US3336317A - Substituted naphthindolizinequinones - Google Patents

Substituted naphthindolizinequinones Download PDF

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US3336317A
US3336317A US442190A US44219065A US3336317A US 3336317 A US3336317 A US 3336317A US 442190 A US442190 A US 442190A US 44219065 A US44219065 A US 44219065A US 3336317 A US3336317 A US 3336317A
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Inman Eric Richard
Smith Hugh Macdonald
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Novartis AG
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JR Geigy AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • This invention relates to intermediates for heterocyclic pigments or dyestuffs and to the manufacture of such intermediates.
  • it relates to 12-aminonaphthindolizinequinones, 14-amino-benzonaphthindolizinequinones as well as to the corresponding 12-nitronaphthindolizin'equinones and l4-nitro-benzonaphthindolizinequinones, from which the aforesaid amino-substituted compounds are derived, and also to processes for their manufacture.
  • the invention comprises compounds of the formulas wherein X, Y and Y are the same or different and each represents hydrogen, halogen of one of the atomic numbers 9, 17 and 35, preferably chlorine or bromine, or an' alkyl or alkoxy radical containing from one to five carbon atoms, and Z is a nitro or an amino group.
  • X, Y and Y are the same or different and each represents hydrogen, halogen of one of the atomic numbers 9, 17 and 35, preferably chlorine or bromine, or an' alkyl or alkoxy radical containing from one to five carbon atoms, and Z is a nitro or an amino group.
  • the numbering of the naphthindolizine ring system is that adopted in Pattersons Ring Index, 2nd, edition, (1960).
  • the invention further comprises a process for the production of amino-substituted naphthindolizinequinones of the above Formulas IA and IB via the corresponding nitro-substituted naphthindolizinequinones.
  • the 1Z-nitronaphthindolizinequinones and 14-nitr0- benzonaphthindolizinequinones according to the invention are obtained by stirring a recrystallized naphthindolizine quinone or benzonaphthindolizinequinone of the formula wherein X, Y and Y have the aforesaid meanings, with concentrated nitric acid, and separating the product, for example, by filtration.
  • this product can be prepared from the corresponding acetyl-substituted naphthindolizinequinone or acetyl-substituted benzonaphthindolizinequinone in which case the acetyl group is displaced by the nitro group.
  • the nitration of the naphthindolizinequinone or the corresponding acetyl-substituted naphthindolizine quinone may be carried out at a temperature of above 0 and not more than 50 C., preferably in the cold (10 to 15 C.).
  • the nitration of the benzonaphthindolizinequinone or the corresponding acetyl-substituted benzonaphthindolizinequinone is preferably carried out at a temperature in the range of from 0 to 100 C.
  • a reduction step which is carried out by heating the nitro-substituted naphthindolizinequinone of Formula IA or IE with a relatively moderate reducing agent, namely: acid stannous chloride; hydrogen in statu nascendi produced from iron powder under Bchamp conditions, from zinc and glacial acetic acid, from zinc and dilute aqueous-sodium hydroxide or from a zinc dust/ ethanol mixture; alkaline ferrous hydroxide; alkaline glucose; aqueous sodium hydrosulfite; aqueous sodium or potassium sulfide or ammonium sulfide.
  • a relatively moderate reducing agent namely: acid stannous chloride; hydrogen in statu nascendi produced from iron powder under Bchamp conditions, from zinc and glacial acetic acid, from zinc and dilute aqueous-sodium hydroxide or from a zinc dust/ ethanol mixture; alkaline ferrous hydroxide; alkaline glucose; a
  • a mild reducing agent is used, on account of the tendency shown by the resulting amino-substituted naphthindolizinequinone to deaminate to the corresponding naphthindolizinequinone when the conditions of reduction prove to be too drastic.
  • the time of heating may vary from a few minutes to approximately 12 hours.
  • the l2-amino-naphthindolizinequinone is isolated from the reaction product, preferably by filtration and washing and it is then purified by recrystallization from a suitable inert solvent, such as o-dichlorobenzene, monochlorobenzene or nitrobenzene.
  • a suitable inert solvent such as o-dichlorobenzene, monochlorobenzene or nitrobenzene.
  • the 1Z-nitronaphthindolizinequinone used as starting material for the reduction step may be substantially pure, or it may be used as a crude product obtained from the above-described nitration step.
  • the 12-aminonaphthindolizinequinones and 14-aminobenzonaphthindolizinequinones of the present invention are useful intermediates in the manufacture of heterocyclic dyestuffs or pigments.
  • the compounds may, for instance, be converted by diazotation and coupling with well known coupling components, preferably of the naphthalene series, to obtain azo pigments.
  • the present invention also comprises a process of producing a benzonaphthindolizinequinone compound having the above formula IB, wherein Z is hydrogen, which comprises hydrolyzing followed by decarboxylating the corresponding naphthindolizinequinone compound having the formula O COOR wherein X, Y and Y have the previous significance and R is an alkyl group containing from one to six carbon atoms.
  • the hydrolysis may be carried out, for example, by contacting the 14-carbalkoxy-benzonaphthindolizinequinone starting material, preferably dissolved in an organic solvent (for example methyl Cellosolve), with an alkali, for example with a hydroxide of an alkali metal or with a hydroxide of an alkaline earth metal.
  • an organic solvent for example methyl Cellosolve
  • the carbalkoxy-benzonaphthindolizinequinone and the alkali may conveniently be heated together to effect the hydrolysis and decarboxylation, for example, by boiling the mixture under reflux conditions.
  • the decarboxylation may also be conveniently carried out by heating the 14-carboxybenzonaphthindolizinequinone under acid conditions, for example in the presence of concentrated hydrochloric acid.
  • the benzonaphthindolizinequinone compounds of the invention when produced by any of the processes described above may, if desired, be isolated and purified by conventional methods.
  • the desired product may, for instance, be recovered by filtration and purified by washing and crystallization. If the product is to be used as an intermediate in a further chemical process, the crude benzonaphthindolizinequinone compound, if desired after partial purification, may be employed.
  • the compounds of the present invention are herein referred to as benzonaphthindolizinequinone compounds and may be regarded as being derivatives of the parent compound, benzo(g)naphth (2,3-b)indolizine.
  • the parent compound is however also known as benz (5,6) indolo (2,1-a) isoquinoline, this nomenclature being used in the First Supplement to the Second Edition of the Ring Index (No. 9287, page 222).
  • EXAMPLE 1 12.35 parts of recrystallised naphthindolizinequinone are stirred into 250 parts by volume of concentrated nitric acid during ten minutes at a temperature of 10 to 15 C. The resulting suspension is stirred at this temperature for 1 hour, after which the crude 12-nitronaphthindolizinequinone is separated by filtration, washed free of acid with cold water and dried. There is thus obtained 9.6 parts by weight of a red powder, of a melting point of 282 to 284 C. (65.8% theoretical yield). This product is purified by crystallization from o-dichlorobenzene, when it is obtained in the form of reddish-orange needles, of a melting point of 284 to 285 C.
  • the starting naphthindolizinequinone (M.P. 239.5") was prepared by conventional hydrolysis and subsequent conventional decarboxylation from 12-ethoxy-carbonylnaphthindolizinequinone.
  • Suryanarayane et al. Proc. Indian Acad. Sci., 39-A, 185-195 (1954); see also Sartori, Chemical Review, 63, p. 288 (1963).
  • the starting naphthindolizinequinone is prepared by stirring 96 parts of 12-ethoxy-carbonylnaphthindolizinequinone into a solution of 24 parts of sodium hydroxide in 1060 parts of ethylene glycol at 160 C.
  • the thick red paste of the sodium salt of the acid thus obtained is decarboxylated by adding 137 parts of glacial acetic acid.
  • the solid product is separated by filtration, washed with water and dried. There is thus obtained 67 parts of naphthindolizinequinone.
  • EXAMPLE 2 115.6 parts of crude 12-acetylnaphthindolizinequinone [Pratt et al., J. Org. Chem, 19, p. 176 (1954); M.P. 205- 206] are dissolved in 580 parts by volume of concentrated nitric acid at 10 C.
  • the 1Z-nitronaphthindolizinequinone crystallizes out after stirring for about 15 minutes and the suspension is stirred for a further 45 minutes at room temperature (about 20 C.) before filtering ofi the solid product, washing free of acid with 200 parts by volume of cold water and drying.
  • the crude product is obtained as a red powder, having a melting point of 279281 (74.7% theoretical yield). It is purified as described in Example 1.
  • EXAMPLE 3 60 parts of crude 12-nitronaphthindolizinequinone are suspended in a solution of parts of sodium sulfide nonahydrate in 1800 parts of water and the suspension is boiled whilst stirring for 15 minutes. After cooling, the product is separated by filtration, washed free of alkali with 2000 parts by volume of hot water and dried, to yield 61 parts of impure 12-arninonaphthindolizinequinone as a dull violet powder.
  • the crude product can be purified by extraction with 500 parts by volume of odichlorobenzene, from which it separates, on cooling, to yield 49.7 parts (92.2% overall yield) of pure material, found to melt indistinctly at 285-287 with softening from 280.
  • Example 2 By repeating Example 2, but using, instead of 12-acetylnaphthindolizinequinone equimolar amounts of starting materials which are substituted in 12-position as indicated under Z in the table below, and possess as substituents X and Y those given in the respective columns of the said table, there are obtained the corresponding 12-nitro derivatives which are converted to the corresponding 12-amino derivatives by the procedure given in Example 3, supra.
  • the corresponding starting materials are produced by the methods given in the fifth column of the table below, using X-substituted 2,3-dichloro-naphthoquinone, and the active methylene compound and the pyridine derivative given in columns 6 and 7 of the table.
  • EXAMPLE 12 7.5 parts ofiron powder (60-mesh) is supended by high-speed agitation in 200 parts of water to which 0.85 part of concentrated hydrochloric acid has been previ-- 'ried out on a thin-layer chromatoplate (Kieselgel G prepared according to Stahl), the reaction is complete. The residue is separated by filtration, washed with cold water and dried. On extraction with o-dichlorobenzene, 3.27 parts of pure 1Z-arninonaphthindolizinequinone are obtained, corresponding to 62.4% of the theoretical yield.
  • EXAMPLE 13 1.46 parts of 12-nitronaphthindolizinequinone, suspended in 100 parts of cold water, are added to the alkaline suspension of ferrous hydroxide resulting from the addition of 13.2 parts of aqueous 20%-sodium hydroxide solution to a solution of 9.2 parts of ferrous sulfate heptahydrate crystals in 100 parts of water. The suspension is heated under reflux for approximately 2 hours until only traces of unchanged nitro starting-material can be detected on a thin-layer chromatoplate (Kieselgel G according to Stahl). The residue is then filtered hot, washed with hot water and dried. On extraction with o-dichlorobenzene, 0.80 part of pure 12- aminonaphthindolizinequinone is obtained, corresponding to 61% of the theoretical yield.
  • EXAMPLE 14 1.46 parts of 12-nitronaphthindolizinequinone, suspended in 50 parts of cold water, are added to a solution 'of'9.0 parts of glucose in 40 parts of water, and parts of aqueous 20%-sodium hydroxide are added to the resulting mixture. The suspension is boiled for 10 minutes, filtered hot and the product washed free of alkali with 'cold water. On drying, 1.33 parts of 12-aminonaphthindolizinequinone are obtained corresponding to 100% of the theoretical yield. The trace of unreacted nitro-compound which the product contains is readily removed by recrystallization from monochlorobenzene.
  • EXAMPLE 15 60 parts of crude 12-acetyl-3-methylnaphthindolizine quinone, obtained from 2,3-dichloro-1,4-naphthoquinone, acetylacetone and 3-methyl-pyridine by the method of R. C. Rice, supra, are stirred into 1400 parts of concentrated nitric acid during two minutes at a temperature of 1015. The resulting suspension is stirred at this temperature for a further 3 minutes, then filtered, washed acid-free with water, and dried. 56.4 parts by weight of 12-nitro-3-methyl-naphthindolizinequinone are obtained as an orange powder, having melting point 280 to 283 C. (93% theoretical yield). It is purified by crystallization from o-dichlorobenzene, to give orange needles, having melting point 285 to 287 C.
  • This product was purified by recrystallization from dimethylformamide after being treated with charcoal and washed with cool ethanol.
  • the pure product was obtained as bright orange, needle shaped crystals, having a melt ing point at 231 C. (with decomposition) and the following elemental analysis: C, 75.1%; H, 4.25%; N, 4.5%; which coincides very well with that calculated for C H O N, namely C, 75.2%; H, 4.3%; N, 4.6%.
  • EXAMPLE 16 7.0 parts of recrystallized 3-methylnaphthindolizinequinone are stirred into 175 parts of concentrated nitric acid during 2 minutes at a temperature of 10 to 15 C. The resulting suspension is stirred at this temperature for a further 3 minutes, then poured into a large volume of ice-water. The crude 12-nitro-3-methy1naphthindolizinequinone is filtered, washed free of acid with water, then successively washed with parts by volume of methanol and parts by volume of chloroform. After drying, 3.65 parts of an orange powder are obtained, having melting point 280 to 282 (44% theoretical yield). It is purified as described in the preceding example.
  • EXAMPLE 17 9.18 parts of 12 nitro 3 methylnaphthindolizinequinone are stirred into a solution of 18.1 parts of sodium sulfide nonahydrate in 275 parts of water and 27.5 parts by volume of methyl Cellosolve, and the mixture refluxed with stirring for 1 hour. After cooling to room temperature, the crude 12-amino-3-rnethylnaphthindolizinequinone is filtered, washed thoroughly with water, and dried, to give 8.65 parts of a dark blue powder (104% theoretical yield). Extraction from inorganic matter is carried out with boiling o-dichlorobenzene, from which the product crystallizes as dark violet plates, having a melting point of 296 to 297.
  • EXAMPLE 18 13.1 parts of finely divided 12-arninonaphthindolizinequinone are suspended in 155 parts by volume of 2 N hydrochloric acid and diazotised at room temperature by adding 18 parts by volume of a 20% solution of sodium nitrite and stirring for 30 minutes.
  • the diazonium chloride forms an olive yellow crystalline suspension which is dissolved by adding 400 parts of water and heating to 60 C.
  • the diazo solution is filtered and added to a suspension of 16.2 parts of acetoacet-2,5-diethoxy-4-chloranilide prepared by dissolving it in dilute sodium hydroxide solution, reprecipitating with dilute acetic acid and adding 60 parts of crystalline sodium acetate.
  • the dyestutf is filtered off on completion of the coupling, washed with cold water and dried.
  • Example 19 33.9 parts of powdered 14-acetylbenzonaphthindolizinequinone are added to 750 parts of concentrated nitric acid and the suspension is stirred at room temperature for 1.5 hours.
  • the product has the following formula:
  • N02 ll 1 N II EXAMPLE 20 To 73.8 parts of 14-carbethoxybenzonaphthindolizinequinone in 966 parts of methyl Cellosolve there is added a solution of 30' parts of sodium hydroxide in 483 parts of methyl Cellosolve, and the resulting mixture is stirred While boiling under reflux for 16.5 hours.
  • the product has the following formula:
  • EXAMPLE 21 148.5 parts of benzonaphthindolizinequinone are stirred into 5250 parts of concentrated nitric acid during a time of 20 minutes. The product is then filtered, washed acidfree with water and dried to give 125.5 parts of 14-nitrobenzonaphthindolizinequinone as a yellow powder. The yield rate is about 75% of the theoretical yield.
  • the product On crystallization from xylene, the product is obtained in the form of yellow, needle-shaped crystals having melting point 337 C.
  • the product is the same as that obtained in Example 19.
  • EXAMPLE 22 29.7 parts of benzonaphthindolizinequinone are stirred with 1502 parts of concentrated nitric acid. After stirring for 30 minutes, the product is filtered off and washed acidfree with water.
  • the resulting filter cake is stirred with a solution of parts of sodium sulfide nonahydrate in 2980 parts of 25% methyl Cellosolve at 80 to C. for 20 minutes.
  • the product is then filtered off, washed free of inorganic salts with water and dried.
  • the product has the following formula:
  • EXAMPLE 23 1.71 parts of 14-nitrobenzonaphthindolizinequinone, suspended in parts of cold water, are added to the alkaline suspension of ferrous hydroxide resulting from the addition of 13.2 parts of aqueous 20% sodium hydroxide solution to a solution of 9.2 parts of ferrous sulfate heptahydrate crystals in 100 parts of water. The suspension is heated at the boiling point under reflux for 2 hours and then filtered while hot, the residue being washed with water.
  • a compound of the formula II I crystallizable in the form of orange, needle-shaped crystals having a melting point of 285 to 287 C.
  • each of X, Y and Y is a member selected from the group consisting of hydrogen, halogen of one of the atomic numbers 9, 17 and 35, alkyl of from 1 to 5 carbon atoms and alkoxy of from 1 to 5 carbon atoms.
US442190A 1963-03-16 1965-03-23 Substituted naphthindolizinequinones Expired - Lifetime US3336317A (en)

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GB10520/63A GB1087221A (en) 1963-03-16 1963-03-16 12-aminonaphthindolizinediones and processes for their manufacture
GB12287/64A GB1090633A (en) 1963-03-16 1964-03-24 Aminobenzonaphthindolizinediones

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4042591A (en) * 1973-05-30 1977-08-16 Sandoz Ltd. Naphthoquinone compounds
US4835158A (en) * 1984-05-03 1989-05-30 Glaxo Group Limited Isoquinoline derivatives
US4851399A (en) * 1986-07-29 1989-07-25 Glaxo Group Limited Isoquinoline derivatives and their use as anti-cancer agents
US4933457A (en) * 1988-01-07 1990-06-12 Glaxo Group Limited Preparation of 5,8,13,14-tetrahydrobenz[5,6]isoindolo[2,1-b]isoquinolin-8,13-dione derivatives
US4959371A (en) * 1986-11-27 1990-09-25 Glaxo Group Limited Isoquinoline derivatives with anti-tumor activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2439120A (en) * 1946-10-26 1948-04-06 Eastman Kodak Co 1-nitro-3-alkylanthrapyridone compounds and process for their preparation
US2850503A (en) * 1958-09-02 Preparation of methyl and ethyl n-
US3121086A (en) * 1961-05-29 1964-02-11 Du Pont Naphthofuroquinolinediones and naphthofuroisoquinolinediones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2850503A (en) * 1958-09-02 Preparation of methyl and ethyl n-
US2439120A (en) * 1946-10-26 1948-04-06 Eastman Kodak Co 1-nitro-3-alkylanthrapyridone compounds and process for their preparation
US3121086A (en) * 1961-05-29 1964-02-11 Du Pont Naphthofuroquinolinediones and naphthofuroisoquinolinediones

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4042591A (en) * 1973-05-30 1977-08-16 Sandoz Ltd. Naphthoquinone compounds
US4835158A (en) * 1984-05-03 1989-05-30 Glaxo Group Limited Isoquinoline derivatives
US4851399A (en) * 1986-07-29 1989-07-25 Glaxo Group Limited Isoquinoline derivatives and their use as anti-cancer agents
US4959371A (en) * 1986-11-27 1990-09-25 Glaxo Group Limited Isoquinoline derivatives with anti-tumor activity
US4933457A (en) * 1988-01-07 1990-06-12 Glaxo Group Limited Preparation of 5,8,13,14-tetrahydrobenz[5,6]isoindolo[2,1-b]isoquinolin-8,13-dione derivatives

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GB1087221A (en) 1967-10-18
CH426836A (de) 1966-12-31
GB1087222A (en) 1967-10-18
GB1090633A (en) 1967-11-15

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