Method for preparing 2-hydroxyl-4-(2, 3-disubstituted benzyloxy)-5-substituted benzaldehyde derivative

Abstract

Provided is a method for preparing 2-hydroxy-4-(2, 3-disubstituted benzyloxy)-5-substituted benzaldehyde derivative represented by formula (I). The method comprises the following steps: (1) preparing 3-aryl-2-substituted toluene derivative 2 by using 3-iodo-2-substituted toluene derivative 1 and aryl boronic acid 5 or aryl boronate as starting materials; (2) preparing a benzyl halide derivative 3 by using 3-aryl-2-substituted toluene derivative 2 as starting materials; and (3) preparing 4-(2, 3-disubstituted benzyloxy)-2-hydroxy-5-substituted benzaldehyde derivative (I) by using benzyl halide derivative 3 and 2,4-dihydroxy-5-substituted benzaldehyde 6. ##STR00001##

Claims

1. A method for preparing 4-(2, 3-disubstituted benzyloxy)-2-hydroxy-5-substituted benzaldehyde derivative (I): ##STR00016## wherein the method comprises the following steps: 1) preparing 3-aryl-2-substituted toluene derivative 2 from 3-iodo-2-substituted toluene derivative 1 and aryl boronic acid 5, or an aryl boronate thereof, as starting materials: ##STR00017## wherein a means that 3-iodo-2-substituted toluene derivative 1 and aryl boronic acid 5, or an aryl boronate thereof, are subjected to a Suzuki-Miyaura coupling reaction to form 3-aryl-2-substituted toluene derivative 2 in the presence of a palladium catalyst and a base; 2) preparing benzyl halide derivative 3 from 3-aryl-2-substituted toluene derivative 2 as a starting material: ##STR00018## wherein b means that 3-aryl-2-substituted toluene derivative 2 is reacted with a halogenating agent under radical-initiating condition to prepare a benzyl halide derivative 3; 3) preparing 4-(2, 3-disubstituted benzyloxy)-2-hydroxy-5-substituted benzaldehyde derivative (I) from benzyl halide derivative 3 and 2,4-dihydroxy-5-substituted benzaldehyde 6 as starting materials: ##STR00019## wherein c means that benzyl halide derivative 3 is reacted with 2, 4-dihydroxy-5-substituted benzaldehyde 6 in a weak basic condition to selectively prepare a 4-(2, 3-disubstituted benzyloxy)-2-hydroxy-5-substituted benzaldehyde derivative (I); wherein: R.sub.1 is selected from fluorine, chlorine, bromine, methyl, and cyano; R.sub.2 is selected from ##STR00020## R.sub.3 is selected from hydrogen, methyl, ethyl, fluorine, chlorine, and bromine; X selected from bromine, chlorine, and iodine.

2. The method according to claim 1, wherein the palladium catalyst is selected from zero-valent palladium and divalent palladium compounds.

3. The method according to claim 2, wherein the zero-valent palladium catalyst is selected from triphenylphosphine palladium and tetrakis(triphenylphosphine)palladium, and the divalent palladium catalyst is PdCl.sub.2 (dppf).

4. The method according to claim 1, wherein the base is selected from alkali metal carbonate and alkali metal acetate.

5. The method according to claim 4, wherein the alkali metal carbonate is selected from cesium carbonate, potassium carbonate, and sodium carbonate, and the alkali metal acetate is selected from sodium acetate and potassium acetate.

6. The method according to claim 1, wherein the halogenating agent is selected from N-bromosuccinimide, N-chlorosuccinimide, phenyltrimethylammonium tribromide, and elemental bromine.

7. The method according to claim 1, wherein the radical initiating condition is the addition of a radical initiator, or light, or a combination thereof.

8. The method according to claim 7, wherein the radical initiator is selected from benzoyl peroxide and m-chloroperoxybenzoic acid.

9. The method according to claim 1, wherein the weak base condition is the addition of an alkali metal hydrogen carbonate or an alkali metal acetate.

10. The method according to claim 9, wherein the alkali metal hydrogen carbonate is selected from sodium hydrogen carbonate and potassium hydrogen carbonate.

Description

DETAILED DESCRIPTION

Example 1. 4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-hydroxybenzaldehyde

2-bromo-3-phenyltoluene

(1) To a 50 ml flask was added 2-bromo-3-iodotoluene (350 mg) and dioxane/water (volume ratio of 5/1) with stirring. The solution was bubbled with argon for 10 min to remove dissolved oxygen. Then, phenyl boronic acid (172.65 mg), cesium carbonate (961.2 mg), and triphenylphosphine palladium (40.91 mg) were sequentially added. The mixture was stirred for 12 h at 80-100 C. under argon protection. The reaction was stopped. After cooling to the room temperature, the mixture was filtered with diatomaceous earth. The filtrate was concentrated under reduced pressure and extracted with water and ethyl acetate for three times. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was filtered and evaporated to dryness in vacuo, to afford 2-bromo-3-phenyltoluene as colorless oil (234 mg) in a yield of 88%. .sup.1H NMR (400 MHz, DMSO-d.sub.6), 7.49-7.29 (m, 7H, ArH), 7.14 (d, 1H, ArH), 2.42 (s, 3H, ArCH.sub.3). MS (FAB): 248 (M+1).

2-bromo-3-phenylbenzyl Bromide

(2) 2-bromo-3-phenyltoluene (234 mg) as a starting material was taken and dissolved in 20 ml of CCl.sub.4 in a 100 ml flask. To this solution was added NBS (178 mg) while stirring. And the mixture was warmed to 80 C. and refluxed. Then benzoyl peroxide (4 mg) was added, and after 2 h, benzoyl peroxide (4 mg) was added again, and the mixture was stirred for another 2 h. The reaction was stopped. After cooling to the room temperature, the mixture was quenched with water, and extracted with dichloromethane and water. The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic layer was filtered and evaporated to dryness in vacuo, to afford 2-bromo-3-phenylbenzyl bromide as yellow oil (262 mg), which was used for the next step without further purification.

4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-hydroxybenzaldehyde

(3) ##STR00008##

(4) 2,4-dihydroxy-5-chlorobenzaldehyde (73.94 mg) was taken and dissolved in 6 ml of anhydrous acetonitrile in a 50 ml flask, and then sodium hydrogen carbonate (98.88 mg) was added. After stirring at the room temperature for 40 min, 2-bromo-3-phenylbenzyl bromide (192 mg, dissolved in 8 ml of DMF) was slowly added to the reaction mixture via a constant pressure dropping funnel, and heated to reflux until the reaction was completed. After cooling to the room temperature, the mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate, then filtrated and evaporated to dryness in vacuo, to afford 4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-hydroxybenzaldehyde as a white solid (192 mg) in a yield of 85%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.99 (s, 1H, OH), 10.03 (s, 1H, CHO), 7.64 (d, 1H, ArH), 7.57 (d, 1H, ArH), 7.45 (m, 4H, ArH), 7.37 (d, 2H, ArH), 6.67 (d, 1H, ArH), 6.59 (s, 1H, ArH), 5.25 (s, 2H, CH.sub.2). MS (FAB): 418(M+1).

Example 2

N-acetylaminoethyl-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy)-5-chlorobenzylamine

4-(2-bromo-3-phenylbenzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzaldehyde

(5) 4-(2-bromo-3-phenylbenzyloxy)-2-hydroxy-5-chlorobenzaldehyde (100 mg) was dissolved in 6 ml of DMF in a 50 ml flask, and then cesium carbonate (127.53 mg) was added. After stirring at the room temperature for 15 min, a solution of m-cyanobenzyl bromide (76.65 mg) in DMF (4 ml) was added dropwise. After the mixture was stirred at 80 C. for 2 h, the reaction was stopped. After cooling to the room temperature, the mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate, then filtrated and evaporated to dryness in vacuo. The crude residue was purified by silica gel column chromatography to afford a white solid (103 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.26 (s, 1H, CHO), 8.00 (s, 1H, ArH), 7.83 (dd, 2H, ArH), 7.72 (d, 1H, ArH), 7.61 (t, 2H, ArH), 7.55-7.23 (m, 7H, ArH), 6.95 (s, 1H, ArH), 6.81 (d, 1H, ArH), 5.35 (s, 2H, CH.sub.2), 5.30 (s, 2H, CH.sub.2). MS (FAB): 509(M+1).

N-Acetylaminoethyl-4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy)-5-chlorobenzyl Amine

(6) ##STR00009##

(7) 4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy)-5-chlorobenzaldehyde (50.8 mg) was dissolved in 5 ml of DMF, and then 2-acetamidoethylamine (31.25 mg) and acetic acid glacial (36.75 mg) were added. After stirring at the room temperature for 20 min, sodium cyanoborohydride (19.23 mg) was added and the mixture was stirred at 25 C. for 14 h. The reaction was stopped. The mixture was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate, then filtrated and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography to afford a white solid (55 mg). .sup.1H NMR (500 MHz, DMSO-d.sub.6) 8.00 (s, 1H, ArH), 7.86 (dd, 2H, ArH), 7.69-7.62 (m, 2H, ArH), 7.53 (d, 2H, ArH), 7.50 (d, 2H, ArH), 7.46 (d, 1H, ArH), 7.41 (t, 3H, ArH), 7.07 (s, 1H, ArH), 5.33 (s, 2H, CH.sub.2), 5.32 (s, 2H, CH.sub.2), 3.89 (s, 2H, CH.sub.2), 3.25 (m, 2H, CH.sub.2), 2.74 (t, 2H, CH.sub.2), 1.83 (s, 3H, COCH.sub.3). MS (FAB): 620(M+1).

Example 3

4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chloro-2-hydroxybenzaldehyde

2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) toluene

(8) The procedure was the same as in Example 1, except that 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used in place of phenyl boronic acid, [1,1-bis (diphenylphosphino)ferrocene]dichloropalladium was used in place of triphenylphosphine palladium, potassium carbonate was used in place of cesium carbonate to afford 2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) toluene as pale yellow oil. .sup.1H NMR (400 MHz, Chloroform-d) 7.21 (d, 2H, ArH), 7.11 (m, 1H, ArH), 6.90 (d, 2H, ArH), 6.86 (d, 1H, ArH), 4.30 (m, 4H, OCH.sub.2CH.sub.2O), 2.48 (s, 3H, CH.sub.3).

4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-2-hydroxy-5-chlorobenzaldehyde

(9) ##STR00010##

(10) The procedure was the same as in Example 1, except that 2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) toluene was used in place of 2-Bromo-3-methyl-1,1-biphenyl to effect bromination; the bromide, without further purification, was reacted directly with 2,4-dihydroxy-5-chlorobenzaldehyde to afford a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.91 (s, 1H, OH), 9.95 (s, 1H, CHO), 7.57 (d, 1H, ArH), 7.45 (d, 1H, ArH), 7.37 (t, 1H, ArH), 7.25 (d, 1H, ArH), 6.84 (d, 1H, ArH), 6.78 (s, 1H, ArH), 6.74 (d, 1H, ArH), 6.59 (d, 1H, ArH), 6.51 (s, 1H, ArH), 5.16 (s, 2H, CH.sub.2), 4.20 (m, 4H, OCH.sub.2CH.sub.2O). MS (FAB): 476(M+1).

Example 4

N-(Hydroxyethyl)-4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-Chloro-2-(3-cyanobenzyloxy)benzylamine

4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chloro-2-(3-cyanobenzyloxy) benzaldehyde

(11) The procedure was the same as in Example 2, except that 4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-2-hydroxy-5-Chlorobenzaldehyde was used in place of 4-(2-bromo-3-phenylbenzyloxy)-2-hydroxybenzaldehyde to afford a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.28 (s, 1H, CHO), 8.01 (s, 1H, ArH), 7.85 (dd, 2H, ArH), 7.74 (d, 1H, ArH), 7.63 (t, 1H, ArH), 7.58 (d, 1H, ArH), 7.46 (t, 1H, ArH), 7.35 (d, 1H, ArH), 6.94 (d, 2H, ArH), 6.87 (s, 1H, ArH), 6.82 (d, 2H, ArH), 5.36 (s, 2H, CH.sub.2), 5.30 (s, 2H, CH.sub.2), 4.29 (m, 4H, OCH.sub.2CH.sub.2O). MS (FAB): 567(M+1).

N-(Hydroxyethyl)-4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-Chloro-2-(3-cyanobenzyloxy)benzylamine

(12) ##STR00011##

(13) The procedure was the same as in Example 2, except that 4-(2-bromo-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-2-(3-cyanobenzyloxy) benzaldehyde was used in place of 4-(2-bromo-3-phenylbenzyloxy)-2-(3-cyanobenzyloxy)-5-Chlorobenzaldehyde to afford an off-white solid powder. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.74 (s, 1H, NH), 8.14 (m, 1H, CONH), 8.00 (s, 1H, ArH), 7.85 (dd, 2H, ArH), 7.63 (t, 1H, ArH), 7.54 (d, 1H, ArH), 7.50-7.37 (m, 2H, ArH), 7.33 (d, 1H, ArH), 6.94 (d, 1H, ArH), 6.86 (s, 2H, ArH), 6.82 (d, 1H, ArH), 6.74 (d, 1H, ArH), 5.27 (s, 2H, CH.sub.2), 5.20 (s, 2H, CH.sub.2), 4.29 (m, 4H, OCH.sub.2CH.sub.2O), 4.13 (s, 2H, CH.sub.2), 3.34-3.39 (m, 2H, CH.sub.2), 2.96 (m, 2H, CH.sub.2), 1.82 (s, 3H, COCH.sub.3). MS (FAB): 678 (M+1).

Example 5

4-(2-methyl-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chloro-2-hydroxybenzaldehyde

(14) ##STR00012##

(15) The procedure was the same as in Example 1, except that 2-methyl-3-iodotoluene was used in place of 2-bromo-3-iodotoluene as the starting material, to afford 4-(2-methyl-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chloro-2-hydroxybenzaldehyde as a white solid. The yield in the last step was 78%. MS (FAB): 411 (M+1).

Example 6

(R)N-[2-(5-cyanopyridine-3-methyleneoxy)-4-(2-methyl-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chlorobenzyl]-3-(pyridin-3-yl)alanine

(16) ##STR00013##

(17) The procedure was the same as in Example 2, except that 5-cyanopyridine-3-methylene bromide was used in place of m-cyanobenzyl bromide, and asparaginate was used in place of 2-acetylaminoethylamine, to afford (R)N-[2-(5-cyanopyridine-3-methyleneoxy)-4-(2-methyl-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-5-chlorobenzyl]-3-(pyridin-3-yl) alanine as a white solid in a yield of 48%. MS (FAB): 678 (M+1)

Example 7

5-bromo-4-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)-2-hydroxybenzaldehyde

(18) ##STR00014##

(19) The procedure was the same as in Example 1, except that 2-cyano-3-iodotoluene was used in place of 2-bromo-3-iodotoluene, and 2, 4-dihydroxy-5-bromobenzaldehyde was used in place of 2, 4-dihydroxy-5-chlorobenzaldehyde, to afford 5-bromo-4-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) benzyloxy)-2-hydroxybenzaldehyde as a white solid. The yield in the last step was 76%. MS (FAB): 467 (M+1).

Example 8

N-(2-acetylaminoethyl)-2-(3-cyanobenzyloxy)-4-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy)benzylamine

(20) ##STR00015##

(21) The procedure was the same as in Example 2, except that 5-bromo-4-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl) benzyloxy)-2-hydroxybenzaldehyde as the starting material, to afford N-(2-Acetylaminoethyl)-2-(3-cyanobenzyloxy)-4-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)benzyloxy) benzylamine as a white solid in a yield of 46%. MS (FAB): 668 (M+1).

(22) Note: Examples 1, 3, 5, and 7 are intermediate 2-hydroxy-4-(2,3-disubstituted benzyloxy)-5-substituted benzaldehyde derivative (I).

(23) Examples 2, 4, 6, and 8 are immunomodulatory compounds prepared on the basis of Examples 1, 3, 5, and 7, respectively.

(24) The compounds of Examples 5, 6, 7, and 8 are known compounds.

Pharmacological Experiments

(25) In vitro activity evaluation: Cisbio HTRF binding assay kit was applied for the detection method of in vitro enzymology level.

Screening Principles and Methods of PD-1/PD-L1 Small Molecule Inhibitors

(26) 1) Principle: PD-1 protein is with HIS tag, and PD-1 ligand PD-L1 is with hFc tag. Eu labeled anti-hFc antibody and XL665 labeled anti-HIS antibody are combined with the above two label proteins respectively. After laser excitation, energy can be transferred from donor Eu to receptor XL665, allowing XL665 to glow. After adding inhibitors (compounds or antibodies), blocking the binding of PD-1 and PD-L1 makes the distance between Eu and XL665 far away, the energy can not be transferred, and XL665 does not glow.

(27) 2) Experimental method: Reagents should be dispensed in the following order. For 384-well white ELISA plate, 2 l of diluent or target compound diluted with diluent was added to each well, and then 4 l of PD-1 protein and 4 l of PD-L1 protein were added per well, incubated for 15 min at the room temperature; and 10 l of anti-Tag1-Eu3.sup.+ and anti-Tag2-XL665 was added per well and incubated for 1 h at the room temperature and the fluorescence signals at 665 nm and 620 nm were measured. HTRF rate=(665 nm/620 nm)*10.sup.4. 8-10 concentrations were detected for each compound and IC.sub.50 was calculated by Graphpad software.

(28) 3. Screening results:

(29) TABLE-US-00001 Example IC.sub.50 (M) Example IC.sub.50 (M) 2 6.23 10.sup.8 4 2.68 10.sup.7 6 3.5 10.sup.8 8 7.12 10.sup.9