DD255339A5 - PROCESS FOR PREPARING 5-BYRIMIDIN CARBOXYLIC ACID COMPOUNDS - Google Patents

Abstract

Described is a process for the preparation of 5-Pyrimidincarbonsaeure compounds of general formula I, in which the radicals have the meaning given in the invention claim, and their pharmacologically acceptable salts. These compounds are drugs with hypotensive action. Formula (I)

Description

"Aryl- (CH ₂ ) _m -C-0-, Y _{2 is} a cycloalkyl, aryl, heterocyclo, carbamoyl, (sub-)

0 0

substituted amino) -C-, carboxyl-, alkoxycarbonyl-, alkyl-C-,

0 0

11 h

Aryl- (CH ₉ ) -C- or heterocyclo- (CH _n ) -C-,

Y _{3 is} a hydroxyl, alkoxy, aryl (CH ₃ ) _m ~ 0, mercapto, alkyl

0 0

thio, aryl (CH _{2) m} -S-, alkyl-C-0-, aryl- _{(CH2) m} ~ C-0-, amino

or substituted amino group,

q has the value 0,1, 2 or 3,

m is 0 or is an integer of 1 to 6, η is 0 or is an integer of 1 to 5, and ρ is an integer of 1 to 5.

Field of application of the invention

The application of the present invention is in the field of drugs for controlling in particular high pressure.

Characteristic of the known state of the art

Publications which underlie the present invention as prior art are currently unknown.

Object of the invention

The aim of the invention is to provide new drugs for controlling high pressure.

Explanation of the essence of the invention

The invention has for its object to provide new drugs for controlling high pressure, namely a method for producing 5-pyrimidinecarboxylic acid compounds of the general formula I according to the invention

RR ₁ NCN

and their pharmacologically acceptable salts in which X represents an oxygen or sulfur atom, R is a hydrogen atom, an alkyl, cycloalkyl, aryl or arylalkyl radical and Ri is a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclo radical, a Group of the general formula

i, i ³

-y- (C "->) -Y ,, -C- (CE.) -Y, or a halogen-substituted J ^ ^ - j 2 ρ 3

Alkyl radical, or R and R ₁ together with the nitrogen atom to which they are attached, a 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, i-piperazinyl. -i-alkyl-i-piperazinyl-^-arylalkyl-i-piperazinyl-^-diarylalkyl-ipiperazinyl or 1-pyrrolidinyl, 1-piperidinyl or 1-azeipinyl group represented by alkyl, alkoxy, alkylthio, halogen, trifluoromethyl or hydroxy, R _{2 is} a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl or aryl radical, a group of the general formula

-C- (CH ₂ J _n -Y _{1 oc} j _he j_ _{e n} halogen-substituted alkyl radical,

^R 6 R _{3 is} a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclo radical, a group of the general formula

^R5 * ^R5

f \

-C- (CH ₂ ) _η - ^γ ₂ '"ί" ^ ^CH 2 "^ p - ^Y 3' or a halogen-substituted - ^R 6 ^ά 5

Is alkyl radical,

R _{4 is} a heterocyclo group or aryl group, preferably a phenyl group which is optionally substituted with up to halogen atoms, alkyl, nitro, cyano, amino, dialkylamino, trifluoromethyl, isothiocyanato or isocyanato groups, R ₅ and R ₆ are independently hydrogen, alkyl, - (CH ₂ ) _q -aryl or (CH ₂ ) _q -cycloalkyl, Y _{1 is} a cycloalkyl, aryl, heterocyclo, hydroxyl, alkoxy, aryl (CH ₂ ) _{m is} -O-, mercapto, alkylthio, aryl- (CH ₂ ) _m -S-, amino, substituted amino, carbamoyl-,

O 0

11 »

(substituted amino) -C-, heterocyclo- (CH ₂ ) _m ~C-, carboxyl-,

0 0.0

Il M Il

Alkoxycarbonyl, alkyl-C-, aryl- (CH ₂ ) -C-, alkyl-C-O- or

Aryl- (CH ₃ ) -CO-,

Y _{2 is} a cycloalkyl, aryl, heterocyclo, carbamoyl, (sub)

O-O

Il M

substituted amino) -C-, carboxyl, alkoxycarbonyl, alkylC-, OO

Il H

Aryl- (CH ₂ ) _m -C- or heterocyclo- (CH ₂ ) _m ~C-,

Y _{3 is} a hydroxyl, alkoxy, aryl (CH ₂ ) _m ~ 0, mercapto, alkyl

0 0

thio, aryl (CH ₂ ) _m -S, alky1 CO, aryl (CH ₂ ) CO, amino or substituted amino group,

q has the value 0,1,2 or 3,

m is 0 or is an integer from 1 to 6,

η has the value 0 or is an integer with a value of 1 to 5 and

ρ is an integer having a value of 1 to 5.

Hereinafter, definitions of various terms are given to describe the compounds of the invention.

These definitions apply to the expressions as used in the description, unless they are otherwise defined in some cases, either individually or as part of a larger group.

The terms "alkyl" and "alkoxy" refer to unbranched and branched radicals. Groups of 1 to 8

Carbon atoms are preferred. ·

The term "halogen-substituted alkyl radical" means alkyl radicals of the type described above in which one or more hydrogen atoms are substituted by chlorine, bromine or fluorine atoms Typical examples are the trifluoromethyl group, which is preferred, the pentafluoroethyl, 2,2,2- Trichloroethyl, chloromethyl or bromomethyl group.

Examples of substituted phenyl groups are phenyl groups which are substituted by 1 to 3 alkyl, alkoxy or alkylthio groups, halogen atoms, nitro, cyano, hydroxyl, amino, alkylamino, etc. The term "aryl radical" denotes a phenyl and substituted phenyl radical. Dialkylamino, trifluoromethyl, isothiocyanato, isocyanato or difluoromethoxy substituted.

The terms "alkenyl" and "alkynyl" mean straight and branched radicals. Radicals of 2 to 8 carbon atoms are preferred.

The term "cycloalkyl" means radicals of 3 to 7 carbon atoms.

The term "halogen" means chlorine, bromine, fluorine and iodine The term "heterocyclo means completely saturated or unsaturated rings of 5 or 6 atoms containing one or two oxygen or sulfur atoms and / or one to four nitrogen atoms, with the proviso that the total number of heteroatoms in the ring is at most 4. The heterocycling is bound by an available carbon atom Preferred monocyclic heterocyclo groups are the 2- and 3-thienyl, 2- and 3-furyl, 2- and 3-pyrrolyl, 2 -, 3- and 4-pyridyl, 2-, 4- and 5-imidazolyl, 2- and 3-pyrrolidinyl, 2-, 3- and 4-piperidinyl and 2-, 3- and 4-azepinyl.

The term "heterocyclo" also includes bicyclic rings in which a 5- or 6-membered ring having oxygen, sulfur and nitrogen atoms of the type described above is fused to a benzene ring and the bicyclic ring is linked through an available carbon atom in the benzene ring. Preferred bicyclic heterocyclo groups are the 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl-, 5-, 6-, 7- or 8-isoquinolinyl, 4-, 5-, 6- or 7-benzothiazolyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7- Benzimidazolyl, 4-, 5-, 6- or 7-benzoxadiazolyl and 4-, 5-, 6- or 7-benzofurazanyl groups.

The term "heterocyclo" also includes monocyclic and bicyelic rings of the type described above which are substituted by at least one alkyl, arylalkyl, diarylalkyl, alkylthio or alkoxy radical, halogen atoms, nitro, oxo, cyano, hydroxyl, amino , Alkylamino, dialkylamino, trifluoromethyl, isocyanato, isothiocyanato or difluoromethoxy groups

The term "substituted amino group" means a group of the general formula -NZiZ ₂ in which Z _{1 is} a hydrogen atom, an alkyl or aryl (CH ₂ ) _m radical and Z _{2 is} an alkyl or aryl (CH ₂ ) _m ^ Is radical, or Z ₁ and Z ₂ together with the nitrogen atom to which they are attached are a 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl , 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl group or a 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl group denoted by alkyl, alkoxy, Alkylthio, halogen, trifluoromethyl or hydroxyl are substituted.

Those compounds of the general formula in which R _{4 is} a heterocyclo, phenyl or phenyl radical substituted by 1 to 3 alkyl radicals, halogen atoms, nitro, cyano, amino, dialkylamino, trifluoromethyl, isothiocyanato or isocyanato groups are novel and as such form an integral part of the invention.

The compounds of general formula I and their pharmacologically acceptable salts are cardiovascular substances. They block calcium entry and vasodilator and are particularly useful for treating hypertension.

The compounds of the invention may also be useful as antiarrhythmics, anti-anginal agents, ischemia and cardiac fibrillation, for the treatment of asthma and myocardial infarction.

For the treatment of hypertension, they may be formulated together with a diuretic or an / 3-adrenergic drug or an angiotensin converting enzyme inhibitor. Suitable diuretics are the thiazide diuretics such as hydrochlorothiazide and bendroflumethiazide. An example of a suitable / 3-adrenergic agent is nadolol and an example of an angiotensin converting enzyme inhibitor is captopril.

The compounds of the general formula I in which X represents a sulfur atom can be prepared by reacting a keto ester of the general formula II

II »

O with an S- (phenylmethyl) -thiopseudourea of the general formula III

NH

or its salt. In general formula II! and in the specification, Z _{3 represents} a hydrogen atom or a methoxy group. The reaction mixture is heated in the presence of sodium acetate. A tautomeric mixture of compounds of general formula IV is formed

-0-R

-O-R-

The reaction of the tautomeric mixture of general formula IV with phosgene in the presence of an organic base and subsequent reaction with an amine of general formula V

RR ₁ NH · (V)

where neither R nor R- is a hydrogen atom, provides the corresponding compound of general formula VI

R

RR ₁ NCN

-OR.

in which neither R nor Ri is a hydrogen atom.

The compounds of the general formula VI, in which one or both of the radicals R and Ri are hydrogen atoms, can be obtained by reacting the more automatic mixture of the general formula IV with an isocyanate of the general formula VII

R ₁ -N = C = O

getting produced.

A compound of general formula VI in which Z _{3 represents} a hydrogen atom can be converted to the corresponding compound of general formula I in which X represents a sulfur atom by treatment with bromotrimethylsilane. A compound of the general formula VI in which Z _{3 is} a methoxy group can be converted by treatment with trifluoroacetic acid and ethanethiol to give the corresponding compound of the general formula I in which X represents a sulfur atom.

Compounds of the general formula IV can be prepared in non-racemic form as follows:

A compound of general formula IV is reacted with phosgene and a racemic alcohol (* -OH) to give a compound of general formula VIII

(VIII)

where R * is the residue of a chiral alcohol. The reaction of the compound of general formula VIII with bromotrimethylsilane (when Z _{3 represents} a hydrogen atom) or with trifluoroacetic acid and ethanethiol (when Z _{3 represents} a methoxy group) affords the corresponding compound of general formula IX

^R 4

_R * "QCN

The diastereomers of the compounds of general formula VIII and IX can be separated by recrystallization or chromatography.

Treatment of the purified diastereomers of a compound of general formula IX with sodium methoxide followed by p-methoxybenzyl chloride affords the corresponding compound of general formula IV in non-racemic form. These non-racemic compounds can be reacted in the manner described above to the non-racemic compounds of the general formula I in which X is a sulfur atom.

The compounds of the general formula I in which X represents an oxygen atom can be prepared by heating a ketoester of the general formula II with O-methylpseudourea

(CH ₃ -OC

^X N

or its salt in the presence of sodium acetate or sodium bicarbonate. A tautomeric mixture of compounds of general formula X is obtained.

The reaction of the tautomeric mixture of general formula X with phosgene in the presence of an organic base and then with an amine of general formula V (R and R ₁ have their broadest importance) provides the corresponding compound of general formula XI.

RR ₁ NCN

-OR.

Alternatively, the compounds of the compounds of general formula XI in which R represents a hydrogen atom can be prepared by reacting a tautomeric mixture of general formula X with an isocyanate of general formula VII.

The compounds of general formula XI can be converted by treatment with hydrochloric acid into the corresponding compounds of general formula I in which X represents an oxygen atom.

Alternatively, a tautomeric mixture of the compounds of formula X can be reacted with p-nitrophenyl chloroformate in the presence of an organic base to give a compound of general formula XII.

The treatment of a compound of general formula XII with an acid and then with an amine of general formula V (R and R ₁ have their broadest importance) provides the corresponding compounds of general formula I.

The non-racemic form of a compound of general formula I in which X represents an oxygen atom can be prepared by forming a diastereomeric mixture of a compound of general formula XI using an optically active amine (ζB. methylbenzylamine). The diastereomers can be separated by conventional methods, for. As chromatography or crystallization. The cleaved diastereomers can be converted to the non-racemic form of a compound of general formula X by treatment with sodium methoxide. The non-racemic form of a compound of general formula X can be prepared to prepare the corresponding non-racemic form of a compound of general formula I via the non-racemic form of an intermediate of general formula XI. For the preparation of the compounds of general formula I in which X represents an oxygen atom and R and R ₁ are derived from optically active amines, the diastereomers of general formula XI can also be converted into compounds of general formula I. The optically active compounds can be separated by chromatography or crystallization.

The non-racemic form of a compound of general formula I in which X represents an oxygen atom can also be prepared initially by reacting a non-racemic compound of general formula IV into the corresponding non-racemic compound of general formula VI according to the methods described above transforms. A non-

racemic compound of the general formula VI can be reacted with an oxidizing agent such as m-chloroperbenzoic acid to a non-racemic compound of general formula I in which X represents an oxygen atom. An alternative process for the preparation of the non-racemic form of a compound of general formula I in which X represents an oxygen atom and R and Ri are each hydrogen atoms comprises reacting the corresponding non-racemic compound of general formula I ₁ wherein R _{1 represents} a hydrogen atom and R is a 1-phenylethyl group, with hydrogen bromide and acetic acid or with trifluoroacetic acid. Those compounds of the general formula I (including their cleaved enantiomers) in which X represents a sulfur atom may also be prepared by first adding a methoxy-containing intermediate of the general formula X (racemic or non-racemic) to the corresponding thio-intermediate (racemic or non-racemic) of the compound of general formula IV and then further processed in the manner described above.

If the reactants described above contain reactive substituents which are not intended to participate in the reaction, it may be necessary first to protect these functional groups, then to carry out the reaction and subsequently to cleave off the protective group.

The compounds of general formula I, which contain a basic or acidic group, form salts with a wide variety of inorganic and organic acids and bases.

The pharmacologically acceptable salts are preferred, but other salts are also suitable for separating or purifying the product. Specific examples of the acids suitable for the preparation of pharmacologically acceptable salts are hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, acetic acid and maye acid. Specific examples of pharmacologically acceptable salts with bases are the alkali metal salts, such as sodium, potassium and lithium salts, and alkaline earth metal salts, such as calcium and magnesium salts. The salts can also be prepared by reacting a compound of general formula I with an equivalent amount of the acid in a medium in which the salt precipitates.

Preferred compounds of the invention are those in which R _{2 is} an alkyl radical, in particular a methyl group, R 3 is an alkyl radical, in particular an isopropyl radical, and R _{4 is} a 3-nitrophenyl radical. R and R ₁ are each hydrogen atoms or one of R and R ₁ is a hydrogen atom and the other is an (S) -I-phenylethyl group.

Exemplary embodiments Example 1

3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid methyl ester A) S- (4-methoxybenzyl) -thiopseudourea hydrochloride

A suspension of 38 g (50, OmMoI) thiourea in 40 ml of anhydrous tetrahydrofuran is cooled under argon as a protective gas to 0 ⁰ C and treated dropwise with 8.0 g (50.0 mmol) of 4-methoxybenzyl chloride. After completion of the addition, the cooling bath is removed and the reaction mixture is stirred for 2 hours at room temperature. Thereafter, the mixture is heated at 60 to 65 ⁰ C for 4 hours. It forms a colorless voluminous precipitation. The reaction mixture is cooled to room temperature and treated with anhydrous diethyl ether. The solid is filtered off and washed with anhydrous diethyl ether. Yield 10.92 g of the title compound, mp 161-163.5 ° C.

C ₉ H ₁₂ N ₂ OS-HCl; C H N S Cl calc .: 46.45. 5.63 12.04 13.78 15.23 Found .: 46.48 5.64 12.25 13.74 15.31

B) Methyl 4-Dihydro-2 - [[(4-methoxyphenyl) -methyl] thio] -6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid A solution of 5.0 g (0, 2 mol) of methyl 2 - [(3-nitrophenyl) methylene] -3-oxobutanoate in 20 ml of dimethylformamide under argon as protective gas at room temperature with 4.65 g (0.02 mol) of S- (4-methoxybenzyl) thiopseudourea hydrochloride and 1.64 g (0.02 mol) of sodium acetate. The mixture is then heated to 65 ± 5 ° C for 3 hours. After cooling, ethyl acetate is added and a small amount of solids are filtered off. The filtrate is washed twice with water, then with aqueous bicarbonate solution and saturated brine. The aqueous washings are extracted with fresh ethyl acetate. The filtrates and washings are combined, dried over magnesium sulfate and evaporated under reduced pressure. There are obtained about 9g of crude product. After recrystallization from acetate / isopropyl ether, 6.8 g of the title compound are obtained from mp 125 to 127.5 ° C. In thin-layer chromatography on silica gel with ethyl acetate / hexane (1: 1), the R _r value is 0.48.

C ₂₁ H ₂₁ N ₃ O ₅ S; C H N S calc .: 59,00 4.95 9.83 7.50 Found .: 58.86 4.82 9.51 7.25.

C) 1 - [(ethylamino) carbonyl] -1,6-dihydro-2 - [[(4-methoxyphenyl) methyl] thio] -4-methyl-6- (3-nitrophenyl) -5- pyrimidincarbonsäuremethylester

A solution of 1.5 g (3.5 mmol) of 1,4-dihydro-2 - [[(4-methoxy-phenyl) -methyl] -thio] -6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid methyl ester In acetone under argon as a protective gas at room temperature with O, _# 5ml (0.45 g, 6.3 mmol) of ethyl isocyanate and 50 mg (0.36 mmol) of powdered potassium carbonate added. The reaction mixture is analyzed by thin-layer chromatography (dichloromethane / methanol, 95: 5). It shows a new spot at a higher Rf value, which did not increase after 1 to 2 hours. Volatiles were distilled off under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, 1 N hydrochloric acid, water and saturated brine. The aqueous fractions were back-extracted with fresh ethyl acetate. The organic fractions were combined, dried over magnesium sulfate and evaporated under reduced pressure. Yield 1.6g crude product.

Chromatography on 250 ml of silica gel and elution with dichloromethane / hexane (2: 1 to 3: 1) followed by dichloromethane / methanol (99.5: 0.5) gives 0.94 g of the title compound.

D) Methyl S-C-alpha-thylaminol-carbonyl-1'-tetrahydro-e-methyl-O-nitropheny-D-thioxo-S-pyrimidine-carboxylic acid 0.94 g (1.89 mmol) of 1 - [(ethylamino) -carbonyl] - Methyl-di-1,6-dihydro-2 - [[(4-methoxyphenyl) -methyl] -thio] -4-methyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylate in 10 ml of anhydrous dichloromethane is stirred under argon as protective gas at room temperature 0.5 ml (0.74 g, 6.5 mmol) of trifluoroacetic acid and 0.35 ml (0.29 g, -4.67 mmol) of ethanethiol were added. The mixture is stirred for 12 hours. Thereafter, volatiles are distilled off under reduced pressure. The residue is digested with isopropyl ether. There are obtained 0.59g of the title compound of mp 244-246 ° C.

C ₁₆ H ₁₈ N ₄ O ₅ S; C H N S calc .: 50.79 4.79 14.81 8.47 Found .: 50.82 4.86 14.54 8.54

Example 2 S-CCDimethylaminol-carbonyU-I ^ .SAtetrahydro-e-methyl ^^ S-oxo-S-nitrophenyO ^ pyriinidin-carboxylic acid i-

methyläthylester

A) 1,4-Dihydro-2-methoxy-6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester

A mixture of 10.0 g of (36, OmMoI) 2 - [(3-nitrophenyl) methylene] -3-oxobutanoic acid 1-methyl ethyl ester, 8.40 g (108 mmol) of sodium bicarbonate and 8.06 g (46.8 mmol) of O-methylpseudourea hydrogen sulfate in 54 ml of dimethylformamide is heated under argon as inert gas for about 272 days at 60 ° C. Thereafter, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is washed six times with water and then with saturated brine, dried over potassium carbonate and evaporated. The residue is passed through a short silica gel column and recrystallized from isopropyl ether / hexane. 9.04 g of the title compound are obtained in yellow crystals.

B) 1 - [(Dimethylamino) carbonyl] -1,6-dihydro-2-methoxy-4-methyl-6- (3-nitrophenyl) -5-pyrimidine-carboxylic acid 1-methyl ethyl ester

A solution of ethyl-3,34g (10, OmMoI) i ^ -dihydro-methoxy-e-methyl-O-nitrophenyl-S-pyrimidinecarboxylate and 6.3 mL (45 mmol) of distilled triethylamine in 10 mL of dichloromethane Ice bath is added dropwise under argon as protective gas with a syringe with 9.2 ml (12 mmol) of a 1.3 molar solution of phosgene in benzene within 3 to 5 minutes. After stirring for 90 minutes at 0 ° C., the reaction mixture is admixed with 3.3 ml (15 mmol) of 40% aqueous dimethylamine solution, sealed with a septum and stirred at room temperature for about 2 to 2 days. The reaction mixture is then evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with saturated brine, dried over potassium carbonate and evaporated. There are obtained 4.75 g of the crude title compound as a brown oil.

C) 3 - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidine-carboxylic acid 1-methyl ethyl ester

A solution of 2.27 g of the crude product of Step B) in 20 ml of tetrahydrofuran and 20 ml of methanol is adjusted to pH 1 with 3.0 ml of 5 N hydrochloric acid and stirred at room temperature for 1 hour. Thereafter, the reaction mixture is evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with saturated brine, dried over magnesium sulfate and evaporated. The residue is recrystallized from a mixture of dichloromethane and isopropyl ether. There are obtained 1.55 g of the title compound as colorless crystals of mp 165 to 166 ⁰ C.

C ₁₈ H ₂₂ N ₄ O ₈ ; C H N calc .: 55.38 5.68 14.35 Found .: 55.44 5.70 14.27

Example 3 S-tCDimethylamino-carbonyl-1-yl-S-tetrahydro-e-methyl-t-nitrophenyl-thioxo-S-pyrimidine-carboxylic acid ethyl ester

A) 1,4-Dihydro-2 - [[(4-methoxyphenyl) methyl] thio] -6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid ethyl ester

A mixture of 13.58 g of ethyl 2 - [(3-nitrophenyl) methylene] -3-oxobutanoate, 12.0 g of S - [(4-methoxyphenyl) methyl] thiopseudo-amino-hydrochloride and 4.18 g (0.051 mol) of sodium acetate 90 ml of dimethylformamide is heated to 7O ⁰ C for 4 hours and stirred. After cooling, the reaction mixture is treated with diethyl ether and washed with water, aqueous sodium bicarbonate solution and brine. Thereafter, the ether solution is dried and evaporated. It leaves behind an oil that is digested with diethyl ether. There are obtained 18.8 g of an off-white solid, mp 95-97 ° C.

B) 1,6-Dihydro-2 - [[(4-methoxyphenyl) methyl] thio] -4-methyl-1 - [(dimethylamino) carbonyl] -6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid ethyl ester

A solution of 0.5 g (1.1 mmol) of the product of step A) in 10 mL of anhydrous tetrahydrofuran is added under argon as a blank at 0 to 5 ° C with 1.0 mL (12.6 mmol) of pyridine and then with 1.16 mL of a 12, 5% solution of phosgene in benzene (1.47 mmol). After 30 minutes of reaction at O to 5 ⁰ C, 1 ml of a 40% aqueous dimethylamine solution is added. The reaction is completed within 30 minutes. The reaction mixture is diluted with ethyl acetate and washed with 1 N hydrochloric acid, water and saturated brine. The aqueous washings are back-extracted with fresh ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. There are obtained 0.6 g of a virtually homogeneous product.

C) e - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid ethyl ester A solution of 1.26 g (2, 46 mmol) of the product of step B) in anhydrous dichloroformethane under argon as a protective gas at room temperature with 0.55 ml (0.82 g, 7.18 mmol) of trifluoroacetic acid and 0.36 ml (0.30 g, 4.78 mmol) of ethanethiol. The reaction is completed within 2 hours. Volatile compounds are distilled off under reduced pressure and the residue is digested with hot isopropyl ether. There are obtained 0.82 g of a product. This product is dissolved in chloroform and filtered off from dark insoluble substances. Finally, the product is digested with isopropyl ether. There are obtained 0.80 g of homogeneous product.

C ₁₇ H ₂₀ N ₄ O ₅ S; C H N S calc .: 52.03 5.14 14.28 8.17 Found .: 52.01 5.19 14,23 7.93

Example 4

1,2,3,4-tetrahydro-6-methyl-3 - [[methyi- (phenylmethyl) amino] carbonyl] -4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid-1-methyläthylester

A) 1,6-Dihydro-1 - [[methyl (phenylmethyl) amino] carbonyl] -2-methoxy-4-methyl-6- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester

A solution of 3.34 g (10 mMol) of the compound of Example 2A) and 6.3 ml (45 mmol) of triethylamine in 10 mM dichloromethane is added dropwise in an ice bath under argon as protective gas by means of a syringe with 9.2 ml of a 1.3 molar solution of phosgene in benzene (12 mmol). The resulting mixture is stirred in the bath for 20 hours. After cooling to ⁰ ° C. with a fresh ice bath, the mixture is admixed with 1.95 ml (15 mmol) of benzylmethylamine and stirred at room temperature for 12 hours. Then the reaction mixture is diluted with dichloromethane and washed with water and saturated brine, dried over potassium carbonate and evaporated. The residue is passed through a short silica gel column and eluted with 20% acetone / hexane. The fractions are combined and evaporated and the residue is digested with isopropyl ether. There are obtained 4.11 g of white crystals, mp 145-146 ⁰ C (softening point 140 ° C).

B)!, A.S ^ -Tetrahydro-e-methyl-S-tlmethyl-tphenylmethyD-amino-carbonyl-A-O-nitrophenyD-a-oxo-S-pyrimidine-carboxylic acid 1-methyl ethyl ester

A suspension of 1.81 g (3.92 mmol) of the compound of step A) in 40 ml of tetrahydrofuran and 40 ml of methanol is treated with 40 ml of 5 N hydrochloric acid. The resulting solution is stirred for 90 minutes at room temperature, then partially evaporated and the residue partitioned between saturated sodium bicarbonate solution and chloroform. The organic phase is washed with saturated brine, dried over magnesium sulfate and evaporated. The residue is recrystallized from dichloromethane / isopropyl ether. Are obtained 1,684g white crystals, melting at 159-161 ⁰ C. Thin-layer chromatography with 7% methanol / dichloromethane gives a single longer spot with an Rf of 0.54.

C ₂₄ H ₂₆ N ₄ O ₆ ; C H N calc .: 61.79 5.62 12,01 Found .: 61.95, 5.64 11.91

Example 5 i-methyl-S-t-methyl-S-tfmethyl-aminol-carbonyl-C5-nitrophenyl O-oxo-S-pyrimidine-carboxylic acid i-methyl ethyl ester A solution of 5.00 g (15, OmMoI) of the compound of Example 2A) and 5.9 ml (45 mmol) of anhydrous triethylamine in 45 ml of distilled dichloromethane is treated dropwise at 0X under argon as protective gas by means of a syringe with 15.0 ml of a 1.2 molar solution of phosgene in benzene (18, OmMoI) , After 3 ^1/2 hours stirring at 0 ⁰ C, the reaction mixture with 1,94ml (22.5 mmol) is added a 40% aqueous methylamine solution. After 45 minutes, the reaction is stopped by the addition of 15 ml of 1 N hydrochloric acid (pH 1), and the reaction mixture is partially evaporated. The residue is diluted with 50 ml of tetrahydrofuran and 25 ml of methanol and diluted again with 15 ml of tetrahydrofuran and 25 ml of methanol and treated again with 15 ml of 1 N hydrochloric acid. After 2 hours of stirring at room temperature, the reaction mixture is partially evaporated. The residue is extracted with ethyl acetate. The organic phases are combined, washed with saturated sodium bicarbonate solution and saturated brine, and evaporated. The residue is recrystallized from warm ethyl acetate / hexane. There are obtained 3.47 g of white crystals. This material is recrystallized again from dichloromethane / isopropyl ether. Are obtained 3,29g colorless crystals, melting at 204-205 ⁰ C. After recrystallization from ethyl acetate / hexane, 2.588 g of colorless crystals of mp 205 to 206 ⁰ C are obtained. Thin layer chromatography with 5% methanol / dichloromethane provides a single spot with an R _f value of 0.45 after visualization with vanillin and heating.

C ₁₇ H ₂₀ N ₄ O ₆ ; C H N calc .: 54.25 5.36 14,89 Found .: 54.40 5.23 14.72.

Example 6 3- (Aminocarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (4-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid 1-methyl ethyl ester

A) 1-carbamoyl-1, e-dihydro-1-methoxy-methyl-1-nitrophenyl-S-pyrimidinecarboxylic acid i-methyl ethyl ester

A solution of 5.00 g (15.0 mmol) of the compound of Example 2 A and 5.88 g (45.0 mmol) of triethylamine in 45 ml of dichloromethane at 0 ⁰ C under argon as a protective gas by means of a syringe with 15.0 ml of a 1.2 molar solution of phosgene in benzene (18, OmMoI). After 3V2stündigem stirring at ^{0 0} C, the reaction mixture with 1.52ml (22.5mMol) of concentrated ammonia solution. After a further 2 hours at room temperature, the reaction mixture is treated again with 0.5 ml (7.5 mmol) of concentrated ammonia solution and stirred for 12 hours at room temperature. Then the reaction mixture is diluted with dichloromethane and washed with water and saturated brine. The organic phase is evaporated and chromatographies. Finally, 2.83 g of the title compound are obtained as a brittle yellow foam.

B) 1-Methylethyl 3- (aminocarbonyl) -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid A solution of 2.82 g (7 , 49 mmol) of the compound of step A) in 30 ml of tetrahydrofuran and 15 ml of methanol is combined with 10 ml of 1 N hydrochloric acid (pH 1) and stirred for 2 hours at room temperature. Thereafter, the reaction is stopped with saturated aqueous sodium bicarbonate solution and the mixture is partially evaporated. The residue is diluted with ethyl acetate, washed with water and brine, dried over potassium carbonate and evaporated. The residue is recrystallized from ethyl acetate. There are obtained 1.44 g of colorless crystals. By recrystallization from ethyl acetate, the

Contamination can not be removed. After recrystallization from acetonitrile, the impurity is removed, but the yield is poor (0.58 g). The recrystallization mixtures are combined and chromatographed with 15% acetone / dichloromethane. After trituration with diethyl ether 1.242 g of the title compound are obtained as colorless crystals by F. 206-207 ⁰ C. Thin layer chromatography with 15% acetone / dichloromethane has a single spot with a Rr value of 0.50. Thin layer chromatography with methanol / dichloromethane gives a single spot with a Rr value of 0.39.

C ₁₅ H ₁₈ N ₄ O _6; C H N calc .: 53.04 5.01 15.46 Found .: 52.78 4.90 15.24

Example 7 i.sup.1-thi-tetrahydro-e-methyl-O-nitrophenyi-oxo-Sd-piperidinylcarbonyD-S-pyrimidinecarboxylic acid i-methyl ethyl ester 3.50 g (10.5 mmol) of the compound of Example 2A) and 4, 39 ml (31.5 mmol) of triethylamine in 33 ml of dichloromethane is added at 0 ° C. under argon as protective gas by means of a syringe with 10.5 ml of a 1.2 molar solution of phosgene in benzene (12.5 mmol). After 3V2Stündigem stirring at 0 ° C, the reaction mixture with 1.56ml (15.7 mmol) piperidine and stirred for 12 hours at room temperature under argon as a protective gas. Then the reaction mixture is diluted with dichloromethane, washed with water and evaporated. The residue is chromatographed. There are obtained 4.94 g of the desired intermediate as a yellow foam. This foam is taken up in 50 ml of tetrahydrofuran and 30 ml of methanol and treated with 15 ml of 1 N hydrochloric acid. After 2 ^1/2 hours stirring at room temperature, the reaction mixture is partially evaporated. The residue is diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and evaporated. The residue is recrystallized from dichloromethane / isopropyl ether. There are obtained 4.12 g of a light yellow solid. This material is recrystallized again. There are obtained 2.75 g of the title compound as colorless crystals of mp 164-165 ⁰ C. Thin layer chromatography with 15% acetone / dichloromethane provides a single spot with an R _r of 0.45.

C ₂₁ H ₂₆ N ₄ O _6; C H N calc .: 58.60 6.09 13.02 Found .: 58.61 6.00 12,91

Example 8

1,2,3,4-tetrahydro-6-methyl-3 - [[(1-methylethyl) amino] carbonyl] -4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid-1-methyläthylester

A solution of 2.10 g (6.3 mmol) of the compound of Example 2A) and 2.64 ml (19 mmol) of triethylamine in 19 ml of dichloromethane is added at ⁰ ° C. under argon as protective gas by means of a syringe with 6.3 ml of a 1.2 molar solution of phosgene in benzene (7.6 mmol). After stirring at ⁰ ° C. for ₂ hours, the reaction mixture is admixed with 0.81 ml (9.5 mmol) of isopropylamine and stirred for 12 hours at room temperature under argon as protective gas. Thereafter, the reaction mixture is diluted with dichloromethane, washed with water and saturated aqueous brine and evaporated. The residue is taken up in a mixture of 18 ml of tetrahydrofuran and 18 ml of methanol, treated with 10 ml of 1 N hydrochloric acid and stirred for 2 hours at room temperature. Thereafter, the reaction mixture is partially evaporated and the residue is partitioned between ethyl acetate and water. The organic phase is washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and evaporated. The residue is recrystallized from isopropyl ether / hexane. 2.16 g (85% of theory) of yellow crystals are obtained. This material is re-installed from dichloromethane / isopropyl ether. There are obtained 1.759 g of colorless crystals of mp 145 to 146 ° C. Thin layer chromatography with 5% ethyl acetate / dichloromethane gives a single spot with an Rf of 0.49.

C ₁₉ H ₂₄ N ₄ O ₆ ; C H N calc .: 56.43 5.98 13.85 Found .: 56.18 5.89 13.45.

Example 9

! ^, S ^ -tetrahydro-e-methyl ^ -O-nitrophenyil ^ -oxo-S-tKphenylmethyO-amino-carbonyll-S-pyrimidinecarboxylic-imethyläthylester

A) dimethyl-dihydro-1-methoxy-methyl-e, S-nitrophenyl-1-phenylphenylmethoxy-carbonyl-S-pyrimidinecarboxylate

A solution of 5.00 g (15, OmMoI) of the compound of Example 2 A and 6.27 ml (45 mmol) of anhydrous triethylamine in 45 ml of dichloromethane is added in an ice bath under argon as a protective gas with 15.0 ml of a 1.2 molar Solution of phosgene in benzene (18, OmMoI) by means of a syringe, after stirring for ⁴ hours at ^{0 0} C, the Reaktipnsgemisch is treated with 2,46ml (22.5 mmol) of benzylamine and stirred for 12 hours at room temperature. Thereafter, the reaction mixture is washed with water and saturated aqueous saline. The organic phase is evaporated and chromatographed with 3% ethyl acetate in dichloromethane. There are obtained 6.20 g of the title compound as a yellow foam. Thin layer chromatography with 5% ethyl acetate / dichloromethane provides a major spot with a Rr value of 0.70.

B) I ^ S ^ -Tetrahydro-e-methyl ^ -IS-nitrophenyO ^ -oxo-S-CttphenylmethyO-aminol-carbonyn-S-pyrimidincarbonsäure-ethyl ethyl ester

A solution of 3.00 g (6.45 mmol) of the compound obtained in A) in a mixture of 50 ml of tetrahydrofuran and 25 ml of methanol is mixed with 6.0 ml of 1 N hydrochloric acid and stirred for 1 hour at room temperature. Thereafter, the reaction is stopped with saturated aqueous sodium bicarbonate solution and the reaction mixture is partially evaporated. The residue is shaken between chloroform and water. The organic phase is washed with saturated aqueous common salt solution, dried over magnesium sulfate and evaporated. The residue is recrystallized from dichloromethane / isopropyl ether. The resulting crystals are recrystallized again. There are obtained 1.84 g of the title compound as a colorless, electrostatic solid of mp. 184-185 ⁰ C. Thin layer chromatography with 5% ethyl acetate / dichloromethane gives a single spot with an R _t of 0.39.

C ₂₃ H ₂₄ N ₄ O ₆ ; C H N calc .: 61.05 5.35 12.38 Found .: 60.97 5.36 12.33

Example 10 3 - [(ethylamino) carbonyl] -1 _<2,3> 4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidine-carboxylic acid-1-methyläthylester A solution of 2.00 g (6.00 mmol) of the compound of Example 2A) and 2.5 ml (18.0 mmol) of ethyl acetate in 12 ml of acetonitrile are added in an ice bath under argon as protective gas by means of a syringe with a 1.3 molar solution of phosgene in toluene The reaction mixture is stirred for 3 hours at ⁰ ° C. and then 0.36 ml (9.0 mmol) of a 70% strength aqueous solution of ethylamine are added, after stirring for 3 hours in an ice belt, the reaction mixture is concentrated by evaporation taken from 24 ml of tetrahydrofuran and 24 ml of methanol and admixed with 4.0 ml of 5N hydrochloric acid After stirring for one hour at room temperature, the reaction mixture is partially evaporated and then treated with saturated aqueous sodium bicarbonate solution The aqueous phase is extracted with ethyl acetate and saturated with brine After chromatography with 5% ethyl acetate in dichloromethane and recrystallization from dichloromethane / isopropyl ether, 1.22 g of colorless crystals of mp 153-155 ⁰ C are obtained. Thin layer chromatography with 5% ethyl acetate / dichloromethane provides a single spot with an Rr value of 0.26.

C ₁₈ H ₂₂ N ₄ O _6; C H N calc .: 55.37 5.68 14.35 Found .: 55.33 5.66 14.31

Example 11 3 - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid

A) tert-butyl tert-butyl di-i-dihydro-methoxy-e-methyl-P-nitrophenoxy-S-pyridinecarboxylate

A mixture of 6.80 g (23.3 mmol) of tert-butyl 2 - [(3-nitrophenyl) methylene] -3-oxobutanoate, 5.22 g (30.3 mmol) of O-methylisourea hydrogen sulfate, and 5.87 g ( 69.9 mmol) Sodium bicarbonate 35 ml of dimethylformamide is stirred for 12 hours at room temperature under argon as protective gas. After a further 23 hours at room temperature, the reaction mixture is heated to 6O ⁰ C in an oil bath for 5V2 hours. It is then partitioned between ethyl acetate and 5% aqueous sodium bicarbonate solution. The organic phase is washed several times with water and then with saturated brine, and dried over potassium carbonate. After evaporation, 9.93 g of the title compound will behave as a crude product in the form of a light brown oil.

B) tert-butyl S-dimethyl trimethyl-carbonyl-1,2,3-tetrahydro-e-methyl-O-nitrophenyl O-oxo-B-pyrimidinecarboxylate

A solution of 1.30 g (3.05 mmol) of the compound of step A) and 1.27 ml (9.15 mmol) of anhydrous triethylamine in 10 ml of dichloromethane is added in an ice bath under argon as a protective gas by means of a syringe with 3, Add 05 ml of a 1.2 molar solution of phosgene in benzene (3.66 mmol). The mixture is stirred for 12 hours, then cooled to ^{0 0} C and treated with 0.40 ml (4.57 mmol) of a 40% aqueous dimethylamine solution. Then the yellow bath is removed and the reaction mixture is stirred for 3 hours at room temperature. Then the mixture is diluted with dichloromethane, washed with water and brine and evaporated. Chromatography with 3% ethyl acetate / dichloromethane provides 0.50 g of the desired intermediate as a yellow foam. The product is taken up in a mixture of 6 ml of tetrahydrofuran and 6 ml of methanol and treated with 2.0 ml of 1 N hydrochloric acid. The mixture is stirred for 2 hours at room temperature and then evaporated. The residue is taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and evaporated. The residue is recrystallized from isopropyl ether / dichloromethane. There are obtained 265 mg of the title compound as colorless crystals of mp 187 to 188 ⁰ C.

C) S-tl-dimethylaminol-carbonyl-i ^^^ - tetrahydro-e-methyl ^ -O-nitrophenyO ^ -oxo-S-pyrimidinecarboxylic acid

A solution of 230 mg (0.59 mmol) of the compound of step B) in 4.0 ml of chloroform is treated with 1.2 ml of trifluoroacetic acid at room temperature under argon as inert gas. After 2V2stündigem stirring, the reaction mixture is evaporated, evaporated again with toluene and the residue from ethanol / diethyl ether recrystallized. There are obtained 134 mg of the title compound as colorless crystals of mp 193 to 195 ⁰ C. Thin layer chromatography with 5% methanol / dichloromethane provides a single spot with an R _r value of 0.21.

Ci ₅ H ₁₆ N ₄ O ₆ ; C H N calc .: 51.72 4.63 16.08 Found .: 51.41 4.57 15.73

Example 12

S-1-aminocarbonyl-1-yl-S-tetrahydro-e-methyl-O-nitropheny-D-oxo-S-pyrimidine-carboxylic acid ethyl ester A) i -dihydro-methoxy-e-methyl-O-nitropheny-D- Ethyl pyrimidinecarboxylate A mixture of 16.46 g (62.6 mmol) of 2 - [(3-nitrophenyl) methylene] -3-oxobutanoic acid ethyl ester, 14.0 g (81.4 mmol) of O-methylisourea hydrogen sulfate and 15.8 g (18.8 mmol) of sodium dicarbonate in 9.4 ml of dimethylformamide is heated for 12 hours at 70 ⁰ C in an oil bath under argon as a protective gas. Thereafter, the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic phase is washed several times with water, then with saturated brine, dried over potassium carbonate and evaporated. The residue is passed through a short silica gel column and recrystallized from isopropyl ether / hexane. It is then digested with 50 ml of 60% strength isopropyl ether / hexane. Are obtained as pale yellow crystals, melting at 101 to 103 ⁰ C 12,32g of the title compound.

B) S-tAniiinocarbonyD-I ^ .S ^ tetrahydro-e-methyl- ^ O-nitrophenyD-a-oxo-B-pyrinidinecarboxylic acid ethyl ester A solution of about 19.8 mmol of the compound of step A) and 11.1 ml (8OmMoI) anhydrous triethylamine in 40 ml of acetonitrile is added in an ice bath under argon as a protective gas by means of a syringe with 20 ml of a 1.2 molar solution of phosgene in toluene (24 mmol). After stirring for 2 hours at ⁰ C the reaction mixture is mit46ml (32 mmol) of a 0,7molaren solution of ammonia in tetrahydrofuran and stirred for 1.3 hours at 0 ⁰ C. Nitrogen is passed through the reaction mixture and it is partially evaporated. The residue is diluted with 100 ml of tetrahydrofuran and 50 ml of methanol and treated with 40 rhi 1 N hydrochloric acid. After stirring for 1 hour, the reaction mixture is treated with saturated aqueous sodium bicarbonate solution. The organic phase is washed with saturated brine, dried over magnesium sulfate and evaporated. The residue is recrystallized from dichloromethane / isopropyl ether. There are obtained 2.7 g of yellow crystals. The solid is thoroughly digested with acetonitrile. There are obtained 2.254 g of the title compound as colorless crystals of mp 213-215 ° C. Thin-layer chromatography with 40% acetone / hexane yields a single spot with a Rr value of 0.42.

C ₁₅ H ₁₆ N ₄ O ₆ ; C H N calc .: 51.72 4.63 16.08 Found .: 51.78 4.67 15,95

Example 13 3- (Aminocarbonyl) -1 _> 2,3,4-tetrahydro-6-methyl-2-oxo-4- [2- (trifluoromethyl) -phenyl] -5-pyrimidihcarboxylic acid ethyl ester

A) 1,4-Dihydro-2-methoxy-6-methyl-4 - [(2-trifluoromethyl) -phenyl] -5-pyrimidinecarboxylic acid ethyl ester

A solution of 2.86 g of (10, OmMoI) 2 - [[2- (trifluoromethyl) -phenyl] -methylene] -3-oxobutanoic acid ethyl ester in 10 ml of anhydrous dimethylformamide is added under argon with 2.10 g (12.2 mmol) of O-methylisourea hydrogen sulfate and 2.0 g (12.2 mmol) of sodium acetate. The resulting suspension is stirred for 12 hours at room temperature and then heated to 55 ⁰ C for 6 hours. Thereafter, the reaction mixture is diluted with ethyl acetate, filtered and the filtrate washed with water, saturated Natriurhbicarbonatlösung and brine. Subsequently, the organic phase is dried over magnesium sulfate and then evaporated. A yellow foam is obtained, which is purified by chromatography with 5% ethyl acetate in methylene chloride. There are 2.17 g of the title compound as a colorless thick oil which solidifies on standing. The product is used in the next step without further purification.

B) Ethyl S-t-alinocarbonyl-l ^. S ^ -tetrahydro-e-methyl-Z-oxo ^ - Urifluoromethyl-phenyl-S-pyrimidine-carboxylic acid ethyl ester A solution of 2.85 g (8.63 mmol) of the compound of Step A) and 4.81 ml (34.5 mmol) of anhydrous triethylamine in 20 ml of acetonitrile is at 0 ⁰ C under argon as a protective gas by means of a syringe with 8.6 ml of a 1.2 molar solution of phosgene in toluene (10.3 mmol ). After stirring for 2 h at 0 ⁰ C, the reaction mixture with 19,7ml 13,8mMol) is added a 0,7molaren solution of ammonia in tetrahydrofuran and stirred for 90 minutes at 0 ⁰ C. Nitrogen is passed through the mixture and the mixture is partially evaporated. The residue is diluted with 40 ml of tetrahydrofuran and 20 ml of methanol and treated with 20 ml of 1 N hydrochloric acid, after stirring for 90 minutes, the mixture is treated with saturated aqueous sodium bicarbonate solution and partially evaporated. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with saturated brine and evaporated. The crude product is digested with 5 to 15% acetone / dichloromethane chromatographies and twice with diethyl ether. There are obtained 790 mg of the title compound as colorless crystals. The crystals shrink in the range of 105 to 115 ° C and then slowly melt at 155 to 160 ⁰ C: The thin layer chromatography with 3% acetone in diethyl ether gives a single spot with a Rr value of 0.61.

C ₁₆ H ₁₆ F ₃ N ₃ O _4; C H N F calc .: 51,75 4.34 11.32 15.35 Found .: 52.05 4.50 10.99 15.64

Example 14

^ (SH-I ^ .S ^ -Tetrahydro-e-methyl-IS-nitrophenyll-Z-oxo-S- ^ i-phenyläthyll-aminol-carbonyl-S-pyrimidinecarboxylic acid ethyl ethyl ester, isomers A and B.

A solution of 2.0 g (6, OmMoI) of the compound of Example 2A) in 10 ml of dichloromethane and 4.2 ml of triethylamine is cooled to 0 ⁰ C and under argon as a protective gas dropwise with 6 ml of a 1.3 molar solution of phosgene in toluene added. It forms a colorless thick precipitate. The reaction is continued for a further 30 minutes at 0 ^° C. with stirring. Thereafter, the mixture is added dropwise with 800 mg (6.6 mmol) of (S) - (-) a-methylbenzylamine. The ice bath is removed and the reaction mixture is stirred for 3 hours at room temperature. Thereafter, the solvent is evaporated and the residue taken up in 10 ml of a 1: 1 mixture of methanol and tetrahydrofuran. The resulting solution is mixed with 2 ml of 2 N hydrochloric acid and stirred for 1 hour at room temperature. The solvent is then distilled off and the residue is extracted with dichloromethane. The extracts are combined, washed with water, aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the solvent is distilled off and the residue is chromatographed on a short silica gel column with 5% ethyl acetate in dichloromethane. The product is recrystallized from dichloromethane / isopropyl ether. 819 mg of colorless crystals of isomer B are obtained. After recrystallization from the same solvent system, the isomer B) is obtained analytically pure from mp 197.5 to 198.5 ⁰ C. [a] _D = 139 ° C (1% chloroform). The mother liquor of the first recrystallization is evaporated and the residue is recrystallized again from dichloromethane / isopropyl ether. There are obtained 301 mg of a mixture of isomers A and B. The mother liquor obtained is evaporated and recrystallized from diethyl ether / hexane. There are obtained 501 mg of pure isomer A from mp 94 to 97 ° C [a] _D = -232 ° C (1%, chloroform).

C ₂₄ H ₂₆ N ₄ O ₆ ; C H N (Isomer A) calc .: 61.79 5.62 12,01 (Isomer B) Found .: 61.94 5.54 11.97 Found .: 61,90 5.57 11,99

Example 15

[SIR11-I ^ S] -tetrahydro-e-methyl-O-nitrophenyl-Z-oxo-S-tfd-phenylethyl-aminol-carbonyl-B-pyrimidine-carboxylic acid-ethyl-ethyl ester, isomers A and B

A solution of 2.0 g (6.0 mmol) of the compound of Example 2 A) in 10 ml of dichloromethane and 4.2 ml of triethylamine is cooled to 0 ⁰ C and under argon as a protective gas dropwise with 6 ml of a 1.3 molar solution of Phosgene in toluene. It forms a colorless thick precipitate. The reaction is continued for a further 30 minutes at 0 ^° C. with stirring. Thereafter, 800 mg of 6.6 mmol (R) - (+) - α-methylbenzylamine are added dropwise. The ice bath is removed and the Reakfionsgemisch stirred for 3 hours at room temperature. The solvent is distilled off and the residue taken up in 10 ml of a 1: 1 mixture of methanol and tetrahydrofuran. The resulting solution is mixed with 2 ml of 2 N hydrochloric acid and stirred for 1 hour at room temperature. Thereafter, the solvent is distilled off and the residue is extracted with dichloromethane. The extracts are combined, washed with water, aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the solvent is distilled off and the residue is chromatographed on a short silica gel column with 5% ethyl acetate and dichloromethane. The product is recrystallized from dichloromethane / isopropyl ether. 530 mg of colorless crystals of isomer B are obtained. After recrystallization from the same solvent system, 380 mg of analytically pure isomer B, mp 187-188 ° C are obtained. [a] _D = -125 ° (1%, chloroform). The mother liquor of the first crystallization is evaporated and the residue recrystallized again from dichloromethal / isopropyl ether. There are obtained 380 mg of a mixture of isomers A and B. The mother liquor obtained is evaporated and recrystallized from diethyl ether / hexane. There are obtained 325 mg of isomer A from mp 145 to 149 ° C. [a] _D = + 236 ° (1%, chloroform).

C ₂₄ H ₂₆ N ₄ O ₆ ; C H N (Isomer A) calc .: 61.79 5.62 12.02 (Isomer B) Found .: 61.84 5.53 12,00 Found .: 61,90 5.57 11,99

Example 16

3- (aminocarbonyl) -4- (2,1,3-benzoxadiazol-4-yl) -1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidine-carboxylic acid-1-methyläthylester

A) 4- (2,1,3-Benzoxadiazol-4-yl) -1,4-dihydro-2-methoxy-6-methyl-5-pyrimidinecarboxylic acid 1-methyl ethyl ester

A mixture of 2.04 g (7.43 mmol) of 2 - [(2,1,3-benzoxadiazol-4-yl) methylene] -3-oxobutanoic acid 1-methyl ethyl ester, 1.87 g (22.3 mmol) of sodium bicarbonate and 1 , 66g (9,66mMol) 0-methylisourea hydrogensulfatin7,5ml dimethylformamide is heated for 12 hours under argon as a protective gas in an oil bath at 65 ⁰ C. Thereafter, the reaction mixture is diluted with ethyl acetate, washed several times with water and then with saturated brine, dried over potassium carbonate and evaporated. The residue is chromatographed on 400 ml of silica gel (Merck) with 10% ethyl acetate in dichloromethane. There are obtained 0.6 g (24% of theory) of the title compound as a dark solid. Thin layer chromatography with 10% ethyl acetate in dichloromethane provides a single spot with an Rr of 0.17.

B) 4- (2,1,3-Benzoxadiazol-4-yl) -1,2,3,4-tetrahydro-6-methyl-3,5-pyrimidinedicarboxylic acid-5- (1-methylethyl) -3- (4 -nitrophenyl) ester

A solution of 0.60 g (1.82 mmol) of the compound of step A) and 0.88 ml (10.9 mmol) of pyridine in 10 ml of dichloromethane is added dropwise in an ice bath under argon as a blanketing gas with a solution of 4.0 mg (2, OmMoI) of 4-nitrophenyl chloroformate in 10 ml of dichloromethane. The reaction mixture is stirred for 1 hour at 0 ⁰ C and then evaporated. The residue is taken up in 20 ml of tetrahydrofuran and 10 ml of methanol and treated with 2 ml of 3 N hydrochloric acid. After stirring for 45 minutes at room temperature, the reaction mixture is evaporated to near dryness, cooled in an ice-bath and treated with saturated sodium bicarbonate solution. This mixture is extracted with ethyl acetate. The ethyl acetate extract is washed with saturated brine, dried over potassium carbonate and evaporated. 0.63 g (74% of theory of the title compound as a brown solid are obtained. Thin layer chromatography with 40% acetone in hexane gives a major spot with an R _r of 0.33.

C) 3- (Aminocarbonyl) -4- (2,1,3-benzoxadiazol-4-yl) -1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidine-carboxylic acid 1- methyläthylester

A solution of 0.63 g (1.35 mmol) of the compound of step B) in 14 ml of distilled tetrahydrofuran is added in an ice bath under argon as protective gas with 2.5 ml of a 0.7 molar solution of ammonia in tetrahydrofuran (1.75 mmol) and stirred at 0 ° C for 1 hour. Thereafter, the reaction mixture is evaporated and the residue is chromatographed on 150 ml of silica gel (Merck) with 40% ethyl acetate in hexane. There are obtained 109 mg of a yellow foam. After recrystallization from isopropyl ether / dichloromethane to obtain 141 mg (37% d. Th.) Of the title compound as a free flowing yellow solid, mp 207-208 ⁰ C. Thin layer chromatography with 4% methanol in dichloromethane provides a single spot with an Rf of 0.27.

Example 17 I ^ .S ^ -tetrahydro-e-methyl-S-IELI methyläthyll-amino-carbonyll ^ fs-nitrophenyO ^ -oxo-S-pyrimidine-carboxylic acid iS) - -

methyl-2- [methyl (phenyl-methyl) -amino] -ethyl ester-hydrocblorid

A) i ^ -dihydro-methoxy-e-methyl-t-nitrophenyO-S-pyrimidinecarboxylic acid-tSJ-i-methyl-1-methylphenylmethyl)

amino-ethyl ester

A mixture of 7.4 g (18.8 mmol) of 2 - [(3-nitrophenyl) methylene] -3-oxobutanoic acid (S) -1-methyl-2- [methyl (phenylmethyl) aminol ethyl ester, 3, 88 g (22.5 mmol) of O-methylisourea hydrogensulfate and 7.89 g (94 mmol) of sodium bicarbonate in 19 ml of dimethylformamide are heated for 12 hours under argon as a protective gas to 65 ° C. in an oil bath. Thereafter, the mixture is partitioned between diethyl ether and water. The organic phase is washed several times with water and saturated brine, dried over potassium carbonate and evaporated. The thickness of the red-colored residue is 5 to 20% on silica gel (Merck).

Acetone chromatographed in dichloromethane. There are obtained 3.77 g (44% of theory) of the title compound as a thick dark oil. Thin layer chromatography with 20% acetone in dichloromethane provides two spots with an Rf of 0.34 and 0.47, respectively.

B) S, -dihydro-e-methyl-O-nitrophenyl-oxo-SS-pyrimidine-dicarboxylic acid SHS1-i-methyl-methyl-phenylmethyl) -amino) -ethyl] -3- (4-nitrophenyl) esters

A solution of 2.20 (4.87 mmol) of the compound of step A) and 2.36 ml (29.2 mmol) of pyridine in 20 ml of dichloromethane is added dropwise in an ice bath under argon as a blanketing gas with a solution of 1.08 g (5.36 mmol) of 4-nitrophenyl chloroformate in 20 ml of dichloromethane. Thereafter, the reaction mixture is stirred in an ice bath for 15 minutes and then evaporated. The residue is again evaporated with methanol to remove residual pyridine. Thereafter, the residue is taken up in 50 ml of tetrahydrofuran and 28 ml of methanol and treated with 5.0 ml of 3 N hydrochloric acid. After stirring at room temperature for 90 minutes, the reaction mixture is poured into ice-cold saturated aqueous sodium bicarbonate solution. The mixture is evaporated to near dryness and the residue extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated brine, dried over potassium carbonate and evaporated. There are obtained 2.38 g (83% of theory) of the title compound as a brown solid. Thin-layer chromatography with 10% acetone in dichloromethane gives two major spots with an Rf of 0.25 and 0.39, respectively.

C) 1,2,3,4-Tetrahydro-6-methyl-3 - [[(1-methylethyl) amino] carbonyl] -4- (3-nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid (S) 1-methyl-2- [methyl (phenylmethyl) amino ethyl ester hydrochloride

A mixture of 2.38 g (0.404 mmol) of the compound of step B) and 0.34 ml (4.04 mmol) of isopropylamine in 8 ml of acetonitrile is stirred for 12 hours at room temperature under argon as inert gas. Thereafter, the reaction mixture is diluted with ethyl acetate, washed three times with saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over potassium carbonate and evaporated. The residue is chromatographed on 300 ml silica gel (Merck) with 5% acetone / dichloromethane. There are obtained 0.84 g of a yellow foam. The foam is taken up in diethyl ether and treated with a solution of hydrogen chloride in diethyl ether. There are obtained 672 mg (30% of theory) of the title compound in the form of electrostatic yellow crystals of mp 110 to 13O ⁰ C (dec.). Thin layer chromatography with 10% acetone in dichloromethane gives two spots with an Rf of 0.38 and 0.46, respectively.

Example 18

1,2,3,4-tetrahydro-3 - [[[(S) -2-ethoxy-2-oxo-1- (phenylmethyl) ethyl] amino] carbonyl] -6-methyl-4- (3 -nitrophenyl) -2-oxo-5-pyrimidinecarboxylic acid-1-methyläthylester

A mixture of 4.0 g (12.0 mmol) of the compound of Example 2A and 6.69 ml (48.0 mmol) of triethylamine in 48 ml of acetonitrile is added dropwise in an ice bath under argon as a protective gas by means of a syringe with 12.0 ml of a 1.3 molar solution of phosgene in toluene (15.6 mmol). After stirring for 1 hour at ⁰ ° C, the reaction mixture is washed with 3.31 g (14.4 mmol) of L-

Phenylalaninäthylester hydrochloride and stirred for 1 hour at room temperature. Thereafter, the reaction mixture is diluted with a mixture of 100 ml of tetrahydrofuran and 100 ml of methanol and mixed with 15 ml (45 mmol) of 3N hydrochloric acid. The mixture is then stirred for 1 hour at room temperature, then cooled in an ice bath and treated with saturated aqueous sodium bicarbonate solution. The resulting mixture is partially evaporated and the residue extracted with ethyl acetate. The ethyl acetate extracts are washed with saturated brine, dried over magnesium sulfate and evaporated.

The residue is chromatographed on 600 ml of silica gel (Merck) with 5% ethyl acetate / dichloromethane. This process gives 2.5 g of a mixture of the two isomers as well as a slowly migrating isomer each as a yellow foam. The slowly migrating isomer B is recrystallized from dichloromethane / isopropyl ether. There are obtained 1.30 g yellowish / white crystals, melting at 132-133 ⁰ C. The mother liquor is combined with the mixture of the two isomers and recrystallized from dichloromethane / isopropyl ether. Another 0.60 g of slowly migrating isomer is obtained as colorless crystals. The filtrate is partially evaporated. Two crystal yields of 2.45 g and 1.39 g of the rapidly migrating isomer A are obtained. These two crystal quantities are combined and recrystallized. 1.34 g (21% of theory) of the rapidly migrating isomer are obtained in the form of bright electrostatic needles of melting point 122 to 124 ^° C. Thin layer chromatography with 10% ethyl acetate in dichloromethane gives a single spot with an R _r of 0.59. [a] _D - + 165 ° (1% chloroform).

The corresponding slowly migrating portions of isomer B are combined and recrystallized. 1.57 g (24% of theory) of colorless, moderately electrostatic needles of melting point 134 to 135 ° C. are obtained. Thin layer chromatography with 10% ethyl acetate in dichloromethane provides a single spot with an R _r value of 0.43 [a] _D = -155 ° (1%, chloroform).

C27H30N4O8; C H N (fast isomer) calc .: 60.21 5.61 10.41 (slow isomer) Found .: 60.24 5.66 10.37 60.17 5.60 10.34

Example 19

1,2,3,4-tetrahydro-6-methyl-3 - [[[2- [methyl (phenylmethyl) amino] ethyl] amino] carbonyl] -4- (3-nitrophenyl) -2- oxo-5-pyrimidinecarboxylic acid-1-methyläthylester

A solution of 2.0 g (6, OmMoI) of the compound of Example 2A) and 1.25 mL (9, OmMoI) triethylamine in 18 mL acetonitrile is added in an ice bath under argon as a shielding gas by means of a 6.0 mL syringe (7.8 mmol) ) a 1.3 molar solution of phosgene in toluene. After stirring for 3 hours at ⁰ ° C., the reaction mixture is treated with a solution of 1.25 ml (9, OmMoI) triethylamine and 1.523 g (9, OmMoI) of N-benzyl-N-methylaminoethylamine in 12 ml of anhydrous tetrahydrofurate under argon as protective gas. The reaction is carried out at 0 ^° C. for 90 minutes. It is then diluted with 24 ml of tetrahydrofuran and 24 ml of methanol and the mixture is mixed with 30 ml of 1 N hydrochloric acid. The reaction mixture is then stirred for 2 hours at room temperature and then treated with saturated aqueous sodium bicarbonate solution. The resulting mixture is partially evaporated and the residue extracted with ethyl acetate. The ethyl acetate extracts are combined, washed with saturated brine, dried over magnesium sulfate and evaporated. There are obtained 3.12 g of a yellow foam, which is chromatographed with 2% methanol in dichloromethane. The product is recrystallized from diethyl ether / isopropyl ether. There are obtained 1.64 g (54% d. Th.) Of colorless crystals, melting at 133 to 135 ⁰ C. Thin layer chromatography with 2% methanol in dichloromethane provides a single spot with an Rf of 0.17.

C ₂₆ H ₃₁ N ₆ O ₆ C H N calc. 61.28 6.13 13.74 gef. 61.33 6.19 13,49

Example 20

W-S-EtDimethylaminoJ-carbonyll-I ^ .S ^ -tetrahydro-e-methyl ^ -O-nitrophenyO-Z-oxo-B-pyrimidincarbonsaure-imethyläthylester

A) SA-dihydro-t-methoxy-phenyl-methyl-thiol-e-methyl-S-nitrophenoxy-SS-pyrimidine-dicarboxylic acid ethyl) ester, 3- [1- [1,1-dimethylethoxyl-carbonyl-Sis-methoxy-carbonyl-SIRI -pyrrolidinyll ester

A solution of 1,4-dihydro-2 - [[(4-methoxyphenyl) methyl] thio] -6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester in 44 ml of pyridine is added at Room temperature under nitrogen as inert gas with 22 ml of a 1.3 molar solution of phosgene in toluene (1.3 equivalents). The mixture is stirred for 2 hours and then treated dropwise with a solution of 8.6 g (35.2 mmol) of HdJ-dimethylethoxycarbonylM-itrans-hydroxy-L-proline methyl ester in 20 ml of pyridine. After stirring for 24 hours at room temperature, thin layer chromatography in a 1: 2 mixture of ethyl acetate and hexane shows that the reaction is incomplete. The mixture is treated with a further 5.4 g (22 mmol) of the proline compound in 15 ml of pyridine and the reaction is carried out for a further 24 hours. Thereafter, the reaction mixture is diluted with 100 ml of ethyl acetate. The organic phase is washed twice with 50 ml of saturated aqueous sodium bicarbonate solution, twice with 50 ml of sodium dihydrogen phosphate solution and twice with 50 ml of water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The foam is chromatographed on 1000 g of silica gel with a 1: 2 mixture of ethyl acetate and hexane. There are obtained 9.3 g (58% of theory) of the title compound as a yellow foam.

B) I ^ S ^ -tetrahydro-e-methyl-O-nitrophenyl O-α-thioxo-SB-pyrimidine-carboxylic acid Sd-methyl-ethyl-di-ester, 3- [5 (S) -methoxycarbonyl) -3 (R) -pyrrolidinyl] esters

9.3 g (12,8mMol) of the compound from Step A) in 11 ml dichloromethane are added dropwise at 0 ⁰ C under nitrogen as protective gas in a mixture of 26 ml of trifluoroacetic acid and 2.6 ml anisole. The mixture is stirred at ⁰ ° C. for 90 minutes. Thereafter, the trifluoroacetic acid is distilled off under reduced pressure. The yellow residue is taken up in 100 ml of dichloromethane. The organic solution is washed with 50 ml of water and twice with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The oily residue is taken up in an 80: 20: 1 mixture of ethyl acetate, hexane and methanol, cooled to -78 ° C and treated with 1 equivalent of a solution of hydrogen chloride in diethyl ether. The light yellow solid is filtered off and dried under reduced pressure. There are obtained 6.0 g (86% of theory) of a mixture of the diastereomers The free base of the mixture is allowed to freeze on Celite immediately prior to chromatographic separation by treating the dichloromethane solution with caustic soda and ether organic ether 60: 40: 1 mixture of ethyl acetate, hexane and methanol and then with a 80: 20: 1 mixture of the same solvent allows the separation into the two isomers A and B. All fractions are acidified with a solution of hydrogen chloride in diethyl ether , 01 g isomer A (57% of theory), yield of isomer B 2.04 g (58% of theory).

C) (-) - 1,2,3,4-Tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid 1-methyl ethyl ester

To a solution of 2.01 g (3.7 mmol) of the isomer A obtained in step B) in 4 ml of methanol is added a solution of sodium methoxide in methanol (2 equivalents). The mixture is stirred at room temperature. After 16 hours, the pH is adjusted to pH 2 with a solution of hydrogen chloride in diethyl ether, and then the mixture is cooled to -78 ° C. The resulting solid is filtered off. From the mother liquors three more quantities of crystals are obtained. Total yield 1.0g (79% of theory). Ia] ₀ = -90.1 "(c = 1, DMSO).

D) (-) - 1,4-Dihydro-2 - [[(4-methoxyphenyl) -methyl] thio] -6-methyl-4- (3-nitrophenyl) -5-pyrimidinecarboxylic acid 1-methyl ethyl ester

884mg (2.6 mmol) of the compound of Step C) is dissolved in anhydrous tetrahydrofuran, the solution is cooled to 0 ⁰ C and treated dropwise (with 393 μΙ 1.1 equiv., 32.9 mmol) of 4-methoxybenzyl chloride. After completion of the addition, the bath is removed and the mixture is stirred for 2 hours at room temperature. Thereafter, the mixture is heated to 65 ⁰ C for 16 hours. Thin layer chromatography with a 35:65 mixture of acetone and hexane shows incomplete reaction. Therefore, again 393μ, 14-methoxybenzyl chloride are added. After 7 hours of reaction at 65 ° C, the reaction mixture is warmed to room temperature and diluted with diethyl ether. Upon cooling to ⁰ ° C., a white solid is formed which is filtered off with suction, washed with diethyl ether and dried. Yield: 636 mg (49% of theory) of the title compound as the hydrochloride.

E) (-) - 3,4-ΟϊΚγαΓΓ-3 - [(αΪΓηβίΙινΐ3Γηϊπο) -ο3ΛοηνΙ] -2 - [[(4-ηΊβίΗοχγρΗβηγΙ) -πιβίήγΙ] -ίΙιϊο] -6-ΓηβίΗγΙ-4- (3-η ^ ΓορΙιβηγΙ ) -5-pyrimidinecarboxylic acid-i-methyläthylester

The free base of the compound obtained in step D) is prepared by washing a dichloromethane solution with sodium bicarbonate. The organic phase is dried, filtered and evaporated under reduced pressure. A green colored foam is obtained. Dissolve 754 mg (1.66 mmol) of the foam in 8.3 mL anhydrous dichloromethane and add 1.2 mL (8.3 mmol, 5 equiv.). Then 2.0 ml (2.66 mmol, 1.6 equiv.) Of a 1.3 molar solution of phosgene in toluene are added to the mixture at ⁰ ° C. After completion of the addition, the bath is removed and the mixture is stirred at room temperature. After 30 minutes, 1.66 ml (excess) of dimethylamine are added and the mixture is stirred for 30 minutes. The reaction mixture is diluted with 50 ml of ethyl acetate, washed twice with 1 N hydrochloric acid and twice with saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. There are 586mg of an oil left behind. The oil is chromatographed on 40 g of silica gel with a 1: 2 mixture of ethyl acetate and hexane. Yield 355 mg (41% of theory) of pure title compound as an oil.

F) (-) - 3 - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidine-carboxylic acid-1 methyläthylester

a solution of the compound obtained in step E) in 6.7 ml of anhydrous dichloromethane is added at 0 ⁰ C under nitrogen as a protective gas with 349 mg (2, OmMoI, 3 equiv.) Of 3-chloroperbenzoic acid. The mixture is stirred for 12 hours at room temperature. This forms a precipitate. The mixture is diluted with 15 ml of ethyl acetate and washed twice with 1 N hydrochloric acid and twice with 1 N sodium hydroxide solution and then with water. The organic phase is dried over magnesium sulfate,

filtered and evaporated under reduced pressure. There are 390mg of an oil left behind. This oil is chromatographed on 39 g silica gel with a 2: 1 mixture of ethyl acetate and hexane. There remains behind an oil which is allowed to stand in diethyl ether for 48 hours and then digested. Are obtained 144mg (55% d. Th.) Of white crystals, mp 152-153 ⁰ C. Mo = -128.6 ° (c = 1.2, chloroform).

C ₁₈ H ₂₂ N ₄ O _6; C H N calc .: 55.38 5.68 14.35 Found .: 55.41 5.68 14.17

Example 21

(+) - 3 - [(dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidine-carboxylic acid-1-methyläthylester

A) (+) - 1,2,3,4-Tetrahydro-6-methyl-4- (3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid 1-methyl ethyl ester

To a solution of 2.04 g (3.7 mmol) of the isomer B obtained in Example 20B) in 18 ml of methanol is added 1.6 ml (7.5 mmol, 2 equiv.) Of sodium methoxide in methanol. The mixture is stirred for 16 hours at room temperature. Thereafter, the pH is adjusted to pH 2 with a solution of hydrogen chloride in diethyl ether and the mixture is cooled to 0 ^° C. for 6 hours. The resulting crystals are filtered off. From the mother liquors, a further three crystal yields are obtained. Total yield 1.12 g (89% of theory). Mo = + 85 ° (c = 0.5, dimethyl sulfoxide).

B) (+) - 1 _/ 4-dihydro-2 - [[(4-methoxy-phenyl) -methyl] -thio] -6-methyl-4- (3-nitrophenyl) -5-pyrimidine-carboxylic acid 1-methyl-ethyl ester

884 mg (2.6 mmol) of the compound of step A) are dissolved in anhydrous tetrahydrofuran, cooled to 0 ° C and treated dropwise with 393 μ \ (32.9mMol, 1.1 equiv.) Of 4-methoxybenzyl chloride. After completion of the addition, the bath is removed and the mixture is stirred for 2 hours at room temperature. Thereafter, the mixture is heated to 65 ° C for 16 hours. Thin layer chromatography with a 35:65 mixture of acetone and hexane showed incomplete reaction. Therefore, an additional 176μ.Ι (0.5 equiv.) Of 4-methoxybenzyl chloride is added. After 7 hours of reaction at 65 ⁰ C, the reaction mixture is warmed to room temperature and diluted with diethyl ether. Thereafter, the mixture is cooled to 0 ^° C. The resulting white crystals are filtered off, washed with diethyl ether and dried. Yield 493 mg (38% of theory) of the title compound as hydrochloride.

C) (+) - 3,4-dihydro-3 - [(dimethylamino) carbonyl] -2 - [[(4-methoxyphenyl) methyl] thio] -6-methyl-4- (3-nitrophenyl) - 5-pyrimidinecarboxylic acid-1-methyläthylester

The free base of the compound obtained in step B) is prepared by washing a dichloromethane solution with sodium bicarbonate. The organic phase is dried, filtered and evaporated under reduced pressure. It leaves behind a green foam. 431 mg (0.95 mmol) of the foam are dissolved in 4.8 ml of anhydrous dichloromethane and admixed with 4.75 mmol (5 equiv.) Of triethylamine. The mixture is then treated dropwise at ⁰ ° C. with 662 μM, Ι (1.5 mmol, 1.6 equiv.) Of a 1.3 molar solution of phosgene in toluene. After completion of the addition, the bath is removed and the mixture is stirred at room temperature. After 30 minutes, 0.95 ml (excess) of dimethylamine are added and the mixture is stirred for 30 minutes. Subsequently, 50 ml of ethyl acetate are added, and the solution is washed twice with 1 N hydrochloric acid and twice with saturated aqueous sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. There remains an oil which is chromatographed on 40 g of silica gel with a 1: 2 mixture of ethyl acetate and hexane. Yield 431 mg (68% of theory) of the pure title compound as an oil.

D) (+) - 3 - [(Dimethylamino) carbonyl] -1,2,3,4-tetrahydro-6-methyl-4- (3-nitrophenyl) -2-oxo-5-pyrimidine-carboxylic acid 1- methyläthylester

A solution of the compound obtained in step C) in 8,2ml of anhydrous dichloromethane is added at 0 ⁰ C under nitrogen as protective gas with 424mg (2.5 mmol, 3 equiv.) Of 3-chloroperbenzoic acid. The mixture is stirred for 12 hours at room temperature. It forms a precipitate. The mixture is diluted with 15 ml of ethyl acetate and washed twice with 1 N hydrochloric acid, twice with 1 N sodium hydroxide solution and then with water. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure. There are 390 mg of an oil left behind. The oil is chromatographed on 39 g of silica gel with a 2: 1 mixture of ethyl acetate and hexane. There are obtained 433 mg of an oil. The oil is allowed to stand in diethyl ether for 48 hours and then digested. Are obtained 153-155 ⁰ C 254mg (67% d. Th.) Of white crystals of F.. Md = + 112.5 ° (c = 1.1, chloroform).

C ₁₈ H ₂₂ N ₄ O _6; C H N calc .: 55.38 5.68 14.35 Found .: 55.32 5.76 14.00

Example 22 S-IAminocarbonyO-i ^^^ - tetrahydro-e-methyl ^ fs-nitrophenyO ^ -oxo-S-pyrimidinecarboxylic-i methyläthylester, +)! -

isomer

A solution of 1.7 g (3.65 mmol) of the isomer of Example 14 in 10 mL of trifluoroacetic acid is heated at 75 ° C for 4 hours. Thereafter, the reaction mixture is cooled to room temperature and the solvent is distilled off. The residue is taken up in ethyl acetate and washed with water, aqueous sodium bicarbonate solution and brine. Thereafter, the ethyl acetate solution is dried over magnesium sulfate and evaporated. There remains behind a yellow foam, which is recrystallized from a mixture of isopropyl ether and diethyl ether. Yield 1.12 g of colorless solid. After recrystallization from isopropyl ether / dichloromethane 870 mg of the pure title compound of mp. 160 to 161 ⁰ C are obtained. Md = + 153 ° (1%, methanol).

C ₁₆ H ₁₈ N ₄ O _6; CHN

Cons .: 53.03 5.01 15.47

Filled: 53.06 5.01 15.47

Example 23 S-IAminocarbonyll-i ^^^ - tetrahydro-e-methyl ^ O ^ nitrophenyO oxo-S-pyrimidinecarboxylic-i methyläthylester, -) -

isomer

A solution of 60 mg (0.13 mmol) of the isomer A of Example i'4in lOmlTrifluoressigsäure is heated to 75 ⁰ C for 4 hours. Thereafter, the reaction mixture is cooled to room temperature and the solvent is distilled off. The residue is taken up in ethyl acetate and washed with water, sodium bicarbonate solution and brine. Thereafter, the ethyl acetate solution is dried over magnesium sulfate and evaporated. There remains behind a yellow foam which is recrystallized from isopropyl ether / dichloromethane. Yield 27 mg of the title compound of mp 160-161 ° C. [a] ₀ = -149 ° (1%, methanol).

C ₁₆ H ₁₈ N ₄ O _6; C H N calc .: 53.03 5.01 15.47 Found .: 53,20 5.12 15.11

Further compounds which can be prepared according to the invention are:

4- (2,3-dichlorophenyl) -1,2,3,4-tetrahydro-6-methyl-3 - [[(methyl) - (phenylmethyl) amino] carbonyl] -2-oxo-5-pyrimidincarbonsäureäthylester,

1,2,3,4-tetrahydro-6-methyl-4- (2-nitrophenyl) -2-oxo-3 - [[(4- (phenylmethyl) -1-piperazinyl] carbonyl] -5-pyrimidincarbonsäureäthylester,

! ^, S ^ -tetrahydro-e-methyl-S-iN-morpholinyl-carbonyll ^ -O-nitrophenyD ^ -oxo-ö-pyrimidine-carboxylic acid ^ -Kmethyl) - (phenylmethyl) amino] ethyl ester,

4- (7-benzofurazanyl) -1,2,3,4-tetrahydro-6-methyl-2-oxo-3 - [[4- (diphenylmethyl) -1-piperazinyl] carbonyl] -5-pyrimidincarbonsäureäthylester,

1,2,3,4-tetrahydro-6-methyl-4- [2- (methylthio) -3-pyridinyl] -3 - [[[(methyl) - [2 - [(methyl- (phenylmethyl) amino] ethyl]] - amino] carbonyl] -2-oxo-5-pyrimidine-carboxylate,

3 - [[(cyclohexyl) - (methyl) amino] carbonyl] -1,2,3,4-tetra-hydro-6-methyl-2-oxo-4- [2- (trifluoromethyl) phenyl] - 5-pyrimidincarbonsäureäthylester,

! ^, S ^ -tetrahydro-e-methyl-S-tKmethyll lphenyö-amino-carbonyll ^ -O-nitrophenyll ^ -oxo-S-pyrimidinecarboxylic-i- (phenylmethyl) -4-piperidinyl,

4- (2-chloro-3-nitrophenyl) -1,2,3,4-tetrahydro-6-methyl-3 - [[(methyl) - (1-methylethyl) amino] carbonyl] -2-oxo- 5-pyrimidinecarboxylic acid-i-diphenylmethyM-piperidinyl ester,

4- (2,3-dichlorophenyl) -1,2,3,4-tetrahydro-6-methyl-3 - [[(methyl) - (phenylmethyl) amino] carbonyl] -2-thioxo-5-pyrimidincarbonsäureäthylester,

! ^, S ^ -tetrahydro-e-methyl ^ -O-nitrophenyll-S-li-piperidinylcarbonyO ^ -thioxo-ö-pyrimidine-carboxylic acid-i-methyläthylester,

1,2,3,4-tetrahydro-6-methyl-4- (2-nitrophenyl) -3 - [[(4- (phenylmethyl) -1-piperazinyl] carbonyl] -2-thioxo-5-pyrimidincarbonsäureäthylester,

! ^, S ^ -tetrahydro-e-methyl-S-IN morpholinylcarbonyD ^ fs-nitrophenyO ^ -thioxo-S-pyrimidine-carboxylic acid ^ -Kmethyl) - (phenylmethyl) amino] ethyl ester,

4- (7-benzofurazanyl) -1,2,3,4-tetrahydro-6-methyl-3 - [[4- (diphenylmethyl) -1-piperazinyl] carbonyl] -2-thioxo-5-pyrimidincarbonsäureäthylester,

1,2,3,4-tetrahydro-6-methyl-4- [2- (methylthio) -3-pyridinyl] -3 - [[[(methyl) - [2 - [(methyl) - (phenylmethyl) amino ] ethyl]] - amino] carbonyl] -2-thioxo-5-pyrimidincarbonsäureäthylester,

3 - [[(cyclohexyl) - (methyl) amino] carbonyl] -1,2,3,4-tetrahydro-6-methyl-2-thioxo-4- [2- (trifluoromethyl) -phenyl] -5- pyrimidincarbonsäureäthylester,

1,2,3,4-tetrahydro-6-methyl-3 - [[(methyl) - (phenyl) amino] carbonyl] -4- [3-nitrophenyl) -2-thioxo-5-pyrimidinecarboxylic acid-1- (phenylmethyl) -4-piperidinyl,

1- (2-chloro-3-nitrophenyl) -1,2,3,4-tetrahydro-6-methyl-3 - [[(methyl) - (1-methylethyl) amino] carbonyl] -2-thioxo- 5-pyrimidine carboxylic acid-i-diphenylmethyl ^ -piperidinylester.

Claims (1)

Process for the preparation of 5-pyrimidinecarboxylic acid compounds of general formula I. RR ₁ NCN and their pharmacologically acceptable salts, characterized in that starting from a compound of general formula VI or XI O
RR ₁ NCN j] C-OR _{3 (VI)} or (XI) the protecting group, wherein X is an oxygen or sulfur atom, R is a hydrogen atom, an alkyl, cycloalkyl, aryl or aralkyl radical and R _{1 is} a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclo, a group of general formula -C- (CH ₂ ) - ^ '"Υ '' ( ' * ~" 2 ^ d "" 3 or a halogensubstituted R ₁ or R ₁ together with the nitrogen atom to which they are bonded are a 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl , 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl or 1-pyrrolidinyl, 1-piperidinyl or 1-azepinyl group represented by alkyl, alkoxy, alkylthio , Halogen, trifluoromethyl or hydroxy, R _{2 is} a hydrogen atom, an alkyl, alkenyl, alkynyl, cycloalkyl or aryl radical, a group of the general formula H -C- (CH ₇ ) -Y ₁ or a halogen-substituted alkyl radical, R _{3 is} a hydrogen atom, an alkyl, cycloalkyl, aryl or heterocyclo radical, a group of the general formula R- R _c ι 5 (5 -C- (CH) -Y, -C- (CH) -Γ or a halogen-substituted * ₅ ⁿ * 6 ^P ; Alkyl radical is, R _{4 is} an aryl or heterocyclic radical, R ₅ and R _{6 are} independently hydrogen, alkyl, - (CH ₂ ) q -aryl or - (CH ₂ ) _q cycloalkyl, Y _{1 is} a cycloalkyl, aryl, heterocyclo, hydroxyl, alkoxy, aryl, (CH ₂ Im-O, mercapto, alkylthio, aryl (CH ₂ ) _m -S, amino, substituted amino , Carbamoyl, O O Il (substituted amino) -C-, heterocyclo- (CH ₉ ) -C-, carboxyl, ο ο ο Il Il Il Alkoxycarbonyl, alkyl-C-, aryl- (CH ₂ ) -C-, alkyl-C-O- or