SE123701C1 - - Google Patents

Description

Inventors: F. H. S. Curd, B. S. Lovell, H. T. Openshaw, L. C. Payman, R. Hull, and A. R. Todd. Priority, requested from 18 May and 6 December 1944 (Great Britain).

The present invention relates to the preparation of novel pyrimidine compounds which are useful as chemotherapeutic agents and in particular as anti-malarial agents and dven as intermediates for their preparation.

The new compounds in question are pyrimidine derivatives of the following formula.

NC - X NH, - CC - Y 1 N - C - NR "- A - In which X represents vdte or a hydrocarbon radical, Y means vate or a neutral substituent or X and Y together may form a simple alkylene chain, R" means vate or an alkyl- or monosubstituted alkyl group, e.g. an alkoxyalkyl or dialkylaminoalkyl group, A means a linking group which is aliphatic or alicyclic or aliphatic-carbocyclic, wherein if A or part of A is an aliphatic chain, the donna may be interrupted by oxygen, sulfur or nitrogen atoms, and NRR ' is a strongly basic amino or substituted amino group, such as alkylamino or dialkylamino or piperidino group or other strongly basic, nitrogen-containing heterocyclic group.

The compounds are prepared according to a method which comprises a reaction between a compound of the formula N = C - XI NH 2 - CC - Y 11 N - CZ and a diamine of the formula NHR "- A - NRR ', the various symbols in these formulas have the same inner table as indicated above and Z represents a reaction bend gene atom or group, such as a halogen atom.

It should be noted that in such cases where one wishes to introduce a substituent of the formula - NR "- A - NHR (R is vate or a hydrocarbon radical), it should usually be necessary to first protect the outermost amino group, e.g. acylation, and then remove the protecting group after the condensation with the pyrimidine compound has been effected.This procedure is in fact a special embodiment of the modified process, which will be described in the following.

The reaction is conveniently carried out by heating the reactants with each other, possibly in the presence of a release or diluent. The reactants may have been used as free bases or, if desired, the aminopyrimidine derivative may be used as the free base and diamine in the form of a salt, e.g. the hydrochloride or acetate, or alternatively the free diamine and a salt of the aminopyrimidine derivative may be used. If desired, the reaction awn can be carried out in the presence of an acid-binding agent, such as e.g. sodium hydroxide.

The reactants are suitably used, but not absolutely intermediate, in approximately stoichiometric proportions. Possibly ken. man anyanda a large excess of diamine, sh that it acts as a solvent. In fact, when using the diprimaric diamines, it is appropriate to work on this.

The flora of the 2-amino-4-halopyrimidines, which are used as starting materials, constitute kanda f Oreningar - cf. Report 1899, vol. 32, p. 29, 24, 1901, vol 34, p. 2817 and 1903, vol. 36, p. 1918. Others can be produced according to the same general methods as described in ddr.

Examples of suitable 2-aminopyrimidine intermediates are 2-amino-4-chloropyrimidine, 2-amino-4-chloro-6-methylpyrimidine, 2-amino-4-chloro-5: 6-dimethylpyrimidine, 2-amino-4-chloro -5-methylpyrimidine, 2-amino-4-chloro-5-ethyl-6-methylpyrimidine, 2-amino-4-chloro-5-bromopyrimidine, 2-amino-4-chloro-5-benzyl-6-methylpyrimidine, 2 -amino-4-chloro-5-phenoxypyrimidine, 2-amino-4-chloro-5: 6-trimethylenepyrimidine and 2-amino-4-chloro-5: 6-tetramethylenepyrimidine and also the corresponding 4-brchino compounds.

Some examples of suitable diamines include ethylenediamine, 2-dimethylaminoethylamine, 2-diethylaminoethylamine, 3-diethylaminopropylamine, 3-dimethylaminopropylamine, 4-diethylaminobutylamine, 4-diethylamino-1-methylbutylamine, 3-diethylamino-1: 2-dimethylamine 3-diethylamino-2-hydroxypropylamine, 2-methylaminoethylamine, 3-butylaminopropylamine, 3 - (- diethylaminoethyloxy) propylamine, 3q-diethylaminoethylmercapto) -propylamine, 5-diethylamino-1-aminopentane, 2-pyrrolidinoethylamine, 1: 3-his- diethylamino-2-aminopropane, N-ethyl-NP-diethylaminoethyl-ethylenediamine, 2-piperidinoethylamine, 3-piperidinopropylamine, p-dimethylaminoethoxyaniline, p-diethylaminoethoxyaniline, p-diethylaminoethylmercaptoaniline, 3-diethylamino-2-methylpropyl-2-aminopropylamine methyl-N- [3-diethylaminoethyl-propylenediamine, β-piperidino-α-methylethylamine, N-methyl-N'-diethylethylenediamine, N-ethyl-N'-diethylethylenediamine and hisq-diethylaminoethyl) -amine.

The present invention also relates to a modified method in which the basic substituent - NR "- A - NEB 'is introduced stepwise. The 2-aminopyrimidine derivative bearing a reaction-derived atom or group in the 4-position is brined to react with an amino compound of the formula NFIR". - A '- B, in which A' represents either all or part of the compound group A, as defined above, and where B represents a reactive group, the sum of which is then converted according to known methods to the group NBR 'or to a group - A "- NRR in such a way that A 'and A' together form the healthy linking group A. The group B may, for example, be a lyodroxy group or a clerivat clarav, which is a reactive ester thereof, for example a halide, or a group, which can be easily transferred to such, after which it is reacted with an amine NHRR 'or an amino-substituted amine-A "-NRR' or a hydroxy- or mercapto-substituted amine HO-A" -NEW or HS-A "-NRR '(or an alkali metal derivative of such a hydroxy or mercapto compound), such that A '- NH - A' ", A '- 0 - A'" or A '- S - A "constitute the aforementioned compound group A. reaction of the aminopyrimidine compound in reaction Tried an acylated diamine NIIR "—A' — NHAc and then hydrolyzed off the asylum group. The free amino group thus obtained can be further modified e.g. by alkylation, conversion to a heterocyclic group, such as piperidino, or by bringing 4-substituted 2-amino-5: 6-dimethylpyrimidines. the same to react with a halogen-substituted amine Hal-A "-NRR 'such that A'-NH-A" forms the linking group A.

The resulting new compounds, which consist of 2-aminopyrimidines, which carry a basic substituent and possibly other substituents in the 5- and 6-positions, are completely new compounds. They are colorless or pale yellow viscous oils or colorless solid crystals, which have valuable properties as antimalarial agents and are also valuable intermediates for the preparation of other valuable agents against malaria. They are highly alkaline and form colorless salts with mineral acids and organic acids. The salts with mineral acids, such as halogenate acids, sulfuric and phosphoric acids, or with lower organic acids, such as acetic acid, lactic acid, tartaric acid and lower alkanesulfonic acids (eg methanesulfonic acid) are water soluble. The salts with higher molecular weight acids, such as ethylene-bis-2: 3-hydroxynaphthoic acid and methylene-his-salicylic acid are less soluble in water.

The present invention should be illustrated below with some exemplary embodiments, without, however, being limited thereby. All stated parts refer to parts by weight.

Example 1. 5.3 parts of 2-amino-4-chloro-5: 6-dimethyl-pyrimidine, prepared according to Berichte 1901, 34, 2817, are heated under reflux for 5 hours with 20 parts of 13-diethylaminoethylamine. The excess diamine is then distilled off under reduced pressure and the remaining oil is dissolved in dilute hydrochloric acid. The solution is made alkaline by adding caustic soda and the oil, which is separated, is extracted with ether. The ether extract is dried over sodium sulfate and the ether is distilled off and the residual oil is distilled in a high vacuum. In this way, 2-amino-4-p-diethylaminoethylamino-5: 6-dimethylpyrimidine is obtained, which is a living oil which slowly crystallizes to form yellowish-white, waxy needles with a melting point of 67-72 ° C.

When working in the same way and starting from the same chloro compound and the appropriate amount of diamine, a number of fairly analogous compounds are obtained. These are listed in the following table, which shows the diamine used and the physical properties of the final product. The melting points, which are marked with an asterisk, do not lead to the base itself but to its bis-3: 5 dinitrobenzoate.

Boiling point at Use diamine-3 mm (bath temp.) 'C. 2β-diethylaminopropylamino 180-190 3h-diethylaminobutylamine 175-180 4β-diethylamino-α-methylbutylamine.11 1 13-dimethylaminoethylamine 150-6γ-dimethylaminopropylamine 155, -46 Melting point ° C. 107-108 58-61 82--83 Softens at 90 Klarnar at 123 75-76 x. Mr 7 8 - - yn-butylaminopropylamine y-di-n-butylaminopropylamine 165-170 190 / 0.25 mm 3 91-94 194 -195 * (decomposition) 9 γ-piperidinopropylamine 170 145.5-146, γ- (N-methyl-N-O-diethylaminoethyl) -aminopropylamine 220-241-13 11 γ- (diethylaminoethoxy) -propylamine 210- 2210 * (decomposition) 12 ethylenediamine sublimes at 150-160 160.5-161, 13 g-diethylaminoethylmethylamine 170-180 154-156 * Example 14.

If you work as described in ex. 1 but using as starting material 2-amino-4-chloro-5-phenoxypyrimidine and fl-diethylaminoethylamine, 2-amino-4-g-diethylaminoethylamino-5-phenoxypyrimidine is obtained in the form of colorless discs or flakes with a melting point of 114-1 ° C.

Example 15.

In the same way, from the same chloropyrimidine and γ-diethylaminopropylamine, 2-amino4-γ-diethylaminopropylamino-5-phenoxypyrimidine is obtained, which forms fine, colorless Maar with a melting point of 130 ° C.

The chloropyrimidine starting material used in the latter two examples was obtained by refluxing phosphorus oxychloride with 2-amino-4-hydroxy-5-phenoxypyrimidine. The latter compound is itself produced by the reaction of guanidine hydrochloride with sodium formylphenoxyacetate ester (see Johnson and Guest, American Chemical Journal, Volume 42, p. 285) in the presence of sodium ethoxide. The chlorine compound has a melting point of 157.5 ° C. The hydroxy intermediate product has a melting point of 255-256 ° C.

Example 16.

Work in the manner described in Example 1 —but starting from 5.7 parts of 2-amino4-chloroethyl-6-methylpyrimidine (prepared according to Berichte 1903, 36, 1918) and 25 parts of b-diethylamino-methylbutylamine, 2-amino- 4- (6-Diethylamino-methylbutylamino) -5-ethyl-6-methylpyrimidine. This is a colorless, viscous oil, which slowly Over & into solid form and forms a white, waxy solid with a melting point of 91-93 ° C.

Example 17. 51 parts of 2-amino4-chloro-5-ethyl-6-methylpyrimidine, 52 parts of p-diethylaminoethylamine and 52 parts of glacial acetic acid are heated together at 100 ° C for 3 hours and then under reflux for a further 1/4 hour. The solution is then cooled and diluted to 5 times its volume with water and a small amount of 2-amino-4, hydroxy-5-ethyl-6-methylpyrimidine, which precipitates and is filtered off. The filtrate was added with a slight excess of 34% sodium hydroxide solution and the oil which precipitated was separated. The aqueous layer is extracted with benzene and the benzene extract is added to the oil. This solution is then dried over solid sodium hydroxide, the benzene is evaporated and the residue is distilled in vacuo. The part boiling at 210 ° C and 6 mm is collected and crystallized from ligroin (boiling point 60-80 ° C). There is thus 2-amino-4-13-diethylaminoethylamino-5-ethyl-6-methylpyrimidine in the form of colorless needles, m.p. 86 ° C.

Example 18.

If, instead of 2-amino-4-chloro-5-ethyl-6-1-methylpyrimidine, 43 parts of 2-amino-4-chloro-6-methylpyrimidine are used (cf. Berichte 1899, volume-; 32, p. 2924), 2-amino-4-fl-diethylaminoethylamino-6-methylpyrimidine, m.p. 70 DEG-72 DEG C. This substance forms a dipicrate, m.p. 216 DEG-218 DEG.

Example 19.

A mixture of 5 parts of 4-chloro-2-amino-6-1-methylpyrimidine and 25 parts of O-diethylamino-α-methylbutylamine is boiled under reflux for 4 hours. The excess diamine is then distilled off under reduced pressure at 170 ° C and the residue is dissolved. The solution is made alkaline by adding solid caustic soda and the viscous oil which separates is extracted with ether The ether solution is dried over anhydrous sodium sulphate and the ether is distilled off The remaining oil is purified by repeated distillation at a pressure of -1 mm. immersed in a metal bath at 170 ° C. 2-amino-4-6-diethylamino-methylbutylamino-6-methylpyrimidine is thus obtained in the form of a yellow, viscous oil.

Example 20.

Work in a similar manner but starting from 25 parts of fl-diethylaminoethylamine () or 5.5 parts of 2-amino-4-chloro-5-benzyl-6-methylpyrimidine and 2-amino-4-g-diethylaminoethylamino-5-benzyl- 6- / // 7 methylpyrimidine, which after distillation under reduced pressure is further purified by recrystallization from 90% ethanol and then has a melting point of 123.5-125 ° C. 2-amino-4-chloro-5-benzyl-6- -methylpyrimidine (m.p. 182.5-183.5 ° C) The gene is prepared to reflux 2-amino-4-hydroxy-5-benzyl-6-methylpyrimidine with phosphorus pentachloride. This latter compound itself has been prepared by the reaction of guanidine hydrochloride with ethyl α-benzylacetoacetate in the presence of sodium ethoxide. It has a melting point of 273-275 ° C. Example 21.

A mixture of 4.2 parts of 2-amino-1-chloroethyl in benzyl-6-methylpyrimidine and 21 parts of 3-diethylaminopropylamine is boiled under reflux for 7 hours and the excess diamine is then removed by distillation under reduced pressure. The solid residue is dissolved in dilute hydrochloric acid and solid caustic soda is added, after which 2-amino-4-γ-diethylaminopropylamino-5-benzyl-6-methylpyrimidine precipitates as a colorless solid, which is filtered off, washed with water and recrystallized from aqueous ethanol. It then has a melting point of 126.5 ° C.

Example 22.

If one works on a similar salt but uses 4 parts of 2-amino-4-chloro-5-benzyl-6-methylpyrimidine and 20 parts of 6-diethylamino-α-methylbutylamine, 2-amino-1-6-diethylamino-α-methylbutylamino-5 -benzyl-6-methylpyrimidine, which is a highly viscous oil, purified by distillation at 2 x 3 mm pressure from a bath at 195-200 ° C.

Working on a similar salt with suitable diamines and 2-amino-4-chloro-5: 6-tetramethylene-pyrimidine, the following compounds are obtained, namely: Example 23. 2-amino-4-f-diethylaminoethylamino-5: 6-tetra -methylenepyrimidine, m.p. 117-118 ° C.

Example 24. --- 2-amino-4-γ-diethylaminopropylamino-5: 6-tetramethylenepyrimidine, m.p. 87-90 ° C and Example 25.

V 2-amino--4-6-diethylamino-α-methylbutylamino5: 6-tetramethylenepyrimidine, m.p. 112.5-133 ° C.

The chloropyrimidine required or required as a starting material in the preparation of the latter three compounds is prepared from 2-amino-4-hydroxy-5: 6-tetramethylene-pyrimidine (cf. Quaterly Journal of the Indian Chemical Society 1927, Volume 4, p. 157). by the action of phosphorus oxychloride. It forms colorless needles with a melting point of 206-207 ° C.

In a similar way, it is obtained by the appropriate slides. the mines and 2-amino-4-chloro-5: 6-trimethylenepyrimidine The following compounds, namely: Example 26. 2-amino-4-19-diethylaminoethylamino-5: 6-trim ethylenepyrimidine, m.p. 83-84 ° C.

Example 27. 2-Amino-4-γ-diethylaminopropylamino -5: 6-trimethylenepyrimidine, m.p. 84.5-85.5 ° C, and Example 28. 2-amino-4-γ-diethylamino-α-methylbutylamino5: 6- trimethylene pyrimidine, m.p. 118119 ° C.

The chloropyrimidine required as a starting material in this example is prepared as follows. 2-Amino-4-hydroxy-5: 6-trimethylenepyrimidine is prepared from 76.4 parts of guanidine hydrochloride, 18.4 parts of sodium, 345 parts of ethanol and 125 parts of ethylcyclopentanone-2-carboxylate in a manner analogous to that described. above for the preparation of 2-amino-4-hydroxy-5-benzyl-6-methylpyrimidine. It crystallizes from hot water in prisms which do not melt below 300 ° C. This compound is then transferred to the chlorofinene by treatment with phosphorus oxychloride on an analogous salt, which is described in connection with 2-amino-4-chloro-5: 6-tetramethylenepyrimidine .

Example 29. 4.5 parts of 2-amino-4-p-aminoethylamino -5: 6-dimethylpyrimidine, prepared according to Example 12, and; 1.8 parts of n-butylaldehyde are dissolved in 100 parts of absolute sic in alcohol and shaken with Irate at atmospheric pressure in the presence of a palladium-barium sulphate catalyst (prepared according to Berichte 1919, volume 52, p. 409). The theoretical volume of vate is slowly absorbed. The catalyst is then filtered off and the alcohol is distilled off from the filter. The residue is distilled in vacuo to give 2-amino-443-n-butylaminoethylamino-5: 6-dimethylpyrimidine as a pale yellow, viscous oil, b.p. 160 DEG-170 DEG C. (4.5 x - mm).

Example 30. Parts of 2-amino-4-chloro-5-bromo-6-methylpyrimidine and 11.7 parts of γ-diethylaminopropylamine are heated under reflux for 6 hours. The reaction mixture is then cooled and the solid thus obtained is dissolved in dilute hydrochloric acid. The base is then precipitated by the addition of caustic soda and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and the ether and excess diamine are distilled off under reduced pressure. The residue is distilled in a high vacuum to give 2-amino-4-γ-diethylaminopropylamino-5-bromo-6-methylpyrimidine as a glazed, viscous oil at a boiling point of 220-2 ° C (2 x -1 mm), which precipitates itself as a solid when it has first words and after crystallization from ligroin has a melting point of 108.5 ° C.

Example 31. 2.23 parts of 2-amino-1-chloro-5-bromo-6-methylpyrimidine, 1.16 parts of β-diethylaminoethylamine and 20 parts of β-ethoxyethanol are heated together under reflux for 5 hours. The mixture was then cooled and water and a small amount of dilute hydrochloric acid were added to obtain a clear solution. The base is then precipitated by adding caustic soda (the temperature is kept below ° C) and extracted with ether. The ether solution is dried over anhydrous sodium sulfate, the ether is distilled off and the residue is distilled in vacuo. 2-Amino-4-p-diethylamino ethylamino-5-bromo-6-methylpyrimidine is obtained on such a salt as a pale yellow oil, which distills from a bath at 200 ° C and a pressure of -2 mm.

The chloropyrimidine used as starting material in these two examples is prepared by reacting phosphorus oxychloride with 2-amino-4-hydroxy-5-bromo-6-methylpyrimidine, which later equation is prepared as described by Jaeger, Annalen 1891. , volume 262, p. 366.

Example 32. 3.5 parts of 2-amino-4-chloro-5-methylpyrimidine and 11.4 parts of diethylaminoethylamine are heated under reflux for a further 6 hours. Excess diamine is then distilled off under reduced pressure and the residue is dissolved in dilute hydrochloric acid. The base is then precipitated by the addition of caustic soda and extracted with ether. The ether solution is dried over anhydrous sodium sulfate and the ether is distilled off. The residue is distilled at a pressure of 3 x -4 mm from the bath at 170 [deg.] C. 2-amino-4-8-diethylaminoethylamino-5-methylpyrimidine is thus obtained as a pale yellow oil. It forms a dipicrate, which crystallizes from ethanol in yellow crystals, m.p. 195-196 ° C.

Example 33.

In a similar manner, 4 parts of the same chloropyrimidine and 14.5 parts of γ-diethylaminopropylamine 2-amino-4-γ-diethylaminopropylamino-5-methylpyrimidine are obtained in the form of an oil which clests at a pressure of 4> <10 mm bath at 180200 ° C. DS all the time at some point during ligroin the oil crystallizes and upon recrystallization from ligroin a substance with a melting point of 70-71 ° C is obtained. The 2-amino-4-chloro-5-methylpyrimidine used as starting material in both of the latter examples are trams-Mild by reacting phosphorus oxychloride with 2-amino-4-hydroxy-5-methylpyrimidine. The hydroxy compound is itself prepared by the reaction of guanidine hydrochloride with sodium α-formylpropionate ester (the content of ethyl formate, ethyl propionate and sodium).

Claims (5)

Patent claim: A process for the preparation of pyrimidine derivatives of the formula II NH, - CC - Y IIII N - C - NR "- A - NRR 'In which X represents vale or a carbon radical, Y vdte or a neutral substituent or X and Y together may form a single alkylene chain, denotes vate or an alkyl- or monosubstituted alkyl group, A Sr is a linking group, such as Sr aliphatic or alicyclic or aliphatic-carbocyclic, wherein if A or part of A Sr or nitrogen atoms, and NRR 'for a strongly basic amino group or substituted amino group, such as alkylamino- or dialkylamino- or piperidino- or other strongly basic, nitrogen-containing heterocyclic group, can denote that a parable of the formula NC - X NH, - CCYN - C - Z are reacted with a diamine of the formula NHR "- A - NRR ', the various symbols in this latter formula having the same meaning as indicated above and Z representing a reaction bend gene. atom or group, such as a halogen. atom. 2. A process according to claim 1, characterized in that the reaction-prone group in the 4-position of the pyrimidine ring consists of a chlorine or bromine atom. 3. According to patent claim 1, it is claimed that a methyl group is present as a substituent in the 6-s -tanning of the pyrimidine ring. 4. A kit according to claim 1, characterized in that methyl groups are present as substituents in both 5- and 6-membered flakes of the pyrimidine ring. Modification of the process set forth in claim 1, characterized in that the basic group in the 4-position of the pyrimidine ring is introduced stepwise, the 2-aminopyrimidine derivative bearing a reactive atom or group being reacted with an amino compound of the formula NUR "- A '- B, wherein A' represents either all or part of the predefined compound group A and B denotes a reactive group, which is then converted to the amino group NRR 'or to a group A "—NRR' according to methods known per se. sfl that A 'and A "together form the connection group A. Stockholm 1948. Nungl. Boktr. PA Norstedt 6 .; Sillier 480089