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Chemical Structure| 70-55-3
Chemical Structure| 70-55-3
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Product Details of [ 70-55-3 ]

CAS No. :70-55-3 MDL No. :MFCD00011692
Formula : C7H9NO2S Boiling Point : -
Linear Structure Formula :- InChI Key :LMYRWZFENFIFIT-UHFFFAOYSA-N
M.W : 171.22 Pubchem ID :6269
Synonyms :
Chemical Name :4-Methylbenzenesulfonamide

Calculated chemistry of [ 70-55-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.14
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 42.4
TPSA : 68.54 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) : -6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.21
Log Po/w (XLOGP3) : 0.82
Log Po/w (WLOGP) : 1.72
Log Po/w (MLOGP) : 0.63
Log Po/w (SILICOS-IT) : 0.4
Consensus Log Po/w : 0.96

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.76
Solubility : 3.0 mg/ml ; 0.0175 mol/l
Class : Very soluble
Log S (Ali) : -1.84
Solubility : 2.47 mg/ml ; 0.0144 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.35
Solubility : 0.774 mg/ml ; 0.00452 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.62

Safety of [ 70-55-3 ]

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

Application In Synthesis of [ 70-55-3 ]

* 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 [ 70-55-3 ]
  • Downstream synthetic route of [ 70-55-3 ]

[ 70-55-3 ] Synthesis Path-Upstream   1~38

  • 1
  • [ 70-55-3 ]
  • [ 79-11-8 ]
  • [ 1080-44-0 ]
Reference: [1] Angewandte Chemie, 1926, vol. 39, p. 1460[2] Chem. Zentralbl., 1930, vol. 101, # I, p. 3485
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 16, p. 293
  • 2
  • [ 7647-01-0 ]
  • [ 15436-23-4 ]
  • [ 90345-62-3 ]
  • [ 70-55-3 ]
  • [ 825-99-0 ]
Reference: [1] Journal of the Chemical Society, 1927, p. 193
  • 3
  • [ 70-55-3 ]
  • [ 63160-12-3 ]
Reference: [1] Chemistry - An Asian Journal, 2013, vol. 8, # 5, p. 883 - 887
[2] Patent: JP2017/52729, 2017, A,
  • 4
  • [ 100-52-7 ]
  • [ 70-55-3 ]
  • [ 63160-12-3 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 12, p. 4894 - 4904
[2] Journal of Organic Chemistry, 2011, vol. 76, # 12, p. 4894 - 4904
[3] Patent: EP2009006, 2008, A1,
  • 5
  • [ 590-28-3 ]
  • [ 70-55-3 ]
  • [ 1694-06-0 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1971, # 10, p. 3600 - 3603
  • 6
  • [ 70-55-3 ]
  • [ 40724-47-8 ]
Reference: [1] Patent: WO2017/216726, 2017, A1, . Location in patent: Page/Page column 629
  • 7
  • [ 2213-63-0 ]
  • [ 70-55-3 ]
  • [ 4029-41-8 ]
Reference: [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1994, vol. 30, # 3, p. 340 - 344[2] Khimiya Geterotsiklicheskikh Soedinenii, 1994, # 3, p. 387 - 392
  • 8
  • [ 56234-52-7 ]
  • [ 70-55-3 ]
  • [ 52667-89-7 ]
Reference: [1] Tetrahedron Letters, 1999, vol. 40, # 52, p. 9363 - 9365
[2] European Journal of Organic Chemistry, 2001, # 22, p. 4233 - 4238
  • 9
  • [ 70-55-3 ]
  • [ 111-40-0 ]
  • [ 56187-04-3 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, p. 1562 - 1571[2] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 8, p. 1731 - 1742
  • 10
  • [ 696-59-3 ]
  • [ 70-55-3 ]
  • [ 17639-64-4 ]
YieldReaction ConditionsOperation in experiment
76% for 2 h; Reflux A mixture of p-toluenesulfonamide (20 g, 116.8 mmol) and 2,5-dimethoxytetrahydrofuran (20 mL, 154 mmole) in acetic acid (100 mL) was heated at reflux for 2 hours. The mixturewas allowed to cool to room temperature, then poured into water (1 L). The mixture was allowed to stand for 1 hour, then the precipitate was isolated by filtration and recrystallised form ethanol to give N-tosylpyrrole (19.72 g, 76percent) as colourless crystals.
Reference: [1] Synthetic Communications, 1995, vol. 25, # 12, p. 1857 - 1861
[2] Journal of Chemical Research, 2009, # 1, p. 14 - 16
[3] Tetrahedron Letters, 2007, vol. 48, # 23, p. 4047 - 4050
[4] Organic Preparations and Procedures International, 2006, vol. 38, # 5, p. 495 - 500
[5] Tetrahedron Letters, 2009, vol. 50, # 34, p. 4807 - 4809
[6] Synlett, 2009, # 14, p. 2245 - 2248
[7] Synthesis (Germany), 2017, vol. 49, # 20, p. 4711 - 4716
  • 11
  • [ 70-55-3 ]
  • [ 17639-64-4 ]
Reference: [1] Organic and Biomolecular Chemistry, 2012, vol. 10, # 26, p. 5119 - 5130
  • 12
  • [ 541-41-3 ]
  • [ 70-55-3 ]
  • [ 5577-13-9 ]
Reference: [1] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2008, vol. 71, # 2, p. 523 - 528
[2] Chemical and Pharmaceutical Bulletin, 2008, vol. 56, # 4, p. 541 - 546
[3] Patent: DE1011414, 1955, ,
[4] Journal of Organic Chemistry, 1971, vol. 36, p. 4102 - 4105
[5] Patent: DE1011414, 1953, ,
[6] Patent: DE965400, 1955, ,
  • 13
  • [ 70-55-3 ]
  • [ 1608-26-0 ]
  • [ 5577-13-9 ]
Reference: [1] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1712 - 1718
  • 14
  • [ 70-55-3 ]
  • [ 5577-13-9 ]
Reference: [1] Tetrahedron Letters, 2016, vol. 57, # 13, p. 1476 - 1478
[2] Tetrahedron Letters, 2016, vol. 57, # 13, p. 1476 - 1478
  • 15
  • [ 70-55-3 ]
  • [ 21187-98-4 ]
YieldReaction ConditionsOperation in experiment
91.9% With N,N-dimethyl-formamide In toluene for 2 h; Reflux In 1000mL90 g (0.53 mol) of p-toluenesulfonamide was added to the reaction flask, N-(hexahydrocyclopenta[c]pyrrole-2-(1H)-yl)aminocarbonyl chloride94.3 (0.5 mol)DMF 6 g, toluene 300 mL. The temperature was raised to reflux temperature for 2 hours,After completion of the reaction, 300 g of water was added. Cooling crystallization, precipitation of white solid,Filtered and dried, and then recrystallized from ethyl acetate to obtain gliclazide 148.62 g (0.46 mol)Yield 91.9percent.
Reference: [1] Patent: CN106831536, 2017, A, . Location in patent: Paragraph 0017; 0019
  • 16
  • [ 93018-67-8 ]
  • [ 302-17-0 ]
  • [ 70-55-3 ]
Reference: [1] Russian Journal of Organic Chemistry, 2000, vol. 36, # 12, p. 1760 - 1764
  • 17
  • [ 473-34-7 ]
  • [ 79-01-6 ]
  • [ 302-17-0 ]
  • [ 83790-89-0 ]
  • [ 93018-67-8 ]
  • [ 70-55-3 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1986, vol. 22, p. 681 - 685[2] Zhurnal Organicheskoi Khimii, 1986, vol. 22, # 4, p. 763 - 768
  • 18
  • [ 70-55-3 ]
  • [ 109-64-8 ]
  • [ 14002-33-6 ]
Reference: [1] Zhurnal Obshchei Khimii, 1938, vol. 8, p. 1547[2] Chem. Zentralbl., 1939, vol. 110, # I, p. 4951
  • 19
  • [ 70-55-3 ]
  • [ 138-41-0 ]
YieldReaction ConditionsOperation in experiment
94.05% at 100℃; for 10 h; Example 11: Weigh 1 mmol of p-carboxybenzenesulfonamide,3,5-dinitro-N-hydroxy-N-methylbenzamide0.05 mmol, cobalt acetate 0.01 mmol,Add 25mL reaction bottle,Add acetic acid 5mL, into the oxygen,The reaction was continued for 10 hours while maintaining the oxygen pressure at 1 atm and raising the temperature to 100 ° C,After completion of the reaction, the reaction mixture was cooled to room temperature. The filtrate was decompressed to remove acetic acid,Acetic acid can be recycled. The residue was repeatedly washed with water to remove the residual acetic acid and the cobalt acetate co-catalyst,A small amount of acetone to remove 3,5-dinitro-N-hydroxy-N-methyl benzamide and a small amount of p-hydroxymethyl benzene sulfonimide, filter cake drying, can be carboxy benzenesulfonamide,The yield of p-toluenesulfonamide was 94.05percent, the conversion of p-toluenesulfonamide was 99.33percent, the selectivity to p-carboxybenzenesulfonamide was 94.68percent. The purity of the product was 95.14percent by Agilent1200 high performance liquid chromatograph.
90% With sodium hydroxide; potassium permanganate In water at 70 - 90℃; for 2 h; Example 3
p-Aminosulfonyl-benzoic Acid
To the solution of 17.1 g (0.1 mol) of p-toluenesulfonamide prepared in Example 1, 20 g (0.5 mol) of sodium hydroxide in 300 ml of water was added in portions 20 g (0.13 mol) of potassium permanganate.
The temperature raised to 70° C. spontaneously, keep the reaction mixture in 90° C. for 2 h.
The mixture was then cooled and filtered, and the filtrate was acidified with HCl.
The resulting precipitate was filtered, and washed with water, dried in vacuo to give the title compound (18.1 g) as white powder, yield 90percent, m.p. 291-292° C.
17.2 g With hydrogenchloride; sodium bromate; sodium bromide In water at 25 - 100℃; for 13 h; This example illustrates the Carboxylazo sulfonamide preparation method of the present invention provides.At room temperature (25 ), the will-methyl-benzenesulfonamide 17.1g (100mmol), sodium bromate 16.6g (110mmol), sodium bromide 0.1g (1mmol) sequentially into 500mL four-necked flask was added 150mL of water as a solvent starting mix means open condensate, temperature was raised to 95 deg.] C, after complete dissolution of the solid (dissolution time of 30min), the reaction solution was added dropwise (dropping of 0.6mL / min) at a concentration of 37percent by weight of concentrated hydrochloric acid 7g (71mmol), to become increasingly red color of the reaction solution, incubated at 100 solids after about 1h, and then reacted with stirring 12h, the reaction solution until the color faded completely off the heating, the reaction mixture was cooled to room temperature, followed suction filtration, washed with water and dried to give 17.2g of white solid with a purity of 97percent, a yield of 83percent by weight.
Reference: [1] Patent: CN105801455, 2016, A, . Location in patent: Paragraph 0048
[2] Patent: US2004/58977, 2004, A1, . Location in patent: Page/Page column 8; 14
[3] American Chemical Journal, 1885, vol. 7, p. 147
[4] Justus Liebigs Annalen der Chemie, 1875, vol. 178, p. 284
[5] Journal of the Chemical Society, 1951, p. 1877,1880
[6] Bollettino Chimico Farmaceutico, 1956, vol. 95, p. 287,290
[7] Rep.Gov.chem.ind.Res.Inst.Tokyo, 1950, vol. 45, p. 295,297[8] Chem.Abstr., 1952, p. 4269
[9] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 6, p. 1873 - 1882
[10] Patent: CN105693565, 2016, A, . Location in patent: Paragraph 0044; 0045; 0046
[11] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 3, p. 1286 - 1293
  • 20
  • [ 7732-18-5 ]
  • [ 7080-50-4 ]
  • [ 138-41-0 ]
  • [ 70-55-3 ]
Reference: [1] Apoth.-Ztg., vol. 44, p. 989,991[2] Chem. Zentralbl., 1929, vol. 100, # II, p. 2225
  • 21
  • [ 55962-05-5 ]
  • [ 64-19-7 ]
  • [ 3240-34-4 ]
  • [ 70-55-3 ]
Reference: [1] Tetrahedron Letters, 2009, vol. 50, # 40, p. 5578 - 5581
  • 22
  • [ 319-89-1 ]
  • [ 1202-36-4 ]
  • [ 527-31-1 ]
  • [ 70-55-3 ]
Reference: [1] Journal of Organic Chemistry USSR (English Translation), 1990, vol. 26, # 4, p. 705 - 711[2] Zhurnal Organicheskoi Khimii, 1990, vol. 26, # 4, p. 823 - 830
  • 23
  • [ 70-55-3 ]
  • [ 292638-85-8 ]
  • [ 100-46-9 ]
  • [ 23574-01-8 ]
  • [ 793-19-1 ]
  • [ 62456-75-1 ]
Reference: [1] Green Chemistry, 2013, vol. 15, # 6, p. 1550 - 1557
  • 24
  • [ 15436-23-4 ]
  • [ 7722-84-1 ]
  • [ 5345-27-7 ]
  • [ 70-55-3 ]
Reference: [1] Journal of the Chemical Society, 1927, p. 193
  • 25
  • [ 86476-54-2 ]
  • [ 41085-71-6 ]
  • [ 784-50-9 ]
  • [ 70-55-3 ]
Reference: [1] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical, 1983, vol. 22, # 9, p. 774 - 777
[2] Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical, 1983, vol. 22, # 9, p. 774 - 777
  • 26
  • [ 70-55-3 ]
  • [ 79-22-1 ]
  • [ 14437-03-7 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With triethylamine In dichloromethane at 0℃; for 0.166667 h;
Stage #2: at 0 - 20℃; for 2.5 h;
General procedure: A solution of a 4-subsituted benzenesulfonamide in dry dichloromethane was placed on an ice bath and cooledto 0 °C after which trimethylamine was added dropwise. The mixture was stirredat 0 °C for 10 min before methyl chloroformate was added dropwise. Afterstirring for an additional 30 min at 0 °C, the ice bath was removed and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was diluted with dichloromethane, washed with 1 M HCl (aq.),water, and brine in sequence, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield the desired 4-substituted methyl(phenylsulfonyl)carbamate.
Reference: [1] Journal of the Chinese Chemical Society, 2007, vol. 54, # 3, p. 771 - 777
[2] Organic Process Research and Development, 2016, vol. 20, # 2, p. 440 - 445
[3] Tetrahedron Letters, 2016, vol. 57, # 13, p. 1476 - 1478
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 3, p. 627 - 643
[5] Journal of Medicinal Chemistry, 2017, vol. 60, # 3, p. 1126 - 1141
  • 27
  • [ 3113-71-1 ]
  • [ 70-55-3 ]
  • [ 96784-54-2 ]
YieldReaction ConditionsOperation in experiment
23 % With pyridine; phosphorus pentachloride; trichlorophosphate In dichloromethane Part A
Preparation of the intermediate 4-nitro-3-tolunitrile, represented by the formula:
A mixture of PCl5 (200 g, 0.96 mole) and p-toluene sulfonamide (90 g, 0.52 mole) was treated with 3-methyl-4-nitrobenzoic acid (82 g, 0.44 mole).
The reaction was stirred at room temperature for 1 hour at which time it was heated to 140°C and the POCl3 (150 ml) distilled from the mixture.
The reaction was cooled to 5°C, pyridine (200 ml) was carefully added and the mixture allowed to stand overnight.
The reaction was carefully diluted to 1 L with H2O and the mixture stirred for 3 hours.
The brown solid was filtered, washed with H2O and triturated with 5 N aqueous NaOH.
The remaining solid was filtered, washed with H2O and dried to afford 60.0 g of a powder.
The solid was stirred in 1200 ml CH2Cl2 and filtered.
The supernatant was evaporated in vacuo and the residue recrystallized from EtOH to give 35.9 g (23 percent) of 4-nitro-3-tolunitrile.
MS(FD), m/e 162 (M+).
Reference: [1] Patent: EP655439, 1995, A2,
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  • [ 4703-15-5 ]
Reference: [1] RSC Advances, 2014, vol. 4, # 24, p. 12119 - 12126
  • 29
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  • [ 57-66-9 ]
Reference: [1] Bollettino Chimico Farmaceutico, 1956, vol. 95, p. 287,290
  • 30
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  • [ 127-65-1 ]
Reference: [1] Synthesis, 2009, # 16, p. 2797 - 2801
[2] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2004, vol. 59, # 1, p. 63 - 72
[3] International Journal of Chemical Kinetics, 2005, vol. 37, # 9, p. 572 - 582
  • 31
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  • [ 127-65-1 ]
Reference: [1] International Journal of Chemical Kinetics, 1995, vol. 27, # 7, p. 663 - 674
  • 32
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  • [ 106058-85-9 ]
Reference: [1] Synthesis (Germany), 2017, vol. 49, # 20, p. 4711 - 4716
  • 33
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  • [ 67-66-3 ]
  • [ 122-66-7 ]
  • [ 531-85-1 ]
  • [ 70-55-3 ]
  • [ 17082-12-1 ]
Reference: [1] Journal of the American Chemical Society, 1931, vol. 53, p. 1478,1481
  • 34
  • [ 62-53-3 ]
  • [ 71100-56-6 ]
  • [ 41384-83-2 ]
  • [ 70-55-3 ]
Reference: [1] Polish Journal of Chemistry, 1992, vol. 66, # 10, p. 1623 - 1626
  • 35
  • [ 21187-98-4 ]
  • [ 70-55-3 ]
  • [ 58108-05-7 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1986, vol. 34, # 7, p. 2957 - 2962
  • 36
  • [ 70-55-3 ]
  • [ 481054-89-1 ]
Reference: [1] Tetrahedron Letters, 2002, vol. 43, # 35, p. 6209 - 6211
  • 37
  • [ 71785-96-1 ]
  • [ 70-55-3 ]
  • [ 1025424-03-6 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 5, p. 2499 - 2512
  • 38
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  • [ 70-55-3 ]
  • [ 13573-28-9 ]
YieldReaction ConditionsOperation in experiment
76% With potassium hydroxide In ethanol for 90 h; Reflux 2.2
Preparation of N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5)
To a solution of KOH (179 g, 3.2 mol) and p-tosylamide (205 g, 1.2 mol) in 1500 mL ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (324 g, 1.0 mol) was added at room temperature and the reaction mixture was heated to reflux for 90 h.
The solvent was removed by evaporation, 2000 mL 1 M KOH was added and the white suspension was left to stir for another 2 h at room temperature.
The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral.
The filter cake was dried under high vacuum to give N-tosyl-2-oxa-6-azaspiro[3.3]heptane (5, 192 g, yield 76percent) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz), 4.42 (s, 4H), 3.85 (s, 4H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.4, 130.9, 130.2, 128.5, 79.1, 59.5, 37.3, 21.3.
69% With potassium hydroxide In ethanol for 45 h; Reflux Step 1
6-(Toluene-4-sulfonyl)-2-oxa-6-azaspiro[3.3]heptane
Procedure:
To a solution of KOH (4.98 g, 0.089 mol) and 4-methylbenzenesulfonamide (5.7 g, 0.033 mol) in 90 ml of ethanol, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9 g, 0.0277 mol) was added at room temperature and the reaction mixture was heated to reflux for 45 h.
The solvent was removed by evaporation, 75 ml of 1 M KOH were added and the white suspension was left to stir for another 2 h at room temperature.
The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral.
The filter cake was dried under high vacuum to give 4.87 g 6-toluene-4-sulfonyl-2-oxa-6-azaspiro[3.3]heptane (69percent) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.70-7.68 (m, 2H), 7.36-7.34 (m, 2H), 4.58 (s, 4H), 3.90 (s, 4H), 2.45 (s, 3H).
64% With potassium hydroxide In ethanol at 90℃; for 72 h; Inert atmosphere Intermediate 1 : 2,6-Diaza-spiro[3.31heptane-2-carboxylic acid tert-butyl ester, oxalic acid salt.6-(Toluene-4-sulfonyl)-2-oxa-6-aza-spiror3.31heptane. To a solution of tribromopentaerythitol (17.886 g, 55 mmol) and p-toluenesulfonamide (11.301 g, 66 mmol) in EtOH (200 ml_) was added KOH (9.875 g, 176 mmol). The reaction vessel was purged with N2 and heated to reflux (90 0C) for three days. The solvent was evaporated in vacuo and the product precipitated by stirring in 1 M KOH (100 ml_) for 2 h. The crude solid was purified (FCC) to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza- spiro[3.3]heptane as a white solid (8.939 g, 64percent). MS (ESI+): calcd for Ci2Hi5NO3S m/z 253.08, found 254.1 (M+H)+. 1H NMR (CDCI3): 7.71 (d, J = 8.2, 2H), 7.37 (d, J = 8.4, 2H), 4.58 (s, 4H), 3.91 (s, 4H).
63% With potassium hydroxide In ethanol; water for 2 h; Reflux To a solution of 3-bromo-2,2-bis(bromomethyl)propanol (127) (3.25 g, 10 mmol) and potassium hydroxide (1.12 g, 20 mmol, in 10 mL water ) in EtOH (20 mL) were added toluene-4-sulfonamide (3.76 g, 22 mmol). The reaction mixture was refluxed for 2 h, evaporated to remove EtOH then diluted with EAOAc (20 mL), washed with H20 (20 mL). The organic layer was washed with brine (20 mL), dried over Na2S04, and filtered, evaporated to give the product to give 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.6 g, 6.3 mmol, yield: 63percent).ESI-MS (M+l): 128 calc. for C7H13N
59% With potassium hydroxide In ethanol at 25 - 100℃; for 48 h; To a solution of p-toluenesulfonamide (57 g, 330 mmol) and potassium hydroxide (49.8 g, 890 mmol) in ethanol (1000 mL) was added 3-bromo-2,2-bis(bromomethyl)propan-1-ol (90 g, 270 mmol) at 25°C then the reaction mixture was stirred at 100°C for 48 h. The mixture was concentrated under reduced pressure, and the crude material was poured into solution of potassium hydroxide (75 mL) and stirred for 2 h, to afford filter cake (3) (10 g, 59percent) as a white solid.LC-MS (ESI) m/z = 254 [M+H].
58% With potassium hydroxide In ethanol at 20℃; for 92 h; Reflux To a solution of KOH (33.2g, 0.59mol) and p-tosylamide (37.9g,0.22mol) in 600ml ethano., 3- Bromo-2,2-bis(bromomethyl)propan- l -ol (154; 60. l g, 0. 19mol) was added at room temperature and the reaction mixture was heated to refluxed for 90h. The solvent was removed by evaporation, 500 ml 1 M KOH was added and the white suspension was left to stir for another 2 hours at room temperature. The mixture was filtered and the white fi lter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 6-tosyl-2-oxa-6-azaspiro[3.3]heptane (155; 30.55 g of product containing 10 molpercent of tosylamide as a white solid). The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be (155; 27.4 g, 58percent). MS (ESI) calcd for C 12H 15NO3S 253.3.
58% With potassium hydroxide In ethanol for 90 h; Reflux To a solution of KOH (33.2 g, 0.59 mol) and p-tosylamide (37.9 g, 0.22 mol) in 600 mL ethanol, 3-Bromo-2,2-bis(bromomethyl)propan-1-ol(60.1 g, 0.19 mol) was added at room temp and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 500 mL 1M KOH was added and the white suspension was left to stir for another 2 h at room temp. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 30.55 g of product containing 10 molpercent of tosylamide as a white solid. The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be 27.4 g (58percent). MS (ESI) calcd for C12H15N03S: 253.3
58% With potassium hydroxide In ethanol at 20℃; for 92 h; Reflux To a solution of KOH (33.2 g, 0.59 mol) and p-tosylamide (37.9 g, 0.22 mol) in 600 mL ethanol, 3-Bromo-2,2-bis(bromomethyl)propan-1-ol(60.1 g, 0.19 mol) was added at room temp and the reaction mixture was heated to reflux for 90 h. The solvent was removed by evaporation, 500 mL 1M KOH was added and the white suspension was left to stir for another 2 h at room temp. The mixture was filtered and the white filter cake was rinsed with water until the washing water was neutral. The filter cake was dried under high vacuum to give 30.55 g of product containing 10 molpercent of tosylamide as a white solid. The overall yield of pure 6-tosyl-2-oxa-6-azaspiro[3.3]heptane was calculated to be 27.4 g (58percent). MS (ESI) calcd for C12H15NO3S: 253.3.
57.7% With potassium hydroxide In ethanol at 90℃; for 48 h; Inert atmosphere To a solution of benzenesulfonamide (8) (5.81 g, 36.9 mmol) in 500 mL of EtOH, 3-bromo-2,2-bis(bromomethyl)propan-1-ol (9) (10 g, 30.8 mmol), KOH (5.53 g, 99 mmol) was added and heated to reflux at 90 °C for 48 h. The solvent was evaporated and 100 mL of 1 M KOH was added and the resultant white suspension was stirred for another 2 h at RT. The mixture was filtered and the residue was rinsed with water until the filtrate was neutral. The filter cake was dried under high vacuum to give crude product (4.5 g). Yield: 57.7percent; off-white solid; 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.69 (d, J = 8 Hz, 2H, Ar-H), 7.49 (d, J = 8.1 Hz, 2H, Ar-H), 4.42 (s, 4H, 2CH2, spiro morpholine), 3.84 (s, 4H, 2CH2, spiro morpholine), 2.42 (s, 3H, CH3); LC-MS (ESI +ve) m/z 254 [M+H]+; HPLC purity: 99.79percent.

Reference: [1] Fitoterapia, 2014, vol. 92, p. 111 - 115
[2] Patent: US2012/252777, 2012, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2010/141817, 2010, A1, . Location in patent: Page/Page column 29
[4] Patent: WO2011/143365, 2011, A1, . Location in patent: Page/Page column 192
[5] Patent: WO2017/15106, 2017, A1, . Location in patent: Page/Page column 40; 42; 138
[6] Angewandte Chemie - International Edition, 2008, vol. 47, # 24, p. 4512 - 4515
[7] Patent: WO2011/59839, 2011, A1, . Location in patent: Page/Page column 142-143
[8] Patent: WO2013/59587, 2013, A1, . Location in patent: Page/Page column 211; 212
[9] Patent: EP2768509, 2017, B1, . Location in patent: Paragraph 0877; 0878
[10] European Journal of Medicinal Chemistry, 2016, vol. 122, p. 475 - 487
[11] ACS Combinatorial Science, 2017, vol. 20, # 6, p. 335 - 343
[12] Chemical Communications, 2018, vol. 54, # 11, p. 1303 - 1306
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