CN110283040B

CN110283040B - Synthetic method of 3-methyl-D3-benzyl bromide

Info

Publication number: CN110283040B
Application number: CN201910469906.0A
Authority: CN
Inventors: 贲昊玺
Original assignee: Nanjing Hao Green Biotechnology Co Ltd
Current assignee: Nanjing Hao Green Biotechnology Co Ltd
Priority date: 2019-05-31
Filing date: 2019-05-31
Publication date: 2020-03-27
Anticipated expiration: 2039-05-31
Also published as: CN110283040A

Abstract

The invention provides a synthetic method of 3-methyl-D3-benzyl bromide, which comprises the following steps: step 1), taking 1, 3-dibromobenzene and deuterated iodomethane as raw materials, and carrying out substitution reaction in the presence of an n-butyllithium solution to obtain a compound I; step 2), taking the compound I prepared in the step 1) and DMF (N, N-dimethylformamide) as raw materials, and carrying out substitution reaction in the presence of N-butyllithium solution to obtain a compound II; step 3) preparing the compounds II and (NaBH) by the step 2)₄) Sodium borohydride is used as a raw material, and reduction reaction is carried out to prepare a compound III; and 4) preparing a compound IV, namely the product 3-methyl-D3-benzyl bromide, by using the compound III prepared in the step 3) and phosphorus tribromide as raw materials. The invention adopts the commercially available deuterated iodomethane as the raw material to synthesize the target product, the deuteration rate is stable and the higher requirement is met (D)>99%）。

Description

Synthetic method of 3-methyl-D3-benzyl bromide

Technical Field

The invention relates to a synthetic method of 3-methyl-D3-benzyl bromide, belonging to the technical field of chemical synthesis.

Background

3-methylbenzyl bromide is a very common chemical, and is generally used as an intermediate.

The structural formula of the stable isotope labeled 3-methylbenzyl bromide, namely 3-methyl-D3-benzyl bromide is as follows:

the 3-methyl-D3-benzyl bromide is mainly used as a medical intermediate to synthesize stable isotope labeled medical active molecules, and provides a labeled block for the research and development of new drugs; can also be used as an intermediate in the material direction to synthesize a new material.

The synthesis method of the stable isotope labeled 3-methyl-D3-benzyl bromide in the prior report adopts the following synthetic route:

the existing synthetic route has the following technical problems;

1) the incomplete exchange of hydrogen and deuterium exists when m-bromotoluene-D3 is synthesized in the first step, and the deuterium substitution rate can reach more than 98% under the condition of enough heavy water (generally more than 100 equivalent) or multiple times of exchange, so that the relative cost is high.

2) The use of NaOD (sodium oxide deuterium) in the synthesis process is expensive and has a high total cost.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a synthetic method of 3-methyl-D3-benzyl bromide.

The invention solves the problem of incomplete exchange of hydrogen and deuterium by using the deuterated iodomethane as the raw material to synthesize the final product, and simultaneously, the cost can be lower and controllable.

The technical scheme of the invention is as follows:

the synthetic method of 3-methyl-D3-benzyl bromide comprises the following synthetic route:

the method comprises the following steps:

step 1), taking 1, 3-dibromobenzene and deuterated iodomethane as raw materials, and carrying out substitution reaction in the presence of an n-butyllithium solution to obtain a compound I;

step 2), taking the compound I prepared in the step 1) and DMF (N, N-dimethylformamide) as raw materials, and carrying out substitution reaction in the presence of N-butyllithium solution to obtain a compound II;

step 3) preparing the compounds II and (NaBH) by the step 2)₄) Sodium borohydride is used as a raw material, and reduction reaction is carried out to prepare a compound III;

and 4) preparing a compound IV, namely the product 3-methyl-D3-benzyl bromide, by using the compound III prepared in the step 3) and phosphorus tribromide as raw materials.

Preferably, the first and second electrodes are formed of a metal,

in the step 1), the molar ratio of 1, 3-dibromobenzene to n-butyllithium to deuterated iodomethane is 1.0: 2.0:2.0.

In the step 2), the molar ratio of the compound I, n-butyllithium and DMF is 1.0:2.0: 2.0.

In the step 3), the molar ratio of the compound II to the sodium borohydride is 1: 1.

In the step 4), the mol ratio of the compound III to the phosphorus tribromide is 1.0: 1.5.

Preferably, the first and second electrodes are formed of a metal,

in the step 1), the reaction conditions for synthesizing the compound I are as follows: reacting for 4-6 hours at-78 ℃ to room temperature under the protection of nitrogen.

In the step 2), the reaction conditions for synthesizing the compound II are as follows: reacting for 2-4 hours at-78 ℃ to room temperature under the protection of nitrogen.

In the step 3), the reaction conditions for synthesizing the compound III are as follows: the reaction was carried out in methanol under ice bath for 2-4 hours.

In the step 4), the reaction conditions for synthesizing the compound IV are as follows: reacting for 1-3 hours at the temperature of-30 ℃ to room temperature under the protection of nitrogen.

The route of the invention adopts the commercially available deuterated iodomethane as the raw material to synthesize the target product, and the deuterated rate is stable and reaches higher requirement (D is more than 99%). The method has the following technical effects:

1) the deuteration rate of the synthesized product is higher than 99 percent.

2) The intermediate m-bromotoluene-D3 has stable deuteration rate which reaches more than 99 percent.

Drawings

FIG. 1 shows HNMR results of the final product of example 1.

Figure 2 is the GCMS results of the final product of example 1.

Detailed Description

EXAMPLE 1 Synthesis of 3-methyl-D3-benzyl bromide

The synthetic experimental procedure in this example is as follows:

the method comprises the following steps:

the reaction route is as follows:

in a low-temperature reaction tank, under the protection of nitrogen, adding 20.31 g of compound 1, 3-dibromobenzene (86.1mmol) into a three-neck flask, adding 60 mL of anhydrous tetrahydrofuran, cooling the liquid nitrogen to the internal temperature of-78 ℃ below, keeping the internal temperature for 20 minutes, slowly adding 68.8 mL of 2.5M n-butyllithium solution (172mmol) dropwise, keeping the internal temperature below-78 ℃ during the period, separating out a large amount of solid, after finishing the dropwise adding, keeping the temperature at-78 ℃ for 30 minutes, adding 10.7 mL of deuterated iodomethane (172mmol) and 20 mL of anhydrous tetrahydrofuran mixed solution dropwise, after the temperature is increased violently, after finishing the dropwise adding slowly, returning to room temperature for 3 hours, adding 120 mL of water, extracting ethyl acetate (40mL 3), washing an organic phase for 1 time, washing with saturated sodium chloride for 1 time, drying and spin-drying. The crude product is distilled under reduced pressure to obtain 12 g of a compound I, and the yield is 53.6%.

Step two:

the reaction route is as follows:

adding 12 g of compound I (68.9mmol) prepared in the last step and 120 mL of anhydrous tetrahydrofuran into a three-necked flask, cooling to-78 ℃ by using nitrogen under the protection of nitrogen, dropwise adding 55 mL of 2.5M n-butyllithium (137.5mmol) solution, separating out a large amount of solids, preserving heat for 30 minutes after completion, dropwise adding 10.2 g of anhydrous DMF (137.6mmo) and 10 mL of anhydrous tetrahydrofuran mixed solution after completion, reacting at room temperature for 2 hours, then adding 120 mL of water, extracting with ethyl acetate (30 mL. multidot.3), washing with water for 1 time, washing with saturated saline for 1 time, drying, and spin-drying to obtain 6g of a crude product of a compound II, wherein the yield of the crude product is 71%, and the crude product is directly used in the next step.

Step three:

the reaction route is as follows:

adding 6g (50mmol) of the crude product of the compound II prepared in the last step into 40mL of methanol, adding 1.82 g of sodium borohydride (48.1mmol) in batches under ice bath, using for 30 minutes, reacting for 1 hour under ice bath after completion, TLC shows that the raw material disappears, adding 40mL of water, extracting with ethyl acetate (25mL 4), washing an organic phase for 1 time, washing with saturated saline solution for 1 time, drying, spin-drying to obtain 6g of a crude product, and performing column chromatography to obtain 3.5 g of a compound III product with the yield of 40.7 in two steps.

Step four:

dissolving 3.46 g of compound III (27.6mmol) prepared in the last step in 30mL of diethyl ether, adding the mixture into a 100 mL three-necked bottle under the protection of nitrogen, cooling to an internal temperature of-30 ℃, dropwise adding a mixed solution of 11.47 g of phosphorus tribromide (42.3mmol) and 5mL of diethyl ether, slowly dropwise adding the mixture, heating to room temperature to react for 1 hour, TLC shows that the raw material disappears, adding a saturated sodium bicarbonate solution under an ice bath to slowly quench, extracting with ethyl acetate (40mL of 3) after completion, washing an organic phase for 1 time, washing the saturated sodium bicarbonate for 1 time with saturated saline solution, drying and spin-drying to obtain a crude product, and performing column chromatography on the crude product to obtain a compound IV product of 3.33 g and GCMS of more than 98%.

The HNMR results are shown in FIG. 1, the GCMS results are shown in FIG. 2, and the obtained product is 3-methyl-D3-benzyl bromide as can be seen from FIGS. 1 and 2.

Claims

The synthesis method of 3-methyl-D3-benzyl bromide is characterized in that the synthesis route is as follows:

the method comprises the following steps:

step 1), taking 1, 3-dibromobenzene and deuterated iodomethane as raw materials, and carrying out substitution reaction in the presence of an n-butyllithium solution to obtain a compound I;

step 2), taking the compound I prepared in the step 1) and DMF (N, N-dimethylformamide) as raw materials, and carrying out substitution reaction in the presence of N-butyllithium solution to obtain a compound II;

step 3) preparing the compounds II and (NaBH) by the step 2)₄) Sodium borohydride is used as a raw material, and reduction reaction is carried out to prepare a compound III;

step 4), preparing a compound IV, namely the product 3-methyl-D3-benzyl bromide, by using the compound III prepared in the step 3) and phosphorus tribromide as raw materials;

in the step 1), the molar ratio of 1, 3-dibromobenzene to n-butyllithium to deuterated iodomethane is 1.0:2.0: 2.0;

in the step 2), the mol ratio of the compound I, n-butyllithium and DMF is 1.0:2.0: 2.0;

in the step 3), the molar ratio of the compound II to the sodium borohydride is 1: 1;

in the step 4), the mol ratio of the compound III to the phosphorus tribromide is 1.0: 1.5.
2. The method of claim 1,

in the step 1), the reaction conditions for synthesizing the compound I are as follows: reacting for 4-6 hours at-78 ℃ to room temperature under the protection of nitrogen;

in the step 2), the reaction conditions for synthesizing the compound II are as follows: reacting for 2-4 hours at-78 ℃ to room temperature under the protection of nitrogen;

in the step 3), the reaction conditions for synthesizing the compound III are as follows: reacting in methanol under ice bath for 2-4 hours;

in the step 4), the reaction conditions for synthesizing the compound IV are as follows: reacting for 1-3 hours at the temperature of-30 ℃ to room temperature under the protection of nitrogen.