide 13.6 g (79.4 wt% yield of 28) of the sulfonyl chloride as an 85: 15 mixture of the para and meta isomers. HRMS Calculated for (M+1) C16H13NO3Cl: 334.0305; Found (M+1): 334.0309.

References: [1]Patent: WO2005/123701,2005,A1 .Location in patent: Page/Page column 38.

10
[ 37928-17-9 ]
[3-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl chloride [ No CAS ]
[ 509074-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid; trifluoroacetic acid; at 3 - 60℃; for 2.2h;Product distribution / selectivity;	Example 14: Preparation of 4-(5-methyl-3-phenyl-4- isoxazolyl)benzenesulfonyl chloride (28).; 5-Methyl-3,4-diphenylisoxazole 18 (5.0 g, 0.0213 mol) was charged to a 100 mL jacketed reactor which was cooled with 0.2C jacket fluid. Trifluoroacetic acid (3.5 mL, 0.045 mol) was charged to the solids to provide a solution at 3C. Chlorosulfonic acid (13.3 mL, 0.201 mol) was added slowly while maintaining the reaction temperature below 20C. The solution was heated to 60C and held for 2.2 hours. The solution was then cooled to 6C and transferred to a 60 mL addition funnel. Toluene (20 mL) and water (20 mL) were charged to the 100 mL jacketed reactor and cooled to 6C. The reaction solution was then added slowly to the 100 mL jacketed reactor while maintaining the temperature below 16C. The multi- phase mixture was transferred to 125 mL separatory funnel. Toluene (20 mL) and water (5 mL) were added and the mixture was shaken. Settling of the mixture resulted in two cloudy phases. The toluene phase was washed twice with 5 mL of water, transferred to a 125 mL flask with a 17 mL toluene rinse, and vacuum distilled to a semi-crystalline concentrate. The concentrate was dissolved in 100 mL of toluene and vacuum distilled to an oil. After initiating crystallization with a glass rod, heptane (11 mL) was added, and the mass broken up to produce an off white powder. The solids were collected by filtration. Portions of 25 mL of heptane were used to aid the transfer of solids to the filter. The cake was dried to provide 7.07 g (100 wt% yield of 28) of the sulfonyl chloride as an 85: 15 mixture of the para and meta isomers. HRMS Calculated for (M+1 ) C16H13NO3Cl: 334.0305; Found: (M+1): 334.0299.

References: [1]Patent: WO2005/123701,2005,A1 .Location in patent: Page/Page column 37-38.

11
[ 897927-43-4 ]
[ 509074-26-4 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 70 - 75℃; for 2.25h;	EXAMPLE 3: Preparation of 4- [ (5-methyl-3-phenyl)-4-isoxazolyl] benzenesulfonyl chloride (step 2) 4- (5-methyl-3-phenyl-4-isoxazolyl) benzene sulfuric acid sodium salt (15 g, 0.0445 mol), toluene (300 ml), thionyl chloride (11.3 ml, 0.1548 mol) & catalytic quantity of DMF (0. 8 ml) are taken together and heated to 70-75C temperature for 2hours. HPLC analysis of the reaction mass showed starting material less than 2%. The reaction mass is then cooled to 5-10 C and water (100 ml) is added and stirred for 15 min. The aqueous and organic layers are separated, the organic layer washed with water (100 ml). The organic layer is dried over sodium sulphate and filtered. The organic layer is distilled under vacuum to remove toluene completely to get crude product (14g). To the crude product (14g) is dissolved in diisopropyl ether (250 ml) at reflux and treated with activated carbon (0.8g) for 15 min. The content is then filtered through flash silica gel (230-400 mesh). The mother liquor is cooled to 0-5C and stirred for an hour to get the crystallization completed. The product is filtered, washed with diisopropyl ether (50 ml). The product obtained is then dried under vacuum at 50-55C (8.3g, HPLC purity = 97. 7%)

References: [1]Patent: WO2005/85218,2005,A1 .Location in patent: Page/Page column 9.

12
[ 37928-17-9 ]
[ 1037546-03-4 ]
[ 509074-26-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 5322 - 5330.

13
[ 509074-26-4 ]
N-hydroxy-4-(3-phenyl-5-methyl-isoxazole-4-yl)-benzenesulfonamide [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 5322 - 5330.

14
[ 141-78-6 ]
[ 509074-26-4 ]
N-hydroxy-4-(3-phenyl-5-methyl-isoxazole-4-yl)-benzenesulfonamide mono-ethyl acetate solvate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		Example 2 N-HYDROXI-4-(3-PHENVL-5-METHVL-ISOXAZOLE-4-VL)-BENZENESULFONAMIDE MONO-ETHVL acetate solvate 6.88 g (0.099 mol) hydroxylamine-hydrochloride was suspended in 50 ml dioxane, cooled to +10 C AND was added solution of 8.1 g (0.099 mole) sodium acetate in 25 ml water. Solution of 11 g (0.033 mole) 3-phenyl-4- (4-chloro-sulfonyl-phenyl)- 5-methyl-isoxazole in 50 mi dioxane was added over a period of 30 minutes. The mixture was stirred for 30 minutes and was added to 600 ml of water and the suspension was stirred for 2 hours. The suspension was filtered and washed 2 times with 100 ml of water. The precipitate was disolved in 300 mi of ethyl acetate, extracted three times with 50 ml water. The organic solution was dried with 5 g of anhydrous magnesium sulfate. After filtration of the magnesium sulfate the solution was evaporated to 80 ml under reduced pressure (40 mbar), while the product is crystallized. This suspension was stirred for 2 hour at-5 C, and washed with 10 ml of cooled (-10 C) ETHYL-ACETATE. After the drying gave 8.5 g (60 %) of the title compound (mp: 96-100 C, decomposition at 108 C) The purity was 99.9 % by HPLC.

References: [1]Patent: WO2005/7620,2005,A2 .Location in patent: Page/Page column 14-15.

15
[ 37928-17-9 ]
[ 1373038-57-3 ]
[ 509074-26-4 ]

References: [1]Synthetic Communications,2012,vol. 42,p. 639 - 649.

16
[ 857259-65-5 ]
[ 509074-26-4 ]

References: [1]Synthetic Communications,2012,vol. 42,p. 639 - 649.
[2]Synthetic Communications,2012,vol. 42,p. 639 - 649.

17
[ 52201-28-2 ]
[ 509074-26-4 ]

References: [1]Synthetic Communications,2012,vol. 42,p. 639 - 649.
[2]Synthetic Communications,2012,vol. 42,p. 639 - 649.
[3]Synthetic Communications,2012,vol. 42,p. 639 - 649.
[4]Synthetic Communications,2012,vol. 42,p. 639 - 649.

18
[ 103-79-7 ]
[ 509074-26-4 ]

19
[ 509074-26-4 ]
[ 181696-35-5 ]

References: [1]Synthetic Communications,2012,vol. 42,p. 639 - 649.

20
[ 509074-26-4 ]
[ 181695-72-7 ]
[ 1373038-60-8 ]

References: [1]Synthetic Communications,2012,vol. 42,p. 639 - 649.

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[ 64-17-5 ]
[ 509074-26-4 ]
4-(5-methyl-3-phenyl-isoxazolyl)benzenesulfonic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.8 g	With pyridine; at 75℃; for 6h;	The reaction flask was added with 8.0 g of 5-methyl-3,4-diphenylisoxazole and 40 g of methylene chloride, and the temperature was lowered to -5 C in an ice bath. 40 g of chlorosulfonic acid was added dropwise, Lt; 0 & gt; C. After the dropwise addition of chlorosulfonic acid, the temperature was slowly raised to 35 C and the reaction was allowed to proceed for 10 h. The reaction mixture was stopped by monitoring the reaction mixture to 5-methyl-3,4-diphenylisoxazole (the developing solvent was ethyl acetate: petroleum ether = 1: 6, v: v). 100g of crushed ice was added to the reaction flask, stirred for 1h, poured into a separatory funnel and allowed to stand for separation, and the lower aqueous phase was separated. The upper organic phase by adding 5g anhydrous sodium sulfate drying 2h, filtered to get a clear liquid. The organic phase was concentrated in vacuo. The concentration was 45 C and the vacuum was -0.08 MPa. And concentrated to dryness to give a pale yellow solid as the main component,The above-mentioned light yellow solid was added to 50g of anhydrous ethanol, stirred to dissolve and clarified, 5.4g of pyridine was added, and the mixture was heated to 75 for 6h. = 1: 8, v: v) to stop the reaction. Hot vacuum concentrated ethanol about 25ml, cooling, stirring crystallization at -5 above 6h. Filtration, crude products were 14.0g.14.0 g of the above crude product was added to 100 ml of water, stirred at a temperature of 25 C for 2 h, and then filtered. Filtration products directly after the addition of ethanol 30ml, heated to 75 reflux to the total solution, the cooling, stirring crystallization at -5 above 6h. Filtration, in refined products tide goods. 50 under the blast drying 6h. To obtain 7.8 g of the final product, ethyl 4- (5-methyl-3-phenyl-isoxazolyl) benzenesulfonate in a yield of 66.8%.

References: [1]Patent: CN105367508,2016,A .Location in patent: Paragraph 0037; 0039; 0040; 0041; 0042-0044; 0046-0049.

22
[ 509074-26-4 ]
[ 198470-84-7 ]

References: [1]Patent: CN107137361,2017,A .
[2]Patent: CN105726496,2019,B .
[3]Patent: CN111100084,2020,A .
[4]Patent: CN113845488,2021,A .

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[ 509074-26-4 ]
N-[[4-(5-methyl-3-phenyl-4-isoxazolyl)phenyl]sulfonyl]propanamide sodium salt [ No CAS ]

References: [1]Patent: CN107137361,2017,A .
[2]Patent: CN105726496,2019,B .
[3]Patent: CN111100084,2020,A .
[4]Patent: CN113845488,2021,A .

24
[ 451-40-1 ]
[ 509074-26-4 ]