CN1217947C - Method for preparation of triazolo pyrimidine derivative - Google Patents
Method for preparation of triazolo pyrimidine derivative Download PDFInfo
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- CN1217947C CN1217947C CN 02122861 CN02122861A CN1217947C CN 1217947 C CN1217947 C CN 1217947C CN 02122861 CN02122861 CN 02122861 CN 02122861 A CN02122861 A CN 02122861A CN 1217947 C CN1217947 C CN 1217947C
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- Prior art keywords
- chemical formula
- manufacture method
- alkyl
- pyrimidine derivative
- triazolo pyrimidine
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- 238000000034 method Methods 0.000 title claims abstract description 45
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical class BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title abstract description 19
- 239000000126 substance Substances 0.000 claims abstract description 77
- 238000004519 manufacturing process Methods 0.000 claims abstract description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 27
- 150000002466 imines Chemical class 0.000 claims abstract description 17
- -1 alkyl cyanogen Chemical compound 0.000 claims abstract description 14
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- 239000002904 solvent Substances 0.000 claims description 29
- 238000006243 chemical reaction Methods 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 18
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000010992 reflux Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 13
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- 230000001476 alcoholic effect Effects 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 229960001701 chloroform Drugs 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical group COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- 239000003377 acid catalyst Substances 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 229910052751 metal Inorganic materials 0.000 claims description 6
- 239000002184 metal Substances 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 235000010755 mineral Nutrition 0.000 claims description 6
- 150000007524 organic acids Chemical group 0.000 claims description 6
- 150000003973 alkyl amines Chemical class 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 150000004985 diamines Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229960003505 mequinol Drugs 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 229910052788 barium Inorganic materials 0.000 claims description 3
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052790 beryllium Inorganic materials 0.000 claims description 3
- ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 3
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052701 rubidium Inorganic materials 0.000 claims description 3
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052712 strontium Inorganic materials 0.000 claims description 3
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium atom Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 2
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 2
- ICGQLNMKJVHCIR-UHFFFAOYSA-N 1,3,2-dioxazetidin-4-one Chemical compound O=C1ONO1 ICGQLNMKJVHCIR-UHFFFAOYSA-N 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 125000003368 amide group Chemical group 0.000 description 6
- 238000001035 drying Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000002562 thickening agent Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HUUBMTMJIQHAEN-UHFFFAOYSA-N triazole-1,4-diamine Chemical class NC1=CN(N)N=N1 HUUBMTMJIQHAEN-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 208000003643 Callosities Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to a method for preparation of a triazolo pyrimidine derivative, with the following chemical formula (I), wherein R1 is selected from a hydrogen atom, the alkyl of C1 to C10, the cycloalkyl of C3 to C6 or the alkenyl of C1 to C4; R2 is selected from the hydrogen atom, halogen, the hydroxyalkyl of C1 to C10 or the alkyl of C1 to C10; R3 is selected from the hydrogen atom, the hydroxyalkyl of C1 to C4 or the alkyl of C1 to C4. The method contains diamine-1, 2, 4-triazol rapidly prepared from alkyl cyanogen dimercapto imino carbonate, and the amino is efficiently protected and de-preserved; alpha, beta-unsaturation acid derivatives and imine are condense in the way of selectivity, and the method has the efficiency for enhancing production efficiency and reducing the cost.
Description
Technical field
The invention relates to a kind of manufacture method with triazolo pyrimidine derivative of following chemical formula (I):
Wherein, R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
2Be to be selected from hydrogen atom, halogen, C
1-C
10Hydroxyalkyl or C
1-C
10Alkyl;
R
3Be to be selected from hydrogen atom, C
1-C
4Hydroxyalkyl or C
1-C
4Alkyl.
Background technology
Therefore as everyone knows, have the compound of chemical formula (I), it is very effective for prevention bronchospasm, can be used for the treatment of with the spasm of muscularis of bronchus or holds the diseases associated that contracts under the arm, for example: asthma or bronchitis etc.
United States Patent (USP) the 3rd, 689 has disclosed preparation in No. 488 and has had the program of chemical formula (I) compound, is summarized as follows:
(a) two amidos-1,2, the preparation of 4-triazole, (one) is as follows for its chemical equation:
(b) preparation of triazolo pyrimidine, (two) are as follows for its chemical equation:
In the manufacturing course of above-mentioned United States Patent (USP), following shortcoming is arranged:
The first, (a) preparation two amidos-1,2, the program of 4-triazole need spend time a couple of days, and efficient is very low;
The second, by two amidos-1,2,4-triazole and have the α of chemical formula (II), the condensation of β-unsaturation acid derivative, and the mixture that produces isomer is a non-selectivity, therefore needs further purifying, causes manufacturing cost higher.
The 3rd, hydrogenolysis phenmethyl group (being the protection of going of amido) need spend 10 days with the triazolo pyrimidine that generation has chemical formula (I), and is very consuming time, by commercial point of view, shows that above-mentioned preparation procedure is that efficient is very low, and both expensive, is not suitable for using.
Summary of the invention
The manufacture method that the purpose of this invention is to provide a kind of triazolo pyrimidine derivative, by preparing two amidos-1,2 fast by dialkyl group cyano group disulfide group imines, the 4-triazole is protected amido and go protection effectively; And selectivity condensation α, β-unsaturation acid derivative and imines overcomes the drawback of prior art, reaches the purpose of enhancing productivity and reducing cost.
The object of the present invention is achieved like this: a kind of manufacture method of triazolo pyrimidine derivative is characterized in that: the chemical formula of this derivative (I) is:
R wherein
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
2Be to be selected from hydrogen atom, halogen, C
1-C
10Hydroxyalkyl or C
1-C
10Alkyl;
R
3Be to be selected from hydrogen atom, C
1-C
4Hydroxyalkyl or C
1-C
4Alkyl;
Its manufacture method comprises following steps at least:
(1) under room temperature and under the appropriate solvent existence, to have the dialkyl group cyano group disulfide group imines of chemical formula V and have the alkylamine of chemical formula (IV), then after reflux, splash into diamine, obtain having chemical formula two amidos-1 of (III), 2, the compound of 4-triazole, this chemistry formula V, (IV) and (III) be respectively:
Wherein R is selected from C
1-C
4Alkyl;
R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
(2) there are compound that will have chemical formula (III) down and aldehyde reaction in organic solvent, make (VI) group with imine moiety that has chemical formula, this chemical formula (VII) and (VI) be with chemical formula (VII):
R wherein
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
8Be to be selected from C
1-C
10Alkyl or phenyl;
(3) under reflux temperature, in the organic solvent of alkali and polymer inhibitor existence, the selectivity condensation has α, β-unsaturation acid derivative of chemical formula (II) and has the imines of chemical formula (VI), formation has the imines of chemical formula (VIII), and this chemical formula (II) and chemical formula (VIII) are respectively:
R wherein
2Be to be selected from hydrogen atom, halogen, C
1-C
10Hydroxyalkyl or C
1-C
10Alkyl;
R
3Be to be selected from hydrogen atom, C
1-C
4Hydroxyalkyl or C
1-C
4Alkyl;
R
5Be to be selected from halogen atom or OR
9, R wherein
9Be to be selected from C
1-C
6Alkyl;
R
6Be to be selected from C
1-C
6Alkyl;
R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
8Be to be selected from C
1-C
10Alkyl or phenyl;
(4) exist down in acid, to reflux temperature, have the triazolo pyrimidine derivative of chemical formula (I) by compound formation with chemical formula (VIII) by room temperature.
In this step (1), be under room temperature, slowly add have chemical formula (IV) alkylamine to the mixture of dialkyl group cyano group disulfide group imines with chemical formula V, then after reflux, splash into diamine, with obtain having chemical formula two amidos-1 of (III), 2, the compound of 4-triazole.
Solvent in this step (1) is selected from water, acetonitrile or alcoholic solvent.This alcoholic solvent is selected from methyl alcohol, ethanol, propyl alcohol or butanols.In this step (2), be under 50-150 ℃, in organic solvent, with normal aldehyde and 1 normal two amidos-1,2 of 1-5 with chemical formula (III) with chemical formula, the reaction of 4-triazole.This step (2) is to carry out under acid catalyst.
This acid catalyst is selected from organic acid or mineral acid.This acid catalyst is selected from acetate, toluenesulphonic acids, sulfuric acid or hydrochloric acid.
Solvent in this step (2) is selected from acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride, 1,2 one ethylene dichloride or alcoholic solvent.This alcoholic solvent is selected from methyl alcohol, ethanol, propyl alcohol or butanols.
In this step (3), be under 40-150 ℃, with the normal α of 1-2 with chemical formula (II), β-unsaturation acid derivative and 1 normal imine reaction with chemical formula (VI).
Solvent in this step (1) is selected from acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride or 1,2 one ethylene dichloride.
Alkali in this step (3) is selected from carbonic acid metal salt or hydrogen-carbonate metal-salt.Metal in this metal-salt is selected from lithium, sodium, potassium, rubidium, caesium, beryllium, magnesium, calcium, strontium or barium.
This alkali is yellow soda ash.This polymer inhibitor is selected from quinhydrones or monomethyl ether quinhydrones.This polymer inhibitor is a mequinol.
Acid in this step (4) is selected from mineral acid or organic acid.This acid is selected from hydrochloric acid, sulfuric acid, acetate or oxalic acid.Solvent in this step (4) is selected from water, methyl alcohol, ethanol, acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride or 1,2-ethylene dichloride.
The invention provides the manufacture method of another kind of triazolo pyrimidine derivative, it is characterized in that: the chemical formula of this derivative (I) is:
R wherein
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
2Be to be selected from hydrogen atom, halogen, C
1-C
10Hydroxyalkyl or C
1-C
10Alkyl;
R
3Be to be selected from hydrogen atom, C
1-C
4Hydroxyalkyl or C
1-C
4Alkyl;
Its manufacture method comprises following steps at least:
(1) under room temperature and under the appropriate solvent existence, the dialkyl group cyano group disulfide group imines that will have chemical formula V prepares two amidos-1,2 with chemical formula (III) fast, the compound of 4-triazole,
Wherein R is selected from C
1-C
4Alkyl;
R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
(2) protection of amido and remove to protect processing procedure;
(3) have α, β-unsaturation acid derivative of chemical formula (II) and have the selectivity condensation of the imines of chemical formula (VI), make (I) triazolo pyrimidine derivative that has chemical formula.
The present invention is further described below in conjunction with preferred embodiment.
Embodiment
Embodiment 1
Manufacture method with triazolo pyrimidine derivative of chemical formula (I) of the present invention comprises four steps at least:
The first step is two amidos 1,2 that effectively preparation has chemical formula (III), the 4-triazole:
The normal alkylamine with chemical formula (IV) of 1-2 wherein is slowly to add under room temperature in the mixture of dialkyl group cyano group disulfide group imines 1 equivalent with chemical formula V and appropriate solvent, then after the reflux, and the normal diamine of one after another drop of adding 1-4,
(3) are as follows for reaction equation:
Two amidos 1,2 with chemical formula (III) of above-mentioned reaction equation (three) preparation, the 4-triazole,
Wherein, R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R is selected from C
1-C
4Alkyl;
Solvent is to be selected from water, the alcoholic solvent of acetonitrile or methyl alcohol, ethanol, propyl alcohol or butanols etc.
Second step was the imines that preparation has chemical formula chemical formula (VI):
Wherein with two amidos 1 with chemistry military (III) of normal aldehydes with chemical formula (VII) of 1-5 and 1 normal first step preparation, 2, the 4-triazole is under 50-150 ℃, and react in the organic solvent that has acid catalyst 0-1 equivalent to exist, (four) are as follows for reaction equation:
The flow process of the imines with chemical formula chemical formula (VI) of above-mentioned reaction equation (four) preparation, wherein, R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
8Be to be selected from C
1-C
10Alkyl or phenyl;
Solvent is the alcoholic solvent that is selected from acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride, 1,2 one ethylene dichloride or methyl alcohol, ethanol, propyl alcohol or butanols etc.;
Catalyzer is organic acid or the mineral acid that is selected from acetate, toluenesulphonic acids, sulfuric acid or hydrochloric acid; Or do not add catalyzer.
The 3rd step was the α with chemical formula (II), β-unsaturation acid derivative and have the condensation of the imines of chemical formula (VI):
The normal α of 1-2 wherein with chemical formula (II), β-unsaturation acid derivative is in alkali 0.1-2 equivalent, and polymer inhibitor 0.005-0.2 equivalent exists down, in reflux temperature 40-150 ℃ organic solvent, with 1 normal imine reaction with chemical formula (VI), (five) are as follows for reaction equation:
The α with chemical formula (II) of above-mentioned reaction equation (five), β-unsaturation acid derivative and have the condensation flow process of the imines of chemical formula (VI),
R wherein
1, R
2, R
3And R
8It is identical with aforementioned definitions,
R
5Be to be selected from halogen atom or OR
9, R wherein
9Be C
1-C
6Alkyl;
R
6Be to be selected from C
1-C
6Alkyl;
Solvent is to be selected from acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride or 1,2 one ethylene dichloride;
Alkali is to be selected from carbonic acid metal salt or hydrogen-carbonate metal-salt, and wherein metal can be lithium, sodium, potassium, rubidium, caesium, beryllium, magnesium, calcium, strontium or barium etc.;
Polymer inhibitor is to be selected from quinhydrones or monomethyl ether quinhydrones.
The 4th step was the triazolo pyrimidine derivative that preparation has chemical formula (I):
The imines that wherein has chemical formula (VIII) is to exist down in sour 0.1-10 equivalent, water and solvent, in room temperature to reflux temperature in hydrolysis, (six) are as follows for reaction equation:
Above-mentioned reaction equation (six) is the manufacturing process that preparation has the triazolo pyrimidine derivative of chemical formula (I),
R wherein
1, R
2, R
3And R
8Identical with aforementioned definitions;
Acid is mineral acid or the organic acid that is selected from hydrochloric acid, sulfuric acid, acetate or oxalic acid etc.;
Solvent is to be selected from water, methyl alcohol, ethanol, acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride or 1,2-ethylene dichloride;
Embodiment 2
Following formula N
5-propyl group-1H-[1,2,4] triazole-3, the preparation of 5-diamines:
In 10 liters of volumes, be equipped with in the four neck flasks of backflow thickener, thermometer, priming funnel and mechanical stirrer, the dimethyl cyano group disulfide group imines of 1200g (8.13mole) is dissolved in the Virahol of 6Kg, under room temperature, in 2 hours, splash into the Tri N-Propyl Amine of 538g (8.94mole), behind the restir reaction mixture 20 minutes, elevated temperature is to reflux temperature, and slowly adds the hydration callosity (concentration 85%) of 1224g (20.8mole), and reaction in 2-3 hour then refluxes.
Then distill out 80% differently and pure down, and cool off resistates to 5-10 ℃ in decompression.After filtration and the drying, obtain the N of white solid
5Propyl group-1H-[1,2,4] triazole-3, the 5-diamines.Output is 1075g (purity is 98%, theoretical value 92%).Fusing point is 148-149 ℃.
Embodiment 3
Following formula N
3-benzylidene-N
5-propyl group-1H-[1,2,4] triazole-3, the preparation of 5-diamines:
Method 1
In the volume that is equipped with backflow thickener, temperature to take into account mechanical stirrer is in 5 liters of flasks, the 251.8g that packs into (1.75mole) N
5-propyl group-1H-[1,2,4] triazole-3,5-diamines, 1.24 liters methyl alcohol and the phenyl aldehyde of 194.8g (1.84mole) then reacted in reflux 6-10 hour.
Determine that with LC it (is N that reaction finishes the back
5-propyl group-1H-[1,2,4] triazole-3, the peak district of 5-diamines is less than 1%), the solvent of 2/3 volume is distilled out in reducing pressure down by mixture.Resistates is cooled to room temperature, then is settled out the N of yellow solid
3-benzylidene-N
5-propyl group-1H-[1,2,4] triazole-3, the 5-diamines.Utilize and filter the collecting precipitation thing, after the drying, obtain N
3-benzylidene-N
5-propyl group-1H-[1,2,4] triazole-3,5-diamines product 381-389g (purity is 98%, the 93-95% of theoretical value).
In the present embodiment, when methyl alcohol replaces with ethanol, toluene or acetonitrile, also can obtain similar result.
When the acetate of 5.2g (0.087mole) is used in the present embodiment, or moves down in the azeotropic state and to dewater, the reaction times can foreshorten to 1-4 hour, and output and purity do not have obvious change
Method 2
In the volume that is equipped with backflow thickener, temperature to take into account mechanical stirrer is 5 liters flask, the N of the 251.8g that packs into (1.75mole)
5-propyl group-1H-[1,2,4] triazole-3,5-diamines, 1.75 liters toluene, the phenyl aldehyde of 203.4g (1.92mole) and the acetate of 5.2g (0.087mole) then reacted in reflux 1-3 hour.In the reaction, the water by product of formation moves down in the azeotropic state and removes.Determine that with LC it (is N that reaction finishes the back
5-propyl group-1H-[1,2,4] triazole-3, the 5-diamines the peak district less than 1%), cooling mixture, and obtain primary N
5-propyl group-1H-[1,2,4] triazole-3, the suspension of 5-diamines, it is not purified can be used for next stage.
Embodiment 4
Following formula 2-(benzylidene-amido)-6-methyl-4-propyl group-4H-[1,2,4] preparation of triazole-[1,5-α] pyrimidine-5-ketone:
Method 3
In the volume that is equipped with backflow thickener, temperature to take into account mechanical stirrer is 5 liters flask, the N of method 2 preparations of the foregoing description 3 of the 401.03g that packs into (1.75mole)
3-benzylidene-N
5-propyl group-1H-[1,2,4] triazole-3, the salt of wormwood of 5-diamines, 253g (1.83mole), methyl 2-methoxyl group-α-Jia Jibingxisuan ester of 250g (1.92mole), the mequinol of 1.1g (0.009mole) and the acetonitrile of 1750ml, then reaction in reflux 24-28 hour.
After distilling out acetonitrile under the decompression, add entry, and with 1, the extraction of 2-ethylene dichloride mixes materialization, with 1, the 2-ethylene dichloride removes from extract, after the drying, obtain 2-(benzylidene-amido)-6-methyl-4-propyl group-4H-[1,2,4] triazole-[1,5-α] pyrimidine-5-ketone product 406-432g (purity is the 77-82% of theoretical value).
When replacing acetonitrile, also obtain similar result with toluene.
Method 4
The salt of wormwood of 253g (1.83mole), methyl 2-methoxyl group-α-Jia Jibingxisuan ester of 250g (1.92mole) and the mequinol of 1.1g (0.009mole) are added in the method 2 of embodiment 3 N for preparing
3-benzylidene-N
5-propyl group-1H-[1,2,4] triazole-3, the suspension of 5-diamines.After backflow 12-20 hour, mixture is cooled to room temperature, and adds 1 liter water.The 2-of solid collected by filtration (benzylidene-amido) 6-methyl-4-propyl group-4H-(1,2,4) triazole [1,5-α] pyrimidine-5-ketone, and filtrate is divided into two-layer, wherein organic layer can utilize among the embodiment 3 again; Not purified original 2-(benzylidene-amido) 6-methyl-4-propyl group-4H-(1,2,4) triazole [1,5-α] pyrimidine-5-ketone is to be used for next stage.
Embodiment 5
Following formula 2-amido-6-methyl-4-propyl group-4H-[1,2,4] preparation of triazole-[1,5-α] pyrimidine-5-ketone:
The 2N hydrochloric acid (3.5mole) of 1750ml is added original 2-(benzylidene-amido) 6-methyl-4-propyl group-4H-(1 for preparing in the method 4 of embodiment 4,2,4) triazole [1,5-α] pyrimidine-5-ketone, heated mixt is to 65-70 ℃, reacted 30 minutes, and down, move down phenyl aldehyde except that hydrolysis in the azeotropic state in decompression.
After removing phenyl aldehyde fully, cooling mixture, and the pH value is transferred to 7-8 with 45% aqueous sodium hydroxide solution.Then filter the suspension that obtains, and after the drying, obtain the 2-amido-6-methyl-4-propyl group-4H-[1 of faint yellow solid, 2,4] triazole-[1,5-α] pyrimidine-5-ketone (purity 98%).Output be 264-275g (for embodiment 3 the 73-76% of theoretical value).
When with the methyl alcohol of 1500ml as solvent, and under room temperature, during hydrolysis methyl alcohol, also can obtain analog result.Additive method is identical, so do not repeat.
Claims (20)
1, a kind of manufacture method of triazolo pyrimidine derivative is characterized in that: the chemical formula of this derivative (I) is:
R wherein
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6 ringsAlkyl or C
4Following thiazolinyl;
R
2Be to be selected from hydrogen atom, halogen, C
1-C
10Hydroxyalkyl or C
1-C
10Alkyl;
R
3Be to be selected from hydrogen atom, C
1-C
4Hydroxyalkyl or C
1-C
4Alkyl;
Its manufacture method comprises following steps at least:
(1) under room temperature and under the appropriate solvent existence, to have the dialkyl group cyano group disulfide group imines of chemical formula V and have the alkylamine of chemical formula (IV), then after reflux, splash into diamine, obtain having chemical formula two amidos-1 of (III), 2, the compound of 4-triazole, this chemistry formula V, (IV) and (III) be respectively:
Wherein R is selected from C
1-C
4Alkyl;
R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl; (2) there are compound that will have chemical formula (III) down and aldehyde reaction in organic solvent, make (VI) group with imine moiety that has chemical formula, this chemical formula (VII) and (VI) be with chemical formula (VII):
R wherein
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
8Be to be selected from C
1-C
10Alkyl or phenyl;
(3) under reflux temperature, in the organic solvent of alkali and polymer inhibitor existence, the selectivity condensation has α, β-unsaturation acid derivative of chemical formula (II) and has the imines of chemical formula (VI), formation has the imines of chemical formula (VIII), and this chemical formula (II) and chemical formula (VIII) are respectively:
R wherein
2Be to be selected from hydrogen atom, halogen, C
1-C
10Hydroxyalkyl or C
1-C
10Alkyl;
R
3Be to be selected from hydrogen atom, C
1-C
4Hydroxyalkyl or C
1-C
4Alkyl;
R
5Be to be selected from halogen atom or OR
9, R wherein
9Be to be selected from C
1-C
6Alkyl;
R
6Be to be selected from C
1-C
6Alkyl;
R
1Be to be selected from hydrogen atom, C
1-C
10Alkyl, C
3-C
6Cycloalkyl or C
4Following thiazolinyl;
R
8Be to be selected from C
1-C
10Alkyl or phenyl;
(4) exist down in acid, to reflux temperature, have the triazolo pyrimidine derivative of chemical formula (I) by compound formation with chemical formula (VIII) by room temperature.
2, the manufacture method of triazolo pyrimidine derivative according to claim 1, it is characterized in that: in this step (1), be under room temperature, slowly to add to have the alkylamine of chemical formula (IV) to the mixture of dialkyl group cyano group disulfide group imines with chemical formula V, then after reflux, splash into diamine, with obtain having chemical formula two amidos-1 of (III), 2, the compound of 4-triazole.
3, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: the solvent in this step (1) is selected from water, acetonitrile or alcoholic solvent.
4, the manufacture method of triazolo pyrimidine derivative according to claim 3 is characterized in that: this alcoholic solvent is selected from methyl alcohol, ethanol, propyl alcohol or butanols.
5, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: in this step (2), be under 50-150 ℃, in organic solvent, with normal aldehyde and 1 normal two amidos-1,2 of 1-5 with chemical formula (III) with chemical formula, the reaction of 4-triazole.
6, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: this step (2) is to carry out under acid catalyst.
7, the manufacture method of triazolo pyrimidine derivative according to claim 6 is characterized in that: this acid catalyst is selected from organic acid or mineral acid.
8, the manufacture method of triazolo pyrimidine derivative according to claim 6 is characterized in that: this acid catalyst is selected from acetate, toluenesulphonic acids, sulfuric acid or hydrochloric acid.
9, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: the solvent in this step (2) is selected from acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride, 1,2-ethylene dichloride or alcoholic solvent.
10, the manufacture method of triazolo pyrimidine derivative according to claim 9 is characterized in that: this alcoholic solvent is selected from methyl alcohol, ethanol, propyl alcohol or butanols.
11, the manufacture method of triazolo pyrimidine derivative according to claim 1, it is characterized in that: in this step (3), be under 40-150 ℃, with the normal α of 1-2 with chemical formula (II), β-unsaturation acid derivative and 1 normal imine reaction with chemical formula (VI).
12, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: the solvent in this step (1) is selected from acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride or 1,2-ethylene dichloride.
13, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: the alkali in this step (3) is selected from carbonic acid metal salt or hydrogen-carbonate metal-salt.
14, the manufacture method of triazolo pyrimidine derivative according to claim 13 is characterized in that: the metal in this metal-salt is selected from lithium, sodium, potassium, rubidium, caesium, beryllium, magnesium, calcium, strontium or barium.
15, the manufacture method of triazolo pyrimidine derivative according to claim 13 is characterized in that: this alkali is yellow soda ash.
16, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: this polymer inhibitor is selected from quinhydrones or monomethyl ether quinhydrones.
17, the manufacture method of triazolo pyrimidine derivative according to claim 16 is characterized in that: this polymer inhibitor is a mequinol.
18, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: the acid in this step (4) is selected from mineral acid or organic acid.
19, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: this acid is selected from hydrochloric acid, sulfuric acid, acetate or oxalic acid.
20, the manufacture method of triazolo pyrimidine derivative according to claim 1 is characterized in that: the solvent in this step (4) is selected from water, methyl alcohol, ethanol, acetonitrile, toluene, dimethylbenzene, chlorobenzene, trichloromethane, methylene dichloride or 1,2-ethylene dichloride.
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|---|---|---|---|
| CN 02122861 CN1217947C (en) | 2002-06-10 | 2002-06-10 | Method for preparation of triazolo pyrimidine derivative |
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| CN1217947C true CN1217947C (en) | 2005-09-07 |
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