WO1997021711A1

WO1997021711A1 - Process for preparing 4-aminopteridine derivatives

Info

Publication number: WO1997021711A1
Application number: PCT/EP1996/005541
Authority: WO
Inventors: Martin Eyer; Wolfgang Pfleiderer; Shahriyar Taghavi-Moghadam
Original assignee: Lonza Ag
Priority date: 1995-12-12
Filing date: 1996-12-11
Publication date: 1997-06-19
Also published as: AU1370497A

Abstract

A new process is disclosed for preparing 4-aminopteridine derivatives having the general formula (I), in which R1 stands for a hydrogen atom, a C¿1?-C4 alkyl group, a substituted or non-substituted aryl group, -NH2, -SR?3, -OR3, -NHR3¿ or -N(R3)2, wherein R3 stands for a C¿1?-C4 alkyl group, and R?2¿ stands for a C¿1?-C4 alkyl group, a substituted or non-substituted aryl group, a substituted or non-substituted heteroaryl group, or -CH2X, wherein X stands for a halogen atom. The process is carried out by reacting a 4,5,6-triaminopyrimidine having the general formula (II), in which R?1¿ has the above-mentioned meaning, or its salt, with a compound having the general formula (III), in which R2 has the above-mentioned meaning, until the end product having the formula (I) is obtained.

Description

Process for the preparation of 4-aminopteridine derivatives

The invention relates to a new process for the preparation of 4-amino-dendiates of the general formula

wherein Rl is a hydrogen atom, a C _j -C4 alkyl group, an aryl group, substituted or unsubstituted, -NH2, -SR ³ , -OR ³ , -NHR ³ or -N (R ³ ) 2, wherein R ^{3 is} a Cι -C4 Is an alkyl group, and R ^ is a C 1 -C 4 alkyl group, an aryl group, substituted or unsubstituted. a heteroaryl group, substituted or unsubstituted, or -CH2X. wherein X is a halogen atom, starting from emem 4,5,6-Tπamιnopyπmιdιn the general formula

where R has the meaning given

4-Aminopteπdιndendvvates are important intermediates for the synthesis of Ptendendvvates such as for the production of folic acid, its antagonist aminoptenen and the cytostatic methotrexate (DE-OS 27 41 383)

Several methods are known for the preparation of 4-amino-dendavates

The CH-PS 630 380 describes a process for the preparation of 2,4-dimin-6-bromomethylpteπdin by direct bromination of 2,4-dimin-6-methylpteπdιn. On the one hand, the product is obtained only in moderate yield. On the other hand, the product has Impurities.

Piper J.R. & Montgomery J.A. (J. Heterocyclic Chem., 1974, 1 1, pp. 279-280) describe a process for the preparation of 2,4-diamondo-6-bromomethylpentine starting from 2,4-

Dιamιno-6-hydroxymethylpteπdιn Here, the 2,4-Dιamιno-6-hydroxymethylptendιn with Tπphenylphosphine dibromide brominated This method also has the disadvantage that the product is only obtained in moderate yield. Another disadvantage is that the bromination reagent has to be used in a 4-fold stochiometric excess

GB-1 414 752 describes a process for the preparation of 2,4-diamino-6-chloromethylptin in which the educt 2,4-diamino-6-hydroxymethylpteridine is chlorinated using thionyl chloride. A disadvantage of this process is that the preparation of the starting material is complicated or is associated with the formation of troublesome, difficult-to-separate by-products (P.H Boyle, W. Pfleiderer, Chem Ber., 1980, 1 13, pp. 1514 ff.).

Shey CF. et al., (Shi Ta Hsueh Pao (Taipei), 1984, 29, S 631 ff, Chem. Abstract 101 - 230476)) describe a 3-step synthesis for the preparation of 2,4-dimin-6-chloro-methylpteπdm. In the first stage, aminomalodinitπltosylate is condensed with chloropyruvalodoxime to the corresponding pyrazine N-oxide, which is then reduced in the second stage to the corresponding pyrazine, which is then converted into the product in the third stage. A major disadvantage of this process is that the product is only obtained in low yield

Yamamoto H et al., (Chem. Ber. 1973, 106, pp. 3175-3193) describe the preparation of 2,4-dimontno-6-phenylpteπdιn starting from the educt 2,4,6-tπacetamιdo-5-nitrosopyπmidin . The starting material is reacted with phenylacetaldehyde. A disadvantage of this process is that the starting material is not accessible in pure form

The object of the present invention was both to provide a more economical process for the preparation of 4-aminopteπdιndendvvates and to provide an economical access to the production of peptides such as, for example, folic acid with this process

This object is achieved with the inventive method according to claims 1 and 6

According to the invention, the process for the preparation of 4-aminopeptide dendvates is carried out in such a way that a 4,5,6-thernaturinopylene of the general formula is used

wherein Rl has the meaning given or its salt with a compound of the general formula

where R ^ has the meaning given in the end product of the formula

where R 1 and R ^ have the meaning given, transferred.

The 4,5,6-triaminopyπmidιne used as starting materials can be prepared in a known manner. For example, 2,4,5,6-tetraaminopyπmιdin of formula II (Rι = NH2) from 2,4,6-Tπamιno-5-nιtroso-pyrmιdιn by hydrogenation with hydrogen / Raney nickel in water and after the catalyst separation z. B. used as salt (Boyle P.H. & Pfleiderer W, Chem. Ber., 1980, 1 13, p. 1514ff).

The hydrochloride or hydrobromide salts are expediently used as the salts of the 4,5,6-amino-pyrimide of the general formula II

The substituent R ^ is a hydrogen atom, a -C4-alkyl group, an aryl group, substituted or unsubstituted, -NH2, -SR ³ , -OR ³ , -NHR ³ or -N (R ³ ) 2- wherein R ^{3 is} a C ] - C4 alkyl group. The substituent R ^ represents a Cj-C4-alkyl group, an aryl group, substituted or unsubstituted, a heteroaryl group, substituted or unsubstituted. or - CH2X, where X is a halogen atom

A halogen atom can mean fluorine, chlorine, bromine or iodine, preferably chlorine or bromine. An unsubstituted aryl group can be phenyl or naphthyl, preferably phenyl. A substituted phenyl group can be tolyl, halophenyl such as fluorine, chlorine, bromine, 3,5-difluorophenyl or C _| -C ₄ -alkoxyphenyl such as methoxy, ethoxy, propoxy or butoxyphenyl mean. Chloφhenyi, methoxyphenyl or tolyl is preferably used as the substituted phenyl group. An unsubstituted heteroaryl group can be pyridinyl, pyπdazinyl, a substituted heteroaryl group can be methylpyπdinyl. A C, -C ₄ -alkyl group can be methyl, ethyl, propyl, i-propyl, butyl, i-butyl or t-butyl, preferably Methyl or ethyl, mean The meaning of -SR ³ can be -SCH ₃ , -SC ₂ H ₅ , -SC ₃ H ₉ , -SC ₄ H, ₃ , preferably

-SCH ₃ ; of -OR ³ , -OCH ₃ , -OC ₂ H ₅ , -OC ₃ H ₉ , -OC ₄ H ₁₃ , preferably -OCH ₃ , of -NHR ³ , -NHCH ₃ , -NHC ₂ H ₅ ; of -N (R ³ ) ₂ , -N (CH ₃ ) ₂ , -N (C ₂ H ₅ ) ₂ , -N (C ₃ H ₇ ) ₂ , -N (C ₄ H,) ₂ , preferably -N (CH ₃ ) ₂ .

The reaction is expediently carried out in an inert solvent. Polar protic or polar aprotic solvents can be used as inert solvents. Water or C 1 -C ₄ alcohols can be used as the polar protic solvent. Methanol, ethanol, propanol or butanol, in particular methanol, is expediently used as the C ₄ -C ₄ alcohol. Dimethylformamide or dimethylacetamide can be used as the polar aprotic solvent The suitable solvents can be used individually or as a mixture

The reaction is expediently carried out at a temperature from 0 ° C. to the reflux temperature of the corresponding solvent, preferably at 20 to 70 ° C.

The 4-aminopteπdιndeπvate can be isolated by workup methods customary in the art and then either in a manner known per se

- In a 6-halomethyl-4H (1H) -pteπdιnon of the general formula

wherein R, has the meaning given and R ² denotes -CH ₂ X, where X is a halogen atom, hydrolyzed (for example according to J. Heterocyclic Chem., 1987, pp. 279ff) and / or by reaction with a compound of the general formula

wherein R ^{4 is} a glutamic acid residue and R ^{5 is} C, -C ₄ alkyl or em hydrogen atom m is a pentene dvate of the general formula

where R 'has the meaning given and Y is oxygen or NH, such as, for example, folic acid (R ¹ = NH ₂ , Y = oxygen, R "= glutamic acid residue, R ⁵ = hydrogen)

be convicted

The 2-amino-6- (bromomethyl) -4H (lH) -pteπdionon, (formula V, R, - NH-, R ₂ = -CH ₂ Br) can, for example, according to Piper et al, (J Heterocyclic Chem, 1987, 24, pp. 279ff) are produced and used for the alkylation of p-aminobenzoyl-L-glutamic acid to folic acid

Folic acid can be obtained by reacting 2,4-dimin-6-bromomethylpteπdιn (formula I, R, = NH ₂ , R ₂ = -CH ₂ Br) with p-aminobenzoyl-L-glutamic acid analogously to the method of Piper JR & Montgomery J A . (J Heterocyclic Chem, 1974, 11, pp 279-280) can be converted into aminopterin, which can then be hydrolyzed to folic acid, for example according to Seeger DR et al. (J Am Chem Soc, 1949, 71, pp 1753-1759) example 1

Production of tetraaminopyrimidine dihydrobromide

51.35 g 2,4,6-triamino-5-nitrosopyrimidine (0.33 mol) and 2 g palladium catalyst (e.g. 5% Pd / C, 50% water) were in a 1 l steel autoclave with a paddle stirrer 350 ml of water suspended and stirred at 60 ° C in 6-7 bar hydrogen until saturation was reached after 2.5 to 3 hours. After cooling and releasing the pressure, 111 g of hydrobromic acid (48% HBr) were added under protective gas and the catalyst was separated off by filtration. The yellow-orange colored, clear filtrate was evaporated to dryness on a rotary evaporator in a water jet vacuum. 98 to 99 g of tetraaminopyrimidine dihydrobromide were obtained as a slightly yellow-colored evaporation residue (content 99.0-99.5%, yield 98-99%).

Example 2

Preparation of 2,4-diamino-6-bromomethyl pteridine

1.00 g (3.31 mM) 2,4,5,6-tetraaminopyrimidine dihydrobrornide was suspended in 20 ml methanol and heated to boiling. A solution of 0.83 g (4.97 mM) of bromopyruvaldoxime in 10 ml was added dropwise to this suspension at the boiling point in the course of 5 minutes

Methanol. A color change to yellow-orange was observed. The mixture was refluxed for a further 30 minutes. The now clear solution was cooled to room temperature and concentrated with. Ammonia solution adjusted to pH = 8, whereby a yellow precipitate precipitated out immediately. The mixture was stirred for a further 30 minutes at this pH and at room temperature. The precipitate was collected on a frit, washed successively with a little methanol and ether and dried at 70 ° C.

0.74 g of vigorous 2,4-diamino-6-bromomethyl pteridine was obtained (yield 88%). According to chromatographic analyzes (TLC, HPLC), this product contained no further impurities.

¹ H-NMR: (DMSO-d ⁶ , 300 MHz), in ppm 4.82, s, 2H:

7.07, s, 2H;

7.98, s, IH;

8.07, s, IH; 8.88, s, IH. Example 3

Production of 2,4-Dιamιno-6-chloromethylpteπdιn

a) in methanol 1.07 g (5 mM) 2,4,5,6-tetraaminopyπmιdιndihydrochloπd were suspended in 50 ml of methanol and heated to boiling. A solution of 0.91 g (7.5 mM) of chloropyruvaldoxime in 10 ml of methanol was added dropwise to this solution at the boiling point in the course of 5 minutes. A color change to yellow-orange was observed. The mixture was then heated under reflux for a further 2 hours. The now clear solution was cooled to room temperature and concentrated with. The ammonia solution was adjusted to pH = 8, a yellow precipitate immediately precipitating out. The mixture was stirred for a further 30 minutes at this pH and at room temperature. The precipitate was collected on a filter, washed successively with a little methanol and ether and dried at 70 ° C. This gave 0.84 g of yellow 2,4-dimin-6-chloromethylpentine (yield 79%). This

According to chromatographic analyzes (TLC, HPLC), the product contained no further impurities

¹ H NMR. (DMSO-d ⁶ , 300 MHz), in ppm 4.89, s, 2H, 6.91, s, 2H,

7.78, s, IH; 7.86, s, I H, 8.94, s, IH

b) in dimethylacetamide

1.0 g (4.69 mmol) 2,4,5,6-1 etraamino-pyπmidinhydrochloπd was suspended in 15 ml of NN-dimethylacctamide (DMAC) and heated at 120 ° C for 10 minutes. The suspension was then left at 70 ° Cool C and at this temperature a solution of 0.85 g (7.04 mmol) of chlororuvaldoxime in 5 ml of DMAC dripped into this suspension within 5 minutes. A color change to yellow-orange was observed

The mixture was then heated at 70 ° C. for a further 2 hours. The now almost clear solution was cooled to room temperature, a beige precipitate slowly precipitating out. The mixture was left to stand at room temperature for a further 3 days. The precipitate was then collected on a frit, washed successively with a little ethanol and ether and dried at 70.degree . 0.60 g was thus obtained

(Yield 52%) of the hydrochloride salt of 2,4-dimin-6-chloromethyl-pππιn, which according to thin-layer chromatographic studies no further impurities Contained In order to release the 2,4-dimin-6-chloromethyl-pteπdιn from its hydrochloride salt, the hydrochloride salt of the product was suspended in 10 ml HτO and adjusted to pH = 8 with concentrated ammonia solution. A yellow precipitate immediately fell out. A further 30 minutes were left stirring at room temperature and pH = 8, the precipitate was filtered off, washed with a little methanol and ether and dried at 70 ° C. In this way, 0.38 g of yellow 2,4-dimin-6-chloromethyl-peptide was obtained (yield 39 %), whose characteristic physical data (melting point, UV, * H-NMR, DC) matched that of the authentic material

Example 4

Preparation of 2,4-dimo-6-methylpteπdιn

1.07 g (5 mM) of 2,4,5,6-tetraamine-pyridium hydrochloride were suspended in 50 ml of methanol and heated to boiling. To this suspension, a solution of 0.65 g (7.46 mM) was added in the heat of boiling within 5 minutes. Pyruvaldoxim in 10 ml of methanol. A strong yellow mixture formed immediately, which after 2 hours at reflux temperature turned into an orange. brown solution passed The solution was allowed to cool to room temperature with conc. Ammonia solution adjusted to pH = 8. A yellow precipitate fell out immediately. The mixture was stirred for another hour at room temperature and pH = 8, the precipitate was filtered off with suction, washed with a little methanol and ether and dried at 100.degree

0.72 g of yellow 2,4-dimin-6-methylptin (yield 81%) was obtained. According to chromatographic analysis (TLC, HPLC), this product contained no further impurities

Η NMR (DMSO-d ⁶ , 300 MHz), in ppm 2.50, s, 3H,

6.47, s, 2H,

7.48, s, 2H, 8.6, s, IH Example 5

As in Example 3a, 4.28 g (20 mM) 2,4,5, 6-tctraaminopyrimidine dihydrochloride in 140 ml ethanol at 75 ° C. for 7 minutes with 3.68 g (30 mM) chlororuvaldoximine 40 ml ethanol. After 2.5 hours at the reflux temperature, unreacted tetraaminopyrimidine hydrochloride was filtered off hot. From the clear orange solution, 2,4-diamino-6-chloromethylpteridine was either by crystallization as hydrochloride or by neutralization, e.g. B. sodium hydroxide solution pH = 8, isolated as a precipitation. Yield: 2.04 g, i.e. 48.4% based on the 2,4,5,6-tetraaminopyrimidine hydrochloride used or 83.9%), based on the 2,4,5,6-tetraaminopyrimidine hydrochloride converted.

Example 6

Preparation of 2,4-diamino-6-ethyl pteridine

1.0 g (4.69 mmol) of tetraaminopyrimidine dihydrochloride was suspended in 50 ml of methanol and heated to boiling. A solution of 0.71 g (7.03 mmol) of oximiminomethyl ethyl ketone in 10 ml of methanol was added dropwise to this suspension at the boiling point in the course of 10 minutes. After 30 minutes, a clear solution was formed, which was then refluxed for a further 30 minutes. After cooling to room temperature, the pH of the solution was concentrated with. Ammonia adjusted to pH = 8, whereby a beige precipitate failed. The precipitate was filtered off, washed with a little methanol / ether and dried at 100 ° C. This gave 0.41 g (yield 46%) of the chromatographically pure product which, according to the 1 H NMR spectrum, consisted only of pure 6-isomer.

¹ H-NMR: (DMSO-d ⁶ , 300 MHz), in ppm 1, 25, (t, 3H);

2.81, (q, 2H); 6.52, (sb, 2H); 7.52, (db, 2H); 8.63, (s, I H.). Example 7

Preparation of 2,4-diamino-6-phenylpteridine

1.0 g (4.69 mmol) of tetraaminopyrimidine dihydrochloride was suspended in 50 ml of methanol and heated to boiling. A solution of 1.05 g (7.04 mmol) of isonitrosoacetophenone in 10 ml of methanol was added dropwise to this suspension at the boiling point in the course of 10 minutes, a slight yellow color occurring immediately. This mixture was then heated under reflux for 2 h. After cooling to room temperature, the pH of the mixture (without separating the precipitate (hydrochloride salt of the product)) with conc. Ammonia adjusted to pH = 8 and stirred at this pH for 15 minutes. The product was then filtered off, washed with methanol / ether and dried at 100 ° C. This gave 1.04 g (yield 93%) of the chromatographically pure product, which had a UV purity of 96%.

1 H NMR: (DMSO-d ^ό , 300 MHz), in ppm 6.68, (sb, 2H);

■ ^' , 48, (m, 3H);

7.82, (d, 2H);

8.30, (m, 2H);

9.33, (s, I H).

Example 8

Preparation of 2,4-diamino-6-tolylpteridine (R ^ = tolyl)

1.06 g (4.69 mmol) of tetraaminopyrimidine dihydrochloride was suspended in 50 ml of methanol and heated to boiling. A solution of 1.27 g (7.04 mmol) of isonitroso- (p-methyl) -acetophenone in 10 ml of methanol was added dropwise to this suspension at the boiling point in the course of 10 minutes, a slight yellow color occurring immediately. This mixture was then heated under reflux for 2 h. After cooling to room temperature, the pH of the mixture (without separating off the precipitate (the hydrochloride salt of the product) was adjusted to pH = 8 with concentrated ammonia and stirred at this pH for 15 minutes. The product was then suctioned off, m, t of methanol / ether and dried at 100 ° C. This gave 1.04 g (88% yield) of the chromatographically pure product which, according to the 1 H-NMR spectrum, consisted only of pure 6-isomer. 1H-NMR (DMSO-d ^6. 300 MHz), m ppm 2.63, (s, 3H),

6.67, (sb, 2H),

7.30, (d, 2H), 7.70, (db. 2H), 8.20, (d, 2H),

9.31, (s, IH)

Example 9

As in Example 3a, 1.09 g (5.00 mmol) of 2,4,5,6-tetraaminopyπmιdιndιhydrochIoπd in a mixture of 47.5 ml of methanol and 2.5 ml of dimethylacetamide at 63 ° C. for 3 minutes with 0, 91 g of chlororuvaldoxime (7.49 mmol) were added to 10 ml of methanol. The mixture was then heated at the reflux temperature until a clear solution had formed after 2.5 hours. The mixture was allowed to cool to 20 ° C., the reaction solution was neutralized by adding concentrated ammonia solution and isolated the precipitated 2,4-dιamιno-6-chloromethylpteπdin by filtration and vacuum drying yield 0.79 g (70%)

Example 10

As in Example 9, 1.08 g (4.96 mmol) of 2,4,5,6-tetraamine-pyridium hydrochloride in a mixture of 45 ml of methanol and 5 ml of dimethylene formamide at 20 ° C. with 0.91 g of chlororuvaldoxime (7.49 mmol) in 10 ml of methanol and stirred at this temperature until a clear solution was obtained after 18 hours. Yield 0.74 g of 2,4-dimin-6-chloromethylptin (64%)

Example 11

As in Example 9, 1.07 g (4.91 mmol) of 2,4,5,6-tetraaminopynmidium and dvdrochloπd in a mixture of 45 ml of methanol and 5 ml of dimethylformamide at 60 ° C. with 0.91 g of chlororuvaldoxime (7.49 mmol) in 10 ml of methanol and heated to the reflux temperature until a clear solution was obtained after 30 minutes. Yield 0.78 g of 2,4-dimino-6-chloromethylpteridine (69%) Example 12

As in Example 9, 1.09 g (4.91 mmol) of 2,4,5,6-tetraaminopyπmιdιndιhydrochloπd in a mixture of 47.5 ml of methanol and 2.5 ml of dimethylformamide at 60 ° C. with 0.79 g of chlororuvaldoxime (6.50 mmol) in 7 ml of methanol and heated to the reflux temperature until a clear solution was obtained after 3 hours. Yield 0.71 g of 2,4-diamino-6-chloromethylpeptide (63%)

Example 13

Production of 2,4-Dιamιno-6-methoxyphenylpteridιn

Analogously to Example 8, 1.06 g (4.69 mmol) of tetraaminopyπmidinedihydrochloπd was reacted with 1.26 g (7.04 mmol) of isonιtroso- (p-methoxy) acetophenone. 1.15 g of product was obtained, corresponding to a yield of 91%.

Example 14

Production of 2,4-Dιamιno-6-chloφhenyIpteπdιn

Analogously to Example 8, 1.06 g (4.69 mmol) of tetraaminopyπmidinedihydrochloπd was reacted with 1.29 g (7.04 mmol) of isonιtroso- (p-chloro) acetophenone. 1.15 g of product were obtained, corresponding to a yield of 90%.

Example 15

Production of 4-Arnιno-6-chloromethyl-pteπdιn

3.00 g (15, 15 mmol) 4,5,6-Tπamιnopyπmιdιndιhydrochloπd were suspended in 90 ml of methanol and heated to boiling. A solution of 2.76 g (22.72 mmol) of chlororuvaldoxime in 30 ml of methanol was added dropwise to this suspension at the boiling point in the course of 10 minutes. A color change to yellow-orange was observed. The mixture was then heated under reflux for a further 2 hours. The now clear red solution was cooled to room temperature and concentrated with conc. Ammonia solution adjusted to pH = 7.5 (pH meter), after which a gray-blue precipitate failed. The mixture was stirred for a further 30 minutes at this pH and at room temperature The precipitate was collected on a frit, washed successively with a little methanol and ether and dried at 70 ° C.

Thus, 1.37 g of gray-blue 4-amino-6-chloromethyl-pteridιn (yield 46%). A further 0.60 g of 4-amino-6-chloromethyl-pteridine (yield 20%) could be isolated by working up the mother liquor of the reaction. According to chromatographic analysis (DC, HPLC), these products contained no further impurities.

1 H-NMR: (DMSO-d6, 250 MHz), in ppm 5.00, (s, 2H)

8.27, (s, IH) 8.36, (s, IH) 8.55, (s, IH) 9.21, (s, IH).

Example 16

Preparation of 4-amino-6-phenyl-pteridine

1.0 g (15.04 mmol) of 4,5,6-triaminopyrimidine dihydrochloride were suspended in 30 ml of methanol and heated to boiling. A solution of 1.13 g (7.57 mmol) of isonitrosoacetophenone in 10 ml of methanol was added dropwise to this suspension at the boiling point in the course of 10 minutes, a slight yellow color occurring immediately. The mixture was then heated under reflux for 2 hours. After cooling to room temperature, the pH of the mixture (without separating the precipitate (the hydrochloride salt of the product)) was concentrated. Ammonia solution adjusted to pH = 7.5 and stirred at this pH for 30 minutes. The product was then filtered off with suction, washed with methanol and ether and dried at 100.degree. This gave 0.99 g (yield 88%) of the chromatographically pure product which, according to the 1 H-NMR spectrum, consisted only of pure 6-isomer.

1 H NMR: (DMSO-d ⁶ , 250 MHz), in ppm 7.54, (m, 3H);

8.21, (s, I H):

8.45, (m, 2H

8.46, (s, IH) 8.52, (s, IH) 9.69, (s, IH) Example 17

Preparation of 4-amino-6-chloromethyl-2-methylthio-pteridine

1.0 g (4.10 mmol) of 4,5,6-triamino-2-methylthiopyrimidine dihydrochloride were suspended in 25 ml of methanol and heated to boiling. One dripped into this suspension in the

Boiling heat within 5 minutes a solution of 0.75 g (6.17 mmol) Chloφyruvaldoxim in 10 ml of methanol. A color change to yellow-orange was observed. After a short time, a clear yellow solution formed, which was then heated under reflux for a further 2 hours. The now clear dark green solution was cooled to room temperature and concentrated. Ammonia solution adjusted to pH = 7.5 (pH meter), after which a gray-blue precipitate failed. The mixture was stirred for a further 30 minutes at this pH and at room temperature. The precipitate was collected on a frit, washed successively with a little methanol and ether and dried at 70 ° C. This gave 0.73 g of gray-blue 4-amino-6-chloromethyl-2-methylthio-pteridine (yield 74%). According to chromatographic analyzes (TLC, HPLC), this product contained no further impurities.

¹ H-NMR: (DMSO-d ⁶ , 250 MHz), in ppm 2.52, (s, 3H)

4.95, (s, 2H) 8.28, (s, 2H)

8.36, (s, I H) 9.09, (s, IH).

Example 18

Preparation of 4-amino-2-methylthio-6-phenyl-pteridine

1.0 g (4.10 mmol) of 4,5,6-triamino-2-methylthopyrimidine dihydrochloride were suspended in 30 ml of methanol and heated to boiling. At the boiling point, a solution of 0.95 g (6.15 mmol) of isonitrosoacetophenone in 10 ml of methanol was added dropwise to this suspension over the course of 10 minutes, a slight yellow color occurring immediately. After a short time, a clear yellow solution formed, which was then heated under reflux for a further 2 hours. After cooling to room temperature, the pH of the solution with conc. Ammonia solution adjusted to pH = 7.5 and stirred at this pH for 30 minutes. The product was then filtered off, washed with methanol and ether and dried at 100 ° C. This gave 1.07 g (yield 97%) of the chromatographically pure product which, according to the 'H-NMR spectrum, consisted of pure 6-isomer. ¹ H-NMR: ^(DMSO-d6, 250 MHz.) In ppm 2.53 (3H s.);

7.53, (m. 3H); 8.33, (s, IH); 8.43, (m. 2H); 8.46, (s, IH); 9.61, (s, IH).

Examples 19 to 31

Analogously to Example 16, the following 4-aminopteridine derivatives of the general formula were started from the corresponding starting materials

manufactured.

Claims

Claims:

Process for the preparation of 4-aminopteridine dvates of the general formula

wherein Rl is a hydrogen atom, a C1-C4 alkyl group, an aryl group, substituted or unsubstituted, -NH2, -SR ³ , -OR ³ , -NHR ³ or -N (R ³ ) 2, wherein R ^{3 is} a C] -C4 - is an alkyl group and R ^ is a C] -C4-alkyl group, an aryl group, substituted or unsubstituted, a heteroaryl group, substituted or unsubstituted, or -Cl-bX, in which X is a halogen atom, characterized in that a 4 , 5,6-Tπamιno- pyrimidine of the general formula

wherein R 'has the meaning given or its salt with a compound of the general formula

wherein R ^ has the meaning given in the end product according to formula I.

2. The method according to claim 1, characterized in that one carries out the reaction in an inert solvent. Method according to claim 2, characterized in that one is inert

Solvent a polar protic or em polar aprotic solvent ve: w ends

Method according to at least one of claims 1 to 3, characterized gekennzcicluiet that one carries out the reaction at a temperature of 20 ° C to the reflux temperature of the corresponding solvent.

5. Process for the preparation of pterin derivatives of the general formula

wherein R ^{1 has} the meaning given in claim 1, Y is oxygen or NH, R ^{4 is} glutamic acid residue and R ^{5 is} C ⁴ -C ⁴ -alkyl or a hydrogen atom, characterized in that em 4,5,6-Tπamιnopyπmιdιn of the general formula

wonn R ^{1 has} the meaning given or its salt with a compound dei general Foi mel

REPLACEMENT BLAπ (RULE 26) wherein R ^{2 is} a CH ₂ X group, wherein X is a halogen atom, into a 4-aminopteridine derivative of the general formula

wherein R ¹ and R ^{2 have} the meaning given, converted this, if appropriate in a manner known per se, into the corresponding 2-amino-6- (halogenomethyl) -4 (1H) -pteridinone and either the 4-aminopteridine derivative of the general formula I or the 2-amino-6- (halogenomethyl) -4 (1H) -pteridinone is used in a manner known per se for the synthesis of the pterine derivatives mentioned.