HU183048B - Process for producing bracket-2s,3r-bracket closed-, bracket-2s,3s-bracket closed-, bracket-2rs,3r-bracket closed- or bracket-2rs,3rs-bracket closed-3-amino-2-hydroxy-propionyl-glycine derivatives - Google Patents

Abstract

For preparing the novel bestatin compounds of the formula <IMAGE> having R1 and R2 in accordance with the preceding Patent Claim 1, an alpha -hydroxybeta -amino acid of the formula <IMAGE> is used as the starting material. The latter is condensed, optionally after having protected the functional groups which are not to participate in the subsequent reaction, with a beta -amino acid of the formula <IMAGE> using a peptide-linking method. Protective groups which may optionally be present are subsequently removed. The optically pure diastereoisomers can be readily obtained from the compounds of the formula (III). The alpha -hydroxybeta -amino acids can be prepared by hydrolysing a corresponding cyanohydrin whose amino group is optionally protected. The novel compounds inhibit certain enzymes which decompose bleomycin and in this way amplify the anti-tumour activity of the bleomycins.

Description

The present invention relates to a novel process for the preparation of 4-arylquinazolin-2 (111) -one compounds, in particular compounds of general formula (I) wherein

R 1 is optionally substituted with fluoro

C 1-6 -alkyl, allyl, propargyl or C 3-7 -cycloalkyl, C 3-6 -cycloalkyl backbone, and C 12 -alkyl having 4 to 7-membered cycloalkyl or benzyl,

R ₂ is a monocyclic aryl group, and

R ₃ and R ₄ each independently represent hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, chlorine, bromine or trifluoromethyl, or R ₃ and R _{4 taken} together to form C 6 and C 7 of the quinazoline backbone the corresponding 4-aryl-5,6,7,8-tetrahydro-2- (1H) -quinazolinones, in particular the compounds of formula (II) - wherein R 1, R ₂ , R ₃ and R ₄ may form a methylenedioxy group; by dehydrogenation of the above inert organic solvent with sulfur. According to the invention, the dehydrogenation is carried out in the presence of an oxide, hydroxide or salt of iron, calcium, zinc or lead.

The sulfur dehydrogenation of 1-alkyl-4-phenyl [or 4- (2'-ticnyl)] - 5,6,7,8-tetrahydro-2 (1H) -quinazoline derivatives is described, inter alia, in U. S. Patent 1,383,255. Example 7 illustrates a reaction of this type. In this example, the final product is recovered in only 35% yield.

It is an object of the present invention to increase the yield of such dehydrogenation reactions. This objective has been achieved by the appropriate choice of catalysts, and the compounds in question can be prepared in much higher yields (above 70%) than those known in the art.

The process according to the invention is generally carried out at a temperature of 125 ° C to 250 ° C, preferably 130 ° C to 200 ° C, particularly preferably 135 ° C to 200 ° C.

The reaction solvent used in the reaction is organic inert organic liquids. Preferred solvents are ethylene glycol, propylene glycol, ethoxyethoxyethanol, dioxane, toluene, xylene and p-cymol. Generally, it is preferable to use hot solvents at the desired reaction temperature, since the reaction may be carried out under reflux. As the solvent, for example, p-cymol may be used, the boiling point of which is in the particularly preferred temperature range.

The molar ratio of sulfur to parent quinazolinone compound can vary within a relatively wide range, however, the molar ratio should generally be at least 1.7: 1. The upper limit of the molar ratio is not critical, but it is not necessary to use sulfur in a molar ratio greater than 6: 1. Sulfur and starting mother? the molar ratio is preferably 1.9: 1 to 4: 1, particularly preferably 2: 1 to 3: 1.

As stated above, the metal compounds may be salts, such as salts with strong acids, such as halides, but metal oxides or metal hydroxides, particularly metal oxides, are preferably used in the reaction. Particularly preferred metal compounds have been found to be calcium oxide, zinc oxide and iron (1H) oxide; of these compounds, iron (II) 2 oxide is highly preferred. Some of the usable metal glass bonds (e.g., calcium chloride) react with sulfur to form an acid, and the metal sulfides formed are unstable or dissolve in the acidic medium. In such cases, it is preferable to add a bidroxide base to the reaction mixture. For example, alkali metal hydroxides or alkaline earth metal hydroxides may be used as the base, however, if the metal compound is added in the form of a hydroxide base, an excess of the metal compound may be used. The base is preferably an alkali metal hydroxide such as potassium or sodium hydroxide.

The molar ratio of metal compound to parent quinazolinone derivative will generally be at least 1.1, preferably at least 1.5: 1. The upper molar ratio ^l Ar3 is not critical, 10: However, additional benefits can not be achieved by using greater than 1 molar. The molar ratio of the metal compound to the starting material is generally from 1.8: 1 to 6: 1, preferably from 2: 1 to 4: 1, more preferably from 2.1: 1 to 3: 1.

When the reaction is carried out in the presence of a hydroxide base, the base will generally be present in a molar ratio of at least 1: 1 to the starting quinazolinone derivative. preferably in a molar ratio of at least 1.5: 1, preferably in a molar ratio of 1.8 to 6: 1, in particular in a molar ratio of 2 to 3: 1.

The process according to the invention may be carried out at a pressure below or above atmospheric pressure, however, the reaction is preferably carried out at atmospheric pressure. The reaction is preferably carried out under an inert gas atmosphere (e.g. nitrogen atmosphere); the inert gas atmosphere may be provided by a single gas injection or by continuous gas flow.

The reaction usually takes about 1-15 hours.

The process of the present invention provides substantially higher yields of target products than the known non-metallic methods. A further disadvantage of the known processes is that the reason for the desired quinazolin-2 (1H) -one derivative is generally provided together with the corresponding 3,4-dihydro compounds.

The compounds of formula (II) are known or can be prepared by known methods from known starting materials.

In the compounds of the formulas I and II, R ₂ is a group of the general formula (H ₁ ) or IV - wherein Y and Y 1 independently of one another are hydrogen, fluorine, chlorine, bromine, C 1-3 alkyl or alkoxy. or trifluoromethyl, provided that when Y and Y 1 are trifluoromethyl, the other substituent may be hydrogen only, and

Y ₂ is hydrogen, fluoro, chloro, bromo, C 1-3 alkyl, or C 1-3 alkoxy.

The compounds of formula I have anti-inflammatory activity. In view of the biological activity in these compounds, R 1 preferably represents a C 1-6 alkyl group or a cyclopropylmethyl group, preferably a C 1-6 alkyl group, most preferably an isopropyl group. Preferably R _{2 is} phenyl, which may be optionally substituted by one or two substituents as previously described. _R2 is particularly preferably a phenyl group or p-fluorophenyl. Compounds of formula (I) -21

In R 183 018, R 1 and R _{4 may} both be hydrogen, but derivatives wherein at least one is C 1 -C 3 alkyl (preferably methyl) or C 13 -alkoxy (e.g. methoxy) are more preferred. For example, the alkyl group may be attached to the C 7 position and the alkoxy group may be attached to the C 6 position, for example.

Particularly preferred compounds of the present invention are 1-isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone and 1-isopropyl-4- (p-fluorophenyl) -7-methyl-2 (1H). -quinazolinone.

The following examples illustrate the invention without limiting it.

Example 1

Preparation of -isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone

A mixture of 200 ml of p-cymol, 40 g of ferric oxide and 7 g of sulfur was heated to reflux (about 175 ° C) and 28.2 g of l-isopropyl-4-phenyl-7- A solution of methyl 5,6,7,8-tetrahydro-2 (II) -quinazolinone in 200 ml of p-cymol (130 ° C) was added dropwise. The resulting solution was refluxed for 3.5 hours; during this time, 1.8 ml of water is collected in a Dean Stark water separator attached to the flask. The reaction mixture was cooled to 28 ° C, filtered through a pad of Celite, and the pad was washed with 4 x 25 mL of toluene. The toluene washings were extracted with 50 ml of 4N aqueous hydrochloric acid and the p-cymol filtrate was extracted with 350 ml of 4N aqueous hydrochloric acid. The acidic extracts are combined, washed with 100 ml of toluene and the toluene wash is discarded. Then 350 ml of toluene and 10 g of 50% aqueous sodium hydroxide solution are added to the acidic solution. The layers were separated, the toluene layer was washed with water (2 x 100 mL), dried over sodium sulfate, filtered, and evaporated in vacuo. The solid residue was crystallized from ethyl acetate. 139 1-isopropyl-4-phenyl-7-methyl-quinazolin-2 (1H) -one is obtained. Yield: 72%.

Example 2 Preparation of 1-isopropyl-4- (p-fluorophenyl) -7-methyl-2 (1H) -quinazolinone in a mixture of xylene, 13.3 g of ferric oxide and 2.5 g of sulfur in nitrogen and 10 g of 1-isopropyl-4- (p-fluorophenyl) -7-methyl-5,6,7,8-tetrahydro-2 (1H) -quinazolinone in 100 ml of xylene are added over a period of 20 minutes. 100-110 ° C). The resulting solution was refluxed for 10 hours; during this time, the Dean -Stark attached to the flask is purged of water. The reaction mixture was cooled to 80 ° C and filtered through a Celite pad.

The filtrate and filter cake were washed with 3 x 50 mL toluene. The filtrates were combined and extracted successively with 200 ml, 100 ml and finally 50 ml of 4N aqueous hydrochloric acid. The acidic extracts were combined, washed with 100 mL of toluene and the toluene wash was discarded. While stirring and cooling, 200 ml of toluene and 115 g of 50% aqueous sodium hydroxide solution were added to the acid solution. The layers were separated and the aqueous layer was extracted with 2 x 100 mL toluene. The toluene layers were combined, washed with water (2 x 00 mL), dried over anhydrous magnesium sulfate, filtered through a Celite pad and the filtrate was evaporated. Yield: 8.8 g (90%) of a yellow crystalline product. Recrystallization from ethyl acetate gave 1-isopropyl-4- (p-fluorophenyl) -7-methyl-2 (1H) -quinazolinone, m.p. 175-176.5 ° C.

Example 3

Preparation of -isopropyl-4-phenyl-7-methyl-2- (1H-quetolinone)

28.2 g of 1-isopropyl-4-phenyl-7-methyl-5,6,7,8-tetrahydro-2 (1H) -quinazolinone, 9.6 g of sulfur, 10 g of sodium hydroxide, 20 g of calcium chloride and 200 ml of 2 - A mixture of (2-ethoxyethoxy) ethanol was heated at 150 ° C for 2 hours under nitrogen. The resulting mixture was cooled to 65 ° C, diluted with 500 ml benzene, cooled to 15 ° C with stirring, and the liquid phase was decanted. The organic layer was washed with water and evaporated. The resulting oily residue was dissolved in a mixture of benzene (100 mL) and 50% aqueous hydrochloric acid (100 mL), stirred at room temperature for 1 hour, then the layers were separated and the acidic phase washed with benzene (50 mL). The acidic phase is then neutralized with 50% aqueous sodium hydroxide solution and extracted with 150 ml of benzene. The benzene extracts were combined, washed with water to neutral, dried over sodium sulfate and finally the benzene solution was evaporated. The crude product obtained is recrystallized from ethyl acetate. Yield: 1-Isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone, m.p. 141-142 ° C.

Example 4 Preparation of i-isopropyl-4- (p-phthalophenyl) -7-methylquinazolin-2 (1H) -one for a mixture of xylene (isomer mixture), 4.3 g sulfur and 6.8 g zinc oxide under nitrogen, with stirring and reflux (at about 138 ° C), 10.0 g of l-isopropyl-4- (fluorophenyl) -7-methyl-5,6,7,8-tetrahydro-2 (1H) quinazolinone is added in 100 ml of xylene (mixture of isomers) preheated to 100-115 ° C. After the addition, which takes about 20 minutes. the mixture was refluxed and filtered through a pad of Celite. The solid was washed with toluene. The wash and the filtrate were extracted four times with 4N aqueous hydrochloric acid and the extract was washed with 100 mL of toluene. The aqueous phase is mixed with 200 ml of toluene and 115 g of 50% aqueous sodium hydroxide solution are added portionwise on an ice bath. The aqueous layer was separated, washed with toluene (2 x 100 mL), and the organic solution was washed with water, dried, filtered and concentrated in vacuo. The resultant yellow crude solid was dissolved in ethyl acetate (100 mL), filtered and the filtrate was concentrated to a final volume of 50 mL and cooled to 0 ° C. The precipitate was recrystallized from ethyl acetate. 1-Isopropyl-4- (p-fluorophenyl) -7-methylquinazolin-2 (1H) -one is obtained.

Example 5

Preparation of -isopropyl-4- (p-fluorophenyl) -7-methylquinazolin-2 (1L) -one

The procedure described in Example 4 was followed, however, using equimolar amounts of lead oxide instead of zinc oxide. The title compound is obtained.

-3-83,018

Example 6

By the method described in any of the preceding Examples, the following compounds are prepared in an equivalent amount of the appropriate starting materials:

The substituents have the meaning given in formula (I) Product melting point [° C] R Y Yi Y ₂ rj R < iC ₃ H ₇ H H 5-CH3 7-CH 145-147 I-C ₃ H ₇ H 4-CH - 7-CH ₃ H 156-157 í-c ₃ h ₇ - - H 7-CH H 154-156 cyclopropylmethyl H H - 6-OCH H 115-116 iC ₃ H ₇ H H - 6-OCH 7-OCH 148-150 iC ₃ H ₇ H H - 7-C ₂ H ₅ H 112-113 -C ₃ H ₇ H 4-OCH ₃ - 7-CH H 163-165 -C ₃ H ₇ H H - 6-C1 7-Cl 167-168 -C ₃ H ₇ H H - 6-CH 8-CH 168-169 ch ₃ H H - H H 142-143 c ₂ h _s H H - H H 183-185 nC ₃ H ₇ H H - H H 131 nC ₄ H ₉ H H - H H 103-104 n-C5H11 H H - H H 121-122 allyl H H - H H 159-160 propargyl H H - H H 181 CII ₃ H 4-C1 - H H 195 ch ₃ 2-OCH 6-OCH3 - H H 166-167 CH? H 3-Cl - H H 95-96 ch ₃ H 3-CFj - H H 165-167 CH? H 2-C1 - 6-Cl H 191-199 i- C ₄ 11 ₉ H H - H H 120-122 i-C ₃ H ₇ H H - 6-CH 7-CH 135-137 c ₂ h ₅ H H - 6-CFj H 180 (sublimation) CH? - - 5-CH H H 104-106 CH? - - 4-CH3 H H 248-250 i-CjH ₇ - - 5-Cl 6 CHjO H 164-165 i-Cjll ₇ H 3-F - - O - CH ₂ -0- 169-170 i — C ₃ H ₇ H 3-OCH3 - - 0 - ch ₂ -0- 189-191 1 -C ₃ H ₇ H 4-F - - 0 - ch ₂ -0- 238-240 -C ₃ H ₇ 3-Cl 4-C1 - - 0 - ch ₂ -0- 239-242 > -CJH ₇ H 2-CH - - 0 - ch ₂ -0- 155-157 1-C ₁ H ₇ H H - 6-Br H 142-143 CH ₂ CF 3 H H - 6-Cl H 185-186 CH ₂ CF ₂ CFj H H - 6-CH3 ' H 175.5 to 176.5 cyclopropylmethyl H H - 6-Cl H 174-175 cyclopropylmethyl H 2-F - 6-C1 H 171-172 cyclohexylethyl H H - 6-C1 H 115-116

PATENT CLAIMS

Claims (19)

A process for the preparation of the 4-arylquinazolin2 (1H) -one of formula (I) wherein R1 is optionally substituted (C1-C6) alkyl, allyl, propargyl, (C3-C7) cycloalkyl, optionally substituted by fluorine; A cycloalkyl backbone having 3 to 6 carbon atoms and a C 4 -C 7 cycloalkylalkyl group containing 1 to 2 carbon atoms or a benzyl group. R 1 is a group of formula III or IV. which Y and Y ι may be the same or different and are hydrogen, fluoro, chloro, C 1 -C 3 alkyl or alkoxy, or trifluoromethyl, with the proviso that if one of Y and Y 1 is trifluoromethyl then the other is hydrogen, and Y ₂ is hydrogen, chloro or C 1-3 alkyl, R ₃ and R ₄ may be the same or different and are selected from hydrogen, C 1-3 alkyl or alkoxy, chlorine, bromine or trifluoromethyl, or R ₃ and K ₄ together form a (. 7-methylenedioxy group) of the corresponding 4-aryl-5,6,7,8-tetrahydro-2 (1H) -quinazolinones of formula (11). wherein R ₁ , R ₁ , R ₃ and R ₄ are dehydrogenated in the above inert solvent medium with sulfur, characterized in that the dehydrogenation is carried out in the presence of an oxide, hydroxide or salt of iron, calcium, zinc or lead. .) 2. A process for the preparation of 4-aryl-ctnoxalin2 (1H) -ones of formula (1) - wherein R 1 and R ₂ are as defined in claim 1, while R ³ and R ⁴ are as defined in claim 1. It may be the same or different and are hydrogen or iq 13 alkyl groups are - in (II) by reacting a 4-aryl-5,6,7,8-tetrahydro-2 (IH) -kinazoUnon - wherein R, R _2, R ₃ and _R4 through dehydrogenation conducted in an inert organic solvent with sulfur in the above 15, wherein the dehydrogenation is carried out in iron (III) oxide. (Priority: 06/09/1977) 3. The process according to claim 1, wherein the dehydrogenation is carried out by a process comprising the steps of 20 and 20 The reaction is carried out at 250 ° C and the molar ratio of inorganic metal compound to parent tetrahydroquinazolinone compound is at least 1: 1. (Priority: 05/09/1978) 4. A process according to claim 2, wherein the dehydrogenation is carried out at 125-250 ° C, the molar ratio of sulfur to the starting tetrahydroquinazolinone compound being at least 1.7: 1, and the iron (III) - a molar ratio of oxide to parent tetrahydroquinazolinone of at least 1, 5: 1. 30 (Priority: 06.09.1977) e 5. Articles 2-4. A process according to any one of claims 1 to 3, wherein the molar ratio of sulfur to the starting tetrahydroquinazolinone compound is It is maintained between 1.9: 1 and 4: 1. 35 (Priority: 05/09/1978) 6. The process of claim 5 wherein the molar ratio of sulfur to parent tetrahydroquinazolinone compound is between 2: 1 and 3: 1. 40 (Priority: 05/09/1978) 7. A process according to any one of claims 1 to 6, wherein the molar ratio of the inorganic metal compound to the starting tetrahydroquinazolinone compound is between 1.8: 1 and 6: 1. 45 (Priority: 05/09/1978) 8. The process of claim 7 wherein the molar ratio of inorganic metal compound to parent tetrahydroquinazolinone compound is between 2: 1 and 4: 1. 50 (Priority 5/9/1978) 9. The process of claim 8, wherein the molar ratio of inorganic metal compound to parent tetrahydroquinazolinone compound is between 2.1: 1 and 3: 1. 55 (Priority: 05/09/1978) 10. A process according to any one of claims 1 to 9, wherein R 1 is C 1-6 alkyl or cyclopropylmethyl. (Priority: 05/09/1978) 11. A process according to claim 10 wherein the compound of formula 11 is wherein R 1 is C 1-6 alkyl. (Priority: 05/09/1978) 12. A process according to claim 11 wherein the compound of formula II is wherein R 1 is isopropyl. (Priority: 05/09/1978) 13. A process according to any one of claims 1 to 3, wherein the compound of formula II is wherein R _{2 is} phenyl optionally substituted with one or two fluorine, chlorine, bromine, C 1 -C 3 alkyl or C 1 -C 3 alkoxy groups; trifluoromethylphenyl. (Priority: 05/09/1978) 14. The process of claim 13, wherein the compound is of formula II wherein R _{2 is} phenyl or p-fluorophenyl. (Priority: 05/09/1978) 15. The process of claim 1, wherein the compound of formula II is one in which at least one of R ₃ and R ₄ is C 1 -C 3 alkyl. (Priority: 05/09/1978) 16. The process of claim 15, wherein the compound of formula II is one in which at least one of R ₃ and R ₄ is methyl. (Priority: 05/09/1978) 17. A process according to claim 16 wherein the at least one methyl group is attached to the 7-position. (Priority: 05/09/1978) 18. A process for the preparation of 1-isopropyl-4-phenyl-7-methyl-2 (1H) -quinazolinone according to any one of claims 1 to 3, wherein the corresponding tetrahydroquinazolinone derivative is dehydrogenated. (Priority: 05/09/1978) 19. A process for the preparation of 1-isopropyl-4- (p-fluorophenyl) -7-methyl-2 (1H) -quinazolinone according to any one of claims 1 to 3, wherein the corresponding tetrahydroquinazolinone derivative is dehydrogenated.