DE1803785A1 - Disubstd-6-oxo-tetrahydro-pyrimidines sedatives - Google Patents

Abstract

as anaesthetics, hypnotics, sedatives and circulatory agents. Compds. of general formula I are prepd. by reaction of 2-azetidinones (II) with lactim ethers (III) in equimol. amts. at 20-300 degrees (pref. 60-280 degrees). (where R1 = H, 1-10C alkyl, Ph (opt. substd. by alkyl, hal and/or NO2) 1-4C alkenyl, phenalkyl with 1 or 2 C in alkylene residue, carbalkoxy, carbalkoxymethyl or alkoxymethyl; R2-4 = H, Ph, alkyl or any two form an alkylene chain; Z = an alkylene chain which may be interrupted by O, S or NMe). II are prepd. from olefines and N-chlorosulphonylisocyanates.

Description

Process for the preparation of 1. 2 - disubstituted 6 oxo 1,4. 5.6 totrahydropyrimidines are 1,3-pentamethylene-6-oxo-1.4.5.6-tetrahydropyrimidines by converting lactimethers with ß-Amino @ carboxylic acids and subsequent elimination of water accessible (DBP 1.082.268 and DBP 1.088.968) or e.g.

from ß aminocarboxylic acid esters and lactimethers and then Alcohol elimination (Compt. Rend. C 365 (1966)).

According to the previous ancestors, the water resp.

Alcohol is split off by azeotropic distillation with dichlorobenzene carried out, which in the case of substituted ß-aminocarboxylic acids often leads to decomposition leads (cf.

J. Prakt. Chem. [4], 30, 18 (1965)).

In addition, the corresponding ß-amino carboxylic acids are shown z. Sometimes very difficult.

The invention relates to a new process for the preparation of 1.2 disubstituted 6 oxo.1.4.5.6 tetra hydropyrimidines of the general formula in which R1 is hydrogen, alkyl with 1 10 carbon atoms, phenyl optionally substituted by halogen atoms, lower alkyl and / or nitro groups, alkenyl with 1 4 carbon atoms, phenalkyl with 12 carbon atoms in the alkylene radical, carbalkoxy, carbalkoxy methyl or alkoxymethyl with 1 6 carbon each atoms in the alkoxy radical, R2, R3 and RA represent hydrogen, phenyl or alkyl with 1 6 carbon atoms, where R1 and R2 and or R3 and R4 or R1 and R4 and / or R2 and R3 via a 3 6 carbon atoms, optionally unsaturated alkylene chain can be connected in the form of a ring, and Z stands for a divalent hydrocarbon radical with 2 bts 15, preferably 3 to 5 carbon atoms, whereby one chain link can be replaced by oxygen, sulfur or the methylimino group, which is characterized in that one 2. azetidinones of the general characterized, @@@ man 2-Azetidlnone of the general formula with lactim ethers of the general formula @a the @@@@ R3 represents a lower alkyl radical, unsets at temperatures between 20 and 3000C, preferably at SO- 2S00C.

The azetidinones used according to the invention. 2 are according to different Procedure available. They are particularly easy to make from olefins and N-chlorosulfonyliso Prepare cyanate (cf. Liebigs Ann. d. Cheoio 661, 111 (1963), Aagew. Chemie 30, 179 (1988)). Azetidinones 2 with carboxy groups and thus the derivatives are after dea Process of the German patent application P 16 70 804.6 accessible. The lactim ethers are accessible by the method of US Pat. No. 2,356,622, while the ß Lactimäther are the subject of German patent application P 17 70.536.5. Lactim ether with heteroatoms are described in U.S. Patent 3,351,832.

The preferred embodiment of the reaction is that one Azetidinone 2 and Lactimäther mix in approximately equimolar amounts, first Temperatures between 60 130 ° C and then heated by He to 80-280 ° the reaction ended with the alcohol formed being distilled off.

For large batches, but especially when using more sensitive ones Azetidinone, however, it is recommended to submit the lactimether to 100 140 ° C to heat and add the azetidinone dropwise or in portions.

give.

Instead of equimolar amounts you can also use one or the other add the starting materials in excess. There is always an excess of lactimether recommended if not reacted azetidinone interferes with the work-up. Because of the high reaction temperatures required in some cases, this is not a problem The reaction is advantageously carried out under an inert gas in order to be oxidized by atmospheric oxygen to avoid. The reaction products obtained can almost always by distillation, in favorable cases also by recrystallization of the reaction mixture be cleaned.

The 1,2-disubstituted G-oxo- 1.4.5.6 tetrallydropyrimldine obtained of the formula I are mostly colorless, weakly basic substances that after the new Procedures are accessible for the first time in many cases.

With the compounds known up to now, he was able to achieve considerable improvements in yield be achieved.

It was surprising that azetidinones 2 as cyclic acid amides such quickly and clearly with a wide variety of lactimethers with cleavage of the azetidinone ring React to 1,2-disubstituted 6 oxo 1,4.5,6-tetrahydropyrimidines.

The compounds thus obtained can be used as anesthetics, hypnotics, Sedatives or circulatory drugs are used.

Example 1 1.2-Di (, dimethyl) -methylene4.4 dimethyl 6 oxo 1.4.5.6- tetrahydropyrimidine 68 g of 4,4-dimethyl 2 methoxyazetin 1 (0.6 mol) were with 49.5 g 4.i dimethylazetidinone 2 (0.5 mol) mixed and refluxed under nitrogen heated. Methanol was continuously separated off via a column, so that in the course of after 6 hours the internal temperature rose from 130 to 170 ° C (bath temperature 200 ° C) and 15 ml of methanol distilled out. To remove the excess azetidinone 2, the reaction mixture was taken up in methylene chloride and 2 hours with 33 % sodium hydroxide solution stirred at room temperature. After separating the brown colored organic phase was dried overnight over caustic potash, then after evaporation of the solvent distilled, at 95 98 ° / 5 5 mm thing a colorless oil over, the crystallized on cooling.

After recrystallization from hexane, 43.4 g (48% of the Tlicorie) were isolated colorless crystals of m.p. 76-77 ° n example 2 1.2 trimethylene 6 oxo 1,4.5.6 tetrahydropyrimidine 14.2 g (0.3 mol) ß propiolactam were in 19.8 g (0.2 mol) γ butyrolactim added methyl ether and dissolved by gentle warming. The homogeneous solution was then left for two hours at a bath temperature of 160 ° C, wherein 6.8 ml of methanol were distilled out through a small column.

The reaction product went at 0.7 mm in the subsequent distillation at 107 1080 as a colorless oil with @ 20 1.5290 above.

Yield 22.7 g (32.3% of theory) Example 3 1.2 Trimethylene 4 methyl 6 oxo 1.4.5.6 tetrahydropyrimidine 99.1 g γ butyrolactim methyl ether (1 mol) were mixed with 85 g of 4-methylazetidinone-2 (1 mol) and heated to 130 ° C r. To For 5 hours, the calculated amount of methanol was distilled out via a small column.

The dark brown BL was then distilled at 3 mm.

143.2 g (88.4% of theory) of colorless oil containing n201.5165 were obtained at 120 ° C above.

Example 4 1.2 Trimethylene 4 phenyl-6 oxo 1,4.5.6 tetrahydropyrimidine 54.5 g of γ butyrolactim methyl ether (0.55 mol) were mixed with 73.5 g of 4-phenylazetidinone 2 (0.5 mol) are added and leave at 1300 for 3 hours. During that time, the methanol was split off completed.

The still hot reaction product was in a mixture of benzene / cyclohexane recorded. On cooling, 89.3 g (83.3% of theory) of colorless needles separated out M.p. 93 940.

Example 5 1,2-trimethylene 4.4.5.5 tetramethyl 6 oxo 1.4.5.6 tetrahydropyrimidine 12.7 g of 3.3.4.4 tetramethylazetidinone-2 (0.1 mol) were mixed with 9.9 g of γ butyrolactim methyl ether (0.1 mol) added, heated to 130 ° C for 2 hours, with 3 g of methanol distilled off, and then left under nitrogen for 4 hours at 280 °. The reaction product was purified by distilling twice. At 111 ° C and 0.3 mm passed 13.8 g (71.1% of theory) of the colorless, oily product over nD20: 1.5026 Example 6 1.2 pentamethylene 6. oxo 1.4.5.6 tetrahydropyrimidine 14.2 g azetidinone 2 (0.2 mol) were added to 25.4 g of # caprolactim methyl ether and stirred and left under nitrogen for 4 hours at a bath temperature of 1500, wherein 4.5 g of methanol were distilled off.

The reaction mixture was mixed with 50 ml of methylene chloride, low Quantities of an insoluble product are filtered off and then fractionated.

At 90-92 ° C. and 1 mm Hg, 29 g (90% of theory) of a colorless product were obtained Oil over that solidified to colorless crystals with a melting point of 34-35 ° on cooling.

Example 7 1.2 Pentamethylene-4 methyl-6 oxo 1.4.5.6 tetrahydropyrimidine 1524 g of # caprolactim methyl ether (12 ilol) were heated to 1300 under nitrogen and 1020 g of 4-methyl azetidinone-2 (12 mol) were added over the course of 1 hour.

After a short time, the elimination of methanol began.

After 3 hours at 130-150 ° was allowed to complete the reaction heated to 180 ° for another 2 hours. A total of 450 ml of methanol distilled off.

The pale yellow reaction product delivered over during the distillation a 20 cm Vigreux. Column 1904 g (88% of theory) of a colorless oil with a boiling point of 86-37 ° at 0.2 mm, which solidified into colorless blocks on standing. M.p. 49,500. One Sample was recrystallized from hexane and then showed an mp of 50,510.

Example 8 1.2. Pentamethylene-4-phenyl-6. oxo 1.1.5.6 tetrahydro pyrimidine 67.4 g of # caprolactim methyl ether (0.53 mol) were mixed with 73.5 g of 4-phenylazetidinone 2 (0.5 mol) are added and slowly heated with stirring. At an internal temperature of 115 ° a violent reaction began with elimination of methanol.

After 90 degrees down at 1400 the reaction was complete. The reaction mixture solidified on cooling to a solid mass, which recrystallizes from benzene / cyclohexane became, 98.1 g (80.9% of theory) as colorless crystals from Mp. 71-72 ° were obtained.

Example 9 1,2-pentamethylene-4,4-dimethyl 6 oxo 1.4.5.6 tetrahydropyrimidine 99 g of 4.4 dimethylazetidinone-2 (1 mol) were heated to 1300 under nitrogen and in the course of one hour with stirring with 127 g t of caprolactim methyl ether (1 mol; relocated. After 2 hours at 130 °, the mixture was heated to 200 ° for a further 30 minutes. To Cooling the reaction mixture to 1000, 200 ml of hexane were added and after further The separated crystals are isolated from cooling.

Yield 178 g (91.7% of theory) with a melting point of 90 °.

Example 10 1.2-pentamethylene 5.5 dimethyl 6 oxo-1.4.5.6 tetrahydropyrimidine 12.7 g of # -caprolactim methyl ether (0.1 mol) were mixed with 9.9 g of 3,3-dimethylazetidinone 2 (0.1 mol) mixed, 3 hours at 130 ° and then 2 hours at 170 ° C et warms @ whereby 3.2 ml of methanol distilled off. The reaction product was then distilled. At 107 ° 0.7 mm, 16.7 g (86.2% of theory) of a colorless went Oil (nD20-15076), which on cooling turns into colorless crystals with a melting point of 35 360 froze.

Example 11 1,2-Pentamethylene-trans 4.5 dimethyl-6 oxo-1.4.5.6 tetrahydropyrimidine 127 g of # -caprolactim methyl ether (1 mol) were mixed with 99 g of 3,4-trans-dimetbylazetidinone-2 mixed, first 3 hours at 1300 and then under nitrogen for 2 hours stirred at 200 °, 40 ml of methanol distilling off.

During the distillation of the reaction mixture went at 96-970C and 0.3 mm 176 g (90.7% of theory) of a colorless oil (nD20-1.5100), which after a long Cool to colorless crystals, which solidify when standing at room temperature become greasy.

Example 12 1,2-Pentamethylene 4.4.5.5 tetramethyl 6-oxo-1.4.5.6 tetrahydropyrimidine 12.7 g of 3.3.4.4-Tetramethyl azetidinon-2 (0.1 mol) were under nitrogen with 12.7 g # -Caprolactim methyl ether (0.1 mol) added, 5 hours at a bath temperature left at 160 ° and then at 300 ° for 1 hour.

On cooling, the reaction mixture froze to a light brown color Crystal mass, from which by recrystallization from hexane with the addition of activated charcoal 18.4 g (83.2% of theory) of colorless crystals with a melting point of 124-125 ° were obtained.

Example 13 1.2 Pentamethylene-4,5-tetramethylene-6-oxo 1.4.5.6 tetrahydropyrimidine 25.0 g of 3,4-tetramethylene azetidinone-2 (0.2 mol) were mixed with 30.5 g of #caprolactim methyl ether (0.24 mol) mixed, n hours with stirring at 1300C and then 2 hours heated to 1500. 7 ml of methanol distilled off.

After cooling, the light brown oil was taken up in dioxane. When left to stand, 35.7 g (31% of theory) of colorless, coarse crystals crystallized of m.p. 82 83 ° aiis.

Example 1.1 1.3 pentamethylene 4 vinyl 6 oxo 1.4.5.6 tetrahydro pyrimidine 50 g of 4-vinylazetidinone-2 (0.515 mol) were mixed with 127 g (1 mol) of # -caprolactimethyl ether mixed and heated to 130 ° under nitrogen with stirring. After 2.5 hours it was the calculated amount of methanol is distilled out. During the subsequent cleaning 58 g of caprolactim ethyl ether were first separated off at 65 ° at 20 mm, then went at 120 ° 1.5 mm 85.0 g (35.2 g of theory) of the reaction product as colorless Oil (nD20-1.5300) over.

Example 15 1.2-Trimethylene 4-vinyl 4-methyl 6 oxo- 1.4.5.6.

tctrahydropyrimidine 11.1 g 4 - metllyl 4 vinylazetidinone 2 (0.1 mol) were mixed with 10.9 g # Butyrolactimmethyläther (0.11 mol) and 3 hours below Stir and leave at 1300 under nitrogen. In the subsequent distillation 10.9 g (61.3% of theory) of the reaction product went as a colorless oil at 118 ° / 2 mm (nD201,5212) about.

Example 16 1.2 Trimethylene 4,5 trimethylene-6-oxo 1,4,5,6-tetrahydropyrimidine 33 g of 3.4 trimethylene azetidinone-2 (0.3 mol) were mixed with 35 g (0.35 mol) of butyrolactine methyl ether mixed and with stirring for 3 hours to 1300 and then another 3 hours 2000 heated, with the theoretical Mengo methanol distilled out, At the Following purification, 41.6 g (77.9% of theory) of the reaction product were obtained at 116 118 °, 0.4 mm as a colorless oil (nD20-1.5416) over.

D Example 17 1.2-pentamethylene 4 n decyl c oxo 1.4.5.6 tetrahydropyrimidine 21.1 g of 4-n decylazetidinone 2 (0.1 mol) were added with 15.2 g # -Caprolactim ethyl ether (0.12 mol) were added and the mixture was stirred at 130 ° for 4 hours. the largest part being dos ge formed methanol distilled out. Subsequently, the remaining volatile substances were in vacuo Fractions removed and the residue u'ikristallisiert from I.exane. It resulted in 22.7 g (74.2% of theory) of the reaction product in the form of colorless needles with a melting point of 53-54 °.

Example 13 1.2 Pentamethylene-4- (3-bromophenyl) -6-oxo-1.4.5.6-tetra hydropyrimidine 22.6 g of 4 (3 bromophenyl) azetidinone 2 (0.1 mol) were mixed with 15.2 g of # -caprolactim ethyl ether (0.12 mol) were added and the mixture was stirred at 130 ° under nitrogen for three hours. Afterward the volatile constituents were removed in vacuo. the residue dissolved in benzene and little insoluble material separated. After concentration, it was recrystallized from Rexan, 20.2 g (63% of theory) of the reaction product in the form of colorless crystals from Melting point 79 80 °.

Example 19 1.2 Pentamethylene-4- (3-nitro-4-chlorophenyl) -6 oxo 1,4,5,6-totrahydropyrimidin 22.7 g of 4 (3-nitro-4 chloropenyl) azetidinone-2 (0.1 mol) were mixed with 15.2 g of #caprolactim methyl ether (0.12 mol) was added and the mixture was stirred under nitrogen at 1300 for 1 hour, the reaction mixture turned red in color. After removing the volatile Constituents, the residue was recrystallized from cyclohexane, with a red brown Oil undissolved zuteklulieb. 19.3 g (60% d.Th.) of the reaction.

product in the form of light yellow needles with a melting point of 96,970.

Example 20 1.2 Pentamethylene 4,5 (4 ', 5' dehydrohexamethylene) -6 oxo 1.4. 5.6 tetrahydropyrimidine 15.1 g 3.4 (4 ', 5' dehydrohexamethylene) -azetidinon 2 (0.1 mol) were admixed with 15.2 g of # caprolactim methyl ether (0.12 mol), 3 hours at 130 ° and then stirred for another 30 minutes at 2000 under nitrogen, wherein the calculated amount of methanol was split off. During the subsequent distillation went at 164-167 ° 0.3 mm 19.0 g (77.3 'of theory) of the reaction product as colorless, Highly viscous oil (nD20-1.5489) over at room temperature.

Claims (2)

Claims lr process for the preparation of 1.2 disubstituted 6-oxo-1.4.5.6-tetrahydropyrimidines of the general formula in which R1 is hydrogen, alkyl with 1-10 carbon atoms, phenyl optionally substituted by halogen atoms, lower alkyl and / or nitro groups, alkenyl with 2-4 carbon atoms, phenalkyl with 1-2 carbon atoms in the alkylene radical, carbalkoxy, carbalkoxmethyl or alkoxymethyl each with 1 6 carbon atoms in the alkoxy radical denotes, R2, R3 and R4 represent hydrogen, phenyl or alkyl with 1 @ 8 carbon atoms, where R1 and R2 and / or R3 and R4 or R1 and R4 and / or R2 and R3 have 3-6 carbon atoms optionally containing unsaturated alkylene chain can be connected in a ring, and Z is a divalent hydrocarbon radical having 2 to 15, preferably 3 to 5 carbon atoms, individual chain links can be replaced by oxygen, sulfur or the methylimino group, characterized in that 2 azetidinones general formula with lactim ethers of the general formula in which R5 is a lower alkyl radical, at temperatures between 20 and 300 ° C, preferably at 60-280 ° C, is reacted. 2) 6-Oxo-1.4.5.6 tetrahydropyrimidines of the formula in which R1 is hydrogen, alkyl with 1-10 carbon atoms, optionally with halogen atoms, lower alkyl and / or nitro groups substituted phonyl, alkenyl with 1-4 carbon atoms, phenalkyl with 1-2 carbon atoms in the alkylene radical, carbalkoxy, carbalkoxymethyl or alkoxymethyl with 1- 6 carbon atoms in the alkoxy radical, R2, R3 and R4 represent hydrogen, phenyl or alkyl with 1-8 carbon atoms, where R1 and R2 and / or R3 and R4 or R1 and R4 and / or R2 and R3 have 3-6 carbon atoms optionally containing unsaturated alkylene chain can be connected in a ring, R1 cannot be hydrogen or phenyl if R2, R3 and R4 are hydrogen and Z is a divalent hydrocarbon radical having 2 to 15, preferably 3 to 5 carbon atoms, individual chain links being replaced by oxygen , Sulfur or the methylimino group can be replaced.