A method for synthesizing 3-(benzyloxy)-1-cyclobutanone

Abstract

The application discloses a synthesis method of 3-(benzyloxy)-1-cyclobutanone. The application relates to the technical field of organic chemical synthesis. The application takes epichlorohydrin as raw material, and first obtains compound (I) by opening ring through benzyl bromide; then, the compound (I) is ring-closed into cyclobutane (II) under alkaline conditions by reacting with diethyl malonate; compound (II) is hydrolyzed and decarboxylated to generate compound (III); then, the carboxylic acid is converted into an amino compound (IV) by performing Curtius rearrangement; finally, the amino group is obtained by oxidation to generate 3-(benzyloxy)-1-cyclobutanone (V). The application provides a simple and convenient industrial production route of 3-(benzyloxy)-1-cyclobutanone, and has the advantages of simple reaction operation, convenient post-treatment, low cost and good industrial production prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic chemical synthesis, and particularly relates to a synthesis method of 3-(benzyloxy)-1-cyclobutanone. BACKGROUND

[0002] Compound 3-(benzyloxy)-1-cyclobutanone is an important pharmaceutical intermediate and is a synthetic material of many drugs and auxiliary reagents. Cyclobutane has a unique rigid backbone structure, which can improve the metabolic stability of drug molecules and the binding efficiency with receptors, and has become the focus of increasing attention in the field of pharmaceutical chemistry in recent years. Among them, 1,3-disubstituted cyclobutane has a curved linear geometry and can be used as a substitute for conformationally restricted ethyl or propyl linkers. At present, a variety of small molecule drugs containing 1,3-disubstituted cyclobutane have entered the clinical stage, including histamine H3 antagonist PF-03654746 for treating cognitive impairment, and reverse agonist TAK-828F of retinoid-related ROR gamma t for treating autoimmune diseases.

[0003]

[0004] As for the synthesis of 3-(benzyloxy)-1-cyclobutanone, the methods reported in the literature mainly include the following methods:

[0005] Method one: Synthesis 2018, 50, 4949-4957. This literature reports a synthesis method of 3-(benzyloxy)-1-cyclobutanone, which uses vinyl benzyl ether and trichloroacetyl chloride in the presence of zinc copper reagent to ring close at room temperature to obtain a dichlorocyclobutanone intermediate, and then zinc powder is used to reduce the dichloro compound to obtain the product. This method needs to use a large amount of zinc copper reagent, and through our experiment, it is found that when a 100g scale experiment is carried out, the reaction has a heat accumulation phenomenon, the reaction temperature cannot be controlled, and the yield is not high, and there is a great risk in industrial production.

[0006]

[0007]

[0008] Method two: WO2013011115. This patent uses epoxy bromopropane and benzyl bromide as raw materials to open the ring under the catalysis of mercuric chloride, and then ring closes with methyl methylthiomethyl sulfone to obtain [3-(methylsulfinyl)-3-(methylthio)]-1-benzyloxy cyclobutane, which is finally oxidized by perchloric acid to obtain 3-(benzyloxy)-1-cyclobutanone.

[0009] The disadvantages of this route are that the methyl methylthiomethyl sulfone raw material is not easy to purchase, the raw material cost is high, and n-butyllithium needs to be used, which requires deep cooling and strict equipment requirements.

[0010] ​

[0011] Method three: in CN111320535, the patent takes 1,3-dibromo-2,2-dimethoxypropane and diisopropyl malonate as starting materials, substitutes and closes under alkaline conditions, then deprotects and deacidifies to obtain 3-oxocyclobutyl carboxylic acid, then performs Hunsdiecker reaction under silver oxide catalysis to obtain 3-bromocyclobutanone, and finally reacts with benzyl alcohol to obtain 3-(benzyloxy)-1-cyclobutanone.

[0012] The patent reaction is simple and convenient, and the raw materials are also cheap and easy to obtain, but when performing Hunsdiecker reaction, equivalent silver oxide is needed, and the cost is difficult to control. Although the reaction of this route is simple, the catalyst is high in price and large in amount, and the industrialization cost is high.

[0013] SUMMARY

[0014] The purpose of the present application is to provide a new method for synthesizing 3-(benzyloxy)-1-cyclobutanone with low cost and high yield.

[0015] The synthesis method of 3-(benzyloxy)-1-cyclobutanone provided by the present application is characterized by taking epichlorohydrin as a raw material, first opening the ring by benzyl bromide to obtain compound (I), then closing the ring to cyclobutane (II) under alkaline conditions with diethyl malonate, hydrolyzing and decarboxylating compound (II) to obtain compound (III), then converting the carboxylic acid into an amino compound (IV) by Curtius rearrangement, and finally obtaining 3-(benzyloxy)-1-cyclobutanone (V) by oxidation of the amino group:

[0016] The synthesis route is as follows:

[0017]

[0018] Further, the specific operation is as follows:

[0019] S1, the raw materials epichlorohydrin and benzyl bromide are opened under the catalysis of a catalyst to obtain an intermediate (I);

[0020] S2, in an organic solvent, the intermediate (I) reacts with diethyl malonate under alkaline conditions, the reaction is heated to the boiling point of the solvent for a period of time, then cooled, filtered, and the filtrate is concentrated to obtain a liquid; the liquid is further heated to a certain temperature for a period of time, then cooled, filtered, and the intermediate (II) is obtained;

[0021] S3, in an organic solvent, the intermediate (II) is hydrolyzed and decarboxylated under alkaline conditions to obtain the intermediate (III);

[0022] S4. In an organic solvent, intermediate (III) undergoes rearrangement reaction with DPPA, and then deprotects the Boc group under acidic conditions to obtain intermediate (IV);

[0023] S5. Intermediate (IV) is oxidized to 3-(benzyloxy)-1-cyclobutanone under the condition of an oxidant.

[0024] Furthermore, the catalyst used in step S1 is mercuric chloride; and / or, the molar ratio of epichlorohydrin to benzyl bromide is 1:1 to 1.5.

[0025] Furthermore, the reaction temperature is 100-150° C., and the reaction time is 5-10 hours.

[0026] Furthermore, in step S2, the molar ratio of intermediate (I): diethyl malonate: base is 1:1-3:1-3; and\or,

[0027] In step S2, the reaction is heated to reflux for 2 to 8 hours; the liquid is further heated to 120 to 125°C for 2 to 5 hours, then cooled and filtered to obtain intermediate (II); and\or,

[0028] In step S2, the organic solvent is methanol, ethanol, tert-butanol or tetrahydrofuran; and\or,

[0029] The base used in step S2 is one or more of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide.

[0030] Furthermore, in step S3, the organic solvent is 30% methanol aqueous solution, 30% ethanol aqueous solution or 30% tetrahydrofuran aqueous solution; and\or,

[0031] The alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium carbonate.

[0032] Furthermore, in step S3, the hydrolysis temperature is 75-80° C.; and\or,

[0033] The decarboxylation temperature is 100-120°C.

[0034] Furthermore, in step S4, the organic solvent is toluene / tert-butanol or tert-butanol; and\or,

[0035] The molar ratio of the intermediate (III) to DPPA is 1:1.2 to 1:2; and\or,

[0036] The base is triethylamine, N,N-diisopropylethylamine or DBU; and\or,

[0037] The acidic condition is ethanolic hydrochloride, ethyl hydrochloride, isopropyl hydrochloride or trifluoroacetic acid.

[0038] Furthermore, in step S5, the molar ratio of the intermediate (IV) to the oxidant is 1:1 to 1:1.5; and\or,

[0039] The reaction temperature is 0-5°C, and the reaction time is 0.5-1 hour.

[0040] Furthermore, in step S5, the oxidant used is m-chloroperbenzoic acid, hydrogen peroxide, sodium chlorite or iodobenzene diacetate; and\or,

[0041] In step S5, the solvent used is ethyl acetate, dichloromethane, tetrahydrofuran or ethanol.

[0042] The present invention uses epichlorohydrin as the starting material and undergoes a five-step reaction process: benzyl bromide ring opening, diethyl malonate ring closure, hydrolytic decarboxylation, Curtius rearrangement, and amino oxidation. A high-purity product is obtained by distillation. This patent provides a simple industrial production route for 3-(benzyloxy)-1-cyclobutanone, which has the advantages of simple reaction operation, convenient post-processing, low cost, and good prospects for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The following is the hydrogen NMR spectrum of the synthetic product 3-(benzyloxy)-1-cyclobutanone of the present invention. DETAILED DESCRIPTION

[0044] The following are specific embodiments of the present invention and the accompanying drawings to further describe the technical solutions of the present invention, but the present invention is not limited to these embodiments.

[0045] Example 1

[0046] Step S1: using epichlorohydrin as a raw material, firstly performing ring opening with benzyl bromide to obtain compound (I);

[0047]

[0048] To a 500ml three-necked reaction flask, add epichlorohydrin (30.0g, 324mmol), start stirring, add mercuric chloride (0.05g, 0.18mmol), and benzyl bromide (58.2g, 340mmol, 1.05eq). Under nitrogen, slowly raise the temperature to 140°C and react for 15 hours. Then, cool to 20-25°C, transfer the reaction solution to a single-necked flask, and distill compound (I) using an oil pump to obtain 59g of a colorless oily liquid with a yield of 71%. 1H-NMR (400MHz, CDCl3): 3.52-3.62(2H,m), 3.67-3.74(2H,m), 3.78-3.86(1H,m), 4.63-4.72(2H,m), 7.28-7.42(5H,m).

[0049] Step S2, compound (I) and diethyl malonate are cyclized under alkaline conditions to form cyclobutane (II);

[0050]

[0051] To a 500ml three-necked flask, add anhydrous ethanol (160ml) and stir. Add sodium ethoxide (12.91g, 189mmol) and stir to dissolve. Add compound (I) (20g, 75.9mmol) and diethyl malonate (14.58g, 91mmol) under nitrogen protection. Raise the temperature to 75-80°C and react for 3 hours. Cool to room temperature, filter the solid, and rinse the filter cake with ethanol. The filtrate is concentrated under reduced pressure to dryness to obtain an oil. The oil is then heated to 120-125°C and reacted for 2 hours. Cool to room temperature, filter the turbid solid again, rinse the filter cake once with ethanol, and concentrate the filtrate to obtain 20.4g of compound (II) with a yield of 88%.

[0052] Step S3, compound (II) is hydrolyzed and decarboxylated to generate compound (III);

[0053]

[0054] In a reaction flask, add water (10 ml), add potassium hydroxide (8.52 g, 152 mmol), stir to dissolve the solid, then cool to 10-15 °C. Add ethanol (30 ml), add compound (II) (8 g, 26 mmol), warm to 75-80 °C, react for 1-2 hours, monitor by sampling, the raw material is completely reacted. Cool to room temperature, transfer the reaction solution to a single-neck flask, concentrate the ethanol under reduced pressure, then add water (20 ml), cool to 10-15 °C, stir, adjust the pH to 1-2 with concentrated hydrochloric acid, extract twice with methyl tert-butyl ether, combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain a light yellow liquid, then add petroleum ether, stir at room temperature for 10 minutes, then slowly cool to 5-8 °C, incubate for 10 minutes, a large amount of solid is precipitated, filter, rinse the filter cake with petroleum ether once, and air dry to obtain white solid 6.5 g. Then add 13 ml of pyridine, stir, slowly warm to 120 °C, react for 5 hours, monitor by sampling, the intermediate is completely reacted, concentrate most of the pyridine under reduced pressure, add methyl tert-butyl ether, adjust the pH to 1-2 with 2N hydrochloric acid, separate, the water layer is extracted once more with methyl tert-butyl ether, combine the organic layers, wash once with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain light brown oily compound (III) 4.04 g, with a yield of 75%.

[0055] Step S4, perform Curtius rearrangement to convert the carboxylic acid into an amino compound (IV);

[0056]

[0057] In a reaction flask, add compound (III) (20 g, 97 mmol), tert-butyl alcohol (100 ml), stir, add N, N-diisopropyl ethylamine (16.2 g, 126 mmol), DPPA (34.7 g, 126 mmol), protect with nitrogen, slowly warm to 80 °C, react for 5 hours, then cool to room temperature, add water, extract twice with ethyl acetate, combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure to obtain an oily liquid. Then add 5N hydrogen chloride isopropyl alcohol solution (60 ml), stir at room temperature for 3 hours, concentrate the solvent, add ethyl acetate, stir for 30 minutes, precipitate the solid, filter to obtain white solid 3-benzyloxy cyclobutylamine hydrochloride 15.1 g, with a yield of 73%.

[0058] Step S5, obtain 3-(benzyloxy)-1-cyclobutanone (V) by oxidation reaction;

[0059]

[0060] Into a reaction flask, 3-benzyloxy-cyclobutylamine (10 g, 56.4 mmol), dichloromethane (100 ml), stirring, nitrogen protection, cooling to 0°C, adding iodine benzene diacetate (36.3 g, 113 mmol) in batches, then adding TEMPO (1.76 g, 11 mmol), reacting for 30 minutes at about 0°C, then slowly warming to room temperature for 30 minutes, sampling monitoring until the raw material is completely reacted. Add 50 ml of water, separate the liquid, continue to extract the water layer with dichloromethane twice, combine the organic layer, wash with saturated sodium bicarbonate once, wash with saturated brine once, dry, filter, and concentrate under reduced pressure to obtain 3-(benzyloxy)-1-cyclobutanone as an oily liquid.

[0061] Distill under reduced pressure with an oil pump to obtain 8.7 g of colorless liquid, with a yield of 88%.

[0062] Figure 1 NMR of hydrogen spectrum of the synthetic product 3-(benzyloxy)-1-cyclobutanone of the present application.

[0063] 1 H-NMR (400 MHz, CDCl3): 3.10-3.25 (4H, m), 4.33-4.39 (1H, m), 4.51 (2H, s), 7.28-7.38 (5H, m).

[0064] The above-mentioned matters not covered are applicable to the prior art.

[0065] Although some specific embodiments of the present application have been described in detail by way of examples, it should be understood that the examples are only for illustration and are not intended to limit the scope of the present application. Those skilled in the art can make various modifications or supplements to the described specific embodiments or use similar ways to replace them without deviating from the direction of the present application or exceeding the scope defined by the appended claims. Those skilled in the art should understand that any modification, equivalent replacement, improvement, etc. made to the above embodiments in accordance with the technical essence of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing 3-(benzyloxy)-1-cyclobutanone, characterized in that: Using epichlorohydrin as the raw material, compound (I) is firstly obtained by benzyl bromide ring opening, and then the ring is closed with diethyl malonate under alkaline conditions to compound (II). Compound (II) is hydrolyzed and decarboxylated to generate compound (III), and then a Curtius rearrangement is performed to convert the carboxylic acid into an amino compound (IV). Finally, the amino group is oxidized to obtain 3-(benzyloxy)-1-cyclobutanone (V): The synthetic route is as follows: The specific operations are as follows: S1, raw materials epichlorohydrin and benzyl bromide, open the ring under the catalysis of a catalyst to obtain compound (I); S2. In an organic solvent, compound (I) reacts with diethyl malonate under alkaline conditions. The reaction temperature is raised to the boiling point of the solvent and refluxed for a period of time, then cooled, filtered, and the filtrate is concentrated to obtain a liquid. The liquid is further heated to a certain temperature and reacted for a period of time, then cooled, filtered, and the compound (II) is obtained. S3, in an organic solvent, compound (II) is hydrolyzed and decarboxylated under alkaline conditions to obtain compound (III); in step S3, pyridine is added, and the decarboxylation temperature is 100-120°C; S4. In an organic solvent, compound (III) undergoes a rearrangement reaction with DPPA, and then removes the Boc protection under acidic conditions to obtain amino compound (IV); the organic solvent is toluene / tert-butanol or tert-butanol; the acidic conditions are ethanolic hydrochloride, ethyl hydrochloride, isopropanol hydrochloride or trifluoroacetic acid; S5. Amino compound (IV) is oxidized to 3-(benzyloxy)-1-cyclobutanone under the condition of an oxidant; In step S5, the molar ratio of the amino compound (IV) to the oxidant is 1:1 to 1:1.5; The oxidants used are iodobenzene diacetate and TEMPO; the specific operation of step S5 is to add 3-benzyloxycyclobutylamine and dichloromethane, stir, protect with nitrogen, cool to 0°C, add iodobenzene diacetate in batches, then add TEMPO, react at about 0°C for 30 minutes, then slowly heat to room temperature for 30 minutes, take samples and monitor until the raw materials are completely reacted.

2. The synthesis method according to claim 1, wherein The catalyst used in step S1 is mercuric chloride; and / or, the molar ratio of epichlorohydrin to benzyl bromide is 1:1-1.

5.

3. The synthesis method according to claim 1, wherein The reaction temperature is 100-150°C, and the reaction time is 5-10 hours.

4. The synthesis method according to claim 1, characterized in that In step S2, the molar ratio of compound (I): diethyl malonate: base is 1:1-3:1-3; and\or, In step S2, the reaction is heated to reflux for 2 to 8 hours; the liquid is further heated to 120 to 125°C for reaction for 2 to 5 hours, then cooled and filtered to obtain compound (II); and\or, In step S2, the organic solvent is methanol, ethanol, tert-butanol or tetrahydrofuran; and\or, The base used in step S2 is one or more of potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide or potassium tert-butoxide.

5. The synthesis method according to claim 1, characterized in that In step S3, the organic solvent is 30% methanol aqueous solution, 30% ethanol aqueous solution or 30% tetrahydrofuran aqueous solution; and\or, The alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide or sodium carbonate.

6. The synthesis method according to claim 1, characterized in that In step S3, the hydrolysis temperature is 75-80°C.

7. The synthesis method according to claim 1, characterized in that In step S4, The molar ratio of the compound (III) to DPPA is 1:1.2 to 1:2; and\or, The base is triethylamine, N,N-diisopropylethylamine or DBU.

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