TRPV3 inhibitor and preparation method thereof
阅读说明：本技术 一种trpv3抑制剂及其制备方法 (TRPV3 inhibitor and preparation method thereof ) 是由 张众音 王聪聪 王克威 吕孟齐 吴晗 王君霞 孙晓颖 于 2020-12-21 设计创作，主要内容包括：本发明公开了一种TRPV3抑制剂,由R-1基团、R基团和R-2基团依次连接形成,其分子结构通式如式1所示：式1；其中,R-1基团结构式为式2,R-3选自-H、-OAc、-OH、卤基、-F-3CO或含苯磺酰氧基的基团中的任一种,R-4选自-H、-OAc或-OH中的任一种；R-2基团选自烷基或式3,R-5选自C或N,R-6选自氢、烷基、卤基或三氟甲基中的任一种,R-7选自氢、卤基、氰基、硝基或三氟甲氧基中的任一种,R-8选自氢或卤基。本发明还公开所述TRPV3抑制剂的制备方法及应用。本发明的TRPV3抑制剂能够特异性抑制TRPV3离子通道,具有巨大的科研和临床价值。(The invention discloses a TRPV3 inhibitor, consisting of R 1 Group, R group and R 2 The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1: formula 1; wherein R is 1 The radical structural formula is 2, R 3 Selected from-H, -OAc, -OH, halo, -F 3 Any one of CO or a phenylsulfonyloxy-containing group, R 4 Any one selected from-H, -OAc or-OH; r 2 The group is selected from alkyl or the formula 3, R 5 Selected from C or N, R 6 Selected from any one of hydrogen, alkyl, halogen or trifluoromethyl, R 7 Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R 8 Selected from hydrogen or halo. The invention also discloses a preparation method and application of the TRPV3 inhibitor. The TRPV3 inhibitor can specifically inhibit TRPV3 ion channel, and has great scientific research and clinical values.)
1. A TRPV3 inhibitor characterized by consisting of R1Group, R group and R2The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
wherein the content of the first and second substances,
R1the structural formula of the radical isR3Selected from-H, -OAc, -OH, halo, -F3Any one of CO or a phenylsulfonyloxy-containing group, R4Any one selected from-H, -OAc or-OH; the structural formula of the R group isR2The radicals being selected from alkyl orR5Selected from C or N, R6Selected from any one of hydrogen, alkyl, halogen or trifluoromethyl, R7Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R8Selected from hydrogen or halo.
2. The TRPV3 inhibitor according to claim 1, wherein when R in formula 24When not-H, R3Selected from-OAc, -OH, halo, -F3CO or phenylsulfonyloxy.
3. The TRPV3 inhibitor according to claim 1, wherein when R in formula 3 is5When is N, R6And R7Selected from-H or alkyl.
4. The TRPV3 inhibitor according to claim 1, wherein R is1Selected from the structural formulas
Any one of the substituent groups.
5. The TRPV3 inhibitor according to claim 1, wherein R is2Selected from the structural formula of-OH, Any one of the substituent groups.
6. The method for preparing the TRPV3 inhibitor according to claim 1, comprising:
1) dissolving an organic acid containing an R1 group and a phenol containing an R2 group in an organic solvent according to a certain proportion, adding a proper amount of EDCI and DMAP, and stirring;
2) adding a proper amount of triethylamine under ice bath, and transferring the reaction to normal temperature and stirring overnight;
3) and after the reaction is finished, quenching the reaction by using a saturated sodium bicarbonate aqueous solution, extracting, washing, drying and filtering to obtain a crude product of the TRPV3 inhibitor.
7. The method of claim 6, further comprising: 4) the resulting purified ester compound, i.e., TRPV3 inhibitor, was purified by silica gel chromatography.
8. The method of claim 6, wherein the quenched reaction in step 3) is followed by extraction with dichloromethane several times, washing with a saturated aqueous solution of sodium chloride, and drying with anhydrous sodium sulfate.
9. The method of claim 1, wherein the molar ratio of organic acid to phenol is 3: 1.5-2; the molar ratio of EDCI to DMAP is 1: 40; preferably, the first and second electrodes are formed of a metal,
the molar ratio of the organic acid to EDCI is 3: 1.6-4; preferably, the molar ratio of the organic acid to triethylamine is 1: 1-2.
10. Use of an inhibitor of TRPV3 as defined in claims 1 to 5 in the manufacture of a medicament for inhibiting the TRPV3 ion channel.
The technical field is as follows:
the invention relates to the technical field of ion channels and organic compound synthesis, in particular to a TRPV3 inhibitor and a preparation method thereof.
Background art:
transient Receptor Potential cation channels (TRPs) are an important non-selective cation channel superfamily located on cell membranes, almost everywhere in each organ of the human bodyThe expression is carried out in cells. TRP channels are divided into 6 subfamilies: TRPC (Canonical, TRPC1-7), TRPV (Vanilloid, TRPV1-6), TRPM (Melastatin, TRPM1-8), TRPP (Polycysteine, TRPP2, TRPP3, TRPP5), TRPML (Mucolipin, TRPML1-3) and TRPA (Ankyrin, TRPA 1). TRP is modulated by various factors including osmotic pressure, pH value, mechanical force, and some internal and external ligands and intracellular signal molecules, which are involved in sensory information transmission such as vision, temperature sensation, pain sensation and touch sensation in vivo, and have the function of modulating intracellular Ca2+Balance, etc. of various important physiological functions. Among them, the temperature-sensitive transient receptor potential channels include TRPV1, TRPV2, TRPV3, TRPV4, TRPM8 and TRPA1, which are expressed in cutaneous sensory neurons on the skin for sensing changes in external temperature, while TRPV1 and TRPV3 are highly expressed in keratinocytes and are likely to be associated with skin inflammation and skin barrier formation.
In 2002, Transient Receptor Potential cation channel, subfamily V, member 3(Transient Receptor Potential channel, subfamily V, member 3, TRPV3) gene was found to be located on human chromosome 17p13.2, approximately 47.5Kbs in full length, containing 18 exons. The mouse TRPV3 gene is located on chromosome 11B4, is about 30Kbs in length, and contains 18 exons. TRPV3 is encoded by a 2370 base pair open reading frame, transcribed from a gene adjacent to TRPV1 and has a 43% homology in structure to the first identified TRPV 1. However, the structure of the TRPV3 channel protein has not been resolved so far. All TRPVs appear to have a similar structure to TRPV1 cryoelectron microscopy structures that have been previously obtained, TRPV3 likewise has a tetrameric structure and has six transmembrane (S1-S6) domains, as well as an N-terminal and a C-terminal intracellular site, where a non-selective cationic pore channel structure is formed between S5 and S6, the N-terminal part of the channel containing six Ankyrin Repeats (ARs), forming Ankyrin Repeats (ARDs) involved in protein-protein interactions.
Ca2+As a very important intracellular second messenger, it is widely involved in signal transduction processes and plays an important role in various biological activities such as muscle contraction, neurotransmission, secretion of enzymes and hormones, cell cycle regulation, and apoptosis。Ca2+As the chemical basis for cellular messengers, Ca is present between the extracellular and cytoplasmic, intracellular calcium stores or between the cytoplasm2+A concentration gradient. It is generally accepted that most of the extracellular free Ca2+The concentration is 101-1010mol/L, which is Ca in cytoplasm compared with the cytoplasm in a resting state2+The concentration is 3 to 4 orders of magnitude higher. When cells are subjected to some stimulus, small amounts of extracellular Ca2+Enter the cell to make intracellular Ca2+The concentration is greatly increased, producing a calcium signal. In addition, when stimulated, intracellular calcium stores Ca2+Also released into the cytoplasm, which is another important pathway for intracellular calcium signaling.
Recent studies have shown that TRPV3 plays a direct role as a cation channel in many signaling processes. First, TRPV3 is an important pathway for intracellular calcium signaling. Extracellular Ca when TRPV3 channel located in cell membrane is opened2+Enter into cells to make intracellular Ca2+The concentration increases dramatically, activating the downstream pathway, which ion current is mainly composed of two phases: a slow first phase followed by a second phase of rapid influx produces a calcium signal. Meanwhile, the N-terminus of the TRPV3 channel contains multiple ankyrin binding sites, and interaction of ankyrin with the TRP channel inhibits inositol triphosphate (IP 3) receptor and ranoladine receptor-mediated intracellular calcium pool Ca2+And (4) releasing. Excessive calcium loading in cells can lead to cell death and skin exfoliation, leading to skin hyperkeratosis, dermatitis, and abnormal hair growth. In addition, TRPV3 on the membrane of keratinocytes can also pass Ca2+The channel forms a complex TGF-alpha/TGFR signaling complex with transforming growth factor alpha (TGF-alpha), Epidermal Growth Factor Receptor (EGFR). Activation of TGFR will result in an increase in TRPV3 channel activity, which in turn stimulates TGF- α release. Neurotransmitters, TGF- α and EGF, etc., act on G protein-coupled receptors and receptor tyrosine kinases, respectively, and activate phosphatidylinositol (IPs) signaling pathways via PLC, producing a second signal, IP3 and Diacylglycerol (DAG). It is presently believed that both of these signal pathways can stimulate the TRPV3 channel. And menthol, cinnamaldehyde and camphor which activate TRPV channel can regulate phospholipasec signaling, resulting in altered cell function.
TRPV3 is a temperature sensitive ion channel that is activated at a temperature range with an activation threshold of 33 ℃ to 37 ℃. Compared to TRPV1 and TRPVA1, it is predominantly expressed in peripheral sensory neurons and neurons directly contributing to itch-inducing activation, with lower expression in sensory Dorsal Root Ganglia (DRG) and Trigeminal Ganglia (TG), but most abundantly expressed in the skin, particularly in epidermal and hair follicle keratinocytes. Thus regulating and influencing the proliferation and differentiation of epidermal keratinocytes, hair growth, the development of sensitive dermatitis and keratoderma. When TRPV3 is activated in keratinocytes, it promotes the release of a variety of factors, including ATP, PGE2, IL-1 α, NO, TGF- α and NGF, which exacerbate the inflammatory process and also dominate the cutaneous itchy fibers, thus producing itchy skin. Therefore, the TRP channel abnormality is closely related to human diseases, and development of a high-efficiency and specific TRPV3 inhibitor is necessary for the diseases, but the research on physiological functions of TRPV3 is slow due to the lack of specific inhibitor tools in the prior art.
The invention content is as follows:
the invention aims to provide an organic compound capable of specifically inhibiting TRPV3 and a preparation method thereof.
The invention provides a TRPV3 inhibitor, consisting of1Group, R group and R2The groups are connected in sequence to form the compound, and the molecular structural general formula of the compound is shown as formula 1:
wherein the content of the first and second substances,
R1the structural formula of the radical isR3Selected from-H, -OAc, -OH, halo, -F3Any one of CO or a benzenesulfonyloxy group-containing group, R4Any one selected from-H, -OAc or-OH; r group structureIs of the formulaR2The radicals being selected from alkyl orR5Selected from C or N, R6Selected from hydrogen, alkyl, halogen
Formula 3
Any one of a group or a trifluoromethyl group, R7Selected from any one of hydrogen, halogen, cyano, nitro or trifluoromethoxy, R8Selected from hydrogen or halo.
In one embodiment according to the present invention, when R in said formula 24When not-H, R3Selected from-OAc, -OH, halo, -F3CO or a phenylsulfonyloxy group.
In one embodiment according to the present invention, in said formula 3, when R is5When is N, R6And R7Selected from-H or alkyl.
In one embodiment according to the invention, R1Selected from the structural formulas
OrAny one of the substituent groups.
In one embodiment according to the invention, said R2Selected from the structural formulas
OrAny one of the substituent groups.
Another aspect of the present invention provides a method for preparing a TRPV3 inhibitor, comprising:
1) will contain R1Organic acids of radicals and containing R2Dissolving the group phenol in an organic solvent according to a certain proportion, adding a proper amount of EDCI and DMAP, and stirring;
2) adding a proper amount of triethylamine under ice bath, and transferring the reaction to normal temperature and stirring overnight;
3) and after the reaction is finished, quenching the reaction by using a saturated sodium bicarbonate aqueous solution, extracting, washing, drying and filtering to obtain a crude product of the TRPV3 inhibitor.
In one embodiment according to the present invention, further comprising: 4) the resulting purified ester compound, i.e., TRPV3 inhibitor, was purified by silica gel chromatography.
In one embodiment according to the present invention, after quenching the reaction in step 3), it is extracted several times with dichloromethane, washed with saturated aqueous sodium chloride solution, and then dried with anhydrous sodium sulfate.
In one embodiment according to the present invention, the molar ratio of the organic acid to the phenol is 3: 1.5-2; the molar ratio of EDCI to DMAP was 1: 40. Preferably, the molar ratio of the organic acid to EDCI is 3: 1.6-4; preferably, the molar ratio of the organic acid to the triethylamine is 1: 1-2.
The invention further provides application of the TRPV3 inhibitor in preparing a reagent for inhibiting TRPV3 ion channel. Preferably, the TRPV3 inhibitor is used for the preparation of a medicament for inhibiting skin itch or inflammation caused by overexpression of TRPV 3.
The invention has the beneficial effects that:
the TRPV3 inhibitor provided by the invention can specifically inhibit a TRPV3 ion channel, can be beneficial to preparing a specific inhibiting reagent of the TRPV3 ion channel, and has a great promoting effect on the research on the properties and characteristics of the TRPV3 ion channel. Meanwhile, the medicine for treating diseases related to enhancement of the TRPV3 ion channel activity can also be prepared. Therefore, the TRPV3 inhibitor provided by the invention has great value for scientific research and clinical research.
The specific implementation mode is as follows:
the following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention and to clearly define the scope of the invention.
EXAMPLE 13 Synthesis of- (trifluoromethoxy) phenylcinnamate
3- (trifluoromethoxy) phenyl cinnamate (3- (trifluoromethyl) cinnamate) having the following chemical formula:
product(s)1H NMR(500MHz,CDCl3)δ7.87(d,J＝16.0Hz,1H),7.60–7.58(m,2H),7.47–7.39(m,3H),7.25(d,J＝ 2.5Hz,2H),7.22–7.16(m,2H),6.61(d,J＝16.0Hz,1H).13C NMR(101MHz,MeOD)δ164.32,161.04,152.35,147.93, 135.22,130.15,129.76,127.94,128.76,128.64,128.57,128.45,115.56,113.93,111.15,107.75.[M+H]+＝309.0733.
The synthetic route is as follows:
cinnamic acid (200mg, 1.5mmol), p-trifluoromethoxyphenol (160.3mg, 0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out at room temperature and dissolved in 6mL of dichloromethane, and triethylamine (0.25mL, 1.8mmol) was added with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. Concentrating the filtrate, and purifying by column chromatographyThe eluent was EtOAc, peloleum ether ═ 1:15, giving the compound as a white powder in 92% yield.
EXAMPLE 2 Synthesis of (E) -4- (3- (3-cyanophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (3-cyanophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E)-4-(3-(3-cyanophenoxy)-3-oxoprop-1-en-1-yl)-1,2-phenylene diacetate
Product(s)1H NMR(500MHz,CDCl3)δ7.83(d,J＝16.0Hz,1H),7.62–7.50(m,3H),7.50–7.41(m,3H),7.30–7.27 (m,1H),6.56(d,J＝16.0Hz,1H),2.32(d,J＝3.6Hz,6H).13C NMR(101MHz,MeOD)δ169.14,169.03,164.33,152.06, 147.92,143.27,142.54,131.27,129.83,129.02,126.45,125.97,125.23,123.87,122.99,118.62,115.54,113.25,20.39, 20.32.[M+H]+＝366.0973.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), m-cyanophenol (83mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of dichloromethane, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases are combined and saturated NaClThe aqueous solution was washed (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 80% yield.
EXAMPLE 3 Synthesis of (E) -4- (3- (3-Nitrophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (3-nitrophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester (E) -4- (3- (3-nitrophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetate
Product(s)1H NMR(500MHz,CDCl3)δ8.15–8.13(m,1H),8.09(t,J＝2.1Hz,1H),7.85(d,J＝16.0Hz,1H),7.60(t,J＝ 8.1Hz,1H),7.55–7.53(m,1H),7.51–7.43(m,2H),7.29(d,J＝8.3Hz,1H),6.58(d,J＝16.0Hz,1H),2.33(d,J＝4.0 Hz,6H).13C NMR(101MHz,MeOD)δ169.14,169.03,164.35,152.23,148.37,147.95,143.27,142.52,131.25,130.06, 127.71,126.48,123.85,122.99,120.74,117.22,115.58,20.39,20.32.[M+H]+＝386.0870.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated, and the concentrate (300mg, 1.06mmol), m-nitrophenol (97mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of dichloromethane, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring, followed by stirringAnd (4) at night. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 81% yield.
Example 4(E) -4- (3- ((4-methylbenzyl) oxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- ((4-methylbenzyl) oxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester (E) -4- (3- ((4-methylb-henyl) oxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetate
Product(s)1H NMR(500MHz,CDCl3)δ7.64(d,J＝16.0Hz,1H),7.39(dd,J＝8.4,2.0Hz,1H),7.34(d,J＝1.9Hz,1H), 7.30(d,J＝7.9Hz,2H),7.20(dd,J＝9.5,8.4Hz,3H),6.41(d,J＝16.0Hz,1H),5.20(s,2H),2.36(s,3H),2.30(d,J＝2.7 Hz,6H).
13C NMR(101MHz,MeOD)δ169.14,169.03,166.57,143.63,143.25,142.52,137.36,133.17,131.22,129.35, 129.27,127.01,127.12,126.47,123.84,122.98,118.02,65.98,21.36,20.34.[M+H]+＝369.1335.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. Concentrating the filtrate, and weighingThe condensate (300mg, 1.06mmol), 4-methylbenzyl alcohol (85.5mg, 0.7mmol), EDCI (268mg, 1.4mmol), and DMAP (4.3mg, 0.035mmol) were dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added with stirring, followed by stirring overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 81% yield.
EXAMPLE 5 Synthesis of (E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetic acid ester (E) -4- (3-oxo-3- (p-tolyloxy) prop-1-en-1-yl) -1, 2-phenylenediacetate
Product(s)1H NMR(500MHz,CDCl3)δ7.79(d,J＝16.0Hz,1H),7.46(dd,J＝8.4,1.6Hz,1H),7.42(d,J＝1.5Hz,1H), 7.28–7.23(m,1H),7.20(d,J＝8.2Hz,2H),7.05(d,J＝8.3Hz,2H),6.57(d,J＝16.0Hz,1H),2.36(s,3H),2.31(d,J＝ 4.1Hz,6H).
13C NMR(101MHz,MeOD)δ169.14,169.03,164.35,148.32,147.97,143.22,142.57,135.24,131.24,129.43, 129.26,126.43,123.88,122.95,121.56,121.39,115.54,21.37,20.39,20.32.[M+H]+＝355.1176.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Placing ice blocks in the reaction system, passing through 2N HClAdjusting to pH 2, extracting with EA/THF 3:1(3 × 20mL), combining the organic phases, washing with saturated aqueous NaCl (2 × 20mL), filtering, and then adding anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), 4-methylphenol (76mg, 0.7mmol), EDCI (268mg, 1.4mmol), and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of dichloromethane, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 81% yield.
Example 6(E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester (E) -4- (3- (4-isopropylphenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetate
Product(s)1H NMR(500MHz,CDCl3)δ7.79(d,J＝16.0Hz,1H),7.46(d,J＝8.4Hz,1H),7.42(s,1H),7.26(s,1H),7.25 (d,J＝2.3Hz,2H),7.08(d,J＝8.4Hz,2H),6.57(d,J＝16.0Hz,1H),2.95–2.90(m,1H),2.32(d,J＝3.7Hz,6H),1.26 (d,J＝6.9Hz,6H).13C NMR(101MHz,MeOD)δ169.14,169.03,164.35,148.58,147.93,145.24,143.27,142.58,131.23, 126.55,126.49,126.41,123.88,122.95,121.33,115.55,33.28,23.34,23.25,20.37,20.28.[M+H]+＝383.1490.
The synthetic route is as follows:
at 0 deg.C, takingCaffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution, and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), 4-isopropylphenol (95mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 83% yield.
Example 7(E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester (E) -4- (3- (3-fluorophenoxy) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetate
Product(s)1H NMR(500MHz,CDCl3)δ7.80(d,J＝16.0Hz,1H),7.47(d,J＝8.4Hz,1H),7.43(s,1H),7.36(dd,J＝15.1, 7.5Hz,1H),7.27(d,J＝8.1Hz,1H),6.96(dd,J＝15.1,8.9Hz,3H),6.55(d,J＝16.0Hz,1H),2.32(d,J＝3.8Hz,6H).
13C NMR(101MHz,MeOD)δ169.14,169.03,164.34,163.36,152.93,147.97,143.28,142.52,131.26,129.42,126.46, 123.87,122.93,117.22,115.57,112.38,109.71,20.37,20.28.[M+H]+＝359.0924.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), m-fluorophenol (78.5mg, 0.7mmol), EDCI (268mg, 1.4mmol) and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.19mL, 1.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 82% yield.
EXAMPLE 8 Synthesis of (E) -4- (3- (2-methylpyridin-4-yl) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester
(E) -4- (3- (2-methylpyridin-4-yl) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetic acid ester (E) -4- (3- (2-methylpyridin-4-yl) -3-oxoprop-1-en-1-yl) -1, 2-phenylenediacetate
Product(s)1H NMR(500MHz,CDCl3)δ8.39(d,J＝2.1Hz,1H),7.82(d,J＝16.0Hz,1H),7.47(dd,J＝15.6,8.9Hz,3H), 7.28(s,1H),7.23(d,J＝8.4Hz,1H),6.57(d,J＝16.0Hz,1H),2.60(s,3H),2.32(d,J＝3.8Hz,6H).13C NMR(101MHz, MeOD)δ169.14,169.03,164.36,152.02,149.47,147.92,143.22,142.57,131.23,131.12,126.76,126.47,123.85,123.76, 122.91,115.57,23.97,20.37,20.28.[M+H]+＝356.1140.
The synthetic route is as follows:
caffeic acid (500mg,2.8mmol) and DMAP (8.5mg,0.07mmol) were placed in 1.4mL pyridine solution at 0 ℃ and acetic anhydride (0.7mL,7mmol) was added and stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (300mg, 1.06mmol), 3-hydroxy-6-methylpyridine (76.4mg, 0.7mmol), EDCI (268mg, 1.4mmol), and DMAP (4.3mg, 0.035mmol) were weighed out and dissolved in 6mL of dichloromethane, and triethylamine (0.19mL, 1.4mmol) was added thereto under stirring, followed by stirring overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 80% yield.
Example 9 Synthesis of (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate
(E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate (E) -3-cyanophenyl 3- (3,4-dihydroxyphenyl) acrylate
Product(s)1H NMR(400MHz,MeOD)δ7.79(d,J＝15.9Hz,1H),7.69–7.58(m,3H),7.56–7.49(m,1H),7.15(d,J＝ 2.0Hz,1H),7.06(dd,J＝8.2,2.0Hz,1H),6.84(d,J＝8.2Hz,1H),6.50(d,J＝15.8Hz,1H).13C NMR(101MHz,MeOD) δ165.46,151.32,148.89,148.14,145.57,130.36,129.14,126.81,126.02,125.33,122.21,117.52,115.19,114.03,112.89, 112.01.[M+H]+＝282.0770.
The synthetic route is as follows:
caffeic acid (200mg, 1.11mmol), m-cyanophenol (88mg, 0.74mmol), EDCI (284mg, 1.48mmol) and DMAP (4.5mg, 0.037mmol) were weighed out at room temperature and dissolved in 6mL of dichloromethane, and triethylamine (0.2mL, 1.48mmol) was added with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:15 to give the compound as a white powder in 88% yield.
Example 10(E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate
(E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate (E) -4-methylbenzyl 3- (3,4-dihydroxyphenyl) acrylate
Product(s)1H NMR(400MHz,MeOD)δ7.57(d,J＝15.9Hz,1H),7.29(d,J＝8.0Hz,2H),7.19(d,J＝7.9Hz,2H),7.04 (d,J＝2.0Hz,1H),6.94(dd,J＝8.2,2.0Hz,1H),6.77(d,J＝8.2Hz,1H),6.29(d,J＝15.9Hz,1H),5.16(s,2H),2.34(s, 3H).13C NMR(101MHz,MeOD)δ169.29,149.84,147.33,147.02,139.32,134.99,130.35,129.56,127.90,123.21, 116.69,115.33,115.22,67.32,21.43.[M+H]+＝285.1120.
The synthetic route is as follows:
at room temperature, caffeic acid (A) is weighed200mg, 1.11mmol), p-methylbenzyl alcohol (90mg, 0.74mmol), EDCI (284mg, 1.48mmol), and DMAP (4.5mg, 0.037mmol) were dissolved in 6mL of a dichloromethane solution, and triethylamine (0.2mL, 1.48mmol) was added thereto with stirring, and the mixture was stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give the compound as a white powder in 91% yield.
EXAMPLE 11 Synthesis of (E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -3-fluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -3-fluoropentyl 3- (4-acetoxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.85(d,J＝16.0Hz,1H),7.61(d,J＝8.1Hz,2H),7.37(dd,J＝15.2,7.6Hz,1H), 7.17(d,J＝8.0Hz,2H),7.03-6.90(m,3H),6.57(d,J＝16.0Hz,1H),2.33(s,3H).13C NMR(101MHz,MeOD)δ169.24, 164.37,163.34,152.92,150.56,147.94,132.02,129.68,129.55,129.47,121.53,121,46,117.28,115.59,112.34,109.78, 20.34.[M+H]+＝301.0880.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL, 2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. Concentrating the filtrateThen, the concentrate (373mg, 1.83mmol), m-fluorophenol (134.5mg,1.2mmol), EDCI (460mg,2.4mmol) and DMAP (7.4mg,0.06mmol) were weighed out and dissolved in 8mL of a dichloromethane solution, and triethylamine (0.33mL,2.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white powder in 83% yield.
EXAMPLE 12 Synthesis of (E) -4-fluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -4-fluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -4-fluoropentyl 3- (4-acetoxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.84(d,J＝16.0Hz,1H),7.61(d,J＝8.5Hz,2H),7.19-7.05(m,6H),6.57(d,J＝ 16.0Hz,1H),2.33(s,3H).13C NMR(101MHz,MeOD)δ169.24,164.35,159.76,150.53,147.93,146.97,132.08,129.67, 129.56,123.26,123.14,121.57,121,48,115.95,115.87,115.56,20.35.[M+H]+＝301.0870.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL, 2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (373mg, 1.83mmol) was weighed,4-fluorophenol (134.5mg,1.2mmol), EDCI (460mg,2.4mmol) and DMAP (7.4mg,0.06mmol) were dissolved in 8mL of a dichloromethane solution, and triethylamine (0.33mL,2.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white powder in 81% yield.
Example 13(E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate
(E) -4- (trifluoromethyl) phenyl 3- (4-acetoxyphenyl) acrylate (E) -4- (trifluoromethylphenyl) phenyl 3- (4-acetoxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.87(d,J＝16.0Hz,1H),7.68(d,J＝8.5Hz,2H),7.62(d,J＝8.6Hz,2H),7.31 (d,J＝8.6Hz,2H),7.18(d,J＝8.5Hz,2H),6.59(d,J＝16.0Hz,1H),2.33(s,3H).13C NMR(101MHz,MeOD)δ169.23, 164.35,154.63,150.56,147.97,132.03,129.67,129.59,127.83,127.65,127.53,124.15,121.94,129.87,121.57,121.48, 115.52,20.36.[M+H]+＝351.0841.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL, 2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. After the filtrate is concentratedThe concentrate (373mg, 1.83mmol), p-trifluoromethylphenol (194.5mg,1.2mmol), EDCI (460mg,2.4mmol) and DMAP (7.4mg,0.06mmol) were weighed out and dissolved in 8mL of a dichloromethane solution, and triethylamine (0.33mL,2.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white powder in 85% yield.
EXAMPLE 14 Synthesis of (E) -2-chloro-4-fluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -2-chloro-4-fluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -2-chloro-4-fluorophenonyl 3- (4-acetoxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.89(d,J＝16.0Hz,1H),7.62(d,J＝8.5Hz,2H),7.25–7.14(m,4H),7.06– 6.99(m,1H),6.61(d,J＝16.0Hz,1H),2.33(s,3H).
13C NMR(101MHz,MeOD)δ169.25,164.35,161.12,150.56,147.92,143.06,132.03,131.58,129.64,129.35, 124.63,121.56,121.48,118.26,115.58,114.09,20.34.[M+H]+＝335.0485.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL, 2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2 × 20mL), filtered and washed with anhydrous NaClWater Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (373mg, 1.83mmol), 2-chloro-4-fluorophenol (175.9mg,1.2mmol), EDCI (460mg,2.4mmol) and DMAP (7.4mg,0.06mmol) were weighed out and dissolved in 8mL of dichloromethane solution, and triethylamine (0.33mL,2.4mmol) was added under stirring and stirred overnight. Saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:12 to give the compound as a white powder in 86% yield.
Example 15 Synthesis of (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate
(E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate (E) -3,4-difluorophenyl 3- (4-acetoxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.84(d,J＝16.0Hz,1H),7.61(d,J＝8.5Hz,2H),7.19(dd,J＝18.6,8.8Hz,3H), 7.10–7.02(m,1H),6.95–6.89(m,1H),6.55(d,J＝16.0Hz,1H),2.33(s,3H).13C NMR(101MHz,MeOD)δ169.23, 164.34,150.52,149.96,148.57,147.93,146.37,132.08,129.64,126.27,121.55,121.38,118.85,117.59,115.53,111.34, 20.33.[M+H]+＝319.0780.
The synthetic route is as follows:
4-Hydroxycinnamic acid (300mg,1.83mmol) and DMAP (22mg,0.18mmol) were put in 1.5mL of a pyridine solution at 0 ℃ and acetic anhydride (0.22mL, 2.28mmol) was added and the mixture was stirred for 2 hours. Ice cubes were placed in the reaction system, adjusted to pH 2 by 2N HCl, extracted with EA/THF 3:1(3 × 20mL), the organic phases combined and washed with saturated aqueous NaCl solution (2 prepared in20mL), filtered and then treated with anhydrous Na2SO4And (5) drying. After the filtrate was concentrated, the concentrate (373mg, 1.83mmol), 3, 4-difluorophenol (156mg,1.2mmol), EDCI (460mg,2.4mmol), and DMAP (7.4mg,0.06mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.33mL,2.4mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as a white powder in 80% yield.
EXAMPLE 16 Synthesis of (E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate
(E) -4-fluorophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate (E) -4-fluorophenyl 3- (4- (trifluoromethyloxy) phenyl) acrylate
Product(s)1H NMR(400MHz,CDCl3)δ7.64(d,J＝8.7Hz,2H),7.58–7.50(m,3H),7.48(d,J＝16.0Hz,1H),7.47– 7.43(m,1H),7.28(d,J＝8.4Hz,2H),6.31(d,J＝16.0Hz,1H).13C NMR(101MHz,MeOD)δ164.34,159.72,149.86, 147.93,146.94,130.24,130.08,129.74,127.54,123.25,123.11,115.95,115.67,115.57,114.22,114.05. [M+H]+＝327.0642.
The synthetic route is as follows:
p-trifluoromethoxycinnamic acid (200mg, 0.86mmol), 4-fluorophenol (64mg, 0.57mmol), EDCI (220mg, 1.15mmol) and DMAP (3.5mg, 0.029mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.16mL, 1.15mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 90% yield.
EXAMPLE 17 Synthesis of (E) -4-methylbenzyl 3- (4- (trifluoromethoxy) phenyl) acrylate
(E) -4-methylbenzyl 3- (4- (trifluoromethoxy) phenyl) acrylate (E) -4-methylbenzyl 3- (4- (trifluoromethloxy) phenyl) acrylate
Product(s)1H NMR(400MHz,CDCl3)δ7.68(d,J＝16.0Hz,1H),7.55–7.52(m,2H),7.31(d,J＝8.0Hz,2H),7.21(t,J ＝8.7Hz,4H),6.44(d,J＝16.0Hz,1H),5.21(s,2H),2.37(s,3H).13C NMR(101MHz,CDCl3)δ166.52,150.44,143.27, 138.26,133.01,132.91,129.52,129.33,128.54,121.67,121.16,121.16,119.10,118.99,66.52,21.23.[M+H]+＝337.1046.
The synthetic route is as follows:
p-trifluoromethoxycinnamic acid (263mg, 1.13mmol), 4-methylbenzyl alcohol (92mg, 0.75mmol), EDCI (288mg, 1.5mmol) and DMAP (4.6mg, 0.038mmol) were weighed out at room temperature and dissolved in 6mL of dichloromethane, and triethylamine (0.2mL, 1.5mmol) was added with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. Concentrating the filtrate, and separating and purifying by column chromatography, wherein the eluent is EtOAc (petroleum ether): 1:50, to obtain white powderCompound, yield 88%.
EXAMPLE 18 Synthesis of (E) -3-cyanophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate
(E) -3-cyanophenyl 3- (4- (trifluoromethoxy) phenyl) acrylate (E) -3-cyanophenyl 3- (4- (trifluoromethloxy) phenyl) acrylate
Product(s)1H NMR(400MHz,CDCl3)δ7.87(d,J＝16.0Hz,1H),7.64(d,J＝8.7Hz,2H),7.58–7.50(m,3H),7.47– 7.43(m,1H),7.28(d,J＝8.4Hz,2H),6.59(d,J＝16.0Hz,1H).13C NMR(101MHz,CDCl3)δ164.38,150.99,150.97, 150.84,145.92,132.39,130.44,129.94,129.60,126.63,125.42,121.65,121.27,119.08,117.88,117.25,113.53. [M+H]+＝334.0690.
The synthetic route is as follows:
p-trifluoromethoxycinnamic acid (200mg, 0.86mmol), m-cyanophenol (68mg, 0.57mmol), EDCI (220mg, 1.15mmol) and DMAP (3.5mg, 0.029mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.16mL, 1.15mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 91% yield.
EXAMPLE 19 Synthesis of (E) -4-fluorophenyl 3- (4-fluorophenyl) acrylate
(E) -4-fluorophenyl 3- (4-fluorophenyl) acrylate (E) -4-fluoropentyl 3- (4-fluoropentyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.72(d,J＝8.2Hz,2H),7.48(d,J＝15.9Hz,1H),7.21(d,J＝8.3Hz,2H),7.19 (d,J＝8.3Hz,2H),7.27(d,J＝8.2Hz,2H),6.31(d,J＝15.9Hz,1H).13C NMR(101MHz,MeOD)δ164.33,162.14, 159.71,147.95,146.92,130.86,130.44,130.28,123.24,123.16,115.94,115.74,115.53,115.45,115.27. [M+H]+＝261.0730.
The synthetic route is as follows:
p-fluorocinnamic acid (210mg, 1.26mmol), 4-fluorophenol (94mg, 0.84mmol), EDCI (323mg, 1.685mmol) and DMAP (5.1mg, 0.042mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.23mL, 1.68mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:80 to give the compound as a white powder in 94% yield.
EXAMPLE 20 Synthesis of 4-methylbenzyl (E) -4- (3-fluorophenyl) acrylate
(E) 4-methylbenzyl (E) -4-methylb enzyl 3- (4-fluorophenyl) acrylate-4- (3-fluorophenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.72(d,J＝8.0Hz,2H),7.48(d,J＝15.9Hz,1H),7.21(d,J＝8.3Hz,2H),7.19 (d,J＝8.3Hz,2H),7.16(d,J＝8.0Hz,2H),6.31(d,J＝15.9Hz,1H),5.16(s,2H),2.34(s,3H).13C NMR(101MHz, MeOD)δ166.52,162.15,143.62,137.32,133.16,130.87,130.44,130.27,129.24,129.09,127.05,126.78,118.02,115.43, 115.29,115,18,65.97,21.34.[M+H]+＝271.1130.
The synthetic route is as follows:
p-fluorocinnamic acid (210mg, 1.26mmol), 4-methylbenzyl alcohol (103mg, 0.84mmol), EDCI (323mg, 1.685mmol) and DMAP (5.1mg, 0.042mmol) were weighed out at room temperature and dissolved in 6mL of a dichloromethane solution, and triethylamine (0.23mL, 1.68mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder in 89% yield.
EXAMPLE 21 Synthesis of (E) -3-cyanophenyl 3- (4-fluorophenyl) acrylate
(E) -3-cyanophenyl 3- (4-fluorophenyl) acrylate (E) -3-cyanophenyl 3- (4-fluorophenyl) acrylate
Product(s)1H NMR(400MHz,CDCl3)δ7.87(d,J＝16.0Hz,1H),7.64(d,J＝8.7Hz,2H),7.58–7.50(m,3H),7.47– 7.43(m,1H),7.28(d,J＝8.4Hz,2H),6.31(d,J＝16.0Hz,1H).13C NMR(101MHz,MeOD)δ164.34,162.12,152.05, 147.92,130.86,130.45,130.27,129.83,129.07,125.93,125.27,118.62,115.57,115.43,115.13,113.0.[M+H]+＝268.0774.
The synthetic route is as follows:
p-fluorocinnamic acid (213mg, 1.28mmol), m-cyanophenol (101mg, 0.85mmol), EDCI (325mg, 1.7mmol) and DMAP (5.2mg, 0.042mmol) were weighed out and dissolved in 6mL of dichloromethane at room temperature, and triethylamine (0.24mL, 1.7mmol) was added with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder in 90% yield.
EXAMPLE 22 Synthesis of (E) -2-chloro-4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
(E) -2-chloro-4-fluorophenyl 3- (4-hydroxyphenyl) acrylate (E) -2-chloro-4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.89(d,J＝16.0Hz,1H),7.62(d,J＝8.5Hz,2H),7.25–7.14(m,4H),7.06– 6.99(m,1H),6.61(d,J＝16.0Hz,1H).13C NMR(101MHz,MeOD)δ164.33,161.15,157.72,147.97,143.02,131.55, 130.64,130.38,127.87,124.64,118.29,115.85,115.67,115.53,114.08.[M+H]+＝293.0381.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL) withThe combined phases were washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (380mg,1.36mmol), 2-chloro-4-fluorophenol (132mg,0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.25mL, 1.8mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (297mg,0.73mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.045mL, 0.8mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (253.3mg,0.8mmol) was added, and the mixture was allowed to warm to room temperature for 1 hour. Quenching with saturated aqueous sodium bicarbonate (20mL), extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography using EtOAc in a ratio of 1:5 to give a white solid compound in 82% yield.
Example 23 Synthesis of (E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate
(E) -4- (trifluoromethyl) phenyl 3- (4-hydroxyphenyl) acrylate (E) -4- (trifluoromethylphenyl) phenyl 3- (4-hydroxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.84(d,J＝15.9Hz,1H),7.68(d,J＝8.3Hz,2H),7.51(d,J＝8.3Hz,2H),7.30 (d,J＝8.2Hz,2H),6.88(d,J＝8.2Hz,2H),6.49(d,J＝15.9Hz,1H).13C NMR(101MHz,MeOD)δ164.36,157.74, 154.67,147.94,130.65,130.48,127.85,127.69,127.63,127.38,124.17,121.96,121.69,115.82,115.68,115.54. [M+H]+＝309.0742.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (380mg,1.36mmol), 4-trifluoromethylphenol (146mg,0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.25mL, 1.8mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (195mg,0.46mmol) was dissolved in 4mL THF at 0 deg.C, acetic acid (0.029mL, 0.5mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (160mg,0.5mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenching with saturated aqueous sodium bicarbonate (20mL), extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give the compound as a white solid in 78% yield.
EXAMPLE 24 Synthesis of (E) -4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
(E) -4-fluorophenyl 3- (4-hydroxyphenyl) acrylate (E) -4-fluorophenyl 3- (4-hydroxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.81(d,J＝15.9Hz,1H),7.50(d,J＝8.3Hz,2H),7.14–7.04(m,4H),6.87(d,J ＝8.3Hz,2H),6.47(d,J＝15.9Hz,1H).13C NMR(101MHz,MeOD)δ164.35,159.73,157.76,147.93,146.93,130.65, 130.47,127.86,123.26,123.11,115.95,115.89,115.83,115.67,115.52.[M+H]+＝259.0772.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (290mg,1mmol), 4-fluorophenol (77mg,0.69mmol), EDCI (266mg, 1.39mmol) and DMAP (4.2mg,0.034mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.2mL,1.39mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (243mg,0.65mmol) was dissolved in 5mL THF solution at 0 deg.C, acetic acid (0.041mL,0.72mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (226mg,0.72mmol), and the reaction mixture was allowed to cool to room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white solid in 83% yield.
EXAMPLE 25 Synthesis of (E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate
(E) -3-fluorophenyl 3- (4-hydroxyphenyl) acrylate (E) -3-fluoropentyl 3- (4-hydroxypentyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.81(d,J＝15.9Hz,1H),7.50(d,J＝8.3Hz,2H),7.36(dd,J＝14.8,7.9Hz,1H), 7.00–6.91(m,3H),6.87(d,J＝8.4Hz,2H),6.47(d,J＝15.9Hz,1H).13C NMR(101MHz,MeOD)δ164.34,163.36, 157.72,152.97,147.92,130.65,130.28,129.43,127.86,117.22,115.86,115.65,115.57,112.31,109.76.[M+H]+＝59.0773.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (290mg,1mmol), m-fluorophenol (77mg,0.69mmol), EDCI (266mg, 1.39mmol), DMAP (4.2mg,0.034mmol) were weighed out and dissolved in 8mL of dichloromethaneTo the solution, triethylamine (0.2mL,1.39mmol) was added under stirring, and the mixture was stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (185mg,0.5mmol) was dissolved in 4mL THF at 0 deg.C, acetic acid (0.031mL,0.55mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (172mg,0.55mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white solid in 78% yield.
Example 26 Synthesis of 4-methylbenzyl (E) -3- (4-hydroxyphenyl) acrylate
(E) 4-methylbenzyl (E) -4-methylidenyl 3- (4-hydroxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.65(d,J＝16.0Hz,1H),7.42(d,J＝8.3Hz,2H),7.31(d,J＝7.6Hz,2H),7.19 (d,J＝7.5Hz,2H),6.83(d,J＝8.2Hz,2H),6.33(d,J＝15.9Hz,1H),5.20(s,2H),2.36(s,3H).13C NMR(101MHz, MeOD)δ166.53,157.77,143.63,137.34,133.17,130.64,130.28,129.28,129.01,127.88,127.03,126.84,118.03,115.84, 115.67,65.96,21.38.[M+H]+＝269.1177.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (340mg,1.22mmol), 4-methylbenzyl alcohol (98mg,0.8mmol), EDCI (310.6mg,1.62mmol) and DMAP (5mg,0.04mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.23mL, 1.62mmol) was added with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:50 to give the compound as a white powder. The product (247mg,0.65mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.04mL, 0.71mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (224mg,0.71mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:6 to give the compound as a white solid in 79% yield.
EXAMPLE 27 Synthesis of (E) -3-cyanophenyl 3- (4-hydroxyphenyl) acrylate
(E) -3-cyanophenyl 3- (4-hydroxyphenyl) acrylate (E) -3-cyanophenyl 3- (4-hydroxyphenyl) acrylate
Product(s)1H NMR(400MHz,CDCl3)δ7.83(d,J＝15.9Hz,1H),7.58–7.48(m,5H),7.46–7.41(m,1H),6.93–6.85 (m,2H),6.47(d,J＝15.9Hz,1H).13C NMR(101MHz,DMSO)δ165.42,160.95,151.23,147.98,131.39,130.25,128.04, 126.29,125.32,118.47,116.38,112.90,112.73.[M+H]+＝266.0818.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (340mg,1.22mmol), m-cyanophenol (95.3mg,0.8mmol), EDCI (310.6mg,1.62mmol) and DMAP (5mg,0.04mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.23mL, 1.62mmol) was added under stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (188mg,0.5mmol) was dissolved in 5mL THF at 0 deg.C, acetic acid (0.031mL, 0.54mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (172mg,0.54mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with ethyl acetate (3X 20mL), combined organic phases and washed with saturated aqueous NaCl (2X 20mL), filtered and then with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography using EtOAc, petroleum ether 1:2 to give a white solid compound in 84% yield.
EXAMPLE 28 Synthesis of (E) -3,4-difluorophenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate
(E) -3,4-difluorophenyl 3- (4- (tosyloxy) phenyl) acrylate (E) -3,4-difluorophenyl 3- (4- (tosyloxy) phenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.79(d,J＝16.0Hz,1H),7.73(d,J＝8.1Hz,2H),7.51(d,J＝8.4Hz,2H),7.33 (d,J＝8.0Hz,2H),7.19(dd,J＝18.7,9.2Hz,1H),7.09-7.02(m,3H),6.91(d,J＝8.9Hz,1H),6.53(d,J＝16.0Hz,1H), 2.46(s,3H).
13C NMR(101MHz,DMSO)δ164.92,150.98,150.82,149.17,148.51,148.37,146.48,145.73,133.44,131.75, 130.91,130.78,128.74,123.10,119.31,118.29,118.26,118.07,112.72,112.53,21.65.[M+H]+＝431.0760.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (540mg,1.94mmol), 3, 4-difluorophenol (168mg,1.29mmol), EDCI (496.5mg,2.59mmol) and DMAP (7.9mg,0.065mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.36mL, 2.59mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL) was extracted,the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (673mg,1.72mmol) was dissolved in 10mL THF at 0 deg.C, acetic acid (0.11mL, 1.9mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (598mg,1.9mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenching with saturated aqueous sodium bicarbonate (20mL), extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. Concentrating the filtrate, separating and purifying by column chromatography, wherein the eluent is EtOAc (petroleum ether): 1:6, and concentrating. The concentrate (165mg,0.6mmol) was dissolved in 5mL of dichloromethane at room temperature, triethylamine (0.17mL,1.2mmol) was added dropwise, p-toluenesulfonyl chloride (121mg,1.2mmol) was added dropwise, and the mixture was stirred for 8 hours. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with dichloromethane (3X 20mL), combined organic phases washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:7 to give a white powder in 73% yield.
Example 29(E) -4- (trifluoromethyl) phenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate
(E) -4- (trifluoromethyl) phenyl 3- (4- (toluenesulfonyloxy) phenyl) acrylate (E) -4- (trifluoromethyl) phenyl 3- (4- (tosyloxy) phenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.82(d,J＝16.0Hz,1H),7.73(d,J＝8.2Hz,2H),7.68(d,J＝8.4Hz,2H),7.52 (d,J＝8.4Hz,2H),7.34(d,J＝8.0Hz,2H),7.29(d,J＝8.3Hz,2H),7.07(d,J＝8.5Hz,2H),6.56(d,J＝16.0Hz,1H), 2.47(s,3H).
13C NMR(101MHz,DMSO)δ164.79,153.85,151.00,146.47,145.86,133.44,132.14,131.74,130.94,130.77, 130.70,128.74,128.66,128.55,127.42,127.39,127.15,126.83,125.85,123.39,123.10,122.17,118.33,21.65. [M+H]+＝463.0829.
The synthetic route is as follows:
4-Hydroxycinnamic acid (400mg,2.4mmol) and imidazole (415mg,6.1mmol) were placed in 3mL DMF at 0 deg.C, and tert-butyldimethylsilyl chlorosilane (918mg,6.1mmol) was added with stirring and stirred for 2 hours. Placing ice cubes in the reaction system, extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl solution (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:5 to give an oily concentrate. The concentrate (380mg,1.36mmol), 4-trifluoromethylphenol (146mg,0.9mmol), EDCI (345mg,1.8mmol) and DMAP (5.5mg,0.045mmol) were weighed out and dissolved in 8mL of dichloromethane, and triethylamine (0.25mL, 1.8mmol) was added thereto with stirring and stirred overnight. Adding saturated NaHCO3Quench the reaction with aqueous solution (20mL), CH2Cl2(3X 20mL), the organic phases were combined and washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:20 to give the compound as a white powder. The product (195mg,0.46mmol) was dissolved in 4mL THF at 0 deg.C, acetic acid (0.029mL, 0.5mmol) was added dropwise, tetrabutylammonium fluoride trihydrate (160mg,0.5mmol) was added, and the mixture was allowed to stand at room temperature for 1 hour. Quenching with saturated aqueous sodium bicarbonate (20mL), extracting with ethyl acetate (3X 20mL), combining the organic phases, washing with saturated aqueous NaCl (2X 20mL), filtering, and adding anhydrous Na2SO4And (5) drying. Concentrating the filtrate, separating and purifying by column chromatography, wherein the eluent is EtOAc (petroleum ether): 1:5, and concentrating. The concentrate (123mg,0.4mmol) was dissolved in 5mL of dichloromethane at room temperature, triethylamine (0.11mL,0.8mmol) was added dropwise, andp-methylbenzenesulfonyl chloride (152.5mg,0.8mmol) was added and stirred for 8 hours. Quenched with saturated aqueous sodium bicarbonate (20mL), extracted with dichloromethane (3X 20mL), combined organic phases washed with saturated aqueous NaCl (2X 20mL), filtered and washed with anhydrous Na2SO4And (5) drying. The filtrate was concentrated and purified by column chromatography eluting with EtOAc, petroleum ether 1:10 to give a white powder in 77% yield.
Example 30(E) Synthesis of methyl 3- (4-hydroxyphenyl) acrylate
(E) Methyl 3- (4-hydroxyphenyl) acrylate (E) -methyl 3- (4-hydroxyphenyl) acrylate
Product(s)1H NMR(500MHz,CDCl3)δ7.64(d,J＝16.0Hz,1H),7.43(d,J＝8.6Hz,2H),6.84(d,J＝8.5Hz,2H),6.30 (d,J＝15.9Hz,1H),5.18(s,1H),3.80(s,3H).
13C NMR(101MHz,DMSO)δ166.52,157.76,143.64,130.68,130.48,127.83,115.89,115.68,115.17,52.05. [M+H]+＝179.0703.
4-Hydroxycinnamic acid (1mmol,164mg) was dissolved in anhydrous methanol (5mL), sulfuric acid (1 drop) was added with stirring at room temperature, and the reaction was heated to reflux for 24 hours. The mixture was cooled and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (30mL) and washed with saturated aqueous sodium bicarbonate (20mL) and saturated aqueous NaCl (2X 20 mL). Filtering, adding anhydrous Na2SO4Drying, concentrating the filtrate, and separating and purifying by column chromatography, wherein the eluent is EtOAc, petroleum ether 1:5, to obtain the compound as a white solid with the yield of 87%.
Example 31 inhibitory Activity assay
Inhibition of TRPV3 channel in compounds by whole cell patch clamp techniqueSex test, HEK-293 cells are planted into a dish, hTRPV3 plasmid is transiently transfected into the HEK-293 cells in the dish the next day, and after 4 hours, the solution is replaced at 37 ℃ and 5% CO2The cells were incubated overnight in the incubator, and on the third day, whole-cell current recordings were performed using a patch-clamp amplification system, followed by perfusion of the extracellular fluid containing 2-APB (50. mu.M) and then the extracellular fluid containing 50. mu.M of the inhibitor and 2-APB (50. mu.M). Recording the maximum outward current mediated by the hTRPV3 channel induced by 2-APB and the outward current mediated by the hTRPV3 channel under the simultaneous action of the inhibitor and 2-APB, and calculating the inhibition rate of the compound under 50 mu M according to the outward current of the whole cell current mediated by the hTRPV3 channel.
Compared with forsythoside B (the inhibition rate of which is 38% at a single concentration of 50 mu M, and the inhibitory activity IC50 is 7 mu M) which is a known potent TRPV3 inhibitor. The inhibition rates of the test compounds on TRPV3 by 1-30 compounds are shown in Table 1.
TABLE 11-30 inhibition of TRPV3 at a single concentration (50. mu.M) by the compounds
Compound numbering
Inhibition ratio (%)
Compound numbering
Inhibition ratio (%)
Compound numbering
Inhibition ratio (%)
1
51.7
11
82.5
21
71.6
2
61.3
12
74.9
22
89.1
3
49.3
13
67.8
23
67.8
4
51.8
14
69.4
24
91.5
5
81.2
15
90.4
25
73.6
6
63.4
16
89.4
26
64.3
7
57.3
17
73.7
27
48.7
8
64.8
18
45.3
28
70.6
9
81.3
19
77.4
29
73.5
10
77.3
20
86.8
30
74.2
Note: compounds 1-30 correspond to the compounds prepared from examples 2-31, respectively.
From the inhibition at a single concentration of 50. mu.M, the inhibition of compounds 1-30 was good at a concentration of 50. mu.M, with compounds 15,16,20,22,24 showing the best inhibition of TRPV3 at this concentration.
TABLE 21-30 inhibition of TRPV1 at a single concentration (50. mu.M) by the compounds
Compound numbering
Inhibition ratio (%)
Compound numbering
Inhibition ratio (%)
Compound numbering
Inhibition ratio (%)
1
4.1
11
4.2
21
5.6
2
3.3
12
3.5
22
3.7
3
3.3
13
2.5
23
4.8
4
3.4
14
3.8
24
2.5
5
4.6
15
3.4
25
2.2
6
2.6
16
2.7
26
3.1
7
2.8
17
2.5
27
2.1
8
3.2
18
3.7
28
2.3
9
2.6
19
4.2
29
1.7
10
2.2
20
5.3
30
3.1
Note: compounds 1-30 correspond to the compounds prepared from examples 2-31, respectively.
The inhibition rate of compound 1-30 to TRPV1 at a concentration of 50 μ M (agonist is 1 μ M capsaicin) was measured by the same method as that for testing TRPV3 activity. As can be seen from the above table, the compounds 1 to 30 had a low inhibitory rate against TRPV1 at a concentration of 50. mu.M, and therefore, the compounds 1 to 30 had a weak inhibitory activity against TRPV 1.
TABLE 31-30 inhibition of TRPV4 at a single concentration (50. mu.M) by the compounds
Compound numbering
Inhibition ratio (%)
Compound numbering
Inhibition ratio (%)
Compound numbering
Inhibition ratio (%)
1
4.3
11
5.4
21
4.7
2
4.1
12
3.4
22
3.7
3
2.5
13
2.7
23
2.8
4
6.3
14
4.6
24
6.3
5
3.7
15
3.7
25
4.2
6
4.5
16
3.4
26
7.3
7
3.8
17
2.7
27
5.8
8
6.5
18
3.7
28
6.2
9
4.6
19
4.6
29
4.3
10
3.8
20
4.8
30
6.3
Note: compounds 1-30 correspond to the compounds prepared from examples 2-31, respectively.
The inhibition rate of compound 1-30 to TRPV4 at a concentration of 50. mu.M (0.1. mu. MGSK-101 as an agonist) was measured by the same method as that for testing the activity of TRPV 3. As can be seen from the above table, the compounds 1 to 30 had a low inhibitory rate against TRPV4 at a concentration of 50. mu.M, and therefore, the compounds 1 to 30 had a weak inhibitory activity against TRPV 4.
As is apparent from tables 2 and 3, the 1-30 compounds have little inhibitory activity against TRPV1 and TRPV4, indicating that the compounds can be applied as a specific, highly potent TRPV3 inhibitor as a candidate drug against skin itch and inflammation caused by overexpression of TRPV 3.
The above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention. The protection scope of the invention is subject to the appended claims.
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