CA1065863A - Process for production of alkyl pyrimido (4,5-b) quinolin-4(3h)-one-2-carboxylates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The cyclization of 2-aminoquinoline-3-carboxamide and nuclear substituted derivatives thereof with a dialkyl:oxalate in the presence of a sodium alkoxide or other suitable base under mild conditions to produce alkyl pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylates. The products are useful as antiallergy agents.

Description

~L~658~3 This invention relates to an improved process for preparing lower alkyl esters of fused pyrimidin-4(3H)-one-2-carboxylic acids and, in particular, alkyl pyrimido~4,5-b]quinoline-4t3H)-one 2-carboxylates.
The preparation of a variety of fused pyrimidines, including alkyl esters of pyrimido~4,5-b~quinoline-4(3H?-one-2-carboxylic acids, by the cyclization of a 2-aminoquinoline-3-carboxamide with a dialkyl oxalate is described in Belgian Patent 813,571, granted October 11, 1974. The pro-cedures descrihed comprise conducting the condensation at temperatures of from 150C. to 185C. with remov~ of by-product water and alcoholO A large excess of the dialkyl oxalate is normally used as solvent and a base, such as a sodium alkoxide or sodium hydride, is sometimes used as catalyst. The reaction requires ~rom several hours to up to two days for completion depend-ing upon the reactants. The yields of cyclized products are, in most instances, rather poor. However, in the one instance wherein a satisfac-tory yield was reportea; namely, the preparation of ethyl 7-fluoropyrim;do-~4~5-b]quinoline-4(3H)-one-2-car~xylate, a molar ratio of diethyl oxalate to 6-fluoro-2-aminoquinoline-3-carboxamide of 15 to 1 and a reaction period of eighteen hours at 160C. was used.

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The condensation of diethyloxalate and anthranilamide (2-1 molar ratio) in the absence of a base at 170-180C. for six hours with product-ion of a 5% yield o$ ethyl 4-quinazolone-2-carboxylate and formation of a bis-substituted oxamide as by-product is reported by Baker et al., J. Org.
Chem. 27, 4672-4674 (1962).
The preparation of ethyl 4-quinazolone-2-carboxylate by the pro-cess of this invention and using the same proportions of anthranilamide (.OS mole), diethyloxalate (0.1 mole) and sodium ethoxide (0.15 mole) as employed by ~aker et al. (loc. cit.) in e~hanol (100 ml.) as solvent at 70-75C. for one hour gave a 78% yield of product in contrast to the 57%
yield reported by Baker et al.
It has now been found, quite unexpectedly and surprisingly in view of the harshness of the prior art conditions that alkyl pyrimido[4,5-b]quin~lin-4(3H~-one-2-carboxylates can be prepared in highly satisfactory and economic yield by reacting an appropriate 2-aminoquinolin-3-carboxamide with an appropriate dialkyl oxalate under relatively mild conditions of temperature and time. It is readily adaptable to large scale reaction, re-quires no special apparatus, avoids formation of bis-substituted oxamides as by-products and does not require removal of by-product alcohol and water.
According to the present invention there is provided a process which comprises reacting a 2-aminoquinoline-3-carboxamide compound having the formula 3 ~ ~H2~l2 R~ R5 wherein R~ is selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms and phenyl;

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10~i58G3 two o$ R2, R3, Rl~ an~ R5 are selected from the g~oup consisting of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, halo, benzyloxy, methylthio and benzylthio, and the balance are selected from the group consisting of hydrogen, alkyl having ~rom one to four carbon a~oms, alkoxy having from one to four carbon atoms and halo, R~ and R3, R3 and R4 ~hen taken together are alkylenedioxy and are selected from the group consisting of methylenedioxy and ethylenedioxy, with from one to three molar equivalents of a dialkyl oxalate wherein çach of the alkyl groups has from one to four carbon atoms at a temperature of from about 20C. to about 100C. in a reaction-inert solvent and in the presence of two to ~hree molar equivalents of base per mole of 2-amino-quinoline-3-carboxamide, and said base being selected fro~ the group con-sisting of sodium alkoxide having from one to four carbon atoms, triphenyl-methylsodium, sodium hydride, sodium amide, sodium 3-aminopropylamide and the corresponding potassium compounds.
The cyclization reaction is summarized by the equation:

2 ROOC BDse ~ ~
H2 ROO~ 2~o_l00C. / ~ COOR

The cyclization products obtained from the above reactants are valuable antiallergy agents as is described in Belgian Patent 813,571.
The cyclization is conducted by reacting the appropriate 2-amino-quinoline-3-carboxamides and appropriate dialkyl oxalate in a molar ratio of from about 1:1 to a~out 1:3 in a reaction-inert solvent medium at a tempera-ture below about 100C., and in the presence of a suitable base. Suitable solvents are alcohols correspond~ng to the alkyl groups of the dialkyl oxalate reactant, an& combinations of such alcohols and xylene, toluene, benzene, dioxane, tetrahydrofuran and other alcohol miscible solvents and . --3--f~ -.. ~ . . _ ... . ..

5~363 dimethylsulfoxide The usa of a solvent does not appear to be necessary for the reaction to occur but is h;ghly advantageous from the standpoin~ of rate and yield of reaction.
The nature of the dialkyl oxalate is not critical to the success of the process of this invention. However, the favored dialkyl oxalates are those wherein the alkyl groups are identical and have from one to four carbon atoms. They are favored as reactants because oE their availability, the valuable antiallergy activity~'of the cyclized products which they pro-duce, their overall ease of reaction in this process and the fact that they permlt use of readily availablè alcohols as solvents and sodium tor potas-sium) alXoxide cyclizing agents in which the alkyl portions of the alcohol and alkoxide correspond to that of the dialkyl oxalate and afford satisfac-tory yields of cyclized product. The use of dialkyl oxalates in which the alkyl groups are different produces a mixture of esters. For this reason, it is preferred to use dialkyl oxalates in which the alkyl groups are the same in order ~o obtain a single product rather than a mixture of esters.
The preferred solvents are alcohols. In order to avoid ester exchange it is, of course, necessary to use as solvent an alcohol corres-ponding to the ester group of the dialkyl oxalate reactant. However, as those skilled in the art will recognize, ester exchange can be avoided or minimized by using as solvent a branched alcohol such as t-butyl alcohol-~
h h~s~ *~1è:ten~ncy:*~enter into`~ster exchange.
The molar ratio of dialkyl oxalate to 2-aminoquinoline-3-carbox-amide reactant is not critical but should be at least 1:1. For reasons of yield of cyclized product and of economy, in general, a ratio of about three molar equivalents of dialkyl oxalate to one of the 2-aminoquinoline-

3-carboxamide reac~ant is preferred. Highe~ ratios appear ~o be of no advantage.
A variety of bases can be used for this cyclization reaction.
Suitable bases are sodium and potassium alkoxides, particularly those wherein - -= : , :

8~;3 the alkoxide moiety corresponds to the alcohol moiety of the dialkyl oxal-ate, sodium and potassium hydridas, amides and 3-aminopropylamides, tri-phenylmethyl sodium and triphenylmethylpotassium.
The base is desirably used in the ratio of two to three molar equivalents per mole of the 2-aminoquinoline-3-carboxamide reactant. It is preferred to use a three to one molar ratio for optimum yield. Higher ratios appear to be of no advantage. Lower ratios tend to reduce the yield of cyclized product. The preferred base is the sod;um alkoxide wherein the alkoxide moiety corresponds to the alkyl moiety of the dialkyl oxala~e.
The reaction is conducted at a temperature below about 100C.
The favored temperature range is from about 20C. to about 100C. It ;s advantageous for reasons of economy, to conduct the reaction at the lowest temperature which is consistent with good reaction rate and yield and which requires a minimum of cooling or heating. This, of course, is readily determined by experimentation. The preferred temperature is thus found to be within the range of about 25C. to about 50Co The lower range is highly satisfactory when using dimethyl and diethyl oxalates as reactants. The upper range is sometimes advantageous when using a dibutyl oxalate as re-actant.
The products of this invention and the pharmaceutically-acceptable cationic salts thereof, are useful for t~e control (prophylactic and thera-peutic treatment)~of allergic symptoms and reactions in mammals, and can be administered either as ndividual therapeutic agents or as mixtures of thera-peutic agents, ~or example, with theophylline or sympathomimetic"~amines.
They can be administered alone, but are generally administered with a pharma-ceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they can be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, aerosol sprays, aqueous suspensions or solutions, injectable solutions, elix;rs, syrups and the like.

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Sudh carriers include solid diluen-ts or ~illers, sterile aqueous media and various non-toxic organic solvents. Moreover, the oral ~harmaceutical com-positions of th;s invention can be suitably sweetened and flavored by means of various agents of the type commonly used for this purpose.
The particular carrier selected and the proportion of active ingredient-to carrier are influenced by the solubility and chemical nature of the therapeutic compounds, the chosen route of administration and the needs of standard pharmaceutical practice. For example, when the compounds of this invention are administered orally in tablet form, excipients such as lactose, sodium citrate, calcium carbonate and dicalcium phosphate can be used. Various disintegrants such as starch, alginic acids and certain complex silicates, toge~har with lubricating agents such as magnesium stearate, sodium lauryl sulphate and talc, can also be used in producing tablets for the oral administration of these compounds. For oral adminis-tration in capsule form, lactose and high molecular weight polyethylene glycols are among the preferred materials for use as pharmaceutically-acceptable car~iers. Where aqueous suspensions are to be used for oral administration, the compounds of this invention can be combined with emu}si-fying or suspending agents.~ Dilubnts such as ethanol~ propylene glycol, glycerine and chloroform ~nd their combinations can be employed as well as other materials.
For the purpose of parenteral administration and inhalation7 solu-tions or suspensions of these compounds in sesame or peanut oil or in aque-ous propylene glycol solutions can be employed, as well as sterile aqueous solutions of the soluble pharmaceutically-acceptable salts described herein.
These particular solutions are espscially suited for intramuscular and sub-cutaneous injection ~urposes should such method of administration be desired.
The aqueous solutions, including those of the salts dissolved in pure dis-tilled water, are also useful ~or in~ravenous injection purposes provided that their pH is properly adjusted beforehand. Such solutions should also be ~:36~i8~3 suitably buffered, if necessary, and ~he liquid diluent first rendered iso-tonic with sufficient saline or glucose.
The compounds can be administered to asthmatic subjects suffering from bronchoconstriction by means of inhalators or other devices which permit the active compounds to come into direct contact with the constricted areas of the tissues of the subject.
Wh~n administered by inhalation, the compositions can comprise (1) a solution ~rrsuspension of the active ingred;ent in a liquid medium o the type mentioned above for administration via a nebulizer; (2) a suspen-sion or solution of the active ;ngredient in a liquid propellant such as dichlorodifluoromethane or chlorotrifluoroethane for administration from a pressurize~ container;~or (3) a mix~ure of the active ingredient and a solid dilubnt ~e.g., lactose) for administration from a powder inhalation device.
Compositions suitable for inhalation by means of a conventional nebulizer will comprise about 0.1 to about 1% of active ingredient, and those for use in pressurized containers will comprise from about 0.5 to about 2~ of active ingredient. Compositions for use as powder inhalants can comprise ratios of active ingredient to diluent of from about 1:0.5 to about 1:1.5.
It is necessary that the active ingredient form a proportion of the composition such that a suitable dosage form will be obtained. Obvious-ly, several dosage unit forms can be administered at about the same time.
Although compositions with less than 0.005% by weight of active ingredient might be used in certain in~tances, it ig preferred to use compositions con-taining not less than 0.005~ of the active ingredient, otherwise, the amount of carrier becomes excessively iarge. Activity increases with the concentra-tion of the active ingredient. The composition may contain 10, 50, 75, 95 or an even higher percentage by weight of the active ingredient.
As regards the dosage regimen of these compounds, the physician will ultimately determine the dosage which will be most suitable for a parti-cular individual, and it will vary with age, weight, and response of the }r~ `

~c;58~3 particular patient as wall as with the nature and extent of the symptoms, the pharmacodynamic charac~eristics of the particular agent to be adminis- -tered, and the route of administration chosen. Generally, small doses will be administered initially, with a gradual increase in the dosage until the optimum level is determined. It will often be found that when the composi-tion is administered orally, larger quantities of the active ingredient will be required to produce the same level as produced by a small quanti~y administered~parentërally.
Having full regard for the foregoing factors, it is considered that an effective daily oral dosage of the compounds of the present inven-tion in humans of from about 10 to about 1500 mg. per day, with a preferred range of about 10 to about 600 mg. per day in single or divided doses, or at about 0.2 to about 12 mg./kg. of body weight will effectively control bronchoconstriction in human subjects. These values are illustra~ive and there may, of course, be individual cases where higher or lower dose ranges are merited.
When administ~red intravenously or by inhalation, the effective daily dose is from about 0.5 to about 400 mg. per day, and preferably from about 0.25 to 200 mg. per day, or at about 0.005 to 4 mg./kg. of ~ody weight in single or divided doses.
EXAMPLE I
Ethyl 7,8-Dimethoxyp~rimido~4,5=b]quinolin-4(3H)-One-2-Carboxylate To a solution of diethyl oxalate (8.8 g., 0.06 mol) and sodium ethoxide (4.0 g., 0.06 mol) in ethanol (160 ml ) at room temperature is added with stirring 2-amino-6,7-dimethoxyquinoline-3-carboxamide (5.0 g., 0.02 mol).
A yellow suspension forms. Within approximately one hour the reaction mixture becomes turbid. After two hours of stirring, diatomaceous earth (3.0 g.) and charcoal (1.3 g.) is added and the mixture stirred an additional fifteen minutes. It is then filtered through diatomaceous earth and the filter cake washed with ethanol (S0 ml.). Th~ filtrate is heated to reflux and glacial ;3 acetic acid (2.4 ml~, 0.04 mol) added. A yellow solid precipitates. After a half-hour oE refluxing, the reaction mixture is cooled to room tempera-ture and then stirred for an additional hour. The product is filtered and dried at 70C. in vacuo. Yield = 6.8 g., 98.8%.
Analysis: Calcd. for C16H15N305, C, 58.35, H,4.59, N, 12.76%
Found: Cg 57~81; H~4.589 N, 12.46%
Repetition of this procedure bu~ usîng ten times the above quantities afforded a 91.7~ yield of product.

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.i Xh~PLE II

The following compounds are prepared accordi.ng to the procedure of Example I but substituting for the reactants used therein equimolar quantities of the appropriate 2-aminoquinoline-3-carboxamide, the appropriate 5 i,dialkyl oxalate and the sodium alcoholates and alcohols in which the alkyl `groups correspond to those of the dialkyl oxalate used.

4 ~ COOR

j¦ 5 ji R Rl ~ R~ R4 R5 TC
ll C2H5 H H H H ~ 11 22-¦! 2 5 F H H 22 ll C2H5 li H H F H 22

5 j! C2H5 H H Cl H H 22 I! C2H5 H H -O-CH2-0- H 22 il CH3 H H OCH3 OCH3 H 22 ll n-C4Hg H H OCH3 OCH3 H 45-50 il C2H5 H H OCH3 H OCH3 30 lO !i CH3 H OCH3 H H OCH3 20 ~¦ n C3H7 H H H OCH3 H 20 ,~ 3 H H OCH3 OCH3 OCH3 25 !I CH3 H H C2H5 O-n-C4Hg H 22 :
i C2H5 H H OC2H5 OC7H7 H 22 15 j i C3H7 H OC2H5 OCH3 H 25 n C4~19 H H H H H 70-75 n C4Hg H Cl H H 11 70-75 ~1 n C4 9 H OCH3 H H 2, C2H5 H H Br H Br 25 i; C2H5 H Cl H H Cl 25 jj 2 5 HSC7H7 SC7H7 H 30 '-¦ C2~15 11 H OCH3 OC7~17 Br 35 ¦! C2H5 H 717 OC7H7 H 25 ll -10- ~

- . :: . .. . : - .:

58~3 R Rl R~ R R~ R r~ '1' C .

2 5 H 11 4 9 H H ~5 j CH3 11 H 3 7 20 ,j C113 H H C~13 CH3 11 25 '~ C2115 11 11 11 t-C4119 11 30 10 1I CH3 H H Cl 13r Cl 22 li 3 7 OCH3 -O-CH2-O- OC113 35 C H5 H 11 o i c3H7 3 22 ~, CH3 H U O-n-C4H9 0-n-C4~19 il 90-100 ii C2H5 H H SCH3 H H 25 15 il~ C2H5 H H SCH3 SCH3 H 25 i C3 7 H H H SCH3 25 i! C2H5 H 1I SC7117 H H 30 '¦ 3 7 7 2 5 11 25 20 !, C2H5 H H OC7H7 OCH3 H 20 i; C2H5 H 7 7 3 OCH3 ~ H 25 ¦~ CH3 H H C1 OC7H7 H 25 ~¦ C2 s 6 5 H H H 22 ~j C2H5 C6H5 H CH3 H H 22 -25 !i CH3 C6H5 H SCH3 H H 22 CH3 CH3 H C1 Br C1 35 n-C4Hg CH3 H F H H 40 ,I n-C3H7 CH3 H 2 2 H 25 'j n-C3H7 C6H5 H -O-CH2-O- H 25 il C2H5 C6H5 H SCH3 H H 25 ~I CH3 n C4Hg H H H i C3 7 1~ i-C3H7 C2H5 Br H H H 22 ll CH3 n C3H7 C1 H H 22 35'1 CH3 n~C4H9 H H H H 22 ~; C2H5 C6H5 H OC7H7 O~CH3 H 25 ¦ CH3 C2H5H HC7 7 3 H H 25 ~I CH3 H sc7H7 H 11 SC7H7 30 !' CH3 H OC7H7 Br H Br 35 40j~ C2H5 iH H SC7H7 C2U5 U 30 .Ij i ~ 5~363 , ~ EX~MPI.~
ij , .~ The procedure of Example I is repeated but-using equimolar quantities~. of the following bases in place of sodium ethoxide:

1: potassium ethoxide 5 jl triphenylmethyl sod:;~m Ij sodium amide , potassium 3-aminopropylamide sodium hydride Il I
~¦ In each instance yields approximating those of Example I
¦lare obtained.
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1, ~

i~ t '3 - 12 -1. i . . .
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.
.~, i .
,.1 i - ~ ' ' : , ..

EXAMPLE IV
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; Ethyl 7,8-Dimethoxypyrimido[4,5-b]~uinolin-4`(3H)-One-2-Carboxylate Diethyloxalate (DEO) and 6,7-dimethoxy-2-aminoquinoline-3-carboxamide (0.02 mole) are reacted in ethanol in the presence of an ~ppropriate ba~e 5 ,'using the conditions of time, temperature and molar ratios o~ reactants ~et ¦orth below. In each instance, substantial cycli~ation occurs to produce the title product, which is recovered by the procedure of Example I.

~I Moles Moles ~1. Time i! DEO Base _ Base Solvent TC. (hr~q.) !l 0.06 KOC2ll5 0.06 160 20 2 LO~¦ 0.06 NaOC2HS 0 04 160 25 2 o.O4 NaOC2H5 0.06 150 25 2 0.06 NaNH2 0.06 200 35 3 ~¦ 0.06 (C6H5)3CNa0.06 200 30 2 ¦~ 0.06 (C6 5)3 0.06 200 30 2 15l 0.02 NaOC2H5 0.04 150 22 2 ! 0.06 ~aNH(cH2)3NH2 0-06 250 50 2 . i !
Il - 13 -Il i ,~

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process which comprises reacting a 2-aminoquinoline-3-carboxamide compound having the formula wherein R1 is selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms and phenyl;
two of R2, R3, R4 and R5 are selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms, halo, benzyloxy, methylthio and benzylthio, and the balance are selected from the group consisting of hydrogen, alkyl having from one to four carbon atoms, alkoxy having from one to four carbon atoms and halo;
R2 and R3, R3 and R4 when taken together are alkylenedioxy and are selected from the group consisting of methylenedioxy and ethylenedioxy, with from one to three molar equivalents of a dialkyl oxalate wherein each of the alkyl groups has from one to four carbon atoms at a temperature of from about 20°C. to about 100°C. in a reaction-inert solvent and in the presence of two to three molar equivalents of base per mole of 2-aminoquinoline-3-carboxamide, and said base being selected from the group consist-ing of sodium alkoxide having from one to four carbon atoms, triphenylmethylsodium, sodium hydride, sodium amide, sodium 3-aminopropylamide and the corresponding potassium compounds.

2. The process of claim 1, wherein the alkyl groups of the dialkyloxalate are the same.

3. The process of claim 2, wherein the reaction-inert solvent is an alcohol having the same number of carbon atoms as does each alkyl group of the dialkyl oxalate.

4. The process of claim 3, wherein the base is a sodium alkoxide derived from the alcohol solvent.

5. The process of claim 4, wherein the temperature is from about 25°C. to about 50°C.

6. The process of claim 5, wherein the dialkyl oxalate is diethyloxalate, the solvent is ethyl alcohol, the base is sodium ethoxide and the temperature is about 25°C.

7. The process of claim 6, wherein the molar ratio of 2-aminoquinoline-3-carboxamide : dialkyl oxalate : base is about 1:3:3.

8. The process of claim 7, wherein the 2-aminoquinoline-3-carboxamide compound is wherein each of R3 and R4 is alkoxy.

9. The process of claim 8, wherein each of R3 and R4 is methoxy.

10. The process of claim 7, wherein the 2-aminoquinoline-3-carboxamide is wherein R3 is benzyloxy and R4 is alkoxy.