CN1315811C - Pyrimidine derivatives and preparing method thereof - Google Patents

Abstract

The present invention provides a pyrimidine derivative and a preparation method thereof, which are pyrimidine derivatives represented by the general formula (I) and their non-toxic salts and in vivo hydrolyzable esters: in the formula: R ₁ and R ₂ are independently selected from H and acyl; R ₃ is selected from H and halogen atoms; R ₄ and R ₅ are independently selected from H and halogen atoms; X is independently selected from H, halogen atoms, SCN, N ₃ , O, S; when X is independently selected from From O and S, there is _R substituent, and _R represents H, alkyl, substituted aryl, substituted heteroaryl, substituted condensed heteroaryl, acyl; it can be used to prepare medicines.

Description

Pyrimidine derivatives and methods for their preparation

technical field

The invention relates to a pyrimidine derivative and a preparation method thereof.

Background technique

Pyrimidine derivatives are a broad class of compounds that can be used in the preparation of drugs or herbicides, such as:

1. It is disclosed in CN1406229A that the general formula (W) is useful as a cell cycle kinase inhibitor.

This specification reports that the compound represented by general formula (W) significantly inhibits the action of cell cycle kinases, shows selectivity for CDK2, CDK4, CDK6, and also inhibits FAK. These properties are believed to be valuable in the treatment of disease states associated with abnormal cell cycle and cell proliferation.

2. Pyrimidine compounds are disclosed as elastase inhibitors in JP-P5-286946, JP-7-505876, JP-7-505877 and J.Med.Chem., 38 , 98 (1995) is useful.

3. In WO98/24806, it is disclosed that it is useful as a serine protease inhibitor.

4. It is disclosed in WO96/33974 and WO98/09949 that it is useful as a chymase inhibitor.

5. It is disclosed in US4601747, US4746353, EP41623 and US4459408 that it is useful as a herbicide.

It can be seen that pyrimidine derivatives can be widely used in the preparation of drugs. The invention provides a novel pyrimidine derivative and a preparation method thereof, which can be used to prepare medicines.

Contents of the invention

The invention provides a novel pyrimidine derivative and a preparation method thereof, which can be used to prepare medicines.

The technical solution adopted by the present invention to solve its technical problems is:

The present invention pyrimidine derivatives and preparation method thereof are characterized in that they are pyrimidine derivatives represented by general formula (I) and their non-toxic salts and in vivo hydrolyzable esters:

In the formula: R ₁ , R ₂ are independently selected from H and acyl; R ₃ is independently selected from H and halogen atoms; R ₄ , R ₅ are independently selected from H and halogen atoms; X are independently selected from H, halogen atoms, SCN , N ₃ , O, S; when X is independently selected from O and S, there is an R ₆ substituent, and R ₆ represents H, alkyl, substituted aryl, substituted heteroaryl, substituted fused heteroaryl, acyl.

The aforementioned pyrimidine derivatives, wherein the pyrimidine derivatives and their non-toxic salts and in vivo hydrolyzable esters are compounds represented by general formula (I-A):

In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms.

The aforementioned pyrimidine derivatives, wherein the pyrimidine derivatives and their non-toxic salts and in vivo hydrolyzable esters are compounds represented by general formula (I-B):

In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms.

The aforementioned pyrimidine derivatives are characterized in that the pyrimidine derivatives and their non-toxic salts and in vivo hydrolyzable esters are compounds represented by general formula (I-C):

In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms; X is independently selected from H, halogen atoms, SCN, N ₃ , O, S; when X is independently selected from O and S, there is R ₆ Substituent, R ₆ represents H, alkyl, substituted aryl, substituted heteroaryl, substituted condensed heteroaryl, acyl.

The aforementioned pyrimidine derivatives, wherein the pyrimidine derivatives and their non-toxic salts and in vivo hydrolyzable esters are selected from:

2-(4-Bromomethyl-pyrimidin-2-yl)isoindole-1,3-butanedione;

2-(4-Dibromomethyl-pyrimidin-2-yl)isoindole-1,3-butanedione;

2-Amino-5-bromo-4-methylpyrimidine;

2-Amino-5-bromo-4-bromomethylpyrimidine;

2-Amino-5-bromo-4-dibromomethylpyrimidine;

2-Amino-5-bromo-4-tribromomethylpyrimidine;

2-Amino-5-bromo-4-azidomethylpyrimidine;

2-Amino-5-bromo-4-thiocyanomethylpyrimidine;

2-Amino-5-bromo-4-hydroxymethylpyrimidine;

4-(2-Amino-5-bromo-pyrimidine)methylthiol;

2-Amino-5-bromo-4-methoxymethylpyrimidine;

2-Amino-5-bromo-4-ethoxymethylpyrimidine;

2-Amino-5-bromo-4-isopropoxymethylpyrimidine;

2-Amino-5-bromo-4-allyloxymethylpyrimidine;

2-Amino-5-bromo-4-benzyloxymethylpyrimidine;

2-amino-3-〖4-(2-amino-5-bromopyrimidine-4-methoxy)-phenyl〗propionic acid;

2-Amino-5-bromo-4-phenoxymethylpyrimidine;

2-Amino-5-bromo-4-p-tolyloxymethylpyrimidine;

2-Amino-5-bromo-4-(o-methylphenoxy)methylpyrimidine;

2-Amino-5-bromo-4-(4-methoxyphenoxy)methylpyrimidine;

2-Amino-5-bromo-4-(2-nitrophenoxy)methylpyrimidine;

2-Amino-5-bromo-4-(4-nitrophenoxy)methylpyrimidine;

2-Amino-5-bromo-4-(2,4-dichlorophenyl)methylpyrimidine;

2-Amino-5-bromo-4-(1-naphthyloxy)methylpyrimidine;

2-Amino-5-bromo-4-(2-naphthyloxy)methylpyrimidine;

2-Amino-5-bromo-4-phenylthiomethylpyrimidine;

(2-Amino-5-bromo-pyrimidin-4-ylmethyl)acetate;

(2-Amino-5-bromo-pyrimidin-4-ylmethyl)benzoate;

(2-Amino-5-bromo-pyrimidin-4-ylmethyl)phenylacetate;

(2-Amino-5-bromo-pyrimidin-4-ylmethyl)acrylate;

(2-amino-5-bromo-pyrimidin-4-ylmethyl)laurate;

(2R)-2-tert-butoxyamide-3-methylbutanoic acid (2-amino-5-bromo-pyrimidin-4-ylmethyl)ester;

2-Amino-5-bromo-4-[(N,N-diisopropylamino)-methyl]pyrimidine;

2-Amino-5-bromo-4-phenylaminomethylpyrimidine;

2-Amino-5-bromo-4-(1-naphthyl)aminomethylpyrimidine;

2-〖(2-Amino-5-bromopyrimidine-4-methyl)amino〗-3-methylbutanoic acid

2-〖(2-Amino-5-bromopyrimidine-4-methyl)amino〗-3-methylpentanoic acid

2-〖(2-Amino-5-bromopyrimidine-4-methyl)amino〗-3-(1H-indol-3-yl)propanoic acid

Or non-toxic salts, in vivo hydrolyzable esters of the above compounds.

The preparation method of pyrimidine derivatives of the present invention is characterized in that: the compound represented by the general formula (I-A) is obtained by 2-(4-methyl-pyrimidin-2-yl)isoindole-1,3-di Ketone (II-A) bromination reaction.

The method for preparing pyrimidine derivatives of the present invention is characterized in that: the compound represented by the general formula (I-B) is obtained by bromination reaction of 2-amino-4-methylpyrimidine (II-B).

The method for preparing pyrimidine derivatives of the present invention is characterized in that the compound represented by general formula (I-C) is obtained by reacting the compound represented by general formula (I-B) with the compound represented by general formula (II-C).

When X is independently selected from O and S, there is an _R6 substituent, and _R6 represents H, alkyl, substituted aryl, substituted heteroaryl, substituted condensed heteroaryl, acyl.

The preparation method of the aforementioned pyrimidine derivatives, wherein the reaction solvent is dichloromethane, chloroform, carbon tetrachloride, methanol, dimethyl sulfoxide, N, N-dimethylformamide, dioxane, acetic acid, water One solvent or a mixed solvent; the brominating agent can be NBS or liquid bromine; the reaction temperature is kept at 20-170°C.

The application of the pyrimidine derivatives of the present invention in the preparation of medicines.

The beneficial effect of the invention is that the structure of the compound is reasonable, the range of raw materials used is wide, the preparation method is simple, the cost of the synthesis process is low, and the product meets the requirements of environmental friendliness and green chemistry.

Detailed ways

After a lot of research, the inventors have found that 2-amino-4-methylpyrimidine derivatives of general formula (I) have good biological activity, can be directly used as medicine or herbicide, or can be used as an intermediate of useful medicine or herbicide .

In the formula: R ₁ , R ₂ are independently selected from H and acyl; R ₃ is independently selected from H and halogen atoms; R ₄ , R ₅ are independently selected from H and halogen atoms; X are independently selected from H, halogen atoms, SCN , N ₃ , O, S; when X is independently selected from O and S, there is a R ₆ substituent, and R ₆ represents H, alkyl, substituted aryl, substituted heteroaryl, substituted fused heteroaryl , acyl.

In order to achieve the purpose of synthesis, I have adopted the method shown in Reaction Scheme 1.

Reaction scheme 1

In reaction scheme 1, R ₁ , R ₂ are independently selected from H and acyl; R ₃ is independently selected from H and halogen atoms; R ₄ , R ₅ are independently selected from H and halogen atoms; X are independently selected from H, halogen atom, SCN, N ₃ , O, S; when X is independently selected from O and S, R ₆ represents H, alkyl, substituted aryl, substituted heteroaryl, substituted condensed heteroaryl, acyl.

In reaction scheme 1, the bromination reagent can be NBS or liquid bromine, and the solvent of all reactions can be dichloromethane, chloroform, carbon tetrachloride, methanol, dimethyl sulfoxide, N,N-dimethylformaldehyde One or a combination of amides, dioxane, acetic acid, and water, and the reaction temperature is kept at 20-170°C.

The pharmaceutically acceptable salts or in vivo hydrolyzable esters of the general formula (1) provided by the present invention also belong to this invention.

within the scope of the invention.

The compound of the present invention can be a crystalline substance or a solvated substance (such as a hydrate), and the substances in both states are within the scope of the present invention. The solvation method is widely known in the prior art and will not be repeated here. .

The present invention is described in detail by the following examples, but the present invention is not limited to these examples. Reagents not mentioned in the examples are purchased from the market and used as they are. Unless otherwise specified, all temperatures are in degrees Celsius.

Example 1: Preparation of 2-amino-5-bromo-4-bromomethylpyrimidine.

Weigh 1.09g (about 0.01mol) of 2-amino-4-methylpyrimidine and place it in a 100ml round bottom flask, add 40ml of dichloromethane or acetic acid, then add 0.76ml of liquid bromine (about 0.015mol) to it, and the reaction solution It is brownish red. The reaction temperature remains between 20-80 degrees. After stirring for 0.5-2 hours, add lye for neutralization. Extracted _{with CH2Cl2} , washed the extract with saturated NaCl. Dry ( _{anhydrous Na2SO4} ). After spin-drying, column chromatography (40 g of silica gel H, eluting with 2% CH ₃ OH/CH ₂ Cl ₂ ) gave 1.4 g of a white solid. Yield 52% [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.31(s, 1H, Pm), 5.09(br.s, 2H, NH2), 4.36(s, 2H, CH2).mp. 184°C (decomposition)

According to the method described in this example, the compound 2-amino-5-bromo-4-methylpyrimidine, 2-amino-5-bromo-4-bromomethylpyrimidine, 2-amino-5-bromo-4-dibromo Methylpyrimidine, 2-amino-5-bromo-4-tribromomethylpyrimidine, 2-(4-bromomethyl-pyrimidin-2-yl)isoindole-1,3-butanedione, 2-( 4-Dibromomethyl-pyrimidin-2-yl)isoindole-1,3-butanedione, only the bromine equivalents were changed accordingly.

Example 2: Preparation of 2-amino-5-bromo-4-thiocyanatomethylpyrimidine.

Weigh 100mg (0.37mmol) of 2-amino-5-bromo-4-bromomethylpyrimidine, 214mg potassium thiocyanide (1.48mmol), put it in a 25ml round bottom flask, add 10ml N,N-dimethylformaldehyde Amide, reflux for 1-5hr. Then add H ₂ O to the system, extract with dichloromethane or ethyl acetate, dry the extract with anhydrous Na ₂ SO ₄ , spin dry and go through column chromatography (silica gel H15g, 30% ethyl acetate/petroleum ether elution ) to obtain 50 mg of white solid. Yield 55%. [ ¹ H]NMR (300 MHz, CDCl ₃ ): δ8.331 (s, 1H, Pm), 5.160 (br.s, 2H, NH2), 4.283 (s, 2H, CH2). mp. 159°C (decomposition).

The method of this example can be used when the compound (II-C) is a salt or an inorganic base. For example, when (II-C) is sodium azide, the reaction gives 2-amino-5-bromo-4-azidomethylpyrimidine; when (II-C) is sodium hydroxide, the reaction gives 2-amino-5-bromo -4-Hydroxymethylpyrimidine; (II-C) is reacted with sodium hydrosulfide to obtain 4-(2-amino-5-bromo-pyrimidine) methyl mercaptan.

Example 3: Preparation of 2-amino-5-bromo-4-methoxymethylpyrimidine.

Weigh 100mg (0.37mmol) of 2-amino-5-bromo-4-bromomethylpyrimidine and place it in a 50ml round bottom flask weighing 20ml of methanol, add 12mg of metal Na (about 0.52mmol), and reflux for 1-2 hours. After spin-dried, the solid residue was washed with water, and separated by column chromatography (silica gel H15g, 3% CH ₃ OH/CH ₂ Cl ₂ ) to obtain 60 mg of a white solid. Yield 73%. TLC (3% _CH3OH / _CH2Cl2 ) _Rf = 0.3. [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.258(s, 1H, Pm), 5.20(br.s, 1H, NH2), 4.51(s, 2H, CH2), 3.53(s, 3H, CH3). mp.211-215°C.

If the compound (II-C) is a hydroxy or mercapto compound, the method of this example can be used but a suitable base is used. For example, when (II-C) is ethanol, the reaction gives 2-amino-5-bromo-4-ethoxymethylpyrimidine; when (II-C) is isopropanol, it should give 2-amino-5-bromo-4 -isopropoxymethylpyrimidine; (II-C) should give 2-amino-5-bromo-4-allyloxymethylpyrimidine when (II-C) is allyl alcohol; send out when (II-C) is benzyl alcohol Should get 2-amino-5-bromo-4-benzyloxymethylpyrimidine; (II-C) should get 2-amino-3-[4-(2-amino-5-bromopyrimidine) when tyrosine -4-methoxyl group)-phenyl〗propionic acid; (II-C) should give 2-amino-5-bromo-4-phenoxymethylpyrimidine when (II-C) is phenol; (II-C) is p-methylpyrimidine When phenol, it should give 2-amino-5-bromo-4-p-tolyloxymethylpyrimidine; when (II-C) is o-cresol, it should get 2-amino-5-bromo-4-(o-methyl Phenoxy) methyl pyrimidine; (II-C) is to get 2-amino-5-bromo-4-(4-methoxyphenoxy) methyl pyrimidine when (II-C) is p-methoxyphenol; (II- When C) is o-nitrophenol, 2-amino-5-bromo-4-(2-nitrophenoxy) methylpyrimidine should be obtained; (II-C) should be obtained when p-nitrophenol is 2- Amino-5-bromo-4-(4-nitrophenoxy) methyl pyrimidine; , 4-dichlorophenyl) methylpyrimidine; (II-C) is 1-naphthol and should get 2-amino-5-bromo-4-(1-naphthyloxy)methylpyrimidine; (II- When C) is 2-naphthol, it should obtain 2-amino-5-bromo-4-(2-naphthyloxy)methylpyrimidine; when (II-C) is benzenethiol, it should obtain 2-amino-5 -Bromo-4-phenylthiomethylpyrimidine.

Example 4: Preparation of 2-amino-5-bromo-4-phenylaminomethylpyrimidine.

Add 1ml of aniline, 255mg (1.84mmol) of anhydrous K ₂ CO ₃ (1.84mmol), 100mg of 2-amino-5-bromo-4-bromomethylpyrimidine (0.37mmol), 10ml of N,N- Dimethylformamide, reflux for 1-5hr. Then add H ₂ O to the system, extract with dichloromethane or ethyl acetate, dry the extract with anhydrous Na ₂ SO ₄ , spin dry and go through column chromatography (silica gel H15g, 30% ethyl acetate/petroleum ether elution ) to obtain 20 mg of a white solid with a yield of 19%. [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.268 (s, 1H, Pm), 7.258-7.199 (m, 2H, Ph), 6.780-6.731 (m, 3H, Ph), 5.155 (br. s, 2H, NH2), 5.086 (br.s, 1H, NH), 4.306 (s, 2H, CH2). mp. Decompose at 160°C.

If the compound (II-C) is an amine compound, the method of this example can be used. For example (II-C) is (N, when N-diisopropylamine reacts to obtain 2-amino-5-bromo-4-[(N, N-diisopropylamino)-methyl] pyrimidine; (II-C) When it is 1-naphthylamine, the reaction obtains 2-amino-5-bromo-4-(1-naphthyl)aminomethylpyrimidine; when (II-C) is valine, the reaction obtains 2-〖(2-amino-5 -Bromopyrimidine-4-methyl)amino〗-3-methylbutanoic acid; (II-C) is the reaction of isoleucine to obtain 2-〖(2-amino-5-bromopyrimidine-4-methyl)amino When -3-methylpentanoic acid (II-C) is tryptophan, the reaction gives 2-〖(2-amino-5-bromopyrimidine-4-methyl)amino〗-3-(1H-indole- 3-yl) propionic acid.

Example 5: Preparation of (2-amino-5-bromo-pyrimidin-4-ylmethyl) acetate.

Weigh 100mg (0.37mmol) of 2-amino-5-bromo-4-bromomethylpyrimidine and 121mg sodium acetate (1.48mmol), put them in a 25ml round bottom flask, add N,N-dimethylformamide to 10ml, Reflux 1-5hr. Then add H ₂ O to the system, extract with dichloromethane or ethyl acetate, dry the extract with anhydrous Na ₂ SO ₄ , spin dry and go through column chromatography (silica gel H15g, 30% ethyl acetate/petroleum ether elution ) to obtain 30 mg of white solid. Yield 32%. [ ¹ H]NMR (CDCl ₃ ): δ8.26 (s, 1H, Pm), 5.1 (br.s, 2H, NH2), 5.09 (s, 2H, CH2), 2.17 (s, 3H, CH3). mp.195-196°C.

When the compound (II-C) is a carboxylic acid compound, the method of this example can be used. For example, when (II-C) is benzoic acid, the reaction gives benzoic acid (2-amino-5-bromo-pyrimidin-4-ylmethyl) ester; when (II-C) is phenylacetic acid, the reaction gives phenylacetic acid (2-amino -5-bromo-pyrimidin-4-ylmethyl) ester; (II-C) reacts to obtain acrylic acid (2-amino-5-bromo-pyrimidin-4-ylmethyl) ester when (II-C) is acrylic acid; (II-C) When it is lauric acid, the reaction gives lauric acid (2-amino-5-bromo-pyrimidin-4-ylmethyl) ester; (II-C) is (2R)-2-tert-butoxyamide-3-methylbutanoic acid The reaction gives (2R)-2-tert-butoxyamide-3-methylbutanoic acid (2-amino-5-bromo-pyrimidin-4-ylmethyl)ester.

Table 1: Physicochemical data of compounds represented by general formula (I-C)

serial number R ₄ R ₅ x R ₆ character Mp./℃ 1 h h h - white solid 170-175 2 h H Br - white solid 184 ^* 3 h Br Br - white solid 133 ^* 4 Br Br Br - white solid 123 ^* 5 h H SCN - white solid 159 ^* 6 h H N ₃ - white solid 127-129 7 h H o CH ₃ (CH ₂ ) ₁₀ C=O white solid 96-97 8 h H o PhC=O white solid 150-152 9 h H o H ₂ C=CHC=O white solid 136-138 10 h H o _CH3C =O white solid 195-196 11 h H o _PhCH2C =O white solid 125-126 12 h H o Boc-Val white foamy solid 35-38 13 h H o _CH3 white solid 211-215 14 h H o (CH ₃ ) ₂ CH white solid 148-150 15 h H o CH ₃ CH ₂ white solid 158-192 16 h H o CH ₂ Ph white solid 151-153 17 h H o H ₂ C=CH white solid 139-140 18 h H S h white solid 212 ^* 19 h H o h pale yellow solid 159-162 20 h H o p-methylphenyl white solid 224 ^* twenty one h H o 1-Naphthyl white solid 165-167 twenty two h H o 2-naphthyl white solid 197-200 twenty three h H o Ph white solid 196-198 twenty four h H o p-Nitrophenyl white solid 195-198 25 h H o o-Nitrophenyl white solid 26 h H o p-Methoxyphenyl white solid 200-204 27 h H S Ph white solid 164-166 28 h H o 2,4-Dichlorophenyl white solid 147-149 29 h H o o-methylphenyl white solid 138-140 30 h H N ((CH ₃ ) ₂ CH) ₂ white solid 81-84 31 h H NH Ph white solid 160 ^* 32 h H NH 1-Naphthyl white solid 203-205

Note: ^* indicates decomposition

Table 2: Physicochemical data of compounds represented by general formula (I-A)

serial number R ₄ R ₅ Traits Mp./℃ 33 H Br   white solid 166 34 H H   white solid 176-178

Table 3: ¹ H NMR data of compounds

serial number NMR 1 [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.19(s, 1H, Pm), 5.00(br.s, 2H, NH2), 2.41(s, 3H, CH3) 2 [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.31(s, 1H, Pm), 5.09(br.s, 2H, NH2), 4.36(s, 2H, CH2) 3 [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.31(s, 1H, Pm), 6.80(s, 1H, CH), 5.31(s, 2H, NH2) 4 [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.41(s, 1H, Pm), 5.29(s, 2H, NH2) 5 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.331(s, 1H, Pm), 5.160(br.s, 2H, NH2), 4.283(s, 2H, CH2) 6 [ ¹ H]NMR (300MHz, CDCl ₃ ): δ8.309(s, 1H, Pm), 5.174(br.s, 2H, NH2), 4.370(s, 2H, CH2) 7 [ ¹ H]NMR (200MHz, CDCl ₃ ): δ8.25(s, 1H, Pm), 5.10(br.s, 2H, NH2), 5.08(s, 2H, CH2-Pm), 2.42(t, 2H , J=7.3Hz, O=C-CH2), 1.23-1.65(m, 18H, -(CH2) ₉ ), 0.85(t, 3H, J=6.3Hz, CH3) 8 [ ¹ H]NMR (200MHz, CDCl ₃ ): δ8.28(s, 1H, Pm), 8.08-8.12(m, 2H, Ph), 8.44-8.58(m, 3H, Ph), 5.32(s, 2H , CH2), 5.05 (br.s, 2H, NH2) 9 [ ¹ H]NMR (200MHz, CDCl ₃ ): δ8.26(s, 1H, Pm), 5.86-6.46(m, 3H, -CH=CH2), 5.16(s, 2H, CH2), 5.10(br. s, 2H, NH2) 10 [ ¹ H]NMR(CDCl ₃ ): δ8.26(s, 1H, Pm), 5.1(br.s, 2H, NH2), 5.09(s, 2H, CH2), 2.17(s, 3H, CH3)

11 [ ¹ H]NMR (200MHz, CDCl ₃ ): δ8.2(s, 1H, Pm), 7.23-7.33(m, 5H, Ph), 5.10(s, 2H, CH2-Pm), 4.62(br.s , 2H, NH2), 3.74 (s, 2H, CH2-Ph) 12 [ ¹ H]NMR (300MHz, CDCl ₃ ): δ8.249(s, 1H, Pm), 5.243(br.s, 2H, NH2), 5.177(s, 2H, CH2), 5.087(d, 1H, J =9.38Hz, C(O)-CH), 2.349-2.242(m, 1H, CH), 1.453(s, 9H, O(CH3) ₃ ), 1.044-0.950(dd, 6H, J ₁ =J ₂ = 7.04Hz, (CH3) ₂ ) 13 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.258(s, 1H, Pm), 5.20(br.s, 1H, NH2), 4.51(s, 2H, CH2), 3.53(s, 3H, CH3) 14 [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.246(s, 1H, Pm), 5.152(br.s, 2H, NH2), 4.492(s, 2H, CH2), 3.75(q, 2H, J=6.2Hz), 1.259-1.228(d, 6H, J=6.2Hz) 15 [ ¹ H]NMR (200MHz, CD ₃ Cl): δ8.228(s, 1H, Pm), 5.151(br.s, 2H, NH2), 3.658-3.586(q, 2H, J=7.2Hz, CH2) , 1.297-1.229 (t, 3H, J=6.8Hz, CH3) 16 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.259(s, 1H, Pm), 7.417-7.240(m, 5H, Ph), 5.179(br.s, 2H, NH2), 4.698(s, 2H, CH2-Pm), 4.540 (s, 2H, CH2-Ph) 17 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.259 (s, 1H, Pm), 5.988-5.929 (m, 1H, -CH=), 5.369-5.238 (2H, m, =CH2), 5.224 (br.s, 2H, NH2), 4.534 (s, 2H, CH2), 4.177-4.158 (d, 2H, J=5.86Hz) 18 [ ¹ H]NMR (200MHz, DMSO-d): δ8.26(s, 1H, Pm), 6.87(br.s, 2H, NH2), 3.78(s, 2H, CH2), 1.2(br.s, 1H, SH) 19 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.262(s, 1H, Pm), 5.170(br.s, 1H, NH2), 3.538(s, 2H, CH2), 1.758(br.s, 1H, OH) 20 [ ¹ H]NMR(DMSO-d6): δ8.34(s, 1H, Pm), 6.83-7.07(dd, 4H, Ph,), 6.95(br.s, 2H, NH2), 4.93(s, 2H , CH2), 2.23(s, 3H, CH3) twenty one [ ¹ H]NMR (300MHz, DMSO-d6): δ8.387(s, 1H, Pm), 8.180-8.155(d, 1H, naphthalene ring), 7.885-7.860(d, 1H, naphthalene ring), 7.551- 7.381 (4H, m, naphthalene ring), 7.016 (s, 1H, naphthalene ring), 6.991 (br.s, 2H, NH2) twenty two [ ¹ H]NMR (300MHz, DMSO-d6): δ8.380(s, 1H, Pm), 7.858-7.192(m, 7H, naphthalene ring), 7.032(br.s, 2H, NH2), 5.103(s , 2H, CH2)

twenty three [ ¹ H]NMR (200MHz, DMSO-d6): δ8.30(s, 1H, Pm), 7.20(m, 4H, Ph), 6.97(m, 3H, 1H-Ph, NH2), 4.96(s, 2H, CH2) twenty four [ ¹ H]NMR (200MHz, DMSO-d6): δ8.36(s, 1H, Pm), 8.22, 8.18, 7.19, 7.15(dd, 4H, J=8Hz, Ph), 7.00(br.s, 2H , NH2), 5.17 (s, 2H, CH2) 25 [ ¹ H]NMR (200MHz, DMSO-d6): δ8.35(s, 1H, Pm), 7.14-7.85(m, 4H, Ph), 6.99(br.s, 2H, NH2), 5.16(s, 2H, CH2) 26 [ ¹ H]NMR (200MHz, DMSO-d6): δ8.31(s, 1H, Pm), 6.97(br.s, 2H, NH2), 6.64-6.66(dd, 4H, Ph), 4.68(s, 2H, CH2), 3.66(s, 3H, CH3) 27 [ ¹ H]NMR (200MHz, DMSO-d6): δ8.30(s, 1H, Pm), 7.30-7.38(m, 5H, Ph), 7.07(br.s, 2H, NH2), 5.71(s, 2H, CH2) 28 [ ¹ H]NMR (300MHz, DMSO-d6): δ8.362 (s, 1H, Pm), 7.589-7.580 (d, 1H, Ph), 7.381-7.343 (dd, 1H, Ph), 7.173-7.143 ( d, 1H, Ph), 6.994 (br.s, 2H, NH2), 5.083 (s, 2H, CH2) 29 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.328(s, 1H, Pm), 7.167-6.833(m, 4H, Ph), 5.171(br.s, 2H, NH2), 5.059(s, 2H, CH2), 2.289 (s, 3H, CH3) 30 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.268 (s, 1H, Pm), 7.258-7.199 (m, 2H, Ph), 6.780-6.731 (m, 3H, Ph), 5.155 (br. s, 2H, NH2), 5.086 (br.s, 1H, NH), 4.306 (s, 2H, CH2) 31 [ ¹ H]NMR (300MHz, CD ₃ Cl): δ8.268 (s, 1H, Pm), 7.258-7.199 (m, 2H, Ph), 6.780-6.731 (m, 3H, Ph), 5.155 (br. s, 2H, NH2), 5.086 (br.s, 1H, NH), 4.306 (s, 2H, CH2) 32 [ ¹ H]NMR (300MHz, CDCl ₃ ): δ8.319 (s, 1H, Pm), 8.017-6.660 (m, 7H, naphthalene ring), 5.215 (br.s, 2H, NH2-Pm), 4.460 ( s, 2H, CH2), 1.8 (br.s, 1H, NH-naphthalene ring) 33 [ ¹ H]NMR (300MHz, CDCl ₃ ): δ9.047 (d, 1H, J=5.28Hz, 6-H-Pm), 8.022-70994 (m, 2H, Ph), 7.875-7.858 (d, J =5.28Hz, 1H, 5-H-Pm), 7.852-7.825(m, 2H, Ph), 6.560(s, 1H, CH) 34 [ ¹ H]NMR (300MHz, CDCl ₃ ): δ8.937(d, 1H, J=4.8Hz, 6-H-Pm), 8.016-7.988(m, 2H, Ph), 7.847-7.819(m, 2H , Ph), 7.573 (d, 1H, J=4.8Hz, 5-H-Pm), 4.538 (s, 2H, CH2)

Determination of herbicidal activity

In the biological activity test of the above-mentioned test samples, using commercialized tribenuron-methyl and other herbicides as a reference, the structure found that this type of compound has good herbicidal activity and herbicidal spectrum, and compounds 4, 14, 31, etc. Commercial herbicides such as tribenuron-methyl have comparable biological activity.

The above are only preferred embodiments of the present invention, and are not intended to limit the present invention in any form. Any simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention still belong to within the scope of the technical solutions of the present invention.

Claims (8)

1. A pyrimidine derivative, characterized in that it is a pyrimidine derivative represented by general formula (I) and a pharmaceutically acceptable salt thereof: In the formula: R ₁ , R ₂ are independently selected from H and acyl; R ₃ is independently selected from H and halogen atoms; R ₄ , R ₅ are independently selected from H and halogen atoms; X are independently selected from halogen atoms, SCN, N _3. O and S; when X is independently selected from O and S, there is an R ₆ substituent, and R ₆ represents H, alkyl, chlorine or methyl or methoxy or nitro substituted aryl or acyl. 2. The pyrimidine derivatives according to claim 1, characterized in that, the pyrimidine derivatives and their pharmaceutically acceptable salts are compounds represented by the general formula (I-B): In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms. 3. The pyrimidine derivatives according to claim 1, characterized in that, the pyrimidine derivatives and their pharmaceutically acceptable salts are compounds represented by the general formula (I-C): In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms; X is independently selected from halogen atoms, SCN, N ₃ , O and S; when X is independently selected from O and S, there is a R ₆ substituent , R ₆ represents H, alkyl, chlorine or methyl or methoxy or nitro substituted aryl, acyl. 4. The pyrimidine derivatives according to claim 1, 2 or 3, characterized in that, the pyrimidine derivatives and their pharmaceutically acceptable salts are selected from: 2-Amino-5-bromo-4-bromomethylpyrimidine; 2-Amino-5-bromo-4-dibromomethylpyrimidine; 2-Amino-5-bromo-4-tribromomethylpyrimidine; 2-Amino-5-bromo-4-azidomethylpyrimidine; 2-Amino-5-bromo-4-thiocyanomethylpyrimidine; 2-Amino-5-bromo-4-hydroxymethylpyrimidine; 4-(2-Amino-5-bromo-pyrimidine)methylthiol; 2-Amino-5-bromo-4-methoxymethylpyrimidine; 2-Amino-5-bromo-4-ethoxymethylpyrimidine; 2-Amino-5-bromo-4-isopropoxymethylpyrimidine; 2-Amino-5-bromo-4-allyloxymethylpyrimidine; 2-Amino-5-bromo-4-benzyloxymethylpyrimidine; 2-amino-3-〖4-(2-amino-5-bromopyrimidine-4-methoxy)-phenyl〗propionic acid; 2-Amino-5-bromo-4-p-tolyloxymethylpyrimidine; 2-Amino-5-bromo-4-(o-methylphenoxy)methylpyrimidine; 2-Amino-5-bromo-4-(4-methoxyphenoxy)methylpyrimidine; 2-Amino-5-bromo-4-(2-nitrophenoxy)methylpyrimidine; 2-Amino-5-bromo-4-(4-nitrophenoxy)methylpyrimidine; 2-Amino-5-bromo-4-(2,4-dichlorophenyl)methylpyrimidine; (2-Amino-5-bromo-pyrimidin-4-ylmethyl)acetate; (2-Amino-5-bromo-pyrimidin-4-ylmethyl)benzoate; (2-Amino-5-bromo-pyrimidin-4-ylmethyl)phenylacetate; (2-Amino-5-bromo-pyrimidin-4-ylmethyl)acrylate; (2-amino-5-bromo-pyrimidin-4-ylmethyl)laurate; (2R)-2-tert-butoxyamide-3-methylbutanoic acid (2-amino-5-bromo-pyrimidin-4-ylmethyl)ester; Or the pharmaceutically acceptable salt of above-mentioned compound. 5. The method for preparing pyrimidine derivatives according to claim 2, characterized in that: the compound represented by the general formula (I-B) is subjected to bromination reaction of 2-amino-4-methylpyrimidine (II-B) get:

In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms. 6. The preparation method of pyrimidine derivatives as claimed in claim 3, characterized in that: the compound represented by the general formula (I-C) is composed of the compound represented by the general formula (I-B) and the compound represented by the general formula (II-C) The response gets:

In the formula: R ₄ and R ₅ are independently selected from H and halogen atoms; X is independently selected from halogen atoms, SCN, N ₃ , O and S; when X is independently selected from O and S, there is a R ₆ substituent , R ₆ represents H, alkyl, chlorine or methyl or methoxy or nitro substituted aryl, acyl. 7. The method for preparing pyrimidine derivatives according to claim 5 or 6, characterized in that: the reaction solvent is dichloromethane, chloroform, carbon tetrachloride, methanol, dimethyl sulfoxide, N,N-dimethyl Formamide, dioxane, acetic acid, one solvent or a mixed solvent in water; the brominating agent is NBS or liquid bromine; the reaction temperature is kept at 20-170°C. 8. The use of the pyrimidine derivatives as claimed in claim 1 in the preparation of medicines.