1H-indazole-3-carboxylic acid [CAS 4498-67-3; InChIKey BHXVYTQDWMQVBI-UHFFFAOYSA-N; Reaxys, A

Query Query

Results

Date

35 reactions in Reaxys

2016-03-08 21h:23m:35s (EST)

O OH

1. Query N NH

Search as: As drawn

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

1/15

2016-03-08 21:29:14

NH

NH

N

O O

OH O

Rx-ID: 548058 View in Reaxys 1/35 Yield 100 %

Conditions & References I.2 :The conversion of the substituted isatins to the corresponding indazole-3- carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H. R., et. al., J Am. Chem. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 °C for 30 min. The burgundy solution was allowed to cool to rt and was maintained for lh. The reaction mixture was cooled to 0 °C and was treated with a 0 °C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 °C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0 °C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the slurry was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. The solid was recrystallized from acetic acid (20 mL/g) to provide the acid as a light yellow solid.. The acid was coupled with 1,4-diazabicyclo[3.2.2]nonane according to procedure A. Stage 1: With sodium hydroxide in water, Time= 1.5h, T= 20 - 50 °C Stage 2: With sulfuric acid, sodium nitrite in water, Time= 1h, T= 0 °C Stage 3: With hydrogenchloride, tin(ll) chloride in water, Time= 1.16667h Patent; MEMORY PHARMACEUTICALS CORPORATION; WO2005/111038; (2005); (A2) English View in Reaxys With sodium hydroxide, sulfuric acid, sulfur dioxide, sodium nitrite, Reagens 4: Zinnchloruer Schad; Chemische Berichte; vol. 26; (1893); p. 218 View in Reaxys With sulfuric acid, sodium nitrite, danach SnCl2 v. Auwers; Dereser; Chemische Berichte; vol. 52; (1919); p. 1345,1348 View in Reaxys v. Auwers; Lange; Chemische Berichte; vol. 55; (1922); p. 1141,1157 View in Reaxys v. Auwers; Dereser; Chemische Berichte; vol. 52; (1919); p. 1345,1348 View in Reaxys Snyder et al.; Journal of the American Chemical Society; vol. 74; (1952); p. 2009,2010 View in Reaxys With hydrogenchloride, sodium hydroxide, sulfuric acid, tin(ll) chloride, sodium nitrite, 1.) 50 - 60 deg C, Multistep reaction Norman, Mark H.; Navas III, Frank; Thompson, James B.; Rigdon, Greg C.; Journal of Medicinal Chemistry; vol.

39; nb. 24; (1996); p. 4692 - 4703 View in Reaxys 48.1a :Example 48 Ethyl 1-methyl-1H-indazole-3-carboxylate and ethyl 2-methyl-2H-indazole-3-carboxylate [0521] 1a) Ethyl 1H-Indazole-3-carboxylate [0522] In a hot solution of 4.1 g (102.5 mmol) of sodium hydroxide in 65 mL of water dissolve 14.7 g (100 mmol) of isatin. Cool this solution to 0° C. and add a solution at 0° C. of 6.9 g (100 mmol) of sodium nitrite in 25 mL of water. Add this reaction medium rapidly to a solution of 19.1 g (194.7 mmol) of concentrated sulfuric acid in 200 mL of water cooled to 0° C. by ice (the temperature of the reaction medium must not exceed 4° C. during the addition). At the end of the addition, stir for 15 minutes. Add to the reaction medium a solution of 54 g (239.3 mmol) of tin chloride dihydrate in 85 mL of concentrated hydrochloric acid cooled to 0° C. Leave to stir for 1 hour. Filter off the precipitate formed. [0523] Heat to reflux for 2 hours a solution of 12 g of the recovered solid in 200 mL of ethanol in the presence of 6 g concentrated sulfuric acid. Evaporate the solvent and take up the oil obtained in dichloromethane.

Wash the organic phase with a 4percent solution of sodium bicarbonate then by a saturated sodium chloride solution.

Dry the organic phase over anhydrous sodium sulfate, filter and evaporate to dryness. Purify the evaporation residue by successive passages through a silica gel column (dichloromethane/absolute ethanol 98/2; dichloromethane/diethyl ether: 80/20) (Int. 125). [0524] Yield: 32percent [0525] Melting point: 135° C. (dichloromethane/absolute ethanol)

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

2/15

2016-03-08 21:29:14

Stage 1: With sodium hydroxide, sodium nitrite in water, T= 0 °C Stage 2: With sulfuric acid in water, Time= 0.25h, T= 0 - 4 °C Stage 3: With hydrogenchloride, tin(ll) chloride in water, Time= 1h, T= 0 °C Patent; Le Borgne, Marc; Na, Young Min; Pagniez, Fabrice; Le Baut, Guillaume; Le Pape, Patrice; Abdala, Hiam; US2004/67998; (2004); (A1) English View in Reaxys 2.3 g

13.1 : Step 1 : lH-Indazole-3-carboxylic acid Step 1 : lH-Indazole-3-carboxylic acid: To a stirred aqueous solution of sodium hydroxide (35 mL, NaOH) was added isatine (5 g, 33.98 mmol) and the mixture was heated to 50 °C. After 10 min, the reaction mixture was cooled down to 0 °C. A precooled (0 °C) aqueous mixture of sodium nitrite (2.34 g, 33.98 mmol) and cone. H2SO4 (3.5 mL) were added to the reaction mass and stirred for 1 h at the same temperature. To the reaction mass were slowly added cone. HC1 (30 mL) and tin chloride (14.8 g, 78.16 mmol). The reaction mixture was further stirred at RT for 16 h. The precipitate obtained was filtered and washed with water to yield 2.3 g of the title product as yellow solid. 1H NMR (300 MHz, DMSOi) δ 7.27 (t, = 7.5 Hz, 1H), 7.43 (t, = 7.2 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 12.85 (br s, 1H), 13.79 (br s, 1H).

Stage 1: With sodium hydroxide in water, Time= 0.166667h, T= 50 °C Stage 2: With sulfuric acid, sodium nitrite in water, Time= 1h, T= 0 °C Stage 3: With hydrogenchloride in water, Time= 16h, T= 22 - 26 °C Patent; GLENMARK PHARMACEUTICALS S.A.; DAS, Sanjib; CHAUDHARI, Sachin Sundarlal; THOMAS, Abraham; PARDESHI, Shailesh Ramesh; DESHMUKH, Vishal Govindrao; WADEKAR, Prashant Dilip; KHAIRATKARJOSHI, Neelima; SHAH, Daisy Manish; BAJPAI, Malini; WO2015/87234; (2015); (A1) English View in Reaxys

O NH

N

N

N

O O

OH O

Rx-ID: 4794778 View in Reaxys 2/35 Yield 100%

Conditions & References 87.4 : (Step 4) (Step 4) Synthesis of indazole-3-carboxylic acid To methyl 1-acetylindazole-3-carboxylate (22.3 g, 0.10 mol) were added sodium hydroxide (8.18 g, 0.20 mol) and water (640 ml) and the resulting mixture was stirred at 60 to 70OEC for 6.5 hours.

The reaction mixture was poured in concentrated HCl (30 ml).

The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give indazole-3-carboxylic acid (17.6 g, 100percent) as a pale yellow solid.

1H-NMR (DMSO-d ) δ: 7.29 (m, 1H), 7.44 (m, 1H), 7.65 (d, J=8.6Hz, 1H), 8.10 (d, J=8.1Hz, 1H), 12.96 (broad s, 1H), 6 13.77 (broad s, 1H).

With sodium hydroxide in hydrogenchloride, water Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

97 %

With sodium hydroxide, water, Time= 1.5h, Heating Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

3/15

2016-03-08 21:29:14

O

O NH N

N

N

OH O

Rx-ID: 31190205 View in Reaxys 3/35 Yield 76 %

Conditions & References 2.B; 3 :A 3 L, half jacketed, 4-necked round bottom flask equipped with a mechanic stirrer, a thermocouple, and a nitrogen inlet, was charged with the wet cake 9, followed by the addition of 900 mL of acetic acid, and 132 g of 31percent HCl solution. The mixture was agitated, heated at 90+/-5° C. for 1 h and then was concentrated to the minimum stirring volume. To the flask was added 150 mL of N,N-dimethylacetamide (DMA). The distillation was continued until a total of 1040 mL of distillate was collected. The mixture was then cooled to 40° C. and 1000 mL of dichloromethane was slowly added. After the addition the mixture was refluxed for at least 1 h, cooled to 15° C. and aged for at least 1 h.

The solid was filtered, the wet cake was washed with 300 mL of dichloromethane, dried under vacuum at 90° C. overnight to give 63 g (76percent yield) of indazole-3-carboxylic acid (2), as pure form B.Example 3Conversion of Form B to Form AA 1 L, half jacketed, 4-necked round bottom flask equipped with a mechanic stirrer, a thermocouple, and a condenser, was charged with 100 g of indazole-3-carboxylic acid (Form B) (0.62 Mol) and 200 mL of N,N-dimethylformamide (DMF). Agitation was started and the mixture was heated to 80° C. The mixture was stirred for 0.5 h to become a clear solution. To this solution was slowly added 600 mL of 5percent hydrochloric acid in 2 h, resulting in precipitation. After addition of the hydrochloric acid, the mixture was stirred for 0.5 h, maintaining the 80° C. temperature.

The mixture then was cooled to 10° C. in approximately 2 h. The mixture was aged for at least 1 h. The solid was filtered, washed with 200 mL of water, and dried under vacuum at 90° C. for 15 h to give 95.1 g (95.1percent) of indazole-3-carboxylic acid (Form A) With hydrogenchloride, acetic acid in dichloromethane, isobutyramide, water, T= 15 - 90 °C , Reflux, Inert atmosphere, Product distribution / selectivity Patent; Kuang, Shan-Ming; Zhang, Pingsheng; US2011/172428; (2011); (A1) English View in Reaxys

71 %

1.2 :Step 2 A 3 L, half jacketed, 4-necked round bottom flask equipped with a mechanic stirrer, a thermocouple, a nitrogen inlet, and an addition funnel, was charged with 35.6 g of oxalyl chloride (280 mMol) and 200 mL of dichloromethane.

The solution was heated to ~40° C. and a solution of 50 g of benzaldehyde phenylhydrazone (8) (255 mMol) in 800 mL of dichloromethane was added slowly.

After the addition the mixture was stirred at ~40° C. for at least 2 h to generate intermediate solution I. A second 3 L, half jacketed, 4-necked round bottom flask equipped with a mechanic stirrer, a thermocouple, a nitrogen inlet, and an addition funnel, was charged with 81.4 g of aluminum chloride (612 mMol) and 200 mL of dichloromethane.

Agitation was started and the intermediate solution I in the first flask was slowly charged while maintaining batch temperature below 30° C. After the addition the mixture was refluxed for at least 2 h.

The mixture was cooled to ~0° C. and 500 mL of water was slowly added while maintaining batch temperature <10° C. After the addition, the mixture was agitated for ~0.5 h.

The agitation was stopped for layer separation.

The bottom organic layer was separated.

To the batch was added 100 mL of dichloromethane.

The mixture was agitated for ~0.5 h.

The agitation was stopped for layer separation.

The bottom organic layer was separated.

The combined organic solution was washed with 400 mL of 10percent HCl, followed by 400 mL of brine.

The organic solution was concentrated to dryness to give 60.1 g intermediate 9 (95percent).

A 500 mL, half jacketed, 4-necked round bottom flask equipped with a mechanic stirrer, a thermocouple, and a nitrogen inlet, was charged with 28.7 g of intermediate (9) (115 mMol), 215 mL of acetic acid, 43 mL of water and 28.7 g of 31percent HCl. The mixture was agitated at 90±5° C. for 1 h and then was concentrated to dryness.

To the flask was added 300 mL of acetic acid.

The mixture was agitated at 115° C. for ~0.5 h, cooled to ambient temperature under agitation, and was aged for at least 1 h.

The solid was filtered, the wet cake was washed with 50 mL of acetic acid, dried under vacuum at 65° C. overnight to give 13.2 g (71percent yield) of 3.

Stage 1: With hydrogenchloride, acetic acid in water, Time= 1h, T= 90 °C

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

4/15

2016-03-08 21:29:14

Stage 2: With acetic acid, Time= 0.5h, T= 115 °C Patent; Brice, Jodie; Cedilote, Miall; Dong, Zhiming; Zhang, Pingsheng; US2012/4412; (2012); (A1) English View in Reaxys

2 Cl – Sn2+

NH

NH

2H O 2

N

O

(v0)

OH

O

O

Rx-ID: 23920644 View in Reaxys 4/35 Yield

Conditions & References

31%

48 : Indazole-3-carboxylic Acid EXAMPLE 48 Indazole-3-carboxylic Acid Isatin (10 g, 0.067 mol) was added to a solution of NaOH (2.8 g, 0.07 mol) in H2O (44 mL) at 50° C. The stirred clear solution was cooled to 0° C. and a solution of sodium nitrite (4.69 g, 0.067 mol) in H2O (17 mL) was added and stirring continued.

A solution of concentrated H2SO4 (12.9 g) in H2O (136 mL) was cooled to 0° C. and added dropwise to the reaction mixture in such a way that the dropper was below the level of the reaction mixture.

Stirring was continued for 15 min and a cooled solution of tin(II) chloride dihydrate (36.7 g, 0.16 mol) in concentrated HCl (58 mL) was added over 20 min.

The reaction mixture was stirred for 1 h and the orange solid was filtered then heated in H2O at 100° C. The insoluble solids were removed by filtration and the product crystallized from the solution affording the title compound as a yellow solid (3.4 g, 31percent).

Mp 261-263° C. d, lit 260-261° C. v.Auwers, Dereser Chem. Ber. 1919, 52, 1343. 1H NMR (300 MHz, DMSO-d6) ppm 7.26-7.31 (m, 1H), 7.40-7.46 (m, 1H), 7.63-7.66 (m, 1H), 8.08-8.10 (m, 1H), 12.95 (s, 1H), 13.80 (s, 1H). MS(EI) m/z 162 [M+].

With sodium hydroxide, sulfuric acid, sodium nitrite in hydrogenchloride, water Patent; Garthwaite, Giti; Selwood, David; Kling, Marcel; Wishart, Grant; US2003/171403; (2003); (A1) English View in Reaxys

Br

NH N

N N

OH

O

O

O

Rx-ID: 38006692 View in Reaxys 5/35 Yield

Conditions & References

85 %

Stage 1: With hydrogenchloride in water, acetic acid, Time= 1h, T= 90 - 100 °C Stage 2: With acetic acid, Time= 1h, T= 115 °C Swamy, Udutha Kumara; Mohan, H. Rama; Prasad, U. Viplava; Suresh; Kumar, T. Laxmi; Asian Journal of Chemistry; vol. 26; nb. 7; (2014); p. 1921 - 1930 View in Reaxys

2 Cl – H O

H

NH

NH

N

O

Sn2+ (v0)

O

OH O

Rx-ID: 24279134 View in Reaxys 6/35 Yield

Conditions & References 5 : Indazole-3-carboxylic acid Indazole-3-carboxylic acid A solution of concentrated sulfuric acid (19.1 g, 0.19 mol) in water (200 ml) prepared in a 2 litre beaker was cooled to 0° C. Isatin (14.7 g, 0.1 mol) was added to a solution of sodium hydroxide (4.1 g, 0.105 mol) in water(65 ml) at 50° C.

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

5/15

2016-03-08 21:29:14

and the dark red solution cooled to 0° C. A solution of sodium nitrite (6.9 g, 0.1 mol) in water (235 ml) at 0° C. was added and the mixture added to the rapidly stirred solution of sulfuric acid during 5 minutes.

The temperature was not allowed to rise above 4° C. (controlled by the addition of ice).

The yellow brown foamy mixture was stirred for a further 15 minutes before being treated with a solution of stannous chloride hydrate (54 g, 0.24 mol) in concentrated hydrochloric acid (85 ml) at 0° C. The mixture was stirred for one hour and the crude product filtered.

The material was recrystallized as follows: about half of the solid was placed in a 1 litre flask and ~500 ml of water was added.

The solution was heated on a hot-plate until boiling and was then filtered hot to give a dark yellow-brown precipitate and an orange-yellow solution.

The solution was left to cool overnight.

The recrystallizing solution was filtered to give a yellow solid and a pale yellow filtrate.

The solid was put in the oven to dry.

The process was repeated with the other half of the crude product and the two mother liquors were pooled together as were the solid products.

The dark yellow-brown substance filtered off during recrystallization was boiled with 150 ml of water, filtered and the resulting solution was left to recrystallize.

It was then treated as above.

The pooled mother liquors were concentrated to 1/3 volume and the solution allowed to crystallize.

The solid thus obtained was added to the rest.

On drying, 7.27 g solid yellow powder product was obtained, with an m.p. 263-264° C. With sodium hydroxide, sulfuric acid, sodium nitrite in hydrochlorid acid, water Patent; Merrell Pharmaceuticals, Inc.; US5955470; (1999); (A1) English View in Reaxys

NH

O

N HO N O

OH O

O

Rx-ID: 17200824 View in Reaxys 7/35 Yield

Conditions & References Reaction Steps: 4 1: 95 percent / cc. H2SO4 / 4 h / Heating 2: 97 percent / H2 / 5percent Pd/C / toluene / Ambient temperature 3: 87 percent / 90percent t-BuONO / acetic acid / 0.5 h / 90 - 95 °C 4: 97 percent / NaOH, water / 1.5 h / Heating With sodium hydroxide, tert.-butylnitrite, sulfuric acid, water, hydrogen, palladium on activated charcoal in acetic acid, toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys Reaction Steps: 4 1: 94 percent / cc. H2SO4 / 4 h / Heating 2: 97 percent / H2 / 5percent Pd/C / toluene / Ambient temperature 3: 83 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 4: 98 percent / NaOH, water / 1.5 h / Heating With sodium hydroxide, tert.-butylnitrite, sulfuric acid, water, hydrogen, palladium on activated charcoal in toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys Reaction Steps: 4 1: 89 percent / SOCl2 / dimethylformamide; 1,2-dichloro-ethane / 35-40 deg C, 2 h then 20 deg C, 2 h 2: 95 percent / H2 / 5percent Pd/C / toluene / Ambient temperature 3: 76 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 4: 96 percent / NaOH, water / 3 h / Heating

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

6/15

2016-03-08 21:29:14

With sodium hydroxide, thionyl chloride, tert.-butylnitrite, water, hydrogen, palladium on activated charcoal in 1,2dichloro-ethane, N,N-dimethyl-formamide, toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys Reaction Steps: 5 1: 89 percent / SOCl2 / dimethylformamide; 1,2-dichloro-ethane / 35-40 deg C, 2 h then 20 deg C, 2 h 2: 92 percent / Fe, aq. NH4Cl / propan-2-ol / 1 h / Heating 3: toluene / rt to 95 deg C 4: 76 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 5: 96 percent / NaOH, water / 3 h / Heating With sodium hydroxide, thionyl chloride, tert.-butylnitrite, water, iron, ammonium chloride in 1,2-dichloro-ethane, N,Ndimethyl-formamide, isopropyl alcohol, toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys O N O

NH N N

O

OH O

O

Rx-ID: 17210908 View in Reaxys 8/35 Yield

Conditions & References Reaction Steps: 3 1: 95 percent / H2 / 5percent Pd/C / toluene / Ambient temperature 2: 76 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 3: 96 percent / NaOH, water / 3 h / Heating With sodium hydroxide, tert.-butylnitrite, water, hydrogen, palladium on activated charcoal in toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys Reaction Steps: 4 1: 92 percent / Fe, aq. NH4Cl / propan-2-ol / 1 h / Heating 2: toluene / rt to 95 deg C 3: 76 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 4: 96 percent / NaOH, water / 3 h / Heating With sodium hydroxide, tert.-butylnitrite, water, iron, ammonium chloride in isopropyl alcohol, toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

O

NH

N

N

N

O O

OH O

Rx-ID: 4769434 View in Reaxys 9/35 Yield 98 %

Conditions & References With sodium hydroxide, water, Time= 1.5h, Heating Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

7/15

2016-03-08 21:29:14

View in Reaxys

O NH

N

N

N

OH

N

O

O

O

Rx-ID: 4797039 View in Reaxys 10/35 Yield

Conditions & References

96 %

With sodium hydroxide, water, Time= 3h, Heating Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

NH

O

N O N O

OH O

O

Rx-ID: 17200913 View in Reaxys 11/35 Yield

Conditions & References Reaction Steps: 3 1: 97 percent / H2 / 5percent Pd/C / toluene / Ambient temperature 2: 87 percent / 90percent t-BuONO / acetic acid / 0.5 h / 90 - 95 °C 3: 97 percent / NaOH, water / 1.5 h / Heating With sodium hydroxide, tert.-butylnitrite, water, hydrogen, palladium on activated charcoal in acetic acid, toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

O

N

O NH

O

N

O OH O

Rx-ID: 17202051 View in Reaxys 12/35 Yield

Conditions & References Reaction Steps: 3 1: 97 percent / H2 / 5percent Pd/C / toluene / Ambient temperature 2: 83 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 3: 98 percent / NaOH, water / 1.5 h / Heating With sodium hydroxide, tert.-butylnitrite, water, hydrogen, palladium on activated charcoal in toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

NH N

HN H 2N

OH O

Rx-ID: 31190195 View in Reaxys 13/35 Yield

Conditions & References Reaction Steps: 4 1: water / 3 h / 25 - 30 °C / Inert atmosphere 2: dichloromethane / 3 h / -40 °C

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

8/15

2016-03-08 21:29:14

3: AlCl3, aluminium chloride / dichloromethane / 0 - 30 °C / Reflux; Inert atmosphere 4: hydrogenchloride; acetic acid / dichloromethane; water; isobutyramide / 15 - 90 °C / Reflux; Inert atmosphere With hydrogenchloride, AlCl3, aluminium chloride, acetic acid in dichloromethane, isobutyramide, water Patent; Kuang, Shan-Ming; Zhang, Pingsheng; US2011/172428; (2011); (A1) English View in Reaxys Reaction Steps: 4 1.1: water / 3 h / 25 - 30 °C 2.1: dichloromethane / 2 h / 40 °C 3.1: AlCl3, aluminium chloride / dichloromethane / 2 h / 30 °C / Reflux 4.1: hydrogenchloride; acetic acid / water / 1 h / 90 °C 4.2: 0.5 h / 115 °C With hydrogenchloride, AlCl3, aluminium chloride, acetic acid in dichloromethane, water Patent; Brice, Jodie; Cedilote, Miall; Dong, Zhiming; Zhang, Pingsheng; US2012/4412; (2012); (A1) English View in Reaxys Reaction Steps: 4 1.1: water / 3 h / 25 - 35 °C 2.1: dichloromethane / 4 h / |Reflux 3.1: AlCl3, aluminium chloride / dichloromethane / 25 °C 3.2: 3 h / |Reflux 4.1: hydrogenchloride / water; acetic acid / 1 h / 90 - 100 °C 4.2: 1 h / 115 °C With hydrogenchloride, AlCl3, aluminium chloride in dichloromethane, water, acetic acid Swamy, Udutha Kumara; Mohan, H. Rama; Prasad, U. Viplava; Suresh; Kumar, T. Laxmi; Asian Journal of Chemistry; vol. 26; nb. 7; (2014); p. 1921 - 1930 View in Reaxys

H N

NH

N

N

OH O

Rx-ID: 31190201 View in Reaxys 14/35 Yield

Conditions & References Reaction Steps: 3 1: dichloromethane / 3 h / -40 °C 2: AlCl3, aluminium chloride / dichloromethane / 0 - 30 °C / Reflux; Inert atmosphere 3: hydrogenchloride; acetic acid / dichloromethane; water; isobutyramide / 15 - 90 °C / Reflux; Inert atmosphere With hydrogenchloride, AlCl3, aluminium chloride, acetic acid in dichloromethane, isobutyramide, water Patent; Kuang, Shan-Ming; Zhang, Pingsheng; US2011/172428; (2011); (A1) English View in Reaxys Reaction Steps: 3 1.1: dichloromethane / 2 h / 40 °C 2.1: AlCl3, aluminium chloride / dichloromethane / 2 h / 30 °C / Reflux 3.1: hydrogenchloride; acetic acid / water / 1 h / 90 °C 3.2: 0.5 h / 115 °C With hydrogenchloride, AlCl3, aluminium chloride, acetic acid in dichloromethane, water Patent; Brice, Jodie; Cedilote, Miall; Dong, Zhiming; Zhang, Pingsheng; US2012/4412; (2012); (A1) English View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

9/15

2016-03-08 21:29:14

NH

N

N

N O

OH

O O

Cl

Rx-ID: 31190208 View in Reaxys 15/35 Yield

Conditions & References Reaction Steps: 2 1: AlCl3, aluminium chloride / dichloromethane / 0 - 30 °C / Reflux; Inert atmosphere 2: hydrogenchloride; acetic acid / dichloromethane; water; isobutyramide / 15 - 90 °C / Reflux; Inert atmosphere With hydrogenchloride, AlCl3, aluminium chloride, acetic acid in dichloromethane, isobutyramide, water Patent; Kuang, Shan-Ming; Zhang, Pingsheng; US2011/172428; (2011); (A1) English View in Reaxys Reaction Steps: 2 1.1: AlCl3, aluminium chloride / dichloromethane / 2 h / 30 °C / Reflux 2.1: hydrogenchloride; acetic acid / water / 1 h / 90 °C 2.2: 0.5 h / 115 °C With hydrogenchloride, AlCl3, aluminium chloride, acetic acid in dichloromethane, water Patent; Brice, Jodie; Cedilote, Miall; Dong, Zhiming; Zhang, Pingsheng; US2012/4412; (2012); (A1) English View in Reaxys

O

NH

HN

N

O O

OH O

Rx-ID: 17203893 View in Reaxys 16/35 Yield

Conditions & References Reaction Steps: 2 1: 83 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 2: 98 percent / NaOH, water / 1.5 h / Heating With sodium hydroxide, tert.-butylnitrite, water in toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

O

O

NH

HN

N

O

OH O

Rx-ID: 17204962 View in Reaxys 17/35 Yield

Conditions & References Reaction Steps: 2 1: 87 percent / 90percent t-BuONO / acetic acid / 0.5 h / 90 - 95 °C 2: 97 percent / NaOH, water / 1.5 h / Heating With sodium hydroxide, tert.-butylnitrite, water in acetic acid Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

10/15

2016-03-08 21:29:14

H 2N

NH N N

O

OH O

O

Rx-ID: 17235975 View in Reaxys 18/35 Yield

Conditions & References Reaction Steps: 3 1: toluene / rt to 95 deg C 2: 76 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 3: 96 percent / NaOH, water / 3 h / Heating With sodium hydroxide, tert.-butylnitrite, water in toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys O HN

NH N

N

O

OH O

O

Rx-ID: 17236347 View in Reaxys 19/35 Yield

Conditions & References Reaction Steps: 2 1: 76 percent / 90percent t-BuONO / toluene / 0.5 h / 90 - 95 °C 2: 96 percent / NaOH, water / 3 h / Heating With sodium hydroxide, tert.-butylnitrite, water in toluene Yoshida, Toyokichi; Matsuura, Noriyasu; Yamamoto, Katsuhisa; Doi, Masahiro; Shimada, Kanji; Morie, Toshiya; Kato, Shiro; Heterocycles; vol. 43; nb. 12; (1996); p. 2701 - 2712 View in Reaxys

NH

HN

N

NH O

OH O

Rx-ID: 21434833 View in Reaxys 20/35 Yield

Conditions & References Reaction Steps: 3 1: 79 percent / hydroxylamine hydrochloride, sodium sulphate, 1 N HCl / H2O / 0.17 h / 100 °C 2: 96percent H2SO4 / 0.25 h / 85 °C 3: aq. H2SO4 / 2.5 h / Heating With hydrogenchloride, sulfuric acid, hydroxylamine hydrochloride, sodium sulfate in water Ferrari, Marinella; Ripa, Alberto; Ripa, Giorgio; Sisti, Massimo; Journal of Heterocyclic Chemistry; vol. 26; (1989); p. 531 - 532 View in Reaxys

H N

NH

N

N

Br

OH O

Rx-ID: 38006678 View in Reaxys 21/35

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

11/15

2016-03-08 21:29:14

Yield

Conditions & References Reaction Steps: 3 1.1: dichloromethane / 4 h / |Reflux 2.1: AlCl3, aluminium chloride / dichloromethane / 25 °C 2.2: 3 h / |Reflux 3.1: hydrogenchloride / water; acetic acid / 1 h / 90 - 100 °C 3.2: 1 h / 115 °C With hydrogenchloride, AlCl3, aluminium chloride in dichloromethane, water, acetic acid Swamy, Udutha Kumara; Mohan, H. Rama; Prasad, U. Viplava; Suresh; Kumar, T. Laxmi; Asian Journal of Chemistry; vol. 26; nb. 7; (2014); p. 1921 - 1930 View in Reaxys

Br

NH N

N

N Cl O

OH O O

Rx-ID: 38006686 View in Reaxys 22/35 Yield

Conditions & References Reaction Steps: 2 1.1: AlCl3, aluminium chloride / dichloromethane / 25 °C 1.2: 3 h / |Reflux 2.1: hydrogenchloride / water; acetic acid / 1 h / 90 - 100 °C 2.2: 1 h / 115 °C With hydrogenchloride, AlCl3, aluminium chloride in dichloromethane, water, acetic acid Swamy, Udutha Kumara; Mohan, H. Rama; Prasad, U. Viplava; Suresh; Kumar, T. Laxmi; Asian Journal of Chemistry; vol. 26; nb. 7; (2014); p. 1921 - 1930 View in Reaxys

NH N

NH N

OH N

O

Rx-ID: 629331 View in Reaxys 23/35 Yield

Conditions & References With hydrogenchloride Pschorr; Hoppe; Chemische Berichte; vol. 43; (1910); p. 2550 View in Reaxys Salkowski,H.; Chemische Berichte; vol. 17; (1884); p. 506; Chemische Berichte; vol. 22; (1889); p. 2139 View in Reaxys

NH N

N-acetylamino-isatin-β oxime

OH O

Rx-ID: 5690193 View in Reaxys 24/35 Yield

Conditions & References With sulfuric acid Neber; Keppler; Chemische Berichte; vol. 57; (1924); p. 782 View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

12/15

2016-03-08 21:29:14

NH N

N-benzylidenamino-isatin

OH O

Rx-ID: 5690194 View in Reaxys 25/35 Yield

Conditions & References With hydrogenchloride Stolle; Becker; Chemische Berichte; vol. 57; (1924); p. 1124 View in Reaxys O NH

HN

N

N O

OH O

O

Rx-ID: 2557298 View in Reaxys 26/35 Yield

Conditions & References With sulfuric acid, Time= 2.5h, Heating Ferrari, Marinella; Ripa, Alberto; Ripa, Giorgio; Sisti, Massimo; Journal of Heterocyclic Chemistry; vol. 26; (1989); p. 531 - 532 View in Reaxys

NH

N

N

N

N-benzylidenamino-isatin

O OH

O O

Cl

Rx-ID: 5739486 View in Reaxys 27/35 Yield

Conditions & References With carbon disulfide, aluminium trichloride Stolle; Becker; Chemische Berichte; vol. 57; (1924); p. 1124 View in Reaxys

O NH

NH

N

N HO

N

OH

O

O

Rx-ID: 21415009 View in Reaxys 28/35 Yield

Conditions & References Reaction Steps: 2 1: 96percent H2SO4 / 0.25 h / 85 °C 2: aq. H2SO4 / 2.5 h / Heating With sulfuric acid Ferrari, Marinella; Ripa, Alberto; Ripa, Giorgio; Sisti, Massimo; Journal of Heterocyclic Chemistry; vol. 26; (1989); p. 531 - 532 View in Reaxys

O N

N

NH

O

N

OH O

Rx-ID: 21993004 View in Reaxys 29/35

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

13/15

2016-03-08 21:29:14

Yield

Conditions & References Reaction Steps: 3 1: tin; hydrochloric acid 2: acid; sodium nitrite 3: concentrated hydrochloric acid With hydrogenchloride, tin, sodium nitrite Salkowski,H.; Chemische Berichte; vol. 17; (1884); p. 506; Chemische Berichte; vol. 22; (1889); p. 2139 View in Reaxys

NH 2

NH N

N OH O

Rx-ID: 22003576 View in Reaxys 30/35 Yield

Conditions & References Reaction Steps: 2 1: acid; sodium nitrite 2: concentrated hydrochloric acid With hydrogenchloride, sodium nitrite Salkowski,H.; Chemische Berichte; vol. 17; (1884); p. 506; Chemische Berichte; vol. 22; (1889); p. 2139 View in Reaxys O HN

OH HO

NH

N

N

O

S OO

E N

OH O

HO

Rx-ID: 5690192 View in Reaxys 31/35 Yield

Conditions & References Neber; Keppler; Chemische Berichte; vol. 57; (1924); p. 782 View in Reaxys

N

NH

H 2N

O– Na +

N

N

O

O

N OH O

Rx-ID: 150583 View in Reaxys 32/35 Yield

Conditions & References Neber; Keppler; Chemische Berichte; vol. 57; (1924); p. 782 View in Reaxys

O

NE

OH

N

NH

H

N

O OH

O

O

O

Rx-ID: 301920 View in Reaxys 33/35 Yield

Conditions & References mit Wasserdampf Stolle; Becker; Chemische Berichte; vol. 57; (1924); p. 1124 View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

14/15

2016-03-08 21:29:14

Cl

H

NH

H

NE N

N

O O

OH O

O

Rx-ID: 5690195 View in Reaxys 34/35 Yield

Conditions & References mit Wasserdampf Stolle; Becker; Chemische Berichte; vol. 57; (1924); p. 1124 View in Reaxys

NH N

OH O

Rx-ID: 5690191 View in Reaxys 35/35 Yield

Conditions & References Patent; Henkel and Cie.; GB816531; (1957); US3023210; (1958); ; nb. 1552; (1960) View in Reaxys Piozzi et al.; Gazzetta Chimica Italiana; vol. 95; (1965); p. 814,817 View in Reaxys Patent; Badische Anilin- u. Soda-Fabrik AG; FR1425219; (1964); ; vol. 65; nb. 13721c; (1966) View in Reaxys

Copyright © 2016 Reed Elsevier Properties SA. All rights reserved. Authorized use only. Reaxys® and the Reaxys® trademark are owned and protected by Reed Elsevier Properties SA and used under license.

15/15

2016-03-08 21:29:14