CN1432553A - Prepn process of dialkoxy tribenzyl halide - Google Patents

Prepn process of dialkoxy tribenzyl halide Download PDF

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Publication number
CN1432553A
CN1432553A CN03102746A CN03102746A CN1432553A CN 1432553 A CN1432553 A CN 1432553A CN 03102746 A CN03102746 A CN 03102746A CN 03102746 A CN03102746 A CN 03102746A CN 1432553 A CN1432553 A CN 1432553A
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oxyl
halogen
preparation
reaction
trityl
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崔正勋
李宇宰
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Bioneer Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen

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

Abstract

The invention relates to a novel method for preparing a dialkoxytrityl halide used as ribose reactance 5'-hydroxyl protecting group in synthetise reaction course of polynucleotide. First, the invention relates to a method of reacting a trihalide toluene with an alkoxy benzene to prepare a dialkoxytrityl halide; second, the invention relates to a method of reacting carbon tetrahalide with an alkoxy benzene to prepare a dihalo dialkoxy phenyl methanol; and reacting the obtained dihalodialkoxyphenylmethanol with benzene to prepare a dialkoxytrityl halide; third, relates to a method of reacting a dialkoxy phenyl ketone with a phosphorus pentahalide to prepare a dihalo dialkoxy phenyl methanol; and reacting the obtained dihalo dialkoxy phenyl methanol with benzene to prepare a dialkoxytrityl halide.

Description

The preparation method of two-oxyl trityl halogen
Technical field
The present invention relates in the polynucleotide synthetic reaction process, be used as the new preparation method of two-oxyl trityl halogen of the reactivity 5 '-hydroxyl protecting group of ribose.Specifically, at first the present invention relates to make trihalogenmethyl benzene and the reaction of-oxyl benzene to generate the method for two-oxyl trityl halogen; Next relates to makes carbon tetrahalide and-oxyl benzene prepared in reaction two (-oxyl phenyl) methylene halide earlier, makes itself and benzene reaction generate the method for two-oxyl trityl halogen then; Relate at last and make two (-oxyl phenyl) ketones and phosphorus pentahalides prepared in reaction two (-oxyl phenyl) methylene halide earlier, make itself and benzene reaction generate the novel method of two-oxyl trityl halogen then.
Background technology
Two-oxyl trityl halogen are in order to protect ribose 5 '-hydroxyl and to suppress side reaction and the normal compound that uses in the polynucleotide synthetic reaction process.The protective material to reactive 5 '-hydroxyl of extensive employing is 4,4 '-dimethoxytrityl chlorine.
At present, two-oxyl trityl halogen be by, in the solvent of ether that contains metal such as magnesium or tetrahydrofuran (THF), add 4-bromine anisole and generate Grignard reagent, make Grignard reagent and Benzoyl chloride or acetate benzoyl oxide prepared in reaction then.
But, this method that past is commonly used, the method that promptly prepares two-oxyl trityl halogen by Grignard reagent, owing to have danger and the ether of use or the preparation difficulty of tetrahydrofuran solvent of high temperature blast, be difficult so adopt this method to take mass production two-oxyl trityl halogen.
Summary of the invention
Purpose of the present invention is exactly for the industrial two-oxyl trityl halogen of mass production, gets rid of and uses the above-mentioned variety of issue that Grignard reagent brought, and provides the efficient height and the low new preparation technology of cost.
The new preparation method who the purpose of this invention is to provide two-oxyl trityl halogen.
The purpose of the invention described above can reach by the following reaction that makes the reaction of trihalogenmethyl benzene and-oxyl benzene generate two-oxyl trityl halogen:
[reaction formula 1]
Figure A0310274600061
In the above-mentioned reaction formula 1, X is a halogen, and R is a chain alkylene.
The purpose of the invention described above can also be passed through: 1) make the reaction of carbon tetrahalide and-oxyl benzene generate the step of two (-oxyl phenyl) methylene halide, 2) two (-oxyl phenyl) methylene halides that produce at first step and the reaction formula 2 of benzene reaction generation two-oxyl trityl halogen are reached:
[reaction formula 2]
In the above-mentioned reaction formula 2, X is a halogen, and R is a chain alkylene.
Purpose of the present invention can also be passed through: 1) make the step of two (-oxyl phenyl) ketones and phosphorus pentahalides prepared in reaction two (-oxyl phenyl) methylene halide, 2) two (-oxyl phenyl) methylene halides that generate at first step and the reaction formula of benzene reaction generation two-oxyl trityl halogen are reached:
[reaction formula 3]
In the above-mentioned reaction formula 3, X is a halogen, and R is a chain alkylene.
In polynucleotide synthetic reaction process, extensively the ribose 5 '-hydroxy-protecting agent that adopts is two-oxyl trityl halogen of comparison costliness.When needs synthesized the reaction of multiple polynucleotide in large quantities, the expensive price of two-oxyl trityl halogen was burdens.In addition, the Grignard reagent that adopts when organic synthesis prepares two-oxyl trityl halogen is a large amount of heat releases in reaction process, are unsuitable for using in a large number in industry generates, and reaction yield also has only 50% simultaneously.Just because of there being these problems, need the new synthetic method of exploitation two-oxyl trityl halogen, it is the precondition of a large amount of polynucleotide building-up reactionss.
Embodiment
Method of the present invention has been described by the following examples in more detail.
But these embodiment just illustrate the present invention, do not represent full content of the present invention.
Embodiment 1:4, the preparation of 4 '-dimethoxytrityl chlorine
In reactor, 2.6 gram (20 mmole) aluminum chlorides are mixed with 22 milliliters of (340 mmole) anisoles, stir after 5 minutes, add 2.8 milliliters of (20 gram mole) benzenyl trichlorides, reacted 24 hours down at 80 ℃ then.After 24 hours, in reactor, add 50 milliliters of toluene and 50 milliliters of 6N HCl, stir and isolate organic layer after 10 minutes.Isolated organic layer is washed with 25 milliliters of 6N HCl.Add after 50 milliliters the water, with 25 milliliters of toluene extractions, with wherein organic layer with last time isolated organic layer mix.In filtering solution, remove toluene, then, the anisole of excessive use is reclaimed more than 80%.After adding 2～3 milliliters of small amount of toluene, add 1.5 milliliters of (20 mmole) Acetyl Chloride 98Min.s again, it was refluxed 30 minutes.Postcooling was to room temperature in 30 minutes.The reaction mixture of cool to room temperature is washed with nucleic acid, after filtering, utilize reliever to carry out drying, produce 6.5 grams 4 by this method, 4 '-dimethoxytrityl chlorine.
Embodiment 2:4, the productive rate of 4 '-dimethoxytrityl chlorine is with the variation of temperature of reaction
In order to investigate 4, the productive rate of 4 '-dimethoxytrityl chlorine is with the variation of temperature of reaction, 154 ℃ before from room temperature to the anisole boiling temperature, with 40 ℃ interval conditioned reaction temperature.At this moment, other conditions are as follows: the mol ratio of reactive material, benzenyl trichloride: anisole: aluminum chloride is constant to be 1: 17: 1, and the reaction times is 24 hours, and other experiment conditions and embodiment 1 are identical.When reacting by above-mentioned condition, under the situation of 0 ℃, 40 ℃, 80 ℃, 120 ℃ and 150 ℃, productive rate is respectively 51%, 62%, 96%, 85% and 83%.By under the method purified situation of recrystallize, productive rate is respectively 42%, 56%, 80%, 71% and 69% the product that obtains.
Embodiment 3:4, the productive rate of 4 '-dimethoxytrityl chlorine is with the variation of the ratio of the water yield between benzenyl trichloride and the anisole
In order to find out that the reactant cumulative water-oil ratio is to 4, the influence of the productive rate of 4 '-dimethoxytrityl chlorine, with benzenyl trichloride: anisole: the ratio of aluminum chloride is between 1: 5: 1 to 1: 20: 1, and anisole content wherein is each to be increased by 2.5 and tests.Simultaneously, in the top condition of further investigation water content to the influence of the highstrung catalytic amount of atmospheric moisture, the amount of aluminum chloride is each to be increased by 0.2 mole and tests.The highest 80 ℃ of homo(io)thermism productive rate in embodiment 1, other conditions are identical with embodiment 1.When the ratio of reactive material is respectively 1: 5: 1,1: 7.5: 1,1: 10: 1,1: 12.5: 1, l: when 15: 1,1: 17: 1,1: 20: 1 and 1: 17: 1.2, corresponding productive rate is respectively 49%, 58%, 72%, 84%, 92%, 96%, 92% and 95%.By under the method purified situation of recrystallize, productive rate is respectively 43%, 50%, 61%, 70%, 79%, 80%, 78% and 78% the product that obtains.
Embodiment 4:4, the productive rate of 4 '-dimethoxytrityl chlorine is with the variation in reaction times
In order to find out 4, the productive rate of 4 '-dimethoxytrityl chlorine is with the variation in reaction times, and the reaction times got respectively 1.5 hours, 3 hours, 6 hours, 12 hours, 18 hours, 24 hours and 27 hours.Temperature of reaction constant in embodiment 1 the highest 80 ℃ of productive rate, the reactant cumulative water-oil ratio constant in embodiment 1 the highest benzenyl trichloride of productive rate: anisole: the ratio of aluminum chloride is 1: 17: 1.Catalyzer is a benzenyl trichloride.Other conditions are identical with embodiment 1.Be respectively 1.5 hours, 3 hours, 6 hours, 12 hours, 18 hours, 24 hours and 27 hours when the reaction times, corresponding productive rate is respectively does not have reaction, 72%, 85%, 88%, 92%, 96% and 95%.By under the method purified situation of recrystallize, productive rate is respectively 61%, 72%, 73%, 77%, 80% and 82% the product that obtains.
Embodiment 5:4, the productive rate of 4 ' dimethoxytrityl chlorine is with the variation of catalyzer
As catalyzer, use FeCl 3Replace benzenyl trichloride, to 4, the productive rate of 4 '-dimethoxytrityl chlorine compares.Temperature of reaction constant in embodiment one the highest 80 ℃ of productive rate, other conditions are identical with embodiment one.The result who tests under the above-mentioned top condition is to benzenyl trichloride and FeCl 3, productive rate is respectively 96% and 36%.By under the method purified situation of recrystallize, productive rate is respectively 80% and 30% the product that obtains.
As mentioned above, if adopt present method to generate two-oxyl trityl halogen, can exempt owing to the explosion hazard that uses Grignard reagent to cause, and can improve productive rate.Simultaneously, owing to carry out the synthetic of polynucleotide by simple generation technology at home, the interior foreign exchange of field of biology flows out so can reduce in the past, and realizes a large amount of industrial production.

Claims (16)

1, the preparation method of two-oxyl trityl halogen, this method comprise the step with trihalogenmethyl benzene and the reaction of-oxyl benzene of following reaction formula 1 expression:
[reaction formula 1]
In the above-mentioned reaction formula 1, X is a halogen, and R is a chain alkylene.
2, the preparation method of two-oxyl trityl halogen as claimed in claim 1, wherein said reaction is catalyzer with the aluminum chloride.
3, the preparation method of two-oxyl trityl halogen as claimed in claim 1, wherein R represents alkyl.
4, the preparation method of two-oxyl trityl halogen as claimed in claim 1, wherein X represents chlorine.
5, the preparation method of two-oxyl trityl halogen as claimed in claim 1, wherein temperature of reaction is 40 to 120 ℃.
6, the preparation method of two-oxyl trityl halogen as claimed in claim 1, wherein temperature of reaction is constant is 80 ℃.
7, the preparation method of two-oxyl trityl halogen as claimed in claim 1 is wherein with 1 mole of trihalogenmethyl benzene and 15～20 moles of excessive-oxyl benzene reactions.
8, the preparation method of two-oxyl trityl halogen as claimed in claim 1 is wherein with 1 mole of trihalogenmethyl benzene and 17 moles of excessive-oxyl benzene reactions.
9, the preparation method of two-oxyl trityl halogen, this method comprise the step of following reaction formula 2 expressions:
1) reaction of carbon tetrahalide and-oxyl benzene generates the step of two (-oxyl phenyl) methylene halide; 2) make 1) two (-oxyl phenyl) methylene halides that generate of step and the step of benzene prepared in reaction two-oxyl trityl halogen;
[reaction formula 2]
In the above-mentioned reaction formula 2, X is a halogen, and R is a chain alkylene.
10, the preparation method of two-oxyl trityl halogen as claimed in claim 9, wherein said reaction is catalyzer with the aluminum chloride.
11, the preparation method of two-oxyl trityl halogen as claimed in claim 9, wherein R represents alkyl.
12, the preparation method of two-oxyl trityl halogen as claimed in claim 9, wherein X represents chlorine.
13, the preparation method of two-oxyl trityl halogen, this method comprise the step of following reaction formula 3 expressions:
1) make the step of two (-oxyl phenyl) ketones and phosphorus pentahalides prepared in reaction two (-oxyl phenyl) methylene halide,
2) two (-oxyl phenyl) methylene halides and the benzene that first step is generated reacts the step that generates two-oxyl trityl halogen;
[reaction formula 3]
Figure A0310274600041
In the above-mentioned reaction formula 3, X is a halogen, and R is a chain alkylene.
14, the preparation method of two-oxyl trityl halogen as claimed in claim 13, wherein said reaction is catalyzer with the aluminum chloride.
15, the preparation method of two-oxyl trityl halogen as claimed in claim 13, wherein R represents alkyl.
16, the preparation method of two-oxyl trityl halogen as claimed in claim 13, wherein X represents chlorine.
CN03102746A 2002-01-17 2003-01-17 Prepn process of dialkoxy tribenzyl halide Pending CN1432553A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107056590A (en) * 2017-05-24 2017-08-18 连云港诺森医药科技有限公司 One kind prepares and purifies the commercial run of 4,4 ' dimethoxytrityl chloromethanes
CN107556355A (en) * 2016-06-30 2018-01-09 上海兆维科技发展有限公司 Double phosphoramidites of a kind of nucleosides and preparation method thereof
CN112430179A (en) * 2020-12-02 2021-03-02 连云港冠昕医药科技有限公司 High-efficiency separation and purification method of 4,4 '-dimethoxytriphenylchloromethane and 4,4' -dimethoxytrityl alcohol
CN112479834A (en) * 2020-12-02 2021-03-12 连云港冠昕医药科技有限公司 Synthesis method of high-purity 4, 4' -dimethoxy triphenylchloromethane

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107556355A (en) * 2016-06-30 2018-01-09 上海兆维科技发展有限公司 Double phosphoramidites of a kind of nucleosides and preparation method thereof
CN107556355B (en) * 2016-06-30 2021-10-22 上海兆维科技发展有限公司 Nucleoside diphosphite amide and preparation method thereof
CN107056590A (en) * 2017-05-24 2017-08-18 连云港诺森医药科技有限公司 One kind prepares and purifies the commercial run of 4,4 ' dimethoxytrityl chloromethanes
CN107056590B (en) * 2017-05-24 2020-11-24 崔小刚 Industrial method for preparing and purifying 4, 4' -dimethoxy triphenylchloromethane
CN112430179A (en) * 2020-12-02 2021-03-02 连云港冠昕医药科技有限公司 High-efficiency separation and purification method of 4,4 '-dimethoxytriphenylchloromethane and 4,4' -dimethoxytrityl alcohol
CN112479834A (en) * 2020-12-02 2021-03-12 连云港冠昕医药科技有限公司 Synthesis method of high-purity 4, 4' -dimethoxy triphenylchloromethane

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