阅读说明：本技术 一种羰基α位单甲基取代化合物的合成方法 (Synthesis method of carbonyl alpha-position monomethyl substituted compound ) 是由 华佳骏 申靖远 卫俊杰 陈诚 周勇 于 2021-09-30 设计创作，主要内容包括：本发明公开了一种羰基α位单甲基取代化合物的合成方法,以取代苯硼酸,2-溴丙烯酸乙酯为原料,以THF和水为溶剂,K-(2)CO-(3)以及催化剂Pd(OAc)-(2)的条件下,氮气保护反应,纯化得到的中间产物溶解于甲醇溶剂中,催化加氢,室温下反应,经过滤,溶剂旋干,即可。本发明羰基α位单甲基取代化合物的合成方法可以方便地得到目标化合物,且参与反应的试剂毒性小,反应条件温和。后处理简单、安全,产品质量好,适合放大生产。(The invention discloses a synthesis method of a carbonyl alpha-monomethyl-substituted compound, which takes substituted phenylboronic acid and 2-ethyl bromoacrylate as raw materials, takes THF and water as solvents, and K 2 CO 3 And catalyst Pd (OAc) 2 Under the condition of (1), dissolving the intermediate product obtained by purification in methanol solvent, catalytic hydrogenation, reacting at room temperature, and purifying byFiltering, and spin-drying the solvent. The synthesis method of the carbonyl alpha-position monomethyl substituted compound can conveniently obtain the target compound, and the reagent participating in the reaction has low toxicity and mild reaction conditions. The post-treatment is simple and safe, the product quality is good, and the method is suitable for large-scale production.)

1. A synthesis method of a carbonyl alpha-position monomethyl substituted compound is characterized in that 1.0eq of substituted phenylboronic acid and 1.2eq of 2-ethyl bromoacrylate are used as raw materials, THF and water are used as solvents, and 3.0eq of K is used as a solvent₂CO₃And 0.02eq of catalyst Pd (OAc)₂Under the protection of inert gas, reacting for 8-16 hours at 50-80 ℃, and purifying to obtain an intermediate product, wherein the chemical formula of the intermediate product is as follows:

and (3) dissolving 1.0eq of the intermediate product in a catalytic hydrogenation solvent, carrying out catalytic hydrogenation, and reacting at room temperature for 3-16 hours.

2. The method for synthesizing a carbonyl α -monomethyl-substituted compound according to claim 1, wherein the reaction formula is as follows:

3. the method for synthesizing a compound substituted by a monomethyl in the α -position of carbonyl as claimed in claim 1, wherein the product of the catalytic hydrogenation reaction is filtered, solvent dried, and the compound substituted by a monomethyl in the α -position of carbonyl is directly obtained quantitatively.

4. The method for synthesizing a compound substituted with a monomethyl at the carbonyl position according to claim 1, wherein the compound substituted with a monomethyl at the carbonyl position is a colorless liquid.

5. The method for synthesizing a carbonyl α -monomethyl-substituted compound according to claim 1, wherein the catalytic hydrogenation solvent is methanol.

6. The method for synthesizing a carbonyl alpha-monomethyl-substituted compound according to claim 1, wherein the volume ratio of the solvent THF to water is 10: 1.

7. the method for synthesizing a carbonyl α -monomethyl-substituted compound according to claim 1, wherein the inert gas is nitrogen.

8. The method for synthesizing a carbonyl alpha-monomethyl-substituted compound according to claim 1, wherein the reaction temperature for the preparation of the intermediate product is 55 ℃, the reaction time is 16 hours, and the reaction time for the hydrogenation of the intermediate product is 16 hours.

Technical Field

The invention belongs to the field of pharmaceutical preparations, and relates to a synthesis method of a carbonyl alpha-position monomethyl-substituted compound.

Background

The carbonyl alpha-monomethyl substituted compound is a common medicine molecular fragment and is widely used for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and the like; it can also be used for symptomatic treatment of soft tissue diseases (such as sprain and strain) and mild and moderate pain (such as dysmenorrhea, postoperative pain, toothache, etc.). The conventional literature synthesis method (Journal of organic chemistry,1984, vol.49, #11, p.2043-2045) is as follows:

in practical application, the following disadvantages exist:

1. the use of a flammable metal reagent NaHMDS is required;

2. the reaction needs to be carried out at low temperature (-78 ℃);

3. the reaction needs to use highly toxic iodomethane;

4. the residual raw materials in the reaction process and the by-products of the two methyl groups can cause great difficulty in the final separation and purification.

Therefore, it is necessary to develop a safer, easier to operate and purify method.

Disclosure of Invention

The invention aims to solve the problems and provide a method for synthesizing a carbonyl alpha-position monomethyl-substituted compound, which has the advantages of low toxicity of reagents participating in the reaction, mild reaction conditions, simple and safe post-treatment. The product has good quality and is suitable for large-scale production.

The invention aims to realize the synthesis method of the carbonyl alpha-position monomethyl substituted compound, which takes 1.0eq of substituted phenylboronic acid and 1.2eq of 2-ethyl bromoacrylate as raw materials, takes THF and water as solvents and 3.0eq of K₂CO₃And 0.02eq of catalyst Pd (OAc)₂Under the condition of (1), under the protection of inert gas, reacting at 50-80 deg.C for 8-16In one embodiment, the intermediate product is purified by the following reaction scheme:

and (3) dissolving 1.0eq of the intermediate product in a catalytic hydrogenation solvent, carrying out catalytic hydrogenation, and reacting at room temperature for 3-16 hours.

The reaction formula in the synthesis method of the carbonyl alpha-position monomethyl substituted compound is as follows:

in the synthesis method of the carbonyl alpha-monomethyl substituted compound, the product of the catalytic hydrogenation reaction is filtered and the solvent is dried in a spinning mode, and the carbonyl alpha-monomethyl substituted compound is directly obtained quantitatively.

In the method for synthesizing the compound substituted by the monomethyl in the alpha position of the carbonyl, the compound substituted by the monomethyl in the alpha position of the carbonyl is colorless liquid.

In the synthesis method of the carbonyl alpha-position monomethyl substituted compound, the catalytic hydrogenation solvent is methanol.

In the synthesis method of the carbonyl alpha-position monomethyl substituted compound, the volume ratio of the solvent THF to water is 10: 1.

in the synthesis method of the carbonyl alpha-monomethyl-substituted compound, the inert gas is nitrogen.

The preparation reaction temperature of the intermediate product of the synthesis method of the carbonyl alpha-position monomethyl substituted compound is 55 ℃, the reaction time is 16 hours, and the hydrogenation reaction time of the intermediate product is 16 hours.

The synthesis method of the carbonyl alpha-position monomethyl substituted compound can conveniently obtain the target compound, and the reagent participating in the reaction has low toxicity and mild reaction conditions. The post-treatment is simple and safe, the product quality is good, and the method is suitable for large-scale production.

Detailed Description

The present invention will be further described with reference to the following examples.

The invention discloses a synthesis method of a carbonyl alpha-monomethyl substituted compound, which takes 1.0eq of substituted phenylboronic acid and 1.2eq of 2-ethyl bromoacrylate as raw materials, takes THF and water as solvents (in the embodiment, the volume ratio of THF to water is 10: 1), and 3.0eq of K₂CO₃And 0.02eq of catalyst Pd (OAc)₂Under the protection of inert gas (nitrogen is used in the examples 1-9), reacting at 50-80 ℃ for 8-16 hours, and purifying to obtain an intermediate product, wherein the intermediate product has the following chemical formula:

dissolving 1.0eq of the intermediate product in a catalytic hydrogenation solvent (methanol is used in examples 1-9), carrying out catalytic hydrogenation, and reacting at room temperature for 3-16 hours.

The reaction formula is as follows:

and filtering the product of the catalytic hydrogenation reaction, and spin-drying the solvent to directly and quantitatively obtain the carbonyl alpha-monomethyl substituted compound (colorless liquid).

Example 1

4-biphenylboronic acid (1.0eq) and ethyl 2-bromoacrylate (1.2eq) were dissolved in THF and water, potassium carbonate (3eq) and a catalytic amount of palladium acetate (0.02eq) were added, and the reaction was carried out at 55 ℃ for 16 hours under nitrogen protection. The reaction was cooled, water was added, extracted with ethyl acetate and column purified to give the intermediate product of example 1:

the yield of this intermediate product was 75%.¹H-NMR(CDCl₃,400MHz)δ7.60-7.63(m,4H),7.52-7.54(m,2H),7.44-7.48(m,2H),7.37-7.39(m,1H),6.39(s,1H),5.96(s,1H),4.31-4.36(q,2H),1.28-1.39(t,3H).

The intermediate product is dissolved in methanol, palladium carbon is added under the condition of nitrogen, and the reaction is carried out for 16 hours under the condition of hydrogen. The palladium-carbon is filtered, and the filtrate is directly dried by spinning, thus obtaining the pure mono-methyl substituted compound at the alpha-position of carbonyl of the example 1:

the whole reaction process is as follows:

the yield of the compound substituted by the single methyl at the alpha-position of the carbonyl group is 92 percent.¹H-NMR(CDCl₃,400MHz)δ7.55-7.59(m,4H),7.34-7.45(m,5H),4.13-4.17(m,2H),3.75-3.77(q,2H),1.53-1.55(d,3H),1.25(t,3H)。

Example 2

The synthesis method of the invention takes 4-trifluoromethoxy phenylboronic acid as a starting material to obtain a carbonyl alpha-position monomethyl substituted compound:

the comprehensive yield of the carbonyl alpha-position monomethyl substituted compound and the intermediate product thereof is 71 percent. The detection result of the carbonyl alpha-position monomethyl substituted compound is as follows¹H-NMR(CD₃OD,400MHz)δ7.38(d,2H),7.21(d,2H),4.08-4.14(m,2H),3.79(q,1H),1.46(d,3H),1.19(t,3H).

Example 3

The synthesis method of the invention takes 3-isopropoxyphenylboronic acid as a starting material to obtain a carbonyl alpha-position monomethyl substituted compound:

the comprehensive yield of the compound substituted by the single methyl at the alpha-position of the carbonyl group and the intermediate product thereof is 77 percent. The results of the test of compounds substituted by a single methyl group at the α -position of carbonyl group in this example are as follows:

¹H-NMR(CD₃OD,400MHz)δ7.18(t,1H),6.76-6.82(m,3H),4.57(q,1H),4.08-4.11(m,2H),3.68(q,1H),1.42(d,3H),1.29(d,6H),1.18(t,3H).

example 4

The synthesis method of the invention takes 4-n-butylbenzene boronic acid as a starting material to obtain a carbonyl alpha-position monomethyl substituted compound:

the overall yield of the compound substituted by a single methyl group at the α -position of carbonyl group and its intermediate product in this example was 77%. The results of the test of compounds substituted by a single methyl group at the α -position of carbonyl group in this example are as follows:

¹H-NMR(CD₃OD,400MHz)δ7.16(d,2H),7.10(d,2H),4.02-4.14(m,2H),3.65-3.70(q,1H),2.57(t,2H),1.53-1.61(m,2H),1.41(d,3H),1.29-1.39(m,2H),1.17(t,3H),0.92(t,3H).

example 5

The synthesis method of the invention takes 4-n-propylphenylboronic acid as a starting material to obtain a carbonyl alpha-monomethyl substituted compound:

the overall yield of the compound substituted by a single methyl group at the α -position of carbonyl group and its intermediate product in this example was 70%. The results of the test of compounds substituted by a single methyl group at the α -position of carbonyl group in this example are as follows:

¹H-NMR(CD₃OD,400MHz)δ7.17(d,2H),7.11(d,2H),4.04-4.13(m,2H),3.66-3.71(m,1H),2.55(t,2H),1.57-1.66(m,2H),1.42(d,3H),1.17(t,3H),0.91(t,3H).

example 6

The synthesis method of the invention takes 4-phenoxyl phenylboronic acid as a starting material to obtain a carbonyl alpha-position monomethyl substituted compound:

the overall yield of the compound substituted by a single methyl group at the α -position of carbonyl group and its intermediate product in this example was 66%. The results of the test of compounds substituted by a single methyl group at the α -position of carbonyl group in this example are as follows:¹H-NMR(CDCl₃,400MHz)δ7.33(t,2H),7.27(d,2H),7.10(t,1H),7.01(d,2H),6.96(d,2H),4.09-4.18(m,2H),3.67-3.72(q,1H),1.50(d,3H),1.23(t,3H).

example 7

The synthesis method of the invention takes 4-tert-butylbenzene boric acid as a starting material to obtain a carbonyl alpha-monomethyl-substituted compound:

the overall yield of the compound substituted by a single methyl group at the α -position of carbonyl group and its intermediate product in this example was 78%. The results of the test of compounds substituted by a single methyl group at the α -position of carbonyl group in this example are as follows:

¹H-NMR(CD₃OD,400MHz)δ7.33(d,2H),7.19(d,2H),4.04-4.14(m,2H),3.66-3.71(q,1H),1.42(d,3H),1.30(s,9H),1.1 8(t,3H).

example 8

The synthesis method of the invention takes 2-biphenyl boric acid as a starting material to obtain a carbonyl alpha-position monomethyl substituted compound:

the overall yield of the compound substituted by a single methyl group at the α -position of carbonyl group and its intermediate product in this example was 77%. The results of the test of compounds substituted by a single methyl group at the α -position of carbonyl group in this example are as follows:

¹H-NMR(CD₃OD,400MHz)δ7.22-7.44(m,9H),4.08-4.11(m,2H),3.87-3.89(q,1H),1.36(d,3H),1.19(t,3H).

the synthesis method of the carbonyl alpha-position monomethyl substituted compound can conveniently obtain the target compound, and the reagent participating in the reaction has low toxicity and mild reaction conditions. The post-treatment is simple and safe, the product quality is good, and the method is suitable for large-scale production.

The above embodiments are provided only for illustrating the present invention and not for limiting the present invention, and those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention, and therefore all equivalent technical solutions should also fall within the scope of the present invention, and should be defined by the claims.