CN116143706B - Synthesis method of diaminopyrimidine oxide - Google Patents
Synthesis method of diaminopyrimidine oxide Download PDFInfo
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
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Abstract
The application relates to the field of chemical synthesis, in particular to a synthesis method of a diaminopyrimidine oxide, which takes 2, 4-dichloropyrimidine as an initial reactant, and comprises the steps of (1) ammonification of 2, 4-dichloropyrimidine in an alcohol solution of ammonia to generate 4-amino-2-chloropyrimidine, (2) secondary ammonification of 4-amino-2-chloropyrimidine and sodium amide in an aprotic solvent to generate 2, 4-diaminopyrimidine, and (3) the 2, 4-diaminopyrimidine generates the target product diaminopyrimidine oxide under the condition of catalytic oxidation.
Description
Technical Field
The application relates to the field of chemical synthesis, in particular to a synthesis method of diaminopyrimidine oxide.
Background
The diaminopyrimidine oxide is one of effective anti-drop components, is a water-soluble enhanced hair-growing active agent, and has the direct effects that: 1. prevent the hair follicle from blocking, and strengthen the hair root to the hair tip; 2. promoting keratin fiber generation composition, increasing hair concentration; 3. softening the collagen fiber net to prevent alopecia; 4. prolonging hair growth cycle and accelerating hair growth; 5. so as to enable the fine and young hair to grow healthily and strengthen the hair. Diaminopyrimidine oxide is now widely used in various brands of hair-growing products because of its excellent hair-growing ability, and is highly appreciated by consumers.
The synthesis of diaminopyrimidine oxide is recently reported, and the reported synthetic routes have the defects:
the preparation methods of aminopyrimidine derivatives are reported in patents US3644364, US3382247, CN87104693, etc., and the products are Minoxidil (Minoxidil) derivatives, and the synthesis route of diaminopyrimidine oxide is not proposed;
the methods of chemical oxidation, microbial catalysis cyclization and the like are adopted in the CN114213340 and the like, so that the operation is complex, the product purification is difficult, and the solution causes microbial residues to influence the product quality;
these synthetic routes all have limitations, which makes it possible to propose a highly efficient chemical synthesis of diaminopyrimidine oxides with good prospects.
Disclosure of Invention
According to the problems, the application provides a diaminopyrimidine oxide synthesis path which has high yield, no microorganism residue, simple and convenient operation process in the ammonification reaction process, no high-pressure operation in the synthesis step and high conversion rate.
The first aspect of the present inventors proposes a method for synthesizing a diaminopyrimidine oxide compound (IV), comprising,
dissolving the compound (II) in aprotic solvent, ammonifying with sodium amide at 40-50deg.C to obtain compound (III) shown in formula (A),
the compound (III) is used as a reaction substrate to prepare a diaminopyrimidine oxide formula (IV),。
in some embodiments, the compound (II) is synthesized in an aprotic solvent at a molar concentration of 0.656mol/L to 0.66mol/L, preferably 0.66mol/L, and/or at a molar ratio of 1:1 to 1:1.2, preferably 1:1.1, to sodium amide, and/or the method is heated in an oil bath using liquid paraffin, vegetable oil, silicone oil, and/or the reaction time is 10 to 14 hours, preferably 10 hours.
In some embodiments, the aprotic solvent is one or more of tetrahydrofuran, dioxane, isopropyl ether during the synthesis of compound (III) from compound (II).
In some embodiments, the ammonification reaction occurs in an inert gas atmosphere during the synthesis of compound (III) from compound (II).
In some embodiments, compound (III) is synthesized by a process of synthesizing compound (IV), including compound (III),
catalytic oxidation of compound (III) to give diaminopyrimidine oxide compound (I)V) is as shown in formula (B),
in some embodiments, the reaction temperature is less than 20-30 ℃, preferably 20 ℃, and/or the molar ratio of compound (III) to oxidant is 1:1.2 to 1:1.74, preferably 1:1.2, and/or the reaction time is 5-7 hours, preferably 5 hours, during the synthesis of compound (IV) from compound (III).
In some embodiments, the reaction catalyst is one or more of sodium tungstate and acetic acid during the synthesis of compound (IV) from compound (III).
In some embodiments, compound (III) is added in portions during the synthesis of compound (IV), wherein the compound (III) is added to an oxidizing agent that is one or more of hydrogen peroxide, peracetic acid, trifluoroperacetic acid, and m-chloroperoxybenzoic acid.
In some embodiments, compound (I) is synthesized by a process of synthesizing compound (II),
comprising the steps of (a) a step of,
ammonifying the compound (I) in an alcohol solution of ammonia to obtain a compound (II) shown as a formula (C),
in some embodiments, the process for synthesizing compound (II) from compound (I) is one or more of methanol, ethanol, isopropanol, and/or the reaction temperature is-20 ℃ to-35 ℃, preferably-25 ℃, and/or the alcoholic solution of ammonia is 1.25mol/L to 2.18mol/L, preferably 1.25mol/L, and/or the reaction time is 3 to 5 hours, preferably 4 hours, and/or the molar ratio of compound (I) to ammonia is 1:2.2 to 1:3, preferably 1:2.2.
In the context of the present application, all numbers disclosed herein are approximations, whether or not the word "about" or "about" is used. Based on the numbers disclosed, there is a possibility that the numerical value of each number may differ by less than + -10% or reasonably as recognized by those skilled in the art. The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur. The term "weight percent" or "percent by weight" or "wt%" is defined as the weight of the individual components in the composition divided by the total weight of all components of the composition and then multiplied by 100%. The terms "above", "below", "within" and the like are understood to include the present number, e.g., two or more means ≡two. The term "% vol" means volume percent. The term "and/or" is understood to mean any one of the selectable items or a combination of any two or more of the selectable items. In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present application. The medicament used in the application can be purchased in public legal markets and is not further purified and optimized.
The application has the advantages that:
(1) The application has high synthetic conversion rate.
(2) Compared with biological fermentation technology, the application has no biological residue.
(3) The synthesis path adopts the step of secondarily ammoniating sodium amide to convert 2-chloro-4-aminopyrimidine into 2, 4-diaminopyrimidine, does not need to be carried out in a high-pressure environment, avoids generating more byproducts at high temperature and high pressure, influences the purification and the yield of the product, and leads to lower overall yield.
Drawings
FIG. 1 shows an HPLC-MS spectrum of compound (III) of step 2 of example 1
FIG. 2 shows HNMR pattern of Compound (IV) of example 1
FIG. 3 shows an HPLC-MS spectrum of compound (IV) of example 1
Detailed Description
The aim of the application is achieved by the following technical scheme:
a chemical synthesis method of diaminopyrimidine oxide is provided, and the synthesis route is as follows:
the method comprises the following steps:
ammoniating 2, 4-chloropyrimidine (compound I) with ammonia gas in polar solvent such as methanol, ethanol and other alcohol solution at-20 to-25 ℃ to obtain 2-chloro-4-aminopyrimidine (compound II) after reaction, concentration and crystallization;
2-chloro-4-aminopyrimidine (compound II) is subjected to secondary ammoniation with sodium amide in an aprotic solvent such as dioxane, tetrahydrofuran, dioxane and isopropyl ether at 40-50 ℃, concentrated and crystallized after reaction, filtered and dried to obtain 2, 4-diaminopyrimidine (compound III);
catalytic oxidation of 2, 4-diaminopyrimidine (compound III) under the catalysis of acid such as acetic acid, sodium tungstate or metal catalyst to obtain target compound diaminopyrimidine oxide (compound IV)
The application is further described below with reference to examples.
Example 1:
step (1): preparation of 2-chloro-4-aminopyrimidine (Compound II):
and 5L of three-port bottles are inserted into a thermometer, a constant-pressure dropping funnel and a nitrogen ball three-way pipe. 2L of 2, 4-dichloropyrimidine (Compound I) (298 g, s,2 mol) solvent ethanol was added, and the mixture was placed in a low-temperature reaction bath and stirred to a temperature of-25 ℃. Adding ammonia ethanol solution (1.2L, 4M) into a constant pressure dropping funnel, slowly dropping into the reaction system, controlling the reaction temperature below-20 ℃, and completely keeping the temperature at-20 ℃ for reaction for 4 hours.
The reaction was followed by HPLC, the reaction was warmed to room temperature completely, about 2L of ethanol was concentrated, 2L of methylene chloride was added, 1.5L of water was supplemented, the mixture was stirred and separated, the aqueous layer was further extracted with 0.8L of methylene chloride, the combined organic phases were washed with 1L of saturated aqueous brine, dried over anhydrous sodium sulfate, filtered and the cake was washed with methylene chloride, and concentrated to give 255g of crude product (yield 98.5%, yellow crystals, HPLC 96%) as pale yellow crystals, which was directly fed to the next reaction without purification.
Step (2): preparation of 2, 4-diaminopyrimidine (Compound III):
a 5L three-port bottle is inserted into a thermometer, a charging plug and a nitrogen ball reflux tube. 2-chloro-4-aminopyrimidine (Compound II) (255 g, s,1.97 mol) and 3L of solvent tetrahydrofuran were added. Stirring and dissolving, blowing nitrogen, ventilating three times, slowly adding sodium amide (85.8 g, s,2.2 mol) and heating to 45 ℃ in an oil bath, and reacting for 16h.
HPLC monitored reaction was complete. The pH was adjusted to about 8 with 30% HCl, insoluble salts were removed by filtration, the filtrate was concentrated to dryness, 3L of anhydrous ethanol was added, 30g of anhydrous sodium sulfate, 10g of activated carbon, 10g of 100-200 mesh silica gel were stirred at room temperature for 3 hours, filtration and concentration to dryness were carried out to obtain 200g of slightly greenish crystals (yield 92.3%, yellowish green crystals, HPLC 95%).
Step (3): preparation of diaminopyrimidine oxide (compound IV):
taking a 5L three-port bottle (thermometer, balloon and glass plug), adding acetic acid (3L), cooling to 5-8deg.C in ice bath, and dripping 30% hydrogen peroxide (360 g) to make internal temperature less than or equal to 20deg.C (the temperature of the material can be slowly raised), and stirring for 30min.
2, 4-diaminopyrimidine (Compound III) (200 g, s,1.82 mol) was added in portions to give an internal temperature of 20℃or less (the addition was slowly warmed), the reaction was carried out at 20℃for 15-20h, methanol was sampled and dissolved, ammonia was used for neutralization, and TLC (EA: meOH=4:1) was conducted with only trace amounts of starting materials.
Concentrating acetic acid under reduced pressure at 40deg.C to obtain light yellowish green mucus, adding 4L water, ice-bathing, slowly dripping ammonia water to adjust pH=8, stirring at 10deg.C for 1 hr to obtain a large amount of precipitate.
Filtering and collecting filter cakes. Heating with 1L of water to reflux to completely dissolve the product, adding 5g of active carbon, decoloring for 1h, maintaining the dissolution temperature, hot filtering, stirring and cooling the filtrate to room temperature for crystallization, aging at room temperature for 1h, filtering to obtain pure white crystals with purity of 98.5%, continuously heating 1L of methanol to reflux to dissolve the filter cake without drying, hot filtering, stirring and cooling the filtrate to room temperature for crystallization, aging at room temperature for 1h, filtering, drying at 45 ℃ with a blast drying oven to obtain 182.7g of pure white crystals with purity of 99.7% and yield of 79.6%.
Example 2:
this example 2 is identical to example 1 except for step (1).
Another method for preparing 2-chloro-4-aminopyrimidine (compound II) in step (1):
and 5L of three-port bottles are inserted into a thermometer, a constant-pressure dropping funnel and a nitrogen ball three-way pipe. 2, 4-dichloropyrimidine (Compound I) (298 g, s,2 mol) was added as a solvent methanol (MeOH) 2.5L and placed in a low temperature reaction bath with stirring to reduce the temperature to-25 ℃. Adding ammonia methanol solution (0.7L, 7M) into a constant pressure dropping funnel, slowly dropping into the reaction system, controlling the reaction temperature below-20 ℃, and completely keeping the temperature at-20 ℃ for reaction for 4 hours.
The reaction was followed by HPLC, the reaction was warmed to room temperature completely, about 2.5L of methanol was concentrated, 2.5L of dichloromethane was added, 1.5L of water was supplemented, the aqueous layer was separated by stirring, the aqueous layer was further extracted with 0.8L of dichloromethane, the combined organic phases were washed with 1L of saturated aqueous brine, dried over anhydrous sodium sulfate, filtered and the filter cake was washed with dichloromethane, and concentrated to give 248g of crude pale yellow crystals (yield 95.8%, yellow crystals, HPLC 96%). The crude product is directly put into the next reaction without purification.
Example 3:
this embodiment 3 may be the same as any of embodiments 1 and 2 except for the step (2).
Another method for preparing 2, 4-diaminopyrimidine (compound III) in step (2):
a 5L three-port bottle is inserted into a thermometer, a charging plug and a nitrogen ball reflux tube. 2-chloro-4-aminopyrimidine (Compound II) (319 g, s,2 mol), solvent Dioxane (1, 4-Dioxane, CAS number: 123-91-1) 3L was added. Stirring and dissolving, blowing nitrogen, ventilating three times, slowly adding sodium amide (85.8 g, s,2.2 mol) and heating to 50 ℃ by an oil bath, and reacting for 10h.
HPLC monitored reaction was complete. The pH was adjusted to about 8 with 30% HCl, insoluble salts were removed by filtration, the filtrate was concentrated to dryness, 3L of anhydrous ethanol was added, 30g of anhydrous sodium sulfate, 10g of activated carbon, 10g of 100-200 mesh silica gel were added, stirred at room temperature for 3 hours, filtered, and concentrated to dryness to give 202g of slightly greenish crystals (yield 91.72%, yellowish green crystals, HPLC 95%).
Example 4:
this example 4 may have the same procedure as in either example 1 or example 2, except for the step (2).
Another method for preparing 2, 4-diaminopyrimidine (compound III) in step (2):
a 5L three-port bottle is inserted into a thermometer, a charging plug and a nitrogen ball reflux tube. 2-chloro-4-aminopyrimidine (Compound II) (319 g, s,2 mol), solvent isopropyl ether (Diisopropyl ether, CAS number: 108-20-3) and 3L were added. Stirring and dissolving, blowing nitrogen, ventilating three times, slowly adding sodium amide (85.8 g, s,2.2 mol) and heating to 50 ℃ by an oil bath, and reacting for 14h.
HPLC monitored reaction was complete. The pH was adjusted to about 8 with 30% HCl, insoluble salts were removed by filtration, the filtrate was concentrated to dryness, 3L of anhydrous ethanol was added, 30g of anhydrous sodium sulfate, 10g of activated carbon, 10g of 100-200 mesh silica gel were stirred at room temperature for 3 hours, filtration and concentration to dryness were carried out to obtain 193g of slightly greenish crystals (yield 87.63%, yellowish green crystals, HPLC 96%).
Example 5:
this example 5 may have the same steps as those of any of examples 1, 2, 3 and 4 except for step (3).
Another method for preparing diaminopyrimidine oxide (compound IV) in step (3):
500ml three-necked flask (thermometer, balloon, glass stopper) was taken, and water (200 m 1) and sodium tungstate (Na 2 WO 4 ) 3g, cooling to 5-8 ℃ in an ice bath, dripping 30% hydrogen peroxide (36 g) to ensure that the internal temperature is less than or equal to 20 ℃ (the feeding can slowly raise the temperature), and completely continuing to stir for 30min.
2, 4-diaminopyrimidine (Compound III) (22 g, s,0.2 mol) was added in portions to give an internal temperature of 30℃or less (the addition was slowly warmed), the reaction was carried out at 35℃for 20h, methanol was sampled for dissolution, and TLC (EA: meOH=4:1) was used for working up the reaction with only trace amounts of starting material.
Concentrating 150ml of water under reduced pressure at 55deg.C to obtain white crystal, aging at 15deg.C, filtering, and collecting filter cake. The crystals were filtered hot with 50ml of water. Pure white crystals were obtained, 98.2% pure, which were further thermally crystallized from 50ml of methanol. 21.66g of pure white crystals with purity of 99.6% are obtained. The total yield was 86.0%.
Example 6:
this example 6 may have the same steps as those of any of examples 1, 2, 3 and 4 except for the step (3).
Another method for preparing diaminopyrimidine oxide (compound IV) in step (3):
500ml three-port bottle (thermometer, balloon, glass plug) was taken, methylene chloride (200 ml) was added to cool to 5-8deg.C in ice bath, 2, 4-diaminopyrimidine (compound III) (22 g, s,0.2 mol) was added in portions to make the internal temperature less than or equal to 30deg.C, 85% m-chloroperoxybenzoic acid (3-Chloroperbenzoic acid, CAS number: 937-14-4) (48.56 g, s,0.24 mol) was added in portions to complete 35 deg.C for 20h, sampled methanol was dissolved, and TLC (EA: meOH=4:1) was used for working up the reaction with only trace amounts of raw materials.
The reaction was completed with a large amount of solids, the system was concentrated to 120ml of dichloromethane, cooled to 20 ℃, filtered, the filter cake was filtered hot with 50ml of methanol, recrystallized, the filter cake was collected, filtered hot with 50ml of water, and recrystallized. And (5) vacuum drying.
22.96g of pure white crystals with purity of 99.5% are obtained. The yield thereof was found to be 91.02%.
Example 7:
step (3): preparation of 2, 4-diaminopyrimidine-3-oxide (compound IV):
preparation of trifluoro peroxyacetic acid:
taking a 5L three-port bottle (thermometer, balloon and glass plug), adding trifluoroacetic acid (342 g,3 mol), cooling to 5-8 ℃ in an ice bath, and dripping 30% hydrogen peroxide (360 g) to ensure that the internal temperature is less than or equal to 20 ℃ (the temperature of the material can be slowly increased during the feeding), and completely continuing stirring for 1h.
The mixed solution of the trifluoro-peroxyacetic acid is added into 3L of dichloromethane and stirred to be uniformly dispersed.
2, 4-diaminopyrimidine (Compound III) (200 g, s,1.82 mol) was added in portions to give an internal temperature of 20℃or less (the addition was slowly warmed), the reaction was carried out at 20℃for 15-20h, methanol was sampled and dissolved, ammonia was used for neutralization, and TLC (EA: meOH=4:1) was conducted with only trace amounts of starting materials.
Concentrating dichloromethane and trifluoroacetic acid at 40deg.C under reduced pressure to obtain light yellow green mucus, adding 4L water, ice-bathing, slowly dripping ammonia water to adjust pH=8, stirring at 10deg.C for 1 hr to obtain a large amount of precipitate, filtering, and collecting filter cake. The crystals were filtered through 1L of water.
Pure white crystals were obtained, 96.5% pure, which were continuously dissolved by heating with 1L of methanol to reflux, and filtered thermally at the temperature of the dissolution, the filtrate was cooled to room temperature for crystallization, and aged for 2h at room temperature. Filtering and drying by a hot air blower at 45 ℃ to obtain 156.1g of pure white crystals with the purity of 99.5%. The yield thereof was found to be 68.6%.
Comparative example 1:
another method for preparing 2, 4-diaminopyrimidine (compound III) in step (2):
a 5L three-port bottle is inserted into a thermometer, a charging plug and a nitrogen ball reflux tube. 2-chloro-4-aminopyrimidine (Compound II) (319 g, s,2 mol) was added, followed by an ethanol solution of ammonia (5L, 5M), and 50g of ammonium chloride was dissolved in 1L of water and mixed into the above solution.
Monitoring the reaction to be complete by HPLC, removing ammonia gas, ethanol and a large amount of water by reduced pressure distillation, adding 3L of absolute ethanol, adding 30g of absolute sodium sulfate and 10g of active carbon, stirring 10g of 100-200 mesh silica gel for 3 hours at normal temperature, filtering and concentrating to dryness to obtain 175.87g of slightly greenish crystals (yield 83.05%, yellowish green crystals and HPLC 97%).
Comparative example 2:
12.9g (0.1 mol) of 4-amino-2-chloropyrimidine, 0.25g of Triethylamine (TEA) and 150mL of ethanol were charged into the autoclave. Controlling the temperature to be 0-5 ℃, introducing 17g (1 mol,10 eq) of ammonia gas, heating to 85 ℃, stirring and reacting for 12 hours under the pressure of about 1Mpa, cooling to 0-5 ℃, sampling, HPLC, detecting the residual 0.17% of raw materials, adding 50g of water into the system, decompressing and concentrating at 40 ℃, cooling to 15-20 ℃, pulping, filtering, adding 50g of water into the filter cake, heating to 65 ℃, slowly cooling to 15-20 ℃, filtering, and drying to obtain 9.53g of 2, 4-diaminopyrimidine, 99.7% of HPLC, and 86.9% of yield.
Comparative example 3:
the comparative example is a one-step synthesis of 2, 4-dichloropyrimidine for preparing 2, 4-diaminopyrimidine.
14.9g (0.1 mol) of 2, 4-dichloropyrimidine and 100mL of ethanol were charged into the autoclave. Controlling the temperature to minus 25 ℃ to minus 20 ℃, introducing 8.5g (0.5 mol,5 eq) of ammonia gas, keeping the temperature at minus 20 ℃ for reaction for 4-5h, monitoring the reaction by HPLC until the conversion of 2, 4-dichloropyrimidine is complete, heating to 0-5 ℃, adding 0.2g of triethylamine, continuously introducing ammonia gas into an autoclave to 0.9MPa, heating to 85 ℃, at this moment, stirring and reacting for 12 h, cooling to 0-5 ℃ for sampling HPLC, detecting the residual 0.17% of raw materials, adding 50g of water into the system, concentrating under reduced pressure at 40 ℃, cooling to 15-20 ℃, pulping, filtering, adding 50g of water into a filter cake, heating to 65 ℃ for material dissolution, slowly cooling to 15-20 ℃, filtering, and drying to obtain 7.27g of 2, 4-diaminopyrimidine, 96.7% of HPLC, and the yield is 66.7%.
While the methods of this application have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the application. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present application.
Claims (10)
1. A synthesis method of diaminopyrimidine oxide formula (IV) is characterized by comprising the following steps of,
the compound (III) is used as a reaction substrate to prepare a diaminopyrimidine oxide formula (IV),。
2. the process according to claim 1, characterized in that the molar concentration of the compound (ii) in aprotic solvent is 0.656mol/L to 0.66mol/L and/or the compound (ii) and sodium amide is 1:1 to 1:1.2 and/or the process is heated in an oil bath with liquid paraffin, vegetable oil, silicone oil and/or the reaction time is 10 to 14h.
3. The method according to claim 1, wherein the aprotic solvent is one or more of tetrahydrofuran, dioxane, isopropyl ether.
4. The method according to claim 1, wherein the ammonification reaction occurs in an inert gas atmosphere.
5. The process according to any one of claims 1 to 4, comprising a compound (III),
the compound (III) is catalyzed and oxidized to obtain diaminopyrimidine oxide with the formula (IV) as shown in the formula (B),
6. the process according to claim 5, wherein the reaction temperature is less than 20-30 ℃ and/or the molar ratio of compound (III) to oxidant is 1:1.2 to 1:1.74, and/or a reaction time of 5 to 7 hours.
7. The method according to claim 5, wherein the reaction catalyst is one or more of sodium tungstate and acetic acid.
8. The method according to claim 5, wherein the compound (III) is added to the oxidizing agent in a batch manner, and/or the oxidizing agent is one or more of hydrogen peroxide, peracetic acid, trifluoroperacetic acid, and m-chloroperoxybenzoic acid.
9. The process according to any one of claims 1 to 4, wherein the synthesis of the compound (II) comprises,ammonifying the compound (I) in an alcohol solution of ammonia to obtain a compound (II) shown as a formula (C),
10. the process according to claim 9, wherein the alcohol is one or more of methanol, ethanol, isopropanol, and/or the reaction temperature is-20 ℃ to-35 ℃, and/or the alcoholic solution of ammonia is 1.25mol/L to 2.18mol/L, and/or the reaction time is 3 to 5 hours, and/or the molar ratio of compound (i) to ammonia is 1:2.2 to 1:3.
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| Li Xiao等.2-Amino-1,3,5-triazine chemistry: hydrogen-bond networks, Takemoto thiourea catalyst analogs, and olfactory mapping of a sweet-smelling triazine.Monatsh Chem.2015,第146卷1529–1539. * |
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