GB2210367A - Preparation of N-aralkylated and N-aryloxyalkylated aminofluoranes - Google Patents

Preparation of N-aralkylated and N-aryloxyalkylated aminofluoranes Download PDF

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GB2210367A
GB2210367A GB8822146A GB8822146A GB2210367A GB 2210367 A GB2210367 A GB 2210367A GB 8822146 A GB8822146 A GB 8822146A GB 8822146 A GB8822146 A GB 8822146A GB 2210367 A GB2210367 A GB 2210367A
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formula
aminofluorane
halogen
hydrogen
process according
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GB8822146A
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GB2210367B (en
GB8822146D0 (en
Inventor
Rudolf Zink
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Novartis AG
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Ciba Geigy AG
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Priority claimed from CH379887A external-priority patent/CH672123A5/en
Priority claimed from CH254588A external-priority patent/CH675247A5/en
Application filed by Ciba Geigy AG filed Critical Ciba Geigy AG
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Publication of GB2210367A publication Critical patent/GB2210367A/en
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D493/00Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10Spiro-condensed systems
    • CCHEMISTRY; METALLURGY
    • C09DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09BORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B11/00Diaryl- or thriarylmethane dyes
    • C09B11/04Diaryl- or thriarylmethane dyes derived from triarylmethanes, i.e. central C-atom is substituted by amino, cyano, alkyl
    • C09B11/10Amino derivatives of triarylmethanes
    • C09B11/24Phthaleins containing amino groups ; Phthalanes; Fluoranes; Phthalides; Rhodamine dyes; Phthaleins having heterocyclic aryl rings; Lactone or lactame forms of triarylmethane dyes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Description

22 0367 1-16707/+ Process for the preparation of N-aralkylated
aminofluoranes The present invention relates to a process for the preparation of N- aralkylated aminofluoranes.
The aralkyl group is usually introduced by reacting the amino compound with an aralkyl halide, for example benzyl chloride or benzyl bromide, the reaction being carried out in polar media as well as in non-polar solvents and in the presence of alkali compounds. These methods, however, have the drawback that the final product is sometimes obtained in insufficient yield when using polycyclic amino compounds.
It is the object of the present invention to provide an improved process which permits an increase in yield and simultaneously affords products for technical use in excellent purity without complicated purification steps.
Specifically, the invention relates to a process for the preparation of Naralkylated aminofluoranes, which comprises reacting a 2-aminofluorane of formula xl 0 /R2 6 ---NH2 13 0 wherein the ring A is unsubstituted or substituted by halogen, nitro, amino, lower alkylamino or di-lower alkylamino, R1 and R3 are each independently of the other hydrogen, halogen, lower alkyl or lower alkoxy, R2 is hydrogen, lower alkyl or lower alkoxy, Xl and X2 are each independently of the other hydrogen, alkyl containing not more than 12 carbon atoms which is unsubstituted or substituted by halogen, hydroxy, cyano or lower alkoxy; or are cycloalkyl, tetrahydrofuryl, aryl or acyl, or -NX1X2 is a 5- or 6-membered, preferably saturated, heterocyclic radical, with an aralkylarylsulfonate of formula (2) Z-S02 -O-Y, wherein Z is an aryl radical and Y is an arylalkyl or aryloxyalkyl radical.
Halogen is, for example, fluorine, bromine, iodine or, preferably, chlorine.
In the definition of the radicals of the fluoranes, lower alkyl and lower alkoxy normally denote those groups or moieties which contain 1 to 5, preferably 1 to 3, carbon atoms. Lower alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, n-butvl, see-butyl, tert-butyl or amvl, while lower alkoxy groups are, for example, methoxy, ethoxy, isopropoxy, tert-butoxy or tert-amyloxy.
Acyl is preferably formyl, lower alkanoyl such as acetyl or propionyl, or benzoyl. Further acyl radicals can be lower alkylsulfonyl, for example methyIsulfonyl or ethylsulfonyl as well as phenylsulfonyl. Cycloalkyl is, for example, cyclopentyl and, preferably, cyclohexyl.
In the meaning of Xl or X2 aryl is preferably phenyl or tolyl.
A heterocyclic radical -NX1X2 is, for example, pyrrolidino, piperidino, pipecolino, morpholino, thiomorpholino or piperazino, for example methylpiperazino. Preferred saturated heterocyclic radicals -NXIX2 are pyrrolidino, piperidino or morpholino.
Xl and X2, each independently of the other, are preferably C,-C8-alkyl, cyclohexyl, phenyl or tolyl or most preferably lower alkyl or as -NX1X2 pyrrolidino The ring A is preferably not further substituted. If it does contain substituents, then these are preferably halogen or di-lower alkylamino.
Particularly good results are obtained by the process of the invention by using a fluorane of the indicated formula in which R2 is hydrogen or, preferably, lower alkyl or, most preferably, methyl.
Suitable aralkylarylsulfonates of formula (2) are those in which the aryl radical Z as well as the arylalkyl or aryloxyalkyl radical Y are unsubstituted or ring-substituted. Preferred substituents are halogens, nitro, trifluoromethyl, lower alkyl, preferably methyl, or lower alkoxy such as methoxy.
Particularly suitable sulfonates are those of formula (2), wherein Y is arylalkyl, for example benzenesulfonates, p-toluenesulfonates, pbromobenzenesulfonates or p-nitrobenzenesulfonates.
Examples of suitable sulfonates for introducing the aralkyl group are: benzyl p-toluenesulfonate, phenethyl benzenesulfonate, phenethyl ptoluenesulfonate, phenpropyl p-toluenesulfonate, a-methylbenzyl ptoluenesulfonate, phenpropyl benzenesulfonate, phenisopropyl ptoluenesulfonate, 4-chlorbenzyl p-toluenesulfonate, 4-methylbenzyl ptoluenesulfonate, 2,5-dimethylbenzyl p-toluenesulfonate, 2,5dichlorbenzyl p-toluenesulfonate, benzyl p-nitrobenzenesulfonate, benzyl p-bromobenzenesulfonate, 2,4-dimethylbenzyl p-toluenesulfonate, 4trifluoromethylbenzyl p-toluenesulfonate, 4-methoxybenzyl ptoluenesulfonate, 2-phenoxyethyl p-toluenesulfonate, 2-phenoxyethyl benzenesulfonate.
4 The preferred alkylsulfonate is benzyl p-toluenesulfonate. 2-Phenoxvethyl p-toluenesulfonate is also preferred.
The aminofluorane and the sulfonate are generally used in approximately stoichiometric proportions such that one aralkyl group, or preferably two aralkyl groups, are introduced per amino group. An excess of, for example, 10-15 % of one of the components is, however, also possible.
The reaction is conveniently carried out at elevated temperature preferably in the range from 80' to 12CC and in the presence of an acid acceptor.
Examples of suitable acid acceptors are alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal bicarbonates, alkali metal carbonates or tertiary nitrogen bases such as pyridine, N-methylpyridine or trialkylamines or also mixtures of these compounds. The preferred acid acceptor is sodium carbonate.
The reaction is preferably conducted in a non-polar, preferably aromatic, solvent, for example, benzene, toluene, xylene, a chlorobenzene such as dichlorobenzene or trichlorobenzene, or nitrobenzene. The preferred solvent is toluene or xylene.
After the condensation reaction the N-aralkylated aminofluorane is isolated in conventional manner, for example removing the solvent by steam distillation, collecting the product by filtration and drying it. If necessary, the aralkylated aminofluorane can be purified by recrystallisation, for example from isopropanol.
In the following Examples, percentages are by weight.
Example 1:.12 g of 2-amino-3-methyl-6-diethylaminofluorane (prepared in accordance with DE-B-2 001 864, Example 6) and 8.7 g of sodium carbonate are stirred in 28 g of toluene and the mixture is heated to 1OCC. Then a solution of 23.6 g of benzyl p-toluenesulfonate (prepared in accordance with Monatshefte-Chemie 82, pp. 452-459, 1951) in toluene is added dropwise at 100'-1050C over 2 hours. The reaction mixture is stirred for 8 hours at 1OCC and then poured into 100 g of water. The toluene phase is separated and washed three times with 50 g of water, dried over sodium sulfate and filtered. The toluene is distilled off under reduced pressure. The crude product is taken up in a small amount bf isopropyl alcohol, isolated in the form of a crystalline product at WC and dried, affording 12 g of a fluorane of formula 0 \ /. \\./ CH3 (CzHs)2N-1 11 1.1 1 Yield: 69 % of theory Melting point: 154-155C.
This compound immediately develops a red colour on acid-modified silica gel.
Example 2: 12 g of 2-amino-3-methyl-6-diethylaminofluorane and 12.4 g of potassium carbonate are heated to 1OCC in 60 ml of toluene. Then a solution of 39.3 g of benzyl p-toluenesulfonate in 51 g of toluene is added at 100-105C over 1 hour. Analysis by liquid chromatography of a sample taken from the reaction mixture shows already the presenc e of 68. 8 % of the condensate of formula (11). The reaction is kept for 1 hour at reflux temperature. Analysis of a fresh sample shows 99.2 % of reaction product.
The reaction product is filtered to remove inorganic salts, the filtrate is concentrated, and the residue is stirred in 75 ml of isopropanol. The crystallised condensate is isolated by filtration and dried, to give 10.5 g of product. Analysis by liquid chromatography shows that the filtrate contains a further 2.1 g of dibenzylaminofluorane of formula (11), but no corresponding monobenzylaminofluorane.
6 Comparison Example 12 g of 2-amino-3-methyl-6-diethylaminofluorane and 12.4 g of potassium carbonate are heated to 1OCC in 60 ml of toluene. Then a solution of 19 g of benzyl chloride in 51 g of toluene are added at 100-105'C over 1 hour. Analysis by liquid chromatography of a sample takeh from the reaction mixture shows that there is still no trace of the condensate of formula (11). The reaction mixture is kept for 1 hour at reflux temperature. Analysis of a fresh sample still shows no trace of dibenzylaminofluorane of formula (11), but only 3.2 % of the corresponding N-monobenzylated aminofluorane.
The reaction mixture is filtered to remove inorganic salts, the filtrate is concentrated, and the residue is stirred in 75 ml of isopropanol. 8.3 g of the starting 2-amino-3-methyl-6-diethylaminofluorane are recovered by isolating the crystallised product by filtration.
The condensa tion progresses slightly by concentrating the filtrate. Analysis by liquid chromatography shows a yield of 1.7 g of monobenzylaminofluorane and 1.1 g of dibenzylaminofluorane.
Example 3: 10 g of 2-amino-3-methyl-6-diethylaminofluorane, 10.4 g of potassium carbonate and 21.9 g of 2-phenoxyethyl p-toluenesulfonate (prepared in accordance with J. Org. Chem. 9 (1944), 235, 238-240) are stirred in 40 ml of xylene (mixture of isomers) for 11 hours at 137-140'C under reflux. A further 50 ml of xylene are added and the reaction mixture is extracted repeatedly with 100 ml of water at 5CC. The xylene phase is then concentrated until the condensate crystallises. The product is isolated by filtration, washed with isopropanol and dried, affording 3. 1 g of the compound of formula (C2Hs)zN-i 0 CH3 (12) //\NH-CH2CH2-0-'//.-.kk' in the form of colourless crystals which melt at 189-191'C. A solution of this compound in toluene develops an instant black colour on acid- modified silica gel.
Example 4: Column chromatography of the filtrate obtained according to Example 3 (silica gel; elution with a 20:1 mixture of toluenelethyl acetate) gives 2.8 g of the fluorane of formula (C2Hs)zN-1 H / 0 H 1 / CH3 (13) \V \N(CHzCH20-'/ \')2 11 -10 with a melting point of 117-119'C after recrystallisation from isopropanolltoluene (10:1).
This compound immediately develops a red colour on acid-modified silica gel.
Example 5: With efficient stirring, 9.6 g of 2-amino-6diethylaminofluorane, 6.9 g of potassium carbonate and 14.6 g of 2phenoxyethyl p-toluenesulfonate are heated in 50 ml of xylene and the mixture is kept under reflux for 22 hours at 133-137'C. To the reaction mixture are added 50 ml of xylene and, at 80% 100 ml of water. The xylene phase is then separated, washed repeatedly with water and concentrated, to give 20 g of crude reaction mixture. The fluorane compounds of formulae (14) and (15) are separated by column chromatography (silica gel; elution with a 10:1 mixture of toluene/ethyl acetate) and are each recrlystallised from isopropanol:
(C2H5)2N- _N(CH2CH2-0(14) m.p. 124-127'C.
8 0 (C2Hs) 2N- (15) m.p. 143-146'C.
The compound of formula (14) develops a green colour, and the compound of formula (15) a black colour, on acid-modified clay.
9

Claims (11)

What is claimed is:
1. A process for the preparation of a N-aralkylated aminofluorane, which comprises reacting a 2-aminofluorane of formula l Xl 0 R2 X>- 6 2-NH2 13 1 A 11 0 \\ /.-o wherein the ring A is unsubstituted or substituted by halogen, nitro, amino, lower alkylamino or di-lower alkylamino, R1 and R3 are each independently of the other hydrogen, halogen, lower alkyl or lower alkoxy, R2 is hydrogen, lower alkyl or lower alkoxy, X, and X2 are each independently of the other hvdrogen, alkyl containing not more than 12 carbon atoms which is unsubstituted or substituted by halogen, hydroxy, cyano or lower alkoxy; or are cycloalkyl, tetrahydrofuryl, aryl or acyl, or -NX1X2 is a 5- or 6-membered heterocyclic radical, with an aralkylarylsulfonate of formula (2) Z-S02 -O-Y, wherein Z is an aryl radical and Y is an arylalkyl or aryloxyalkyl radical.
2. A process according to claim 1, which comprises the use of an aralkylarylsulfonate of formula (2), wherein Y is the arylalkyl radical.
3. A process according to claim 1, wherein the aralkylarylsulfonate is an arylalkyl p-toluenesulfonate, an arylalkyl p-bromobenzenesulfonate or an arylalkyl p-nitrobenzenesulfanate.
- 10
4. A process according to claim 1, wherein the aralkylarylsulfonate is benzyl p-toluenesulfonate.
5. A process according to claim 1, wherein the aralkylarylsulfonate is 2phenoxyethyl p-toluenesulfonate.
6. A process according to claim 1, which comprises the use of a fluorane compound of formula (1), wherein R2 is hydrogen or lower alkyl.
7. A process according to claim 1, which comprises the use of a fluorane compound of formula (1), wherein Ra is methyl.
8. An aminofluorane of the formula Xl 0 \ / \'/R2 6 ?2 2-1-NH-YI A3 1 A 1 wherein the ring A is unsubstituted or substituted by halogen, nitro, amino, lower alkylamino or di-lower alkylamino, R, and R3 are each independently of the ther hydrogen, halogen, lower alkyl or lower alkoxy, R2 is hydrogen, lower alkyl or lower alkoxy, X, and X2 are each independently of the other hydrogen, alkyl containing not more than 12 carbon atoms which is unsubstituted or substituted by halogen, hydroxy, cyano or lower alkoxy; or are cycloalkyl, tetrahydrofuryl, aryl or acyl, or -NXIX2 is a 5- or 6-membered heterocyclic radical, and Y1 represents an aryloxyalkyl radical.
9. The aminofluorane of claim 8, wherein Y1 is 2-phenyloxyethyl.
10. The aminofluorane of claim 8, wherein R2 is methyl.
11. The aminofluorane of claim 8, wherein Xl and X2 are lower alkyl or NXIX2 is pyrrolidino, piperidino or morpholino.
FO 7.11PElsm Published 1988 at The Patent Office. State House. 6671 High Holborn. London WC1R 4TP. Further copies may be obtained from The Patent Office, Sales Branch, St Mai7 Cray. OrpL-gton. Kent 73RS 3RD Printed by Multiplex techmques ltd, St MaiT Cray, Kent. Con. 1'87
GB8822146A 1987-09-30 1988-09-21 Process for the perparation of n-aralkylated and/or n-aryloxy-alkylated aminofluoranes Expired - Lifetime GB2210367B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH379887A CH672123A5 (en) 1987-09-30 1987-09-30 N-aryl:alkyl:amino:fluoran(s) prepn.
CH254588A CH675247A5 (en) 1988-07-05 1988-07-05 N-aryl:alkyl:amino:fluoran(s) prepn.

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GB8822146D0 GB8822146D0 (en) 1988-10-26
GB2210367A true GB2210367A (en) 1989-06-07
GB2210367B GB2210367B (en) 1991-06-12

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GB2210367B (en) 1991-06-12
GB8822146D0 (en) 1988-10-26
DE3832756A1 (en) 1989-04-13

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