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CN118103355A - Hydrogenation synthesis method for preparing pyrazine carboxylic acid derivatives serving as fluorescent tracers - Google Patents

Hydrogenation synthesis method for preparing pyrazine carboxylic acid derivatives serving as fluorescent tracers Download PDF

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CN118103355A
CN118103355A CN202280064821.4A CN202280064821A CN118103355A CN 118103355 A CN118103355 A CN 118103355A CN 202280064821 A CN202280064821 A CN 202280064821A CN 118103355 A CN118103355 A CN 118103355A
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郑骏浩
关体红
皇甫港怀
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
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    • 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
    • C07D241/20—Nitrogen atoms

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Abstract

Relates to a hydrogenation synthesis method of pyrazine carboxylic acid derivatives used as fluorescent tracers, in particular to a method for preparing 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxyl-2-hydroxyethyl ] carbamoyl } pyrazine.

Description

Hydrogenation synthesis method for preparing pyrazine carboxylic acid derivatives serving as fluorescent tracers Technical Field
The present invention relates to a process for the preparation of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxylic acid-2-hydroxyethyl ] carbamoyl } pyrazine for use as fluorescent tracers in medical diagnostics.
Background
The pyrazine derivatives have potential application prospects in the aspect of evaluating renal functions as fluorescent tracers. As a fluorescent tracer of great clinical application value, studies of3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine (hereinafter also referred to as "compound of formula 1" or "compound 1") have been widely conducted, but few synthetic routes of this compound are reported at present.
In 2011, raghavan Rajagopalan et al optimized the synthesis of compound 1, reducing the number of reaction steps (j.med.chem., 2011,54,5048-5058). In the synthesis method, 3, 6-diaminopyrazine-2, 5-dicarboxylic acid serving as a raw material is subjected to amidation, palladium catalytic hydrogenation and other steps to obtain a compound 1:
However, the 2 nd step of the route uses hydrogen as a hydrogen source, and not only pressurization but also long reaction time are required in industrial production; hydrogen is inflammable and explosive gas, and has great potential safety hazard in industrial production.
Thus, there is still a need to develop a method suitable for the industrial production of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine with high safety and high efficiency.
Disclosure of Invention
The invention aims to overcome the problems in the prior art, avoid using flammable and explosive hydrogen and reduce the potential safety hazard in industrial production.
A further object of the invention is: the reaction time is shortened while achieving yields and quality of compound 1 equivalent to those of the prior art (e.g., raghavan Rajagopalan et al, j. Med. Chem.,2011,54,5048-5058.). This is of great importance for industrial production.
The above object is achieved by providing a process for the preparation of the present invention suitable for the industrial production of compound 1.
In general, the present invention provides a novel process for preparing 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine of formula 1 (hereinafter also referred to as "compound 1"), comprising the steps of:
Subjecting a compound of formula 5 (hereinafter also referred to as "compound 5") to a hydrogen-donating reaction with a hydrogen-donating reagent in a solvent in the presence of a suitable metal catalyst to provide the 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine of formula 1,
Wherein the solvent is selected from an alcohol or an aqueous alcohol solution.
Detailed Description
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive (inclusive) or open-ended and do not exclude other unrecited elements or method steps, although not necessarily present (i.e., the terms also encompass the terms "consisting essentially of … …" and "consisting of … …").
As used herein, the term "hydrogen-borrowing reaction", also known as hydrogen transfer reaction, refers to the dehydrogenation of a relatively inert organic compound with a metal catalyst to form a metal hydride, while activating the organic compound and participating in a subsequent reaction to form an intermediate, after which the metal hydride re-reduces the intermediate to form a new product. The organic compound is referred to as a "hydrogen borrowing reagent".
As used herein, the term "room temperature" refers to about 20 to 25 ℃.
The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.
In a first aspect, the present invention provides a process for preparing 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine of formula 1 characterized in that the process comprises the steps of:
Subjecting a compound of formula 5 to a hydrogen-borrowing reaction with a hydrogen-borrowing reagent in a solvent in the presence of a suitable metal catalyst to provide the 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine of formula 1,
Wherein the solvent comprises an alcohol or an aqueous alcohol solution.
The hydrogen-borrowing reagent used in the method of the present invention is preferably a reagent suitable for industrial production. The use of certain reagents may present a manufacturing hazard and is therefore not preferred. For example, ammonium formate is prone to sublimation, and thus causes problems of clogging the piping.
In some embodiments, the hydrogen-donating agent is selected from the group consisting of formic acid and alkali metal formate, cyclohexadiene, and isopropanol.
In some embodiments, the molar ratio of the compound of formula 5 to the hydrogen-borrowing reagent is about 1:2 to 1:20, preferably about 1:2 to 1:10, such as about 1:2.5, about 1:4, about 1:5, about 1:6, or about 1:8.
In some embodiments, the metal catalyst is palladium on carbon (Pd/C). The mass fraction of palladium in the Pd/C catalyst may be about 5 to 20%, preferably about 10%. For example, the Pd/C catalyst may contain about 50w/w% water.
In some embodiments, the mass ratio of the compound of formula 5 to the metal catalyst is about 10:1 to 10:3, preferably about 10:2.
In some embodiments, the solvent is an alcohol.
In other embodiments, the solvent is an aqueous alcohol solution. The volume ratio of alcohol to water in the aqueous alcohol solution may be from about 1:10 to 10:1, preferably from about 1:8 to 8:1, more preferably from about 4:1 to 8:1.
In some of the above-described embodiments, the amount of the alcohol may be about 4 to 40 times (v/w), such as about 10, 15, 25, 30, or 35 times (v/w), the amount of the compound of formula 5, whether or not the solvent includes water.
The alcohol may be selected from methanol, ethanol, isopropanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
In some embodiments, the hydrogen-borrowing reaction is conducted at a temperature of about 20 ℃ to 100 ℃, preferably about 20 ℃ to 80 ℃. In some preferred embodiments, the hydrogen-borrowing reaction is conducted at a temperature of about 50 ℃ to 70 ℃. In some preferred embodiments, the hydrogen-assisted reaction is performed at room temperature.
In some embodiments, the hydrogen-assisted reaction is carried out for about 1 to 12 hours, preferably about 2 to 12 hours, more preferably about 2 hours, 10 hours or 12 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
In some preferred embodiments, the hydrogen-assisted reaction is carried out at a temperature of about 70 ℃ for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
The conversion of the compound of formula 5 into the compound of formula 1 can be monitored by detecting the residual amount of the compound of formula 5 in the reaction by, for example, thin Layer Chromatography (TLC).
The resulting compound of formula 1 may be isolated and purified by the following steps:
(1) After the hydrogen-assisted reaction is completed, filtering the reaction mixture, washing the filter cake with an aqueous alcohol solution until the filtrate is pale yellow, and combining the obtained filtrates;
(2) Concentrating the filtrate to obtain a crude product of the compound of the formula I;
(3) Adding an appropriate amount of acetonitrile or water to the crude product of the compound of formula I and slurrying for a suitable time (e.g., about 1 to 4 hours);
(4) Filtration and drying of the filter cake under reduced pressure at a suitable temperature (e.g., about 40 to 45 ℃) gives the compound of formula I.
The aqueous alcohol solution described in step (1) may be, for example, an aqueous alcohol solution. The aqueous ethanol solution may have a water content of about 25% to 40% (v/v), preferably about 30% to 36% (v/v).
In a second aspect, the invention provides a process as described in the first aspect above, characterized in that the hydrogen-donating agent is a combination of formic acid and an alkali metal formate.
In some embodiments, the molar ratio of the formic acid to the alkali metal formate is from about 1:6 to 6:1, preferably from about 1:1 to 5:1, more preferably from about 1:2 to 5:1.
In some embodiments, the molar ratio of the compound of formula 5 to the sum of the formic acid and the alkali metal formate is from about 1:2 to 1:20, for example from about 1:4 to 1:18, from about 1:6 to 1:16, or from about 1:8 to 1:12. In some preferred embodiments, the molar ratio is about 1:5 to 1:10, for example about 1:6 to 1:8, more preferably about 1:6.
In some preferred embodiments, the alkali metal formate is sodium formate or potassium formate, preferably potassium formate.
The combination of formic acid and alkali metal formate can be obtained by adding formic acid alone and alkali metal formate or a mixture thereof to the reaction system, or can be formed in situ by reacting an excess of formic acid with an appropriate amount of the corresponding alkali metal base in the reaction system. The base may be selected from potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate, and any combination thereof.
In some preferred embodiments, the solvent is an aqueous alcohol solution. The volume ratio of alcohol to water in the aqueous alcohol solution may be from about 1:10 to 10:1, preferably from about 1:8 to 8:1, more preferably from about 4:1 to 8:1. The amount of alcohol may be about 10 to 40 times (v/w), preferably about 10 to 35 times (v/w), for example 15, 25 or 30 times (v/w), the amount of the compound of formula 5. In some preferred embodiments, the alcohol is selected from methanol, ethanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
In some embodiments, the hydrogen-borrowing reaction is conducted at a temperature of about 50 ℃ to 80 ℃, preferably at about 50 ℃, about 60 ℃, or more preferably about 70 ℃.
In some embodiments, the hydrogen-assisted reaction is carried out for about 2 to 12 hours, preferably about 2 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
The process allows for yields and quality of compound 1 equivalent to those reported by Raghavan Rajagopalan et al (j. Med. Chem.,2011,54,5048-5058).
In some more preferred embodiments, the hydrogen-assisted reaction is carried out at a temperature of about 70 ℃ for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
In some particularly preferred embodiments, the present invention provides a process as described above, characterized in that the hydrogen-borrowing reagent is a combination of formic acid and potassium formate in a molar ratio of about 1:2 to 5:1;
The molar ratio of the compound of formula 5 to the sum of the formic acid and the potassium formate is from about 1:5 to 1:10, more preferably about 1:6;
The solvent is an aqueous solution of methanol or ethanol, wherein the volume ratio of methanol or ethanol to water is about 4:1 to 8:1;
the amount of methanol or ethanol is about 15 to 35 times (v/w) the amount of the compound of formula 5;
the metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (e.g., the Pd/C catalyst contains about 50w/w% water);
the mass ratio of the compound of formula 5 to the Pd/C catalyst is about 10:2; and
The hydrogen-assisted reaction is carried out at a temperature of about 50 ℃ to 70 ℃ for about 2 to 12 hours, more preferably at a temperature of about 70 ℃ for about 2 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
The resulting compound of formula 1 may be isolated and purified by the steps as described above for the first aspect. In some embodiments, the separation and purification process may further include the step of adding an appropriate amount of acid (e.g., the same molar amount as the alkali metal base used to form the alkali metal formate in situ) to the combined filtrates and mixing. For example, when the combination of formic acid and alkali metal formate is formed in situ as described above, the same molar amount of acid as the alkali metal base used to form the alkali metal formate in situ can be added to the combined filtrates. The acid is preferably hydrochloric acid. The resulting mixture is then concentrated to give the crude compound of formula I.
In a third aspect, the present invention provides a process as described in the first aspect above, characterised in that the hydrogen-borrowing reagent is cyclohexadiene.
In some embodiments, the molar ratio of the compound of formula 5 to the cyclohexadiene is from about 1:2 to 1:5; preferably about 1:2 to 1:3.
In some embodiments, the solvent is an alcohol, preferably methanol or ethanol, more preferably ethanol.
In some embodiments, the amount of the alcohol is about 4 to 10 times (v/w), such as about 4, about 6, or about 8 times (v/w), the amount of the compound of formula 5.
In some embodiments, the hydrogen-assisted reaction is carried out at room temperature for about 10 to 12 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
In some embodiments, the invention provides a method as described above, characterized in that the hydrogen-borrowing reagent is cyclohexadiene;
the molar ratio of the compound of formula 5 to the cyclohexadiene is from about 1:2 to 1:3;
The solvent is methanol or ethanol, and the amount of the methanol or ethanol is about 4 to 6 times (v/w) the amount of the compound of formula 5;
the metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (e.g., the Pd/C catalyst contains about 50w/w% water);
the mass ratio of the compound of formula 5 to the Pd/C catalyst is about 10:2; and
The hydrogen-assisted reaction is carried out at room temperature for about 10 to 12 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
The resulting compound of formula 1 may be isolated and purified by the steps as described above for the first aspect.
Advantageous effects
The method of the invention avoids the use of flammable and explosive hydrogen and greatly reduces the potential safety hazard in industrial production. The method of the invention has the advantages of thorough debenzylation reaction and no side reaction basically. Moreover, by adjusting the reaction conditions (e.g., the ratio of reactants and the reaction temperature), the process of the present invention is able to shorten the reaction time from more than 10 hours reported by Raghavan Rajagopalan et al to about 2 hours or less, thereby greatly shortening the production time, while achieving the same yield and quality of compound 1 as reported by Raghavan Rajagopalan et al (j. Med. Chem.,2011,54,5048-5058). The method of the invention also avoids the problem of clogging the piping caused by sublimation when ammonium formate is used. The method has low equipment requirement, simple and convenient operation, high yield, high safety and cost benefit, is suitable for industrial production, and has important application value.
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
The experimental method without specific conditions noted in the embodiments of the present invention is generally conventional conditions or conditions suggested by the manufacturer of the raw materials or goods; reagents of unspecified origin are typically conventional reagents commercially available or may be prepared from known reagents by conventional methods.
Reagent and instrument
1.HRMS
Instrument model: agilent 1290Q-TOF-6545A;
Reagent: formic acid, trifluoroacetic acid, acetonitrile, methanol.
2.LC/MS
Instrument for measuring and controlling the intensity of light ：Waters 2767 Sample Manager、Waters 515 HPLC Pump、Waters2489UV/Visible Detector、Waters 3100 Mass Detector;
Reagent: purified water, acetonitrile.
The mass spectrum is measured by an LC-MS instrument, and the ionization mode can be ESI or APCI.
Thin Layer Chromatography (TLC) used either the plummet yellow sea HSGF254 or the Qingdao GF254 silica gel plate. The specification of the silica gel plate used is 0.15 mm-0.2 mm, and the specification of the silica gel plate used for thin layer chromatography separation and purification is 0.4 mm-0.5 mm.
Column chromatography generally uses 200-300 mesh silica gel of yellow sea as carrier.
The various starting materials and reagents are either commercially available or are synthesized according to known methods, and are used without further purification unless otherwise indicated.
Example 1: preparation of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine
To a 250mL reaction flask, 20mL of purified water and 0.56g of KOH were added, after complete dissolution, 2.76g of HCOOH and 80mL of ethanol were added, after stirring for 5min, 5.00g of Compound 5 and 1g of 10% Pd/C (containing 50%) were added at room temperature, and heated under reflux at 70℃for 2h, TLC monitoring showed that the reaction was complete and Pd/C was filtered off with celite while hot. The filter cake was washed with aqueous ethanol (30% H 2 O, V/V) until the filtrate was pale yellow, and the filtrates were combined. To the filtrate, 10ml of 1N hydrochloric acid was added, followed by stirring for 15 minutes and then concentrating under reduced pressure to dryness. The resulting solid was slurried with 50mL of acetonitrile/water for 2h and then filtered. The filter cake was dried under reduced pressure at 40℃for 12 hours to give 2.19g of the title compound as a solid (molar yield: 65%).
LC-MS：RT＝3.02min,[M-H]＝370.9.
HRMS：[M+H +]＝373.1110.
1H NMR[500Hz,DMSO-d6]δ8.47(d,2H),6.78(s,4H),4.47(dt,2H),3.90(dd,2H),3.76(dd,2H).
Comparative example 1: preparation of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine
The procedure of example 1 was repeated except that KOH was not added.
Specifically, 20mL of purified water was added to a 250mL reaction flask, followed by 2.76g of HCOOH and 80mL of ethanol, and after stirring for 5min, 5.00g of Compound 5 and 1g of 10% Pd/C (50% aqueous) were added at room temperature and heated under reflux at 70℃for 2h. TLC monitoring showed little visible target compound, with a large amount of starting material point remaining.
Example 2: preparation of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine
To a 250mL reaction flask, 20mL of purified water and 2.23g of KOH were added, after complete dissolution, 2.76g of HCOOH and 160mL of ethanol were added, after stirring for 5min, 5.00g of Compound 5, 1g of 10% Pd/C (50% aqueous) were added at room temperature, and heated under reflux at 60℃for 10h, TLC monitoring showed that the reaction was complete and Pd/C was filtered off with celite while hot. The filter cake was washed with aqueous ethanol (30% H 2 O, V/V) until the filtrate was pale yellow, and the filtrates were combined. To the filtrate, 40ml of 1N hydrochloric acid was added, followed by stirring for 15 minutes and then concentrating under reduced pressure to dryness. The resulting solid was slurried with 30mL of water for 2h and then filtered. The filter cake was dried under reduced pressure at 40℃for 12 hours to give 2.12g of the title compound as a solid (molar yield: 63%).
LC-MS：RT＝3.02min,[M-H]＝370.9.
HRMS and 1 H NMR data were as in example 1.
Example 3: preparation of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine
To a 250mL reaction flask, 20mL of purified water and 2.23g KOH were added, after complete dissolution, 2.76g HCOOH and 80mL methanol were added, after stirring for 5min, 5.00g of Compound 5, 1g of 10% Pd/C (50% aqueous) were added at room temperature, and heated to reflux at 50℃for 12h, TLC monitoring showed that the reaction was complete and Pd/C was filtered off with celite while hot. The filter cake was washed with aqueous ethanol (36% H 2 O, V/V) until the filtrate was pale yellow, and the filtrates were combined. To the filtrate, 40mL of 1N hydrochloric acid was added, followed by stirring for 15min, concentration under reduced pressure to 25mL, and filtration. The filter cake was slurried with 50mL of water for 2h and then filtered. The filter cake was dried under reduced pressure at 40℃for 12 hours to give 1.85g of the title compound as a red solid (molar yield: 55%).
LC-MS：RT＝3.02min,[M-H]＝370.9.
HRMS and 1 H NMR data were as in example 1.
Example 4: preparation of 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine
To a 250mL reaction flask was added 20mL ethanol and 5.00g of compound 5, 2g of cyclohexadiene and 1g of 10% Pd/C (50% aqueous) and reacted at room temperature for 12h, TLC monitoring showed the reaction was complete, and Pd/C was filtered through celite. The filter cake was washed with aqueous ethanol (36% H 2 O, V/V) until the filtrate was pale yellow, and the filtrates were combined. The filtrate was concentrated to dryness, slurried with 20mL of water for 2h, and then filtered. The filter cake was dried under reduced pressure at 40℃for 12 hours to give 2.20g of the title compound as a red solid (molar yield: 65%).
LC-MS：RT＝3.02min,[M-H]＝370.9.
HRMS and 1 H NMR data were as in example 1.
In addition to the embodiments described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims (18)

  1. A process for preparing 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine of formula 1, comprising the steps of:
    Subjecting a compound of formula 5 to a hydrogen-borrowing reaction with a hydrogen-borrowing reagent in a solvent in the presence of a suitable metal catalyst to provide the 3, 6-diamino-2, 5-bis { N- [ (1R) -1-carboxy-2-hydroxyethyl ] carbamoyl } pyrazine of formula 1,
    Wherein the solvent comprises an alcohol or an aqueous alcohol solution.
  2. The process according to claim 1, characterized in that the hydrogen-donating agent is selected from the group consisting of formic acid and alkali metal formates, cyclohexadiene and isopropanol; and/or
    The molar ratio of the compound of formula 5 to the hydrogen-borrowing reagent is about 1:2 to 1:20, preferably about 1:2 to 1:10, for example about 1:2.5, about 1:4, about 1:5, about 1:6 or about 1:8.
  3. The process according to claim 1 or 2, characterized in that the metal catalyst is palladium on carbon (Pd/C);
    preferably, the mass fraction of palladium in the Pd/C catalyst is from about 5 to 20%, preferably about 10% (e.g. the Pd/C catalyst contains about 50w/w% water).
  4. A process according to any one of claims 1 to 3, characterized in that the mass ratio of the compound of formula 5 to the metal catalyst is about 10:1 to 10:3, preferably about 10:2.
  5. The process according to any one of claims 1 to 4, wherein the solvent is an alcohol.
  6. The process according to any one of claims 1 to 4, wherein the solvent is an aqueous alcohol solution;
    preferably, the volume ratio of alcohol to water in the aqueous alcohol solution is from about 1:10 to 10:1, preferably from about 1:8 to 8:1, more preferably from about 4:1 to 8:1.
  7. The method according to any one of claims 5 to 7, characterized in that the amount of alcohol is about 4 to 40 times (v/w), such as about 10, 15, 25, 30 or 35 times (v/w), the amount of the compound of formula 5.
  8. The method according to any one of claims 5 to 7, characterized in that the alcohol is selected from methanol, ethanol, isopropanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
  9. The process according to any one of claims 1 to 8, characterized in that the hydrogen-borrowing reaction is carried out at a temperature of about 20 ℃ to 100 ℃, preferably about 20 ℃ to 80 ℃, more preferably room temperature or about 50 ℃ to 70 ℃; and/or
    The hydrogen-assisted reaction is carried out for about 1 to 12 hours, preferably about 2 to 12 hours, more preferably about 2 hours, 10 hours or 12 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
  10. The process according to any one of claims 1 to 9, characterized in that the hydrogen-donating agent is a combination of formic acid and an alkali formate;
    Preferably, the molar ratio of formic acid to alkali metal formate is from about 1:6 to 6:1, preferably from about 1:1 to 5:1, more preferably from about 1:2 to 5:1; and/or
    Preferably, the molar ratio of the compound of formula 5 to the sum of the formic acid and the alkali metal formate is from about 1:2 to 1:20, preferably from about 1:5 to 1:10, more preferably about 1:6.
  11. Process according to claim 10, characterized in that the alkali formate is sodium formate or potassium formate, preferably potassium formate.
  12. The method according to claim 10 or 11, characterized in that the solvent is an aqueous alcohol solution according to any one of claims 6 to 8; and/or
    The amount of the alcohol is about 10 to 40 times (v/w), preferably about 15 to 35 times (v/w), the amount of the compound of formula 5, preferably the alcohol is selected from methanol, ethanol and mixtures thereof, preferably methanol or ethanol, more preferably ethanol.
  13. The process according to any one of claims 10 to 12, characterized in that the hydrogen-borrowing reaction is carried out at a temperature of about 50 ℃ to 80 ℃, preferably at about 50 ℃, about 60 ℃ or more preferably about 70 ℃; and/or
    The hydrogen-assisted reaction is carried out for about 2 to 12 hours, preferably about 2 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1;
    Preferably the hydrogen-assisted reaction is carried out at a temperature of about 70 ℃ for about 2 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
  14. The method of claim 1 wherein the hydrogen-donating agent is a combination of formic acid and potassium formate in a molar ratio of about 1:2 to 5:1;
    The molar ratio of the compound of formula 5 to the sum of the formic acid and the potassium formate is from about 1:5 to 1:10, more preferably about 1:6;
    The solvent is an aqueous solution of methanol or ethanol, wherein the volume ratio of methanol or ethanol to water is about 4:1 to 8:1;
    the amount of methanol or ethanol is about 15 to 35 times (v/w) the amount of the compound of formula 5;
    the metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (e.g., the Pd/C catalyst contains about 50w/w% water);
    the mass ratio of the compound of formula 5 to the Pd/C catalyst is about 10:2; and
    The hydrogen-assisted reaction is carried out at a temperature of about 50 ℃ to 70 ℃ for about 2 to 12 hours, more preferably at a temperature of about 70 ℃ for about 2 hours, to complete the conversion of the compound of formula 5 to the compound of formula 1.
  15. The process according to any one of claims 1 to 9, characterized in that the hydrogen-borrowing reagent is cyclohexadiene;
    Preferably, the molar ratio of the compound of formula 5 to the cyclohexadiene is from about 1:2 to 1:5; preferably about 1:2 to 1:3.
  16. The process according to claim 15, characterized in that the solvent is an alcohol, preferably methanol or ethanol, more preferably ethanol; and/or
    The amount of the alcohol is about 4 to 10 times (v/w), such as about 4, about 6 or about 8 times (v/w), the amount of the compound of formula 5.
  17. The method according to claim 15 or 16, characterized in that the hydrogen-assisted reaction is carried out at room temperature for about 10 to 12 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
  18. The method of claim 1, wherein the hydrogen-donating agent is cyclohexadiene;
    the molar ratio of the compound of formula 5 to the cyclohexadiene is from about 1:2 to 1:3;
    The solvent is methanol or ethanol, and the amount of the methanol or ethanol is about 4 to 6 times (v/w) the amount of the compound of formula 5;
    the metal catalyst is Pd/C, wherein the mass fraction of palladium in the Pd/C catalyst is about 10% (e.g., the Pd/C catalyst contains about 50w/w% water);
    the mass ratio of the compound of formula 5 to the Pd/C catalyst is about 10:2; and
    The hydrogen-assisted reaction is carried out at room temperature for about 10 to 12 hours to complete the conversion of the compound of formula 5 to the compound of formula 1.
CN202280064821.4A 2021-09-24 2022-09-23 Hydrogenation synthesis method for preparing pyrazine carboxylic acid derivatives serving as fluorescent tracers Pending CN118103355A (en)

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