FI59097C - PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ANIMAL THERMAL PYRIMIDO (4,5-B) QUINOLIN-4 (3H) -ONI-2-CARBOXYL SYRADERAT - Google Patents

Description

ΓΒΐ «« NOTICE CQ097 4CT »lBJ (11) UTLÄGCNINOSSKRIFT 3 yUy (^ JjPvR C (45) Patent granted 10 06 1031 £ rC2? Patent meddelat vy / (51) Kv.ik.3 / In * .a.3 c 07 D 471/04 · FINLAND —FINLAND (21) P * tui «lh« k * mu · - PK «MaMeknln (731626 (22) H» k * ml «ptlvt - Anabknlngidag 03.06.75 (23) AlkupUvi — GIM (h * tad | 03.06.75 (41) Tullut JulklMkil - Bllvlt offmtllf 06.01.76

Pstmtti and rakistari halittu * / 441 Nlhtlvlkslpuion | * kuL | ullud «un pvm. -

Petän * · och ragistantyralaan An * ek * n utiud och uti. * Krift * n pubhond 27.02.8l (32) (33) (31) Requested «cuoikuit — S« | ird prieritu 05.07.71+ USA (US) ^ 8591 * 5 (71) Pfizer Inc., 235 East l + 2nd Street, New York, NY, USA (72) Thomas Henry Althuis, Groton, Conn., Leonard Joseph Czuba, New London,

Conn., Saul Bernard Kadin, New London, Conn., Hans-Jurgen Ernst Hess,

Old Lyme, Conn., USA (71+) Oy Kolster Ab (5I +) Method for the preparation of therapeutically useful pyrimido / I +, 5-b7-quinolin-1 + (3H) -one-2-carboxylic acid derivatives - For the preparation of therapeutic agents pyrimido / l + 5 + b7kinolin-l (3H) -one - 2-karboxy1syraderivat

The invention relates to a process for the preparation of therapeutically useful pyrimido- [1,5-b] quinolin-1 + (3H) -one-2-carboxylic acid derivatives of the formula I

R 1 + -? - COR 0 wherein R 0 is hydroxy or alkoxy of 1-1 + carbon atoms, and R 3 and are independently (a) hydrogen, alkoxy of 1 to 3 carbon atoms or benzyloxy, or (b) hydroxy or 1-1 + alkanoyloxy containing a carbon atom, provided that at least one of these radicals is selected from group (b), and for the preparation of their pharmaceutically acceptable cationic salts.

The compounds of the invention have been found to have antiallergic activity. They prevent allergic reactions and are of particular use — 2,59097 are suitable for the prevention of allergic bronchial asthma.

Compounds of a similar type are described in FI 5558. However, the compounds described do not inhibit allergic reactions as well as the compounds prepared by the method of the invention which have a strong antiallergic effect in mammals, including man, by an intal-type mechanism. Unlike intal, many of these compounds are effective when administered intraperitoneally and orally as well as by inhalation into a vein.

By "pharmaceutically acceptable cationic salts" is meant alkali metal salts, e.g. sodium and potassium, alkaline earth salts, e.g. calcium and magnesium, aluminum salts, ammonium salts and organic bases, e.g. amines such as triethylamine, tri-n-butylamine, piperidine, triethanolamine, salts with diethylaminoethylamine, Ν, Ν'-dibenzylethylenediamine and pyrrolidine.

Among the compounds prepared by the process of the invention are .... . ..3.I.

in good condition those compounds of formula I in which R and R are hydrogen, hydroxy or 3.1.

alkoxy, provided that when R or R is hydroxy, the other is alkoxy.

The following compounds of formula I are of particular interest: r? R ^ _ OH 0CH3 0CH3 oh

Compounds of formula I in which R 0 is alkoxy are also valuable intermediates in the preparation of compounds in which the group C 0 R 0 is replaced by carboxy or carbamyl.

3.4. ...

Compounds in which R or R is benzyloxy are intermediates for compounds in which CO 2 R 0 is hydroxy, alkanoyloxy.

The antiallergic properties of the compounds of this invention have been determined by the Passive Skin Sensitization Assay (PJH) (Ovary, J. Immun., 81, 1958). In the PIH assay, normal animals are injected subcutaneously with blood serum antibodies from actively sensitized animals. An antigen mixed with a dye, e.g., Evans blue, is then injected into the vein of the animals. The increased capillary permeability caused by the antigen-antibody reaction causes the dye to leak from the antibody injection site. The experimental animals are then killed and the intensity of the reaction is determined by measuring the diameter and intensity of the blue color of the inner surface of the animals' skin.

The process according to the invention is characterized in that the compound of formula II

R3 CONH2 r1, ~ ^ A. „„ 2 ”59097 • 2.1; ... wherein R and R are as defined above, are reacted with a dialkyl oxalate, and when R or R is benzyloxy, the resulting benzyl ethers are debenzylated, if desired, to give a hydroxy group, and if desired, a compound in which R 0 is 1 to 1 carbon atoms is hydrolyzed. alkoxy, to the corresponding compound wherein R 0 is hydroxy.

The compounds of formula I can be prepared by methods using an unchanged carbocyclic ring and the quinoline and pyrimidine systems are formed by various methods. The general basis for these methods is the formation of the β-aminoquinoline-3-carboxamide or 3-carboxylic acid or its ester from an unchanged carbocyclic ring and the subsequent use of the quinoline system as the basic pyrimidine ring former. The general guidelines for these methods are summarized in the steps below, where R 'is hydroxy, alkoxy, or amino: H CN. . .

j (reactions A) .COR '

—Ii C = 0 J -> R_ —S

3 C = 0 3 j \ CN

Ri-k ^ -N ° 2 + ^

Ψ IV

0 R3-W_Z R3 - C0R '(reactions B) /

H CN

<Y ". K

'ΛΛ ·,

The preferred method for the yield and quality of the final product of formula I is apparent from reactions A. Alternative methods, e.g. from reactions B, can also be used as described below.

59097

In both reactions A and B, the carboxylic aldehyde or ketone is a condensator with an active methylene nucleophile. The required carbocyclic aldehyde or ketone is known or can be prepared by methods known in the art. By "active methylene nucleophile" is meant a compound having a relatively acidic methylene group, i. a methylene group bonded to one and preferably two electron withdrawing groups. Examples are -CN, -COCl, -C (NH) NH 4, COR ', -C (NH) -O-alkyl or CO-alkyl.

The condensation is carried out in the presence of an unreacted solvent, i.e. a solvent which is not altered by the reaction, although it may participate in the reaction as a catalyst or form a salt with the reactant or product.

Suitable solvents include alkanols, e.g. methanol, ethanol, isopropanol, n-butanol and n-hexane, chlorinated solvents, e.g. methylene chloride, ethylene chloride, chloroform and carbon tetrachloride, pyridine, aromatic hydrocarbons, e.g. benzene, toluene, xylene. and Ν, Ν'-dimethylformamide. Other solvents can be found by simple experiments. The preferred solvent is methanol, especially when piperidine is used as a catalyst, due to the satisfactory yield, ease of separation and purity of the products. Sometimes a mixture of piperidine and pyridine is a useful solvent.

A catalyst is often used to improve condensation even when the nucleophiles have two activating groups such as in cyanoacetic acid derivatives. Suitable catalysts include ammonia, primary, secondary and tertiary amines, e.g. n-butylamine, diethylamine, triethylamine, pyridine, piperidine, pyrrolidine, alkali metal alkoxides and fluorides, stannofluoride and basic amine-type ions. , polystyrene containing polyamine groups and De-Acidite G (polystyrene containing diethylamino groups).

The amount of catalyst used is not critical but can vary widely, i. from about 0.1 to about 100 parts by weight based on the weight of the reactive carboxylic aldehyde. The preferred amount of catalyst is from about 10% to about 30% by weight of the reactive carboxylic aldehyde.

The reaction is carried out at a temperature of about 0 ° to about 50 ° C and generally at about ambient temperature for about a quarter to five hours. In general, the products separate from the reaction mixture as solids and are isolated by filtration. Unsolidified products are isolated by evaporating the solvent or pouring a large volume of the product into an insoluble liquid.

When o-nitrobenzaldehyde or R 1 - (2-nitrophenyl) ketone is used as the reactant (reactions A), a N-cyano-4- (2-nitrophenyl) -acrylamide derivative is obtained, e.g., an amide in which R ' NH2, which must be reduced and cyclized to give the desired 2-aminoquinoline-3-carboxylic acid derivative. The reduction of the nitro group to the amino group takes place using various reagents. Briefly, any reagent that selectively or substantially reduces a nitro group to an amino group can be used. Examples of such reagents are metal-acid combinations, e.g. ferric acetic acid, ferric hydrochloric acid, stannous hydrochloride hydrochloric acid, zinc hydrochloric acid and zinc dust base, and hydrogenating catalysts, e.g. platinum, nickel and palladium.

The reduced product appears to cyclize immediately or almost immediately to give the 2-aminoquinoline-3-carboxylic acid derivative.

When o-aminobenzaldehyde (Reactions B) is used as the reactant, the condensation product formed with cyanoacetic acid cyclizes very rapidly to the 2-aminoquinoline-3-carboxylic acid derivative as described above for the reaction product of Reactions A.

A condensed pyrimidine ring substituted with a carboxylic acid ester group at its 2-position is formed by reacting 2-aminoquinoline-3-carboxamide (Formula V where R '= NH 2) with a dialkyl oxalate (WZ is (COR0 ^)) · Also other reagents such as (semi -oxalic acid dialkyl ester (carbalkoxy-formimidate), oxamic acid alkyl ester) can be used.

The reagent WZ (oxalic acid derivative) used in methods A and B can then, for example, be of the formula W-COR °, in which W is -CCOCl, -CN, -CORR, -CO-alkyl, -C (NH) NH2 or -C (NH ) 0-alkyl.

The reaction between the 2-aminoquinoline-3-carboxylic acid derivative and the reagent W-Z is carried out in an unreacted solvent, preferably a solvent which allows the alcohol and water of the by-products to be removed by distillation. Examples of solvents for this cyclization include aromatic hydrocarbons, e.g., xylene, toluene, and benzene, excess dialkyl oxalate reagent selected, tetralin, and decalin.

Suitable solvents are readily determined by experiment. When the reagent - W-Z is dialkyl oxalate, the preferred solvent is an excess of dialkyl oxalate because it is capable of dissolving the reagents and allows easy removal of alcohol and water from the by-products. Although the reaction temperature is not critical, the reaction is generally carried out at an elevated temperature to remove alcohol and water.

When dialkyl oxalate is used as the solvent, a suitable temperature is from about 150 ° to about 185 ° C. With more reactive oxalic acid derivatives (W-Z), e.g. ethyl oxalyl chloride, lower temperatures can be used. Sometimes a final condensation or heating step is necessary to achieve maximum cyclization and yield of the desired pyrimido (1,5-quinolin-M3H) -one-2-carboxylic acid derivative.

The addition of a small amount of base, e.g. sodium hydride or alkali metal alkoxy, may sometimes promote ring cycling.

When the use of reagent W-Z results in the formation of a 2-cyano derivative rather than a 2-COR derivative, the cyano group is converted to the corresponding 2-carboxamide by acid hydrolysis. When W-Z is a monoacid halide of a semi-alkyloxalic acid ester, an acid acceptor, i. an organic or inorganic base, e.g.

6 59097 Triethylamine, pyridine, sodium methoxide or sodium hydroxide to neutralize the acid formed as a by-product.

-. 3 1+

Compounds of formula I in which R or R is benzyloxy are intermediates of the corresponding hydroxy compounds and their acyl derivatives. The most convenient debenzylation is performed by treating the benzyl ether with trifluoroacetic acid. The debenzylated products are obtained as their trifluoroacetate salts. Hydroxy blasts are intermediates in the preparation of the corresponding alkanoyloxy and benzoyloxy derivatives by acylation with a suitable acid anhydride, e.g. acetic anhydride. A catalytic amount of p-toluenesulfonic acid is generally used to accelerate the reaction.

The compounds of this invention and their pharmaceutically acceptable cationic salts are useful in the prophylactic and therapeutic treatment of allergic symptoms and reactions in mammals and may be administered alone or in admixture with e.g. sympathomimetic amines of theophylline, orally, parenterally or by inhalation. They may be administered as such, but will generally be administered with a pharmaceutical carrier selected according to the route of administration and pharmaceutical practice.

Typical routes of administration and butylene compositions are described in detail in FI publication 55,658.

It is essential that the active ingredient of the composition allow a suitable dosage. Thus, multiple dosage unit forms can be administered almost simultaneously. Although in some cases compositions containing less than 0.005% by weight of active ingredient may be used, it is preferable to use compositions with more than 0.005% of active ingredient so that the proportion of carrier does not become too high. The activity increases as the concentration of the active ingredient increases. The composition may contain 10, 50, 75, 95% by weight or more of active ingredient.

In the passive skin sensitization test of the compounds according to the invention, an excellent correlation is obtained between the activity of these compounds and the allergic asthma treated with them. The response of the substances to the passive skin sensitization test was determined using male Charles River Wistar rats, weight 170-210 g. Reactive antiserum was prepared according to Mota, Immunology, 7, 681 (I96I) using egg albumin and B. pertussis. Egg albumin hyperimmune antiserum was prepared according to Orange et al., J. Exptl. Med., 127, 7 ^ 7 (1968). Two days before antibody administration, the reactive antiserum is injected into the depilated hindquarters of a normal rat, five hours before administration, hyperimmune antiserum is similarly injected, and five hours later, 60 mg of histamine dihydrochloride is injected into the skin to measure antihistamine and unspecified type inhibition. The compounds of the present invention or saline solution are then administered intravenously, followed immediately by 2.5 mg of Evan blue and 5 mg of egg albumin in saline. Evan blue and egg albumin are given orally five minutes after dosing. Thirty minutes later, the animals are killed with chloroform and the skin of the back 1 59097 is removed for examination. The color intensity of each injection is determined using a diameter scale of 0.1, 0.5, 1, 2, 3 or k mm. The diameters of the injection sites of eight animals are added together and compared to control groups treated with saline. The difference is expressed as a percentage inhibition of the compound.

The compounds of the invention have been tested by the above method and the activity results are expressed as a percentage protective effect.

| T N ~ H j R N ^ c0ro

Table I

Antiallergic effect of pyrimido-η 5 -ha.nolin-M 3 H) -one-2-carboxylic acid derivatives (formula I) ab) 3f \

Intravenous 'Oral' RR mg / kg% mg / kg% oc2h5 ch3coo OCH 3 100 10 10, 003 53 oc2H5 OH OCH 0.03 97 30 6 0.01 98 0.003 9b 0.0003 38 oh OH OCH 3 100 3 0 , 01 86, 003 90 0- (nC ^ H) OH OCH 3 100 10 6? 2, 003 52 0— (n-C ^ Hg) CH3C00 0CH3 3 100 10 36 0C2H5 OH H 0.3 92 10 13 0, 03 21 3 1 OH OH H 3 100 0,03 91, 003 b 0C2Hr OCH OH 0,003 0 ^ 0,3 100 _ _3j0_100_ - * yi The references indicate the average of two or more determinations.

It will be appreciated that when administered to a human, the effective daily dose of the compounds of the invention will be from about 10 to about 1500 mg, preferably from about 10 to about 600 mg in one or more doses, i.e. from about 0.2 to about 12 mg / kg body weight, keuhkoputkisupistumaa. These amounts are examples and may be higher or lower in individual cases.

When administered intravenously or by inhalation, the effective daily dose is from about 0.5 to about 1 + 00 mg, preferably from about 0.25 to 200 mg, i.e. from about 0.005 to 1+ mg / kg body weight in one or more doses.

Example 1

Ethyl 7-benzyloxy-e-methoxypyrimido [5,5-b] quinolin-1 + (3H) -one-2-carboxylate A) o-cyano-3- (2-nitro-1 + -methoxy-5- benzyloxyphenyl) acrylamide 2.1 g (0.0237 moles) of piperidine and 22.0 g (0.263 moles) of 2-cyanoacetamide were added to a suspension of 0.237 moles of 3-benzyloxy-1-methoxy-6-nitrobenzaldehyde in 500 ml of methanol. . The mixture was heated to reflux for two hours, then cooled in an ice bath and filtered. The bright yellow filter cake was washed with 300 ml of cold isopropanol and air dried. Yield 1 + 5 by weight #, m.p. 157_158 ° C.

Using the above preparation method and the appropriate alkoxy-substituted nitrobenzaldehyde, the following compounds were prepared: 0 ____. C0NHo R3—

* · R 1 -CN

no2 O) 'R mp ° C Yield% 0C2H5 0C7Ht 167-167.5 (dec.) 73 och3 oc7ht 182-3 52 OC7H7 H 125-6 1 + 7 B) 6-Benzyloxy-7-methoxy-2 -aminokinoli ini-3-carboxamide was added to 65 », 2 g (1.22 mol) of iron powder over a half hour to a suspension of 0.271 mole of the method A) in 750 ml of 50% acetic acid-Ν, Ν-dimethylformamide at 75 ° C . After the addition of iron powder was complete, the mixture was heated at 90 ° C for four hours and filtered hot. The filter cake was washed with 150 ml of hot acetic acid. The dark red filtrate was gradually added to 1500 ml of 1N hydrochloric acid, the pink precipitate was isolated by filtration and recrystallized from excess (10 #) sodium hydroxide solution. The solid 9 59097 was filtered, washed with cold isopropanol and dried to give the title compound as yellow crystals. Yield 80%, m.p. 261 + -266 ° C.

By repeating the above method B) and using the appropriate C (-cyano-fc- (2-nitrophenyl) acrylamide of method A), the following compounds were prepared:

CONH

r4 - R3_R ^ _Sp. ° C_Yield% 0C2H5 OC ^ 279-60 (dec.) 73 0CH3 0C7H? 282-3 (dec.) 95 "OC H 238-9 91 * C) Ethyl 4-benzyloxy-e-methoxypyrimidoyl *, 5-b] quinolin-1 * (3H) -one -2-carboxylate

To a round bottom flask equipped with a stirrer, condenser and Dean-Stark apparatus and containing 50 ml of diethyl oxalate and 80 ml of xylene was added, at reflux, 0.012 moles of the product of method B). Xylene, water and ethanol were removed by distillation and recovered over four hours. After complete removal of the xylene, the reaction mixture was heated to 185 ° C, cooled to about 100 ° C and slowly poured into 300 mL of chloroform. The chloroform solution was cooled and the resulting brown precipitate was removed by filtration. The filtrate was decolorized with charcoal, concentrated and cooled to give a crystalline mass.

The crystals were dissolved in hot chloroform, charcoal was added to the solution, and concentrated to give pale yellow crystals, yield 25%, m.p. 27 ^ -275 ° C.

A mixture of 0.5 g (2 mmol) of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide, 0.1 + 3 g (1 * 1 * mmol) of ethyl cyanoformate and 30 ml of benzene was heated under reflux for three days. The mixture was cooled, filtered and the solid extracted with chloroform. Concentration of the chloroform extract gave a product which was recrystallized from chloroform.

Using Method C) above and the appropriate alkoxy-substituted 2-aminoquinoline-3-carboxamide and the appropriate oxalic acid ester from B) above, the following compounds were prepared:

R3-NH

r1 + -Uv / L <£ -1

the COR

ίο 5 9097

a I

R o _R_R_Sp. ° C_Yield% OCgH 0C2H5 0CtH 21 + 1-2 (dec.) 1 + 1 OC2H5 0CH3 0CtHt 25 ^ -5 (dec.) 8 0-n-C1 + H9 OC ^ H OCH3 261-2 (dec.) 13 OC2H5 OCt ^ H 256-7 (dec.) 32 D) 7-Tentyloxy-8-methoxypyrimidoyl +, 5-b7-quinolin-1 + (3H) -one-2-carboxylic acid

7.1+ mmol of ethyl 7-benzyloxy-8-methoxypyrimido [1,5-b] quinolin-1 + (3H) -one-2-carboxylate in 37.5 ml of 5% aqueous sodium hydroxide solution were stirred for 20 hours at room temperature. The ester dissolved in 10 minutes and gradually formed a slightly colored precipitate. The reaction mixture was acidified by the slow addition of 13 ml of 10 liters of aqueous hydrochloric acid. A slightly colored precipitate dissolved and a yellow precipitate formed. The acid mixture was stirred for 1 + 5 minutes and filtered. The filter cake was washed with water and dried in vacuo.

The other products shown in C were hydrolyzed according to method D) to give the corresponding acids.

Example 2

Ethyl 7-hydroxy-8-methoxy pyrimido [5-b] quinolin-k (3H) -one-2-carboxylate titrifluoroacetate

A solution of 250 mg (0.68 mmol) of ethyl 7-benzyloxy-8-methoxy-pyrimido [1,5-b] quinolin-1 - (3H) -one-2-carboxylate in 5 ml of trifluoroacetic acid heated to reflux for 2.5 hours. Alternatively, the mixture was stirred for three days at room temperature. The reaction mixture was then poured into 25 ml of ether and the resulting bright yellow trifluoroacetate salt was isolated by filtration, washed with ether and dried, yield 191+ mg, 72%, m.p. 279 ° C.

Analysis:

Calculated for C 12 H 11 N 2 CF 2 OOH. 1/2 H 2 O: C 1 + 6.58, H 3.1 + 2, N 9.58%

Found: C 1 + 6.8 L, H 3, 1 + 1, N 9.21%.

By repeating the procedure described above using 862 mg (0.199 mmol) of the corresponding n-butyl ester instead of ethyl ester, and 8 ml of trifluoroacetic acid and heating under reflux for 3.5 hours, n-butyl-7-hydroxy-8-methoxy-pyrimido [5 ~ b / quinoline-1 + (3H) -one-2-carboxylate trifluoroacetate, 0.67 g, 71 +% ·, m.p. 21 + 0 ° C (decomposes).

u.

f 11 59097

Analysis:

Calculated for C 18 H 19 N 2 O 2 COOH: C 49.89, H 3.96, N 9.18, F 12.46%

Found: C 49.93, H 3.97, N 8.79, F 11.17%

In a similar manner, ethyl 7-benzyloxypyrimido [4,1] b (311) -one-2-carboxylate is debenzylated to give ethyl 7-hydroxypyrimido [4,5-b] quinolin-4 (3H) -one. 2-carboxylate hemitrifluoroacetate, yield 74%, m.p. 274-275 ° C (decomposes).

Analysis:

Calculated for C 20 H 12 N 2 .1 / 2 CF 4 COOH: C 57.43, H 3.66, N 13.39%

Found: C 57.75, H 4.05, N 13.65%

Example 3 7-Hydroxy-8-methoxypyrimido [4,5-b] quinolin-4 (3H) -one -2-carboxylic acid 200 mg (0.456 ramol) of ethyl 7-hydroxy-8-methoxypyrimido [4,5-b] quinolin-4 (3H) -one-2-carboxylate was added to 5 ml of 0.1 N sodium hydroxide solution and added dropwise with stirring under $ 15 sodium hydroxide solution until complete dissolution.

The mixture was stirred for 18 hours at room temperature and then strongly acidified with trifluoroacetic acid. The precipitate formed was isolated by filtration, washed with water and isopropyl alcohol and air-dried. Yield 114 mg, m.p. 28 ° C (decomposes).

Analysis:

Calculated for 2 H 2 O: C 48.29, H 4.02, N 13.00%

Found: C 47.3, H 3.32, N 12.73%

Similarly, 210 mg of ethyl 7-hydroxypyrimido [4,5-b] quinolin-4 (3H) -one-2-carboxylate hemitrifluoroacetate was converted to 7-hydroxypyrimido [4,5-b] quinolin-4 (3H) -one-2- carboxylic acid, yield 191 mg, 91%, m.p. 34 ° C (decomposes).

Example 4

Ethyl 7-methoxy-β-hydroxypyrimido [4,5-b] quinolin-4 (3H) -one-2-carboxylate. A solution of 198 mg (0.488 mmol) of ethyl 7-methoxy-8-benzyloxy-pyrimido [4,5-b] quinolin-4 (3H) -one-2-carboxylate in 4 ml of trifluoroacetic acid was stirred at room temperature for eight days. 15 ml of ether were added and the yellow precipitate was isolated by filtration. The precipitate was dissolved in chloroform, and the solution was filtered through diatomaceous earth to remove a small amount of insoluble matter.

The color was removed from the filtrate with charcoal and concentrated in vacuo to a small volume. The solid formed was filtered off and dried, yield 9 mg, m.p. 265-266 ° C (decomposes).

Example 5

Ethyl 7-acetoxy-8-methoxypyrimido [4,5-b] quinolin-4 (3H) -one-2-carboxylate thi-p-toluenesulfonate.

A mixture of 4 ml of acetic anhydride, 250 mg (0.572 mmol) of ethyl 7-12,59097 hydroxy-8-methoxypyrimido [1,5-b] quinolin-1 · (3H) -one-2-carboxylate trifluoroacetate hemihydrate and 100 mg (0.572 mmol) of p-toluenesulfonic acid monohydrate was heated at 100 ° C for 24 hours. The acetic anhydride was then removed from the reaction mixture in vacuo. The solid residue was dissolved in hot chloroform and decolorized with activated charcoal. 1+ volume of benzene was added to a colorless solution, which was then cooled on ice. The crystals were isolated by filtration and air dried. Yield 17H mg, 58%, m.p. 215 ~ 217 ° C.

Analysis:

Calculated for C 20 H 23 N 2 O 2 S: C 5 ^ 3, H k, 37, N 7.98%

Found: C 53.7k, H k, 2O, N 7.24%.

The procedure described above was repeated using 200 mg (0.137 mmol) of the corresponding n-butyl ester trifluoroacetate salt instead of the ethyl ester trifluoroacetate salt. The product was isolated by concentrating the chloroform solution to 1/3 volume and filtering off the solid, which precipitates more easily than precipitation with benzene. Yield 30 mg, 18%, m.p. 260-26 ° C (dec.).

β *

Claims (1)

3. With 14 oxalate, and when R or R is benzyloxy, the resulting benzyl ether is debenzylated, if desired, to give a hydroxy group, and if desired, a compound in which R 0 is alkoxy containing 1-1 + carbon atoms is hydrolyzed to the corresponding compound in which R 0 is is hydroxy.