DEW0010930MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: March 31, 1953 Announced on December 1, 1955

GERMAN PATENT OFFICE

PATENT APPLICATION

CLASS 12p GROUP 7oi W 10930 IVb / 12 p

George H. Hitchings and Elviro A. Falco, Tuckahoe, N. Y. (V. St. A.)

have been named as inventors

The Wellvome Foundation Limited, London

Representative: Dr. M. Eule, patent attorney, Munich 13

proceedings
for the preparation of 2.4 ^J diamino-5-benzylpyrimidine derivatives

The present invention relates to a method for the preparation of 2,4-diamino-5-benzylpyrimidine derivatives.

It has been found that 2,4-diamino-5-benzylpyrimidines of the general formula (I)

NH,

H ₂ N

V- CH, - <

N "

R ¹

R ⁴

, R ²

in which R ^{1 is} a methoxy or ethoxy group, R ^{2 is} an ethoxy group or a chlorine or bromine atom and R ³ and R * are hydrogen or a methoxy or ethoxy group, a chlorine or bromine atom, have exceptionally high antibacterial properties, which they for Make surface treatment of wounds particularly suitable. They maintain their effectiveness even in the presence of body fluids and are therefore also of value for the treatment of general infections.

These substances can be prepared from a suitable hydrocinnamic acid ester (II) (in which R is a low molecular weight alkyl group), which is formylated (III) and with guanidine to the

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speaking.; - Ammo ~. | -oxypyrimidindenYat (IV) condensed will. The subsequent conversion into the Dianiiiioverbindimg can by chlorination and Animating can be effected or by exchanging the OH group for a Mcrcapto group and then Amination according to the in British patents 671926 and 671927 and in the USA, -Pat procedure described in writing 2415793.

COJ

CIL

CII ..

κ ·!

(II)

K ¹

HCOOKt

CO ₂ K

CH -CHO

CH.

R ¹

W-

(III)

OH

[(H ₂ N) ₂ C = NH]

CH,

(IV)

R ¹

+ X ^R1

13 4

^1V

The compounds according to the invention can also be prepared by appropriately substituted Glycinnamic acid nitrile derivatives formylated and the resulting oxymethylene hydrozinite nitrile compounds converted into alkoxymethylene derivatives (enol ethers), which then, reacted with guanidine, the 2,4-D1-amino-5-benzylpyrimidine derivativesc directly give ci ". This synthesis takes the following Course:

CHOH CHO

R ⁵ CHoCII., CN I HCOOCIL i ^> R ⁵ CILC-N or (R ⁵ CHoCHCN)

[CHoNo or HC (OC ₂ Hj) ₃ ]

N
HoN _χ

NIL, υ r ο ru

..- ClUV < ^[ t ^H ' ^N > » ^C - ™ L R ⁵ CHo-LcN or

wherein CIIoK '' 'is the substituted 5-benzyl group of Formula (I) is.

The one which comes close to the pyrimidine derivatives obtainable in terms of its constitution in terms of its constitution 2,. | -Diamino-5- (3 ', 4'-diinetlx> xybcnzyl) -pyrimidine has already been mentioned in the literature and was named after the those in the phenyl radical of the benzyl group Siibstitueiiten may contain, known working method produced, which consists in that guanidine with a corresponding «-Formylhydrocinnaschäureester condensed and in the obtained a-Ainin () -.-) - () xy-5-ben /, yI]) yriinidine derivatives the / | st; 'indigenous Oxyginj) |> e transferred to the aminogruj) pe.

The value and importance of according to the invention Compounds produced lies in the fact that they are within the scope of their aforementioned antibacterial ·]] properties towards the organism Proteus vulgaiis are active against which none of the previously common antibacterial agents

R ⁵ CH ₂ '

, OCH, - /

'CN

z. B. the sulfonamides, are active. This organism often occurs in urinary infections and is currently very difficult to control. It was determined, that the aforementioned known compound 2, 4-diamino-5- (3 ', 4'-dimethoxybenzyl) - pyrimidine probably also has such an activity that it does, however, when dosed to the patient by the oral route which result in an adequate concentration of the substance in the urine, too intolerable Side effects of general ailment, vomiting and muscle uncoordination, which leads to make them unusable for such therapeutic purposes. The obtainable according to the invention Compounds, especially the compound 2, 4-diamino-5- (3'-ethoxy-4'-metlioxybcnzyl) -pyrimidine and the compound 2, 4-diamino- (3 ', 4'-dimethoxy-5'-bromobenzyl) -pyrimidine have such side effects in such a therapeutic application only to a much lesser extent, which is entirely acceptable, and is in contrast to the

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mentioned known compound clinically usable and thus very much superior to this.

The present invention is intended to be explained in greater detail by the following examples will.

Example ι

2,4-diamino-5- (3 ', 4'-dimethoxy-5'-bromobenzyl) pyrimidine

ίο A. Manufacture of ethyl 3,4-dimethoxy-5-bromocinnamate. Aus3,4-dimethoxy-5-bromocinnamic acid (i62g) (FB Wittmer and LC Racford, Journal of Organic Chemistry, Vol. Ίο, p 527 [ΐ945]) was obtained by 15 hours' heating with 1.5 1 of ethanol and 3 cm ³ Sulfuric acid produced under reflux of the ethyl ester. The ester was worked up in the normal manner by extracting from an alkaline solution into ether. The yield was 150 g of crude ester.

B. Preparation of ethyl (3,4-dimethoxy-5-bromophenyl) propionate. The above ester was reduced using Raney nickel catalyst in ethanol alsLösungsmittelmit WasserstoffbeiZimmertemperatur, wherein a ratio of about 40 g of the compound in 150 cm ³ of ethanol and 10 g of catalyst was used. After the catalyst had been separated off and the solvent had evaporated in vacuo, the reduced ester was distilled in vacuo: b.p. ₁₀ = 205 to 210 °.

C. Preparation of 2-amino-4-oxy-5- (3 ', 4'-dimethoxy-5'-bromobenzyl) pyrimidine. ^{A mixture of 150 g of the ester described in Section B above and 150 cm 8 of} ethyl formate was added to 30 g of sodium wire in ether dried over sodium (in a round bottom flask equipped with a reflux condenser). This mixture was allowed to stand for about 48 hours (the sodium lumps were occasionally broken) after which time most of the sodium metal had disappeared. A guanidine solution (prepared from 62.5 g of guanidine hydrochloride in about 300 cm ^{3 of} ethanol and 15 g of sodium, dissolved in about 300 cm ^{3 of} ethanol) was filtered into this mixture. The ether was allowed to evaporate on the steam bath and the remaining ethanol mixture was refluxed for 16 hours with occasional stirring (to remove the sticky precipitate from the bottom of the flask). The mixture was then poured into 3 liters of water and neutralized with glacial acetic acid. At this stage, it was advantageous to adjust the _pH value with ammonium hydroxide to about Pp ₁ 8. The mixture was allowed to stand for about 12 hours, with occasional rubbing with a glass rod. The precipitate was filtered off, washed first with water and then several times with ether. The purified compound melted at 238-240 ⁰ after recrystallization from a large volume of ethanol.

D. Chlorination of 2-amino-4-oxy-5- (3 ', 4'-dimethoxy-5'-bromobenzyl) pyrimidine. 55 g of the dry, crude pyrimidine derivative described under C were added to a mixture of 300 cm ^{3 of phosphoryl chloride and 10 g of phosphorus pentachloride.} This mixture was ^{heated at the reflux condenser for x} / ₂ hours, whereupon it became clear (a total of about ι hour). The excess phosphoryl chloride was removed in vacuo and the syrupy residue was poured onto 1 kg of crushed ice with constant stirring (to avoid local heating). The mixture was then immediately made alkaline with concentrated ammonium hydroxide (p _H 9), wherein the reaction was kept cold by addition of more ice. The mixture was allowed to stand for keeping with occasional adding Ämmoniurnhydroxyd to the _pH value at about 9 several hours. The mixture was then filtered, sucked dry and the still moist substance was dried in a desiccator.

E. Preparation of 2,4-diamino-5- (3 ', 4'-dimethoxy-5-bromobenzyl) pyrimidine. The crude chlorine compound was placed in a bomb with about 500 cm ^{3 of} ammonia in ethanol (saturated at ⁰ °) and heated at 155 ° for 16 hours. The contents of the bomb were evaporated on a steam bath to dryness, and the residue was dissolved in a hot solution of 30 cm ⁸ glacial acetic acid and 500 cm was added ³ of water, filtered, cooled and 4o ° / ₀ sodium sodium hydroxide to a _pH value of 9 to 10 set. This procedure was repeated with the acetate-insoluble contents; the two alkaline precipitates were combined and (g 22 per 600 cm ³⁾ with the addition of carbon from 95 ° / _o sodium recrystallized ethanol. The compound was a white, crystalline solid which melted at 201-202 °.

Example 2

2,4-diamino-5- (2'-methoxy-5'-chlorobenzyl) pyrimidine

A. 2-Amino-4-oxy-5- (2'-methoxy-5'-chlorobenzyl) pyrimidine. The raw sodium formyl compound of the ester prepared from 26 g of ethyl 2-methoxy-5-chlorohydrocinnamate, 9 g of ethyl formate and 2.45 g of sodium in dry ether according to the method described in Example 1C was treated with a guanidine solution (obtained from 10 g of guanidine hydrochloride and 2.4 g of sodium in ethanol) condensed to the 2-amino-4-oxy-pyrimidine derivative, which melted ^{at 278 to 284 0.}

B. from 6 g of the thus obtained 2-amino-4-oxypyrimidinderivats was obtained after treatment with phosphoryl chloride and phosphorus pentachloride, and then (as described in Examples D and ι ι Ε) with ammonia in alcohol at 155 ⁰ the white crystalline 2,4 -Diamino-5- (2'-methoxy-5'-chlorobenzyl) -pyrimidine, which melted ^{at 169 to 171 0 after recrystallization from ethanol.}

Example 3

2,4-diamino-5- (3'-ethoxy-4'-methoxybenzyl) -

pyrimidine. _iao

A. 2-Amino-4-oxy-5- (3'-ethoxy-4'-methoxybenzyl) pyrimidine. A solution of ethyl 3-ethoxy-4-methoxyhydrocinnamate in ether (90 g) was obtained by adding 90 g of ethyl formate in the presence of 8.5 g of sodium wire according to that in Example 1C procedures described. The raw sodium

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Foniiyl compound was condensed with a guanidine solution (obtained from 35 g of guanidine hydrochloride and 8.5 g of sodium in ethanol) to give the corresponding 2-alino-4-oxypyrmiidine derivative.
I '. From 10 g of the rolling 2-amino-4-oxypyriinidinderivals described above (according to the method given in Examples 1) and IC), 2 _> 4-Diamiiio-5- (3'-ethoxy-4'-iiiethoxybeiizyl) was obtained ) -pyrirnidine, which melted after recrystallization from ethanol at 197 to KjS '.

Example 4

_Ir pyrimidine - 2,4-diamino-5- (3'-ätlioxy-4'-methoxy-5'-l> rombenzyl)

A.2-An] ino-4-oxy-5- (3'-ethoxy-4'-methoxy-5'-l) roml) enzyl) -pyi'iiiii (lin. This compound was prepared from 105 g of 3-ethoxy-4-ini'th () xy-5-bromohydroziintic acid ethyl ester, 30 g of ethyl formate and 7.2 g

ao natrinmdralit in ether, with subsequent treatment with a guanidine solution (from 30 g of guanidine hydrochloride and 7.2 g of sodium in ethanol) according to the guidelines given in Example 1C.

B. The 2,4-1) amino compound was obtained according to the method given in examples il) and lE using 20 g of the crude 2-amino-4-oxypvriinidine derivative. After chlorination and amination, the product was recrystallized from ethanol to give colorless flakes with a melting point from 193 to 203 '.

lie is pi el 5

2,4-Diaiiiino-5- (3'-Etlioxy-4'-methoxy-5'-broin-.τ-chlorobenzyl) -pyrimidine

A. 2-Amino-. | -Oxy-5- (3'-ethoxy-4 'methoxy-5' bromo-A'-chlorobenzyl) -pyrimidine. This connection was established according to that described in Example iC Process by formylating 50 g of 3-Ä (hoxy-4-niethoxy-5-broin-.v-chlorohydrocinnamate with 15 g of ethyl formate in the presence of 4.1 g of sodium wire in ether, followed by Condensation with guanidine solution (from 13.2 g guanidine hydrochloride and 4.1 g of sodium in ethanol).

B. The crude 2-amino-4-oxypyrimidiiiderivat (10 g) was with 6ocnr 'l'hosphoryl chloride and 2 g of phosphorus pentachloride Heated for 1 hour and the crude chlorinated product thus obtained was at 155 ° aminated with ammonia in alcohol (according to

The procedure given in Example 1 IC). ICs were crystallized once from ethanol and then treated with alcoholic hydrochloric acid to give the 2,4-diamino-5 - (; j'-eth () xy-4'-iiiethoxy-5'-bromo-.v-chlorobenzyl) -pyrimidine hydrochloride result, which decomposed ^{at 240 0.}

Example G

2,4-diamino-5- (3 ', 4'-dimethoxy-5'-clilobenzyl) pyrimidine

A. 2 - Amino - 4 - oxy - 5 - (3 ', 4' - dimethoxy - 5 '- chlorobenzyl) pyrimidine. This compound was obtained by formylating ethyl 3,4-dimethoxy-5-chlorobenzylhydrocinnamate (81 g) with 81 g of ethyl formate in the presence of 6.9 g of sodium in 500 cm ^{3 of} dry ether. The sodium formylhydrocinnamate was treated with guanidine solution (from 30 g of guanidine hydrochloride and 6.9 g of sodium in 500 cm ^{3 of} ethanol) as in Example ι C to give the crude 2-amino-4-oxy compound.

B. From 20 g of the above compound were obtained by ChlorierungmitPhosphorylchlorid and phosphorus pentachloride followed by treatment with ammonia in alcohol at 155 ⁰ (as described in Examples D and ι ι e) the 2,4-diamino-5- (3 ', 4 '-dimethoxy-5'-chlorbenzy]) - pj'rimidine, which melted ^{at 188 to 189 0 after recrystallization from methanol.}

Claims (1)

PATENT CLAIM: Process for the preparation of 2,4-diamino-5-benzylpyrimidine derivatives the general formula NH ₂ HoN- / v-CH, - N " in which R ^{1 is} a methoxy or ethoxy group, R ^{2 is} an ethoxy group or a chlorine or bromine atom and R ³ and R ^{1 are} hydrogen or a methoxy or ethoxy group, a chlorine or bromine atom, characterized in that guanidine is substituted with an appropriately tt-formylhydrocinnamic acid ester or a «-alkoxymethylene hydrocinnamic acid nitrile is reacted and that in the former case the 2-amino-4-oxypyrimidine derivative formed in this way is converted in a manner known per se into the 2,4-diaminopyrimine compound. Referred publications:
German Patent No. 864556;
Journal of the American Chemical Society, 73, 3758-3762 (1951). © 509 597/55 11.55