CN114957263A - Preparation method of drug intermediate - Google Patents
Preparation method of drug intermediate Download PDFInfo
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- CN114957263A CN114957263A CN202210655178.4A CN202210655178A CN114957263A CN 114957263 A CN114957263 A CN 114957263A CN 202210655178 A CN202210655178 A CN 202210655178A CN 114957263 A CN114957263 A CN 114957263A
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- triazolo
- pyrazine
- trifluoromethyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229940079593 drug Drugs 0.000 title claims abstract description 10
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 15
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000008569 process Effects 0.000 claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 33
- 238000003756 stirring Methods 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 229910000828 alnico Inorganic materials 0.000 claims description 12
- 239000000543 intermediate Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 5
- 238000003760 magnetic stirring Methods 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 238000010907 mechanical stirring Methods 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 claims description 2
- 238000006297 dehydration reaction Methods 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 claims 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 2
- 238000009987 spinning Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000011949 solid catalyst Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical group [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- -1 2-trifluoromethyl-5 Chemical class 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 238000004817 gas chromatography Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 5
- 239000000498 cooling water Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229910052759 nickel Inorganic materials 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000033616 DNA repair Effects 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 1
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of a drug intermediate 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine, which is characterized in that 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine is subjected to hydrogenation reaction under the action of a three-way catalyst to generate the 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine. The product obtained by the method has the purity as high as 99.8 percent and the yield as high as 99.2 percent, and the production cost is reduced. The invention overcomes the difficulties of low product purity and low yield in the prior art. The preparation method has the characteristics of milder and safer reaction conditions, simple and convenient operation, high yield, low cost, good quality and the like, and has wide application prospect. The invention emphasizes that the final hydrogenation process adopts a ternary solid catalyst on the catalyst by optimizing the synthesis conditions, so that the cost of the catalyst is greatly reduced. The synthesis process has cheap and easily available starting material 2-aminopyrazine, mild reaction condition, total yield up to about 45% and greatly reduced production cost.
Description
Technical Field
The invention belongs to the technical field of synthesis of drug intermediates, and particularly relates to a preparation method of a drug intermediate 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine.
Background
PARP refers to a polyadenylic diphosphribose polymerase, which plays a key role in the DNA repair pathway. PARP inhibitors are one cancer therapy targeting poly ADP-ribose polymerase and are the first anticancer drugs successfully using the synthetic lethal concept to gain approval for clinical use. In the invention, 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine is a key intermediate of fluxaparide.
The synthesis documents of 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine are not reported, and the reaction equation of the prior art is as follows:
in the existing synthesis process, palladium-carbon is an ultra-precious metal catalyst, so that the economic benefit is poor, the catalytic efficiency is low, the yield is only 94%, the purity is only 97%, the existing process needs to be improved, and a suitable industrialized process is developed.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a preparation method of a drug intermediate 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine, wherein the 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine is subjected to hydrogenation reaction under the action of a three-way catalyst to generate the drug intermediate 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine; the reaction equation is as follows:
wherein, the three-way catalyst is a nickel-containing three-way catalyst.
Preferably, the three-way catalyst is selected from one or more of alnico, alnico and alnico; preferably alnico, alnico.
Preferably, the mass ratio of the 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine to the three-way catalyst is 1: 0.02-0.1; preferably 1: 0.1.
Preferably, the pressure of hydrogen in the hydrogenation reaction is controlled to be 50-70 KG; preferably 60 to 70 KG.
Preferably, the temperature of the hydrogenation reaction is controlled to be 78-110 ℃.
Preferably, the hydrogenation reaction comprises the following steps: adding 1 part by mass of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine and 0.02-0.1 part by mass of a ternary catalyst into a hydrogenation reaction kettle, performing nitrogen replacement on a system, pressurizing hydrogen, starting stirring, heating, reacting at 78-110 ℃ and under the hydrogen pressure of 50-70KG, releasing heat in the reaction, reacting at 78-90 ℃ and under the hydrogen pressure of 50-70KG in the initial stage, and reacting at 100-110 ℃ and under the hydrogen pressure of 60-70 KG in the later stage; when the hydrogen pressure does not decrease, keeping the temperature for 4 hours at 100-110 ℃ under the hydrogen pressure of 60-70 KG, and sampling and analyzing: the product content is more than 99 percent (gas chromatography, raw material decomposition), and the reaction is finished; after the reaction is finished, stopping stirring, standing, decompressing, absorbing liquid, filtering, recovering the catalyst, and carrying out rotary reduced pressure distillation on the filtrate to obtain brown oily matter, namely 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine.
Preferably, the stirring is mechanical stirring or magnetic stirring; magnetic stirring is preferred.
Preferably, 2-aminopyrazine and ethyl trifluoroacetate are used as raw materials, and the 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine is obtained through amidation reaction, substitution reaction, dehydration cyclization reaction and hydrogenation reaction.
Specifically, the method comprises the following steps: taking 2-aminopyrazine as a starting material, reacting with ethyl trifluoroacetate to obtain amide, chlorinating by phosphorus pentachloride, reacting chloride with hydroxylamine to obtain a hydroxylamine intermediate, cyclizing by polyphosphoric acid to obtain 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine, and hydrogenating in the presence of a ternary catalyst to obtain a target compound, namely 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine; the reaction equation is as follows:
wherein, the three-way catalyst is a nickel-containing three-way catalyst.
The invention has the advantages and beneficial effects that:
the invention provides a preparation method of a drug intermediate 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine, which comprises the steps of carrying out catalytic hydrogenation reaction on the 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine by adopting a nickel-containing three-way catalyst, filtering the obtained substance, and distilling under reduced pressure to obtain a brown oily product, namely the 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine; the product obtained by the method has the purity as high as 99.8 percent and the yield as high as 99.2 percent, and reduces the production cost.
The invention overcomes the difficulties of low product purity and low yield in the prior art.
The preparation method has the characteristics of milder and safer reaction conditions, simple and convenient operation, high yield, low cost, good quality and the like, and has wide application prospect.
The invention emphasizes that the final hydrogenation process adopts a ternary solid catalyst on the catalyst by optimizing the synthesis conditions, so that the cost of the catalyst is greatly reduced.
The synthesis process has cheap and easily available starting material 2-aminopyrazine, mild reaction condition, total yield up to about 45% and greatly reduced production cost.
Detailed Description
The following further describes embodiments of the present invention with reference to examples. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
The invention provides a preparation method of a drug intermediate 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine, which comprises the following steps: the preparation method comprises the following steps of adopting 2-aminopyrazine as a starting material, reacting with ethyl trifluoroacetate to obtain amide, chlorinating by phosphorus pentachloride, reacting chloride with hydroxylamine to obtain a hydroxylamine intermediate, cyclizing by polyphosphoric acid to obtain 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine, and finally hydrogenating in the presence of a nickel-containing ternary catalyst to obtain a target compound, namely 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine.
Specifically, the hydrogenation reaction comprises the following steps:
adding 1 part by mass of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine and 0.02-0.1 part by mass of nickel-containing ternary catalyst into a hydrogenation reaction kettle, performing nitrogen replacement on a system, pressurizing hydrogen, starting stirring, heating, reacting at 78-110 ℃ under the hydrogen pressure of 50-70KG, releasing heat in the reaction, reacting at 78-90 ℃ under the hydrogen pressure of 50-70KG in the initial stage, and reacting at 100-110 ℃ under the hydrogen pressure of 60-70 KG in the later stage; when the hydrogen pressure does not drop, the temperature is maintained for 4 hours at 100-110 ℃ under the hydrogen pressure of 60-70 KG, and sampling analysis is carried out: the product content is more than 99% (gas chromatography, raw material decomposition), and the reaction is finished; after the reaction is finished, stopping stirring, standing, decompressing, absorbing liquid, filtering, recovering the catalyst, and carrying out rotary reduced pressure distillation on the filtrate to obtain brown oily matter, namely 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine;
wherein:
the three-way catalyst is selected from one or more of alnico, alnico and alnico; preferably alnico, alnico.
The stirring is mechanical stirring or magnetic stirring; magnetic stirring is preferred.
The specific embodiment of the invention is as follows:
example 1
Adding 49g of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine into a hydrogenation kettle, adding 5g of aluminum nickel iron, adding 200g of ethyl acetate, sealing, performing nitrogen replacement for three times, pressurizing by hydrogen for 70KG, starting stirring, stirring cooling water, and heating; when the material temperature is 78-110 ℃, the hydrogen pressure is 70KG for reaction, the reaction releases heat, when the temperature is 78-90 ℃ in the initial stage, the 50-70KG pressure is reacted, and when the temperature is 100-110 ℃ in the later stage, the 60-70 KG pressure is reacted; when the hydrogen pressure does not drop, the temperature is maintained for 4 hours at 100-110 ℃ under the hydrogen pressure of 60-70 KG, and sampling analysis is carried out: the product content was 99.8% (gas chromatography, decomposition of raw material), the reaction was complete; stopping stirring, standing, releasing pressure, sucking liquid, filtering, rotating and distilling under reduced pressure to obtain 49.5g of brown oily matter with the yield of 99%, and determining that the brown oily matter is 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine with correct structure by nuclear magnetic resonance.
HNMR(DM-SO,500MHz)，δ:2.87(br,1H)，3.15(t,2H)，3.98 (s,2H)，4.14(t,2H)；MS(EI):193.09，[M+H]+。
Example 2
Adding 49g of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine into a hydrogenation kettle, adding 5g of aluminum nickel iron, adding 200g of ethyl acetate, sealing, performing nitrogen replacement for three times, pressurizing by hydrogen for 70KG, starting stirring, stirring cooling water, and heating; when the material temperature is 78-110 ℃, the hydrogen pressure is 70KG for reaction, the reaction releases heat, when the temperature is 78-90 ℃ in the initial stage, the pressure is 50-70KG for reaction, and when the temperature is 100-110 ℃ in the later stage, the pressure is 60-70 KG for reaction; when the hydrogen pressure does not drop, the temperature is maintained for 4 hours at 100-110 ℃ under the hydrogen pressure of 60-70 KG, and sampling analysis is carried out: the product content was 99.7% (gas chromatography, decomposition of raw material), and the reaction was complete; stopping stirring, standing, releasing pressure, sucking liquid, filtering, rotating and distilling under reduced pressure to obtain 49.6g of brown oily matter with the yield of 99.2%, and determining that the brown oily matter is 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine in a correct structure by nuclear magnetic resonance.
Example 3
Adding 49g of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine into a hydrogenation kettle, adding 5g of aluminum nickel iron, adding 200g of ethyl acetate, sealing, performing nitrogen replacement for three times, pressurizing by hydrogen for 70KG, starting stirring, stirring cooling water, and heating; when the material temperature is 78-110 ℃, the hydrogen pressure is 70KG for reaction, the reaction releases heat, when the temperature is 78-90 ℃ in the initial stage, the pressure is 50-70KG for reaction, and when the temperature is 100-110 ℃ in the later stage, the pressure is 60-70 KG for reaction; when the hydrogen pressure is not reduced, the temperature is maintained for 4 hours at the temperature of 110 ℃ and the hydrogen pressure of 60-70 KG, and sampling analysis is carried out: the product content was 99.9% (gas chromatography, decomposition of raw material), the reaction was complete; stopping stirring, standing, releasing pressure, sucking liquid, filtering, rotating and distilling under reduced pressure to obtain 49.7g of brown oily matter with the yield of 99.4 percent, and determining that the brown oily matter is 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine with correct structure through nuclear magnetic resonance.
Example 4
Adding 49g of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine into a hydrogenation kettle, adding 5g of aluminum nickel iron, adding 200g of ethyl acetate, sealing, performing nitrogen replacement for three times, pressurizing by hydrogen for 70KG, starting stirring, stirring cooling water, and heating; when the material temperature is 78-110 ℃, the hydrogen pressure is 70KG for reaction, the reaction releases heat, when the temperature is 78-90 ℃ in the initial stage, the pressure is 50-70KG for reaction, and when the temperature is 100-110 ℃ in the later stage, the pressure is 60-70 KG for reaction; when the hydrogen pressure does not drop, the temperature is maintained for 4 hours at 100-110 ℃ under the hydrogen pressure of 60-70 KG, and sampling analysis is carried out: the product content was 99.8% (gas chromatography, decomposition of raw material), the reaction was complete; stopping stirring, standing, releasing pressure, sucking liquid, filtering, rotating and distilling under reduced pressure to obtain 49.5g of brown oily matter with the yield of 99 percent, and determining that the brown oily matter is 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine with a correct structure by nuclear magnetism.
Example 5
Adding 49g of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine into a hydrogenation kettle, adding 5g of aluminum nickel iron, adding 200g of ethyl acetate, sealing, performing nitrogen replacement for three times, pressurizing by hydrogen for 70KG, starting stirring, stirring cooling water, and heating; when the material temperature is 78-110 ℃, the hydrogen pressure is 70KG for reaction, the reaction releases heat, when the temperature is 78-90 ℃ in the initial stage, the pressure is 50-70KG for reaction, and when the temperature is 100-110 ℃ in the later stage, the pressure is 60-70 KG for reaction; when the hydrogen pressure does not decrease, keeping the temperature of the hydrogen pressure of 60-70 KG for 4 hours at 100-110 ℃, and sampling and analyzing: the product content was 99.9% (gas chromatography, decomposition of raw material), the reaction was complete; stopping stirring, standing, releasing pressure, sucking liquid, filtering, rotating and distilling under reduced pressure to obtain 49.6g of brown oily matter with the yield of 99.2 percent, and determining that the brown oily matter is 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine with correct structure through nuclear magnetic resonance.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the technical principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (9)
1. A preparation method of a drug intermediate is characterized in that 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine is subjected to hydrogenation reaction under the action of a three-way catalyst to generate the 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine.
2. The method for preparing the pharmaceutical intermediate according to claim 1, wherein the three-way catalyst is selected from one or more of alnico, and alnico.
3. The method for preparing a pharmaceutical intermediate according to claim 1, wherein the mass ratio of the 2-trifluoromethyl (1,2,4) triazolo (1,5- α) pyrazine to the three-way catalyst is 1: 0.02-0.1.
4. The method for preparing a pharmaceutical intermediate according to claim 1, wherein the hydrogen pressure in the hydrogenation reaction is controlled to 50 to 70 KG.
5. The method for preparing the pharmaceutical intermediate according to claim 1, wherein the temperature of the hydrogenation reaction is controlled to be 78-110 ℃.
6. The process for the preparation of a pharmaceutical intermediate according to claim 1 or 2, characterized in that it comprises the following steps: adding 1 part by mass of 2-trifluoromethyl (1,2,4) triazolo (1, 5-alpha) pyrazine and 0.02-0.1 part by mass of ternary catalyst into a hydrogenation reaction kettle, performing nitrogen replacement on the system, pressurizing hydrogen, starting stirring, and reacting at 78-110 ℃ under the hydrogen pressure of 50-70 KG; after the reaction is finished, stopping stirring, standing, decompressing, absorbing liquid, filtering, spinning and distilling filtrate to obtain brown oily matter, namely 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1, 5-alpha) pyrazine.
7. The method for producing a pharmaceutical intermediate according to claim 6, wherein the stirring is mechanical stirring or magnetic stirring.
8. The method for preparing a pharmaceutical intermediate according to claim 1, wherein 2-aminopyrazine and ethyl trifluoroacetate are used as raw materials, and the 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1,5- α) pyrazine is obtained through amidation reaction, substitution reaction, dehydration cyclization reaction and hydrogenation reaction.
9. The method for preparing a pharmaceutical intermediate according to claim 8, wherein 2-aminopyrazine is used as a starting material, and is reacted with ethyl trifluoroacetate to form amide, chlorinated with phosphorus pentachloride, and the chloride is reacted with hydroxylamine to form a hydroxylamine intermediate, which is cyclized with polyphosphoric acid to form 2-trifluoromethyl (1,2,4) triazolo (1,5- α) pyrazine, and the target compound, 2-trifluoromethyl-5, 6,7, 8-tetrahydro (1,2,4) triazolo (1,5- α) pyrazine, is obtained by hydrogenation in the presence of a three-way catalyst.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014953A1 (en) * | 2002-10-07 | 2006-01-19 | Dooseop Kim | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN101014598A (en) * | 2004-06-21 | 2007-08-08 | 默克公司 | Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2007136603A2 (en) * | 2006-05-16 | 2007-11-29 | Merck & Co., Inc. | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2019137358A1 (en) * | 2018-01-09 | 2019-07-18 | 江苏恒瑞医药股份有限公司 | Method for preparing parp inhibitor and intermediate thereof |
-
2022
- 2022-06-10 CN CN202210655178.4A patent/CN114957263A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060014953A1 (en) * | 2002-10-07 | 2006-01-19 | Dooseop Kim | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
| CN101014598A (en) * | 2004-06-21 | 2007-08-08 | 默克公司 | Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2007136603A2 (en) * | 2006-05-16 | 2007-11-29 | Merck & Co., Inc. | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| WO2019137358A1 (en) * | 2018-01-09 | 2019-07-18 | 江苏恒瑞医药股份有限公司 | Method for preparing parp inhibitor and intermediate thereof |
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