阅读说明：本技术 芳香醚类化合物的制备方法 (Process for producing aromatic ether compound ) 是由 吴亮 周琛 邓一军 于 2020-06-22 设计创作，主要内容包括：本发明公开一种芳香醚类化合物的制备方法。该制备方法包括如下步骤：c)在溶剂中,在催化剂和碱存在下,化合物V与化合物6反应,得化合物VII,即可；<Image he="256" wi="700" file="DDA0002550241900000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,化学式中各基团的定义如说明书中所述；所述溶剂为选自水、四氢呋喃、2-甲基四氢呋喃、乙酸乙酯和二氧六环中的二元以上的溶剂体系。本发明的芳香醚类化合物的制备方法,能够极大地提高上述反应的转化率,进而会提高该步的收率及整条反应路线的总收率；极大地简化了制备化合物VII的后处理及纯化操作,只需简单地将反应液过滤,将滤饼洗涤,干燥,即可得到纯度很高的化合物VII,适于工业放大生产。(The invention discloses a preparation method of an aromatic ether compound. The preparation method comprises the following steps: c) reacting a compound V with a compound 6 in a solvent in the presence of a catalyst and alkali to obtain a compound VII; wherein, the definition of each group in the chemical formula is described in the specification; the solvent is a binary or higher solvent system selected from water, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and dioxane. The preparation method of the aromatic ether compound can greatly improve the conversion rate of the reaction, and further improve the yield of the step and the total yield of the whole reaction route; greatly simplifies the post-treatment and purification operation of preparing the compound VII, and can obtain the compound VII with high purity by simply filtering the reaction liquid, washing and drying the filter cake, thereby being suitable for industryAnd (5) carrying out scale-up production.)

1. A method for preparing a compound shown as a formula VII is characterized by comprising the following steps:

c) reacting a compound V with a compound 6 in a solvent in the presence of a catalyst and alkali to obtain a compound VII;

wherein ring a is an aromatic ring or a heteroaromatic ring, preferably a 6-to 10-membered aromatic ring or a 5-to 10-membered heteroaromatic ring, more preferably a benzene ring, a naphthalene ring, a pyridine ring or a quinoline ring; the hydroxyl group is attached to a carbon on ring A;

each R₁Each independently selected from-R₂、

k is 0 to the maximum number of rings A that can be substituted; preferably k is an integer from 0 to 6; more preferably k is an integer of 0 to 4; further preferably k is 0, 1 or 2, most preferably k is 1;

the solvent is a binary or higher solvent system selected from water, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and dioxane.

2. The process according to claim 1, wherein in step c) compound V ism and n are each independently 0, 1,2 or 3; preference is given to

3. The process according to claim 1, wherein the compound of formula VII is prepared by reacting a compound of formula VII,

in step c), the compound V isThe compound VII ism and n are each independently 0, 1,2 or 3;

preferably, the compound V isThe compound VII ism and n are each independently 0, 1,2 or 3;

more preferably, the compound V isThe compound VII is

Even more preferably, the compound V isThe compound VII is

4. The process of any one of claims 1 to 3, wherein in step c), the solvent is a binary solvent system or a ternary solvent system selected from the group consisting of water, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and dioxane.

5. The process of any one of claims 1 to 3, wherein in step c), the solvent is any one of binary solvent systems of water/tetrahydrofuran, water/2-methyltetrahydrofuran and water/ethyl acetate; or any one of ternary solvent systems of water/2-methyltetrahydrofuran/tetrahydrofuran and water/2-methyltetrahydrofuran/dioxane; the solvent is preferably a water/tetrahydrofuran binary solvent system or a water/2-methyltetrahydrofuran/tetrahydrofuran ternary solvent system; more preferably a water/2-methyltetrahydrofuran/tetrahydrofuran ternary solvent system;

in the binary solvent system, the volume ratio of water to the organic solvent is preferably 10:15 to 15:0.1, more preferably 0.8:1 to 1.2:1, and still more preferably 1: 1;

in the ternary solvent system, the volume ratio of the three is preferably 10:15:15 to 15:5:5, more preferably 3:2:1 to 2.25:0.5:1, and even more preferably 2:1: 1.

6. The process according to any one of claims 1 to 5 for the preparation of a compound of formula VII,

in step c), the catalyst is a quaternary ammonium phase transfer catalyst, preferably one or more of tetrabutylammonium hydroxide, tetrabutylammonium acetate, tetrabutylammonium hydrogen sulfate and tetrabutylammonium chloride, more preferably tetrabutylammonium hydroxide;

preferably, in step c), the base is selected from one or both of sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate;

preferably, in step c), the molar ratio of said compound V to said catalyst is from 1:0.01 to 1:0.3, preferably from 1:0.05 to 1:0.2, more preferably 1: 0.1;

preferably, in step c), the molar ratio of the compound V to the base is from 1:2.5 to 1:15, preferably from 1:6 to 1:10, more preferably from 1:6 to 1:8, even more preferably from 1:7 to 1: 8;

preferably, in step c), the molar ratio of said compound V to said compound 6 is from 1:1 to 1:5, preferably from 1:2 to 1:3, more preferably from 1:2.5 to 1: 2.7;

preferably, in step c), the volume/mass ratio of the solvent to the compound V is from 20mL/g to 50mL/g, preferably from 24mL/g to 45mL/g, more preferably from 25mL/g to 40mL/g, even more preferably from 25mL/g to 35mL/g, still even more preferably 30 mL/g;

preferably, in step c), the reaction temperature of the reaction is from 20 ℃ to 35 ℃, preferably from 25 ℃ to 30 ℃.

7. The process of any one of claims 1 to 6, wherein step c) is preceded by the further step of:

b) hydrolyzing the compound 3 in a solvent in the presence of alkali to obtain a compound 4,

in step b), the solvent is preferably a mixed solvent of 2-methyltetrahydrofuran and water; the base is preferably lithium hydroxide;

preferably, step b) is preceded by the further steps of:

a) in a solvent, in the presence of alkali, a compound 1 reacts with a compound 2 to obtain a compound 3,

in step a), the solvent is preferably dichloromethane; the base is preferably one or both of triethylamine and diisopropylethylamine, and triethylamine is more preferred.

8. A preparation method of a compound shown as a formula VIII is characterized by comprising the following steps:

d) reacting compound 4 with compound VII in the presence of a base in a solvent to obtain compound VIII,

wherein ring A is an aromatic ring or a heteroaromatic ring, preferably a 6-to 10-membered aromatic ring or a 5-to 10-membered heteroaromatic ring, more preferably a benzene ring,A naphthalene ring, a pyridine ring or a quinoline ring; -OCH₂Cl is attached to the carbon on ring A;

each R₁Each independently selected from-R₂、 -NO₂、-NO、

k is 0 to the maximum number of rings A that can be substituted; preferably k is an integer from 0 to 6; more preferably k is an integer of 0 to 4; further preferably k is 0, 1 or 2, most preferably k is 1;

the compound VII is prepared according to the preparation method of the compound shown in the formula VII in any one of claims 1 to 7;

in step d), the solvent is preferably one or more of DMF, NMP and ACN, more preferably DMF;

in step d), the base is preferably one or more of potassium carbonate, cesium carbonate and sodium carbonate, more preferably potassium carbonate;

in step d), the molar ratio of said compound 4 to said base is preferably 1-1.5:1, more preferably 1.2: 1;

in step d), the molar ratio of said compound 4 to said compound VII is preferably 1-1.5:1, more preferably 1.2: 1;

in step d), the ratio of the volume of the solvent to the mass of the compound 4 is preferably 8:1 to 12:1mL/g, more preferably 10:1 mL/g;

in step d), the reaction temperature of the reaction is preferably 20 ℃ to 30 ℃.

9. The method according to claim 8, further comprising a step e) of separating and purifying the compound VIII after the step d); said step e) preferably comprises the steps of: dissolving the compound VIII obtained in the step d) in a normal solvent, and then mixing the compound VIII with an anti-solvent to obtain a crystal of the compound VIII;

wherein the positive solvent is preferably ethyl acetate; the anti-solvent is preferably petroleum ether.

10. The process according to claim 8 or 9, wherein the compound VII isThe compound VIII is

Technical Field

The invention relates to a preparation method of an aromatic ether compound.

Background

Nitroxoline (Nitroxoline), a commercially available antibacterial agent, has long been used to treat urinary tract infections. Recent findings indicate that nitroxoline is also very effective in inhibiting angiogenesis and inhibiting growth and invasion of cancer cells, and is currently being developed for anti-tumor applications. Human pharmacokinetic studies show that nitroxoline can be rapidly absorbed into blood circulation, but the first-pass effect of the liver on the drug is serious, so that the biological half-life of the nitroxoline is very short (according to a one-arm, open and multi-center clinical second-phase experiment carried out by Jiangsu Asian Rainbow medicine science and technology Limited in China, the half-life of the nitroxoline is 1.22-1.44 hours), and frequent administration is required. In order to maintain continuous drug exposure, nitroxoline drugs are generally prescribed for Three (TID) or four (QID) times a day, which not only results in economic loss and adverse patient compliance, but also increases the sustained damage of the drug to the normal body. Meanwhile, due to low water solubility of the nitroxoline, the nitroxoline is often required to be prepared into a quick-release preparation, so that the solubility is improved, and the production cost is increased invisibly.

Prodrugs (produgs) are compounds obtained by chemically modifying active drugs, and are converted into the original drugs by the action of enzymes in vivo to exert pharmacological effects. Prodrugs have found wide application in drug development, which has been successfully studied and achieved good application results in a variety of different drugs. Some of the drawbacks of the parent drug (active agent) due to its physicochemical properties can be solved by prodrug strategy, such as: 1) eliminating bad odor of medicine; 2) the blood concentration is improved; 3) improving the fat solubility or water solubility of the medicine; 4) prolonging the action time of the medicine; 5) changing the administration route of the drug, etc.

((5-nitroquinolin-8-yl) oxy) methylisobutyryl-L-prolinate is a prodrug of nitroxoline which solves the above-mentioned disadvantages of nitroxoline. At present, only patent application WO 2020/063824A 1 discloses a process for the preparation of ((5-nitroquinolin-8-yl) oxy) methylisobutyryl-L-prolinate, which is specified below:

however, in the above preparation method, the conversion rate of the first step reaction is low, which in turn leads to low yield of the step and ultimately to low yield of the overall synthetic route.

Disclosure of Invention

In order to solve the technical problem that the conversion rate of the first step reaction in the preparation method is low, the invention provides a preparation method of an aromatic ether compound.

Accordingly, it is an object of the present invention to provide a process for the preparation of a compound of formula VII, comprising the steps of:

c) reacting a compound V with a compound 6 in a solvent in the presence of a catalyst and alkali to obtain a compound VII;

wherein ring a is an aromatic ring or a heteroaromatic ring, preferably a 6-to 10-membered aromatic ring or a 5-to 10-membered heteroaromatic ring, more preferably a benzene ring, a naphthalene ring, a pyridine ring or a quinoline ring; the hydroxyl group is attached to a carbon on ring A;

each R₁Each independently selected from -NO₂、NO、-S-R₂、-OR₂and-X; wherein each R is₂Each independently selected from C₁-C₂₀Alkyl, preferably C₁-C₆Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl; x is selected from halogen, preferably fluorine, chlorine, bromine or iodine;

k is 0 to the maximum number of rings A that can be substituted; preferably k is an integer from 0 to 6; more preferably k is an integer of 0 to 4; further preferably k is 0, 1 or 2, most preferably k is 1;

the solvent is a binary or higher solvent system selected from water, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and dioxane.

In a preferred embodiment of the present invention, the process for preparing the compound of formula VII according to the present invention, wherein in step c), the compound V ism and n are each independently 0, 1,2 or 3; preference is given tom and n are each independently 0, 1,2 or 3; more preferably

Further more preferably

In another preferred embodiment of the present invention, the process for the preparation of the compound of formula VII according to the present invention, wherein in step c), the compound V is

The compound VII ism and n are each independently 0, 1,2 or 3;

preferably, the compound V is

The compound VII ism and n are each independently 0, 1,2 or 3;

more preferably, the compound V is

The compound VII is

Even more preferably, the compound V is

The compound VII is

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VII according to the present invention, wherein in step c), the halogen is fluorine, chlorine, bromine or iodine.

In another preferred embodiment of the present invention, the method for preparing the compound represented by formula VII according to the present invention, wherein, in step c), the solvent is selected from a binary solvent system or a ternary solvent system of water, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate and dioxane.

In another preferred embodiment of the present invention, the method for preparing the compound represented by the formula VII according to the present invention, wherein, in the step c), the solvent is any one of binary solvent systems of water/tetrahydrofuran, water/2-methyltetrahydrofuran and water/ethyl acetate; or any one of ternary solvent systems of water/2-methyltetrahydrofuran/tetrahydrofuran and water/2-methyltetrahydrofuran/dioxane; the solvent is preferably a water/tetrahydrofuran binary solvent system or a water/2-methyltetrahydrofuran/tetrahydrofuran ternary solvent system; more preferred is a water/2-methyltetrahydrofuran/tetrahydrofuran ternary solvent system. In the binary solvent system, the volume ratio of water to the organic solvent is preferably 10:15 to 15:0.1, more preferably 0.8:1 to 1.2:1, and still more preferably 1: 1. In the ternary solvent system, the volume ratio of the three is preferably 10:15:15 to 15:5:5, more preferably 3:2:1 to 2.25:0.5:1, and even more preferably 2:1: 1; the volume ratio of the three substances refers to the volume ratio of the three substances appearing in the ternary system in sequence.

In another preferred embodiment of the present invention, the method for preparing the compound represented by formula VII according to the present invention, wherein, in step c), the catalyst is a conventional quaternary ammonium phase transfer catalyst, preferably one or more of tetrabutylammonium hydroxide, tetrabutylammonium acetate, tetrabutylammonium hydrogen sulfate and tetrabutylammonium chloride, more preferably tetrabutylammonium hydroxide.

In another preferred embodiment of the present invention, the method for preparing the compound represented by formula VII according to the present invention, wherein, in step c), the base is one or two of sodium bicarbonate and potassium bicarbonate, preferably sodium bicarbonate.

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VII according to the present invention, wherein in step c), the molar ratio of the compound V to the catalyst is 1:0.01 to 1:0.3, preferably 1:0.05 to 1:0.2, more preferably 1: 0.1.

In another preferred embodiment of the present invention, the compound of formula VII according to the present invention is prepared by a process, wherein in step c), the molar ratio of the compound V to the base is 1:2.5 to 1:15, such as 1:3, preferably 1:6 to 1:10, more preferably 1:6 to 1:8, even more preferably 1:7 to 1: 8.

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VII according to the present invention, wherein in step c), the molar ratio of the compound V to the compound 6 is 1:1 to 1:5, preferably 1:2 to 1:3, more preferably 1:2.5 to 1: 2.7.

In another preferred embodiment of the present invention, the volume/mass ratio of the solvent to the compound V in step c) is 20mL/g to 50mL/g, preferably 24mL/g to 45mL/g, more preferably 25mL/g to 40mL/g, even more preferably 25mL/g to 35mL/g, and most preferably 30 mL/g.

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VII according to the present invention, wherein, in step c), the reaction temperature of the reaction is 20 ℃ to 35 ℃, preferably 25 ℃ to 30 ℃.

In another preferred embodiment of the present invention, the method for preparing the compound represented by formula VII according to the present invention, wherein step c) may further comprise the following steps:

b) hydrolyzing the compound 3 in a solvent in the presence of alkali to obtain a compound 4,

in step b), the solvent is preferably a mixed solvent of 2-methyltetrahydrofuran and water; the base is preferably lithium hydroxide.

The step b) can be further preceded by the following steps:

a) in a solvent, in the presence of alkali, a compound 1 reacts with a compound 2 to obtain a compound 3,

in step a), the solvent is preferably dichloromethane; the base is preferably one or both of triethylamine and diisopropylethylamine, and triethylamine is more preferred.

The invention further provides a preparation method of the compound shown in the formula VIII, which is characterized by comprising the following steps:

d) reacting compound 4 with compound VII in the presence of a base in a solvent to obtain compound VIII,

wherein ring a is an aromatic or heteroaromatic ring, preferably a 6-to 10-membered aromatic or 5-to 10-membered heteroaromatic ring, more preferably a benzene, naphthalene, pyridine, quinoline ring; -OCH₂Cl is attached to the carbon on ring A;

each R₁Each independently selected from-R₂、 -NO₂、-NO、-S-R₂、-OR₂and-X; wherein each R is₂Each independently selected from C₁-C₂₀Alkyl, preferably C₁-C₆Alkyl, more preferably methyl, ethyl, n-propyl or isopropyl; x is selected from halogen, preferably fluorine, chlorine, bromine or iodine;

k is 0 to the maximum number of rings A that can be substituted; preferably k is an integer from 0 to 6; more preferably k is an integer of 0 to 4; further preferably k is 0, 1 or 2, most preferably k is 1;

the compound VII is prepared according to the preparation method of the compound shown in the formula VII.

In a preferred embodiment of the present invention, the method for preparing the compound represented by formula VIII according to the present invention, wherein, in step d), the solvent is one or more of DMF, NMP and ACN, preferably DMF.

In another preferred embodiment of the present invention, the preparation method of the compound represented by formula VIII according to the present invention, wherein, in step d), the base is one or more of potassium carbonate, cesium carbonate and sodium carbonate, preferably potassium carbonate.

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VIII according to the present invention, wherein in step d), the molar ratio of the compound 4 to the base is 1-1.5:1, preferably 1.2: 1.

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VIII according to the present invention, wherein, in step d), the molar ratio of the compound 4 to the compound VII is preferably 1-1.5:1, more preferably 1.2: 1.

In another preferred embodiment of the invention, the ratio of the volume of the solvent to the mass of the compound 4 in the step d) is 8:1mL/g to 12:1mL/g, preferably 10:1 mL/g.

In another preferred embodiment of the present invention, the process for preparing the compound represented by formula VIII according to the present invention, wherein, in step d), the reaction temperature of the reaction is 20 ℃ to 30 ℃.

According to the preparation method of the compound shown in the formula VIII, the step e) of separating and purifying the compound 8 can be further included after the step d). Said step e) preferably comprises the steps of: dissolving the compound VIII obtained in the step d) in an ortho solvent, and then mixing with an anti-solvent to obtain crystals of the compound VIII. Said step e) more preferably comprises the steps of: mixing the mixed solution obtained after the reaction in the step d) with water, and separating the liquid to obtain an organic phase; extracting the organic phase by ethyl acetate, dewatering, and concentrating under reduced pressure to obtain a crude product; and dissolving the crude product by using a normal solvent, and mixing the crude product with an anti-solvent to obtain crystals of the compound VIII.

Wherein, the water removal can be carried out by adopting saturated salt water; preferably, after the saturated brine is dehydrated, it is dried over anhydrous sodium sulfate, and after filtration, the concentration under reduced pressure is further performed.

Among them, the positive solvent is preferably ethyl acetate.

Among them, the antisolvent is preferably petroleum ether.

In another preferred embodiment of the present invention, the preparation method of the compound represented by the formula VIII according to the present invention, wherein the compound VII isThe compound VIII is

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the aromatic ether compound can greatly improve the conversion rate of the first step reaction, and further improve the yield of the step and the total yield of the whole reaction route (the reaction route for preparing the compound VIII). The preparation method of the aromatic ether compound greatly simplifies the post-treatment and purification operation of the prepared compound VII, the compound VII with high purity can be obtained only by simply filtering the reaction liquid, washing and drying the filter cake, and the compound VII in the filtrate can also be extracted by simple concentration and crystallization, thereby avoiding the purification means which are difficult to implement in industry such as column chromatography and the like, therefore, the preparation method is suitable for industrial scale-up production.

Detailed Description

The present invention will be described in more detail with reference to the following examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.

Hereinafter, TEA is triethylamine; DCM is dichloromethane; 2-Me-THF is 2-methyltetrahydrofuran; TBAOH is tetra-n-butylammonium hydroxide; THF is tetrahydrofuran; DMF is N, N-dimethylformamide.

Hereinafter, LCMS is Agilent 1260 definition II liquid phase + G6125B single quadrupole mass spectrum.

Hereinafter, the purity of the sample was analyzed by using a Kinetex EVO C18(50 × 4.6.6 mm, 5 μm,

) Performing gradient elution with acetonitrile-water as mobile phase, flow rate of 1.5mL/min, and detection wavelength of 210nm and 254 nm.

Hereinafter, the model of the hydrogen spectrum is WNMR-I-400 MHz.

Hereinafter, silica gel column chromatography using 200-mesh 300-mesh silica gel from Bectona yellow sea silica gel as a carrier.