CN117946013A - Method for synthesizing 5, 6-dihalogen-3-aminopyrazine-2-methyl formate by one-pot method - Google Patents
Method for synthesizing 5, 6-dihalogen-3-aminopyrazine-2-methyl formate by one-pot method Download PDFInfo
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- CN117946013A CN117946013A CN202410104330.9A CN202410104330A CN117946013A CN 117946013 A CN117946013 A CN 117946013A CN 202410104330 A CN202410104330 A CN 202410104330A CN 117946013 A CN117946013 A CN 117946013A
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- aminopyrazine
- methyl formate
- halogen source
- halogenated
- butyl
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 19
- 150000002367 halogens Chemical class 0.000 claims abstract description 19
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- INCSQLZZXBPATR-UHFFFAOYSA-N methyl 3-aminopyrazine-2-carboxylate Chemical compound COC(=O)C1=NC=CN=C1N INCSQLZZXBPATR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000001308 synthesis method Methods 0.000 claims abstract description 6
- VYNGFCUGSYEOOZ-UHFFFAOYSA-N triphenylphosphine sulfide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=S)C1=CC=CC=C1 VYNGFCUGSYEOOZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 6
- FRZPYEHDSAQGAS-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[N+]=1C=CN(C)C=1 FRZPYEHDSAQGAS-UHFFFAOYSA-M 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 150000007973 cyanuric acids Chemical class 0.000 claims description 5
- 125000002346 iodo group Chemical group I* 0.000 claims description 5
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- -1 and more preferably Substances 0.000 claims description 3
- BSKSXTBYXTZWFI-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;acetate Chemical compound CC([O-])=O.CCCC[N+]=1C=CN(C)C=1 BSKSXTBYXTZWFI-UHFFFAOYSA-M 0.000 claims description 2
- KYCQOKLOSUBEJK-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;bromide Chemical compound [Br-].CCCCN1C=C[N+](C)=C1 KYCQOKLOSUBEJK-UHFFFAOYSA-M 0.000 claims description 2
- FHDQNOXQSTVAIC-UHFFFAOYSA-M 1-butyl-3-methylimidazol-3-ium;chloride Chemical compound [Cl-].CCCCN1C=C[N+](C)=C1 FHDQNOXQSTVAIC-UHFFFAOYSA-M 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000012752 auxiliary agent Substances 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 13
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- PXKPKGHXANCVMC-UHFFFAOYSA-N 3-butyl-1-methyl-1,2-dihydroimidazol-1-ium;trifluoromethanesulfonate Chemical compound OS(=O)(=O)C(F)(F)F.CCCCN1CN(C)C=C1 PXKPKGHXANCVMC-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000007350 electrophilic reaction Methods 0.000 description 2
- 238000007336 electrophilic substitution reaction Methods 0.000 description 2
- CNXSIRHOIFRMOB-UHFFFAOYSA-N methyl 3-amino-6-bromopyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(Br)=CN=C1N CNXSIRHOIFRMOB-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- KAIPKTYOBMEXRR-UHFFFAOYSA-N 1-butyl-3-methyl-2h-imidazole Chemical compound CCCCN1CN(C)C=C1 KAIPKTYOBMEXRR-UHFFFAOYSA-N 0.000 description 1
- UFOUSHWZVOIJKK-UHFFFAOYSA-N 3-amino-5,6-dichloropyrazine-2-carboxylic acid Chemical compound NC1=NC(Cl)=C(Cl)N=C1C(O)=O UFOUSHWZVOIJKK-UHFFFAOYSA-N 0.000 description 1
- ZAGZIOYVEIDDJA-UHFFFAOYSA-N 3-aminopyrazine-2-carboxylic acid Chemical compound NC1=NC=CN=C1C(O)=O ZAGZIOYVEIDDJA-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- YIROYDNZEPTFOL-UHFFFAOYSA-N 5,5-Dimethylhydantoin Chemical class CC1(C)NC(=O)NC1=O YIROYDNZEPTFOL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 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 description 1
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- USYMCUGEGUFUBI-UHFFFAOYSA-N methyl 3-amino-5,6-dichloropyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(Cl)=C(Cl)N=C1N USYMCUGEGUFUBI-UHFFFAOYSA-N 0.000 description 1
- MEYTYCRWYBFDOW-UHFFFAOYSA-N methyl 3-amino-6-bromo-5-chloropyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(Br)=C(Cl)N=C1N MEYTYCRWYBFDOW-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a synthesis method of 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate, which comprises the following steps: (1) Reacting 3-aminopyrazine-2-carboxylic acid methyl ester with a first halogen source to generate 6-halogeno-3-aminopyrazine-2-carboxylic acid methyl ester; (2) The 6-halogeno-3-aminopyrazine-2-methyl formate is further reacted in the same reaction system by a catalyst and a second halogen source one-pot method to generate the 5, 6-dihalo-3-aminopyrazine-2-methyl formate. The synthesis method provided by the invention has the advantages that the yield and purity are high through the specific catalyst and the catalytic auxiliary agent, the production efficiency is effectively improved, the production period is shortened, the production cost and the energy consumption are reduced, and the reaction safety is improved.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate by a one-pot method.
Background
Methyl 5, 6-dihalo-3-aminopyrazine-2-carboxylate can be used as intermediate for researching pyrazine medicines with diuretic and natrium-excreting effects, and the medicines are suitable for treating oedema, hypertension or other diseases related to liquid or electrolyte (especially sodium and chloride ions) retention.
The existing synthetic route of the 5, 6-dihalo-3-aminopyrazine-2-methyl formate mainly comprises the following steps:
Route one
Patent WO2007/61360A2 reports that the 6-bromo-3-aminopyrazine-2-carboxylic acid methyl ester is obtained by taking 3-aminopyrazine-2-carboxylic acid methyl ester as a raw material and bromine, patent US2021/188855A1 reports that the 6-bromo-3-aminopyrazine-2-carboxylic acid methyl ester is taken as a starting raw material, and the 6-bromo-5-chloro-3-aminopyrazine-2-carboxylic acid methyl ester is obtained by 2-step synthesis.
The route starts to synthesize the target product by 3 steps from 3-aminopyrazine-2-methyl formate, the literature reports that the total yield is 10-20%, the yield of the key step in the second step is about 20%, the production cost is high, the production efficiency is low, m-chloroperoxybenzoic acid and phosphorus oxychloride dangerous materials are used in the reaction process, the dangerous coefficient of the technological process is large, and the three-waste treatment cost is high.
Route two
The patent WO2020/243155A1 reports that 3-aminopyrazine-2-methyl formate is used as a starting material to synthesize 5-chloro-3-aminopyrazine-2-methyl formate through a two-step reaction, and then the 5-chloro-3-aminopyrazine-2-methyl formate is synthesized into 6-bromo-5-chloro-3-aminopyrazine-2-methyl formate through a conventional electrophilic reaction by bromine at the 6-position.
The route starts with 3-aminopyrazine-2-methyl formate to synthesize a target product in 3 steps, and the literature reports that the yield of the first step is over 95 percent, but the second step generates a mixture of 6-chlorine and 5-chlorine due to poor chlorine selectivity on nitrogen oxides, so that the conversion rate is low, the difficulty in separation and purification is high, the yield is about 17 percent, and the total yield is low.
Route three
Methyl 3-aminopyrazine-2-carboxylate is used as a starting material, sulfonyl chloride is used as a chloro reagent for synthesizing methyl 5, 6-dichloro-3-aminopyrazine-2-carboxylate in a chloro manner, which is reported in patent GB1082060A and the like.
The patent reports that the yield is 82%, but hazardous reagent sulfonyl chloride is used in the reaction process, and the treatment process inevitably has high pollution and high cost.
In summary, in the existing preparation process of the 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate, the problems of complicated production process, high risk of the process, low total yield, low productivity, large wastewater amount, serious pollution and high production cost exist.
Disclosure of Invention
It is known that at present, reagents such as N-halosuccinimide, dihalogenated dimethyl hydantoin, halogenated isocyanuric acid (halogenated means chloro, bromo and iodo) are used for replacing a hydrogen atom with a halogen atom in an electrophilic substitution mode at the ortho-para position of an aromatic hydrocarbon substituted by amino, and the electrophilic substitution reaction of the meta position of the amino group is difficult to occur due to low electron cloud density. The invention aims to provide a novel one-pot method for synthesizing 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate by activating a catalyst. Mainly solves the problems of low productivity, high cost, large risk coefficient and environmental protection in the prior art.
The technical scheme adopted by the invention for solving the problems is as follows:
a synthesis method of 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate comprises the following steps:
Wherein X 1＝Cl、Br、I;X2 =cl, br, I, and X 1 and X 2 may be the same or different
The synthesis steps comprise:
(1) Reacting 3-aminopyrazine-2-carboxylic acid methyl ester with a first halogen source to generate 6-halogeno-3-aminopyrazine-2-carboxylic acid methyl ester;
(2) The 6-halogeno-3-aminopyrazine-2-methyl formate is further reacted in the same reaction system by a catalyst and a second halogen source one-pot method to generate the 5, 6-dihalo-3-aminopyrazine-2-methyl formate.
Preferably, in the step (1), the first halogen source is selected from one or more of N-halogenated succinimide, dihalodimethylhydantoin, halogenated isocyanuric acid, N-halogenated-N-methoxybenzenesulfonamide, 2-halogenated-1, 4-dioxane, and further preferably, the halogen source is N-halogenated succinimide, and the halogen means is chloro, bromo and iodo; the molar ratio of the 3-aminopyrazine-2-methyl formate to the first halogen source is 1 (1-1.05).
Preferably, in the step (1), the solvent is selected from one or more of acetonitrile, chloroform, DMF and DCM, and more preferably, the solvent is DMF; the volume ratio of the 3-aminopyrazine-2 methyl formate to the solvent is 1: (5-20).
Preferably, in the step (2), the second halogen source is selected from one or more of N-halogenated succinimide, dihalodimethylhydantoin, halogenated isocyanuric acid, N-halogenated-N-methoxybenzenesulfonamide, 2-halogenated-1, 4-dioxane, and further preferably, the second halogen source is N-halogenated succinimide, and the halogenated meaning is chloro, bromo and iodo; the ratio of 3-aminopyrazine-2-carboxylic acid methyl ester to halogen source is 1: (2-3).
Preferably, in said step (2), the catalyst used is selected from the group consisting of 1-butyl-3-methylimidazolium triflate, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium bromide, 1-butyl-3-methylimidazolium acetate, 1-butyl-3-methylimidazolium triflate, and further preferably the catalyst used is 1-butyl-3-methylimidazolium triflate; the catalyst is used in an amount of 1-5% of the molar amount of the 3-aminopyrazine-2 methyl formate.
Preferably, in the step (2), a promoter triphenylphosphine sulfide is added in addition to the catalyst 1-butyl-3-methylimidazole triflate, and the amount of the promoter is 1-3wt% of 3-aminopyrazine-2-methyl formate. As the halogen atom substitution reaction in the second stage is different from the conventional amino ortho electrophilic reaction, the reaction activity is very poor, and the inventor discovers that the reaction activity, the reaction rate and the yield in the second stage can be greatly improved through compounding the triphenyl phosphine sulfide and the catalyst.
According to the method disclosed by the invention, the 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate can be conveniently prepared, 2 halogen atoms after halogenation can be conveniently regulated and controlled according to the first halogen source, and the second halogen source can be the same or different, so that a flexible and convenient synthesis strategy is provided.
Compared with the prior art, the invention has the following beneficial effects:
1. provides a synthesis method of 6-bromo-5-chloro-3-aminopyrazine-2-methyl formate with high yield. The total yield is 80-86%, which is obviously better than the existing method.
2. By shortening the reaction steps, the production efficiency is effectively improved, the production period is shortened, the production cost and the energy consumption are reduced, and the reaction safety is improved.
Drawings
FIG. 1 is a HNMR spectrum of the product obtained in example 1.
FIG. 2 is a HNMR spectrum of the product obtained in example 5.
FIG. 3 is a HNMR spectrum of the product obtained in example 6.
Detailed description of the preferred embodiments
The preparation process according to the invention is further illustrated and described below by way of specific examples.
Example 1
Step (1):
1.5L of DMF is added into a 3L three-mouth bottle, 153.1g (1.0 mol) of 3-aminopyrazine-2-methyl formate is added into the system under stirring after nitrogen replacement, the temperature is reduced to 10 ℃ by an ice water bath, 178.0 g (1.0 mol) of NBS is slowly added in batches, the temperature is controlled below 20 ℃, the addition is completed after 1 hour of use, and after the reaction is carried out for 2 hours under the temperature of 20 ℃, the reaction of the raw materials is detected by HPLC.
Step (2):
The ice water bath is removed, 333.8gNCS (2.5 mol), 2.9g of 1-butyl-3-methylimidazole trifluoro methanesulfonate (0.01 mol) and 3.1g of triphenylphosphine sulfide are added, the system is heated to 90 ℃ for reaction for 16 hours, sampling HPLC (high performance liquid chromatography) to detect that the 6-bromo-3-aminopyrazine-2-methyl formate is reacted completely, the system is cooled to room temperature, 3.0L of water is slowly poured under stirring, isopropyl acetate is extracted for 1L multiplied by 3 times, an organic phase is combined and then washed by sodium chloride aqueous solution for 1 time, washing by 1 time, 15g of active carbon is added into the organic phase for stirring and decoloring, sodium sulfate is dried and then filtered, and a product of 5-bromo-6-chloro-3-aminopyrazine-2-methyl formate is obtained by spin-drying filtrate for 219.8g of yellow solid. Purity 98.3% and yield 82.5%. HNMR is shown in figure 1, solvent deuterated DMSO.
The reaction temperature was controlled after the NCS, 1-butyl-3-methylimidazole triflate and triphenylphosphine sulfide were added in step (2) without change, and the yield and purity of the product methyl 5-bromo-6-chloro-3-aminopyrazine-2-carboxylate were recorded, and the results are shown in Table 1 below.
TABLE 1 influence of temperature on the reaction
| Temperature (temperature) | Purity of | Yield is good |
| 60℃ | 90.8％ | 71.5％ |
| 70℃ | 96.3％ | 78.2％ |
| 80℃ | 98.1％ | 81.4％ |
| 90℃ | 98.2％ | 82.3％ |
| 100℃ | 97.5％ | 82.2％ |
It can be seen that at 90 deg.c, both purity and yield are improved. The subsequent example step (2) was also carried out at 90 ℃.
Example 2
Other conditions and operations were the same as in example 1 except that the amount of triphenylphosphine sulfide added in step (2) was 4.6g. Through testing, the purity of the product 5-bromo-6-chloro-3-aminopyrazine-2-methyl formate is 98.2%, and the yield is 83.4%.
Example 3
Other conditions and operations were the same as in example 1 except that the amount of triphenylphosphine sulfide added in step (2) was 1.5g. Through testing, the purity of the product 5-bromo-6-chloro-3-aminopyrazine-2-methyl formate is 98.4%, and the yield is 80.2%.
Example 4
Other conditions and operations were the same as in example 1 except that triphenylphosphine sulfide was not added in step (2). Through testing, the purity of the product 5-bromo-6-chloro-3-aminopyrazine-2-methyl formate is 97.5%, and the yield is 74.2%.
Example 5
Other conditions and procedures were the same as in example 1 except that NBS was replaced with an equimolar amount of 225.0g (1.0 mol) NIS in step (1). Through testing, the purity of the product 5-iodo-6-chloro-3-aminopyrazine-2-methyl formate is 96.4%, and the yield is 81.7%. HNMR is shown in figure 2.
Example 6
1.5 L DMF was added to a 3 l three-necked flask, 153.1g (1.0 mol) of methyl 3-aminopyrazine-2-carboxylate was added to the system under stirring after nitrogen replacement, ice water was cooled to 10℃and 133.5g (1.0 mol) of NCS was slowly added in portions, the temperature was controlled below 20℃and after 1 hour of addition, 333.8gNCS (2.5 mol) of 2g of 1-butyl-3-methylimidazole triflate (0.05 mol) and 3.1g of triphenylphosphine sulfide were added after 2 hours of reaction at 20℃and the system was heated to 90℃for 14 hours, and after the reaction of 3-aminopyrazine-2-carboxylate was detected by sampling HPLC, the treatment method was identical to that in example 1, the purity of the product 5, 6-dichloro-3-aminopyrazine-2-carboxylate was 98.6% and the yield was 85.7%. HNMR is shown in figure 3.
Comparative example 1
Other conditions and operations were the same as in example 1 except that the catalyst 1-butyl-3-methylimidazole triflate was not added in step (2). Through testing, the HPLC detection system has no target product of 6-bromo-5-chloro-3-aminopyrazine-2-methyl formate. Indicating that the reaction cannot proceed only with the cocatalyst triphenylphosphine sulfide.
Claims (9)
1. A synthesis method of 5, 6-dihalogenated-3-aminopyrazine-2-methyl formate comprises the following synthetic routes:
Wherein X 1＝Cl、Br、I;X2 =cl, br, I, and X 1 and X 2 may be the same or different;
the synthesis method comprises the following steps:
(1) Reacting 3-aminopyrazine-2-carboxylic acid methyl ester with a first halogen source to generate 6-halogeno-3-aminopyrazine-2-carboxylic acid methyl ester;
(2) The 6-halogeno-3-aminopyrazine-2-methyl formate is further reacted in the same reaction system by a catalyst and a second halogen source one-pot method to generate the 5, 6-dihalo-3-aminopyrazine-2-methyl formate.
2. The method according to claim 1, wherein in the step (1), the first halogen source is selected from one or more of N-halosuccinimide, dihalodimethylhydantoin, halogenated isocyanuric acid, N-halo-N-methoxybenzenesulfonamide, 2-halo-1, 4-dioxane, and the halo means chloro, bromo and iodo.
3. The method of synthesis according to claim 2, wherein the molar ratio of methyl 3-aminopyrazine-2-carboxylate to the first halogen source is 1 (1-1.05).
4. The method according to claim 1, wherein in the step (1), the solvent is selected from one or more of acetonitrile, chloroform, DMF, DCM, and more preferably, the solvent is DMF; the volume ratio of the 3-aminopyrazine-2 methyl formate to the solvent is 1: (5-20).
5. The method according to claim 1, wherein in the step (2), the second halogen source is selected from one or more of N-halogenated succinimide, dihalodimethylhydantoin, halogenated isocyanuric acid, N-halogenated-N-methoxybenzenesulfonamide, and 2-halogenated-1, 4-dioxane, and the halogenated meaning is chloro, bromo, and iodo.
6. The method according to claim 5, wherein the ratio of methyl 3-aminopyrazine-2-carboxylate to halogen source is 1: (2-3).
7. The method according to claim 5, wherein the catalyst used in the step (2) is selected from the group consisting of 1-butyl-3-methylimidazolium triflate, 1-butyl-3-methylimidazolium chloride, 1-butyl-3-methylimidazolium bromide, 1-butyl-3-methylimidazolium acetate and 1-butyl-3-methylimidazolium triflate.
8. The method of claim 7, wherein the catalyst is used in an amount of 1 to 5% by mole of methyl 3-aminopyrazine-2 carboxylate.
9. The method according to claim 1, wherein in the step (2), a promoter triphenylphosphine sulfide is further added, and the promoter is 1-3wt% of 3-aminopyrazine-2-carboxylic acid methyl ester.
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