CN110283040A - The synthetic method of 3- methyl D 3- benzyl bromine - Google Patents

The synthetic method of 3- methyl D 3- benzyl bromine Download PDF

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CN110283040A
CN110283040A CN201910469906.0A CN201910469906A CN110283040A CN 110283040 A CN110283040 A CN 110283040A CN 201910469906 A CN201910469906 A CN 201910469906A CN 110283040 A CN110283040 A CN 110283040A
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raw material
compound
methyl
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benzyl bromine
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CN110283040B (en
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贲昊玺
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Nanjing Hao Green Biotechnology Co Ltd
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Nanjing Hao Green Biotechnology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/269—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of only halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/14—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a kind of synthetic method of 3- methyl D 3- benzyl bromine, the method includes the following steps: step 1), with 1,3- dibromobenzene and deuterated iodomethane for raw material, in the presence of n-butyllithium solution, substitution reaction occurs, chemical compounds I is made；Step 2, with chemical compounds I and DMF(N prepared by step 1), dinethylformamide) it is raw material, in the presence of n-butyllithium solution, substitution reaction occurs, compound ii is made；Compound ii and (NaBH is made with step 2 in step 3)4) sodium borohydride be raw material, occur reduction reaction, be made compound III；Compounds Ⅳ, i.e., product 3- methyl D 3- benzyl bromine of the invention is made using the compound III of step 3) preparation and phosphorus tribromide as raw material in step 4).The present invention uses commercially available deuterated iodomethane for raw material, synthesizes target product, deuterated rate is stable and reaches high requirement (D > 99%).

Description

The synthetic method of 3- methyl D 3- benzyl bromine
Technical field
The present invention relates to a kind of synthetic methods of 3- methyl D 3- benzyl bromine, belong to chemosynthesis technical field.
Background technique
3- methyl benzyl bromine is a kind of chemicals being in daily use, and is used generally as intermediate.
The 3- methyl benzyl bromine of stable isotope labeling, the i.e. structural formula of 3- methyl D 3- benzyl bromine are as follows:
3- methyl D 3- benzyl bromine is mainly used for medicine intermediate, synthesizes the medicinal activity molecule of stable isotope labeling, is New drug development provides label stripping and slicing；It can also be used for the intermediate in material direction, synthesize new material.
The synthetic method of the 3- methyl D 3- benzyl bromine of the stable isotope labeling of existing report uses following synthetic route:
Existing synthetic route has following technical problem；
1) when the first step synthesizes m-bromotoluene-D3, there are hydrogen deuteriums to exchange incomplete problem, in enough heavy water situations Under (generally higher than 100 equivalents) or repeatedly exchange deuterated rate and can achieve 98% or more, relative cost is high.
2) more expensive using NaOD (deuterium sodium oxide molybdena) price in synthesis process, totle drilling cost is higher.
Summary of the invention
The purpose of the present invention is overcome the deficiencies of the prior art and provide a kind of synthetic method of 3- methyl D 3- benzyl bromine.
The present invention is exchanged not exclusively by solving hydrogen deuterium using the method that deuterated iodomethane is Material synthesis final product Problem, while can accomplish that cost is relatively low and controllable.
Technical scheme is as follows:
The synthetic method of 3- methyl D 3- benzyl bromine, synthetic route are as follows:
The method includes the following steps:
Step 1) in the presence of n-butyllithium solution, occurs to replace anti-with 1,3- dibromobenzene and deuterated iodomethane for raw material It answers, chemical compounds I is made；
Step 2), with the chemical compounds I and DMF (n,N-Dimethylformamide) of step 1) preparation for raw material, in n-BuLi In the presence of solution, substitution reaction occurs, compound ii is made；
Compound ii and (NaBH is made with step 2) in step 3)4) sodium borohydride be raw material, occur reduction reaction, be made Compound III；
Compounds Ⅳ is made using the compound III of step 3) preparation and phosphorus tribromide as raw material in step 4), i.e., of the invention Product 3- methyl D 3- benzyl bromine.
Preferably,
In the step 1), the molar ratio of 1,3- dibromobenzene, n-BuLi and deuterated iodomethane is 1.0:2.0:2.0.
In the step 2), the molar ratio of chemical compounds I, n-BuLi and DMF is 1.0:2.0:2.0.
In the step 3), the molar ratio of compound ii and sodium borohydride is 1:1.
In the step 4), the molar ratio of compound III and phosphorus tribromide is 1.0:1.5.
Preferably,
In the step 1), the reaction condition for synthesizing chemical compounds I is as follows: under nitrogen protection, -78 degree to reacting at room temperature 4-6 hours.
In the step 2), the reaction condition for synthesizing compound ii is as follows: under nitrogen protection, -78 spend to anti-at room temperature It answers 2-4 hours.
In the step 3), the reaction condition for synthesizing compound III is as follows: in methyl alcohol, reacting 2-4 hours under ice bath.
In the step 4), the reaction condition for synthesizing compounds Ⅳ is as follows: under nitrogen protection, -30 degree are anti-to room temperature It answers 1-3 hours.
This route of the invention uses commercially available deuterated iodomethane for raw material, synthesizes target product, deuterated rate is stable and reaches To high requirement (D > 99%).It has the following technical effect that
1) the deuterated rate of synthetic product is tall and big in 99%.
2) the deuterated rate of intermediate m-bromotoluene-D3 is stablized, and reaches 99% or more.
Detailed description of the invention
Fig. 1 is the HNMR result of 1 final product of embodiment.
Fig. 2 is the GCMS result of 1 final product of embodiment.
Specific embodiment
Embodiment 1 synthesizes 3- methyl D 3- benzyl bromine
Compound experiment method process is as follows in the present embodiment:
Step 1:
Reaction route is as follows:
In low temperature reaction vessel, under nitrogen protection, by 20.31 g of compound 1, there-necked flask is added in 3- dibromobenzene (86.1mmol) Son is added 60 milliliters of anhydrous tetrahydro furan, and liquid nitrogen cooling is to Nei Wen -78 DEG C hereinafter, keeping after twenty minutes, 68.8 millis being slowly added dropwise Rise 2.5M n-butyllithium solution (172mmol), keep in temperature at -78 DEG C hereinafter, period has a large amount of solids to be precipitated, be added dropwise to complete Afterwards, -78 DEG C after heat preservation 30 minutes, 10.7 milliliters of deuterated iodomethane (172mmol) is added dropwise and 20 milliliters of anhydrous tetrahydro furans mix Liquid, heating acutely, after the completion of being slowly added dropwise, after being back to room temperature reaction 3 hours, are added 120 milliliters of water, ethyl acetate extraction (40mL*3), organic phase are washed 1 time, and saturated sodium-chloride washs 1 time, dry, are spin-dried for.Crude product uses and is evaporated under reduced pressure to chemical compounds I 12 grams, yield 53.6%.
Step 2:
Reaction route is as follows:
There-necked flask is added in 12 g of compound I (68.9mmol) made from previous step, 120 milliliters of anhydrous tetrahydro furans, Nitrogen protection, liquid nitrogen are cooled to -78 DEG C, and 55 milliliters of 2.5M n-BuLi (137.5mmol) solution are added dropwise, and have a large amount of solids to analyse Out, after the completion, 30 minutes are kept the temperature, 10.2 grams of anhydrous DMFs (137.6mmo), 10 milliliters of anhydrous tetrahydro furan mixing is added dropwise after the completion Liquid after reacting at room temperature 2h, adds 120 milliliters of water after the completion, and ethyl acetate extracts (30mL*3), washes 1 time, saturated common salt It is water washing 1 time, dry, it is spin-dried for, obtains 6 grams of crude product of compound ii, crude yield 71% is directly used in next step.
Step 3:
Reaction route is as follows:
By compound ii crude product 6g (50mmol) made from previous step, 40 milliliters of methanol are added, under ice bath, is added portionwise 1.82 grams of sodium borohydrides (48.1mmol) used time 30 minutes, are reacted 1 hour under ice bath after the completion, and TLC shows that raw material disappears, and add 40 milliliters of water, ethyl acetate extracts (25mL*4), and organic phase is washed 1 time, saturated common salt water washing 1 time, dry, is spin-dried for, obtains slightly 6 grams of product, column chromatographs to obtain 3.5 g of compound, III product, two step yields 40.7%.
Step 4:
By 3.46 g of compound III (27.6mmol) made from previous step, it is dissolved in 30 milliliters of ether, under nitrogen protection, adds Enter in 100 milliliters of there-necked flasks, after being cooled to Nei Wen -30 DEG C, be added dropwise 11.47 grams of phosphorus tribromides (42.3mmol), 5 milliliters of ether it is mixed Liquid is closed, after the completion of being slowly added dropwise, after being warmed to room temperature reaction 1 hour, TLC shows that raw material disappears, and saturated sodium bicarbonate is added under ice bath Solution is slowly quenched, and ethyl acetate (40mL*3) extracts after the completion, and organic phase is washed 1 time, and saturated sodium bicarbonate washs 1 time, satisfies With brine It 1 time, it is dry, be spin-dried for, obtain crude product, crude product column chromatographs to obtain 3.33 grams of compounds Ⅳ product, GCMS > 98%.
HNMR result as shown in Figure 1, GCMS result as shown in Fig. 2, the product that can be seen that from Fig. 1 and Fig. 2 be 3- Methyl D 3- benzyl bromine.

Claims (3)

  1. The synthetic method of 1.3- methyl D 3- benzyl bromine, which is characterized in that synthetic route is as follows:
    The method includes the following steps:
    In the presence of n-butyllithium solution, substitution reaction occurs for step 1) with 1,3- dibromobenzene and deuterated iodomethane for raw material, Chemical compounds I is made；
    Step 2), with the chemical compounds I and DMF (n,N-Dimethylformamide) of step 1) preparation for raw material, in n-butyllithium solution In the presence of, substitution reaction occurs, compound ii is made；
    Compound ii and (NaBH is made with step 2) in step 3)4) sodium borohydride be raw material, occur reduction reaction, be made compound Ⅲ；
    Compounds Ⅳ, i.e., product of the invention is made using the compound III of step 3) preparation and phosphorus tribromide as raw material in step 4) 3- methyl D 3- benzyl bromine.
  2. 2. the method according to claim 1, wherein
    In the step 1), the molar ratio of 1,3- dibromobenzene, n-BuLi and deuterated iodomethane is 1.0:2.0:2.0；
    In the step 2), the molar ratio of chemical compounds I, n-BuLi and DMF is 1.0:2.0:2.0；
    In the step 3), the molar ratio of compound ii and sodium borohydride is 1:1；
    In the step 4), the molar ratio of compound III and phosphorus tribromide is 1.0:1.5.
  3. 3. the method according to claim 1, wherein
    In the step 1), the reaction condition for synthesizing chemical compounds I is as follows: under nitrogen protection, -78 degree to reacting 4-6 at room temperature Hour；
    In the step 2), the reaction condition for synthesizing compound ii is as follows: under nitrogen protection, -78 degree to reacting 2-4 at room temperature Hour；
    In the step 3), the reaction condition for synthesizing compound III is as follows: in methyl alcohol, reacting 2-4 hours under ice bath；
    In the step 4), the reaction condition for synthesizing compounds Ⅳ is as follows: under nitrogen protection, -30 degree to room temperature reaction 1-3 Hour.
CN201910469906.0A 2019-05-31 2019-05-31 Synthetic method of 3-methyl-D3-benzyl bromide Active CN110283040B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115304460A (en) * 2022-08-16 2022-11-08 深圳鼎邦生物科技有限公司 Synthesis method of decanal-1,2,2,3,3-d 5

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Publication number Priority date Publication date Assignee Title
WO2017015474A1 (en) * 2015-07-21 2017-01-26 Concert Pharmaceuticals, Inc. Deuterated meclizine
CN108218789A (en) * 2018-03-12 2018-06-29 钦州学院 13 deuterated methyl Telmisartan of carbon and its preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017015474A1 (en) * 2015-07-21 2017-01-26 Concert Pharmaceuticals, Inc. Deuterated meclizine
CN108218789A (en) * 2018-03-12 2018-06-29 钦州学院 13 deuterated methyl Telmisartan of carbon and its preparation method and application

Non-Patent Citations (1)

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Title
KOFI OFOSU-ASANTE等: "Preparation and Pyrolysis of O-(Alkylphenyl)methyl and 0-(Alkylnaphthyl)methyl Illinois No.6 Coals. Role of Dealkylation Reactions in Gaseous Hydrocarbon Formation", 《ENERGY & FUELS》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115304460A (en) * 2022-08-16 2022-11-08 深圳鼎邦生物科技有限公司 Synthesis method of decanal-1,2,2,3,3-d 5
CN115304460B (en) * 2022-08-16 2024-02-13 深圳鼎邦生物科技有限公司 Synthesis method of decanal-1, 2, 3-d5

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