CN117510306A - Preparation method of 3-phenanthryl alcohol - Google Patents

Abstract

The invention discloses a preparation method of 3-phenanthritol. The method uses compound 3-tert-butoxyphenylboronic acid and o-bromobenzaldehyde to couple to obtain 3'-tert-butoxy-[1,1'-biphenyl ]-2-formaldehyde, then 2-(chloromethoxy)-2-methylpropane reacts with magnesium shavings in tetrahydrofuran to form a Grignard reagent, which is then reacted with 3'-tert-butoxy-[1,1'- Biphenyl]-2-formaldehyde substitution, p-toluenesulfonic acid reflux and water removal to obtain 3'-tert-butoxy-2-(2”-tert-butoxyvinyl)-1,1'-biphenyl, and finally methyl The sulfonic acid ring is closed and the tert-butyl protection is removed to obtain 3-phenanthrenol. Through the introduction of tert-butyl protection, the present invention can not only increase the steric hindrance, reduce the isomers during ring closure, and make the deprotection conditions easier, The obtained product can be obtained with a purity of more than 99.0% without column chromatography treatment.

Description

A kind of preparation method of 3-phenanthrol

Technical field

The invention relates to a preparation method of 3-phenanthrenol and belongs to the technical field of organic chemical synthesis.

Background technique

3-Phenanthanol, CAS 605-87-8, phenanthrene compounds are widely found in natural products. Because of their unique photoelectric and biological properties, they are used as starting materials for photosensitive elements or pharmaceutical intermediates. Among them, 3-phenanthrenol can be synthesized as a CE inhibitor, which can be used to treat CPT-11 anti-cancer drug prodrug. It can also be used as the phenanthrene-based core or skeleton to synthesize chiral ligands or catalysts. This type of chiral ligand Monomers or catalysts are widely used in asymmetric synthesis.

So far, three main methods have been reported for the synthesis of 3-phenanthrenol: First, the literature [Synthesis, 2021, vol.53, #14, p.2512-2516] reports the use of 3-methoxyphenylboronic acid and o- Bromobenzaldehyde is used as raw material, and 3'-methoxy-[1,1'-biphenyl]-2-carbaldehyde is obtained through coupling, which is then mixed with (methoxymethyl)triphenylphosphorus chloride in tert-butanol Nucleophilic substitution with potassium gives 3'-methoxy-2-(2"-methoxyvinyl)-1,1'-biphenyl, followed by ring closure under the action of methanesulfonic acid, and then deprotection to give 3-phenanthrene Alcohol, the total yield is 65.8%. When the ring is closed in this method, the ratio of 3-methoxyphenanthrene to 1-methoxyphenanthrene is 4:1, which requires column chromatography for separation, deprotection requires ultra-low temperature, and requires high equipment; reaction The equation is expressed as follows:

Second, the literature [European Journal of Medicinal Chemistry, 2018, vol.149, p.79-89] reports the coupling of 3-methoxyphenylboronic acid and 1-bromo-2-(2-methoxyvinyl)benzene Obtain 3'-methoxy-2-(2"-methoxyvinyl)-1,1'-biphenyl (enol ether), then close the ring under the action of methanesulfonic acid, and finally demethylate and protect to obtain 3 -Phenanthanol, the raw materials in this method are not easy to obtain, and there is still the problem of methoxy ortho-para activity, so that 3-methoxyphenanthrene and 1-methoxyphenanthrene still need column chromatography for separation; the reaction equation is expressed as follows:

Third, the literature [Tetrahedron Letters, 2000, vol.41, #42, p.8079-8082] reports the use of 2-nitronaphthalene and trans-1-methoxy-3-(trimethylsiloxy)- 1,3-butadiene undergoes Diels-Alder reaction at high temperature to obtain 3-phenanthritol, with an isolation yield of 21%, and the difficulty of purification increases; the reaction equation is expressed as follows:

In the above synthetic routes, there is the problem of difficult separation of product isomers. Therefore, it is necessary to develop new directions for the synthesis process of 3-phenanthrol and provide better reaction routes to meet the growing market demand.

Contents of the invention

In order to overcome the above technical shortcomings, the present invention proposes a preparation method of 3-phenanthrol, which uses the compound 3-tert-butoxyphenylboronic acid and o-bromobenzaldehyde to couple to obtain 3'-tert-butoxy-[1, 1'-Biphenyl]-2-carbaldehyde, then 2-(chloromethoxy)-2-methylpropane reacts with magnesium shavings in tetrahydrofuran to form a Grignard reagent, which is then reacted with 3'-tert-butoxy-[ 1,1'-Biphenyl]-2-carboxaldehyde was substituted, and p-toluenesulfonic acid was refluxed and eliminated with water to obtain 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'- biphenyl, and finally methanesulfonic acid ring closure and removal of tert-butyl protection to obtain 3-phenanthrenol. The introduction of tert-butyl protection in the present invention can not only increase steric hindrance and reduce isomers during ring closure, but also deprotection conditions It is easier to obtain products with a purity of over 99.0% without column chromatography.

The preparation method of 3-phenanthrenol according to the present invention includes the following steps:

The first step (coupling reaction): Couple 3-tert-butoxyphenylboronic acid, o-bromobenzaldehyde, potassium carbonate aqueous solution, and tetrakis(triphenylphosphorus)palladium in an organic solvent to obtain 3'-tert-butoxy -[1,1'-biphenyl]-2-carbaldehyde; the reaction equation is expressed as follows:

The second step (Grignard reaction): Dissolve 2-(chloromethoxy)-2-methylpropane in tetrahydrofuran, add magnesium chips and iodine to the reaction flask, and add dropwise about 10% of 2-(chloromethoxy)-2-methylpropane. The tetrahydrofuran solution of methoxy)-2-methylpropane is slowly heated to trigger, and the remaining tetrahydrofuran solution of 2-(chloromethoxy)-2-methylpropane is added dropwise to obtain the Grignard reagent; the reaction equation is expressed as follows :

The third step (substitution and elimination reaction): Dissolve 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde in tetrahydrofuran. After cooling, add the Grignard reagent in the second step and add saturated Quench with ammonium chloride, concentrate the organic phase under reduced pressure, replace other organic solvents, add anhydrous p-toluenesulfonic acid, heat under vacuum and heat to reflux to separate water, to obtain 3'-tert-butoxy-2-(2"- Tert-butoxyvinyl)-1,1'-biphenyl; the reaction equation is expressed as follows:

Step 4 (ring closing, deprotection reaction): Mix 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl and dichloromethane, cool down, Add methanesulfonic acid to close the ring, then add anisole and methanesulfonic acid to heat up and deprotect to obtain 3-phenanthranol. The reaction equation is expressed as follows:

Further, in the above technical solution, in the first step, the coupling temperature is selected from 80-100°C.

Further, in the above technical solution, in the third step, the vacuum degree of the vacuum reflux water separation is selected from -0.02 to -0.04Mpa, and the temperature is selected from 60-85°C.

Further, in the above technical solution, in the fourth step, the ring closure of the methanesulfonic acid is to close the para ring of enol ether and tert-butoxy group at 0°C, wherein 3'-tert-butoxy-2 The molar ratio of -(2"-tert-butoxyvinyl)-1,1'-biphenyl to methanesulfonic acid is 1:1.

Further, in the above technical solution, in the fourth step, the deprotection involves adding methanesulfonic acid to remove the tert-butoxy group protection at elevated temperature.

Invent beneficial effects

Compared with the existing technology, the equipment requirements are not high. The introduced tert-butyl group can increase steric hindrance and is more inclined to para-ring closure with the tert-butoxy group. The isomers are greatly reduced. The final reaction solution detects 3-phenanthranol. The ratio to 1-phenanthranol is 50:1.

Instructions with pictures

Figure 1 is the HNMR spectrum of 3-phenanthrenol obtained in Example 6.

Specific embodiments

Example 1

Mix 19.4g (0.1mol) of 3-tert-butoxyphenylboronic acid, 20g (0.108mol) of o-bromobenzaldehyde, 47g of potassium carbonate (0.34mol), 1.39g (1.2mmol) of tetrakis(triphenylphosphorus)palladium, and water. 140g and 240g acetonitrile were mixed in the reaction bottle, replaced with nitrogen, heated to 80°C and reacted for 12 hours, cooled to 40°C, concentrated under reduced pressure to remove most of the acetonitrile, cooled to room temperature, added isopropyl acetate for extraction, and the organic phase was treated with sodium chloride The aqueous solution was washed, dried over anhydrous magnesium sulfate, and concentrated to obtain 25.4 g of 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde as oil, HPLC 91.7%, which was directly used in the next step. ¹ HNMR (400MHZ, CDCl3): δ10.09(s,1H),8.13(d,1H),8.01-7.76(m,2H),7.62-7.55(m,1H),7.50-7.43(m,1H) ,7.38-7.11(m,2H),7.09-6.95(m,1H),1.40(s,9H).

Example 2

Mix 19.4g (0.1mol) of 3-tert-butoxyphenylboronic acid, 20g (0.108mol) of o-bromobenzaldehyde, 47g of potassium carbonate (0.34mol), 1.39g (1.2mmol) of tetrakis(triphenylphosphorus)palladium, and water. 140g and 300g of 1,4-dioxane were mixed in the reaction bottle, replaced with nitrogen, raised to 100°C and reacted for 7 hours, then cooled to 60°C, concentrated under reduced pressure to remove most of the 1,4-dioxane, and cooled to After room temperature, isopropyl acetate was added for extraction, the organic phase was washed with sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated to obtain 25.5g of 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde as oil. , HPLC92.2%; used directly in the next step.

Example 3

In advance, 14.7 g (0.12 mol) of 2-(chloromethoxy)-2-methylpropane was dissolved in 150 mL of ultra-dry tetrahydrofuran. Add 3.5g (0.144mol) magnesium chips, 1 grain of iodine and 10mL ultra-dry tetrahydrofuran to the reaction bottle, dropwise add the above-mentioned about 10% 2-(chloromethoxy)-2-methylpropane tetrahydrofuran solution, and slowly raise the temperature. To trigger, add the remaining tetrahydrofuran solution of 2-(chloromethoxy)-2-methylpropane dropwise, raise the temperature to 60°C, react for 4 hours, and cool to room temperature for later use.

Example 4

Dissolve 25.4g (0.1mol) of 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde in 150mL of tetrahydrofuran, cool to -10~-5℃, and add dropwise the second step above Use 0.12 mol of his reagent, and control the dropping temperature at 0-10°C. After the dropwise addition, react at 0-10°C for 3 hours, slowly raise the temperature to 20°C, add saturated ammonium chloride to quench, add ethyl acetate, and let stand. Separate layers, extract the water phase with ethyl acetate, concentrate the organic phase under reduced pressure, replace toluene to KF <0.05%, add 1.0g of anhydrous p-toluenesulfonic acid, raise the temperature to 60°C under vacuum, reflux and separate water for 6 hours, and reduce the pressure. Concentrate to remaining 3V, add isopropyl ether, cool to 0°C and beat to obtain 26.3g of off-white solid 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl. , yield 81%, HPLC 99.1%. ¹ H NMR (400MHz, CDCl3): δ8.11 (d, 1H), 7.56-7.25 (m, 5H), 7.25-7.06 (m, 1H), 7.05-6.86 (m,1H),6.54(d,1H),5.41(d,1H),1.41(s,9H),1.35(s,9H).

Example 5

Dissolve 25.4g (0.1mol) of 3'-tert-butoxy-[1,1'-biphenyl]-2-carbaldehyde in 150mL of tetrahydrofuran, cool to -10~-5℃, and add dropwise the second step above Use 0.12 mol of his reagent, and control the dropping temperature at 0-10°C. After the dropwise addition, react at 0-10°C for 3 hours, slowly raise the temperature to 20°C, add saturated ammonium chloride to quench, add ethyl acetate, and let stand. Separate layers, extract the water phase with ethyl acetate, concentrate the organic phase under reduced pressure, replace xylene to KF <0.05%, add 1.0g anhydrous p-toluenesulfonic acid, heat to 85°C under vacuum, reflux and separate water for 4 hours, reduce Concentrate to a residual volume of 4V, add isopropyl ether, cool to 0°C and beat to obtain 27.8g of off-white solid 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl. , yield 85.6%, HPLC 98.6%.

Example 6

Add 26g (0.08mol) of 3'-tert-butoxy-2-(2"-tert-butoxyvinyl)-1,1'-biphenyl and 600mL of dichloromethane into the reaction bottle, mix, and cool to - 5~0℃, slowly add 7.7g methanesulfonic acid (0.08mol), react overnight at 0℃, take a sample and check that there is no raw material left, add anisole and methanesulfonic acid, raise the temperature to 40-50℃, react for 6 hours for deprotection, carbonate Wash with sodium hydrogen aqueous solution, wash with sodium chloride aqueous solution, concentrate under reduced pressure to remove most of the dichloromethane, cool to 0°C, and leave to crystallize to obtain 14g of 3-phenanthrol, yield 90.2%, HPLC 99.4%. ¹ HNMR (400MHz ,DMSO-d6): δ10.05(s,1H),8.60(d,1H),8.06(d,1H),7.91(d,1H),7.82(d,1H),7.72(d,1H), 7.59-7.66(m,3H),7.20(dd,1H).

The above are only preferred specific embodiments of the present invention, but the protection scope of the present invention is not limited thereto. Any person familiar with the technical field can, within the technical scope disclosed in the present invention, adopt the technical solutions of the present invention. Equivalent substitutions or changes of the inventive concept thereof shall be included in the protection scope of the present invention.

Claims (6)

1. A preparation method of 3-phenanthrol is characterized by comprising the following reaction routes:

the method comprises the following steps:

the first step: coupling 3-tert-butoxy phenylboronic acid, o-bromobenzaldehyde, potassium carbonate aqueous solution and tetra (triphenylphosphine) palladium in an organic solvent to obtain 3 '-tert-butoxy- [1,1' -biphenyl ] -2-formaldehyde;

and a second step of: dissolving 2- (chloromethoxy) -2-methylpropane in tetrahydrofuran, dropwise adding 10% of 2- (chloromethoxy) -2-methylpropane tetrahydrofuran solution into a reaction bottle added with magnesium scraps and iodine, slowly heating to initiate, and dropwise adding the rest of 2- (chloromethoxy) -2-methylpropane tetrahydrofuran solution to obtain a Grignard reagent;

and a third step of: dissolving 3' -tert-butoxy- [1,1' -biphenyl ] -2-formaldehyde in tetrahydrofuran, cooling, adding a second Grignard reagent, adding saturated ammonium chloride for quenching, concentrating an organic phase under reduced pressure, replacing other organic solvents, adding anhydrous p-toluenesulfonic acid, heating under vacuum until reflux and water diversion are carried out, and obtaining 3' -tert-butoxy-2- (2 ' -tert-butoxyvinyl) -1,1' -biphenyl;

fourth step: mixing 3' -tert-butoxy-2- (2 ' -tert-butoxyvinyl) -1,1' -biphenyl with dichloromethane, cooling, adding methanesulfonic acid for ring closure, then adding anisole and methanesulfonic acid, heating and deprotecting to obtain 3-phenanthryl alcohol.

2. The method for producing 3-phenanthrol according to claim 1, wherein: in the first step, the organic solvent is acetonitrile or 1, 4-dioxane.

3. The method for producing 3-phenanthrol according to claim 1, wherein: in the first step, the molar ratio of the 3-tert-butoxyphenylboronic acid, the o-bromobenzaldehyde, the potassium carbonate and the tetra (triphenylphosphine) palladium is 1:1.05-1.10:3.0-3.5:0.01-0.02.

4. The method for producing 3-phenanthrol according to claim 1, wherein: in the second step, the molar ratio of the 2- (chloromethoxy) -2-methylpropane to the magnesium turnings to the iodine is 1:1.2:0.005-0.01.

5. The method for producing 3-phenanthrol according to claim 1, wherein: in the third step, the organic solvent is selected from toluene or xylene.

6. The method for producing 3-phenanthrol according to claim 1, wherein: in the third step, the molar ratio of the 3 '-tert-butoxy- [1,1' -biphenyl ] -2-formaldehyde to the Grignard reagent is 1:1.2.