GB2080291A - 6-Hydrazono-pyrido[2,1- b]quinazolin-11-ones, the salts thereof and processes for their preparation - Google Patents
6-Hydrazono-pyrido[2,1- b]quinazolin-11-ones, the salts thereof and processes for their preparation Download PDFInfo
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Abstract
Compounds of the general formula <IMAGE> (wherein R, R<1> and R<2>, which may be the same or different, each represents a hydrogen or halogen atom or a nitro, carboxy, cyano, C1-4 alkoxy, C1-4 alkyl, amino, or hydroxy group or an alkoxycarbonyl group in which the alkoxy contains 1 to 4 carbon atoms; or R and R<1> together represent a methylenedioxy group, and R<2> represents a hydrogen atom; R<3> represents a hydrogen atom or a C1-4 alkyl group; R<4> represents a hydrogen atom or a C1-4 alkyl group, a naphthyl or pyridyl group or a phenyl group substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C1-4 alkyl, C1-4 alkoxy, phenoxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl in which the alkoxy moiety contains 1 to 4 carbon atoms, alkanoyl in which the alkyl moiety contains 1 to 4 carbon atoms, methylenedioxy, trifluoromethyl, phenyl and mono- or di-alkylamino in which the alkyl moiety contains 1 to 4 carbon atoms; and each dotted line represents an optional further bond and the salts, optical and geometrical isomers and tautomers thereof are intermediates in the preparation of Rutaecarpine and the analogues thereof. The compounds of formula I may be prepared by reaction of a pyrido[2,1-b]quinazolin-11-one with a diazonium salt or with hydrazine or a derivative thereof.
Description
SPECIFICATION
6-Hydrazono-pyrido[2,1 -bjquinazolin-1 1-ones, the salts thereof and processes for their
preparation
The present invention relates to new 6-hydrazone-pyrido[2,1-b]quinazolin-11-ones, the salts,
geometrical and optical isomers and tautomers thereof as well as to processes for their preparation.
The new compounds may be used as intermediates in the preparation of alkaloids, especially in
the preparation of Rutaecarpine and the analogues thereof.
Pvrido[2.1=b]quinazolin-11-ones are known partly as alkaloids (Chem. Comm, 267 [1965] ;
Austral J. Chem. 151 [1966]; Chem. Ber. 68,2221 [1935]; J. Chem. Soc. 4694 [1956]; Chem. Ber. 95, 2182 [1962] and partly as compounds possessing favourable physiological properties (German Federal
Republic Patent No.2812585, Belgian Patent Nos. 849,542 and 847,011).
Known pyrido[2,1-b]quinazolin-11-ones are disclosed in Moshy: Heterocyclic Systems with
bridgehead nitrogen atoms, Vol. 2, 1153-1159, Interscience Publishers, Inc., New York, 1961.
The present invention however is based on the discovery of novel 6-hydrazono-pyrido[2,1 b]quinazolin-1 does, the salts thereof and processes for their preparation.
Thus according to one feature of the present invention there are provided compounds of the
general formula
(wherein
R, R' and R2, which may be the same or different, each represents a hydrogen or halogen atom or a nitro, carboxy, cyano, C14 alkoxy, C14 alkyl, amino, or hydroxy group or an alkoxycarbonyl group in which the alkoxy moiety contains 1 to 4 carbon atoms; or R and R1 together represent a methylenedioxy group, and R2 represents a hydrogen atom;
R3 represents a hydrogen atom or a C14 alkyl group;; - - R4 represents a hydrogen atom, a C14 alkyl group, a naphthyl or pyridyl group or a phenyl group substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C,, alkyl, C 1-4 alkoxy, phenoxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl in which the alkoxy moiety contains 1 to 4 carbon atoms, alkanoyl in which the alkyl moiety contains 1 to 4 carbon atoms, methylenedioxy, trifluoromethyl, phenyl and mono- ar di-alkylamino in which the alkyl moiety contains
1 to 4 carbon atoms; and
each dotted line represents an optional further bond) and the salts, optical and geometrical isomers and tautomers thereof.
As stated above the compounds of formula I are especially useful as intermediates in the preparation of Rutaecarpine and the analogues thereof. The use of compounds of formula I and the salts thereof for such a purpose is described and claimed in two of our copending patent applications filed 23rd June 1 981, one of which patent applipation is entitled "lndolo[2',3' ;3;4]pyrido[2, 1 -b]quinazolin5-ones, the salts thereof and processes for their preparation", the other being entitled "A process for the preparation of indolo[2',3';3,4]pyrido[2,1-b]quinazolin-5-ones".
Especially preferred compounds of the invention, by virtue of their utility as intermediates inciude the following compounds: 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline, (#)6-phenylhydrazono-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazollne
6-phenylhydrazono-1 1 -oxo-1 ,2,3,4,6,7,8,9-octahydro- 1 H-pyrido[2, 1 -b]quinazoline,
(i) 6-phenylhydrazono-9-methyl-1 1 -oxo-1 ,2,3,4,6,7,8,9-octahydro-1 1 H-pyrido[2,1 -b] quinazoline,
6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-2-carboxylic acid,
and the salts thereof.
The compounds of the present invention may be prepared, for example, by any one of the following processes (a) to (c), which processes constitute further features of the present invention: (a) for the preparation of compounds of the invention wherein R4 is other than hydrogen or C1-4 alkyl, the reaction of a compound of the formula
(wherein R, R1, R2 and R3 are as hereinbefore defined, each dotted line represents an optional further
bond and R3 represents a hydrogen atom or a formyl group) or a salt thereof with a diazonium salt of the
formula:: [R4 - N2]n8 X (III)
(wherein 134, is as defined for R4 above with the proviso that R4, is other than a hydrogen atom or a C,, alkyl group, X represents the stabilising anion and n represents the charge on the anion) and if desired
converting a compound of formula I obtained into a salt thereof or converting a salt of a compound of formula I into a free compound of formula I,
(b) for the preparation of compounds of the invention wherein R4 is other than hydrogen or C1-4 alkyl, the reaction of a pyrido[2,1-b]quinazolin-11-one of the formula :
(wherein R, R1, R2 and R3 are as hereinbefore defined, each dotted line represents an optional further bond and R7 and R8, which may be the same or different, each represents an alkyl group) or a salt thereof with a compound of formula Ill (as hereinbefore defined) and if desired converting a compound of formula I obtained into a salt thereof or converting a salt of a compound of formula I into a free compound of formula 1, (c) the reaction of a compound of the formula::
(wherein R, R, R and R are as hereinbefore defined, each dotted line represents an optional further bond, R9 represents a hydrogen or halogen atom and R10 represents a halogen a halogen atom) or a salt thereof with a compound of the formula
(wherein R4 is as hereinbefore defined) and if desired converting a compound of formula I obtained into a salt thereof or converting a salt of a compound of formula I into a free compoud of formula I.
Process variant (a) i.e. the reaction of the compound of general formula Il with the diazonium salt of general formula Ill is conveniently effected using a compound of formula Ill in which X represents a halogen atom and n is 1, but X is preferably chlorine; the reaction advantageously being effected according to (Parmerter: org. Reactions,10, p. 1-142 [1959]; Phillips: Org. Reactions 10, p.
143-178 [1959]).
According to a preferred embodiment of process (a) the reaction is conveniently effected below 500 C, e.g. -10 to +500C preferably at -10 to 200 C. The reaction may be effected by adding a given compound of formula ll to a solution of the diazonium salt of general formula Ill or the other way round.
The components may preferably be used in an equimolar amount, but one of the components may optionally be used in a smail excess. The reaction may be conducted preferably in aqueous medium, if desired in the presence of a water-miscible inert organic solvent.
Alkanoic acids e.g. C24 alkanoic acids preferably acetic acid and/or propionic acid; acid amides preferably N,N-dimethyl-formamide; alcohols preferably methanol, ethanol, propanol and/or isopropanol; ketones such as acetone and/or methyl ethyl ketone; and/or aromatic bases preferably pyridine, may be employed as the inert organic solvent. The reaction may preferably be carried out in the presence of an acid binding agent. Alkali alkanoates, preferably sodium acetate and/or potassium acetate; alkali metal hydroxides preferably sodium hydroxide and/or potassium hydroxide; or alkali metal carbonates preferably sodium carbonate, potassium carbonate and/or sodium bicarbonate etc. may be used as the acid binding agent.
According to process variant (b) a compound of general formula IV is reacted with a diazonium salt of general formula Ill.
A compound of formula IV is preferably used in which R7 and R8, which may be the same or different, each represents a C14 alkyl group. A compound of formula Ill is preferably used in which X represents a halogen atom and n is 1, but X is preferably chlorine. Process variant (b) is preferably effected as described in relation to process variant (b).
According to process variant (c) a compound of general formula V is reacted with a hydrazine of general formula VI. A compound of formula V is preferably used in which R9 and R'O, which may be the same or different, each represents a chlorine or bromine atom. In another preferred embodiment a compound of formula VI is preferably used in which 139 represents a hydrogen or bromine atom and 1310 represents a bromine atom. The reaction is conveniently effected in the presence of an inert solvent.
Alkanols, preferably methanol, ethanol, propanol, iso-propanol etc; alkanoic acids, preferably acetic acid or propionic acid, acid amides, such as N,N-dimethylformamide and/or aromatic bases preferably pyridine may be used as the inert solvent. The enumerated solvents may optionally be mixed with water and then the reaction may be conducted in a mixture of water and a water-miscible organic solvent. If desired an acid binding agent may be employed. The substances detailed as acid binding agents for process variant (a) may also be used in (c). An excess of the hydrazine of general formula VI may also serve as an acid binding agent. According to a preferred embodiment of the process 1 to 8 moles, preferably 2.5 to 4.5 moles of hydrazine of general formula VI may be used per mole of the compound of general formula V.The reaction may be conducted at a temperature of from OOC to 1 600C, and when using a solvent(s) preferably at the boiling point of the reaction mixture. The reaction time may vary from 30 minutes to 10 hours depending upon the reactants. Compounds of general formula I obtained in the course of process variants (a), (b) or (c) precipitate from the reaction mixture or precipitate upon aqueous dilution and can be isolated by filtration, centrifuging or other conventional methods.
The compounds of general formula I form salts with organic or inorganic acids, thus salts such as the hydrochlorides, hydrobromide, sulphate, phosphate, perchlorate, maleate, acetate etc. may be prepared.
Compounds of general formula I containing at least one carboxyl group form salts with bases, such as alkali metal salts, e.g. sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, or salts with tertiary amines, such as triethylamine salts or ethanolamine salts etc.
The present invention includes the preparation of optical and geometrical isomers and tautomers of the compounds of formula I. Optical isomerism occurs in formula I when R3 is other than hydrogen.
The structures of the geometrical isomers are illustrated by the general formula IA and IB
The structures of the possible tautomers are shown by the reaction scheme A.
Reaction scheme A
A free compound of general formula I may be obtained from its corresponding salt, formed with an acid or base, by methods known per se.
A compound of general formula I may be converted to an acid addition salt by reaction with an organic or inorganic acid. The salt formation may be performed by methods known per sue e.g comprising reacting a compound of the formula I with a corresponding acid in molar equivalent amount or in excess in the presence of an inert organic solvent.
Compounds of general formula I containing a carboxyl group may be converted to salts by reaction with a suitable base, such as an alkali metal hydroxide, an alkaline earth metal hydroxide, or an organic amine by methods known per se.
Most of the starting materials are known. Starting materials of general formulae II, IV and V are disclosed in: Kokai Tokkyo Koho 78 130 435 and Belgian Patents Nos. 849 542 and 847 011 and in
German (Federal Republic) Patents Nos. 2 812 585 and 2 812 586, Mosby: Heterocyclic Systems with bridgehead nitrogen atoms, Vol. 2, p. 1153-1159, Interscience Publishers, Inc. New York, 1961, Him.
Geterocycl. Soed. 1976, 1564-1569, 1979, 684 691. Where such starting materials are not specifically known they may be prepared by processes analogous to those disclosed in the above mentioned references.
Further details of the invention are found in the following Examples which are given by way of illustration only.
EXAMPLES 1-22 0.1 mole of the aniline derivative is mixed with 5 ml of 28 V1W% hydrochloric acid solution in 1:1 dilution and the mixture cooled to -50C. A solution of 0.69 g (0.01 mole) sodium nitrite in 5 ml of water is slowly added dropwise with steady stirring and cooling. The reaction mixture is then stirred for 30
minutes at a temeprature ranging from -50C to OOC, after which the pH of the reaction mixture is adjusted to 4 by the addition of sodium acetate. The mixture is diluted with 5 ml of glacial acetic acid and a solution of 2.0 g (0.01 mole) of 11 -oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1 -a]quinazoline in 10 ml of 50 Vol% acetic acid is added dropwise.The reaction mixture is stirred for 3 hours at -50C to OOC.
The mixture is then allowed to stand overnight in a refrigerator. The precipitated crystals are filtered and washed with water. The 11 -oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1 -b]quinazolines obtained are purified if necessary by recrystallization from n-propanol. The prepared compounds are summarized in
Table 1.
EXAMPLES 23-24 The processes of these Examples are conducted according to the process described in relation to Examples 1-22 but 1 1-oxo-1,2,3,4,6,7,8,9-octahydro-1 1H-pyrido[2,1-b]quinazoline is used as starting material instead of 11 -oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1 -b]quinazoline.
The compounds prepared are summarized in Table 2.
TABLE 1
Compound of the general formula
(I) Analysis %
Yield Empirica Calculated Found
Example R R R R R4 Mp. % formula C H N C H N 1 H H H H Ph 182-184 90 C18H16N4O 71.03 5.29 18.41 70.97 5.27 18.28 2 H H H H 4-Cl-Ph 191-192 94 C18H15N4OCl 63.81 4.46 16.53 64.01 4.57 16.25 3 H H H H 4-Me-Ph 187-188 88 C19H18N4O 71.67 5.69 17.59 72.13 5.60 17.48 4 H H H H 4-Br-Ph 180-183 84 C18H15N4OBr 56.41 3.94 14.61 56.24 3.85 14.51 5 H H H H 4-CF3-Ph 195-197 83 C19H15N4OF3 61.28 4.06 15.04 61.89 4.12 14.86 6 H H H H 4-PhO-Ph 178-180 83 C24H20N4O2 72.71 5.08 14.13 72.50 4.96 14.07 7 H H H H 3-Cl-Ph 181-183 89 C18H15N4OCl 63.81 4.46 16.53 63.95 4.58 16.65 8 3-Cl H H H Ph 219-222 65 C18H15N4OCl 63.81 4.46 16.53 63.84 4.58 16.71 9 3-Cl H H H 4-Cl-Ph 227 64 C18H14N4OCl2 58.08 3.79 15.05 58.04 3.73 14.72 10 H H H 9-Me Ph 185-186 75 C19H18N4O 71.67 5.69 17.59 71.52 5.66 17.53 11 H H H H 1-naphthyl 192-193 86 C22H18N4O 70.57 4.84 14.96 70.55 4.84 14.40 12 H H H H 2-naphthyl 220 96 C2H18N4O 70.57 4.84 14.96 70.33 4.65 14.87 TABLE 1 (Continued)
Compound of the general formula
(I) Analysis %
Yield Empirica Calculated Found
Example R R R R R4 Mp. % formula C H N C H N 13 H H H H 4-Ac-Ph 255 81 C20H18N4O2 69.34 5.23 16.17 69.33 5.35 16.28 14 3-Cl H H H 4-Me-Ph 231 64 C19H17N4OCl 58.72 4.65 14.42 58.88 4.78 16.18 15 H H H H 4-HO-Ph 225/b/ 84 C18H17N4O2Cl 60.59 4.80 15.70 60.69 4.85 15.88 16 H H H H 4-MeO-Ph 223 92 C19H19N4O2Cl 61.53 5.16 15.10 62.10 5.23 14.90 17 H H H H 4-NO2-Ph 250/b/ 92 C18H16N5O3Cl 56.17 4.18 18.19 56.04 4.19 18.89 18 H H H H 4-F-Ph 245 90 C18H16N4OFCl 60.25 4.49 15.61 60.59 4.46 15.02 19 H H H H 4-HOOC-Ph 298/b/ 91 C19H16N4O3.HCl 59.30 4.45 14.55 59.39 4.60 14.52 20 H H H H 3-pyridyl 188 23 C17H15N5O.HCl 59.74 4.72 20.49 59.97 4.65 20.61 21 H H H H 4-CN-Ph 217 82 H19H15N5O.HCl 62.38 4.41 19.14 62.24 4.50 19.32 22 2-MeO 3-MeO H H Ph 230/b/ 88 C20H20N4O3 65.92 5.53 15.37 65.72 5.28 15.21
TABLE 2
Compound of the general formula
(I) Analysis %
Yield Empirica Calculated Found
Example R R R R R4 Mp. % formula C H N C H N 23 H H H H Ph 205-208 85 C18H20N4O 70.10 6.53 18.16 69.93 6.51 18.07 24 H H H g-Me Ph 190-193 83 C19H22N4O 70.78 6.87 17.37 70.55 6.91 17.27 EXAMPLE 25 6-Phenylhydrazono-6,7,8,9-tetrahydro-1 1 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline
10.8 g (0.03 mole) of 6,6-dibromo-6,7,8,9-tetrahydro-1 1-oxo-1 1H-pyrido[2,1-b]quinazoline and 13.0 g (0.12 mole) of phenyl hydrazine are heated in 120 ml ethanol for 4 hours. The precipitated
crystals are filtered after cooling.When evaporating the mother liquor further crystals are precipitated,
which are filtered and washed with some alcohol. The combined filtered product is suspended in 150 ml of water containing 8.4 g (0.06 mole) of sodium acetate following which it is filtered and washed with
water. 8.4 g (81%) of 6-phenylhydrazono-6,7,8,9-tetrahydro-1 1 oxo-1 1 H-pyrido[2,1 -blquinazoline are
obtained which after recrystallization from isopropanol melts at 177-1 790C and which does not give
any divergence of melting point when mixed with the product of Example 1.
EXAMPLE 26
6-P henylhydrazono-9-methyl- 11 -oxo-6,7,8,9-tetrahydro- 11 H-pyrido[2,1 -b]quinazoline
3.74 g (0.01 mole) of 6,6-dibromo-9-methyl-1 1 -oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1-a]quinazoline abd 4,32 g (0.04 mole) of phenyl hydrazine are heated in 40 ml of ethanol for 10 hours.
The precipitated crystals are filtered after cooling. The filtered product is suspended in 100 ml of water
containing 2.72 g (0.02 mole), sodium acetate, filtered and washed with water. 2.4 g (75%) orange 6 phenylhydrazono-9-methyl-1 1 -oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1-b]quinazoline are obtained which after recrystallization from ethanol melts at 1 85-1 870C.
Analysis for the formula C19H'8N4O calculated: C 71.67% H 5.69% N 17.59% found: C 71.62% H 5.58% N 17.55%.
EXAMPLE 27 6-Phenylhydrnzone-1 1 -oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1 -b]quinazoline
2.f9 g (0.01 mole) of 6-bromo-11-oxo-6,7,8,9-tetrahydro-11 H-pyrido[2,1-b]quinazoline and
2.16 g (0.02 mole) of phenyl hydrazine are heated in 30 ml of ethanol for 6 hours at 800C. The ethanol is
then concentrated to a third of its volume. The mixture is then allowed to crystallize in an ice-box. The
precipitated yellow crystals are filtered, and washed with ethanol and water. 2.1 g (69%) of 6 phenylhydrazono-l 1 -oxo-6,7,8,9-tetrahydro-l 1 H-pyrido[2,1 -b]quinazoline are obtained, which after recrystallization from isopropanol melt at 179-180 C. When the product of this Example is mixed with the product according to Example 1 or Example 25 there is no difference in melting point.
Analysis for the formula C18Ht6N4O calculated: C71.03% H 5.29% N 18.41%
found: C 70.88% H 5.25% N 18.38%.
EXAMPLE 28 6-Phenylhydrazono-6,7,8,9-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline
0.93 g (0.9 ml, 0.01 mole) of aniline are dissolved in 5 ml of 38 V/W% of hydrochloric acid in 1:1
dilution and the solution is cooled to -50C. A solution of 0.65 g (0.01 mole) of sodium nitrite in 5 ml of
water is added dropwise with steady cooling and stirring. The reaction mixture is stirred for 30 minutes
at a temperature of -50C to 0 C after which the pH of the solution is adjusted to 4 by the addition of
sodium acetate and the mixture diluted with 1 ml of acetic acid.To the solution of the diazonium salt a
solution of 2.55 g of 9-(dimethylamino-methylene)-1 1-oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1-b]
quinazoline in 25 ml of dimethylformamide is slowly added dropwise at -50C. The reaction mixture is
stirred at 0 C for 3 hours whereafter it is allowed to stand overnight in an ice-box. The mixture is then diluted with water and the precipitated crystals are filtered and washed with water.2.61 g (86%) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-11 H-pyrido[2,1-b]quinazoline are obtained which after recrystallization from isopropanol melt at 1 82-1 840 C. Moreover the product does not show any difference in melting point when mixed with the product of Example 1.
Analysis for the formula C18H16N4O calculated: C 71.03% H 5.29% N 18.41% found: C 70.93% H 5.24% N 18.33%
EXAMPLE 29 6-Phenylhydrazono-6,7,8,9-tetrahydro-11 -oxo-11H-pyrido[2,1-b]quinazoline hydrdochloride
0.93 g (0.01 mole) of aniline are dissolved in 5 ml of 38 V/W% hydrochloric acid at a dilution of 1:1 and the mixture cooled to --50 C. A solution of 0.69 g (0.01 mole) of sodium nitrite in 5 ml of water is added dropwise under steady stirring and cooling. The reaction mixture is stirred for half ad hour at -50C to 0 C whereafter the pH of the solution is adjusted to 4 by the addition of sodium acetate and the solution is diluted with 10 ml of acetic acid. A solution of 2.28 g (0.01 mole) of 6-formyl-1 1 -oxo- 6,7,8,9-tetrahydro-1 1 H-pyrido[2,1 -b]quinazoline in 30 ml of acetic acid is slowly added dropwise to the reaction mixture. The mixture is stirred for 1 hour at a temperature below 0 C and the solution is then allowed to stand in the refrigerator. The precipitated crystals are filtered and washed with water. 3.1 g (91%) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-1 1H-pyrido[2,1-bquinazoline hydrochloride are obtained melting at 2550C.
Analysis on the basis of C18H17N4OCI calculated: C 63.60% H 5.04% N 16.48% CI 10.16% found: C 63.44% H 4.98% N 16.59% Cl 10.11%
EXAMPLES 30 to 33
The procedure described in relation to Examples 1-22 is followed, but in Example 30, 2,3,4- trimethoxy-1 1-Oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1-b]quinazoline is used as starting material; in
Example 31 11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2.1-b]quinazolin-2-carboxylic acid is used as starting material ; in Example 32 ethyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-2carboxylate is used as starting material; and in Example 33 1 1-oxo-6,7,8,9-tetrahydro-1 1 H-pyrido[2,1b]quinazoline is used. 6-Phenylhydrazono-1 1 -oxo-6,7,8,9-tetrahydro-1 1 H-pyndo[2, 1 -b]quinazolines are obtained as shown in Table 3. The products are recrystallized from n-propanol.
EXAMPLES 34 to 44
The procedure described in relation to Examples 23 and 24 is followed, but 11 -oxo- 1,2,3,4,6,7,8,9-octahydro-11 H-pyrido[2,1 -b]quinazolines are used as starting materials. Thus 6 phenylhydrazono-4-oxo-1 ,2,3,4,6,7,8,9-octahydro-1 1 H-pyrido[2,1 -b]quinazolines are obtained as shown in Table 4.
In Examples 42 and 43 crystals precipitated from the diazo-coupling reaction mixture are suspended in a 5% V/W% sdium hydroxide solution and the aqueous solution is shaken with chloroform.
The chloroform solution is dried over anhydrous sodium sulphate, evaporated and the residue crystallized.
EXAMPLE 45 6-Phenylhydrazono-1 1 -oxo-1 ,2,3,4,6,7,8,9-octahydro-1 1 H-pyrido[2, 1 -b]quinazol'ine hydrochloride
0.45 g (0.005 mole) of aniline is dissolved in 3 ml of hydrochloric acid (36 V/\N%) at a dilution of 1:1 and the solution cooled to -50C. A solution of 0.35 g (0.005 mole) of sodium nitrite in 3 ml of water is added dropwise. The reaction mixture is stirred for half an hour at-5 C to 0 C whereafter the pH of the solution is adjusted to 4 by adding sodium acetate.A solution of 1.23 g (0.005 mole) of 6 formyl-1 1 -oxo-1 ,2,3,4,6,7,8,9-octahydrn-1 1 H-pyrido[2,1 -b]quinazoline in 1 5 ml of 75 V% acetic acid is slowly added dropwise to the reaction mixture and the solution is stirred for 3 hours at a temperature below 0 C whereafter the mixture is allowed to stand overnight in a refrigerator and diluted with 30 ml water. The precipitated crystals are filtered and washed with water. 1.3 g (73%) of 6-phenylhydrazono11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1-b]quinazoline hydrochloride are obtained melting at 242-244 C.
Analysis for the formula C19H23N4OCI calculated: C 63.59% H 6.46% N 15.61% Cl 9.88% fined: C 63.21% Il 6.28% N 15.75% Cl 9.65%.
Compounds of the formula I TABLE 3
Compound of the general formula
(I) Analysis %
Yield Empirica Calculated Found
Example R R R R R4 Mp. % formula C H N C H N 30 2-OMe 3-OMe 4-OMe H Ph 187-77 77 C21H22N4O4 63.94 5.62 14.20 64.03 5.88 14.28 31 2-COOH H H H Ph 257/b/ 30 C19H16N4O3 65.51 4.62 16.08 65.56 4.66 16.01 32 2-COOEt H H H Ph 201 85 C21H20N4O3 67.00 5.35 14.88 67.03 5.45 14.85 33 H H H H 4-EtOOC-Ph 214 92 C22H20N 4O3 61.09 5.09 13.57 61.25 4.99 13.58
HCl
Compounds of the formula I TABLE 4
Compound of the general formula
(I) Analysis %
Yield Empirica Calculated Found
Example R R R R R4 Mp. % formula C H N C H N 34 H H H H 4-Cl-Ph 220 73 C16H19N4OCl 63.06 5.59 16.34 63.24 5.51 16.32 35 H H H 9-Me 4-Cl-Ph 207-208 70 C19H21N4OCl 63.95 5.93 15.70 64.14 6.17 15.78 36 H H H 9-Me 4-NO2-Ph 168-170 79 C19H21N5O3HCl 56.50 5.49 17.34 56.15 5.44 17.00 37 H H H H 4-Me-Ph 203-204 46 C19H22N4O 70.78 6.88 17.38 70.63 6.56 17.17 38 H H H 9-Me 4-Me-Ph 187-188 74 C20H24N4O 71.40 7.19 16.66 71.17 6.96 16.72 39 H H H 9-Me 4-Et-Ph 154-155 49 C21H26N4O 71.97 7.48 15.99 71.58 7.52 16.03 40 H H H 9-Me 4-MeO-Ph 161-162 42 C20H24N4O2 68.16 6.86 15.90 68.43 6.95 15.80 41 H H H 9-Me 2-naphthyl 177-179 11 C23H24N4O 74.17 6.50 15.04 74.13 6.40 14.72 42 H H H 8-Me Ph 219 59 C19H12N4O 70.78 6.87 17.37 70.83 6.82 17.40 43 H H H 9-Me 3,5-diCl-Ph 227-228 33 C19H20N40Cl2 58.33 6.15 14.31 58.40 5.23 14.27 44 H H H 7.Me Ph 200 59 C19H22N4O 70.78 6.87 17.37 70.91 6.75 17.45
Claims (34)
1. Compounds of the general formula
(wherein
R, R' and R2, which may be the same or different, each represents a hydrogen or halogen atom or a nitro, carboxy, cyano, C1-4 alkoxy, C14 alkyl, amino, or hydroxy group or an alkoxycarbonyl group in which the alkoxy moiety contains 1 to 4 carbon atoms; or R and R' together represent a methylenedioxy group, and R2 represents a hydrogen atom;
R3 represents a hydrogen atom or a C,, alkyl group;
R4 represents a hydrogen atom or a C,, alkyl group, a naphthyl or pyridyl group or a phenyl group substituted by 1 to 3 substituents, which may be the same or different, selected from halogen, C,, alkyl, C14 alkoxy, phenoxy, hydroxy, nitro, amino, cyano, carboxy, alkoxycarbonyl in which the alkoxy moiety contains 1 to 4 carbon atoms, alkanoyl in which the alkyl moiety contains 1 to 4 carbon atoms, methylenedioxy, trifluoromethyl, phenyl and mono- or di-alkylamino in which the alkyl moiety contains 1 to 4 carbon atoms; and
each dotted line represents an optional further bond and the salts, optical and geometrical isomers and tautomers thereof.
2. 6-P henylhydrazono-l 1 -oxo-6,7,8,9-tetrahydro- 1 1 H-pyrido[2, 1 -b]quinazoline.
3. (+) 6-Phenylhydrazono-9-methyl-11 -oxo-6,7,8,9-tetrahydro- 11H-pyrido[2,1 -b]quinazoline.
4. 6-Phenylhydrazono-11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-yrido[2,1-b]quinazoline.
5. (#) 6-Phenylhydrazono-9-methyl-11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido[2,1b]quinazoline.
6. 6-Phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazolin-2-arboxylic acid.
7. A salt of a compound as claimed in any one of claims 2 to 6.
8. A compound as claimed in claim 1, otrher than as claimed in any one of claims 2 to 6, as herein specifically disclosed.
9. A process for the preparation of a compound as claimed in claim 1 (wherein R4 is other than hydrogen or C14 alkyl) which comprises reacting a compound of the formula
(wherein R, R, R and R are as defined in claim 1, each dotted line represents an optional further bond
and R6 represents a hydrogen atom or a formyl group) wth a diazonium salt of the formula :: Tie [R# - N2]n X (III)
(wherein R4, is as defined for R4 in claim 1 with the proviso that R4 is other than a hydrogen atom or a C 1-4 alkyl group, X represents the stabilizing anion and n represents the charge on the anion) and if
desired converting a compound of formula I obtained into a salt thereof or converting a salt of a
compound of formula I into a free compound of formula I.
10. A process as claimed in claim 9 wherein a compound of formula Ill is used in which X
represents a halogen atom and n is 1.
11. A process as claimed in claim 10 wherein X represents a chlorine atom.
1 2. A process for the preparation of compounds as claimed in claim 1 (wherein R4 is other than
hydrogen or 1-4 alkyl) in which comprises reacting a pyrido[2,1-b]quinazolin-1 1-one of the formula:
(wherein R, R1, R2 and R3 are as defined in claim 1, each dotted line represents an optional further bond and R7 and R8, which may be the same or different, each represents an alkyl group) with a compound of formula Ill (as defined in claim 9) and if desired converting a compound of formula I obtained into a salt thereof or converting a salt of a compound of formula I into a free compound of formula I.
13. A process as claimed in claim 12 wherein a compound of formula IV is used in which R7 and R8, which may be the same or different, each represent a C,, alkyl group.
14. A process as claimed in claim 12 or claim 13 wherein a compound of formula Ill is used in which X represents a halogen atom and n is 1.
1 5. A process as claimed in claim 14 wherein X represents a chlorine atom.
1 6. A process as claimed in any one of claims 9 to 1 5 wherein the reaction is effected at a temperature of from -1 00C to +500 C.
1 7. A process as claimed in claim 1 6 wherein the reaction is effected at a temperature of from -10 to +2O0C.
18. A process as claimed in any one of claims 9 to 1 7 wherein the reaction is effected in the presence of an aqueous medium.
1 9. A process as claimed in claim 18 wherein the aqueous medium comprises a water-miscible inert organic solvent.
20. A process as claimed in claim 19 wherein the inert organic solvent comprises a C2~4 alkanoic acid.
21. A process as claimed in claim 20 wherein the alkanoic acid is acetic acid.
22. A process as claimed in any one of claims 19 to 21 wherein the inert organic solvent comprises a C14 alkanol.
23. A process for the preparation of compounds as claimed in claim 1 which comprises reacting a compound of the formula
(wherein R, R1, R2 and R3 are as defined in claim 1, each dotted line represents an optical further bond, 139 represents a hydrogen or halogen atom and 1310 represents a halogen atom) with a compound of the formula
(wherein R4 is as defined in claim 1) and if desired converting a compound of formula I obtained into a salt thereof or converting a salt of a compound of formula I into a free compound of formula I.
24. A process as claimed in claim 23 wherein a compound of formula V is used in which R9 and
R10, which may be the same or different each represents a chlorine or bromine atom.
25. A process as claimed in claim 23 wherein a compound of formula V is used in which R9 represents a hydrogen or bromine atom and R10 represents a bromine atom.
26. A process as claimed in any one of claims 23 to 25 wherein the reaction is effected at a temperature of from 0 to 1 600C.
27. A process as claimed in any one of claims 23 to 26 wherein the reaction is effected in the presence of an inert organic water-miscible solvent.
28. A process as claimed in claim 27 wherein the water-miscible solvent comprises a C24 alkanoic acid.
29. A process as claimed in claim 28 wherein the alkanoic acid is acetic acid.
30. A process as claimed in any one of claims 27 to 29 wherein the water-miscible solvent comprises a C14 alkanol.
31. A process as claimed in any of claims 23 to 26 wherein the reaction is effected in the presence of water.
32. A process as claimed in any one of claims 9 to 31 substantially as herein described.
33. A process for the preparation of a compound as claimed in claim 1 substantially as herein described in any one of the Examples.
34. A compound as claimed in claim 1 when prepared according to a process as claimed in any one of claims 9 to 33.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU801559A HU183173B (en) | 1980-06-24 | 1980-06-24 | Process for producing 6-hydrazono-pyrido-aracket-2,1-b-bracket closed-quinazolin-11-ones |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2080291A true GB2080291A (en) | 1982-02-03 |
| GB2080291B GB2080291B (en) | 1984-01-18 |
Family
ID=10955013
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8119298A Expired GB2080291B (en) | 1980-06-24 | 1981-06-23 | 6-hydrazono-pyrido (2,1-b) quinazolin-11-ones the salts thereof and processes for their preparation |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5738781A (en) |
| AT (1) | AT379393B (en) |
| AU (1) | AU544360B2 (en) |
| BE (1) | BE889339A (en) |
| CA (1) | CA1167842A (en) |
| CH (1) | CH648312A5 (en) |
| CS (1) | CS296285A2 (en) |
| DD (1) | DD160060A5 (en) |
| DE (1) | DE3124577A1 (en) |
| DK (1) | DK277281A (en) |
| ES (1) | ES503266A0 (en) |
| FI (1) | FI70897C (en) |
| FR (1) | FR2485534A1 (en) |
| GB (1) | GB2080291B (en) |
| GR (1) | GR74608B (en) |
| HU (1) | HU183173B (en) |
| IL (1) | IL63061A (en) |
| IT (1) | IT1144814B (en) |
| NL (1) | NL8102935A (en) |
| NO (1) | NO157142C (en) |
| PL (2) | PL129635B1 (en) |
| PT (1) | PT73248B (en) |
| SE (1) | SE441829B (en) |
| SU (2) | SU1192614A3 (en) |
| YU (1) | YU42722B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ194196A (en) * | 1979-07-17 | 1983-07-15 | Ici Australia Ltd | -(quinoxalin-2-yl(oxy or thio) phen (oxy or ylthio)-alkanoic acid derivatives or precursors |
| AT377586B (en) * | 1981-06-30 | 1985-04-10 | Erba Farmitalia | METHOD FOR PRODUCING SUBSTITUTED PYRROLO- (2,1-B) -QUINAZOLINES AND PYRIDO (2,1-B) -QUINAZOLINES |
| JPS5987269A (en) * | 1982-11-12 | 1984-05-19 | Nissan Motor Co Ltd | Fuel injection valve |
| JPS61126367A (en) * | 1984-11-24 | 1986-06-13 | Mitsubishi Heavy Ind Ltd | Fuel injection device |
| JPS61129457A (en) * | 1984-11-27 | 1986-06-17 | Mitsubishi Heavy Ind Ltd | Multi-fuel-valve injector |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU178496B (en) * | 1977-12-29 | 1982-05-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing 6,7,8,9-tetrahydro-4h-pyrido/1,2-a/pyrimidine derivatives with antiallergic activity |
-
1980
- 1980-06-24 HU HU801559A patent/HU183173B/en not_active IP Right Cessation
-
1981
- 1981-06-09 IL IL63061A patent/IL63061A/en unknown
- 1981-06-18 CS CS852962A patent/CS296285A2/en unknown
- 1981-06-18 NL NL8102935A patent/NL8102935A/en not_active Application Discontinuation
- 1981-06-22 ES ES503266A patent/ES503266A0/en active Granted
- 1981-06-22 FR FR8112209A patent/FR2485534A1/en active Granted
- 1981-06-22 GR GR65305A patent/GR74608B/el unknown
- 1981-06-23 BE BE0/205178A patent/BE889339A/en not_active IP Right Cessation
- 1981-06-23 AT AT0277081A patent/AT379393B/en not_active IP Right Cessation
- 1981-06-23 CH CH4143/81A patent/CH648312A5/en not_active IP Right Cessation
- 1981-06-23 YU YU1564/81A patent/YU42722B/en unknown
- 1981-06-23 IT IT67869/81A patent/IT1144814B/en active
- 1981-06-23 SU SU813301195A patent/SU1192614A3/en active
- 1981-06-23 PL PL1981235214A patent/PL129635B1/en unknown
- 1981-06-23 FI FI811970A patent/FI70897C/en not_active IP Right Cessation
- 1981-06-23 DE DE19813124577 patent/DE3124577A1/en not_active Withdrawn
- 1981-06-23 DK DK277281A patent/DK277281A/en not_active Application Discontinuation
- 1981-06-23 SE SE8103940A patent/SE441829B/en not_active IP Right Cessation
- 1981-06-23 GB GB8119298A patent/GB2080291B/en not_active Expired
- 1981-06-23 PT PT73248A patent/PT73248B/en unknown
- 1981-06-23 AU AU72081/81A patent/AU544360B2/en not_active Ceased
- 1981-06-23 PL PL1981231826A patent/PL129623B1/en unknown
- 1981-06-23 CA CA000380416A patent/CA1167842A/en not_active Expired
- 1981-06-23 NO NO812143A patent/NO157142C/en unknown
- 1981-06-24 JP JP9813381A patent/JPS5738781A/en active Pending
- 1981-06-26 DD DD81231194A patent/DD160060A5/en not_active IP Right Cessation
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1982
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