CN111995583A - Synthesis method of 1, 5-dimethylpyrimidine-2 (1H) -ketone - Google Patents
Synthesis method of 1, 5-dimethylpyrimidine-2 (1H) -ketone Download PDFInfo
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Abstract
The invention provides a synthesis method of 1, 5-dimethyl pyrimidine-2 (1H) -ketone, which relates to the field of organic synthesis, and is characterized in that 2-chloro-5-methylpyrimidine and acid are stirred and react in an oil bath to obtain 5-methyl pyrimidine-2 (1H) -keto acid type salt, and the 5-methyl pyrimidine-2 (1H) -ketone acid salt reacts with alkali and methyl iodide in an organic solvent to prepare the 1, 5-dimethyl pyrimidine-2 (1H) -ketone. The synthesis method has the advantages of easily available raw materials, mild reaction conditions, high selectivity, good operability of post-treatment and high product purity, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the field of chemical intermediate organic synthesis, in particular to a synthetic method of 1, 5-dimethylpyrimidine-2 (1H) -ketone.
Background
1, 5-dimethyl pyrimidine-2 (1H) -ketone is an important drug intermediate and has wide application range. 1, 5-dimethylpyrimidin-2 (1H) -one derivatives such as the 4-deoxy product of uridine, 1- (. beta. -D-ribofuranosyl) -2-pyrimidinone is a potent inhibitor of bacterial growth. Derivatives also include nonylphenol dopamine D1 receptor agonists, which have a functionally selective, potent in vivo activity and therapeutic potential in a variety of neuropsychiatric disorders such as Parkinson's Disease (PD), Alzheimer's disease and schizophrenia.
At present, as for the synthetic route of 1, 5-dimethylpyrimidin-2 (1H) -ketone, Wightman, Holy and Uchytilvova et al in literature reports in the prior art adopt the following routes:
wherein the condition a is 1mol sodium methoxide solution (MeONa. MeOH), methyl iodide (CH)3I) 1,4-dioxane (1, 4-dioxane); condition b is hydrazine hydrate (N)2H4·H2O), water (H)2O), heating and refluxing; condition c is silver oxide (Ag)2O), water (H)2O)。
The process has the disadvantages that the starting material 1 is not commercially available, the route is multiple and the time is long; the total yield is not high. The used reagents sodium methoxide and hydrazine hydrate are dangerous chemicals, and sodium methoxide is easily decomposed in water and has the characteristics of strong basicity, strong corrosivity, flammability and explosiveness; hydrazine hydrate, which is smoky in humid air, has strong basicity and hygroscopicity. The reaction requires careful handling, careful dosing and correct workup. The synthetic route is uneconomical, unsafe and unsuitable for scale-up.
Disclosure of Invention
The invention aims to provide a synthesis method of 1, 5-dimethylpyrimidine-2 (1H) -ketone with low cost, high purity and high yield, and solves the technical problems that the cost of raw materials is high and the raw materials are not suitable for amplification in the prior art.
In order to achieve the above purpose, the invention provides the following technical scheme: a synthetic method of 1, 5-dimethyl pyrimidine-2 (1H) -ketone comprises the following steps:
the specific synthesis steps comprise:
1) reacting the compound (1), namely 2-chloro-5-methylpyrimidine, with acid for 2 to 8 hours under the condition of heating and stirring, condensing and refluxing, and obtaining a compound (2), namely 5-methylpyrimidine-2 (1H) -keto acid type salt after complete reaction;
2) reacting the compound (2) 5-methylpyrimidine-2 (1H) -ketone acid salt with alkali and methyl iodide in an organic solvent at room temperature for 12-18H, and filtering, washing, eluting by column chromatography and drying the reaction solution sequentially by using kieselguhr after complete reaction to obtain the compound (3)1, 5-dimethylpyrimidine-2 (1H) -ketone.
Further, the acid in the step 1) is hydrochloric acid, phosphoric acid, sulfuric acid or trifluoroacetic acid.
Further, in the step 1), the acid is hydrochloric acid, and the mass fraction of the hydrochloric acid is 10%; the dosage ratio of the compound (1), 2-chloro-5-methylpyrimidine and hydrochloric acid is 1 g: (8 ml-12 ml).
Further, the compound (1) 2-chloro-5-methylpyrimidine in the step 1) reacts with acid under the conditions of heating and stirring for 4-6 h.
Further, the reaction temperature of the compound (1) 2-chloro-5-methylpyrimidine in the step 1) and acid under the heating and stirring conditions is 40-110 ℃.
Further, the organic solvent in the step 2) is methanol, acetone or dioxane.
Further, the organic solvent in the step 2) is acetone, and the dosage ratio of the compound (2) 5-methylpyrimidine-2 (1H) -keto acid salt to acetone is 1 g: (10 ml-20 ml).
Further, the base in the step 2) is sodium methoxide, potassium carbonate or sodium hydrogen.
Further, the base in the step 2) is potassium carbonate, and the molar ratio of the 5-methylpyrimidine-2 (1H) -keto acid salt of the compound (2) to the potassium carbonate and methyl iodide is 1: (2-3): (1-2).
According to the technical scheme, the synthesis method of the 1, 5-dimethylpyrimidine-2 (1H) -ketone provided by the technical scheme of the invention has the following beneficial effects:
the invention discloses a synthesis method of 1, 5-dimethyl pyrimidine-2 (1H) -ketone, which adopts 2-chlorine-5-methyl pyrimidine and acid to stir and react in an oil bath to obtain 5-methyl pyrimidine-2 (1H) -keto acid type salt, and 5-methyl pyrimidine-2 (1H) -ketone acid salt reacts with alkali and methyl iodide in an organic solvent to prepare the 1, 5-dimethyl pyrimidine-2 (1H) -ketone. The technical scheme has the following advantages:
(1) the invention provides a new synthetic route for synthesizing 1, 5-dimethyl pyrimidine-2 (1H) -ketone, and provides a new method for preparing a compound 1, 5-dimethyl pyrimidine-2 (1H) -ketone.
(2) The raw materials and reagents used in the invention are commercially available, the synthetic route is only two steps, the route is short, the reaction steps are few, and the preparation is simple and convenient; and the raw materials are commercially available, the cost is low, the selectivity is good, the post-treatment is simple, the operability is good, the yield is high, and the scale-up production is easy.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a drawing showing the preparation of 1, 5-dimethylpyrimidin-2 (1H) -one according to the invention1H-NMR spectrum.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the drawings of the embodiments of the present invention. It is to be understood that the embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The use of "including" or "comprising" and like terms in the description and claims of this patent application is intended to mean that the element or item presented before "comprising" or "comprises" is inclusive of the feature, integer, step, operation, element, and/or component listed after "comprising" or "comprising," and does not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.
The starting materials and reagents used in the present invention are commercially available, and in the present disclosure, "room temperature conditions" means a temperature range of 10 ℃ to 30 ℃.
A synthetic method of 1, 5-dimethyl pyrimidine-2 (1H) -ketone comprises the following steps:
the specific synthesis steps comprise:
1) reacting the compound (1), namely 2-chloro-5-methylpyrimidine, with acid for 2 to 8 hours under the condition of heating and stirring, condensing and refluxing, and obtaining a compound (2), namely 5-methylpyrimidine-2 (1H) -keto acid type salt after complete reaction; wherein the acid is hydrochloric acid, phosphoric acid, sulfuric acid or trifluoroacetic acid; when hydrochloric acid with the mass fraction of 10% is selected as a reactant to react with the compound (1) 2-chloro-5-methylpyrimidine, the dosage ratio of the compound (1) 2-chloro-5-methylpyrimidine to dilute hydrochloric acid is 1 g: (8 ml-12 ml) and the reaction temperature is 40-110 ℃.
2) Reacting the acid salt of the compound (2) 5-methylpyrimidine-2 (1H) -ketone with alkali and methyl iodide in an organic solvent at room temperature for 12-18H, and sequentially filtering, washing, eluting by column chromatography and drying the reaction solution after complete reaction by using kieselguhr to obtain the compound (3)1, 5-dimethylpyrimidine-2 (1H) -ketone. Wherein the organic solvent is methanol, acetone or dioxane, and the alkali is sodium methoxide, potassium carbonate or sodium hydrogen; when the organic solvent is acetone and the base is potassium carbonate, the dosage ratio of the 5-methylpyrimidine-2 (1H) -keto acid type salt of the compound (2) to the acetone is 1 g: (10 ml-20 ml), the molar ratio of the compound (2) 5-methylpyrimidine-2 (1H) -keto acid salt to the potassium carbonate and methyl iodide is 1: (2-3): (1-2).
The following will further describe the synthesis method of 1, 5-dimethylpyrimidin-2 (1H) -one according to the present invention in detail with reference to the following specific examples and the accompanying drawings. The reaction solution is heated by using an oil bath in the specific implementation process of the invention, but the invention is not limited to the heating mode of the oil bath, and other heating modes can also be adopted, such as water bath, electric heating, steam heating and the like. The ion A in the synthetic route represents an acid ion.
Example 1
1) Synthesis of (2) 5-methylpyrimidin-2 (1H) -one hydrochloride
Adding the compound (1) 2-chloro-5-methylpyrimidine (100g, 0.78mol, 1eq) and 10% diluted hydrochloric acid 1L (2.91mol, 3.74eq) into a reaction bottle, under the protection of nitrogen, carrying out condensation reflux, stirring in an oil bath at the reaction temperature of 100 ℃ for 4 hours, directly concentrating the reaction solution after the reaction is completed, and carrying out rotary drying to obtain the compound (2) 5-methylpyrimidine-2 (1H) -ketone hydrochloride 110g with the yield of 96.48%.
2) Synthesis of Compound (3)1, 5-dimethylpyrimidin-2 (1H) -one
Adding a compound (2) 5-methylpyrimidine-2 (1H) -ketone hydrochloride (110g, 0.75mol, 1eq) and 2L of acetone into a reaction flask, then adding potassium carbonate (259g, 1.88mol, 2.5eq), methyl iodide (138g, 0.97mol, 1.3eq) and reacting for 12H at room temperature, after the reaction is completed, sequentially filtering the reaction liquid through kieselguhr, washing the reaction liquid with acetone, performing spin-drying on a column (EtOAc: MeOH: 2:1), and drying to obtain 79g of a yellow solid of the compound (3)1, 5-dimethylpyrimidine-2 (1H) -ketone, wherein the yield is as follows: 84.8 percent.
Nuclear magnetic spectrum of compound (3)1, 5-dimethylpyrimidin-2 (1H) -ketoneAs shown in the attached figure 1 of the drawings,1H-NMR(600MHz,CDCl3)8.49(d,J＝3.1Hz,1H),7.44(d,J＝2.5Hz,1H),3.55(s,3H),2.14–2.06(m,3H)。
example 2
1) Synthesis of Compound (2) 5-methylpyrimidin-2 (1H) -one hydrochloride
Adding (1) 2-chloro-5-methylpyrimidine (10g, 0.078mol, 1eq) and 100mL 10% diluted hydrochloric acid (0.291mol, 3.74eq) into a reaction flask, carrying out nitrogen protection, carrying out condensation reflux, stirring in an oil bath at 100 ℃ for reaction for 2H, directly concentrating the reaction solution after the reaction is completed, and carrying out rotary drying to obtain 6.5g of compound (2) 5-methylpyrimidine-2 (1H) -one hydrochloride with the yield of 57.01%.
2) Synthesis of Compound (3)1, 5-dimethylpyrimidin-2 (1H) -one
After the reaction was completed, the pad was filtered through celite, washed with acetone, and the product was dried to obtain 4.18g of compound (3)1, 5-dimethylpyrimidin-2 (1H) -one as a yellow solid, yield, after adding compound (2) 5-methylpyrimidin-2 (1H) -one hydrochloride (6.5g, 0.044mol, 1eq) and 120mL of acetone to a reaction flask, adding sodium methoxide (5.99g, 0.11mol, 2.5eq), methyl iodide (8.18g, 0.058mol, 1.3eq), reacting at room temperature for 12H: 75.93 percent.
Example 3
1) Synthesis of Compound (2) 5-methylpyrimidin-2 (1H) -one hydrochloride
Adding (1) 2-chloro-5-methylpyrimidine (10g, 0.078mol, 1eq) and 100mL 10% diluted hydrochloric acid (0.291mol, 3.74eq) into a reaction flask, carrying out nitrogen protection, carrying out condensation reflux, stirring in an oil bath at 110 ℃ for 8H, directly concentrating the reaction solution after the reaction is completed, and carrying out rotary drying to obtain 11.17g of compound (2) 5-methylpyrimidine-2 (1H) -one hydrochloride with the yield of 97.97%.
2) Synthesis of Compound (3)1, 5-dimethylpyrimidin-2 (1H) -one
The compound (2) 5-methylpyrimidin-2 (1H) -one hydrochloride (11.17g, 0.076mol, 1eq) and 200mL of acetone were charged into a reaction flask, then sodium hydrogen (60% mass fraction) (7.62g, 0.19mol, 2.5eq), iodomethane (14.06g, 0.099mol, 1.3eq) were added, and the reaction was allowed to react at room temperature for 12 hours, after completion of the reaction, the reaction solution was filtered through celite, washed with acetone, and spin-dried on a column (EtOAc: MeOH ═ 2:1) to give compound (3)1, 5-dimethylpyrimidin-2 (1H) -one 5.96g of a yellow solid, yield: 63.00 percent.
Example 4
Example 4 differs from example 1 in that the synthesized product in step 1) is compound (2) 5-methylpyrimidin-2 (1H) -one phosphate, 10g of compound (1) 2-chloro-5-methylpyrimidin in step 1), the amount of 10% by mass of dilute phosphoric acid used is 108mL (0.11mol, 1.50eq), and the final product compound (3)1, 5-dimethylpyrimidin-2 (1H) -one phosphate is 6.3g of yellow solid, yield: 38.92 percent.
Example 5
Example 5 differs from example 1 in that the synthesized product in step 1) was compound (2) 5-methylpyrimidin-2 (1H) -one sulfate, compound (1) 2-chloro-5-methylpyrimidin in step 1) 10g, 30% mass fraction diluted sulfuric acid in an amount of 96mL (0.11mol, 1.50eq), and the final product compound (3)1, 5-dimethylpyrimidin-2 (1H) -one sulfate was 13g of a yellow solid, yield: 80.28 percent.
Example 6
Example 6 differs from example 1 in that the product synthesized in step 1) was compound (2) 5-methylpyrimidin-2 (1H) -one trifluoroacetate, in step 1) compound (1) 2-chloro-5-methylpyrimidin 10g, amount of trifluoroacetic acid 26.61g (0.23mol, 3eq), 1, 5-dimethylpyrimidin-2 (1H) -one trifluoroacetate 3.1g yellow solid yield: 17.78 percent.
Example 7
Example 7 differs from example 1 in that in the synthesis of the product (2) 5-methylpyrimidin-2 (1H) -one hydrochloride in step 1), the compound (1), 2-chloro-5-methylpyrimidin (100g, 0.78mol, 1eq), 10% by mass of dilute hydrochloric acid 1L (2.91mol, 3.74eq) is stirred in an oil bath at 45 ℃ for 4H under nitrogen protection and under reflux condensation. The final product compound (3), 1, 5-dimethylpyrimidin-2 (1H) -one hydrochloride, 2.3g yellow solid, yield: 20.17 percent.
Example 8
Example 8 differs from example 1 in that in the synthesis of the product (2) 5-methylpyrimidin-2 (1H) -one hydrochloride in step 1), the compound (1), 2-chloro-5-methylpyrimidin (100g, 0.78mol, 1eq), 10% by mass of dilute hydrochloric acid 1L (2.91mol, 3.74eq) is stirred in an oil bath at 75 ℃ for 4H under nitrogen protection and under reflux condensation. The final product compound (3), 1, 5-dimethylpyrimidin-2 (1H) -one hydrochloride, 6.7g yellow solid, yield: 58.77 percent.
By comparing example 1, example 2 and example 3, in step 1), the yield of the product compound (2), 5-methylpyrimidine-2 (1H) -keto acid form salt, does not change much with a longer reaction time, but decreases with a shorter reaction time and a lower yield of the product compound (2), 5-methylpyrimidine-2 (1H) -keto acid form salt, compared with example 1 under preferable reaction conditions; in step 2), the yield of the product compound (3), 1, 5-dimethylpyrimidin-2 (1H) -one, is reduced by selecting different bases, sodium methoxide and sodium hydride.
Comparison of example 4, example 5 and example 6, in step 1), the yield of the product compound (3), 1, 5-dimethylpyrimidin-2 (1H) -one, was reduced by choosing a different acid, phosphoric acid, sulfuric acid or trifluoroacetic acid, relative to example 1 under preferred reaction conditions; example 3, example 7 and example 8, different reaction temperatures were chosen, 45 ℃, 75 ℃ and product yields were lower and increased with increasing temperature, relative to example 1 under the preferred reaction conditions; the temperature is raised to 110 ℃ again at 100 ℃, and the yield of the product is not changed greatly.
The synthesis method can be obtained by combining the embodiments, and the invention is mainly characterized in that a new method for synthesizing 1, 5-dimethylpyrimidine-2 (1H) -ketone is provided, reaction raw materials which can be commercially obtained in the prior art are selected, the synthesis reaction is carried out under mild reaction conditions through experimental exploration, the post-treatment process of reaction liquid is simple, the product yield is high, and the method can be used for large-scale commercial industrial production.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (10)
1. A method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -ketone is characterized in that the synthetic route is as follows:
the specific synthesis steps comprise:
1) reacting the compound (1), namely 2-chloro-5-methylpyrimidine, with acid for 2 to 8 hours under the condition of heating and stirring, condensing and refluxing, and obtaining a compound (2), namely 5-methylpyrimidine-2 (1H) -keto acid type salt after complete reaction;
2) reacting the compound (2) 5-methylpyrimidine-2 (1H) -ketone acid salt with alkali and methyl iodide in an organic solvent at room temperature for 12-18H to obtain the compound (3)1, 5-dimethylpyrimidine-2 (1H) -ketone after complete reaction.
2. The method of synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 1, wherein the acid in step 1) is hydrochloric acid, phosphoric acid, sulfuric acid, or trifluoroacetic acid.
3. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 2, wherein in the step 1), the acid is hydrochloric acid, and the mass fraction of the hydrochloric acid is 10%; the dosage ratio of the compound (1), 2-chloro-5-methylpyrimidine and hydrochloric acid is 1 g: (8 ml-12 ml).
4. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 1, wherein in the step 1), the compound (1), 2-chloro-5-methylpyrimidine, is reacted with an acid under heating and stirring conditions for 4 to 6 hours.
5. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 1, wherein the reaction temperature of the compound (1) 2-chloro-5-methylpyrimidine in the step 1) with an acid under heating and stirring conditions is 40 ℃ to 110 ℃.
6. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 1, wherein the organic solvent used in step 2) is methanol, acetone, or dioxane.
7. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 6, wherein the organic solvent used in step 2) is acetone, and the amount ratio of the compound (2) 5-methylpyrimidine-2 (1H) -keto acid salt to acetone is 1 g: (10 ml-20 ml).
8. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 1, wherein the base in step 2) is sodium methoxide, potassium carbonate, or sodium hydrogen.
9. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 8, wherein the base in step 2) is potassium carbonate, and the molar ratio of the 5-methylpyrimidine-2 (1H) -keto acid salt of compound (2) to potassium carbonate and methyl iodide is 1: (2-3): (1-2).
10. The method for synthesizing 1, 5-dimethylpyrimidin-2 (1H) -one according to claim 1, wherein in the step 2), after the acid salt of the compound (2) 5-methylpyrimidin-2 (1H) -one completely reacts with a base and methyl iodide in an organic solvent at room temperature, the reaction solution is filtered through diatomite, washed, eluted by column chromatography and dried in this order to obtain the compound (3)1, 5-dimethylpyrimidin-2 (1H) -one as a yellow solid.
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