HU185318B - Process for preparing pyrimid 0/6,1-a/ isoquinolin-4-one derivatives - Google Patents

Abstract

The present invention relates to a process for the preparation of pyrimido [6,1-a] isoquinolin-4-one derivatives of formula III or IV. In the formula - R 1 and R 4 may be the same or different and represent a hydrogen atom, a C 1-4 alkoxy group or a halogen atom; - R 5 is hydrogen or C 1-4 alkoxy; R6 is hydrogen or C1-C4 alkyl; - X is O or S; and - Y represents a halogen atom, a C 1-4 alkoxy group or a (C 1 -C 4) alkyl thio group, with the proviso that at least one of R 1, R 4 and R 5 is other than hydrogen, such that one ( Compound V - R1, R4, R5, and R6 are as defined hereinabove, with a compound of formula Rx-C-Ry Ii. X 'is wherein X' is oxygen, Rx and Ry are C 1-4 alkoxy. The compounds are prepared by known methods and the compounds of formulas (III) and (IV) obtained can also be converted into other compounds of formula (III) or (IV) by known methods. The compounds are useful intermediates in the preparation of a pyrimido [6,1-a] isoquinolin-4-one derivative substituted with a 2-position N-containing group. -1-

Description

The present invention relates to novel pyrimidol-6,1-a-isoquinolin-4-one derivatives of formula (III) or (IV). In the formula

R ¹ and R ⁴ may be the same or different and are hydrogen, C 1-4 alkoxy or halogen;

R ⁵ is hydrogen or C 1-4 alkoxy;

R ^{e is} hydrogen or C 1-4 alkyl;

X is O or S; and

Y represents a halogen atom, a C 1-4 alkoxy group or a (C 1-4 alkyl) thio group, with the proviso that at least one of R ¹ , R ⁴ and R ⁵ is other than hydrogen.

Can be represented by formula (III) or (IV), formulas of new compounds are valuable intermediates which are substituted pyrimido [6 a], groups nutraceuticals, specifically mainly antihypertensive, bronchodilating and allergy against ² activity 2-position N-containing can be used with excellent results for the preparation of isoquinolin-4-one derivatives. The preparation of these therapeutic compounds is disclosed in Hungarian Patent Application No. HO-2081. ²

Compounds of similar structure are disclosed in L. Capuano and K. Mueller, Chem. Bér. 108, 1541 <1975). In particular, this article (III) to compounds of formula addresses, wherein R ^1, R ⁴ and R ⁵ are hydrogen, and f. X is oxygen cut-off sulfur.

The (111) and (IV) - wherein R ^1, R ^4, R ^5, R ^6, X cs Y previous meanings - (V) Compounds of general formula - wherein R ^1, R ^4, R ^s and R ^{6 is} a compound of the formula - and R ^{x is} -CR ^y -

X '

- where

X 'represents an oxygen atom,

R * and R ^y represent a C4-C4 alkoxy group, which may be "cleaved" and optionally further prepared by known reaction steps (see Shaw and Wooley, Bér. 98, 1505 (2965)).

The reagent R ^x -CR ^y used is · II

Most preferred of the compounds X 'is diethyl carbonate, wherein R ^x and R ^y are both ethoxy. The reaction is carried out in the presence of a base. ⁵ as a base alkáüfém alkoxide such as sodium methoxide, sodium etilátoí, potassium methoxide, potassium ethoxide; an alkali metal hydride such as sodium hydride; or a organic base such as an alkylamine such as triethylamine. The reaction can be carried out in either a non-polar or a polar solvent. Suitable solvents are, for example, aromatic hydrocarbons such as benzene, toluene, methanol or ethanol, ethers such as dioxane or tetrahydrofuran or, for example, dimethylsulfoxide, dimethylformamide or hexamethylphosphoric triamide. The reaction can be accelerated and completed by heating the reaction mixture, for example to the boiling point of the solvent.

Compounds of formula (III) wherein R ^{6 is} hydrogen, R ¹ , R ⁴ , R ⁵ and X can be converted to compounds of formula (III) wherein R ^{6 is} 1-4 by conventional alkylation as defined above. while the other substituents have the same meaning.

Compounds of formula (III) wherein X is sulfur, R ¹ , R ⁴ , R ⁵ and R ⁶ may be prepared in a known manner from the corresponding compounds of X where X is oxygen, e.g. sulfide 3 in a manner known per se.

Compounds of formula (III) wherein X is O, R ¹ , R ⁴ , R ⁵ and R ⁶ may be converted to compounds of formula (IV) where Y is halogen, the other substituents being known in the art. and the resulting compounds, wherein Y is preferably chlorine, can be converted by treatment with an alkali metal alcoholate to the corresponding compounds of formula (IV) wherein Y is C 1-4 alkoxy.

Compounds of formula (IV) having from 1 to 4 carbon atoms for the Y site may also be prepared by reacting the corresponding compounds of formula (III) wherein X is oxygen with a trialkyl oxonium fluoroborate such as triethyloxonium fluoroborate. The reaction is carried out in the presence of a solvent such as a halogenated aliphatic hydrocarbon. A suitable solvent is, for example, dichloromethane.

Compounds of formula (IV) wherein Y is (C 1 -C 4) alkylthio are prepared from the corresponding compounds of formula (ΠΙ) wherein X is sulfur, in a known manner, with an alkyl halide, e.g. treatment with methyl iodide.

^! In the preparation of 5 (III) and (IV) compounds of the formula used with (V) general formula compounds starting - R ^1, R ^4, R ^s and R ⁶ in the previous meanings - can be prepared in known procedures (CA 64, 6627 (1966 ), and Dutch Patent No. 6,401,827).

Those of the starting material of formula (V) wherein R ^{6 are} hydrogen atoms - R ^1, R ⁴ and R ⁵ in the previous meanings, - the compounds (VI) - R ^1, R ⁴ and R ⁵ have the above meanings - and They may be prepared by reaction of other acids, such as formic acid, trifluoroacetic acid or polyphosphoric acid. The reaction can be accelerated or completed by heating the reaction mixture to, for example, 80 ° C to 150 ° C.

> ° The compounds of formula (VI) may also be prepared by known methods [C. A. 64, 6627 (1969), 6,401,827 to Liebigs Ann. Chem., 1606 (1973)].

Further details of the present invention are illustrated by the following examples without limiting the invention to the examples.

Example 1

6,7-Dimethoxy-1-carbamoylmethylene-1,2,3,4-tetrahydroisoquinoline

10.0 g of polyphosphoric acid are heated to 100 ° C and ⁶⁵ g of 1.0 g of 6,7-dimethoxy-1-cyanomethylene-1,2,3,4,4-21 are added.

185,318 tetrahydroisoquinoline. The reaction mixture was heated for one hour, then leached with crushed ice and basified with 30% aqueous sodium hydroxide. The mixture was extracted with chloroform and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. A white solid remains.

Yield: 0.7 g, m.p. 156-158 ° C.

Example 2

9,10-Dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6, l-a] isoquinolin-2,4-dione

A solution of 5.0 g of 6.7 dimethoxy-1-carbamoylmethylene-1,2,3,4-tetrahydroisoquinoline and 12.0 g of sodium metal oxide in 600 ml of ethanol is heated in ethanol. To the solution was added 150.0 ml of diethyl carbonate. The reaction mixture was refluxed for 2.5 hours. The solvent was removed in vacuo and the residue acidified to give a white precipitate. Yield: 4.80 g. The product crystallizes from dimethylformamide. Melting point: 323-325 ° C.

Example 3

9,10-Domethoxy-3-methyl-3,4,5,7-tetrahydro-2H-pyrimido [6,1-a] isoquinoline-2,4-dione

4,11 g of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6,11a] -isoquinoline-2,4-dione, 0.75 g of anhydrous sodium hydride and 100 ml of dimethyl- The formamide mixture was heated at 100 ° C for 15 minutes and then cooled to room temperature. Methyl iodide (10 mL) was then added. After 12 hours at 100 ° C, the solvent was removed in vacuo and the residue treated with cold water. The solid was filtered off and recrystallized from ethyl acetate / methylene chloride. Yield: 4.0 g, m.p. 260-262 ° C.

Example 4

9,10-Dimethoxy-3-isopropyl-3,4,6,7-tetrahydro-2Hpirimido- [6, l-a] isoquinolin-2,4-dione

In analogy to the procedure described in Example 3, 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a] isoquinoline-2,4-dione is reacted with isopropyl iodide. Yield: 50%, m.p. 190-192 ° C.

Example 5

9,10-Dimethoxy-2-thio-3,4,6,7-tetrahydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 10.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6,11a] isoquinoline-2,4-dione and 9.0 g of phosphorus pentasulfide in 200 ml of pyridine was refluxed for 5 hours. boil. The pyridine is evaporated in vacuo. The residue was treated with dilute aqueous hydrochloric acid and extracted with methylene chloride. The resulting methylene chloride extract was dried over anhydrous sodium sulfate and evaporated to dryness. This gives a white powder which can be crystallized from a mixture of chloroform and ether. Yield. 10.0 g, m.p. 236-237 ° C.

Example 6

9,10-Dimethoxy-3-diethyl-2-thio-3,4,6,7-tetrahydro-4H-pyrimido [6,1-a] isoquinolin-4-one

To a solution of 0.5 g of 9,10-dimethoxy-3-methyl-3,4,6,7-tetrahydro-2H-pyridinido [6,1-a] isoquinoline-2,4-dione in 10 ml of pyridine was added 1.0 g of phosphorus pentasulfide. The mixture was refluxed for 15 hours. The solvent was removed in vacuo and the residue was extracted several times with methylene chloride. The combined methylene chloride extracts were first washed with dilute aqueous hydrochloric acid, water, dried over sodium sulfate and then evaporated to dryness. The residue was chromatographed to give the desired title compound. Yield: 0.25 g, m.p. 230-231 ° C.

Example 7

9,10 Dimethoxy-2-chloro-6,7-dihydro-4H-pyrimidol-6,1-a] isoquinolin-4-one

A mixture of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a] isoquinoline-2,4-dione (30.0 g) and phosphorus oxychloride (300 ml) was kept on a steam bath for 4 hours. The excess phosphorus oxychloride was distilled off under reduced pressure. The residue was poured into aq: aqueous sodium hydroxide solution and the precipitated yellow solid was filtered off. The product was purified by column chromatography on silica gel using chloroform as the eluent. Yield: 28.0 g, m.p. 235-236 ° C.

Example 8

9.10- Dimethoxy-2-butoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

A mixture of 1.0 g of sodium hydroxide and 50.0 ml of n-butanol is mixed with 1.46 g of 9,10-dimethoxy-6,7-dihydro-2-chloro-4H-pyrimido [6,11a] isoquinolinA-one . The reaction mixture is refluxed for 6 hours and the solvent is evaporated under reduced pressure. The residue was treated with water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated. This leaves a white solid. Recrystallization from chloroform / ether gave 0.7 g of the title compound. Melting point: 158-159 ° C.

Example 9

9.10- Dimethoxy-2-ethoxy-6,7-dihydro-4H-pyrimido [6,1-a] isoquinolin-4-one

3.0 g of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido [6,1-a] isoquinoline-2,4-dione and 15.0 g of triethyloxonium fluoride

A solution of -3185 3 iS borate in 100 mL of dichloromethane was stirred overnight. The reaction mixture was washed with aqueous sodium carbonate solution, the organic layer was separated and dried over anhydrous sodium sulfate. After evaporation of the solvent, 1.8 g of the title compound are obtained. Melting point: 212-214 ° C.

Example 10

9,10-dimethoxy-2-methylmercapto-6,7-dihydro-4Hpiriinido [6, l-a] isoquinolin-4-one hydroiodide

A suspension of 10.0 g of 9,10-dinethoxy-2-thio-3,4,6,7-tetrahydro-4H-pyrimido [6,11a] isoquinolin-4-one in 200 ml of tetrahydrofuran 1 is mixed with 20 ml of methyl iodide, and the resulting reaction mixture is refluxed for 4 hours. A brine precipitate was obtained which was filtered off. Recrystallization from chloroform / methanol gave 10.50 g of the title compound, m.p. 220-225 ° C (dec.).

The compounds of formulas 111 and IV listed in the following table can be prepared analogously.

Spreadsheet

R ¹ + R ⁴ R ^s R ⁶ X Y M.p. 2 H H 11 0 260 ° C 2 H H - - cl 179-180 ° C 9.10 (OCH ₃ ) ₂ H H s - 236-237 ° C 9.10 (OCH ₃ ) ₂ H - - SCH ₃ 203-205 ° C 9.10 (OCH?) ₂ H - - cl 235-236 ° C 9.10 (OCH ₃ ) ₂ H - - OBu 158-159 ° C T10 (OH) ₂ H H 0 - > 260 ° C 9.10 (OCH ₃ ) j 11-OCH for ₃ h 0 - 215-218 ° C 9.10 (OCH ₃ ) ₂ 11-OCH ₃ - - cl 176-175 ° C H, 10-Cl H H 0 - > 250 ° C H, 10-Cl 11 - - - cl > 250 ° C 9, ιο (οαι ₃ ) ₂ H ch ₃ 0 - 260-262 ° C 9.10 (OCH ₃ ) ₂ H ch ₃ s - 230-231 ° C 9.10 (OCH ₃ ) ₂ H CH (CH ₃ ) ₂ .0 - 190-192 ° C

Example 11

General procedure for the preparation of compounds of formula I starting from compounds of formulas III and IV.

A compound of formula III (X = S) or a compound of formula IV (Y = Cl, SCH ₃ , OBu) is heated in an equimolar amount of an amine of formula NHR ² R ^{3 in the} presence of a base or an acid acceptor. The base is preferably an excess of the reactive amine itself. The reaction may advantageously be carried out in the solvents listed above. The reaction mixture can be refluxed for 2 to 10 hours. The solvent was evaporated under reduced pressure. The residue was treated with water and extracted with an organic solvent. The extract was dried over anhydrous sodium sulfate and the filtrate was concentrated to dryness. The residue is purified by chromatography and / or recrystallized to give the desired compound which is optionally converted into its salt.

Claims (4)

Patent Claim Point Process for the preparation of pyrimido3 [6,11a] isoquinolin-4-one derivatives of formula (III) or (IV): wherein R ¹ and R ⁴ may be the same or different and are hydrogen, C 1 -C 4 alkoxy or halogen; R ⁵ is hydrogen or C 1-4 alkoxy; R ^{6 is} hydrogen or C 1-4 alkyl; X is O or S, and Y is halogen, C1-4 alkoxi0 group or a (1-4C) alkylthio group, with the proviso that at least one substituent is hydrogen, R ^1, R ⁴ and R ^s are meanings - preparation, characterized in that one (V) general Compound 5 formula - R ^1, R ^4, R ^s and R ⁶ are as defined above, is - CR a R ^y of formula II Reacting with compound X ', where 3 X 'represents an oxygen atom, R * and R ^y 1— Represents C4-alkoxy - optionally alkylating a compound of (III) a compound of formula I wherein X is oxygen, ^{R1, R4, R5} and ^R6 are as defined above meanings, and converting a 5 (IV) compound of Formula I wherein Y is halogen, R ^1, R ⁴ and R ^s are as defined above meanings, and optionally this compound was further alkoxylation is converted to a formula (IV) is a compound of formula wherein Y 1 Represents a -C4 alkoxy group, 0 R ¹ , R ⁴ and R ^{s are} as defined in the scope; or optionally a compound (III) a compound of formula I wherein X is oxygen, R ^1, R ^4, R ^s and R ⁶ are as defined above meanings, is reacted with a trialkoxioxonium-fluorboráttal converting an ^L 5 (IV) compound wherein Y is C 1 -C 4 alkoxy, R ¹ , R ^4, and R ^{5 are} as defined herein; or optionally converting a compound of formula (III) wherein X is O, R ¹ , R ⁴ , R ^5, and R ⁶ into a > θ substituent to a compound of formula (III) wherein X is sulfur; ^{R1, R4, R5} and ^R6 are as defined above, and the resulting compound of formula (III) is optionally converted by alkylation of a (IV) vegyü'5 Lett wherein Y is (1-4C) alkyl It is a thio group, ^{R1, R4} and ^R5 are as defined above meanings; or optionally alkylating a compound of formula III wherein R ^{6 is} hydrogen, R ¹ , R ⁴ , R ⁵ and X are as defined herein to a compound of formula III wherein R ^{6 is} alkyl R ¹ , R ⁴ , R ⁵ and X have the meanings indicated.