CN105085418B - A kind of diphenyl replaces the synthetic method of pyrazine compounds - Google Patents
A kind of diphenyl replaces the synthetic method of pyrazine compounds Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 31
- 150000003216 pyrazines Chemical class 0.000 title claims abstract description 15
- 235000010290 biphenyl Nutrition 0.000 title claims abstract description 8
- 239000004305 biphenyl Substances 0.000 title claims abstract description 8
- 125000006267 biphenyl group Chemical group 0.000 title claims abstract description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 23
- 239000013110 organic ligand Substances 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims abstract description 18
- 239000000654 additive Substances 0.000 claims abstract description 18
- 230000000996 additive effect Effects 0.000 claims abstract description 18
- -1 accelerator Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- XPDWGBQVDMORPB-UHFFFAOYSA-N trifluoromethane acid Natural products FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- HJDKCHUESYFUMG-UHFFFAOYSA-N cycloocta-1,5-diene;nickel Chemical compound [Ni].C1CC=CCCC=C1 HJDKCHUESYFUMG-UHFFFAOYSA-N 0.000 claims description 4
- FGOSNANIQLJNSZ-UHFFFAOYSA-N acetonitrile copper Chemical compound [Cu].CC#N.CC#N.CC#N.CC#N FGOSNANIQLJNSZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229940113115 polyethylene glycol 200 Drugs 0.000 claims description 2
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 230000035484 reaction time Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000010949 copper Substances 0.000 description 14
- 235000002639 sodium chloride Nutrition 0.000 description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 9
- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 7
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XTEGARKTQYYJKE-UHFFFAOYSA-M Chlorate Chemical compound [O-]Cl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical group C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 description 3
- 229960003019 loprazolam Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- IYEQGAAVSZBXQW-UHFFFAOYSA-L [Cu+2].[O-]C(=O)C(F)(F)F.FC(C(=O)CC(C)=O)(F)F.[O-]C(=O)C(F)(F)F Chemical compound [Cu+2].[O-]C(=O)C(F)(F)F.FC(C(=O)CC(C)=O)(F)F.[O-]C(=O)C(F)(F)F IYEQGAAVSZBXQW-UHFFFAOYSA-L 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- QAMFBRUWYYMMGJ-UHFFFAOYSA-N hexafluoroacetylacetone Chemical compound FC(F)(F)C(=O)CC(=O)C(F)(F)F QAMFBRUWYYMMGJ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- JRTIUDXYIUKIIE-KZUMESAESA-N (1z,5z)-cycloocta-1,5-diene;nickel Chemical compound [Ni].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 JRTIUDXYIUKIIE-KZUMESAESA-N 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HUTNOYOBQPAKIA-UHFFFAOYSA-N 1h-pyrazin-2-one Chemical class OC1=CN=CC=N1 HUTNOYOBQPAKIA-UHFFFAOYSA-N 0.000 description 1
- PTZIVVDMBCVSMR-UHFFFAOYSA-N 2,3-diphenylpyrazine Chemical class C1=CC=CC=C1C1=NC=CN=C1C1=CC=CC=C1 PTZIVVDMBCVSMR-UHFFFAOYSA-N 0.000 description 1
- NTJMGOWFGQXUDY-UHFFFAOYSA-N 2H-azirine Chemical class C1C=N1 NTJMGOWFGQXUDY-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FNYLWPVRPXGIIP-UHFFFAOYSA-N Triamterene Chemical compound NC1=NC2=NC(N)=NC(N)=C2N=C1C1=CC=CC=C1 FNYLWPVRPXGIIP-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- XSDQTOBWRPYKKA-UHFFFAOYSA-N amiloride Chemical compound NC(=N)NC(=O)C1=NC(Cl)=C(N)N=C1N XSDQTOBWRPYKKA-UHFFFAOYSA-N 0.000 description 1
- 229960002576 amiloride Drugs 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002068 microbial inoculum Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- FQZNIRNFJJOWTI-UHFFFAOYSA-N pyrazin-2-ylphosphonic acid Chemical class OP(O)(=O)C1=CN=CC=N1 FQZNIRNFJJOWTI-UHFFFAOYSA-N 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960001288 triamterene Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
The present invention relates to the synthetic method for replacing pyrazine compounds there is provided diphenyl shown in a kind of lower formula (III), methods described includes：Into organic solvent, in the presence of catalyst, organic ligand, accelerator and acid additive, lower formula (I) compound and formula (II) compound is reacted, so that the formula (III) compound is obtained,Wherein, R1‑R3It is each independently H or C1‑C6Alkyl.Methods described passes through to the appropriately selected with combining of catalyst, organic ligand, accelerator, acid additive and organic solvent, purpose product is obtained so as to high yield, and the reaction time is short, reaction temperature is low, it is easily controllable, preferable reaction effect has been reached, has been had a good application prospect and industrial production potential in organic synthesis field especially medicine intermediate synthesis field.
Description
Technical field
The present invention relates to a kind of synthetic method of nitrogen-containing heterocycle compound, relate more specifically to a kind of diphenyl pyrazine class
The synthetic method of compound, belongs to medicine intermediate synthesis field.
Background technology
In medicinal chemistry art, pyrazine compounds are the important class formations of heterocycle containing N- of chemical field, and it is deposited extensively
It is among natural products and pharmaceutical preparation.Such as following medicine containing pyrazine class formation is widely used：Protect potassium profit
Urine agent amiloride, triamterene are used equally for treatment hypertension and heart failure；Pyrazinamide and Mo Lan acid amides can be used as resisting
Microbial inoculum is to treat pulmonary tuberculosis etc..
Just because of such important effect of pyrazine compounds, the novel method for synthesizing of research and development pyrazine compounds must
Far-reaching influence will be produced to chemical industry, medicine and other fields.
Between in the past few decades, in the prior art it has been reported that the synthesis technique of some pyrazine compounds, for example：
(" the Synthesis of Pyrazine-phosphonates and- such as Francisco Palacios
Phosphine Oxides from 2H-Azirines or Oximes”,Organic Letters,2002,4,2405-
2408) a kind of reaction method that pyrazine compounds are prepared by oxime is reported, its reaction equation is as follows：
(" the N-H Insertion Reactions of Boc-Amino Acid Amides such as Hana Matsushita:
Solution-and Solid-Phase Synthesis of Pyrazinones and Pyrazines”,Organic
Letters, 2004,6,4627-4629) report it is a kind of use rhodium catalyst, by α-diazonium-'beta '-ketoester class compound for raw material
The synthetic method of pyrazine is prepared, its reaction equation is as follows：
As above affiliated, although disclosing the synthetic method of a variety of pyrazine compounds in the prior art, these methods are deposited
The shortcomings of technique is harsh, regioselectivity is bad.
Therefore, the problem of needing to improve for these, the present inventor is on the basis of lot of documents is had access to, it is proposed that a kind of
Diphenyl replaces the synthetic method of pyrazine compounds, and which employs the composite catalyzing of the particular combination comprising plurality of reagents composition
Mutual cooperation, the effect of Synergistic are there is between system, and these reagents, so that target in high yield has been finally reached,
With extensive commercial application potentiality.
The content of the invention
In order to overcome many defects as indicated above, present inventor has performed in-depth study and exploration, paying
After enough creative works, so as to complete the present invention.
Of particular note is that：In the application documents that another piece of the present inventor is submitted on the same day, discovery ought be produced finally
When two adjacent substituents of thing are phenyl, relative to it is different when non-phenyl situation, yield, which has, significantly to be reduced, and is
This, inventor is had found by studying, and is probably now because the increase of steric effect and cloud density, so as to increase anti-
The difficulty answered, for the situation continued by studying, and then finds the selection by suitable organic ligands, is remarkably improved hexichol
Yield when base replaces, so as to complete the present invention.
Specifically, technical scheme and content are related to a kind of substitution Pyrazine of diphenyl shown in lower formula (III)
The synthetic method of compound, methods described includes：Into organic solvent, in catalyst, organic ligand, accelerator and acid additive
In the presence of, lower formula (I) compound and formula (II) compound is reacted, so that the formula (III) compound is obtained,
Wherein, R1-R3It is each independently H or C1-C6Alkyl.
In the present invention, unless otherwise specified, otherwise all Me for being related to organic group represent methyl, Et represent ethyl,
T-Bu represents the tert-butyl group.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the catalyst is organocopper compound and double (1,5- cyclo-octadiene) nickel
(Ni(COD)2) mixture, wherein, organocopper compound and double (1,5- cyclo-octadiene) nickel (Ni (COD)2) mol ratio be 1:
0.5-1, for example, can be 1:0.5、1:0.7、1:0.9 or 1:1.
Wherein, the organocopper compound is trifluoroacetylacetone (TFA) copper, hexafluoroacetylacetone copper, [(CH3CN)4Cu]PF6
(the acetonitrile copper of hexafluorophosphoric acid four) or double (triphenylphosphine) cuprous nitrate (Cu (PPh3)2NO3) in any one, be most preferably
[(CH3CN)4Cu]PF6。
In the synthetic method of the present invention, the organic ligand is any one in following formula L1-L4,
Most preferably L1.
The present invention the synthetic method in, the accelerator be N- normal-butyl-N- crassitudes Bromide, N- just
It is any in butyl-N- crassitudes chlorate or double (fluoroform sulphonyl) inferior amine salts of N- normal-butyl-N- crassitudes
Double (fluoroform sulphonyl) inferior amine salts of one kind, most preferably N- normal-butyls-N- crassitudes.
In the synthetic method of the present invention, the acid additive is Loprazolam or p-methyl benzenesulfonic acid, is most preferably
P-methyl benzenesulfonic acid.
In the synthetic method of the present invention, the organic solvent is DMF (DMF), DMSO (two
Methyl sulfoxide), it is ethanol, isopropanol, benzene, NMP (1-METHYLPYRROLIDONE), any one in PEG-200 (polyethylene glycol 200)
Kind, most preferably PEG-200.
Wherein, the consumption of the solvent is not particularly limited, and those skilled in the art can carry out suitable selection and true
It is fixed, for example carry out and post-process according to convenient reaction and suitably selected.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and formula (II) compound is 1:
1.5-2.5, for example, can be 1:1.5、1:2 or 1:2.5.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and catalyst is 1:0.04-
0.08, i.e., the mole dosage of described formula (I) compound and the organocopper compound and pair (1,5- ring pungent two that constitute the catalyst
Alkene) nickel (Ni (COD)2) total moles consumption ratio be 1:0.04-0.08, for example, can be 1:0.04、1:0.06 or 1:0.08.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and organic ligand is 1:0.1-
0.14, for example can be 1:0.1、1:0.12 or 1:0.14.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and accelerator is 1:0.1-0.15,
For example can be 1:0.1、1:0.12、1:0.14 or 1:0.15.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and acid additive is 1:0.1-
0.2, for example can be 1:0.1、1:0.15 or 1:0.2.
In the synthetic method of the present invention, reaction temperature is 70-90 DEG C, for example, can be 70 DEG C, 80 DEG C or 90 DEG C.
In the synthetic method of the present invention, the reaction time is 4-7 hours, for example, can be 4 hours, 5 hours, 6 hours
Or 7 hours.
In the synthetic method of the present invention, the post processing after reaction terminates is specific as follows：After reaction terminates, filtering,
Filtrate is naturally cooled into room temperature, saturated aqueous common salt is then added, then fully vibration washing is extracted 2-3 times with chloroform, merged
Organic phase, vacuum distillation, residue is crossed 300-400 mesh silica gel column chromatographies and separated, using volume ratio as 1:3 ethyl acetate and
The mixed liquor of petroleum ether is as leacheate, so as to obtain the formula (III) compound.
In summary, the invention provides the synthetic method that a kind of diphenyl replaces pyrazine compounds, methods described is led to
Cross to the appropriately selected with combining of catalyst, organic ligand, accelerator, acid additive and organic solvent, so as to high yield
The pyrazine compounds of diphenyl substitution are obtained, and the reaction time is short, reaction temperature is low, it is easy to control, reached preferably
Reaction effect, has a good application prospect and industrialized production in organic synthesis field especially medicine intermediate synthesis field
Potentiality.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose only be used for enumerate the present invention, not to the present invention real protection scope constitute it is any type of it is any limit, it is more non-will
Protection scope of the present invention is confined to this.
Embodiment 1
At room temperature, into appropriate organic solvent PEG-200, formula (I) compound, 150mmol above formulas on 100mmol are added
(II) compound, 10mmol organic ligand L1,4mmol catalyst (are 2.7mmol [(CH3CN)4Cu]PF6With 1.3mmol Ni
(COD)2Mixture), double (fluoroform sulphonyl) inferior amine salts of 10mmol accelerant Ns-normal-butyl-N- crassitude and
10mmol acid additive p-methyl benzenesulfonic acid, then heats to 70 DEG C, and is sufficiently stirred for reaction 7 hours at such a temperature.
After reaction terminates, filtrate is naturally cooled to room temperature, then adds saturated aqueous common salt by filtering, fully vibration washing,
Then extracted 2-3 times with chloroform, merge organic phase, vacuum distillation, residue is crossed 300-400 mesh silica gel column chromatographies and separated,
Using volume ratio as 1:3 ethyl acetate and the mixed liquor of petroleum ether are as leacheate, so as to obtain formula (III) compound, produce
Rate is 94.8%.
1H NMR(CDCl3,400MHz):δ 8.04 (d, J=8.4Hz, 2H), 7.67 (s, 1H), 7.63 (d, J=8.8Hz,
2H), 4.56 (q, J=7.2Hz, 2H), 2.72 (s, 3H), 1.49 (t, J=7.2Hz, 3H).
Embodiment 2
Reaction equation be the same as Example 1, specific operation process is as follows：
At room temperature, into appropriate organic solvent PEG-200, formula (I) compound described in 100mmol is added, described in 200mmol
Formula (II) compound, 6mmol catalyst (are 3mmol [(CH3CN)4Cu]PF6With 3mmol Ni (COD)2Mixture),
Double (fluoroform sulphonyl) inferior amine salts of 12mmol organic ligands L1,12mmol accelerant N-normal-butyl-N- crassitude and
15mmol acid additive p-methyl benzenesulfonic acid, then heats to 80 DEG C, and is sufficiently stirred for reaction 5 hours at such a temperature.
After reaction terminates, filtrate is naturally cooled to room temperature, then adds saturated aqueous common salt by filtering, fully vibration washing,
Then extracted 2-3 times with chloroform, merge organic phase, vacuum distillation, residue is crossed 300-400 mesh silica gel column chromatographies and separated,
Using volume ratio as 1:3 ethyl acetate and the mixed liquor of petroleum ether are as leacheate, so that the formula (III) compound is obtained,
Yield is 95.1%.
Characterize data be the same as Example 1.
Embodiment 3
Reaction equation be the same as Example 1, specific operation process is as follows：
At room temperature, into appropriate organic solvent PEG-200, formula (I) compound described in 100mmol is added, described in 250mmol
Formula (II) compound, 8mmol catalyst (are 5.2mmol [(CH3CN)4Cu]PF6With 2.8mmol Ni (COD)2Mixture),
Double (fluoroform sulphonyl) inferior amine salts of 14mmol organic ligands L1,15mmol accelerant N-normal-butyl-N- crassitude and
20mmol acid additive p-methyl benzenesulfonic acid, then heats to 90 DEG C, and is sufficiently stirred for reaction 4 hours at such a temperature.
After reaction terminates, filtrate is naturally cooled to room temperature, then adds saturated aqueous common salt by filtering, fully vibration washing,
Then extracted 2-3 times with chloroform, merge organic phase, vacuum distillation, residue is crossed 300-400 mesh silica gel column chromatographies and separated,
Using volume ratio as 1:3 ethyl acetate and the mixed liquor of petroleum ether are as leacheate, so that the formula (III) compound is obtained,
Yield is 94.7%.
Characterize data be the same as Example 1.
Embodiment 4
Reaction equation be the same as Example 1, specific operation process is as follows：
At room temperature, into appropriate organic solvent PEG-200, formula (I) compound described in 100mmol is added, described in 200mmol
Formula (II) compound, 7mmol catalyst (are 4mmol [(CH3CN)4Cu]PF6With 3mmol Ni (COD)2Mixture),
Double (fluoroform sulphonyl) inferior amine salts of 11mmol organic ligands L1,13mmol accelerant N-normal-butyl-N- crassitude and
14mmol acid additive p-methyl benzenesulfonic acid, then heats to 90 DEG C, and is sufficiently stirred for reaction 6 hours at such a temperature.
After reaction terminates, filtrate is naturally cooled to room temperature, then adds saturated aqueous common salt by filtering, fully vibration washing,
Then extracted 2-3 times with chloroform, merge organic phase, vacuum distillation, residue is crossed 300-400 mesh silica gel column chromatographies and separated,
Using volume ratio as 1:3 ethyl acetate and the mixed liquor of petroleum ether are as leacheate, so that the formula (III) compound is obtained,
Yield is 94.9%.
Characterize data be the same as Example 1.
Embodiment 5-24
Embodiment 5-8：In addition to the organocopper compound in catalyst is replaced with into trifluoroacetylacetone (TFA) copper, other operations are equal
It is constant, so that embodiment 1-4 is repeated, obtain embodiment 5-8.
Embodiment 9-12：In addition to the organocopper compound in catalyst is replaced with into hexafluoroacetylacetone copper, other operations
It is constant, so that embodiment 1-4 is repeated, obtain embodiment 9-12.
Embodiment 13-16：Except the organocopper compound in catalyst is replaced with into (Cu (PPh3)2NO3) outside, other operations
It is constant, so that embodiment 1-4 is repeated, obtain embodiment 13-16.
Embodiment 17-20：Except the one-component that catalyst is replaced with to total consumption that consumption is original two heavy constituent
[(CH3CN)4Cu]PF6Outside, other operations are constant, so that embodiment 1-4 is repeated, obtain embodiment 17-20.
Embodiment 21-24：Except the one-component Ni that catalyst is replaced with to total consumption that consumption is original two heavy constituent
(COD)2Outside, other operations are constant, so that embodiment 1-4 is repeated, obtain embodiment 21-24.
As a result it see the table below 1.
Table 1
" -- " represent without.
From the data of upper table 1, as exclusive use [(CH3CN)4Cu]PF6Or Ni (COD)2During as catalyst, product production
Rate is significantly reduced.And when using other organocopper compounds, yield is also significantly lower than [(CH3CN)4Cu]PF6When effect.This
Demonstrate only while using [(CH3CN)4Cu]PF6With Ni (COD)2Bicomponent catalyst, production the most excellent could be obtained
Produce rate.
Embodiment 25-40
Embodiment 25-28：In addition to organic ligand L1 is replaced with into L2, other operations are constant, so that reality is repeated
A 1-4 is applied, embodiment 25-28 is obtained.
Embodiment 29-32：In addition to organic ligand L1 is replaced with into L3, other operations are constant, so that reality is repeated
A 1-4 is applied, embodiment 29-32 is obtained.
Embodiment 33-36：In addition to organic ligand L1 is replaced with into L4, other operations are constant, so that reality is repeated
A 1-4 is applied, embodiment 33-36 is obtained.
Embodiment 37-40：In addition to organic ligand L1 is omitted, other operations are constant, so that reality is repeated
A 1-4 is applied, embodiment 37-40 is obtained.
As a result 2 be see the table below.
Table 2
“*”：The yield of the embodiment 40 of correspondence embodiment 4 is 67.3%
As can be seen here, in organic ligand L1-L4, L1 has best effect；And when without using any organic ligand,
Yield has significant reduction.
Embodiment 41-52
Embodiment 41-44：In addition to accelerator to be replaced with to N- normal-butyl-N- crassitude Bromides, other operations are equal
It is constant, so that embodiment 1-4 is repeated, obtain embodiment 41-44.
Embodiment 45-48：In addition to accelerator to be replaced with to N- normal-butyl-N- crassitude chlorates, other operations are equal
It is constant, so that embodiment 1-4 is repeated, obtain embodiment 45-48.
Embodiment 49-52：In addition to accelerator is omitted, other operations are constant, so that embodiment is repeated
1-4, obtains embodiment 49-52.
As a result 3 be see the table below.
Table 3
As can be seen here, when there is accelerator, yield, but N- normal-butyl-N- crassitudes can significantly increased
Double (fluoroform sulphonyl) inferior amine salts have best facilitation effect.
Embodiment 53-60
Embodiment 53-56：In addition to acid additive is replaced with into Loprazolam, other operations are constant, so as to repeat
Embodiment 1-4, obtains embodiment 53-56.
Embodiment 57-60：In addition to acid additive is omitted, other operations are constant, so that implementation is repeated
Example 1-4, obtains embodiment 57-60.
As a result 4 be see the table below.
Table 4
As can be seen here, when there is acid additive, yield can be being significantly increased, but the effect of p-methyl benzenesulfonic acid will show
Write and be higher than Loprazolam, the farther yield being higher than when acid additive is not used.
Embodiment 61-66
In addition to organic solvent therein is replaced with into following organic solvent, it is other operation it is constant, with embodiment 1-4 phases
With mode and implement embodiment 61-66 respectively, use the yield of organic solvent, embodiment corresponding relation and corresponding product
It is as shown in table 5 below.
Table 5
It can be seen that by upper table 5, in these organic solvents, PEG-200 has best solvent effect.
In summary, the invention provides a kind of synthetic method of diphenyl pyrazine class compound, it is right that methods described passes through
Catalyst, organic ligand, accelerator, acid additive and organic solvent it is appropriately selected with combining, obtained so as to high yield
Purpose product, and the reaction time is short, reaction temperature is low, it is easy to control, reached preferable reaction effect, in organic synthesis neck
Domain especially medicine intermediate synthesis field has a good application prospect and industrial production potential.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention
Enclose.In addition, it will also be appreciated that after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention
Change, modification and/or variation are planted, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (6)
1. diphenyl shown in a kind of lower formula (III) replaces the synthetic method of pyrazine compounds, methods described includes：To organic molten
In agent, in the presence of catalyst, organic ligand, accelerator and acid additive, lower formula (I) compound and formula (II) compound is carried out
Reaction, so that the formula (III) compound is obtained,
Wherein, R1-R2It is each independently H or C1-C6Alkyl；
The catalyst is the mixture of organocopper compound and double (1,5- cyclo-octadiene) nickel, wherein, organocopper compound with
The mol ratio of double (1,5- cyclo-octadiene) nickel is 1:0.5-1, the organocopper compound is the acetonitrile copper of hexafluorophosphoric acid four
The organic ligand is following formula L1,
The accelerator is double (fluoroform sulphonyl) inferior amine salts of N- normal-butyl-N- crassitudes；
The acid additive is p-methyl benzenesulfonic acid；
The organic solvent is polyethylene glycol 200.
2. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1.5-2.5.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of catalyst are
1:0.04-0.08。
4. synthetic method as claimed in claim 1, it is characterised in that：The mol ratio of formula (I) compound and organic ligand
For 1:0.1-0.14
5. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of accelerator are
1:0.1-0.15。
6. the synthetic method as described in claim any one of 1-5, it is characterised in that：Formula (I) compound and acid additive
Mol ratio be 1:0.1-0.2.
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