Preparation method of ilastrant intermediate

Abstract

The invention provides a method for preparing an ilastrant intermediate (namely a compound of a formula V or a salt thereof), 4-bromo-3-nitroanisole is used as a raw material of # imgabs0, and (+ / -) 6-(2-amino-4-methoxyphenyl)-5, 6, 7, 8-tetrahydronaphthalene-2-alcohol is obtained through a one-pot Suzuki coupling reaction and reductive hydrogenation. According to the method, the reaction steps are simplified, and the operation process is reduced. Compared with the prior art, the preparation process provided by the invention has the advantages that the obtained product is economic and efficient, the yield and the purity are higher, and the preparation process is more suitable for industrial production; the compound of the formula (V) or the salt thereof can be used for preparing alalisset.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing an elastostrat intermediate (+ / -)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol. Background Art

[0002] Compound of formula (V) (+ / -) 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol It is a key intermediate for the synthesis of Elacestrant. Elacestrant, chemical name: ((R)-6-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol dihydrochloride) is a selective estrogen receptor α (ERα) modulator / degrader (SERM / SERD) that has the effect of treating ER+ cancers including breast cancer. The US FDA approved Elacestrant for marketing in January 2023 for the treatment of ER+ / HER2-, ESR1-mutated advanced or metastatic breast cancer that has progressed after at least one line of endocrine therapy.

[0003] Elastran is a new type of non-steroidal SERD oral drug, the first approved one, which has been clinically proven to be safe and effective. As a superior version of SERD, it has great potential to replace fulvestrant, which was first approved for marketing in 2002 but requires intramuscular injection, has low bioavailability and poor accessibility.

[0004] The synthesis method of elastomeric is reported in patent CN 113348163 A. The synthesis route is as follows:

[0005]

[0006] In this synthesis method, the expensive starting material 7-benzyloxy-3-bromo-1,2-dihydronaphthalene is used to carry out Suzuki reaction to prepare boric acid ester, which is not conducive to production cost control; the hydroxyl and amino protecting groups are removed respectively through two steps, and the steps are relatively long. In addition, the post-processing operation of this method is cumbersome, there is a lot of waste liquid, and the environmental pressure is high. The existence of these problems is not conducive to industrial production. Therefore, it is necessary to develop a method for preparing (+ / -) 6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol with mild conditions, easy control, safety and environmental protection, short reaction steps, economy, and suitable for industrial production. Summary of the invention

[0007] In order to overcome the deficiencies of the prior art, the present invention aims to provide a method for preparing (+ / -)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol which has a simple route, is safe, environmentally friendly, easy to operate, and economical and efficient.

[0008] The technical solution of the present invention is as follows:

[0009] An intermediate of elastostat A preparation method comprising the steps of:

[0010] (1) the compound of formula I is reacted with biboric acid pinacol ester to undergo Suzuki reaction to obtain a compound of formula II;

[0011]

[0012] (2) the compound of formula II undergoes a Suzuki reaction with the compound of formula III to obtain a compound of formula IV;

[0013]

[0014] (3) the compound of formula IV is subjected to hydrogenation reduction to obtain a compound of formula V;

[0015]

[0016] Furthermore, step (1) is to carry out Suzuki reaction of the compound of formula I with diboric acid pinacol ester in the first solvent in the presence of a palladium catalyst and a base to obtain a compound of formula II.

[0017] Furthermore, in step (1), the molar ratio of the compound of formula I to diboric acid pinacol ester is 1:1.05-1.5, preferably 1:1.2;

[0018] The reaction temperature is 65-100°C, preferably 80-85°C;

[0019] The reaction time is 1-8h, preferably 5-7h;

[0020] The palladium catalyst is selected from one or more combinations of palladium / carbon, tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride;

[0021] The mass ratio of the palladium catalyst to the compound of formula I is 0.5%-5%:1, preferably 1.5-2.0%:1;

[0022] The reaction base is selected from a combination of one or more of sodium carbonate, potassium phosphate, potassium acetate, potassium bicarbonate, potassium carbonate, and sodium bicarbonate;

[0023] The molar ratio of the base to the compound of formula I is 2-3.5:1, preferably 2.5:1;

[0024] The first solvent is selected from one or more combinations of acetone, 1,4-dioxane, ethylene glycol methyl ether, methanol, ethanol, isopropanol, toluene, and N,N-dimethylformamide.

[0025] Further, step (2) is to carry out Suzuki reaction of the compound of formula II with the compound of formula III in the presence of a palladium catalyst and a base in the second solvent and the reaction system of step (1), and obtain the compound of formula IV after purification.

[0026] Further, in step (2), the molar ratio of the compound of formula II to the compound of formula III is 1:1.10-1.4, preferably 1:1.25;

[0027] The reaction temperature is 65-120°C, preferably 80-95°C;

[0028] The reaction time is 1-16h; preferably 6-8h;

[0029] The palladium catalyst is selected from one or more combinations of palladium / carbon, tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride;

[0030] The mass ratio of the palladium catalyst to the compound of formula II is 0.5%-5%:1, preferably 1.5-2.0%:1;

[0031] The reaction base is selected from a combination of one or more of sodium carbonate, potassium phosphate, potassium acetate, potassium bicarbonate, potassium carbonate, sodium bicarbonate, and cesium carbonate;

[0032] The molar ratio of the base to the compound of formula II is 2-3.5:1; preferably 2.5-3.0:1;

[0033] The second solvent is selected from one or more combinations of acetone, 1,4-dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, toluene, N,N-dimethylformamide, and water.

[0034] The volume ratio of the second solvent to water is 1:1-10:1; preferably 4:1

[0035] The refining solvent is selected from one or more combinations of dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, isopropyl acetate, acetone, n-heptane, isopropyl ether, tetrahydrofuran and water.

[0036] Furthermore, step (3) is to subject the compound of formula IV to hydrogenation reduction in the presence of a palladium catalyst in a third solvent to obtain a compound of formula V.

[0037] Further, the reaction temperature in step (3) is 20-40°C, preferably 30-35°C;

[0038] The reaction time is 1.5-10h, preferably 4-6h;

[0039] The hydrogenation pressure is 0.2-1.0 MPa; preferably 0.5-0.6 MPa;

[0040] The palladium catalyst is selected from a combination of one or more of palladium / carbon, palladium hydroxide / carbon, and platinum / carbon;

[0041] The mass ratio of the palladium catalyst to the compound of formula IV is 1%-15%:1;

[0042] The third solvent is selected from one or more combinations of methanol, tetrahydrofuran, acetone, ethanol, acetonitrile and isopropanol.

[0043] The technical solution of the present invention has the following beneficial effects compared with the prior art:

[0044] After extensive and in-depth research, the present invention selects 4-bromo-3-nitroanisole as a starting material to prepare its boric acid ester, and carries out Suzuki reaction with 7-benzyloxy-3-bromo-1,2-dihydronaphthalene, and obtains (+ / -)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol by hydrogenation debenzylation and reduction of nitro group. The total yield of the method can reach more than 80%, and the method has the advantages of short steps, good product purity, less three wastes, simple operation, easy control of conditions, simple post-treatment, economical and efficient, and is suitable for large-scale industrial production. Based on this, the present invention is completed. DETAILED DESCRIPTION

[0045] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0046] Example 1

[0047] (1) A solution of 4-bromo-3-nitroanisole (I) (1 equivalent) and diboronic acid pinacol ester (1.2 equivalents) was dissolved in 6 volumes of 1,4-dioxane, KOAc (2.5 equivalents) and Pd(dppf)Cl2 (1.8% by weight of the compound of formula I) were added, and the atmosphere was replaced with nitrogen and heated to 80-85°C for 6 hours. (2)

[0049] Suzuki reaction: After the reaction is completed by HPLC monitoring, the solution containing the compound of formula II (theoretical amount 1 equivalent) and KOAc obtained in step (1) is cooled to 20-30°C, purified water (1.5 volumes) and 7-benzyloxy-3-bromo-1,2-dihydronaphthalene (formula III) (1.25 equivalents) are added, and the mixture is replaced with nitrogen and heated to 90-93°C for 8 hours.

[0050] Purification: After the reaction is completed by HPLC monitoring, the reaction is cooled to 30-35°C, filtered, and the solid is washed with 1,4-dioxane. The aqueous phase is separated, the collected organic phase is cooled to 18-25°C, 9 volumes of purified water are added and stirred for ≥1.5 hours, filtered, and the filter cake is washed with 4 volumes of purified water to collect the crude product; the crude product is heated to 65-70°C with 4.5V isopropanol to dissolve, slowly cooled to 10-20°C, filtered, and the filter cake is washed with 0.5V isopropanol to obtain the wet product, which is dried to obtain 7-(phenoxy)-3-(4-methoxy-2-nitrobenzene)-1,2-dihydronaphthalene (Formula IV), with a purity of ≥98.3% and a yield of ≥90%.

[0051] (3) 7-(Phenoxy)-3-(4-methoxy-2-nitrobenzene)-1,2-dihydronaphthalene (Formula IV) was added to methanol (10.0V), and palladium / carbon (10% of the mass of compound IV) was added. The gas was replaced with nitrogen twice and then replaced with hydrogen three times. The hydrogen pressure was controlled at 0.5-0.6 MPa and the reaction temperature was 30-35°C for 6 hours.

[0052] After the reaction was completed by HPLC monitoring, the product was filtered, the filter cake was washed with methanol (2.0V), the filtrate was concentrated, and acetonitrile was evaporated to precipitate the solid, which was filtered and dried to obtain (+ / -)6-(2-amino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalene-2-ol (Formula V) with a purity of ≥96.0% and a yield of ≥93%.

[0053] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing an elastostat intermediate, characterized in that: The elastomeric intermediate is shown in Formula V The method comprises the steps of: (1) The compound of formula I undergoes a Suzuki reaction with biboric acid pinacol ester to obtain a compound of formula II; the compound of formula I is The compound of formula II is (2) The compound of formula II undergoes a Suzuki reaction with the compound of formula III to obtain a compound of formula IV; the compound of formula III is The compound of formula IV is (3) The compound of formula IV is subjected to hydrogenation reduction to obtain the compound of formula V.

2. The preparation method according to claim 1, characterized in that: Step (1) is to carry out Suzuki reaction of the compound of formula I with diboric acid pinacol ester in a first solvent in the presence of a palladium catalyst and a base to obtain a compound of formula II.

3. The preparation method according to claim 2, characterized in that: In step (1), the molar ratio of the compound of formula I to diboric acid pinacol ester is 1:1.05-1.5, preferably 1:1.2; The reaction temperature is 65-100°C, preferably 80-85°C; The reaction time is 1-8h, preferably 5-7h; The palladium catalyst is selected from one or more combinations of palladium / carbon, tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride; The mass ratio of the palladium catalyst to the compound of formula I is 0.5%-5%:1, preferably 1.5-2.0%:1; The reaction base is selected from a combination of one or more of sodium carbonate, potassium phosphate, potassium acetate, potassium bicarbonate, potassium carbonate, and sodium bicarbonate; The molar ratio of the base to the compound of formula I is 2-3.5:1, preferably 2.5:1; The first solvent is selected from acetone, 1,4-dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, toluene, N, A combination of one or more of N-dimethylformamide.

4. The preparation method according to claim 1, characterized in that: Step (2) is to carry out Suzuki reaction between the compound of formula II and the compound of formula III in the presence of a second solvent, the palladium catalyst and the base in the reaction system of step (1), and obtain the compound of formula IV after purification.

5. The preparation method according to claim 4, characterized in that: In step (2), the molar ratio of the compound of formula II to the compound of formula III is 1:1.10-1.4, preferably 1:1.25; The reaction temperature of formula (II) and formula (III) is 65-120°C, preferably 80-95°C; The reaction time is 1-16h; preferably 6-8h; The palladium catalyst is selected from one or more combinations of palladium / carbon, tetrakis(triphenylphosphine)palladium, palladium chloride, palladium acetate, and 1,1'-bis(diphenylphosphino)ferrocenepalladium chloride; The mass ratio of the palladium catalyst to the compound of formula II is 0.5%-5%:1, preferably 1.5-2.0%:1; The reaction base is selected from a combination of one or more of sodium carbonate, potassium phosphate, potassium acetate, potassium bicarbonate, potassium carbonate, sodium bicarbonate, and cesium carbonate; The molar ratio of the base to the compound of formula II is 2-3.5:1; preferably 2.5-3.0:1; The second solvent is selected from acetone, 1,4-dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, toluene, N, One of N-dimethylformamide or a combination with water; The volume ratio of the second solvent to water is 1:1-10:1; preferably 4:1; The refining solvent is selected from one or more combinations of dichloromethane, ethyl acetate, ethanol, methanol, isopropanol, isopropyl acetate, acetone, n-heptane, isopropyl ether, tetrahydrofuran and water.

6. The preparation method according to claim 1, characterized in that: Step (3) is to subject the compound of formula IV to hydrogenation reduction in the presence of a palladium catalyst in a third solvent to obtain a compound of formula V.

7. The preparation method according to claim 6, characterized in that: The reaction temperature of step (3) is 20-40°C, preferably 30-35°C; The reaction time is 1.5-10h, preferably 4-6h; The hydrogenation pressure is 0.2-1.0 MPa; preferably 0.5-0.6 MPa; The palladium catalyst is selected from a combination of one or more of palladium / carbon, palladium hydroxide / carbon, and platinum / carbon; The mass ratio of the palladium catalyst to the compound of formula IV is 1%-15%:1; The third solvent is selected from one or more combinations of methanol, tetrahydrofuran, acetone, ethanol, acetonitrile and isopropanol.

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