CN112062745A - Preparation method of 9, 9' -dimethylxanthene - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 37
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 26
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- 239000000047 product Substances 0.000 claims abstract description 15
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- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
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- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- SWGQITQOBPXVRC-UHFFFAOYSA-N methyl 2-bromobenzoate Chemical compound COC(=O)C1=CC=CC=C1Br SWGQITQOBPXVRC-UHFFFAOYSA-N 0.000 description 2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/78—Ring systems having three or more relevant rings
- C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D311/82—Xanthenes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 9, 9' -dimethyl xanthene, which comprises the following steps: dissolving diphenyl ether in a solvent, cooling, dropwise adding n-butyllithium for reaction, then dropwise adding acetone at low temperature, returning to room temperature, adding water for quenching, separating out an organic phase, concentrating the ether solvent, and purifying an obtained crude product by column chromatography to obtain the product 9, 9' -dimethylxanthene. The preparation method takes low-cost diphenyl ether as an initial raw material, constructs a dilithiation intermediate through hydrogen capture reaction of the diphenyl ether and n-butyllithium, and then prepares the final product 9, 9' -dimethylxanthene through nucleophilic substitution reaction of the dilithiation intermediate and acetone. The preparation method does not need to adopt expensive xanthone as a starting material and does not need to use trimethyl aluminum which is an explosive chemical (which is superior to a xanthone methylation method); the method has the highest separation yield of 85 percent and higher reaction yield.
Description
Technical Field
The invention relates to the technical field of organic phosphine ligand synthesis, in particular to a preparation method of 9, 9' -dimethyl xanthene.
Background
In 2010, nobel chemical awards to american scientists Richard Heck (Richard f. Heck), japanese scientist root bank yi (Ei-ichi Negishi), and Suzuki (Akira Suzuki). The three scientists developed a palladium-catalyzed cross-coupling process in organic synthesis that was very competitive. In fact, the methods invented by the three scientists have been widely applied to scientific research and industrial production in the fields of pharmacy, electronic industry, advanced materials and the like. It is worth noting that the organic phosphine ligand for regulating and controlling the reaction selectivity is a necessary prerequisite for the industrial application of the cross-coupling method. Therefore, the organic phosphine ligand becomes a novel chemical product with wide application and is a fine chemical product with high added value, the market capacity reaches hundreds of millions of scales, and the organic phosphine ligand belongs to the key support range of the national industrial technical policy.
4, 5-bis (diphenylphosphino) -9, 9' -dimethyl xanthene (XantPhos for short) is taken as an important organic phosphine ligand, plays a key role in important catalytic reactions such as Buchwald-Hartwig amination and Suzuki coupling since catalytic reactions are introduced in the last 90 th century, is widely applied to synthesis of various new medicines and new materials, and has important social significance and wide market prospect.
For example, 2008 merck corporation developed a new class of highly selective mGluR antagonists. The molecule exerts neuroprotective effects in vitro and in vivo models and shows a certain potential in the treatment of pain, anxiety, depression, epilepsy and neurodegenerative diseases (schizophrenia, alzheimer's disease, parkinson's disease, etc.). The metabotropic glutamate receptor mGluR, one of the important members of metabotropic glutamate receptors, plays an important role in central nervous system signaling. The selective mGluR antagonist can block mGluR-mediated signal channels and play a series of physiological functions of analgesia, antianxiety, antidepressant and the like. At present, the discovery and optimization of selective mGluR antagonists has become a hotspot in the research of new drug industries. The medicine has great market prospect in the future, and part of the synthesis process is as follows:
in the developed synthesis process, the most critical step is the coupling reaction of the isoindolone and the triazole fragment. Merck researchers can efficiently realize the construction of a C-C bond and the efficient synthesis of the mGluR antagonist by regulating and controlling catalytic amount of XantPhos.
9,9 '-dimethylxanthene, an important precursor of 4, 5-bis diphenylphosphine-9, 9' -dimethylxanthene, is the key to the synthesis of XantPhos (see above). Therefore, it is necessary to study the efficient synthesis of 9, 9' -dimethylxanthene. Currently, there are three general synthetic methods for 9, 9' -dimethylxanthene, which are described in detail below:
(1) xanthone methylation process
The earliest method for synthesizing 9, 9' -dimethylxanthene was reported by Julius Rebek in 1990J. Am. Chem. SOC.1990, 1128902-8906.) the synthesis method is shown in the figure. The method takes the expensive xanthone as the raw material, and synthesizes 9, 9' -dimethylxanthene through methylation reaction of the xanthone and trimethyl aluminum, and the reaction yield is about 70-80%. The xanthone methylation method uses expensive xanthone as a main raw material, resulting in high cost and uneconomical process, and furthermore, trimethylaluminum is a highly dangerous explosive chemical, which increases the production risk level of the process, which limits the industrial application of the method.
(2) Phenol condensation process
The second method is the phenol condensation method developed by yellow vitamin at the university of Reddingdan in 2006 (CN 1821239A). The method takes low-cost phenol and acetone as starting raw materials, and prepares the 9, 9' -dimethylxanthene by a one-pot method under the catalysis of strong acid methanesulfonic acid. The method has low cost of raw materials, but the phenol used in the process needs 10 times of molar quantity, and the reaction yield is only 10-20 percent calculated by the phenol. In addition, the use of 10 times of phenol increases the difficulty of post-treatment after the reaction, and is inconvenient for industrial scale-up production.
(3) Coupling ring closing method
In 2016, Lodi Mahendar reported the synthesis of 9, 9' -dimethylxanthene (R) by a three-step methodRSC Adv. 2016, 6, 20588-20597.). The method comprises the steps of taking methyl O-bromobenzoate as an initial raw material, firstly synthesizing a benzyl alcohol intermediate through a nucleophilic substitution reaction with a methyl Grignard reagent, then coupling phenol and a carbon-bromine bond to construct a C-O bond under the catalysis of CuI, and finally carrying out an intramolecular friedel-crafts alkylation reaction on the benzyl alcohol and an aromatic ring under the catalysis of boron trifluoride diethyl etherate to obtain the final 9, 9' -dimethylxanthene. Compared with the phenol condensation method, the method has better reaction yield, and simultaneously, the method avoids the use of expensive raw material xanthone. However, the method needs three steps for synthesis, and the price of the starting material methyl o-bromobenzoate is still high.
In view of the broad market prospect of 9, 9' -dimethylxanthene, the research on the process route with lower cost, simpler operation and higher product purity is promoted.
Disclosure of Invention
The invention provides a preparation method of 9,9 '-dimethylxanthene, which has the advantages of low raw material cost, high reaction yield, simple post-treatment, no need of adopting expensive xanthone as an initial raw material, one-step synthesis of 9, 9' -dimethylxanthene from diphenyl ether, simple post-treatment and environmental friendliness.
The technical scheme for realizing the invention is as follows:
the preparation method of the 9, 9' -dimethylxanthene comprises the following steps: dissolving diphenyl ether in a solvent, cooling, dropwise adding n-butyllithium for reaction, capturing hydrogen to form a dilithiated intermediate, dropwise adding acetone at low temperature, returning to room temperature, adding water for quenching, separating liquid to separate out an organic phase, concentrating an ether solvent, and performing column chromatography purification on an obtained crude product (a mobile phase is n-hexane) to obtain a final product 9, 9' -dimethylxanthene, wherein the content of the product is higher than 99% by liquid-phase chromatography detection.
In the invention, diphenyl ether firstly generates hydrogen capture reaction with n-butyl lithium to produce a dilithiation intermediate in situ, and then the dilithiation intermediate generates nucleophilic substitution reaction with acetone to generate the final product 9, 9' -dimethylxanthene.
The solvent is at least two of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, dioxane or dibutyl ether.
Dissolving diphenyl ether in a solvent, cooling to-30 ℃ to-78 ℃, and dropwise adding n-butyllithium to react for 3-12 h.
The mass ratio of diphenyl ether, n-butyllithium and acetone is 1: (2-3): (1-1.5).
The invention has the beneficial effects that: the preparation method takes low-cost diphenyl ether as an initial raw material, constructs a dilithiation intermediate through hydrogen capture reaction of the diphenyl ether and n-butyllithium, and then prepares the final product 9, 9' -dimethylxanthene through nucleophilic substitution reaction of the dilithiation intermediate and acetone. The preparation method does not need to adopt expensive xanthone as a starting material and does not need to use trimethyl aluminum which is an explosive chemical (which is superior to a xanthone methylation method); the method has the highest separation yield of 85 percent and higher reaction yield (superior to a phenol condensation method); the reaction starts from diphenyl ether, and the final product 9, 9' -dimethylxanthene is synthesized in one step (compared with a three-step coupling ring closing method). The preparation method has the advantages of low cost of raw materials, high reaction yield, simple post-treatment and strong industrial application prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a schematic representation of 9, 9' -dimethylxanthene prepared in example 11H-NMR spectrum;
FIG. 2 is a schematic representation of 9, 9' -dimethylxanthene prepared in example 113C-NMR spectrum.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without inventive effort based on the embodiments of the present invention, are within the scope of the present invention.
Example 1
The synthesis of 9, 9' -dimethylxanthene comprises the following steps:
adding 1.7g (10 mmol) of diphenyl ether and 50ml of anhydrous tetrahydrofuran into a 100ml Schlenk bottle, then placing the reaction bottle into a low-temperature reaction bath, stirring and cooling to-78 ℃, then dropwise adding 8ml (20 mmol, concentration of 2.5M) of n-butyllithium into the reaction bottle by using an injector, after reacting for 3 hours, dropwise adding 0.58g (10 mmol) of acetone, then adding 20ml of water to quench and react, separating out an organic phase, rotationally evaporating and rotationally drying the organic solvent, purifying the obtained crude product by column chromatography to obtain 1.79g of light yellow solid, purifying the product by column chromatography to obtain the light yellow solid, and finally obtaining the product1H-NMR and13the structure was determined to be 9, 9' -dimethylxanthene by C-NMR in 85% yield and the product purity was 99.5% by liquid chromatography.
Example 2
The synthesis of 9, 9' -dimethylxanthene comprises the following steps:
adding 1.7g (10 mmol) of diphenyl ether and 50ml of anhydrous methyl tert-butyl ether into a 100ml Schlenk bottle, then placing the reaction bottle into a low-temperature reaction bath, stirring and cooling to-50 ℃, then dropwise adding 10ml (25 mmol, the concentration is 2.5M) of n-butyllithium into the reaction bottle by using an injector, after reacting for 6 hours, dropwise adding 0.7g (12 mmol) of acetone, then adding 20ml of water to quench and react, separating out an organic phase, rotationally evaporating and rotationally drying the organic solvent, purifying the obtained crude product by column chromatography to obtain 1.49g of a light yellow solid, purifying the product by column chromatography to obtain 1.49g of a light yellow solid, and purifying the product by column1H-NMR and13the structure was determined to be 9, 9' -dimethylxanthene by C-NMR, the yield was 71%, and the purity of the product by liquid chromatography was 99.1%.
Example 3
The synthesis of 9, 9' -dimethylxanthene comprises the following steps:
adding 1.7g (10 mmol) of diphenyl ether and 50ml of anhydrous ether into a 100ml Schlenk bottle, then placing the reaction bottle in a low-temperature reaction bath, stirring and cooling to-30 ℃, then dropwise adding 12ml (30 mmol, concentration of 2.5M) of n-butyllithium into the reaction bottle by using an injector, after 12 hours of reaction, dropwise adding 0.87g (15 mmol) of acetone, then adding 20ml of water to quench the reaction, separating out an organic phase, rotationally evaporating and rotationally drying the organic solvent, purifying the obtained crude product by column chromatography to obtain 1.66g of light yellow solid, purifying the product by column chromatography to obtain 1.66g of light yellow solid, and finally obtaining the product by column chromatography1H-NMR and13the structure was determined to be 9, 9' -dimethylxanthene by C-NMR in 79% yield and the product purity by liquid chromatography was 99.2%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (4)
- A process for the preparation of 9, 9' -dimethylxanthene, characterized by the steps of: dissolving diphenyl ether in a solvent, cooling, dropwise adding n-butyllithium for reaction, then dropwise adding acetone at low temperature, returning to room temperature, adding water for quenching, separating out an organic phase, concentrating the ether solvent, and purifying an obtained crude product by column chromatography to obtain the product 9, 9' -dimethylxanthene.
- 2. The method of producing 9, 9' -dimethylxanthene according to claim 1, characterized in that: the solvent is at least two of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, dioxane or dibutyl ether.
- 3. The method of producing 9, 9' -dimethylxanthene according to claim 1, characterized in that: dissolving diphenyl ether in a solvent, cooling to-30 ℃ to-78 ℃, and dropwise adding n-butyllithium to react for 3-12 h.
- 4. The method of producing 9, 9' -dimethylxanthene according to claim 1, characterized in that: the mass ratio of diphenyl ether, n-butyllithium and acetone is 1: (2-3): (1-1.5).
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2020
- 2020-09-17 CN CN202010978313.XA patent/CN112062745A/en active Pending
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