CN109824725B - Preparation method of 4-phosphate-2H-chromene derivative - Google Patents

Preparation method of 4-phosphate-2H-chromene derivative Download PDF

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CN109824725B
CN109824725B CN201910179347.XA CN201910179347A CN109824725B CN 109824725 B CN109824725 B CN 109824725B CN 201910179347 A CN201910179347 A CN 201910179347A CN 109824725 B CN109824725 B CN 109824725B
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phosphate
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ethyl acetate
chromene
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CN109824725A (en
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肖强
宋贤荣
张宇星
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Jiangxi Science and Technology Normal University
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Abstract

The invention discloses 4-phosphate-2HThe preparation method of the-chromene derivative comprises the steps of taking o-propargyl alcohol phenol as a raw material, adding an organic solvent to fully dissolve the o-propargyl alcohol phenol at room temperature, adding a compound containing P (O) -OH, reacting at 80 ℃ for 3-6 hours, and after the reaction is finished, separating and purifying the reaction product by silica gel column chromatography to obtain 4-phosphate-2H-chromene derivatives. The method has the characteristics of simple and easily obtained raw materials, mild reaction conditions, simple and convenient operation, short reaction time, less pollution and the like, and is a chemical synthesis method with better popularization and application prospects.

Description

Preparation method of 4-phosphate-2H-chromene derivative
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to 4-phosphate-2HA process for the preparation of chromene derivatives.
Background
Organic phosphate ester compounds are very important organic compounds and organic intermediate building blocks in organic synthesis, and the compounds have good catalytic activity, optical activity and biological activity, so that the organic phosphate ester compounds have wide application in the fields of biology, optical active materials, medicine and the like. Meanwhile, the organic phosphorus compound is also indispensable in the living body, such as ADP, ATP, RNA, organic phospholipid bilayer and the like in the human body. However, it is difficult to find out natural organophosphate compounds in nature, and most of phosphorus exists in nature in the form of inorganic salts, and most of organophosphate compounds known at present are synthesized by chemical means.
Further, 2HThe-chromene skeleton compound is a very important compound, has certain pharmacological properties, is an important intermediate for synthesizing a plurality of natural compounds and pharmaceutically active molecules at present, and has certain health care effect. Thus, pair 2HThe functional group synthesis of the chromene skeleton compound has very important application prospect and theoretical guidance, and is concerned by organic synthesizers. Although the 4-position functionalization 2 is currently constructedHThere are many methods for the construction of chromene derivatives, but for the construction of 4-phosphate-2H-colorThe literature on alkene derivatives has not been reported to date.
Based on organic phosphates and 2HThe extensive application of chromene derivatives in the fields of organic synthesis, medicinal chemistry, material science and the like develops an atom economic, efficient and green synthesis strategy to construct 4-phosphate-2HParticularly important are chromene derivatives.
Disclosure of Invention
The invention aims to provide 4-phosphate-2 with cheap and easily obtained reagents, mild reaction conditions, simple process operation, short reaction time and less pollutionHA process for the preparation of chromene derivatives.
4-phosphate-2 of the inventionHProcess for the preparation of chromene derivatives from o-propargyl alcohol phenol (C)
Figure 338498DEST_PATH_IMAGE001
) Adding an organic solvent into the raw materials at room temperature to fully dissolve the raw materials, then adding a compound containing P (O) -OH, reacting for 3 to 6 hours at the temperature of 80 ℃, and after the reaction is finished, separating and purifying the reaction product by silica gel column chromatography to obtain the compound shown in the formula (A)
Figure 641303DEST_PATH_IMAGE002
) 4-phosphoric acid ester-2 as shownH-a chromene derivative;
Figure 123100DEST_PATH_IMAGE003
Figure 786031DEST_PATH_IMAGE001
) 、
Figure 935253DEST_PATH_IMAGE004
Figure 408960DEST_PATH_IMAGE002
),
wherein the formula (A) is
Figure 581315DEST_PATH_IMAGE001
) Or formula (A)
Figure 533090DEST_PATH_IMAGE002
) R in (1)1~R4Each independently is H, CH3、X(F、Cl、Br)、OCH3Any one of the above; r5And R6Each independently is any one of aryl, alkoxy, aryloxy and alkyl; ar (Ar)1And Ar2All are aryl groups substituted by different substituents.
The reaction is represented by the following formula:
Figure DEST_PATH_IMAGE005
wherein the mass of the organic solvent is 10-30 times of that of the o-propargyl alcohol phenol compound, and the organic solvent is any one of 1, 2-dichloroethane, 1, 2-dichloromethane, tetrahydrofuran, dioxane, acetonitrile and nitromethane.
In the present invention, the ratio of the amounts of the o-propargylphenol and the p- (o) -OH group-containing compound is preferably 1:1.5 to 2.5, more preferably 1: 2.0.
in the reaction process of the invention, TCL is used for tracking the reaction progress time, and the reaction time is recommended to be 4-8 hours, preferably 8 hours.
The reaction temperature of the method is controlled to be 60-80 ℃, and preferably 80 ℃.
The method provided by the invention comprises the following steps: o-propargyl alcohol phenol (C)
Figure 287551DEST_PATH_IMAGE001
) Dissolving the mixture in an organic solvent at room temperature, adding a compound containing P (O) -OH, reacting at 80 ℃ for 3-6 hours, and separating and purifying a reaction product after the reaction is finished to obtain 4-phosphate-2H-chromene derivatives.
The separation and purification of the invention can adopt the following steps: adding the reaction solution into a saturated sodium bicarbonate solution, adding ethyl acetate, fully stirring, standing and layering; the separated aqueous layer was extracted with ethyl acetateCombining the ethyl acetate extract and the separated organic layer, washing with saturated saline solution and drying with anhydrous sodium sulfate; evaporating to remove ethyl acetate solvent, and separating and purifying by silica gel column chromatography to obtain 4-phosphate-2H-chromene derivatives.
Compared with the prior art, the invention has the beneficial effects that: 1. providing a new synthesis strategy to construct; 2. the reaction of the invention does not need a catalyst, and the condition is mild; 3. the method has simple and convenient operation and wide substrate applicability, and can obtain 4-phosphate-2 with different substituentsH-a chromene derivative; 4. the invention has the advantages of simple and easily obtained raw materials, short reaction time and less pollution.
Detailed Description
Example 1: diphenyl- (2, 2-diphenyl-2)HPreparation of (E) -chromen-4-yl) -phosphinic acid esters
Figure 197738DEST_PATH_IMAGE006
Representative implementation procedure: sequentially adding o-propargyl alcohol phenol into a reaction bottle at room temperature
Figure 654127DEST_PATH_IMAGE001
-1 (300 mg, 1 mmol) and 5 ml of dry 1, 2-dichloroethane, then diphenylphosphoric acid (436 mg, 2 mmol) was added to the reaction flask, and then the reaction was left to react at 80 ℃ for 3 hours. Tracking the reaction progress by TLC, after the reaction is finished, adding a saturated sodium bicarbonate solution into the reaction solution, adding ethyl acetate, fully stirring, and standing for layering; extracting the separated water layer with ethyl acetate, mixing the ethyl acetate extract and the separated organic layer, washing with saturated saline solution, and drying with anhydrous sodium sulfate; evaporating to remove ethyl acetate solvent, and separating and purifying by silica gel column chromatography to obtain diphenyl- (2, 2-diphenyl-2)HChromen-4-yl hypophosphite 410 mg, reaction yield 82%.1H NMR (400 MHz, CDCl3): δ 6.13 (d, J = 1.2 Hz, 1 H), 6.90 – 6.93 (m, 3 H), 7.09 – 7.21 (m, 11 H), 7.43 – 7.53 (m, 5 H), 7.55 – 7.61 (m, 2 H), 7.90 – 7.95 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ 83.9, 111.9, 112.0, 116.7, 118.3, 118.4, 121.1, 121.8, 126.9, 127.5, 127.9, 128.7, 128.9, 129.8, 130.7, 131.1, 131.7, 131.8, 132.6, 132.7, 142.2, 142.3, 144.4, 153.6. 31P NMR (160 MHz, CDCl3): δ 31.3. HRMS (ESI, m/z): calcd for C33H25O3P: [M+H]+ = 501.1614; found: 501.1616。
Example 2: dibenzyl- (2, 2-diphenyl-2)HPreparation of (E) -chromen-4-yl) phosphates
Figure 612856DEST_PATH_IMAGE007
Sequentially adding o-propargyl alcohol phenol into a reaction bottle at room temperature
Figure 471090DEST_PATH_IMAGE001
-2 (300 mg, 1 mmol) and 5 ml of dry 1, 2-dichloroethane, then dibenzyl phosphate (556 mg, 2 mmol) was added to the reaction flask, the reaction was then left to react at 80 ℃ for 3 hours, and the progress of the reaction was followed by TLC. The separation and purification steps are the same as in example 1 to obtain diphenyl- (2, 2-diphenyl-2)HChromen-4-yl) phosphate 476 mg, reaction yield 85%.1H NMR (400 MHz, CDCl3): δ 5.11 (s, 2 H), 5.13 (s, 2 H), 6.06 (s, 1 H), 6.82 (t, J = 7.6 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 7.15 – 7.29 (m, 17 H), 7.35 – 7.37 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ 70.1, 83.8, 111.6, 111.7, 116.5, 117.8, 117.9, 121.0, 121.9, 126.9, 127.6, 128.0, 128.1, 128.6, 128.7, 130.7, 135.1, 135.2, 141.8, 141.9, 144.5, 153.4. 31P NMR (160 MHz, CDCl3): δ -6.1. HRMS (ESI, m/z): calcd for C35H29O5P: [M+H]+ = 561.1825; found: 561.1825。
Example 3: diphenyl- (2, 2-di (p-methylphenyl) -2HPreparation of (4-chromen-yl) -phosphinic acid esters
Figure 535867DEST_PATH_IMAGE008
Sequentially adding o-propargyl alcohol phenol into a reaction bottle at room temperature
Figure 682815DEST_PATH_IMAGE001
-3 (328 mg, 1 mmol) and 5 ml of dry 1, 2-dichloroethane, then diphenyl phosphate (436 mg, 2 mmol) was added to the reaction flask, the reaction was left at 80 ℃ for 4 hours, and the progress of the reaction was followed by TLC. The separation and purification steps are the same as in example 1 to obtain diphenyl- (2, 2-di (p-methylphenyl) -2HChromen-4-yl phosphinate 423 mg, reaction yield 80%.1H NMR (400 MHz, CDCl3): δ 2.26 (s, 6 H), 6.10 (d, J = 1.2 Hz, 1 H), 6.86 – 6.90 (m, 2 H), 6.95 – 7.00 (m, 8 H), 7.14 – 7.18 (m, 1 H), 7.41 – 7.49 (m, 5 H), 7.55 – 7.59 (m, 2 H), 7.89 – 7.94 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ 20.9, 83.8, 112.2, 112.3, 116.6, 118.3, 118.4, 120.9, 121.7, 126.8, 128.5, 128.6, 128.8, 129.9, 130.5, 131.2, 131.6, 131.7, 132.5, 132.6, 137.0, 141.6, 142.0, 142.1, 153.6. 31P NMR (160 MHz, CDCl3): δ 31.0. HRMS (ESI, m/z): calcd for C35H29O3P: [M+H]+ = 529.1927; found: 529.1925。
Example 4: diphenyl- (2, 2-di (p-methoxyphenyl) -2HPreparation of (4-chromen-yl) -phosphinic acid esters
Figure 241972DEST_PATH_IMAGE009
Sequentially adding o-propargyl alcohol phenol into a reaction bottle at room temperature
Figure 220293DEST_PATH_IMAGE001
-4 (360 mg, 1 mmol) and 5 ml of dry 1, 2-dichloroethane, then diphenyl phosphate (436 mg, 2 mmol) was added to the reaction flask, the reaction was left at 80 ℃ for 3 hours, and the progress of the reaction was followed by TLC. Separation and purification procedure as in example1 to obtain diphenyl- (2, 2-di (p-methoxyphenyl) -2HChromen-4-yl phosphinate 364 mg, reaction yield 65%.1H NMR (400 MHz, CDCl3): δ 3.74 (s, 6 H), 6.08 (d, J = 1.2 Hz, 1 H), 6.68 (d, J = 8.8 Hz, 4 H), 6.86 – 6.92 (m, 2 H), 7.01 (d, J = 8.8 Hz, 4 H), 7.15 – 7.19 (m, 1 H), 7.42 – 7.50 (m, 5 H), 7.56 – 7.60 (m, 2 H), 7.89 – 7.94 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ 55.1, 83.5, 112.4, 112.5, 113.1, 116.6, 118.3, 118.4, 120.9, 121.7, 128.2, 128.6, 128.8, 129.9, 130.5, 131.2, 131.6, 131.7, 132.5, 132.6, 136.8, 142.0, 142.1, 153.6, 158.7. 31P NMR (160 MHz, CDCl3): δ 31.1. HRMS (ESI, m/z): calcd for C35H29O5P: [M+H]+ = 561.1825; found: 561.1824。

Claims (3)

1. A method for synthesizing 4-phosphate-2H-chromene derivatives is characterized by comprising the following steps: the method comprises the steps of taking o-propargyl alcohol phenol (I) as a raw material, adding an organic solvent to dissolve at room temperature, then adding a compound containing P (O) -OH, reacting at 80 ℃ for 3-6 hours, and after the reaction is finished, separating and purifying a reaction product by silica gel column chromatography to obtain a 4-phosphate-2H-chromene derivative shown as a formula (II);
Figure 573010DEST_PATH_IMAGE001
(Ⅰ),
Figure 896675DEST_PATH_IMAGE002
(Ⅱ),
wherein R1-R4 in the formula (I) and the formula (II) are respectively and independently any one of H, CH3, F, Cl, Br and OCH 3; r5 and R6 are independently any one of aryl, alkoxy, aryloxy and alkyl; ar1 and Ar2 are aryl groups substituted by different substituents; the organic solvent is one of 1, 2-dichloroethane and nitromethane.
2. The method of claim 1, wherein the method comprises the steps of: the amount ratio of the raw material feeding substances is that the o-propargyl alcohol phenol: the compound containing P (O) -OH is 1:1.5 to 2.5.
3. The method of claim 1, wherein the method comprises the steps of: the separation and purification method comprises the following steps: adding the reaction solution into a saturated sodium bicarbonate solution, adding ethyl acetate, fully stirring, and standing for layering; extracting the separated water layer with ethyl acetate, mixing the ethyl acetate extract and the separated organic layer, washing with saturated saline solution, and drying with anhydrous sodium sulfate; the ethyl acetate solvent is removed by evaporation, and then the 4-phosphate-2H-chromene derivative is obtained by silica gel column chromatography separation and purification.
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CN110526940A (en) * 2019-08-19 2019-12-03 江西科技师范大学 A kind of preparation method of 4- (2H- chromene)-thio phosphine (phosphorus) acid esters
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528758A (en) * 2006-10-28 2009-09-09 默克专利有限公司 [(4-oxo-4h-chromen-3-yl)-hydroxy methyl]- or [(4-oxo-4h-chromen-3-yl)-methyl]-phosphonic acid derivates
CN102239164A (en) * 2008-12-05 2011-11-09 安斯泰来制药有限公司 2h-chromene compound and derivative thereof
CN108947953A (en) * 2018-05-16 2018-12-07 江西科技师范大学 A kind of synthetic method of flavone derivative
CN109232501A (en) * 2018-10-10 2019-01-18 江西科技师范大学 A kind of preparation method of 4- p-methyl benzenesulfonic acid ester -2H- chromene

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9309217B2 (en) * 2014-05-01 2016-04-12 Northwestern University Catalytic enantioselective synthesis of 2-aryl chromenes and related phosphoramidite ligands and catalyst compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101528758A (en) * 2006-10-28 2009-09-09 默克专利有限公司 [(4-oxo-4h-chromen-3-yl)-hydroxy methyl]- or [(4-oxo-4h-chromen-3-yl)-methyl]-phosphonic acid derivates
CN102239164A (en) * 2008-12-05 2011-11-09 安斯泰来制药有限公司 2h-chromene compound and derivative thereof
CN108947953A (en) * 2018-05-16 2018-12-07 江西科技师范大学 A kind of synthetic method of flavone derivative
CN109232501A (en) * 2018-10-10 2019-01-18 江西科技师范大学 A kind of preparation method of 4- p-methyl benzenesulfonic acid ester -2H- chromene

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Acid-promoted cyclization of 2-propynolphenols leading to 4-tosyloxy-2H-chromenes";Ren L. et al;《Tetrahedron Letters》;20181211;第60卷;第332页 *
"Convenient and Highly Efficient Routes to 2H-Chromene and 4-Chromanone Derivatives: Iodine-Promoted and p-Toluenesulfonic Acid Catalyzed Cascade Cyclizations of Propynols";Yi Feng Q. et al;《Chem. Eur. J》;20151231;第21卷;第3480-3487页 *
"Copper-Catalyzed Cascade Cyclization of 2-Propynolphenols :Access to 4-Phosphorylated 2H-Chromenes";Ren L. et al;《Adv.Synth. Catal》;20171231;第359卷;第3962-3967页 *

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