CN113214164B - A kind of synthetic method of leberoxine intermediate 2,4-dimethylpyrimidine-5-ol - Google Patents

Abstract

The invention discloses a synthesis method of an intermediate 2,4-dimethylpyrimidine-5-ol of Lebo Lei Sheng, and aims to solve the problems of safety risk and serious environmental pollution of industrial production of 2,4-dimethylpyrimidine-5-ol. The invention takes benzoic acid as a starting material, and firstly, the benzoic acid and chloropropanone are subjected to esterification reaction; then carrying out alkylation reaction and ring closing reaction with N, N-dimethylformamide dimethyl acetal and acetamidine hydrochloride; finally, benzoic acid is removed through hydrolysis reaction to obtain 2,4-dimethylpyrimidine-5-ol. The method adopts benzoic acid widely existing in nature as main material, solves health problem caused by production, and has advantages of no toxicity, low EHS risk, low cost, high production efficiency, yield not less than 60%, and purity not less than 99.0%.

Description

A kind of synthetic method of leberoxine intermediate 2,4-dimethylpyrimidine-5-ol

technical field

The invention belongs to the technical field of organic chemistry, in particular to a method for synthesizing 2,4-dimethylpyrimidine-5-ol, a key intermediate for the synthesis of orexin receptor antagonist Dayvigo.

Background technique

The orexin receptor antagonist Dayvigo is used to treat adult insomnia, which is characterized by disturbances in onset and/or sleep maintenance. Dayvigo is a small molecule compound developed by Eisai as a dual orexin receptor antagonist, which inhibits appetite by competitively binding to two orexin receptors (OX1R and OX2R). Neurotransmission, regulates sleep-wake rhythms. Blocking the binding of the wake-promoting neuropeptide orexin to the receptors OX1R and OX2R is considered to inhibit the arousal drive, the drug binds to the orexin receptors OX1R and OX2R, and acts as a competitive antagonist, with a stronger inhibitory effect on OX2R, REM and non-REM sleep drives can be inhibited, so it is expected to provide patients with faster sleep onset and sleep maintenance. Results of clinical studies have shown that Dayvigo is effective not only in primary insomnia, but also in insomnia associated with other diseases such as depression (SUNRISE 2). In addition to insomnia, the product is undergoing a Phase 2 clinical study in patients with Irregular Sleep-Wake Rhythm Disorder (ISWRD) with mild to moderate Alzheimer's dementia.

2,4-Dimethylpyrimidine-5-ol is a key intermediate in the synthesis of orexin receptor antagonist Dayvigo, and its synthetic routes mainly include the following three:

Route 1: The synthetic route disclosed in WO 2012/039371 is as follows. The synthetic route uses 2,4-dichloro-5-methoxypyrimidine as the starting material, uses Pd(PPh ₃ ) ₄ as the catalyst, and conducts the synthesis with trimethylaluminum After the methyl substitution reaction is completed, the hydrolysis reaction is carried out with boron tribromide to obtain 2,4-dimethylpyrimidin-5-ol.

Route 2: The synthetic route disclosed in WO 2013/123240 is as follows, the route takes 2,4-dichloro-5-methoxypyrimidine as the starting material, adopts NiCl ₂ (dppp) ₂ catalyst, and carries out methylation with Grignard methyl magnesium chloride. After the reaction is completed, tert-butanol/potassium tert-butoxide is used for hydrolysis to obtain 2,4-dimethylpyrimidin-5-ol.

The above-mentioned two synthetic routes have problems in their production: the raw materials used 2,4-dichloro-5-methoxypyrimidine, Pd(PPh ₃ ) ₄ , NiCl ₂ (dppp) ₂ etc. are expensive, and trimethylaluminum It has certain dangers with methylmagnesium chloride and will cause certain harm to the health of operators.

Route 3: The synthetic route disclosed in WO2016/021539 is as follows. The synthetic route takes p-nitrophenol as a starting material and undergoes an esterification reaction, then carries out an alkylation reaction with DMFDEA, and then cyclizes, and finally removes p-nitrophenol through a hydrolysis reaction. 2,4-dimethylpyrimidin-5-ol was obtained.

Compared with Route 1 and Route 2, this route can use cheap and readily available raw material p-nitrophenol, easily control the regioselectivity of substituents, and easily control impurities. But this route takes p-nitrophenol as the main raw material, and there will also be a large amount of p-nitrophenol impurities in the reaction (4) of this route in the production process. p-Nitrophenol is highly toxic and irritating. It decomposes and releases toxic nitrogen oxide flue gas when heated. It also has certain safety risks for industrial production and also has the problem of serious environmental pollution.

SUMMARY OF THE INVENTION

In view of the deficiencies of the above problems, the present invention provides a method for synthesizing 2,4-dimethylpyrimidin-5-ol, an intermediate of Lebron, aiming to solve the problem of 2,4-dimethylpyrimidin-5-ol in the The safety risk of industrial production and the problem of heavy environmental pollution. The present invention takes benzoic acid as the starting material, firstly carries out esterification reaction with chloroacetone; Reaction; finally, 2,4-dimethylpyrimidine-5-ol is obtained by de-benzoic acid through hydrolysis reaction. The method uses benzoic acid, which widely exists in nature, as the main raw material, and solves the health problems caused in production. The raw material is non-toxic, and has the advantages of "low EHS risk, low cost, and high production efficiency".

The technical scheme of the present invention is: a synthetic method of the intermediate 2,4-dimethylpyrimidine-5-ol of Lebron, which is characterized by comprising the following steps:

1) dissolving benzoic acid in the reaction solvent, adding a halogenated methyl ketone and an alkali catalyst to carry out esterification to obtain benzoic acid-2-oxypropyl ester;

2) dissolving benzoic acid-2-oxypropyl ester in the reaction solvent, first adding a base catalyst and DMFDEA, carrying out the alkylation reaction of the first stage, adding acetamidine hydrochloride after the completion of the reaction to carry out ring-closing reaction to obtain 2 ,4-dimethylpyrimidin-5-yl benzoate;

3) Dissolving 2,4-dimethylpyrimidin-5-yl benzoate in a reaction solvent, adding a base catalyst to carry out a hydrolysis reaction to obtain 2,4-dimethylpyrimidin-5-ol.

The synthetic route is as follows:

Further, in the step 1), a potassium iodide catalyst is also added, and the amount thereof is 0.5-2% of the benzoic acid.

Further, the step 1) halomethyl ketone is chloroacetone, bromoacetone, iodoacetone and the like.

The base catalyst used in the steps 1), 2) and 3) can be an inorganic base or an organic base, and the inorganic base can be potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide In any one, the organic base is any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine and pyridine.

The reaction solvent used in the steps 1), 2) and 3) is selected from toluene, tetrahydrofuran, N,N-dimethylformamide, N,N-diethylformamide, dimethyl sulfoxide, dioxygen Any one or at least two of hexacyclic ring, methyl tert-butyl ether, methanol, ethanol, propanol, isopropanol and water are mixed into a homogeneous mixture in any proportion; the mass volume of the benzoic acid and the reaction solvent The ratio is 1:1～20, and the unit is g/ml.

Further, the reaction temperature of the step 1) is 30-50°C, and the reaction temperature of the step 2) is 40-50°C.

Preferably, the technical scheme of the present invention is:

1) Add benzoic acid and chloroacetone into the reaction solvent tetrahydrofuran, add potassium carbonate and potassium iodide catalyst below 40°C of temperature control, react at 30～50°C for 10～20 hours, and obtain benzoic acid-2-oxypropyl ester through post-processing ;

2) Dissolving benzoic acid-2-oxypropyl ester in reaction solvent methanol, adding DMFDEA, warming up to 40～50 DEG C and reacting for 3～5 hours; adding methanol, potassium carbonate and acetamidine hydrochloride after the first stage reaction is completed The reaction is carried out for 5 to 10 hours, and finally 2,4-dimethylpyrimidin-5-yl benzoate is obtained after post-treatment;

3) Add the potassium hydroxide aqueous solution dropwise to the tetrahydrofuran solution of 2,4-dimethylpyrimidin-5-yl benzoate, after the dropwise addition, react at room temperature for 1 to 3 hours, and obtain 2,4- Dimethylpyrimidin-5-ol.

Preferably, in the step 1), the molar ratio of benzoic acid, chloroacetone and potassium carbonate is 1:1.0-1.2:1.5-2.5, preferably 1:1.05:2.0.

Preferably, in the step 2), the molar ratio of benzoic acid-2-oxypropyl ester, DMFDEA, potassium carbonate and acetamidine hydrochloride is 1:1.0～1.2:2～5:1.2～1.8, preferably 1:1.1 :3.0:1.5.

Preferably, in the step 2), the molar ratio of 2,4-dimethylpyrimidin-5-yl benzoate to potassium hydroxide is 1:1.5-2.5, preferably 1:2.

Further, the post-processing of the step 1) is specifically: cooling the reaction solution, adding purified water dropwise, separating the water phase, washing the organic phase, concentrating, then adding n-heptane for cooling and crystallization, washing the crystals and drying under reduced pressure to obtain target compound.

Further, the post-processing of the step 2) is specifically as follows: adding water to the reaction solution, distilling off part of the methanol and then adding isopropyl acetate for extraction; then separating the water phase, after washing and concentrating the organic phase, adding n-heptane to cool down and analyze. The crystals were washed and dried under reduced pressure to obtain the target compound. Further, the solid was washed with a mixture (1:5) of isopropyl acetate and n-heptane.

Further, the post-processing of the step 3) is specifically as follows: after the reaction is completed, add acid to adjust pH=6.5-7.0; concentrate the system until no fraction is dropped, then add isopropanol for extraction, filter (remove undissolved salt), The organic phase was decolorized and concentrated, then acetonitrile was added to the obtained residue, the temperature was raised to 50-60°C, stirred, then cooled for 1-2 hours, and then crystallized for 1-2 hours, filtered, washed, and dried under reduced pressure to obtain the target compound.

The beneficial effects of the invention are as follows: the method uses benzoic acid widely existing in nature as the main raw material, solves the health problem caused in the production, the raw material is non-toxic, and has the advantages of "low EHS risk, low cost, high production efficiency, and high yield. ≥60%, purity ≥99.0%" advantage.

Description of drawings

Figure 1 is the mass spectrum of the product 2,4-dimethylpyrimidin-5-ol.

Detailed ways

Example 1

1) Preparation of benzoic acid-2-oxypropyl ester

A mixture of 20 g of benzoic acid, 15.9 g of chloroacetone and 100 ml of tetrahydrofuran was stirred at room temperature, 45.27 g of potassium carbonate and 0.2 g of potassium iodide catalyst were added to the reaction mixture under temperature control of 40 ° C, and the resulting mixture was stirred at 40 ° C for reaction 16 hours.

After completion of the reaction, the reaction mixture was cooled in an ice bath, and then 40 ml of purified water was added dropwise to the reaction mixture. The aqueous phase was separated and washed with 10% sodium chloride aqueous solution. After washing, the organic phase was concentrated to no fractions, 100 ml of n-heptane was added and the temperature was lowered at 5°C for crystallization for 0.5 hours, and the turbid system was filtered. The obtained solid was washed with n-heptane and dried under reduced pressure to obtain 27.1 g of the target compound with a molar yield of 93% and a purity of 99.3%.

2) Preparation of 2,4-dimethylpyrimidin-5-yl benzoate

20 g of benzoic acid-2-oxypropyl ester was dissolved in 60 ml of methanol as a reaction solvent, 14.7 g of N,N-dimethylformamide dimethyl acetal was added, the temperature was raised to 45° C., and the reaction was carried out for 4 hours. After the first stage reaction was completed, 100 ml of methanol, 45.6 g of potassium carbonate and 15.6 g of acetamidine hydrochloride were added, and the reaction was carried out for 8 hours. After the second-stage reaction, 200 ml of water was added, and then 150 ml of isopropyl acetate was added after the appropriate methanol was concentrated. Then the aqueous phase was separated, washed with 50 ml of 10% sodium chloride aqueous solution, the organic phase was concentrated and 80 ml of n-heptane was added to cool for crystallization, and then the precipitated solid was filtered. The obtained solid was washed with 20 ml of a mixed solution of isopropyl acetate and n-heptane (1:5), and dried under reduced pressure to obtain 20.5 g of the target compound with a molar yield of 80% and a purity of 98.5%.

3) Preparation of 2,4-dimethylpyrimidin-5-ol

21.8 g of potassium hydroxide aqueous solution (45 wt. %) were constantly added dropwise to a solution of 20 g of 2,4-dimethylpyrimidin-5-ylbenzoate in tetrahydrofuran (100 ml of tetrahydrofuran). After dripping, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, concentrated hydrochloric acid was added dropwise to the reaction system under temperature control, and pH was adjusted to 6.8. The system was concentrated to no fraction, then isopropanol was added to extract the product, and the undissolved salt was removed by filtration. The isopropanol organic phase of the obtained product was added with activated carbon and stirred at room temperature to remove color. After filtration, the organic phase was concentrated to no fractions, 20 ml of acetonitrile was added to the obtained residue, the temperature was raised to 55° C., stirred, and then cooled to an ice bath for crystallization for 1.5 hours, and then filtered. The obtained solid was washed with acetonitrile, and then dried under reduced pressure to obtain 9.6 g of the target compound with a molar yield of 88% and a purity of 99.5%. The mass spectrum of the product is shown in Figure 1, [M+H] ⁺ =125.07.

Example 2

1) Preparation of benzoic acid-2-oxypropyl ester

A mixture of 100 g of benzoic acid, 79.5 g of chloroacetone and 500 ml of tetrahydrofuran was stirred at room temperature, 226 g of potassium carbonate and 1 g of potassium iodide catalyst were added to the lower reaction mixture under temperature control below 40 ° C, and the resulting mixture was stirred at 40 ° C for 16 hours . The reaction mixture was cooled in an ice bath, and then 200 ml of purified water was added dropwise to the reaction mixture. The aqueous phase was separated and washed with 10% aqueous sodium chloride solution. After washing, the organic phase was concentrated to no fractions, 500 ml of n-heptane was added, and the temperature was lowered to 5°C for crystallization for 0.5 hours, and then the turbid system was filtered. The obtained solid was washed with n-heptane and dried under reduced pressure to obtain 138.4 g of the target compound with a molar yield of 95% and a purity of 99.5%.

2) Preparation of 2,4-dimethylpyrimidin-5-yl benzoate

100 g of benzoic acid-2-oxypropyl ester was dissolved in 300 ml of methanol as a reaction solvent, 73.5 g of N,N-dimethylformamide dimethyl acetal was added, the temperature was raised to 45° C., and the reaction was carried out for 4 hours. After the first stage reaction was completed, 500 ml of methanol, 228 g of potassium carbonate and 78 g of acetamidine hydrochloride were added, and the reaction was carried out for 8 hours. After the second stage reaction, 1000 ml of water was added, and then 750 ml of isopropyl acetate was added after the appropriate methanol was concentrated. Then the aqueous phase was separated, washed with 250 ml of 10% sodium chloride aqueous solution, the organic phase was concentrated and 400 ml of n-heptane was added to cool for crystallization, and then the precipitated solid was filtered. The obtained solid was washed with 100 ml of a mixed solution of isopropyl acetate and n-heptane (1:5), and dried under reduced pressure to obtain 106.3 g of the target compound with a molar yield of 83% and a purity of 98.7%.

3) Preparation of 2,4-dimethylpyrimidin-5-ol

A solution of 100 g of 2,4-dimethylpyrimidin-5-ylbenzoate in tetrahydrofuran (500 ml of tetrahydrofuran) was constantly added dropwise 109 g of potassium hydroxide aqueous solution (45 wt. %). After dripping, the reaction was carried out at room temperature for 2 hours. After the reaction was completed, concentrated hydrochloric acid was added dropwise to the reaction system under temperature control, and the pH was adjusted to 6.8. The system was concentrated to no fraction, then 800 ml of isopropanol was added to extract the product, and the undissolved salt was removed by filtration. The isopropanol organic phase of the obtained product was added with activated carbon and stirred at room temperature to remove color. After filtration, the organic phase was concentrated to no fractions, 100 ml of acetonitrile was added to the obtained residue, the temperature was raised to 55° C., stirred, and then cooled to an ice bath for crystallization for 1.5 hours, and then filtered. The obtained solid was washed with acetonitrile, and then dried under reduced pressure to obtain 49.1 g of the target compound in a molar yield of 90% and a purity of 99.4%.

The method of the present invention has been described through preferred embodiments, and it is obvious that those in the relevant art can make adjustments, modifications and combinations of the methods and applications described in the present invention where necessary within the context and scope of the present invention. , to realize and apply the technology of the present invention. Those skilled in the art can also learn from the content of the present invention, and realize by appropriately improving the process parameters. It should be particularly pointed out that all similar improvements and adjustments are obvious to those skilled in the art, and should be regarded as being included in the present invention.

Claims (4)

1. the synthetic method of a kind of Lei Bo Leisheng intermediate 2,4-dimethylpyrimidine-5-alcohol, is characterized in that, 1) Add benzoic acid and chloroacetone into the reaction solvent tetrahydrofuran, add potassium carbonate and potassium iodide catalyst below 40°C of temperature control, react at 30～50°C for 10～20 hours, and obtain benzoic acid-2-oxypropyl ester through post-processing ; 2) Dissolving benzoic acid-2-oxypropyl ester in reaction solvent methanol, adding N,N-dimethylformamide dimethyl acetal, warming up to 40～50°C and reacting for 3～5 hours; the first stage After the reaction is completed, methanol, potassium carbonate and acetamidine hydrochloride are added to react for 5 to 10 hours, and finally 2,4-dimethylpyrimidin-5-yl benzoate is obtained after post-treatment; 3) Add the potassium hydroxide aqueous solution dropwise to the tetrahydrofuran solution of 2,4-dimethylpyrimidin-5-yl benzoate, after the dropwise addition, react at room temperature for 1 to 3 hours, and obtain 2,4- Dimethylpyrimidin-5-ol. 2. the synthetic method of a kind of leberoxine intermediate 2,4-dimethylpyrimidin-5-ol as claimed in claim 1, is characterized in that, the post-processing of described step 1) is specially: reaction solution The temperature is lowered, purified water is added dropwise, the aqueous phase is separated, the organic phase is washed and concentrated, and n-heptane is added to lower the temperature for crystallization, and the crystals are washed and dried under reduced pressure to obtain the target compound. 3. the synthetic method of a kind of leberoxine intermediate 2,4-dimethylpyrimidine-5-ol as claimed in claim 1, is characterized in that, the post-processing of described step 2) is specially: reaction solution Add water, evaporate part of methanol, then add isopropyl acetate for extraction; then separate the water phase, wash and concentrate the organic phase, add n-heptane to cool down and crystallize, wash the crystals, and dry under reduced pressure to obtain the target compound. 4. the synthetic method of a kind of Lei Bo Leisheng intermediate 2,4-dimethylpyrimidine-5-ol as claimed in claim 1, it is characterized in that, the post-processing of described step 3) is specially: the reaction is completed Then add acid to adjust pH=6.5-7.0; concentrate the system until no fractions drop, add isopropanol for extraction, filter, decolorize and concentrate the organic phase, add acetonitrile to the obtained residue, heat up to 50～60℃ and stir Then, the temperature was lowered for 1 to 2 hours, and the mixture was filtered, washed, and dried under reduced pressure to obtain the target compound.

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