Preparation method of rubaburon intermediate 2-thiophenephenol

Abstract

The invention provides a preparation method of a rubabron intermediate 2-thiophenephenol, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: reacting a compound IV with a hydroxyl protecting group reagent under the action of a catalyst to obtain a compound III, carrying out Grignard reaction on a compound VI and magnesium to obtain a compound V, carrying out coupling reaction on the compound III and the compound V to obtain a compound II, and removing a protecting group from the compound II to obtain a compound I. The preparation method of the rubabron intermediate 2-thiophenephenol is mild in reaction condition, high in atom utilization rate, high in yield, high in product quality and beneficial to large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing 2-thiophenephenol, a lubabegron intermediate. Background Art

[0002] Lubabegron is an effective modulator of β-adrenergic receptors and is commonly used as a drug to reduce ammonia emissions from animals and their excreta. Studies have shown that adding lubabegron to feed during the growth period before cattle are slaughtered can significantly reduce ammonia emissions from bovine animals. Lubabegron is one of the most commonly used bovine feed additives in the world, and in major cattle-raising countries, the market demand for this drug is relatively large.

[0003] At present, the synthesis methods of 2-thiophenephenol, the intermediate of lubabenon, at home and abroad are mainly the following:

[0004] According to the reference (Journal of Heterocyclic Chemistry, 1985, 22(6), 1667-1669), butyl lithium reagent is reacted with 2-bromothiophene to prepare thienyl lithium, which is then reacted with the substrate aryl ether to obtain 2-(2-methoxyphenyl)thiophene, which is then reacted with pyridine hydrochloride at 200°C for 12 hours and hydrolyzed to demethylate to obtain the product 2-thiophene phenol.

[0005] According to the reference (Bioorganic and Medicinal Chemistry Letters, 2002, 12(3), 471-475), aryl boronic acid ether substrates were used to undergo Suzuki coupling reaction with halogenated thiophene via palladium catalyst to obtain 2-(2-methoxyphenyl)thiophene intermediate, which was then hydrolyzed and demethylated with pyridine hydrochloride at 220°C to obtain the product.

[0006] Referring to the invention patent with publication number KR101454693B1, 2-methoxyphenylboronic acid is used as a substrate, palladium acetate and triphenylphosphine are used as catalysts and potassium phosphate is used as a base, and a Suzuki coupling reaction is carried out with 2-bromothiophene to obtain a 2-(2-methoxyphenyl)thiophene intermediate, and then pyridine hydrochloride is used to react at 200°C for 12 hours, and hydrolysis and demethylation are carried out to obtain the product.

[0007] Referring to the invention patent with publication number CN115521299A, the synthetic route of lubaberon intermediate 2-thiophenephenol is to add a catalyst to the Grignard reagent prepared from o-bromoanisole and react it with 2-bromothiophene in a heat preservation manner. After completion, 2-(2-methoxyphenyl)thiophene is obtained, which is then mixed with pyridine hydrochloride and reacted at a high temperature of 180-220°C for 1-6 hours. After the reaction is completed, the 2-thiophenephenol product is obtained by treatment.

[0008] In all these synthesis methods, 2-thiophenephenol is obtained by hydrolyzing methoxyphenylthiophene. The pyridine hydrochloride used has a high melting point and a large amount of hydrochloride. The reaction conditions require a high temperature of 200°C and a long reaction time to achieve complete hydrolysis and demethylation. Most importantly, in actual industrial production, the reaction time needs to be extended to 60-90 hours to complete the reaction, which has the problem of long reaction time and low actual reaction efficiency. Summary of the invention

[0009] The present invention aims at the problems existing in the prior art and provides a method for preparing 2-thiophene phenol, an intermediate of lubaberon. The present invention uses 2-halogenated phenol as a raw material to react with a protecting group reagent, protects the hydroxyl group, and then reacts with a Grignard reagent of 2-halogenated thiophene to obtain a coupling product, and obtains the final product 2-thiophene phenol after acid hydrolysis. The method of the present invention uses the Grignard reaction as the main reaction, and obtains the lubaberon intermediate 2-thiophene phenol through four steps of reaction. Compared with the predecessors' Grignard method and Suzuki coupling reaction route, the method selects low-priced starting raw materials, greatly improves the reaction efficiency and conversion rate, reduces the cost, and effectively improves the market competitiveness of lubaberon products.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] In a first aspect, the present invention provides a method for preparing 2-thiophenephenol, an intermediate of lubabenon, comprising the following steps:

[0012] Step 1, reacting compound IV with a hydroxyl protecting group reagent in the presence of a catalyst to obtain compound III. The synthetic route is as follows:

[0013]

[0014] Step 2, subjecting compound VI and magnesium to a Grignard reaction to obtain compound V. The synthetic route is as follows:

[0015]

[0016] Step 3, compound III and compound V are subjected to coupling reaction to obtain compound II. The synthetic route is as follows:

[0017]

[0018] Step 4, compound II is subjected to a deprotection reaction to obtain compound I. The synthetic route is as follows:

[0019]

[0020] The X1 and X2 are independently selected from one of F, Cl, Br or I; and R is a protecting group of a hydroxyl group.

[0021] Furthermore, the hydroxyl protecting group reagent in step 1 is one of hexamethyldisiloxane, hexamethyldisilazane, trimethylchlorosilane, trimethylbromosilane, trimethyliodosilane, tris(trimethylsilyl)amine, 1,3-diphenyl-1,3-bis(trimethylsilyloxy)disiloxane, tert-butyl chloroformate, di-tert-butyl dicarbonate, benzyl chloride and benzyl bromide.

[0022] Furthermore, the reaction temperature in step 1 and step 2 is 0-55°C; in step 3, the coupling reaction temperature is 80-110°C; and in step 4, the deprotection reaction temperature is 25-100°C.

[0023] Furthermore, X1 is Cl or Br; X2 is Cl or Br; and the protecting group of the hydroxyl group is one of trimethylsilyl, benzyl or tert-butyl.

[0024] Preferably, the protecting group of the hydroxyl group is trimethylsilyl.

[0025] Furthermore, the solvents for the reactions in step 1 and step 2 are each independently selected from at least one of anhydrous ether, anhydrous ethylene glycol dimethyl ether, anhydrous diethylene glycol dimethyl ether, anhydrous toluene, anhydrous xylene, anhydrous hexane, anhydrous ethanol or anhydrous tetrahydrofuran.

[0026] Furthermore, the solvent is an anhydrous solvent.

[0027] Furthermore, the catalyst in step 1 is selected from at least one of triethylamine, N-methylmorpholine, scandium trifluoromethanesulfonate, trifluoromethanesulfonic acid, potassium carbonate or sodium hydroxide.

[0028] Preferably, the catalyst in step 1 is N-methylmorpholine, scandium trifluoromethanesulfonate or sodium hydroxide.

[0029] Furthermore, in step 1, the molar ratio of compound IV, hydroxyl protecting group reagent and catalyst is 1:(1-2):(0.05-1.5).

[0030] Preferably, in step 1, the molar ratio of compound IV, hydroxyl protecting group reagent and catalyst is 1:(1-1.5):(0.05-1).

[0031] Furthermore, in step 2, the molar ratio of compound VI to magnesium is 1:(1-1.5).

[0032] Preferably, the molar ratio of compound VI to magnesium in step 2 is 1:(1-1.2).

[0033] Furthermore, the catalyst for the coupling reaction in step 3 is at least one of nickel acetate, nickel chloride, bis(triphenylphosphine)nickel chloride or tetrakis(triphenylphosphine)nickel.

[0034] Preferably, the catalyst for the coupling reaction in step 3 is nickel acetate.

[0035] Furthermore, in step 3, the molar ratio of compound III, compound V and catalyst is 1:(1-1.5):(0.01-0.05).

[0036] Preferably, in step 3, the molar ratio of compound III, compound V and catalyst is 1:1.2:0.01.

[0037] Furthermore, in step 4, the deprotection group is removed using an acid, and the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, oxalic acid or citric acid.

[0038] Preferably, the acid is at least one of hydrochloric acid, hydrobromic acid and trifluoroacetic acid.

[0039] The technical effects achieved by the present invention are:

[0040] (1) The present invention uses 2-halogenated phenol as raw material, which is cheap and saves costs.

[0041] (2) The present invention protects the hydroxyl group, and then obtains the product 2-thiophenephenol through Grignard reaction, coupling reaction and acid hydrolysis. Only four steps are required, which shortens the reaction process and improves the reaction efficiency and conversion rate.

[0042] (3) The present invention protects the hydroxyl group and then obtains the product 2-thiophenephenol through Grignard reaction, coupling reaction and acid hydrolysis, without having to go through the harsh conditions of methoxyphenylthiophene hydrolysis, thereby improving production efficiency. DETAILED DESCRIPTION

[0043] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0044] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing specific embodiments rather than for limiting the scope of protection of the present invention.

[0045] When the embodiment gives a numerical range, it should be understood that, unless otherwise specified in the present invention, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present invention belongs.

[0046] It is worth noting that, unless otherwise specified, the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0047] The following sources of raw materials are provided for illustrative purposes:

[0048] Magnesium: industrial grade magnesium chips, Shanxi Fuhengdi Metal Materials Co., Ltd.;

[0049] Anhydrous tetrahydrofuran: industrial grade, Jiangsu Heshili New Materials Co., Ltd.;

[0050] o-Bromophenol, o-Chlorophenol: reagent grade, purity 98%, MacLean, Shanghai MacLean Biochemical Technology Co., Ltd.;

[0051] TMSCl: reagent grade, purity 99%, Anaiji Chemical, Anhui Zesheng Technology Co., Ltd.;

[0052] Hydrochloric acid: industrial grade or refined grade, Wanhua Chemical (Ningbo) Chlor-Alkali Co., Ltd.;

[0053] Embodiment 1:

[0054] Step 1, replace nitrogen three times in a 250mL four-necked bottle, add 120g toluene, 30g (0.17mol) of o-bromophenol and 26.2g (0.26mol) of N-methylmorpholine in sequence under the protection of nitrogen flow, add 24.2g (0.23mol) of TMSCl dropwise at 15-20°C, and react at 45°C for 2 hours. Add 80g of drinking water and stir for 20 minutes, stand for separation, extract the upper organic phase with 80g of 0.5% acetic acid aqueous solution, stand for separation, extract the organic phase with 80g of drinking water again, and evaporate the solvent to obtain 42.1g of crude (2-bromophenoxy)trimethylsilane, with a GC purity of 96.5% and a yield of 95.3%.

[0055] Step 2: Replace nitrogen in a 250mL four-necked bottle three times. Under the protection of nitrogen flow, add 4.5g (0.18mol) of magnesium chips and 60mL of anhydrous tetrahydrofuran in sequence. Add 27.7g (0.17mol) of 2-bromothiophene dropwise at 15-20°C. Control the temperature at 45°C to react for 2 hours to obtain a tetrahydrofuran solution of 2-thienylmagnesium bromide for later use.

[0056] Step 3: Replace nitrogen in a 250 mL four-necked bottle three times, add the crude (2-bromophenoxy)trimethylsilane and 0.3 g (1.7 mmol) of nickel acetate in step 1 in sequence under the protection of nitrogen flow, and slowly drip the tetrahydrofuran solution of 2-thienylmagnesium bromide in step 2 into the reaction bottle, and control the temperature at 100° C. After dripping, keep the temperature at 90-100° C. for 2 hours.

[0057] Step 4, cool the reaction bottle in step 3 to below 10°C, add a 10% hydrochloric acid aqueous solution dropwise until the pH of the solution is less than 2, control the temperature at 45°C, and stir for 2 hours. After the reaction is completed, stand and stratify, take the upper organic phase, concentrate, and then distill under reduced pressure to obtain a crude 2-thiophenephenol product, which is then recrystallized from hexane to obtain 28.0 g of the product, with a GC purity of 99% and a yield of 92%.

[0058] Embodiment 2:

[0059] Step 1, replace nitrogen three times in a 250mL four-necked bottle, add 120g toluene, 21.8g (0.17mol) of o-chlorophenol and 26.2g (0.26mol) of N-methylmorpholine in sequence under the protection of nitrogen flow, add 24.2g (0.23mol) of TMSCl dropwise at 15-20°C, and react at 45°C for 2 hours. Add 80g of drinking water and stir for 20 minutes, stand for separation, extract the upper organic phase with 80g of 0.5% acetic acid aqueous solution, stand for separation, extract the organic phase with 80g of drinking water again, and evaporate the solvent to obtain 33.6g of crude (2-chlorophenoxy)trimethylsilane, with a GC purity of 97.2% and a yield of 95.8%.

[0060] Step 2: Replace nitrogen in a 250 mL four-necked bottle three times. Under the protection of nitrogen flow, add 4.5 g (0.18 mol) of magnesium chips and 60 mL of anhydrous tetrahydrofuran in sequence. Add 20.1 g (0.17 mol) of 2-chlorothiophene dropwise at 15-20 ° C. Control the temperature at 45 ° C to react for 2 hours to obtain a tetrahydrofuran solution of 2-thienylmagnesium bromide for use.

[0061] Step 3: Replace nitrogen in a 250 mL four-necked bottle three times, add the crude (2-chlorophenoxy)trimethylsilane and 0.3 g (1.7 mmol) of nickel acetate in step 1 in sequence under the protection of nitrogen flow, and slowly drip the tetrahydrofuran solution of 2-thienylmagnesium chloride in step 2 into the reaction bottle, and control the temperature at 100° C. After dripping, keep the temperature at 90-100° C. for 2 hours.

[0062] Step 4, cool the reaction bottle in step 3 to below 10°C, add a 10% hydrochloric acid aqueous solution until the solution pH is less than 2, control the temperature at 45°C, and stir for 2 hours. After the reaction is completed, stand and stratify, take the upper organic phase and concentrate, then distill under reduced pressure to obtain a crude 2-thiophenephenol product, and then recrystallize from hexane to obtain 27.5g of the product, GC purity 99%, and yield 91%.

[0063] Embodiment 3:

[0064] Step 1, replace nitrogen three times in a 250mL four-necked bottle, add 120g toluene, 30g (0.17mol) of o-bromophenol and 4.18g (8.5mmol) of scandium trifluoromethanesulfonate in sequence under the protection of nitrogen flow, add 44.5g (0.20mol) of di-tert-butyl dicarbonate dropwise at 15-20°C, and react at 45°C for 2 hours. Add 80g of drinking water and stir for 20 minutes, stand for separation, extract the upper organic phase with 80g of 0.5% acetic acid aqueous solution, stand for separation, extract the organic phase with 80g of drinking water again, and evaporate the solvent to obtain 36.6g of crude 1-bromo-2-tert-butoxybenzene, with a GC purity of 96.0% and a yield of 90.3%.

[0065] Step 2: Replace nitrogen in a 250mL four-necked bottle three times. Under the protection of nitrogen flow, add 4.5g (0.18mol) of magnesium chips and 60mL of anhydrous tetrahydrofuran in sequence. Add 27.7g (0.17mol) of 2-bromothiophene dropwise at 15-20°C. Control the temperature at 45°C to react for 2 hours to obtain a tetrahydrofuran solution of 2-thienylmagnesium bromide for later use.

[0066] Step 3: Replace nitrogen in a 250 mL four-necked bottle three times, add the crude 1-bromo-2-tert-butoxybenzene in step 1 and 0.3 g (1.7 mmol) of nickel acetate in sequence under the protection of nitrogen flow, and slowly drip the tetrahydrofuran solution of 2-thienylmagnesium bromide in step 2 into the reaction bottle, and control the temperature at 100° C. After dripping, keep the temperature at 90-100° C. for 2 hours.

[0067] Step 4: Cool the reaction flask in step 3 to below 10°C, drop 57g of 48% hydrobromic acid solution, control the temperature at 90°C-100°C, and stir for 2 hours. After the reaction is completed, stand and separate, take the upper organic phase, concentrate, and then distill under reduced pressure to obtain a crude 2-thiophenephenol product, which is then recrystallized from hexane to obtain 25.7g of the product, with a GC purity of 99% and a yield of 85%.

[0068] Embodiment 4:

[0069] Step 1, replace nitrogen in a 250mL four-necked bottle three times, add 120g of ethanol, 30g (0.17mol) of o-bromophenol, 6.8g (0.17mol) of sodium hydroxide in sequence under the protection of nitrogen flow, add 31.9g (0.187mol) of benzyl bromide dropwise at 15-20°C, and react for 2 hours at a temperature below 45°C. Add 80g of drinking water and stir for 20 minutes, stand for separation, extract the upper organic phase with 80g of 0.5% acetic acid aqueous solution, stand for separation, extract the organic phase with 80g of drinking water again, and evaporate the solvent to obtain 41.9g of crude 2-benzyloxybromobenzene, with a GC purity of 95.0% and a yield of 89.1%.

[0070] Step 2: Replace nitrogen in a 250mL four-necked bottle three times. Under the protection of nitrogen flow, add 4.5g (0.18mol) of magnesium chips and 60mL of anhydrous tetrahydrofuran in sequence. Add 27.7g (0.17mol) of 2-bromothiophene dropwise at 15-20°C. Control the temperature at 45°C to react for 2 hours to obtain a tetrahydrofuran solution of 2-thienylmagnesium bromide for later use.

[0071] Step 3: Replace nitrogen in a 250 mL four-necked bottle three times, add the crude 2-benzyloxybromobenzene in step 1 and 0.3 g (1.7 mmol) of nickel acetate in sequence under the protection of nitrogen flow, and slowly drip the tetrahydrofuran solution of 2-thienylmagnesium bromide in step 2 into the reaction bottle, and control the temperature below 100° C. After dripping, keep 90-100° C. for 2 hours.

[0072] Step 4: Cool the reaction flask in step 3 to below 10°C, dropwise add 38.7 g of trifluoroacetic acid, and stir at 45°C for 2 hours. After the reaction is completed, stand and stratify, take the upper organic phase, concentrate, and then distill under reduced pressure to obtain a crude 2-thiophenephenol product, which is then recrystallized from hexane to obtain 25.4 g of the product, with a GC purity of 99% and a yield of 84%.

[0073] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing 2-thiophenephenol, an intermediate of lubabenon, characterized in that: The following steps are involved: Step 1: Compound IV reacts with a hydroxyl protecting group reagent under the action of a catalyst to obtain compound III. Synthesis route: Step 2, subjecting compound VI to a Grignard reaction with magnesium to obtain compound V. Synthesis route: Step 3, coupling reaction of compound III and compound V to obtain compound II. Synthesis route: Step 4, deprotecting compound II to obtain compound I. Synthesis route: The X1 and X2 are independently selected from one of F, Cl, Br or I; and R is a protecting group of a hydroxyl group.

2. The preparation method according to claim 1, characterized in that: The reaction temperature in step 1 and step 2 is 0-55°C; in step 3, the coupling reaction temperature is 80-110°C; and in step 4, the deprotection reaction temperature is 25-100°C.

3. The preparation method according to claim 1, characterized in that: The X1 is Cl or Br; the X2 is Cl or Br; the protecting group of the hydroxyl group is one of trimethylsilyl, benzyl or tert-butyl, preferably trimethylsilyl.

4. The preparation method according to claim 1, characterized in that: The solvents for the reactions in step 1 and step 2 are each independently selected from at least one of anhydrous ether, anhydrous ethylene glycol dimethyl ether, anhydrous diethylene glycol dimethyl ether, anhydrous toluene, anhydrous xylene, anhydrous hexane, anhydrous ethanol or anhydrous tetrahydrofuran, and the solvent is an anhydrous solvent.

5. The preparation method according to claim 1, characterized in that: The catalyst in step 1 is selected from at least one of triethylamine, N-methylmorpholine, scandium trifluoromethanesulfonate, trifluoromethanesulfonic acid, potassium carbonate or sodium hydroxide, preferably at least one of N-methylmorpholine, scandium trifluoromethanesulfonate or sodium hydroxide.

6. The preparation method according to claim 1, characterized in that: In the step 1, the molar ratio of compound IV, hydroxyl protecting group reagent and catalyst is 1:(1-2):(0.05-1.5), preferably 1:(1-1.5):(0.05-1).

7. The preparation method according to claim 1, characterized in that: The molar ratio of compound VI to magnesium in step 2 is 1:(1-1.5), preferably 1:(1-1.2).

8. The preparation method according to claim 1, characterized in that: The catalyst for the coupling reaction in step 3 is at least one of nickel acetate, nickel chloride, bis(triphenylphosphine)nickel chloride or tetrakis(triphenylphosphine)nickel, preferably nickel acetate.

9. The preparation method according to claim 1, characterized in that: The molar ratio of compound III, compound V and catalyst in step 3 is 1:(1-1.5):(0.01-0.05), preferably 1:1.2:0.

01.

10. The preparation method according to claim 1, characterized in that: In step 4, the deprotection group is removed by using an acid, wherein the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, oxalic acid or citric acid, preferably at least one of hydrochloric acid, hydrobromic acid and trifluoroacetic acid.

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