CN116082335A - Preparation method of diaryl ether compound - Google Patents
Preparation method of diaryl ether compound Download PDFInfo
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- CN116082335A CN116082335A CN202310059683.7A CN202310059683A CN116082335A CN 116082335 A CN116082335 A CN 116082335A CN 202310059683 A CN202310059683 A CN 202310059683A CN 116082335 A CN116082335 A CN 116082335A
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- diaryl ether
- ether compound
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- -1 diaryl ether compound Chemical class 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 51
- 238000000034 method Methods 0.000 claims abstract description 43
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 40
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 20
- 229940125782 compound 2 Drugs 0.000 claims abstract description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 20
- 239000003513 alkali Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 229940125904 compound 1 Drugs 0.000 claims abstract description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 10
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical class [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical group CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 abstract description 8
- 230000035484 reaction time Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000007809 chemical reaction catalyst Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 8
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 7
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 2
- NLSCHDZTHVNDCP-UHFFFAOYSA-N caesium nitrate Chemical compound [Cs+].[O-][N+]([O-])=O NLSCHDZTHVNDCP-UHFFFAOYSA-N 0.000 description 2
- FLJPGEWQYJVDPF-UHFFFAOYSA-L caesium sulfate Chemical compound [Cs+].[Cs+].[O-]S([O-])(=O)=O FLJPGEWQYJVDPF-UHFFFAOYSA-L 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- ZOAIGCHJWKDIPJ-UHFFFAOYSA-M caesium acetate Chemical compound [Cs+].CC([O-])=O ZOAIGCHJWKDIPJ-UHFFFAOYSA-M 0.000 description 1
- ZMCUDHNSHCRDBT-UHFFFAOYSA-M caesium bicarbonate Chemical compound [Cs+].OC([O-])=O ZMCUDHNSHCRDBT-UHFFFAOYSA-M 0.000 description 1
- LYQFWZFBNBDLEO-UHFFFAOYSA-M caesium bromide Chemical compound [Br-].[Cs+] LYQFWZFBNBDLEO-UHFFFAOYSA-M 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- ATZQZZAXOPPAAQ-UHFFFAOYSA-M caesium formate Chemical compound [Cs+].[O-]C=O ATZQZZAXOPPAAQ-UHFFFAOYSA-M 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of diaryl ether compound with higher yield, belonging to the field of organic synthesis. The preparation method of the diaryl ether compound provided by the invention has the following reaction formula:
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of a diaryl ether compound.
Background
According to various patent reports of WO2007059257A1, WO201179274A1, WO2022003575A1, WO2022006386A1 and the like, the compound 3 is an important molecular building block and can be used for preparing various medicines.
In the prior art, compound 3 is usually prepared by a method of Linear synthesis (as described in WO2022006386 a), the synthetic route of compound 3a is as follows:
however, in this route, the yield of the multi-step reaction is low, and thus the yield of compound 3 is limited.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a method for producing a diaryl ether compound with a higher yield, the method comprising at least the following reactions:
preferably, the reaction of the convergent synthesis (Convergent synthesis) is included:
in the above formula, X is any one of F, cl, br or I,
D 1 、D 2 and D 3 Independently of one another N or CR 3 ，
R 1 、R 2 And R is 3 Independently of each other, is any one of hydrogen, cyano, nitro, azido, alkyl, alkenyl, alkoxy, aryloxy, haloalkyl,
R 4 is nitro or nitroso.
Specifically, the present invention provides the following two methods for preparing diaryl ether compounds.
Method 1:
method 1 provides a process for preparing a diaryl ether compound having such characteristics as the following reaction formula:
in the above formula, X is any one of F, cl, br or I,
D 1 、D 2 and D 3 Independently of one another N or CR 3 ，
R 1 、R 2 And R is 3 Independently of each other, is any one of hydrogen, cyano, nitro, azido, alkyl, alkenyl, alkoxy, aryloxy, haloalkyl,
the method comprises the following steps:
mixing compound 1 or its salt, compound 2, solvent and alkali reagent for reaction to obtain the product,
wherein the solvent is N, N-dimethylacetamide.
In the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that: wherein, the compound 1 is
R 1 Is any one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 haloalkyl.
In the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that: wherein, the compound 2 is
X is any one of F, cl, br or I.
In the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that: wherein the alkali reagent is any one or more of potassium carbonate, sodium carbonate or cesium carbonate.
In the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that: wherein the mass volume ratio of the compound 2 to the solvent is 1g: (2.5-8) mL.
In the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that: wherein the molar ratio of the compound 1 to the compound 2 is (1.2-1.5): 1, the molar ratio of the base reagent to the compound 2 is (1.5-2.5): 1.
in the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that: wherein the reaction temperature is 120-160 ℃.
The method for producing a diaryl ether compound according to method 1 may further have the feature of comprising the steps of:
adding (1.2-1.5) parts of compound 1, 1 part of compound 2 and (1.5-2.5) parts of alkali reagent into a solvent according to a molar amount, heating to 120-160 ℃ under an inert atmosphere, reacting for 6-48 h, and performing post-treatment to obtain the compound 3.
In the method for producing a diaryl ether compound provided in method 1, there may be further provided a feature that the post-treatment comprises the steps of:
cooling the reaction liquid to 10-20 ℃, adding water, extracting with an organic solvent, and taking an organic phase, and performing column chromatography or recrystallization or crystallization to obtain the catalyst.
Method 2:
method 2 provides a process for preparing a diaryl ether compound having such characteristics as the following reaction formula:
in the above formula, X is any one of F, cl, br or I,
D 1 、D 2 and D 3 Independently of one another N or CR 3 ，
R 1 、R 2 And R is 3 Independently of each other, is any one of hydrogen, cyano, nitro, azido, alkyl, alkenyl, alkoxy, aryloxy, haloalkyl,
the method comprises the following steps:
mixing compound 1 or salt thereof, compound 2, solvent, alkali reagent and catalyst for reaction to obtain the product,
wherein the catalyst is cesium salt.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein, the compound 1 is
R 1 Is any one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 haloalkyl.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein, the compound 2 is
X is any one of F, cl, br or I. />
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein the alkali reagent is any one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide or potassium tert-butoxide.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein, the cesium salt is any one or more of cesium carbonate, cesium fluoride, cesium sulfate, cesium nitrate, cesium chloride, cesium iodide, cesium bromide, cesium iodide, cesium formate, cesium bicarbonate and cesium acetate.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein the molar ratio of the catalyst to the compound 2 is (0.02-0.3): 1.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein the solvent is any one or more of N, N-dimethylacetamide, N-dimethylformamide or N-methylpyrrolidone.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein the mass volume ratio of the compound 2 to the solvent is 1g: (2.5-8) mL.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein the molar ratio of the compound 1 to the compound 2 is (1.2-1.5): 1, the molar ratio of the base reagent to the compound 2 is (1.5-2.5): 1.
in the method for producing a diaryl ether compound provided in method 2, there may be further provided the following features: wherein the reaction temperature is 120-160 ℃.
The diaryl ether compound preparation method provided in the method 2 may further have such a feature that it comprises the steps of:
adding (1.2-1.5) parts of compound 1, 1 part of compound 2, (1.5-2.5) parts of alkali reagent and (0.02-0.3) parts of catalyst into a solvent according to a molar amount, heating to 120-160 ℃ under an inert atmosphere, reacting for 6-48 h, and performing post-treatment to obtain the compound 3.
In the method for producing a diaryl ether compound provided in method 2, there may be further provided a feature that the post-treatment comprises the steps of:
cooling the reaction liquid to 10-20 ℃, adding water, extracting with an organic solvent, and taking an organic phase, and performing column chromatography or recrystallization or crystallization to obtain the catalyst.
Effects and effects of the invention
According to the method for producing a diaryl ether compound of the present invention, since N, N-dimethylacetamide is used as a reaction solvent, the present invention can produce a target compound in a high yield.
According to the preparation method of the diaryl ether compound, cesium salt is used as a catalyst for the reaction, so that the reaction time can be effectively shortened, and the reaction yield can be further improved.
Detailed Description
The present invention will be described in detail with reference to the following examples, so that the technical means, the creation characteristics, the achievement of the purpose and the effect achieved by the present invention are easily understood.
In the examples below, each chemical reagent is a commercially available product unless otherwise specified.
In the examples described below, DMAc is N, N-dimethylacetamide, DMSO is dimethylsulfoxide, DMF is N, N-dimethylformamide, NMP is N-methylpyrrolidone, DMF-DMA is N, N-dimethylformamide dimethylacetal.
Example 1 ]
Preparation of Compound 1a
This example provides a method for preparing compound 2a, which has the following reaction formula:
the method comprises the following steps:
1L of 3wt% sodium hydroxide aqueous solution, 100g of compound 4 (0.729 mol,1.0 eq) was added to the reaction vessel, cooled to 0-5 ℃, 68.9g of hydrazine hydrate (85 wt%,1.17mol,1.6 eq) was added dropwise, and the reaction was stirred at 0-5 ℃ for 16 hours under controlled temperature, filtered, and the filter cake was washed with water and dried to obtain 62.9g of compound 1a as a black solid in a yield of 70.1% and a liquid phase purity of 99.6%.
Example 2 ]
Preparation of Compound 6
This example provides a method for preparing compound 6, having the following reaction formula:
the method comprises the following steps:
under the protection of nitrogen, 25g of compound 5 (194 mmol,1.0 eq) is added into 75mL of ethanol, the temperature is controlled at 25 ℃, 27.8g of DMF-DMA (233 mmol,1.2 eq) is added, the temperature is raised to 65 ℃, stirring reaction is carried out for 4h, the temperature is reduced to 25 ℃, 16.2g of hydroxylamine hydrochloride (233 mmol,1.2 eq) is added, the reaction is kept at the temperature for 1h, the reaction solution is added into 175mL of 8wt% sodium bicarbonate aqueous solution for quenching reaction, the solid is filtered, taken out, washed once by water and dried, 32.1g of compound 6 is obtained, the yield is 96.1%, and the purity is 99.2%.
Example 3 ]
Preparation of Compound 2a
This example provides a method for preparing compound 2a, which has the following reaction formula:
the method comprises the following steps:
70g of Compound 6 (408 mmol,1.0 eq) was added to 500mL of toluene, the temperature was raised to 45 ℃, 116g of trifluoroacetic anhydride (553mmol, 1.35 eq) was added, the reaction was continued with stirring under heat preservation for 5h, the solvent was distilled off under reduced pressure, the temperature was lowered to 10 ℃, 200mL of water and 200mL of methylene chloride were added, extraction was carried out, the organic phase was taken, the saturated aqueous sodium chloride solution was washed once, concentrated under reduced pressure, and recrystallized from ethanol to give 40.9g of Compound 2a, yield 65.3% and purity 98.5%.
Example 4 ]
Preparation of Compound 3a
This example provides a process for the preparation of compound 3a, having the following formula:
the method comprises the following steps:
20g of Compound 2a (130 mmol,1.0 eq), 20.8g of Compound 1a (169 mol,1.3 eq) and 45g of potassium carbonate (326 mmol,2.5 eq) were added to 60mL of DMAc, the mixture was heated to 150℃under nitrogen protection, stirred for 16h, cooled to 15℃and 400g of water were added, the mixture was stirred at 15℃for 30min, solids were precipitated, filtered, the solids were taken, washed once with water and dried at 60℃for 12h to give 25.7g of Compound 3a in 82.3% yield.
Example 5 ]
Screening of reaction conditions
This example screens the reaction conditions on the basis of example 4, comprising the steps of:
20g of Compound 2a (130 mmol,1.0 eq), 20.8g of Compound 1a (169 mol,1.3 eq) and 2.5eq of alkaline reagent are added into the reaction solvent, the temperature is raised to the reaction temperature under the protection of nitrogen, the reaction is stirred for 16h, the temperature is reduced to 15 ℃, 400g of water is added, the temperature is kept at 15 ℃ and stirred for 30min, solids are separated out, the solid is filtered, washed once, and dried for 12h at 60 ℃.
The screening results are shown in Table 1.
TABLE 1 screening of reaction conditions
| Sequence number | Alkali reagent | Reaction solvent | Reaction temperature | Yield is good |
| 1 | Potassium carbonate | 60mLDMF | 150℃ | 70.1％ |
| 2 | Potassium carbonate | 60mLDMAc | 130℃ | 81.2％ |
| 3 | Potassium carbonate | 60mLDMSO | 150℃ | 12.8％ |
| 4 | Potassium carbonate | 60mLNMP | 150℃ | 22.0％ |
| 5 * | Potassium carbonate | 60mLDMAc | 150℃ | 46.1％ |
| 6 | Potassium carbonate | 140mLDMAc | 150℃ | 87.1％ |
| 7 | Sodium hydroxide | 60mLDMAc | 150℃ | 47.9％ |
| 8 | Potassium tert-butoxide | 60mLDMAc | 150℃ | 41.9％ |
* The reaction time was 10h.
As is clear from Table 1, when potassium carbonate is used as the alkali agent, the reaction yield is higher than when sodium hydroxide and potassium t-butoxide are used as the alkali agent. When DMF and DMAc are used as reaction solvents, the reaction yield is obviously improved compared with the case that DMSO and NMP are used as reaction solvents. When the reaction temperature is 130-150 ℃, higher reaction yield can be obtained, wherein the reaction yield is slightly higher at 150 ℃. Furthermore, it is clear from the combination of condition 5 of Table 1 and example 4 that the reaction was completed under the above conditions for about 16 hours.
Example 6 ]
Preparation of Compound 3a
This example provides a process for the preparation of compound 3a, having the following formula:
the method comprises the following steps:
20g of Compound 2a (130 mmol,1.0 eq), 20.8g of Compound 1a (169 mol,1.3 eq), 45g of potassium carbonate (326 mmol,2.5 eq) and 21g of cesium carbonate (64 mmol,0.05 eq) were added to 60mL of DMAc, the temperature was raised to 150℃under nitrogen protection, the reaction was stirred for 10h, the temperature was lowered to 15℃and 400g of water was added, the temperature was kept at 15℃and stirred for 30min, solids were precipitated, filtered, the solids were taken, washed once with water and dried for 12h at 60℃to give 28.4g of Compound 3a, the yield was 91.0%.
Example 7 ]
Screening of reaction conditions
This example screens the reaction conditions on the basis of example 6, comprising the steps of:
20g of Compound 2a (130 mmol,1.0 eq), 20.8g of Compound 1a (169 mol,1.3 eq), 2.5eq of alkaline reagent and catalyst are added into 60mL of DMAc, the mixture is heated to 150 ℃ under the protection of nitrogen, stirred and reacted for 10h, cooled to 15 ℃, 400g of water is added, the mixture is stirred for 30min at 15 ℃ and solid is separated out, filtered, the solid is taken out, washed once with water and dried for 12h at 60 ℃.
The screening results are shown in Table 2.
TABLE 2 screening of reaction conditions
| Sequence number | Alkali reagent | Catalyst | Yield is good |
| 1 | Cesium carbonate | - | 94.5％ |
| 2 | Potassium carbonate | 0.2eq cesium carbonate | 92.5％ |
| 3 | Potassium carbonate | 0.2eq potassium iodide | 57.4％ |
| 4 | Potassium carbonate | 0.2eq cuprous iodide | 11.2％ |
| 5 | Potassium carbonate | 0.2eq copper powder | 15.6％ |
| 6 | Potassium carbonate | 0.2eq cesium fluoride | 86.2％ |
| 7 | Sodium hydroxide | 0.2eq cesium carbonate | 83.6％ |
| 8 | Potassium carbonate | 0.1eq cesium carbonate | 92.3％ |
As is clear from Table 2, when cesium salt is used as a base reagent or a catalyst, the reaction yield is significantly improved as compared with cuprous salt or potassium salt. It was found that when copper or a cuprous salt was used as the catalyst in combination with the conditions 5 of Table 1 and the conditions 4 to 5, the reaction was not promoted but suppressed, resulting in a decrease in the reaction yield. In addition, it was found from the results of the combination of example 6 that the cesium carbonate was used as a catalyst in an amount of 0.05 to 0.2eq, and that the reaction time was shortened while the product was obtained in a high yield.
Effects and effects of the examples
According to the method for producing a diaryl ether compound according to the above-described example, since N, N-dimethylacetamide is used as a reaction solvent, the objective compound can be produced in a high yield.
According to the preparation method of the diaryl ether compound, cesium salt is used as a catalyst for the reaction, so that the reaction time can be effectively shortened, and the reaction yield can be further improved.
Further, because DMAc is used as a reaction solvent, the reaction yield is obviously improved.
Further, because cesium salt is used as a catalyst, not only is the reaction time effectively shortened, but also the reaction yield is greatly improved.
Further, since only 0.05eq of cesium salt is needed for the catalytic reaction, the reaction cost can be effectively reduced.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. A method for preparing a diaryl ether compound, which is characterized by the following reaction formula:
in the above formula, X is any one of F, cl, br or I,
D 1 、D 2 and D 3 Independently of one another N or CR 3 ，
R 1 、R 2 And R is 3 Independently of each other, is any one of hydrogen, cyano, nitro, azido, alkyl, alkenyl, alkoxy, aryloxy, haloalkyl,
the method comprises the following steps:
and mixing the compound 1 or salt thereof, the compound 2, a solvent and an alkali reagent for reaction, wherein the solvent is N, N-dimethylacetamide.
2. The method for producing a diaryl ether compound according to claim 1, characterized in that:
wherein the compound 1 is
R 1 Is any one of hydrogen, C1-C10 alkyl, C1-C10 alkoxy and C1-C10 haloalkyl.
3. The method for producing a diaryl ether compound according to claim 1, characterized in that:
wherein the compound 2 is
X is any one of F, cl, br or I.
4. The method for producing a diaryl ether compound according to claim 1, characterized in that:
wherein the alkali reagent is any one or more of potassium carbonate, sodium carbonate or cesium carbonate.
5. The method for producing a diaryl ether compound according to claim 1, characterized in that:
wherein the mass volume ratio of the compound 2 to the solvent is 1g: (2.5-8) mL.
6. A method for preparing a diaryl ether compound, which is characterized by the following reaction formula:
in the above formula, X is any one of F, cl, br or I,
D 1 、D 2 and D 3 Independently of one another N or CR 3 ，
R 1 、R 2 And R is 3 Independently of each other, is any one of hydrogen, cyano, nitro, azido, alkyl, alkenyl, alkoxy, aryloxy, haloalkyl,
the method comprises the following steps:
mixing compound 1 or salt thereof, compound 2, solvent, alkali reagent and catalyst for reaction to obtain the product,
wherein the catalyst is cesium salt.
7. The method for producing a diaryl ether compound according to claim 6, characterized in that:
wherein the compound 1 is
R 1 Is hydrogen, C1-C10 alkyl, C1-C10 alkoxy,Any one of C1-C10 haloalkyl.
8. The method for producing a diaryl ether compound according to claim 6, characterized in that:
wherein the compound 2 is
X is any one of F, cl, br or I.
9. The method for producing a diaryl ether compound according to claim 6, characterized in that:
wherein the alkali reagent is any one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide or potassium tert-butoxide.
10. The method for producing a diaryl ether compound according to claim 6, characterized in that:
wherein the molar ratio of the catalyst to the compound 2 is (0.02-0.3): 1.
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