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Product Details of [ 16133-25-8 ]

CAS No. :16133-25-8 MDL No. :MFCD03452747
Formula : C5H4ClNO2S Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 177.61 Pubchem ID :-
Synonyms :

Calculated chemistry of [ 16133-25-8 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 37.32
TPSA : 55.41 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.69 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.19
Log Po/w (XLOGP3) : 0.97
Log Po/w (WLOGP) : 2.09
Log Po/w (MLOGP) : -0.11
Log Po/w (SILICOS-IT) : 0.91
Consensus Log Po/w : 1.01

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.93
Solubility : 2.09 mg/ml ; 0.0117 mol/l
Class : Very soluble
Log S (Ali) : -1.72
Solubility : 3.37 mg/ml ; 0.019 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.56
Solubility : 0.485 mg/ml ; 0.00273 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.79

Safety of [ 16133-25-8 ]

Signal Word:Danger Class:8
Precautionary Statements:P234-P260-P264-P280-P301+P330+P331+P310-P303+P361+P353+P310+P363-P304+P340+P310-P305+P351+P338+P310-P390-P405-P406-P501 UN#:3265
Hazard Statements:H290-H314 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 16133-25-8 ]

* 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 [ 16133-25-8 ]
  • Downstream synthetic route of [ 16133-25-8 ]

[ 16133-25-8 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 636-73-7 ]
  • [ 16133-25-8 ]
YieldReaction ConditionsOperation in experiment
94% for 3 h; Heating / reflux A mixture of pyridine-3-sulfonic acid (10.3 g, 64.8 mmol), phosphorus pentachloride (20.82 g, 100 mmol) and phosphorus oxychloride (10 mL, 109 mmol) was heated to reflux for 3 h (according to J. Org. Chem. 1989, 54(2), 389.). Evaporated to dryness to give a yellow solid, dissolved in ice water and methyl-tert-butyl ether, added cautiously sat. NaHCO3-sol. until neutralized, saturated with solid NaCl, separated phases, dried organic layer over Na2SO4. Removal of the solvent in vacuum to give the title compound as an orange liquid (10.85 g, 94percent). MS (ISP) 178.1 [(M+H)+] and 180.0 [(M+2+H)+].
90% for 8 h; Reflux A 3-pyridine sulfonyl chloride is synthesized by using 3-pyridine sulfonic acid as a starting material in U.S. Patent Nos. CN200680040789, US2006 / 217387, Merck & apos; s US5416099A1,Method for 3-pyridine sulfonic acid in phosphorus pentachloride and phosphorus oxychloride reflux for 8 hours or more to be completed after the reaction with a greater amount of water quenching reaction,After the extraction, distillation,Distillation method to obtain high purity 3-pyridyl sulfonyl chloride,The yield of this method can reach more than 90percent.
89.6% at 25 - 80℃; for 12 h; Inert atmosphere Pyridine-3-sul on l chloride (A4) A3 A4 To a mixture of A3 (9.00 g, 56.6 mmol) in SOCl2 (108.00 mL) was added DMF (5.00 mL) in one portion at 25°C under N2. The mixture heated to 80 °C and stirred for 12 hours, after which LCMS analysis indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to give A4 (9.00 g, yield: 89.6percent), which was used in the next step without further purification. 1H NMR (400 MHz, CDC13) δ: 8.98(s, 1H), 8.91 (d, / = 5.6 Hz, 1H), 8.72 (d, / = 8.0 Hz, 1H), 8.07-8.10 (m, 1H).
88% at 20 - 110℃; for 17 h; Heating / reflux Pyridine-3-sulfonic acid (125 g, 0.78 m) was placed in a 1L, 3-necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330 ml, 3.8 m, 4.5 eq). The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp. approx. 110° C.) over the next hour, kept at this temperature for approx. 3.5 hr then allowed over the next 12 hr to cool back to ambient temperature. Gas evolution was observed during this time. The volatiles were stripped under reduced pressure (at 12 mmHg/40° C.) and yellow semi-solid residue was diluted with DCM (1 L). The slurry was poured slowly into the stirred, ice-cold sat. aq. bicarbonate, maintaining pH=7. Gas evolution was observed. The organic layer was separated and aqueous layer was back-extracted with DCM. The combined extracts were washed with cold sat. aq. bicarbonate, brine and dried with magnesium sulfate. The solids were filtered off and filtrate evaporated, leaving pyridine-3-sulfonyl chloride as a pale yellow, oily liquid, 123 g (93percent pure; 88percent theory).
88%
Stage #1: at 20 - 110℃; for 17 h; Heating / reflux
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Pyridine-3 -sulfonic acid (125 g, 0.78 m) was placed in a IL, 3 -necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330ml, 3.8 m, 4.5 eq) . The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp, approx. HO0C) over the next hour, kept at this temperature for approx. 3.5 hr then allowed over the next 12 hr to cool back to ambient temperature. Gas evolution was observed during this time. The volatiles were stripped under reduced pressure (at 12 mmHg/40°C) and yellow semi-solid EPO <DP n="77"/>residue was diluted with DCM (IL) . The slurry was poured slowly into the stirred, ice-cold sat. aq. bicarbonate, maintaining pH=7. Gas evolution was observed. The organic layer was separated and aqueous layer was back-extracted with DCM. The combined extracts were washed with cold sat. aq. bicarbonate, brine and dried with magnesium sulfate. The solids were filtered off and filtrate evaporated, leaving pyridine-3- sulfonyl chloride as a pale yellow, oily liquid, 123 g (93percent pure; 88percent theory). 1H-NMR, CDCl3, (δ) : 9.26 (d, IH), 8.98 (dd, IH), 8.34 (m, IH), 7.62 (m, IH) . 13C-NMR, CDCl3, (δ) : 155.3, 147.4, 140.9, 134.6, 124.2. MS (m/z) : 178.0 [M+1] .L-penicillamine (150 g, 1.0 m) was dissolved with stirring in DI water (1500 ml) , cooled in ice-bath to +8°C and treated with formalin (150 ml, 37percent aq.) . The reaction mixture was stirred at +8°C for 2 hr, then cooling bath was removed and stirring continued for 12 hr. The clear solution was concentrated under reduced pressure (14 mmHg/50°) leaving white residue. The solids were re-suspended, then dissolved in hot MeOH (2500 ml) and left standing at ambient temperature for 12 hr. The white, fluffy precipitate was filtered off and rinsed with cold methanol. The filtrate was concentrated and set to crystallize again. The collected precipitate was combined with the first crop and dried in vacuum oven for 24 hr at 55°C at 45 mmHg. The yield of (R) -5 , 5-dimethylthiazolidine-4-carboxylic acid was 138 g (>99percent pure; 86percent theory) . 1H-NMR, DMSO-d6, (δ) : 4.25 (d, IH), 4.05 (d, IH), 3.33 (s, IH), 1.57 (s, 3H), 1.19 (s, 3H). 13C-NMR, DMSO-d6, (6): 170.8, 74.4, 57.6, 51.8, 28.9, 27.9. MS (m/z): 162.3 [M+l] . In a 4L reactor equipped with mechanical stirrer and thermometer, a buffer solution was prepared from potassium monobasic phosphate (43 g, 0.31 m) and potassium dibasic phosphate (188.7 g, 1.08 m) in DI water (2L). The (R) -5,5- EPO <DP n="78"/>dimethylthiazolidine-4-carboxylic acid (107 g, 0.675 m) was added and stirred until complete dissolution. The solution was cooled in an ice-bath to +80C. A separately prepared solution of pyridine-3-sulfonyl chloride (124 g, 0.695 m) in DCM (125 ml) was added dropwise to the reactor with vigorous stirring over the 1 hr. The pH of reaction mixture was monitored and after 4 hr, found to be pH=5 and adjusted to pH=6 by addition of solid bicarbonate. The mixture was allowed to warm up to ambient temperature over 18 hr. The pH was adjusted to 2 with dil . aq. sulfuric acid, stirred for 1 hr and precipitated yellow solids were filtered off, rinsed with water to neutral. The solid cake was transferred into 2L Erlenmayer flask, suspended in DCM (500 ml) with occasional swirling for 5 min and filtered off again. The filter cake was washed with DCM and air-dried. The yield of the title compound, (R) -5, 5 -dimethyl - 3- (pyridin-3-ylsulfonyl) thiazolidine-4-carboxylic acid was 148.9 g (98percent pure; 73percent theory). 1H-NMR, DMSO-d6, (δ) : 9.05 (d, IH), 8.89 (m, IH), 8.32 (m, IH), 7.69 (m, IH), 4.68 (q, 2H), 4.14 (s, IH), 1.35 (s, 3H), 1.29 (s, 3H). 13C-NMR, DMSO-d6, (δ) : 170.0, 154.3, 147.9, 135.8, 134.1, 124.8, 72.6, 54.3, 50.2, 29.4, 25.0. MS (m/z) : 303.2 [M+l] .
87.9% With phosphorus pentachloride In chlorobenzene at 105℃; for 3 h; Example 1 (chlorobenzene solvent) 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0141) Pyridine-3-sulfonic acid (10.7 g, 68.5 mmol) and phosphorus pentachloride (15.7 g, 75.4 mmol) were suspended in chlorobenzene (15 mL) at room temperature. After heating and stirring at an inside temperature of 105±5°C for about 3 hr, the mixture was cooled to room temperature. Toluene (50 mL) and water (30 mL) were added into another kolben, and the mixture was cooled to an inside temperature of 5±5°C. The reaction solution was added dropwise at not more than an inside temperature of 15°C, and the dropping funnel was washed well with a mixed solution of toluene and water (1:1, 20 mL). After cooling to an inside temperature of 5±5°C, 50percent aqueous potassium carbonate solution (39 mL) was added dropwise at not more than an inside temperature of 20°C, and the mixture was adjusted to pH 7.5±0.5. After partitioning at room temperature, the organic layer was washed with 5percent brine (40 mL), and concentrated to about 20 mL under reduced pressure. Toluene (40 mL) was added and the mixture was concentrated again to about 20 mL. An operation of adding acetonitrile (40 mL) and concentrating the mixture to about 20 mL was repeated three times to give an acetonitrile solution of pyridine-3-sulfonylchloride (quantified yield 10.7 g, 87.9percent, total amount 20.3 g, 52.7 w/wpercent acetonitrile solution). (0142) To the acetonitrile solution (total amount) of pyridine-3-sulfonylchloride obtained above were added acetonitrile (45 mL), 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (10.0 g, 52.9 mmol), N,N-dimethylpyridin-4-amine (0.646 g, 5.29 mmol) and triethylamine (10.4 mL, 74.1 mmol), and the mixture was heated to an inside temperature of 45±5°C. After stirring at an inside temperature of 45±5°C for 1.5 hr, the mixture was cooled to room temperature, and water (30 mL) was added dropwise. The mixture was adjusted to pH 4 - 5 with 0.5M hydrochloric acid (about 20 mL). The seed crystal of the title compound was added and, after confirmation of crystal precipitation, water (60 mL) was added dropwise. After stirring at room temperature for 30 min and at 5±5°C for 1 hr, the precipitated crystals were collected by filtration. The crystals were washed twice with a mixed solution of acetonitrile and water (1:2, 30 mL) cooled to 5±5°C in advance, and dried at an outer temperature of 50°C under reduced pressure to give the title compound (15.5 g, isolation yield 88.7percent). 1H NMR (500 MHz, CDCl3) δ 6.68 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J = 8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.82 (dd, J = 4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
85% With phosphorus pentachloride In trichlorophosphate at 120℃; Reference Example 18: Pyridine-3-sulfonyI chloride. A mixture of pyridine-3-sulfonic acid (3 g, 18.8 mmol), phosphorus pentachloride (6.04 g, 29.0 mmol) and phosphorus oxychloride (15 mL) was heated at12O0C overnight. Excess phosphorus oxychloride was evaporated under reduced pressure, the residue quenched with ice and partitioned between water and diethyl ether.The pH of the aqueous phase was adjusted by addition of-solid sodium bicarbonate to pH 7-8, then the organic layer was separated and washed successively with sat. sodium bicarbonate solution, water and brine. The organice phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which was dried under high vacuum to afford pyridine-3-sulfonyl chloride (2.83 g, 85percent) as a solid.
83.9% With phosphorus pentachloride In chlorobenzene at 119 - 122℃; In 100mL four-necked flask, pyridine-3-sulfonic acid 15.9g (0.100 mol) and put the monochlorobenzene 23.9g, was heated with stirring to 120 ° C. While maintaining the internal temperature at 119~122 ° C, it was placed in every 5 minutes for 20 split the phosphorus pentachloride 20.4g (0.098 mol). After the addition completion of the phosphorus pentachloride and stirred for an additional 1 hour. When the reaction liquid was subjected to gas chromatography (GC) analysis of the concentration of the pyridine-3-sulfonyl chloride was 29.5 wtpercent. Moreover, it was calculated from the amount of the reaction liquid (54.3 g), pyridine-3-sulfonyl chloride The yield in the reaction solution is 90.2percent by-produced 5-chloropyridine-3-sulfonyl chloride area by GC analysis ratio (5-chloropyridine-3-sulfonyl chloride / pyridine-3-sulfonyl chloride) was 0.02percent.The reaction solution was concentrated under reduced pressure to 3.6kPa at 90 ° C, followed by distilling off the monochlorobenzene and by-product phosphorus oxychloride. Then, 94 ° C, then vacuum distillation under the conditions of 0.4 kPa, to give a pyridine-3-sulfonyl chloride 14.9 g. Pyridine-3-sulfonyl chloride yield was 83.9percent. The area ratio by GC analysis and pyridine-3-sulfonyl chloride 99.99percent 5-chloro-3-sulfonyl chloride was 0.01percent.
75% With phosphorus pentachloride In trichlorophosphate for 4 h; Reflux Step 1:
Preparation of pyridin-3-sulfonyl chloride
Pyridin-3-sulfonic acid (5.0 g, 31.4 mmol) was added with phosphorous pen- tachloride (9.8 g, 47.1 mmol) and phosphorous oxychloride (10 ml), stirred underreflux for 4 hours, and then the mixture was concentrated to remove phosphorous oxy chloride. The reaction mixture was added with ice water and diethyl ether, stirred, and then extracted into the organic layer. The resulting separated organic layer was washedwith a saturated sodium bicarbonate solution, and the organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4.1 g of a title compound (yield: 75percent).[563] 1H NMR (500 MHz, CDCb): 8.91 (s, lH), 8.84 (d, lH), 8.43 (dd, lH), 7.57 (t, lH) [564]
66% at 130℃; for 20 h; 3-Pyridine sulfonic acid (4.0 g, 25.1 mmol, 1 eq) and PCl5 (5.75 g, 27.70 mmol, 1.1 eq) were heated at 130 °C for 20 h.
After cooling, ice was added and the mixture was extracted with EtOAc (*3).
The combined organic layers were washed with saturated aqueous NaHCO3 (*1), brine (*1) and dried over sodium sulphate.
After filtration and evaporation of the solvent a yellow oil is obtained. (2.94 g, 66percent).
1H NMR (300 MHz, CDCl3) δ 9.17 (d, J = 2.4 Hz, 1-H) 8.91 (dd, J = 4.9/1.5 Hz, 1-H), 8.26 (ddd, J = 8.3/2.5/1.8 Hz, 1-H), 7.57 (ddd, J = 8.3/4.9/0.6 Hz, 1-H); 13C NMR (75 MHz, CDCl3) δ 155.6, 147.5, 141.0, 139.7, 124.4; IR (KBr) 3045, 1625, 1522, 1375, 1247, 1173 cm-1.
64% at 135℃; for 2.5 h; [0310] A mixture of pyridine-3 -sulfonic acid (5.0 g, 31.4 mmol, 1.0 eq) and PC15 (14.2 g, 69.1 mmol, 2.2 eq) was refluxed at 135 °C for 2.5 hrs. The resulting mixture was cooled to r.t., triturated with chloroform, filtered and dried to give 3.6 g of Compound Int-18 (64percent yield) as a white solid.
92% With phosphorus pentachloride In toluene STR121
3-Pyridylsulfonyl chloride (23-10)
3-Pyridylsulfonic acid (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole), suspended in 150 mL toluene and heated to reflux overnight.
The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 30.7 g (92percent) of 23-10 as a yellow oil, which was used in the next step without purification.
1 H NMR (300 MHz, CDCl3) δ 9.27 (1H, s), 8.98 (1H, d, 8.35 (1H, d), 7.62 (1H, dd).
0.70 g With phosphorus pentachloride In toluene for 16 h; Reflux Pyridine-3-sulfonyl chloride
Phosphorus pentachloride (1.57 g, 7.5 mmol) was added to a stirred solution of pyridine-3-sulfonic acid (1.00 g, 6.3 mmol) in toluene (5 mL).
The mixture was heated at reflux for 16 hours and then cooled to room temperature.
The mixture was filtered through celite, and the celite was washed with benzene (2*10 mL).
The combined filtrates were concentrated under reduced pressure to give crude pyridine-3-sulfonyl chloride (0.70 g, 100percent), which was used directly in the next step without further purification.

Reference: [1] Journal of the American Chemical Society, 1992, vol. 114, # 12, p. 4889 - 4898
[2] Patent: US2006/217387, 2006, A1, . Location in patent: Page/Page column 25
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 13, p. 2409 - 2421
[4] Patent: CN106432067, 2017, A, . Location in patent: Paragraph 0090
[5] Patent: WO2016/90317, 2016, A1, . Location in patent: Page/Page column 73
[6] Patent: US2006/13799, 2006, A1, . Location in patent: Page/Page column 55
[7] Patent: WO2006/127584, 2006, A1, . Location in patent: Page/Page column 60; 75-77
[8] Patent: EP2963019, 2016, A1, . Location in patent: Paragraph 01410; 0141; 0145
[9] Patent: WO2008/62182, 2008, A1, . Location in patent: Page/Page column 114
[10] Patent: JP5826964, 2015, B1, . Location in patent: Paragraph 0046; 0047
[11] Patent: WO2015/50412, 2015, A1, . Location in patent: Paragraph 558; 559; 561; 562; 563
[12] Journal of Organic Chemistry, 1989, vol. 54, # 2, p. 389 - 393
[13] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 58 - 66,9
[14] Patent: WO2018/85348, 2018, A1, . Location in patent: Paragraph 0310
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[17] J. Franklin Inst., 1943, vol. 236, p. 316,318
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  • 2
  • [ 462-08-8 ]
  • [ 16133-25-8 ]
YieldReaction ConditionsOperation in experiment
91%
Stage #1: With hydrogenchloride; sodium nitrite In water at -5 - 0℃; Large scale; Green chemistry
Stage #2: With thionyl chloride; sulphurous acid; copper(l) chloride In water at 0 - 4℃; for 1.5 h; Large scale; Green chemistry
Step A: Add 400 kg of water to the reactor, drop to 0 ° C and then drop 109.24 kg of thionyl chloride. After dropping thionyl chloride, the control temperature is at 4 ° C. After the dropwise addition, 232 g of cuprous chloride , To obtain an aqueous solution of sulfurous acid, stand-by;Step B: Add 82.04 kg of hydrochloric acid to 36percent hydrochloric acid in another reactor, add 20 kg of 3-aminopyridine, cool to -5 ° C, drop an aqueous solution of sodium nitrite (containing 15.84 kg of sodium nitrite, 32 kg of water) Dropping the process to control the temperature at 0 , after the drop is completed, the temperature control at 0 , stand;Step C: The solution obtained in Step B was added dropwise to the reactor of Step A. The reaction temperature was dropwise at 0 ° C, after completion of the dropwise addition, the mixture was stirred at 0 ° C for 1.5 h. After completion of the reaction, 300 L of dichloromethane , The mixture was stirred and allowed to stand for three times. The resulting organic phase was distilled, cooled to 0 ° C, stirred with water (350 L), and the resulting organic phase was dried with anhydrous sodium sulfate.Step D: The organic phase obtained in step C was evaporated to dryness to give 3-pyridylsulfonyl chloride.
52.1%
Stage #1: With hydrogenchloride; sodium nitrite In water at -20℃; for 2 h;
Stage #2: With copper(II) choride dihydrate; sulfur dioxide In dichloromethane; water at -5 - 0℃; for 1 h;
50.0 g (0.53 mol) of 3-aminopyridine was added to 34.9 g of 35percent hydrochloric acid and stirred to prepare an aqueous hydrochloric acid solution of 3-aminopyridine. In addition, 35.9 g (0.52 mol, 0.98 mol equivalent to 3-aminopyridine) of sodium nitrite was added to 54.0 g of water and stirred to prepare an aqueous solution of sodium nitrite. 131 g of hydrochloric acid was placed in a 500 mL four-necked brown colben and cooled to -20 ° C. An aqueous hydrochloric acid solution of 3-aminopyridine and an aqueous solution of sodium nitrite were simultaneously added dropwise to hydrochloric acid in a temperature range of -20 ± 2 ° C. over 2 hours with stirring. After completion of the dropwise addition, the mixture was further stirred for 30 minutes in a temperature range of -20 ± 2 ° C. to obtain an aqueous solution of pyridine-3-diazonium salt650 g of dichloromethane was placed in 1000 mL four-necked brown bottle and cooled to 0 ° C., and 119 g (1.86 mol) of sulfur dioxide gas was blown into the solution to dissolve. 0.9 g (0.006 mol) of copper (II) chloride dihydrate was added and cooled to -5 ° C., and an aqueous solution of pyridine-3-diazonium salt was added over a period of 1 hour at a temperature range of -5 ± 2 ° C. Was added dropwise. After completion of the dropwise addition, the mixture was further stirred for 1 minute at a temperature range of -5 ± 2 ° C. The copper catalyst was removed by filtration while maintaining the temperature of the reaction solution at -5 ± 5 ° C., and then the organic layer and the aqueous layer were separated. It was extracted with 195 g of dichloromethane × 3 times at a temperature of -5 ± 5 ° C. and mixed all together to obtain 1353 g of an organic layer. GC analysis of this organic layer revealed that the concentration of pyridine-3-sulfonyl chloride was 3.76percent by mass and the yield was 54.0percent. The obtained organic layer was washed with 50 g of water while maintaining the temperature at 3 ± 2 ° C., and then dehydrated using 20 g of magnesium sulfate at room temperature. After removing the magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure (30 to 35 ° C.,> 67 kPa) to remove dichloromethane. Subsequently, distillation under reduced pressure (110 ° C., 1.3 kPa) gave 49.0 g (0.276 mol, yield 52.1percent) of pyridine-3-sulfonyl chloride.
Reference: [1] Patent: CN106432067, 2017, A, . Location in patent: Paragraph 0052; 0054-0083
[2] Patent: JP2016/175885, 2016, A, . Location in patent: Paragraph 0023; 0025; 0026
[3] Organic Process Research and Development, 2009, vol. 13, # 5, p. 875 - 879
  • 3
  • [ 42899-76-3 ]
  • [ 16133-25-8 ]
YieldReaction ConditionsOperation in experiment
92.9% at 85℃; 21.4 g (0.100 mol) of pyridine-3-sulfonyl chloride hydrochloride and 42.8 g of monochlorobenzene were placed in a 200 mL four-necked flask, and the slurry Liquid). The internal pressure was adjusted to 23 kPa using a vacuum pump and heated to 85 ± 5 ° C. for 5 hours (dehydrochlorination). After 5 hours, the contents of the flavor became almost transparent liquid. Thereafter, monochlorobenzene was distilled off under reduced pressure (100 ° C., 27 kPa). Subsequently, distillation under reduced pressure (110 ° C., 1 kPa) gave 16.5 g (0.0929 mol, yield 92.9percent) of pyridine-3-sulfonyl chloride.
Reference: [1] Patent: JP6165374, 2017, B1, . Location in patent: Paragraph 0019
[2] Patent: WO2008/54288, 2008, A1, . Location in patent: Page/Page column 90
  • 4
  • [ 626-55-1 ]
  • [ 16133-25-8 ]
Reference: [1] Journal of Organic Chemistry, 2003, vol. 68, # 21, p. 8274 - 8276
[2] Synlett, 2011, # 8, p. 1117 - 1120
[3] Organic Letters, 2011, vol. 13, # 18, p. 4876 - 4878
  • 5
  • [ 636-73-7 ]
  • [ 16133-25-8 ]
YieldReaction ConditionsOperation in experiment
92% With phosphorus pentachloride In toluene 5-[2-(Piperidin-4-yl)ethyl]thieno-[2,3-b]thiophene-2-N-[3-2(S)-(2-ethoxyethanesulfonylamino)propionic acid]carboxamide (2-14)
3-4 was treated with 2-13 and this intermediate was deprotected as described for 1-10 to give pure 2-14.
1 H NMR (300 MHz, D2 O) δ1.03 (3H, t), 1.20-1.53 (5H, m), 1.75 (2H, bd), 2.60 (2H, bs), 2.73 (2H, bt), 3.34 (6H, m), 3.50 (1H, m), 3.75 (4H, m), 4.27 (1H, m), 6.80 (1H, s), 7.62 (1H, s).
STR38 3-Pyridylsulfonyl chloride (2-15)
3-pyridylsulfonic acid (30 g, 0.188 mole) was added to PCl5 (46.8 g, 0.225 mole), suspended in 150 mL toluene and heated to reflux overnight.
The suspension was cooled and concentrated to yield a yellow oil, which was diluted with benzene, filtered through a pad of celite and concentrated to give 30.7 g (92percent) of 2-15 as a yellow oil, which was used in the next step without purification.
1 H NMR (300 MHz, CDCl3) δ9.27 (1H, s), 8.98 (1H, d, 8.35 (1H, d), 7.62 (1H, dd).
Reference: [1] Patent: US5397791, 1995, A,
  • 6
  • [ 16133-26-9 ]
  • [ 16133-25-8 ]
Reference: [1] Heterocycles, 2007, vol. 71, # 9, p. 1975 - 1990
  • 7
  • [ 110-91-8 ]
  • [ 636-73-7 ]
  • [ 16133-25-8 ]
Reference: [1] Patent: US2003/187254, 2003, A1,
  • 8
  • [ 636-73-7 ]
  • [ 10026-13-8 ]
  • [ 16133-25-8 ]
Reference: [1] Patent: US6479519, 2002, B1,
  • 9
  • [ 110-87-2 ]
  • [ 13325-10-5 ]
  • [ 16133-25-8 ]
  • [ 173843-37-3 ]
Reference: [1] Patent: US5760054, 1998, A,
  • 10
  • [ 110-86-1 ]
  • [ 16133-25-8 ]
Reference: [1] Monatshefte fuer Chemie, 1939, vol. 72, p. 77,88
[2] Journal of the American Pharmaceutical Association (1912-1977), 1948, vol. 37, p. 99
  • 11
  • [ 16133-25-8 ]
  • [ 63636-89-5 ]
Reference: [1] Patent: US5837708, 1998, A,
  • 12
  • [ 16133-25-8 ]
  • [ 2922-45-4 ]
YieldReaction ConditionsOperation in experiment
85% at 40℃; for 0.5 h; Inert atmosphere Under the protection of the Ar, 3 - pyridine sulfonyl chloride (1.457 g) is added in excess ammonia water (4.5 ml, ammonia content: 25 - 28percent), the temperature of the 40 °C reaction, 30 min after stopping the reaction, steaming and the removal of unreacted ammonia, adding 10 ml water precipitated yellow solid, filtering ethanol after heats crystallization (1.1 g, 85percent),
71% With ammonia In tetrahydrofuran; 1,4-dioxane at 20℃; for 1 h; Intermediate 78 : Pyridine-3-sulfonamide; To a solution of pyridine-3 -sulphonyl chloride (1 g, 5.6 mmol, 1 eq, commercially available from Davos) in THF (5 mL) is added ammonia in dioxane (23.9 mL, 2 M, 47.9 mmol, 8.5 eq). The resulting suspension is stirred at room temperature for 1 h. The solvent is removed and the residue is taken up in DCM. The organic phase is washed with a saturated aqueous solution of NH4CI then brine and the DCM is removed under reduced pressure to afford, after drying under <n="87"/>vacuum at 400C, 637 mg (71percent) of the title compound as a yellowish powder. 1H NMR (DMSO- dtf) δ 9.20-8.90 (m, IH), 8.85-8.75 (m, IH), 8.40-8.05 (m, IH), 7.80-7.40 (m, 3H).
17% at 100℃; for 3 h; Pyridine-3-sulfonyl chloride (1.00 g, 6.13 mmol, 1 eq) and ammonium carbonate (1.77 g, 18.4 mmol, 3 eq) were heated at 100 °C for 3 h.
After cooling and evaporation, the residue was purified by column chromatography, using PE/EtOAc 4:6 as eluant to give 4 as yellowish solid. (0.16 g, 17percent).
Mp 106-108 °C dec. 1H NMR (300 MHz, DMSO-d6) δ 8.96 (d, J = 2.4 Hz, 1-H), 8.77 (dd, J = 4.6/1.5 Hz, 1-H), 8.16 (dd, J = 8.3/1.8 Hz, 1-H), 7.60 (m, 3-H); 13C NMR (75 MHz, DMSO-d6) δ 153.1, 146.9, 140.7, 134.2, 124.6; MS (ESI) m/z 159 (M + H)+; IR (KBr) 3308, 2681, 1568, 1347, 1171 cm-1. Anal. Calcd for C5H6N2O2S: C, 37.97; H, 3.82; N, 17.71. Found: C, 38.15; H, 73.90; N, 18.10.
9% With ammonium hydroxide In methanol at 20℃; for 20 h; General procedure: Standard Procedure D for the Preparation of Sulfonamides (0054) A solution of sulfonyl chloride in methanol and ammonium hydroxide solution was stirred at 0° C. or room temperature. After the reaction was complete, methanol was removed under reduced pressure. The solution was extracted with ethyl acetate. The combined organic layers were dried over MgSO4(s), filtered, and concentrated to give the desired products without further purification. Step 1.
3-Pyridinesulfonamide
Following standard procedure D, pyridine-3-sulfonyl chloride (0.450 g, 2.53 mmol), methanol (3.0 mL), and ammonium hydroxide solution (15 mL) were used to carry out the reaction.
After the reaction was stirred at room temperature for 20 h and work-up, 3-pyridinesulfonamide (35.7 mg, 9percent) was obtained as a green solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.96 (s, 1H), 8.78 (d, 1H), 8.19-8.16 (m, 1H), 7.64-7.60 (m, 3H).

Reference: [1] Heterocycles, 2007, vol. 71, # 9, p. 1975 - 1990
[2] Patent: CN107098846, 2017, A, . Location in patent: Paragraph 2373-2376
[3] Patent: WO2008/101979, 2008, A1, . Location in patent: Page/Page column 85-86
[4] Journal of the American Chemical Society, 1992, vol. 114, # 12, p. 4889 - 4898
[5] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 58 - 66,9
[6] Patent: US2017/253569, 2017, A1, . Location in patent: Paragraph 0054; 0484-0485
[7] Monatshefte fuer Chemie, 1939, vol. 72, p. 77,88
[8] Journal of Organic Chemistry, 1991, vol. 56, # 11, p. 3470 - 3472
[9] Crystal Growth and Design, 2012, vol. 12, # 9, p. 4567 - 4573
[10] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2267 - 2272
  • 13
  • [ 16133-25-8 ]
  • [ 65001-21-0 ]
Reference: [1] Patent: WO2018/85348, 2018, A1, . Location in patent: Paragraph 0311
  • 14
  • [ 16133-25-8 ]
  • [ 881674-56-2 ]
  • [ 881677-11-8 ]
YieldReaction ConditionsOperation in experiment
90.6% With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃; for 2 h; Take 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 300 g, 4-dimethylaminopyridine 37.5 g, N,N-diisopropylethylamine 300 g, 1L acetonitrile, and add to the reaction flask.300 g of pyridine-3-sulfonyl chloride was dissolved in 1L of acetonitrile, and added dropwise to the above reaction system at 20-30[deg.] C., and the addition was completed in about 1 hour.After the dripping, the system was heated to 40-50°C, and the reaction was continued for 1 hour until the raw material was consumed completely.The system was cooled down to 30° C., and 1.8 L of purified water was added to quench the reaction. The pH was adjusted to 4 to 5 with 0.5 mol/L HCl, and a yellow solid precipitated.To the system, 3.6 L of purified water was added and stirred at 0 to 10C for 1 hour.After suction filtration, the filter cake was washed with 900 ml of acetonitrile: purified water (1:2) and 900 ml of purified water, and dried under reduced pressure at 50° C. to obtain 475 g of a brown powdery solid with a yield of 90.6percent.
88.7% With dmap; triethylamine In acetonitrile at 45℃; for 1.5 h; Example 1 (chlorobenzene solvent) 5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde (0141) Pyridine-3-sulfonic acid (10.7 g, 68.5 mmol) and phosphorus pentachloride (15.7 g, 75.4 mmol) were suspended in chlorobenzene (15 mL) at room temperature. After heating and stirring at an inside temperature of 105±5°C for about 3 hr, the mixture was cooled to room temperature. Toluene (50 mL) and water (30 mL) were added into another kolben, and the mixture was cooled to an inside temperature of 5±5°C. The reaction solution was added dropwise at not more than an inside temperature of 15°C, and the dropping funnel was washed well with a mixed solution of toluene and water (1:1, 20 mL). After cooling to an inside temperature of 5±5°C, 50percent aqueous potassium carbonate solution (39 mL) was added dropwise at not more than an inside temperature of 20°C, and the mixture was adjusted to pH 7.5±0.5. After partitioning at room temperature, the organic layer was washed with 5percent brine (40 mL), and concentrated to about 20 mL under reduced pressure. Toluene (40 mL) was added and the mixture was concentrated again to about 20 mL. An operation of adding acetonitrile (40 mL) and concentrating the mixture to about 20 mL was repeated three times to give an acetonitrile solution of pyridine-3-sulfonylchloride (quantified yield 10.7 g, 87.9percent, total amount 20.3 g, 52.7 w/wpercent acetonitrile solution). (0142) To the acetonitrile solution (total amount) of pyridine-3-sulfonylchloride obtained above were added acetonitrile (45 mL), 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (10.0 g, 52.9 mmol), N,N-dimethylpyridin-4-amine (0.646 g, 5.29 mmol) and triethylamine (10.4 mL, 74.1 mmol), and the mixture was heated to an inside temperature of 45±5°C. After stirring at an inside temperature of 45±5°C for 1.5 hr, the mixture was cooled to room temperature, and water (30 mL) was added dropwise. The mixture was adjusted to pH 4 - 5 with 0.5M hydrochloric acid (about 20 mL). The seed crystal of the title compound was added and, after confirmation of crystal precipitation, water (60 mL) was added dropwise. After stirring at room temperature for 30 min and at 5±5°C for 1 hr, the precipitated crystals were collected by filtration. The crystals were washed twice with a mixed solution of acetonitrile and water (1:2, 30 mL) cooled to 5±5°C in advance, and dried at an outer temperature of 50°C under reduced pressure to give the title compound (15.5 g, isolation yield 88.7percent). 1H NMR (500 MHz, CDCl3) δ 6.68 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J = 8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 1.9 Hz, 1H), 8.82 (dd, J = 4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
87.9% With dmap; N,N-diethyl-N-isopropylamine In acetonitrile at 15 - 50℃; for 3 h; Large scale Volonadezan Intermediate II 2.0Kg, N,N-dimethyl-4-aminopyridine 109g, Diethylisopropylamine 1.9Kg Acetonitrile 16L, pyridine-3-sulfonyl chloride 1.9Kg Acetonitrile 6L And then added dropwise at a temperature of 15°C to 25°C,After dripping, heat to 40°C to 50°C and stir for 3 hours.After cooling to 0 ~ 10 °C, add 12 L of water dropwise, cool to 0 ~ 10 °C, and stir for 1 hour.Filtration, drying at 40° C. to 50° C. (-0.08 to −1.0 MPa) for 8 to 12 hours gives Warnarazan Intermediate III 3.07 Kg with a yield of 87.9percent, which is directly input to the next step.
87% With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 50℃; for 1 h; 5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (7.0 g, 37.00 mmol), N,N-dimethylpyridine-4-amine (0.902 g, 7.38 mmol), diisopropylethylamine (6.69 g, 51.80 mmol) and acetonitrile (28 mL) were added to a four-necked flask, then pyridine-3-sulfonyl chloride (7.89 g, 44.42 mmol) was added dropwise, and the mixture was washed well with acetonitrile (3.5 mL).
The mixture was stirred at an inside temperature of 40-50° C. for about 1 hr, and cooled to an inside temperature of 25-35° C., and water (21 mL) was added dropwise at the same temperature.
Then the mixture was adjusted to pH 4-5 at room temperature with 0.5N hydrochloric acid (8 mL), and water (41 mL) was added dropwise at room temperature.
After stirring at room temperature for 30 min, the inside temperature was cooled to 0-10° C., and the mixture was stirred for 1 hr.
The precipitated crystals were collected by filtration, washed with acetonitrile (14 mL)/water (28 mL) cooled to 5° C., and dried under reduced pressure at 50° C. until a constant weight was reached to give the title compound (10.6 g, yield 87.0percent).
1H-NMR (CDCl3, TMS, 500 MHz) δ (ppm): 6.68 (d, J=1.6 Hz, 1H), 7.02 (dd, J=8.2, 8.2 Hz, 1H), 7.14-7.19 (m, 2H), 7.38 (dd, J=8.2, 4.9 Hz, 1H), 7.44-7.48 (m, 1H), 7.72 (ddd, J=8.2, 2.5, 1.6 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.82 (dd, J=4.7, 1.6 Hz, 1H), 9.90 (s, 1H).
86.7% With N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 50℃; for 1.5 h; Example 4
5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrole-3-carbaldehyde
5-(2-Fluorophenyl)-1H-pyrrole-3-carbaldehyde (5.00 g, 26.43 mmol), N,N-dimethylpyridin-4-amine (0.65 g, 5.29 mmol), diisopropylethylamine (4.78 g, 37.00 mmol) and acetonitrile (18.5 ml) were added in a four neck flask, and a solution of pyridine-3-sulfonyl chloride (5.63 g, 31.71 mmol) in acetonitrile (5 ml) was added.
Acetonitrile (1.5 ml) was further added, and the mixture was stirred at the internal temperature of 40-50° C. for 1.5 hr.
The internal temperature was cooled to 30° C., and water (15 ml) was added dropwise.
The mixture was adjusted to pH 4-5 with 0.5 N hydrochloric acid.
Seed crystals (2.5 mg) of the title compound were added, and then water (about 30 ml) was added dropwise.
After stirring at the internal temperature of 20-30° C. for 0.5 hr, the internal temperature was cooled to 0-10° C., and the mixture was stirred for 1 hr.
The precipitated crystals were collected by filtration, washed with a cold mixed solution of acetonitrile and water (1:2, 7.5 ml), and water (7.5 ml*2), and dried under reduced pressure at 50° C. until a constant weight was reached to give the title compound (7.57 g, yield 86.7percent).
1H-NMR (300 MHz, CDCl3) δ (ppm): 6.68 (d, J=1.7 Hz, 1H), 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72 (m, 1H), 8.15 (d, J=1.8 Hz, 1H), 8.58 (d, J=1.7 Hz, 1H), 8.82 (dd, J=4.8, 1.5 Hz, 1H), 9.90 (s, 1H).
elemental analysis (C16H11N2O3SF). Calculated: C, 58.17; H, 3.36; N, 8.48; O, 14.53; S, 9.71; F, 5.75.Found: C, 58.32; H, 3.46; N, 8.54; S, 9.76; F, 5.62.melting point 106-108° C.
86.6% With dmap; triethylamine In dichloromethane for 2 h; 10.00 g of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde, 1.29 g of 4-dimethylaminopyridine (DMAP), 7.49 g of triethylamine, and 1 L of dichloromethane were put into the reactor, and the temperature was reduced by stirring. 11.26 g of pyridine-3-sulfonyl chloride was added dropwise, and the reaction was stirred for 2 hours after the dropwise addition.Add water 20ml quench reaction, followed by 20ml of water, the mass percentage concentration of 20percent sodium chloride solution 20ml washing, distillation, add 70ml 75percent ethanol solution to heat the solution, cooling crystallization, filtration, washing, drying to obtain 1-(3- Pyridinesulfonyl)-5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde 15.12 g.Yield 86.60percent.
68% With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 1.08 h; 200 mg of intermediate VI-1 was dissolved in 15 ml of anhydrous tetrahydrofuran, and the temperature was lowered to 0 ° C, then 1.3 ml of 1 M bistrimethylsilylamide lithium was added dropwise, and the reaction was continued at 0 ° C after the addition was completed. After a minute, 213 mg of pyridine-3-sulfonyl chloride was further added, followed by incubation at 0 ° C for 5 minutes, and then the reaction was continued to room temperature for 1 hour. After completion of the reaction, the reaction was quenched by the addition of sodium hydrogen carbonate solution, and the mixture was evaporated to dryness. column chromatography to give the compound of formula VII-1, 237 mg of a white solid, yield 68percent
15.5 g With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 40 - 50℃; for 2 h; Acetonitrile (50 ml) was added to the reaction flask at room temperature,5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (10 g)4-dimethylaminopyridine (1.3 g)And N, N-diisopropylethylamine (13 g),40 ~ 50 stirring reaction 2 hours after the thin layer chromatography to complete the reaction.Adding 1mol / L hydrochloric acid solution to the reaction system to adjust pH = 4 ~ 5,Add water (60ml) and stir.filter,dry,To give 5- (2-fluorophenyl) -1 - [(pyridin-3-yl) sulfonyl] -1H-pyrrole-3-carbaldehyde(15.5 g, yellow solid).
15 g With triethylamine In acetonitrile at 45℃; for 1.5 h; 5- (2-fluorophenyl) pyrrole-3-carbaldehyde 10g, 4- dimethylaminopyridine 1.3g, triethylamine 7.5g and acetonitrile (40ml) added to the reaction flask, stirred at room temperature; pyridine-3-sulfonyl chloride 11.3g and acetonitrile (10ml), the reaction flask was added dropwise; the reaction was heated to 45 1.5 hours; cooled to 25 , was added water (30ml); the system with concentrated hydrochloric acid adjusted to ph 4-5, stirred for half an hour at 25 deg.] C; was cooled to 0-5 deg.] C stirred for 1 hour; the filter cake with acetonitrile: water (1: 2) 30ml rinsed again with water (20ml) was rinsed 2 times, 50 deg.] C and dried in vacuo to give 5- (2-fluorophenyl yl) -1- (pyridin-3-sulfonyl) pyrrole-3-carbaldehyde 15g;

Reference: [1] Patent: CN106478601, 2017, A, . Location in patent: Paragraph 0036; 0037
[2] Patent: EP2963019, 2016, A1, . Location in patent: Paragraph 0142; 0146
[3] Patent: CN107586288, 2018, A, . Location in patent: Paragraph 0035-0037
[4] Patent: US2018/186736, 2018, A1, . Location in patent: Paragraph 0142; 0143
[5] Patent: US2011/306769, 2011, A1, . Location in patent: Page/Page column 28-29
[6] Patent: CN107778286, 2018, A, . Location in patent: Paragraph 0057-0058
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 9, p. 4446 - 4456
[8] Patent: CN108558831, 2018, A, . Location in patent: Paragraph 0166-0169
[9] Patent: CN106478597, 2017, A, . Location in patent: Paragraph 0029; 0030; 0031; 0032
[10] Patent: CN104860926, 2017, B, . Location in patent: Paragraph 0058-0061
  • 15
  • [ 16133-25-8 ]
  • [ 881677-11-8 ]
YieldReaction ConditionsOperation in experiment
299.6 g at 30℃; for 0.5 h; Inert atmosphere (2) To the reaction of step (1), 556.7 g of pyridine-3-sulfonyl chloride was slowly added dropwise to control the reaction temperature at 30 ± 2 ° CAfter the addition was complete, the air was replaced with nitrogen, the nitrogen pressure was controlled to 0.01 MPa, and the reaction was carried out for 0.5 hour. The reaction mixture was pressure filtered into a distillation kettle, and the solvent was distilled off under reduced pressure to distillate,The inside temperature was controlled below 50 ° C and the degree of vacuum was ≥ 0.07 MPa. After completion of the concentration, 420 g of ethyl acetate and 3360 g of n-hexane were added and 18.9 g of activated carbon was added with stirring. The mixture was heated to 60 ° C for 1 hour, filtered and cooled to 5 And the mixture was dried at a temperature of 40 ° C and a vacuum of ≥ to 0.08 MPa for 5 hours to obtain a crude product of the compound (I).(3) To a recrystallization kettle, 1873.8 g of methanol was added, and the mixture was stirred and the crude compound (I) obtained in step (2)Product, close the feed port, replace the air with nitrogen to keep the pressure ≥0.01MPa, heated to 50 dissolved 15min to clarify, cooling crystallization to 0 , heat crystallization 1 hour, centrifuge, wash the cake with methanol, The wet product was charged into a double cone dryer and replaced with a small flow of nitrogen under reduced pressure for 3 times. The drying temperature was 30 to 40 ° C and the degree of vacuum was ≥ 0.08 MPa. After drying for 1 hour, Vacuum alternately replaced three times, the drying temperature rose to 40 ~ 50 continue to dry for 2 hours; then nitrogen and vacuum alternately replaced 3 times, the drying temperature rose to 50 ~ 60 continue to dry for 2 hours, after cooling 299.6 g of the compound (1) was obtained. HPLC compound (1) content of 99.89percent, single largest impurity 0.04percent
Reference: [1] Patent: CN106397404, 2017, A, . Location in patent: Paragraph 0035-0037; 0039; 0040; 0043; 0044; 0051; 0052
  • 16
  • [ 16133-25-8 ]
  • [ 881677-11-8 ]
YieldReaction ConditionsOperation in experiment
304.3 g at 30℃; for 0.5 h; Inert atmosphere (2) to the step (1) in the reaction slowly dropping 477.2g pyridine - 3 - sulfonyl chloride, control the reaction temperature is 30 ± 2 °C, after dropping, replace the nitrogen after the air, control nitrogen pressure ≥ 0.01 mpa, thermal insulation stirring for 0.5 hours, the reaction mix the hydraulic filters to in distillation, distillation under reduced pressure until the solvent is recovered to non-distillate, nylon control in 50 °C following, vacuum degree ≥ - 0.07 mpa, concentrated end, adding 405g ethyl acetate and 2430g hexane, added under mixing 11.3g activated carbon, heating up to 70 °C decoloring 0.5 hours, filter press, the temperature crystallization to 3 °C, thermal crystallization 1.5 hours, centrifugal, and 50 °C, vacuum degree ≥ - 0.08 mpa depressurized and dried under the 4 hours, to obtain compound (I) crude 315.3g. (3) added to the re-crystallized in the 1576.5g methanol, opening stirring, adding step (2) of the resulting compound (I) crude, the feeding inlet is closed, replace the nitrogen air to keep pressure ≥ 0.01 mpa, raising the temperature to 60 °C dissolved 20min to clarify, lowering the temperature to 2 °C, thermal crystallization 1.5 hours, centrifugal, washing the filter cake with methanol, after drying, discharging, the wet product into the double-cone dryer, injecting the small flow under reduced pressure nitrogen replacement is to be performed 3 times, control the drying temperature is 30 - 40 °C, vacuum degree ≥ - 0.08 mpa, drying 2 hours, nitrogen and vacuum alternately replaced 3 times, the drying temperature is raised to 40 - 50 °C continue to drying 2 hours; then nitrogen and vacuum alternately replaced 3 times, the drying temperature is raised to 50 - 60 °C continue to drying 1 hour, after lowering the discharge shall be 304.3g compound (1) of the finished product. HPLC compounds (1) content 99.76percent, a single maximum impurity 0.06percent.
Reference: [1] Patent: CN106397404, 2017, A, . Location in patent: Paragraph 0051; 0052; 0055; 0056; 0059; 0060
  • 17
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  • [ 881677-11-8 ]
Reference: [1] Patent: CN108503621, 2018, A,
  • 18
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  • [ 1083326-26-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2017, vol. 60, # 9, p. 3795 - 3803
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Chemical Structure| 6684-39-5

[ 6684-39-5 ]

2-Chloro-5-pyridinesulfonyl chloride

Similarity: 0.67

Chemical Structure| 636-73-7

[ 636-73-7 ]

Pyridine-3-sulfonic acid

Similarity: 0.64