CN114163434A

CN114163434A - Preparation method of alkynyl-containing compound and intermediate thereof

Info

Publication number: CN114163434A
Application number: CN202111060516.1A
Authority: CN
Inventors: 温剑锋; 冯建鹏; 吴天助; 蔡民民; 滕尚军
Original assignee: Healthquest Pharma Inc; Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Current assignee: Healthquest Pharma Inc; Yasheng Pharmaceutical Group Hong Kong Co ltd; Suzhou Yasheng Pharmaceutical Co ltd
Priority date: 2020-09-10
Filing date: 2021-09-10
Publication date: 2022-03-11
Anticipated expiration: 2041-09-10
Also published as: WO2022053014A1; CN114163434B; CN116514808A

Abstract

The present invention provides methods for preparing alkynyl-containing compounds of formula (I) and intermediates and related compounds thereof as shown below. Pharmaceutical compositions comprising the compounds and methods of treating cancer therewith are also provided.

Description

Preparation method of alkynyl-containing compound and intermediate thereof

Technical Field

Provided herein are methods of making compounds containing alkynyl moieties and methods of their use for treating cancer. Certain compounds related to the methods are also provided.

Background

Cancer has a major impact on society worldwide. Cancer is the second most common cause of death in humans following cardiovascular disease. The national cancer institute estimates that in 2015, approximately 1,658,370 new cancer cases will be diagnosed in the united states and 589,430 people will die from the disease.

Chronic Myelogenous Leukemia (CML) is a cancer of certain hematopoietic cells that begins in the bone marrow. CML cells contain an aberrant gene, BCR-ABL, leading to uncontrolled growth and proliferation of CML cells. BCR-ABL is a protein called tyrosine kinase. Tyrosine Kinase Inhibitors (TKIs) targeting BCR-ABL are standard therapeutics for CML.

Imatinib

Is the first drug for specifically targeting BCR-ABL tyrosine kinase protein to treat CML. However, the emerging acquired resistance of imatinib has become a major challenge for clinical management of CML. More than 100 drug-resistance-associated BCR-ABL mutants have been identified clinically, with "gatekeeper" T315I being the most common mutant, accounting for approximately 15-20% of all clinically acquired mutants. Ren et al, J.Med chem.2013,56, 879-894.

Efforts have been made to identify new BCR-ABL inhibitors to overcome imatinib resistance. Compound 6 is a novel orally bioavailable Bcr-Abl inhibitor that is effective against a broad spectrum of drug mutants, including T3151. Compound 6 and its preparation are described in PCT publication WO 2012/000304. However, the preparation method of compound 6 disclosed in WO2012/000304 involves many synthesis steps, many kinds of chemical reagents, and harsh reaction conditions, including purification by high performance liquid chromatography using a pressure-resistant sealed tube, high reaction temperature in each synthesis step. Therefore, the known methods limit large-scale production.

Thus, there is a need for an efficient and cost-effective route to compound 6. The invention provides a new method for preparing a compound 6, which has mild reaction conditions, can obtain higher yield and can be used for large-scale industrial production.

Disclosure of Invention

In certain embodiments, provided herein are methods for preparing a compound of formula (Γ):

wherein the process comprises reacting a compound of formula (II ') with a compound of formula (III) to provide a compound of formula (I'), as shown in scheme VI below:

scheme VI:

wherein R is₁,R₂,R₃,R₇,R₈,R₉And R₁₀As defined herein or elsewhere.

In certain embodiments, provided herein is a method of preparing a compound of formula (I):

wherein the process comprises reacting a compound of formula (II) with a compound of formula (III) to provide a compound of formula (I), as shown in scheme I below:

scheme I:

wherein R is₁、R₂And R₃As defined herein or elsewhere.

In certain embodiments, provided herein are methods of preparing compound 6 having the structure:

wherein the method comprises reacting a compound of formula 4 and a compound of formula 5 to provide compound 6, or a pharmaceutically acceptable salt thereof, as shown in scheme V below:

scheme V:

in some embodiments, the process of schemes I-VII is an amidation reaction performed under nitrogen or inert gas blanket

And/or, in the amidation reaction, the solvent comprises an ether solvent, DMF, N-dimethylacetamide, DMSO, N-methylpyrrolidone, toluene, or acetonitrile;

and/or, in the amidation reaction, the volume/mass ratio of solvent to the compound of formula (II') or (II) or formula 4 is (about 5 to about 17) mL:1 g;

and/or, in the amidation reaction, the base is an organic base and/or an inorganic base;

and/or, in the amidation reaction, the molar ratio of base to compound of formula (II') or (II) or formula 4 is (about 1.5 to about 10): 1;

and/or, in the amidation reaction, the base is added in portions to the mixture of the remaining materials;

and/or, in the amidation reaction, the molar ratio of the compound of formula (III) or formula 5 to the compound of formula (II') or (II) or formula 4 is (about 0.8 to about 1.5): 1;

and/or, in the amidation reaction, the reaction temperature of the amidation reaction is in the range of about-80 ℃ to about 10 ℃;

and/or, in the amidation reaction, optionally, the work-up of the amidation reaction comprises washing the reaction solution with water and/or brine.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

The term "about" is used herein to mean about, within the range, approximately, or about. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated values. In general, the term "about" is used herein to modify a numerical value above and below the 10% variance of the stated value.

The term "including" means "including but not limited to".

As used herein, the terms "treat," "treating," and "treatment" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, including but not limited to a therapeutic benefit. In some embodiments, the treatment is performed after the onset of one or more symptoms. In some embodiments, treatment may be performed without symptoms. For example, a subject may be treated prior to the onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other predisposing factors), or treatment may be continued after symptoms have resolved, so that the example prevents or delays recurrence.

Therapeutic benefits include eradication and/or amelioration of the underlying disease being treated, such as cancer; it also includes eradicating and/or ameliorating one or more symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be afflicted with the underlying disorder. In some embodiments, "treating" or "treatment" includes one or more of: (a) inhibiting a disorder (e.g., alleviating one or more symptoms caused by a disorder, and/or alleviating the extent of a disorder); (b) slowing or arresting the development of one or more symptoms associated with the disease (e.g., stabilizing the disease and/or delaying the progression or worsening of the disease); and/or (c) ameliorating the disease (e.g., causing regression of clinical symptoms, ameliorating the disease, delaying disease progression, and/or improving quality of life).

As used herein, "administration" or "administering" of a compound provided herein, e.g., a compound of formula 6 or a pharmaceutically acceptable salt thereof, includes delivering the compound or a pharmaceutically acceptable salt thereof, or a prodrug or other pharmaceutically acceptable derivative thereof, to a patient using any suitable formulation or route of administration, e.g., as described herein.

As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit the desired biological or medical response, including when administered to a subject to treat a disease, the amount of the compound sufficient to effect treatment of the disease. The effective amount will vary depending on the condition, its severity and the age, weight, etc. of the subject to be treated. An effective amount may be one or more doses (e.g., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint). An effective amount can be considered to be administered in an effective amount if a desired or beneficial result can or has been achieved in combination with one or more other agents. The appropriate dose of any co-administered compounds may optionally be reduced due to a combination, addition or synergy of the compounds.

As used herein, a "patient" for which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young, middle-aged, or elderly)) and/or other primates (e.g., cynomolgus monkeys, rhesus monkeys).

As used herein, "pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable salts are described in detail, for example, in j.pharmaceutical Sciences,1977,66,1-19 by s.m.berge et al. Pharmaceutically acceptable salts of compound 6 include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids or with organic acids such as acetic, oxalic, maleic acids, tartaric, citric, succinic or malonic acid or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. While pharmaceutically acceptable counterions would be preferred for the preparation of pharmaceutical formulations, other anions are fully acceptable as synthetic intermediates. Thus, when these salts are chemical intermediates, they may be pharmaceutically undesirable anions such as iodide, oxalate, triflate and the like.

In some embodiments, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of formula (I') or (I)) and a pharmaceutically acceptable excipient. In some embodiments, provided herein are pharmaceutical compositions comprising a compound of formula (I) and optionally a pharmaceutically acceptable excipient. In some embodiments, provided herein are pharmaceutical compositions comprising compound 6 and optionally a pharmaceutically acceptable excipient.

In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound provided herein (e.g., a compound of formula (I') or (I))) or a pharmaceutical composition provided herein. In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) and optionally a pharmaceutically acceptable excipient. In some embodiments, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient.

In some embodiments, provided herein is a medical use of a pharmaceutical composition comprising a compound of formula (I') or (I) and optionally a pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of cancer. In some embodiments, provided herein is a medical use of a pharmaceutical composition comprising compound 6 and optionally a pharmaceutically acceptable excipient in the manufacture of a medicament for the treatment of cancer.

In some embodiments, the cancer is a hematologic malignancy. In certain embodiments, the hematologic malignancy is leukemia. In certain embodiments, the hematological malignancy is chronic myelogenous leukemia.

In certain embodiments, the patient has chronic myelogenous leukemia that is resistant to current tyrosine kinase inhibitor therapy. In certain embodiments, the chronic myelogenous leukemia patient with resistance to current tyrosine kinase inhibitor therapy is caused by a BCR-ABL mutation. In certain embodiments, the BCR-ABL mutation is T315I, E255K/V, G250E, H396P, M351T, Q252H, Y253F/H, or BCR-ABL^WTAnd (4) mutation. In certain embodiments, the BCR-ABL mutation is a T315I mutation.

In some embodiments, disclosed herein are high purity compounds of formula (I') prepared by the method shown in scheme VI. In some embodiments, disclosed herein are high purity compounds of formula (I) prepared by the methods shown in scheme I. In certain embodiments, disclosed herein is high purity compound 6 prepared by the method shown in scheme V. In some embodiments, disclosed herein are high purity compounds of formula (I') prepared by the method shown in scheme VI. In some embodiments, disclosed herein are high purity compounds of formula (I) prepared by the methods shown in scheme I. In certain embodiments, disclosed herein is high purity compound 6 prepared by the method shown in scheme V.

In certain embodiments, the pharmaceutical composition comprising a compound of formula (I') or (I) is administered once every 1 day, 2 days, or 3 days during a treatment cycle. The treatment period may be a 20-40 day, preferably 25-35 day, more preferably 28 day treatment period. In certain embodiments, the pharmaceutical composition comprising compound 6 is administered once every 1 day, 2 days, or 3 days during the treatment cycle. The treatment period may be 20-40 days. Preferably 25-35 days, more preferably 28 days.

In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises a compound of formula (I') or (I) in an amount of about 30mg, about 40mg, or about 45 mg. In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises compound 6 in an amount of about 30mg, about 40mg, or about 45 mg.

In certain embodiments, a pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises a compound of formula (I') or (I) in an amount of about 50mg or about 60 mg. In certain embodiments, the pharmaceutical composition is administered once every other day, wherein the pharmaceutical composition comprises compound 6 in an amount of about 50mg or about 60 mg.

In certain embodiments, the pharmaceutical composition is formulated as a dosage unit that is administered daily, or every other day (QOD), or every third day, particularly every other day.

The pharmaceutical compositions provided herein for oral administration may be provided in solid, semi-solid, or liquid dosage forms for oral administration. Oral administration, as used herein, also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast dissolving tablets, chewable tablets, capsules, pills, strips, lozenges, troches, lozenges, cachets, pills, medicated chewing gums, bulk powders, effervescent or non-effervescent powders or granules, oral sprays, solutions, emulsions, suspensions, medicaments, sprays, elixirs, and syrups, and in addition to the active ingredient, the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye-migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending agents and dispersants, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.

Suitable binders or granulators include, but are not limited to, starches, for exampleSuch as corn STARCH, potato STARCH, and pregelatinized STARCH (e.g., STARCH)

) (ii) a Gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as gum arabic, alginic acid, alginates, lichen aetheri extract, panwar gum, ghatti gum, mucilage of the isabogol shell, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone (PVP),

Larch arabinogalactan, tragacanth gum powder and guar gum; celluloses, such as ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), and microcrystalline celluloses, e.g.

PH-101、

PH- 103、

pH-105 and

RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, glucose, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. In the pharmaceutical compositions provided herein, the binder or filler may be present from about 50% to about 99% by weight.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient amounts, can impart to certain compressed tablets the property of allowing disintegration in the mouth by chewing. Such compressed tablets may be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar, bentonite, cellulose, such as methylcellulose and carboxymethylcellulose; wood products, natural sponges, cation exchange resins, alginic acids, gums, e.g. guar gum and guar gum

HV; citrus pulp, crosslinked cellulose, such as crosslinked carboxymethyl cellulose, crosslinked polymers, such as crospovidone; crosslinked starch, calcium carbonate, microcrystalline cellulose such as sodium starch glycolate, potassium polacrilin; starches, such as corn starch, potato starch, tapioca starch, pregelatinized starch, clay and algae. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein can comprise from about 0.5 to about 15% or from about 1 to about 5% by weight of disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, glycols, such as glyceryl behenate and polyethylene glycol (PEG), stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like; zinc stearate, ethyl oleate, ethyl laurate, agar and starch; lycopodium and silica or silica gels, e.g.

200 and

the amount of lubricant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein can comprise from about 0.1 to about 5 weight percent of a lubricant.

Suitable glidants include, but are not limited to, colloidal silicon dioxide,

And asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified, water-soluble FD&C dye and water-insoluble FD suspended on alumina hydrate&C dyes and lakes. Lakes are a combination of dyes that form an insoluble form by adsorbing a water-soluble dye onto a hydrated oxide of a heavy metal. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends that impart a pleasant taste sensation, such as mint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, gum acacia, gum tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (M: (M))

20) Polyoxyethylene sorbitan monooleate 80 (C)

80) Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, sodium oleate,

Suitable preservatives include, but are not limited to, glycerin, methyl and propyl p-hydroxybenzoates, benzoic acid, sodium benzoate, and alcohol. Suitable wetting agents include, but are not limited toPropylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerol, sorbitol, ethanol, and syrup. Non-aqueous liquids suitable for use in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

It will be appreciated that many carriers and excipients may serve multiple functions, even in the same formulation.

The pharmaceutical compositions provided herein for oral administration can be provided as compressed tablets, abrasive tablets, chewable lozenges, fast-dissolving tablets, composite compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the effects of stomach acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with a sugar coating, which may help to mask unpleasant tastes or odors and protect the tablets from oxidation. Film coated tablets are compressed tablets covered with a thin layer of water soluble material or film. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings have the same general characteristics as sugar coatings. Multiple compressed tablets are compressed tablets made through more than one compression cycle, including layered tablets, compression-coated tablets, or dry-coated tablets.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients as described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical compositions provided herein for oral administration may be provided in the form of soft or hard capsules, which may be made from gelatin, methyl cellulose, starch, or calcium alginate. Hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two parts, one part sliding over the other, thereby completely enclosing the active ingredient. Soft Elastic Capsules (SEC) are soft spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4328,245, 4409,239 and 4410,545. The capsules may also be coated as known to those skilled in the art to alter or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein for oral administration may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed in the form of globules in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcoholic solution may comprise a pharmaceutically acceptable acetal, such as the di (lower alkyl) acetal of a lower alkyl aldehyde, for example acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethyl alcohol. Elixirs are clear, sweetened and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugar (e.g., sucrose), and may also contain preservatives. For liquid dosage forms, for example, the polyethylene glycol solution may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate metered administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing an active ingredient and a dialkylated mono-or polyalkylene glycol, including 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms may also contain one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Pharmaceutical compositions provided herein for oral administration may be provided in non-effervescent or effervescent, granular and powder forms to reconstitute liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may be used in all dosage forms described herein.

The pharmaceutical compositions provided herein for oral administration may be formulated as immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

A process for preparing a compound of formula (Γ):

comprising reacting a compound of formula (II'):

with a compound of formula (III):

providing a compound of formula (I') in a solvent and in the presence of a base,

wherein

R₁Is H, C₁-C₄Alkyl, or is-C (═ O) O- (C)₁-C₄Alkyl groups);

R₂is H or C₁-C₄An alkyl group;

R₃is that

-NH₂,-NHC(＝O)Me,

Or is

R₇Is H or hydroxy;

R₈is H or hydroxy;

R₉is H or hydroxy; and

R₁₀is H or hydroxy.

In certain embodiments, provided herein are methods for preparing a compound of formula (I):

comprising reacting a compound of formula (II):

with a compound of formula (III):

providing a compound of formula (I) in a solvent and in the presence of a base,

wherein

R₁Is H, C₁-C₄Alkyl, or-C (═ O) O- (C)₁-C₄Alkyl), R₂Is H or C₁-C₄Alkyl, and

R₃is that

-NH₂,-NHC(＝O)Me,

In one embodiment, the process is as shown in scheme I below:

scheme I:

in one embodiment, it is assumed that the compound of formula (I') or (I) is not compound 6

In one embodiment, -CH₂-R₃The group is located para to the-NH-group.

In one embodiment, the compound of formula (I) is a compound of formula (I-A):

in one embodiment, CH₂-R₃The group is para to the-CF 3 group.

In one embodiment, the compound of formula (I) is a compound of formula (I-B).

In one embodiment, the compound of formula (I) is a compound of formula (I-C):

in one embodiment, the compound of formula (I') is a compound of formula (I-D):

in one embodiment, R₁Is H. In one embodiment, R₁Is C₁-C₄Alkyl, in one embodiment, R₁Is methyl, and in one embodiment, R₁Is a tertiary butyl group, and in one embodiment, R₁is-C (═ O) O- (C)₁-C₄Alkyl), in one embodiment, R₁is-C (═ O) O- (C)₁-C₄Alkyl), in one embodiment, R₁is-C (═ O) OMe, and in one embodiment, R₁is-C (═ O) O-tert-butyl.

In one embodiment, R₂Is H, in one embodiment, R₂Is C₁-C₄Alkyl, in one embodiment, R₂Is methyl.

Exemplary R₁、R₂Combinations thereof and corresponding compounds of formula (II) are provided in table 1.

TABLE 11

In one embodiment, instead of the methyl ester of formula (II ') or (II), a corresponding acid compound (e.g., compound 39) may be used to react with the compound of formula (III) to prepare the compound of formula (I') or (I) or a pharmaceutically acceptable salt thereof.

Exemplary R₃And the corresponding compounds of formula (III) are provided in table 2.

TABLE 2

In one embodiment, provided herein are compounds of formula (I-D):

wherein:

R₇is H or hydroxy;

R₈is H or hydroxy;

R₉is H or hydroxy;

R₁₀is H or hydroxy; and

provided that R is₇、R₈、R₉And R₁₀At least one of which is a hydroxyl group;

or a pharmaceutically acceptable salt thereof.

In one embodiment, R₇Is H, in one embodiment, R₇Is a hydroxyl group.

In one embodiment, R₈Is H, in one embodiment, R₈Is a hydroxyl group

In one embodiment, R₉Is H, in one embodiment, R₉Is a hydroxyl group.

In one embodiment, R₁₀Is H, in one embodiment, R₁₀Is a hydroxyl group

In one embodiment, R₇、R₈、R₉And R₁₀At least one of which is a hydroxyl groupIn one embodiment, R₇、R₈、R₉And R₁₀One is hydroxy and R₇、R₈、R₉And R₁₀The other three of (a) is H.

In certain embodiments, provided herein are methods for preparing a compound of formula (I-a):

wherein the process comprises reacting a compound of formula (II) with a compound of formula 5 to provide a compound of formula (I-a), as shown in scheme II below;

scheme II:

in certain embodiments, provided herein are methods for preparing a compound of formula (I-B), or a pharmaceutically acceptable salt thereof,

wherein the process comprises reacting a compound of formula (II) with a compound of formula 22 to provide a compound of formula (I-B), as shown in scheme III below.

Scheme III:

in certain embodiments, provided herein is a method of making a compound of formula (I-C):

wherein the process comprises reacting a compound of formula 4 with a compound of formula (III) to provide a compound of formula (I-C), as shown in scheme IV below: .

Scheme IV:

in some embodiments, provided herein are methods of preparing compound 6 by amidation reactions with compounds of formula 4 and 5 in a solvent and in the presence of a base as shown below;

in certain embodiments, provided herein are methods for preparing a compound of formula (I-D), or a pharmaceutically acceptable salt thereof;

wherein the process comprises reacting a compound of formula (II' -A) with a compound of formula 5 to provide a compound of formula (I-D), as shown in scheme VII below:

scheme VII

In some embodiments, the amidation reaction (e.g., between compound 4 and compound 5, or between a compound of formula (II') or (II) and a compound of formula (III)) may be carried out under nitrogen or inert gas.

In some embodiments, the solvent in the amidation reaction includes, but is not limited to, ether, DMF (N, N-dimethylformamide), N-dimethylacetamide, DMSO (dimethyl sulfoxide), N-methylpyrrolidone, toluene, and acetonitrile, or a mixture thereof.

In some embodiments, the solvent in the amidation reaction is ether, DMF, N-dimethylacetamide, N-methylpyrrolidone, or toluene. In some embodiments, the solvent is an ether solvent.

In some embodiments, the ether solvent in the amidation reaction may be THF (tetrahydrofuran), 2-methyltetrahydrofuran, or dioxane. In some embodiments, the ether solvent is THF.

In some embodiments, the amount of solvent in the amidation reaction may be an amount conventional in the art for amidation reactions, or the amount of solvent is the volume/mass ratio of solvent to the compound of formula (1). II') or (II) or formula 4, e.g., (about 5 to about 17) mL:1g, or e.g. (about 10 to about 15) mL:1g, or (about 15) mL:1g of the total weight of the composition. In some embodiments, the base in the amidation reaction may be an organic base and/or an inorganic base.

In some embodiments, the organic base is, but is not limited to, pyridine, C₁-C₄Alcohols and/or amines, e.g. -N (R)₁)(R₂)(R₃) Wherein each R is₁、R₂And R₃Independently represent hydrogen or C₁-C₄An alkyl group.

In some embodiments, C₁-C₄Alkali metal salts of alcohols are, but not limited to, conventional C used in amidation reactions in the art₁-C₄Alkali metal salts of alcohols, for example potassium tert-butoxide and/or sodium tert-butoxide.

In some embodiments, -N (R)₁)(R₂)(R₃) Is Et₃N、DIPEA、(i-Pr)₂NH and Bu₃N, e.g. Et₃N or (i-Pr)₂NH, typically Et₃N。

In some embodiments, the inorganic base is, but is not limited to, an alkali metal carbonate and/or an alkali metal hydroxide.

In some embodiments, the alkali metal carbonate is, for example, K₂CO₃And/or Cs₂CO₃。

In some embodiments, the alkali metal hydroxide is, for example, NaOH and/or KOH.

In some embodiments, the amount of base used in the amidation reaction may be an amount conventional in the art for use in amidation reactions. In some embodiments, the molar ratio of base to compound of formula (II') or (II) or formula 4 is, for example, (about 1.5 to about 10):1, for example (about 1.5 to about 8.0):1, for example (about 1.5 to about 6):1, for example (about 1.5 to about 5.0):1

In some embodiments, the base may be added to the reaction mixture in portions during the amidation reaction.

In some embodiments, the molar ratio of the compound of formula (III) or formula 5 to the compound of formula (II') or (II) or formula 4 is, for example, (about 0.8 to about 1.5):1, e.g., (about 0.9 to about 1.3):1, e.g. (about 1.2 to about 1.3): 1.

in some embodiments, the reaction temperature for the amidation reaction is in the range of, for example, about-80 ℃ to about 10 ℃, e.g., about-65 ℃ to about-60 ℃, about-60 ℃ to about-40 ℃, about-30 ℃ to about-20 ℃, about-20 ℃ to about 15 ℃, or about 0 ℃ to about 10 ℃.

In some embodiments, the progress of the amidation reaction may be monitored by TLC, HPLC, and other methods known to those skilled in the art. The completion of the reaction can be judged by those skilled in the art based on the scale of the reaction, the conversion of the raw material, the reaction efficiency (i.e., the relationship between the yield and the reaction time), the formation of impurities, and the like. To obtain the preferred yield and purity. The reaction time is in the range of about 2 hours to about 20 hours, for example about 2 hours to about 12 hours. In some embodiments, the reaction time is from about 2h to about 4 h.

In some embodiments, the post-treatment of the amidation reaction may be a post-treatment commonly used in the art for amidation reactions, and may include washing the reaction solution with water and saturated saline in this order, removing the solvent, adding water to the slurry, filtering, and drying.

In some embodiments, after the reaction mixture is post-treated with saturated brine, the reaction mixture may be mixed with the amino acid compound immediately before removing the solvent, and then washed with saturated brine.

In some embodiments, the amino acid compound is cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, sodium edetate, and dithiocarbamates, such as cysteine or N-acetyl-L-cysteine, typically N-acetyl-L-cysteine.

In some embodiments, the molar ratio of amino acid compound to compound of formula (II') or (II) or formula 4 is about 0.7 to 1.0: 1.

In some embodiments, the method for removing the solvent may be concentrated under reduced pressure.

In some embodiments, the amidation reaction is carried out under nitrogen or inert gas, the solvent comprises DMF and/or THF, the base comprises potassium tert-butoxide, sodium tert-butoxide or Et₃N, the molar ratio of base to compound of formula (II ') or (II) or formula 4 is (about 1.5 to 6):1, the molar ratio of compound of formula (III) or formula 5 to compound of formula (II') or (II) or formula 4 is (about 0.8 to 1.5):1, and the amidation reaction is carried out at about-60 ℃ to about 10 ℃

In some embodiments, the compound of formula 4 is prepared by deprotecting a compound of formula 3 in a solvent as shown below;

in some embodiments, the deprotection reaction may be performed under nitrogen or inert gas protection.

In some embodiments, the deprotection reaction may be carried out in the presence of an acid. In some embodiments, the acid may be, but is not limited to, hydrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid.

When the deprotection reaction is carried out in the presence of an acid, the solvent may be a conventional solvent used in the deprotection reaction under such conditions, and may be C₁-C₄Alcohols (e.g. methanol and/or ethanol, typically methanol), chloroalkanes, THF or acetonitrile.

In some embodiments, the deprotection reaction may be performed in the absence of an acid. For example, the deprotection reaction starting material consists only of the solvent and the compound of formula 3.

When the deprotection reaction is carried out in the absence of an acid (for example, the raw material for the deprotection reaction consists only of a solvent and the compound of formula 3), the solvent may be a solvent commonly used in the present invention. Under these conditions, deprotection reactions occur. May be, but is not limited to, acetonitrile, ethylA mixed solvent of nitrile and water, or C₁-C₄A mixed solvent of alcohol and water, wherein, C₁-C₄The mass ratio of alcohol to water is about, for example, 3 to 5:1, C₁-C₄Alcohols include, for example, methanol, ethanol, isopropanol, or mixtures thereof, such as methanol and/or ethanol. In some embodiments, the solvent is methanol. In some embodiments, C₁-C₄The mixed solvent of alcohol and water is, for example, a mixed solvent of methanol and water at a mass ratio of 3:1, usually C₁-C₄A mixed solvent of alcohol and water.

In some embodiments, the mass ratio of solvent to compound of formula 3 in the deprotection reaction is, for example, (about 10 to about 15): 1.

In some embodiments, the reaction temperature of the deprotection reaction is in the range of, for example, about 30 ℃ to about 80 ℃, such as about 60 ℃ to about 80 ℃, about 60 ℃ to about 60 ℃ about 70 ℃, or about 60 ℃ to about 65 ℃.

In some embodiments, the progress of the deprotection reaction may be monitored by TLC, HPLC, and other methods known to those skilled in the art. One skilled in the art can judge the completion of the reaction based on the scale of the reaction, conversion of the starting material, efficiency of the reaction (i.e., the relationship of yield to reaction time), formation of impurities, etc., to obtain a preferred yield and purity. The reaction time is, for example, in the range of about 10 hours to about 36 hours, such as about 10 hours to about 18 hours.

In some embodiments, work-up of the deprotection reaction may include cooling and filtration.

In some embodiments, the temperature to be achieved by cooling may be from about 20 ℃ to about 25 ℃.

In some embodiments, the post-treatment may also include immediate dry recrystallization, immediate recrystallization after filtration, or direct recrystallization without drying. The recrystallization method may be dissolving by heating and precipitating by cooling.

In some embodiments, the solvent used for recrystallization is, but is not limited to, for example, C₁-C₄Alcohols, further examples of which include methanol, ethanol, isopropanol, or mixtures thereof. In some casesIn the examples, the solvent is methanol or ethanol. In some embodiments, the solvent is methanol.

In some embodiments, the mass ratio of solvent used for recrystallization to the compound of formula 4 may be (about 5 to about 15):1, for example (about 5 to about 10): 1.

In some embodiments, in the method of heating to dissolve and cooling the precipitate, the dissolution temperature is, for example, in the range of about 50 ℃ to about 70 ℃, such as about 60 ℃ to about 70 ℃.

In some embodiments, in the method of heating to dissolve and cool the precipitate, the cooling may be slow cooling, fast cooling, or gradient cooling. In some embodiments, it may be gradient cooling. The temperature can be lowered by about 5 ℃ to 1.5 hours every 1 hour. The gradient cooling may begin at a temperature of about 40 ℃ to about 50 ℃.

One skilled in the art can evaluate the completion of the reaction based on precipitation conditions, etc., to obtain a preferred yield and purity. The recrystallization time is, for example, in the range of about 8 hours to about 40 hours, such as about 8 hours to about 10 hours.

In some embodiments, the deprotection reaction can be performed under the protection of nitrogen or inert gas, the raw materials for the deprotection reaction only consist of a solvent and the compound of formula 3, and the solvent is C₁-C₄Alcohol and water, the temperature of the deprotection reaction being in the range of about 60 ℃ to about 65 ℃.

In one embodiment, the compound of formula (II) is prepared by a process comprising reacting compound 1:

with a compound of formula (IV):

providing a compound of formula (II) in a solvent and in the presence of a base, a catalyst and a catalyst ligand.

In some embodiments, the compound of formula 3 may be prepared by Sonogashira coupling of the compound of formula 1 and the compound of formula 2 in a solvent and in the presence of a base, a catalyst, and a catalyst ligand, as shown below:

in one embodiment, the compound of formula (II') is prepared by a process comprising reacting a compound of formula (V):

wherein X is halogen, with a compound having formula (VI):

providing a compound of formula (II') in a solvent and in the presence of a base, a catalyst and a catalyst ligand.

In one embodiment, X is iodine. In one embodiment, X is bromine. In one embodiment, X is chlorine.

In some embodiments, the Sonogashira reaction (e.g., between compound 1 and compound 2, or between compound 1 and compound of formula (IV), or between compounds of formula (V) and formula (VI)) can be carried out under nitrogen or inert gas.

In some embodiments, the solvent in the Sonogashira reaction may be a conventional solvent used in Sonogashira reactions in the art, such as (1) including N-methylpyrrolidone, DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), N-dimethylacetamide, acetonitrile, toluene, dioxane, and THF (tetrahydrofuran), (2) N-methylpyrrolidone, DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), N-dimethylacetamide, or acetonitrile; in some embodiments, the solvent in the Sonogashira reaction may be a conventional solvent used in the Sonogashira reaction in the art, for example, (1) includes N-methylpyrrolidone, DMSO (dimethyl sulfoxide), DMF (N, N-dimethylformamide), N-dimethylacetamide, acetonitrile, toluene, dioxane and THF (tetrahydrofuran), (2) N-methylpyrrolidone, DMSO (dimethylsulphoxide), DMF (N, N-dimethylformamide), N-dimethylacetamide or acetonitrile; or (3) N-methyl acetone, DMF (N, N-dimethyl formamide), or N, N-dimethyl ethyl acetone.

In some embodiments, the volume/mass ratio of solvent to compound of formula (IV) or formula 2 is, for example, (about 5 to about 10) mL:1g, such as (about 7 to about 10) mL:1g of the total weight of the composition.

In some embodiments, in the Sonogashira reaction, the catalyst may be a conventional catalyst used in Sonogashira reactions in the art, such as a palladium catalyst. The palladium catalyst may comprise PdCl₂(PPh₃)₂、Pd(dppf)₂Cl₂、Pd(dppf)₂Cl₂And/or palladium on carbon. In some embodiments, the catalyst is PdCl₂(PPh₃)₂Or Pd (dppf)₂Cl₂。

In some embodiments, the molar ratio of catalyst to compound of formula (IV) or formula 2 is, for example, (about 0.01 to about 0.05):1, e.g., (about 0.01 to about 0.03): 1.

In some embodiments, the catalyst ligand for the Sonogashira reaction includes, for example, a copper compound, which in some embodiments may be, for example, CuI, CuBr, Cu, and/or triphenylphosphine₂O, CuO and/or copper acetate in some embodiments, the catalyst ligand is CuI or CuBr.

In some embodiments, the molar ratio of catalyst ligand to catalyst is, for example, (about 0.8 to about 1.2): 1. In some embodiments, the molar ratio of catalyst ligand to catalyst is 1: 1.

In some embodiments, in the Sonogashira reaction, the base may be, for example, an organic base and/or an inorganic base.

In some embodiments, the organic base may be a conventional organic base used in Sonogashira reactions in the art, e.g., comprising pyridine, C₁-C₄Alkali metal salts of alcoholsand/or-N (R)₄)(R₅)(R₆) Wherein R is₄、R₅And R⁶Each of which independently represents hydrogen or C₁- C₄An alkyl group.

In some embodiments, C₁-C₄The alkali metal salt of the alcohol may be, but is not limited to, potassium tert-butoxide and/or sodium tert-butoxide.

In some embodiments, -N (R)₄)(R₅)(R₆) E.g. including Et₃N、DIPEA、(i-Pr)₂NH and/or Bu₃And N is added. In some embodiments, -N (R)₄)(R₅)(R₆) Is Et₃N or DIPEA. In some embodiments, -N (R)₄)(R₅)(R₆) Is Et₃N。

In some embodiments, the inorganic base may be a conventional inorganic base used in Sonogashira reactions in the art, including, for example, alkali metal carbonates and/or alkali metal hydroxides.

In some embodiments, the alkali metal carbonate is, for example, K₂CO₃And/or Cs₂CO₃.

In some embodiments, the molar ratio of base to compound of formula (IV) or formula 2 in the Sonogashira reaction is, for example, (about 1.0 to about 1.5): 1. The ratio is (about 1.2 to about 1.3): 1.

in some embodiments, the molar ratio of the compound of formula 1 to the compound of formula (IV) or formula 2 in the amidation reaction is, for example, (about 0.95 to about 2.0):1, e.g., (about 1.2 to about 1.5): 1. In some embodiments, the molar ratio is (about 1.2 to about 1.3): 1.

In some embodiments, the reaction temperature of the Sonogashira reaction is, for example, from about 40 ℃ to about 80 ℃, e.g., from about 65 ℃ to about 75 ℃, typically from about 65 ℃ to about 70 ℃.

The progress of the Sonogashira reaction can be monitored by TLC, HPLC and other methods known to those skilled in the art. One skilled in the art can evaluate the completion of the reaction based on the scale of the reaction, conversion of the starting material, efficiency of the reaction (i.e., yield versus reaction time), formation of impurities, etc., to obtain a preferred yield and purity. The reaction time is, for example, in the range of about 2 hours to about 12 hours, such as about 2 hours to about 5 hours. In some embodiments, it is from about 2 hours to about 3 hours.

In some embodiments, the post-treatment of the Sonogashira reaction may be a conventional post-treatment used in amidation reactions in the art, including mixing with water and filtration.

In some embodiments, the post-treatment of the Sonogashira reaction may further comprise mixing with an amino acid compound prior to mixing with water.

In some embodiments, amino acid compounds useful for removing heavy metals include, but are not limited to, cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, sodium edetate, and/or dithiocarbamates, for example. In some embodiments, the amino acid compound is cysteine or N-acetyl-L-cysteine. In some embodiments, the amino acid compound is N-acetyl-L-cysteine.

In some embodiments, the molar ratio of amino acid compound to compound of formula (IV) or formula 2 is, for example, (about 0.1 to about 0.5): 1.

In some embodiments, the temperature of mixing with the amino acid compound can be in the range of about 35 ℃ to about 45 ℃.

In some embodiments, the mixing time with the amino acid compound can be from about 4h to about 5 h.

In some embodiments, the mixing temperature for mixing with water may be in the range of about 20 ℃ to about 25 ℃.

In some embodiments, the filtration process may further comprise washing with water.

In some embodiments, the post-treatment of the Sonogashira reaction may further comprise pulping immediately after filtration.

In some embodiments, the solvent used for pulping may be, but is not limited to, ethyl acetate and n-heptane. The volume ratio of ethyl acetate to n-heptane was about 1: 1.

In some embodiments, the volume/mass ratio of solvent to crude filter cake used for pulping may be (about 5 to about 7) mL:1 g.

In some embodiments, the Sonogashira reaction can be carried out under nitrogen or inert gas, the solvent is N-methylpyrrolidone, DMF or acetonitrile, the catalyst is PdCl₂(PPh₃)₂Or Pd (dppf)₂Cl₂The molar ratio of catalyst to compound of formula (IV) or formula 2 is (about 0.01 to about 0.05):1, catalyst ligand CuI or CuBr, catalyst ligand to catalyst molar ratio (about 0.8 to about 0.05) of about 1.2):1, base Et₃N, the molar ratio of base to compound of formula (IV) or formula 2 is, for example, (about 1.0 to about 1.5):1, the molar ratio of compound of formula 1 to compound of formula (IV) or formula 2 is, for example, (about 0.95 to about 1.3):1, and the temperature of the Sonogashira reaction is from about 65 ℃ to about 75 ℃.

In some embodiments, the compound of formula 4 may be prepared by a deprotection reaction of the compound of formula 3 in a solvent, as shown below:

the reaction conditions for the deprotection reaction can be referred to the above conditions.

the conditions of the Sonogashira reaction can be referred to the above conditions.

In some embodiments, the present invention also provides a compound of formula 3 or a compound of formula 4,

embodiments of the invention may be combined without departing from the common general knowledge in the art.

The reagents and raw materials used in the invention are all commercial products.

In some embodiments, the present invention provides compounds of formula (I') or (I) or formula 6 prepared by the methods described herein.

Without being bound by a particular theory, the advantageous effects achieved by the methods provided herein include the following:

i. the invention adopts a new design route. According to the structural characteristics of the compound 6, cheap and easily-obtained reaction raw materials are selected, the method is convenient to operate, mild in reaction conditions, capable of avoiding using harsh reaction equipment such as a sealing tube and the like, and capable of meeting the requirements of industrial production by simplifying post-treatment recrystallization and preventing multiple column chromatography.

The design route of the invention is novel, and the reaction route is shorter. The target product can be obtained only by three steps of reaction. Compared with the existing route, the method shortens the reaction route, reduces expensive and complex raw materials, has the advantages of high yield, good purity, controllable cost and the like, and can effectively ensure the quality of the intermediate and the subsequent final products.

in the early stage of the invention, amino acid is added for a plurality of times in the coupling and amidation reaction processes to prevent heavy metal from being excessive, thereby not only protecting the environment, but also effectively ensuring the heavy metal contained in the active component. The medicinal components meet pharmacopoeia standards.

The invention adopts a new design route to obtain two new intermediates of the compound of the formula 3 and the compound of the formula 4.

In some embodiments, compounds listed in table 3 are provided

TABLE 3

Detailed Description

Examples

The following examples further illustrate but do not limit the invention. It should be noted that various modifications and improvements can be made by those skilled in the art without departing from the inventive concept of the present invention, and all of them are included in the scope of the present invention.

The specific conditions not disclosed in the experimental methods of the following examples may be selected in accordance with conventional methods and conditions, and may also be selected in accordance with the product specifications.

The "room temperature" in the following examples means 20 ℃ to 25 ℃ unless otherwise specified. The term "h" as used herein refers to hours.

Example 1

Step 1:

n-methylpyrrolidone (137.6g) was heated to 30-35 ℃ under nitrogen protection to give compound of formula 1 (14.4g,1.3eq) and compound of formula 2 (19.14g,1eq), bis (triphenylphosphoric acid) palladium dichloride (0.46g, 0.01eq) and cuprous iodide (0.113g, 0.01eq) were added in sequence, and triethylamine (9.45g, 1.5eq) was then added under nitrogen protection. The reaction mixture was heated to 65 to 75 ℃ and held at this temperature for 2 hours. The process control of the reaction is carried out by liquid phase detection. When the content of the compound of formula 2 is less than or equal to 0.1%, the reaction is terminated. After the reaction, the reaction solution was cooled to 35 to 45 ℃ and N-acetyl-L-cysteine (1g, 0.1eq) was added directly. The reaction was carried out with stirring for 4 to 5 hours. The resulting product was cooled to room temperature, precipitated with water, centrifuged, and washed with pure water to give a crude filter cake. After the cake was vacuum-dried, a mixture of ethyl acetate and n-heptane (wherein the volume ratio of ethyl acetate to n-heptane was 1:1, and the mixed solvent of ethyl acetate and n-heptane was 5mL) was added to the cake per gram of cake (per gram of cake) and made into a slurry. The resulting slurry was vacuum dried to give the compound of formula 3 in 85.97% yield and 98.2% purity.

NMR data for the compound of formula 3¹HNMR(400MHz,d-DMSO):δppm:8.93(1H,d,J＝2.0Hz)；8.63(1H, d,J＝2.0Hz)；8.49(1H,s)；8.11(1H,d,J＝2.0Hz)；7.92(1H,dd,J1＝1.6Hz；J2＝8.0Hz)；7.52(1H,d,J＝8.0Hz)； 3.88(3H,s)；2.59(3H,s)；1.65(9H,s).

Step 2:

Methanol (160g) and water (50g) were added to the compound of formula 3 (20g, 1.0eq) in this order under nitrogen, and the reaction was stirred under reflux for 18 hours with process control. The resulting product was cooled to room temperature and filtered to give a filter cake (without oven drying). Adding methanol with the mass 10 times of that of the filter cake for recrystallization, stirring the obtained mixture at 60-70 ℃ for 8-10 h, cooling to 40-50 ℃, and slowly generating solid precipitates at the cooling speed of 5 ℃ every 1-1.5 h in a gradient cooling process. The resulting mixture was filtered, the filter cake was washed with methanol and dried under vacuum to give the compound of formula 4 in 91% yield and 99.7% purity.

NMR data for the compound of formula 4¹HNMR(400MHz,d-DMSO):δppm:8.73(1H,d,J＝2.0Hz)；8.52(1H, t,J＝2.0Hz)；8.21(1H,d,J＝2.0Hz)；8.06(1H,s)；7.86(1H,dd,J1＝2.0Hz；J2＝8.0Hz)；7.49(1H,dd,J1＝1.6 Hz；J2＝7.6Hz)；3.86(3H,s)；2.56(3H,s).

Step 3:

THF (448mL), compound of formula 4 (29.1g, 1eq) and compound of formula 5 (24.6g, 0.9eq) were added under nitrogen blanket and cooled to-65 deg.C to-60 deg.C with stirring. At this temperature, potassium tert-butoxide (19 g. times.3) was added in portions at 0.5h intervals. The process control of the reaction is carried out by liquid phase detection. After 2 hours, the reaction temperature rose to-5 to 0 ℃. Washing the reaction solution with purified water, stirring for 0.5-1 h, washing with brine, and separating to obtain an organic phase. The organic phase was added with N-acetyl-L-cysteine (11.41g, 0.7eq), stirred, washed with brine for neutralization, and concentrated under reduced pressure. The resulting filter cake is washed with purified water and made into slurry. The obtained product is washed by pure water again and dried in vacuum to obtain the compound shown in the formula 6, wherein the yield is 88.2 percent, and the purity is 98.6 percent.

NMR data for the compound of formula 6¹H NMR(400MHz,d-DMSO):δppm:10.53(1H,s)；8.75(d,J＝2.0)； 8.53(d,J＝2.4)；8.24(1H,s)；8.23(d,J＝2.4)；8.21(d,J＝1.6)；8.09(dd,J1＝1.6；J2＝8.4)；7.94(dd,J1＝2.0；J2＝8.0)； 7.71(d,J＝8.8)；7.53(d,J＝8.0)；3.56(2H,s)；2.59(3H,s)；2.34-2.35(8H,m),2.16(3H,s).

The carbon spectrum data is¹³C NMR(100MHz,d-DMSO):δppm:20.38,45.65,52.64,54.67,57.41,88.26, 91.86,111.76,113.98,117.19,122.14,123.43,127.35(q),124.30(q),128.10,129.89,130.49,131.15,132.02, 132.13,132.93,133.66,138.15,143.65,150.55,164.64.

Example 2

The Sonogashira reaction was carried out with reference to the reaction parameters of the rows in Table 4 (the other parameters were the same as in the first step of example 1), and the yield was calculated from the compound of formula 2 as shown in the last column of Table 4.

Table 4

Example 3

The amidation reaction was carried out according to the reaction parameters of the rows in Table 5 (other parameters were the same as in the third step of example 1), and the yields calculated as the molar amounts of the compounds of formula 4 or 5 are shown in the last column of Table 5.

TABLE 5

Example 4 preparation of Compound 8

5-bromo-2-fluoro-4-methylpyridine (25.02g, 131.7mmol, 1.0eq), NBS (46.93g, 263.3mmol, 2.0eq), AIBN (4.52g, 26.3mmol, 0.2eq), HOAC (1.61g) were dissolved in CAN (300mL) and heated under reflux for 8 hours, the organic phase was concentrated to dryness and purified by column chromatography (n-heptane: EA: 50:1) to give an orange oil (30.15 g).

A mixture of the oil product obtained in the previous step (20.53g,76mmol,1.0eq), calcium carbonate (40.15g,400mmol,5.3eq) in 1, 4-dioxane (200mL) and water (200mL) was added and heated to 100 ℃ for reaction overnight. The reaction solution was cooled to room temperature and filtered. The filtered product was washed with ethyl acetate, and ethyl acetate (200mL) and water (200mL) were added to the filtrate. The liquid was separated and the organic phase was collected. The aqueous phase was extracted with ethyl acetate, the organic phases combined, concentrated to dryness and column chromatographed (DCM: MeOH ═ 150:1-100:1-50:1) to give 3.27g of product.

A mixture of the product obtained in the previous step (3.22g,15.6mmol,1.0eq), DMP (9.93g,23.4mmol,1.5eq) in DCM (100mL) was heated to 25 deg.C under nitrogen and reacted for 1.5 h. After the reaction was complete, sodium thiosulfate solution (100mL) and sodium bicarbonate solution (100mL) were added. The aqueous phase was extracted with ethyl acetate and the organic phases were combined and concentrated to dryness to give a pale yellow oil (3.11 g).

A mixture of the oily product obtained in the previous step (3.02g, 14.8mmol, 1.0eq) and hydrazine hydrate (80%) (0.92g, 14.7mmol, 1.0eq) was dissolved in 12mL of anhydrous ethanol under nitrogen and then slowly dropped in portions. After 3 hours of reaction at 25 ℃, the reaction mixture was filtered and dried to give compound 8(2.08 g).

¹H NMR(400MHz,DMSO-d₆)δ8.33(s,1H),8.24(s,2H),7.81(d,J＝2.1Hz,1H),7.28(d,J＝ 1.5Hz,1H).LC-MS:219.90,217.90.

EXAMPLE 5 preparation of Compound 10

To a mixture of LDA (15ml, 34.81mmol, 1.5eq) and THF (20ml) was added a solution of 2-fluoro-5-bromopyridine (4.02g, 23.01mmol, 1.0eq) in tetrahydrofuran under nitrogen at-60 ℃ to-70 ℃, the mixture was stirred at-60 ℃ to-70 ℃ for 15 minutes, ethyl formate (2.51g, 34.81mmol, 1.5eq) was added and stirred at-60 ℃ to-70 ℃ for 20 minutes. 40mL of 10% tetrahydrofuran citrate solution was added below-60 ℃ and 30mL of water was added. After the reaction was completed, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to dryness to give 2-fluoro-5-bromopyridine-3-carbaldehyde (4.21 g).

To a mixture of LDA (3.8ml,8.70mmol,1.5eq) and 5ml THF was added a solution of 2-fluoro-5-bromopyridine (1.02g,5.80mmol,1.0eq) in tetrahydrofuran under nitrogen at-60 deg.C to-70 deg.C. The mixture was stirred at-60 ℃ to-70 ℃ for 15 minutes, the product from the previous step (1.41g, 6.95mmol, 1.2eq) and 15ml THF were slowly added in several portions at-60 ℃ to-70 ℃ and the reaction was stirred at-60 ℃ to-70 ℃ for 15 minutes, after which the temperature was controlled below-60 ℃.10 mL of 10% citric acid in tetrahydrofuran was added followed by 10mL of water. The organic phase was washed with water and sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated to dryness to give a brownish red oil, which was purified by thin layer chromatography to give compound 10 as a pale yellow oil (0.12 g).

¹H NMR(400MHz,DMSO-d₆)8.35(d,J＝2.5Hz,2H),8.33–8.24(m,2H),6.76(d,J＝4.5Hz, 1H),6.00(d,J＝4.4Hz,1H).LC-MS:382.90,381.85,380.80,378.90.

EXAMPLE 6 preparation of Compound 12

To a mixture of LDA (15ml, 34.81mmol, 1.5eq) and THF (20ml) was added a solution of 2-fluoro-5-bromopyridine (4.02g, 23.01mmol, 1.0eq) in tetrahydrofuran under nitrogen at-60 deg.C to-70 deg.C. The mixture was stirred at-60 ℃ to-70 ℃ for 15 minutes, ethyl formate (2.51g, 34.81mmol, 1.5eq) was added and stirred at-60 ℃ to-70 ℃ for 20 minutes. 40ml of a 10% tetrahydrofuran citrate solution was added thereto at a temperature of-60 ℃ or lower, and 30ml of water was added thereto. After the reaction was completed, the aqueous phase was extracted with ethyl acetate, and the organic phases were combined and concentrated to dryness to give 2-fluoro-5-bromopyridine-3-carbaldehyde (4.21 g).

Under nitrogen, a mixture of 2-fluoro-5-bromopyridine-3-carbaldehyde (1.57g,7.34mmol,1.0eq) and 15ml of absolute ethanol and 80% hydrazine hydrate (0.24g,3.67mmol, 0.5eq) were slowly added dropwise in portions. The reaction was carried out overnight at 25 ℃ and filtered to dryness to give Compound 12(0.46 g).

¹H NMR(400MHz,Chloroform-d)δ8.76(d,J＝1.0Hz,2H),8.70–8.60(m,2H),8.41(dt,J＝ 2.4,1.2Hz,2H).LC-MS:406.90,405.85,404.90,402.90.

Example 7 preparation of Compound 19

To a mixture of compound 19-1(2.0g) in tetrahydrofuran (19ml) was slowly added a 1N borane tetrahydrofuran solution (33 ml). The reaction mixture was then heated to reflux, cooled to room temperature and 2N HCl (6ml) was added. The mixture was refluxed for 1 hour, cooled to room temperature and concentrated to afford a solid. The solid was slurried in a mixed solution of DCM (100ml) and EtOAc (50ml) and filtered to provide a solid. The solid was dried under vacuum to give compound 19-2(2.14 g).

A mixture of compound 19-2(0.5g) and trimethylamine in dichloromethane (20ml) was cooled to 0 ℃ and a dichloromethane solution of acetyl chloride was added dropwise. After the dropwise addition, the reaction mixture was warmed to room temperature. The organic phase was washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified on silica gel column to give compound 19.

¹H NMR(400MHz,DMSO-d₆)δ8.13(t,J＝5.2,1H),7.13(d,J＝8.0,1H),6.88(d,J＝2.4,1H), 6.76(dd,J1＝8.4,J2＝2.0,1H,5.48(br,1H),4.22(d,J＝5.2,2H),1.85(s,3H).MS:M+H+＝233.00.

Example 8 preparation of Compound 23

After cooling a mixture of compound 23-1(20.11g,108.04mmol,1.0eq) and THF (200ml) to-20 deg.C to-30 deg.C under nitrogen, DIBAL-H toluene solution (216ml,1.5mol/l,324.13mmol,3.0eq) was slowly added in portions. The temperature is kept between minus 20 ℃ and minus 30 ℃ for 30 minutes, and then the temperature is increased to between 25 ℃ and 30 ℃ for reaction for 4 to 5 hours. Cooled to 0 ℃ and isopropanol (20ml), saturated sodium potassium tartrate solution (500ml) and ethyl acetate (500ml) were added. The aqueous phase was extracted with ethyl acetate (200ml), and the organic phases were combined and concentrated to dryness to give compound 23-2(21.7 g).

To a mixture of compound 23-2(4.0g, 21.16mmol, 1.0eq), ethyl acetate (40ml) and toluene (4.0g) was added 1M HCl solution (20ml) and stirred for 10 min. Sodium hydroxide solution (16ml 1M) was added and stirred. The organic phase was washed with sodium chloride solution (50 ml). To the separated organic phase were added p-toluenesulfonic acid (0.44g, 2.33mmol, 0.11eq), piperazine (1.82g, 21.16mmol, 1.0eq) and ethyl acetate (10 ml). The temperature was cooled to 50 ℃ and sodium triacetoxyborohydride (9.64g, 45.49mmol, 15 equiv.) was added. The reaction time was 1.5 hours. After the reaction was completed, a saturated sodium bicarbonate solution was added to the reaction system until no bubbles were released. The solution was separated and the organic phase was concentrated to dryness to afford compound 23 as crude product. The crude product was purified by column chromatography to give compound 23(0.50 g).

¹H NMR (400MHz, chloroform-d) δ 7.53(d, J ═ 8.3Hz,2H),6.93(d, J ═ 2.5Hz,2H),6.81(dd, J ═ 8.3, 2.5Hz,2H),3.76(s,4H),3.55(d, J ═ 1.7Hz,4H),2.48(s,8H). LC-MS:433.05.

Example 9 preparation of Compound 24

Compound 24-1(15.0g, 80.60mmol, 1.0eq) was combined with THF (150 ml). After cooling to-30 ℃ to-40 ℃, DIBAL-H (161.2ml, 1.5m toluene solution, 241.81mmol, 3.0eq) was added slowly in portions. The temperature is maintained at-30 ℃ to-40 ℃ for 30 minutes and then at 25 ℃ to 30 ℃ for 3 to 4 hours. The reaction mixture was cooled to 0 to 10 ℃. The reaction was quenched by the addition of isopropanol (100ml) and potassium sodium tartrate solution was added. The mixture was extracted with ethyl acetate (400ml), dried and concentrated to give compound 24-2(15.19 g).

To a mixture of compound 24-1(15.0g, 80.60mmol, 1.0eq), 1.5g of 10% Pd/C and dry methanol (120ml) was added dropwise several drops of concentrated hydrochloric acid under nitrogen. The reaction mixture was connected to hydrogen. The reaction was carried out at room temperature for three hours. After filtration, the filtrate was rotary dried to give compound 24-3(14.9 g).

Under nitrogen, compound 24-2(15.19g, 80.35mmol, 1.0eq) and compound 24-3(14.9g, 78.35mol, 0.97eq), sodium triacetoxyborohydride (36.61g, 172.75mmol), 2 ethyl. The acetates (150ml) were mixed and heated to 30 ℃ for 5-6 hours. The reaction solution was quenched with sodium bicarbonate solution and the separated solution was concentrated to dryness. Compound 24(2.0g) was obtained by column chromatography.

¹H NMR(400MHz,DMSO-d₆)δ7.15(t,J＝7.9Hz,2H),6.94(dd,J＝8.1,1.2Hz,2H),6.86(dd, J＝7.7,1.2Hz,2H),5.57(s,4H),3.77(s,4H).LC-MS:364.00.

EXAMPLE 10 preparation of Compound 29

To a mixture of sulfuric acid, iodine (0.88eq) and sodium periodate (0.44eq) was added p-toluic acid (1.0 eq). The reaction was maintained at room temperature for 2-3 hours, and then the reaction solution was poured into ice water, stirred, and filtered. Recrystallizing the filter cake with ethanol to obtain the compound 29-1.

Compound 29-1 was dissolved in methanol and sulfuric acid, and heated under reflux. The reaction solution was concentrated to dryness and then dissolved in ethyl acetate. The organic phase was washed with sodium bicarbonate solution, separated, dried, filtered and concentrated to afford compound 29-2.

The compound 29-2(1.0eq) was dissolved in ethyl acetate, and trimethylsilylene (3.0eq), bis (triphenylphosphine) palladium dichloride (0.02eq), cuprous iodide (0.02eq), and triethylamine (6.0eq) were added to the reaction solution. The organic phase was washed with water and saturated brine, separated, dried, filtered and concentrated to afford compound 29-3.

Compound 29-3 was dissolved in methanol, cooled, and then potassium carbonate was added. The reaction was completed at room temperature. Cold water was added to the reaction solution, and dichloromethane was extracted. After separation of layers, the organic phase was dried, filtered, concentrated and purified by column chromatography to afford compound 29.

¹H NMR(400MHz,DMSO-d₆)δ7.92(s,2H),4.60(s,2H),3.86(s,3H),2.55(s,3H).MS: M+H⁺＝199.10.

Example 11 preparation of Compound 33 and Compound 34

A mixture of bis (triphenylphosphine) palladium dichloride (0.31g), cuprous iodide (84mg) and triethylamine (6.71g) was added to compound 33-1(10g) and acetonitrile (76g) under nitrogen. The reaction mixture was stirred for 20 hours at 60-70 ℃ and then filtered directly through silica gel to give a dark green liquid. The dark green liquid was concentrated, triturated with n-heptane for 20 hours and filtered to give compound 33.

Compound 33:¹H NMR(400MHz,DMSO-d₆):δ7.92(d,J＝9.2,2H),7.86(d,J＝7.6,2H),7.45(m, 2H),6.06(s,1H),5.78(s,1H),3.84(s,J＝6.0,1H),2.42(s,3H).MS:M+H⁺＝349.20.

compound 34 can be isolated from the preparation of compound 33 or from the methods described herein.

Compound 34:¹H NMR(400MHz,DMSO-d₆):δ8.77(s,1H),8.09(s,1H),7.88～7.99(m,4H),6.47 (s,1H),6.27(s,1H),5.39(s,1H),3.93～3.98(m,6H),3.84(d,J＝9.2,3H),2.47(s,3H),2.40(s,3H),2.14(s, 3H).

EXAMPLE 12 preparation of Compound 35

Compound 35 may be prepared in a manner similar to the procedures described in international publication No. WO2009/143404 (e.g., page 107-108) and international publication No. WO2010/124047 (e.g., page 50), the entire contents of which are incorporated herein by reference.

Compound 35 can also be isolated from the methods described herein.

¹H NMR(400MHz,DMSO-d₆):δ8.76(s,1H),8.63(s,1H),8.49(s,1H),8.09(s,1H),7.89(d,J＝8.4, 1H),7.51(d,J＝7.6,1H),3.88(3H,s),2,58(s,3H),1.71(s,9H).

Example 13 preparation of Compound 36

Compound 4(2g) was mixed with anhydrous tetrahydrofuran (50mL), cooled to 0 deg.C, and sodium hydride (328mg) was added. The reaction mixture was then stirred at 0 ℃ for 1 hour, then methyl chloroformate (777mg) was added. After the dropwise addition, the temperature was raised to 20 ℃ and the mixture was stirred for 48 hours. Water (20mL) was added to stop the reaction. The mixture was stirred and filtered to provide compound 36 as a white solid,

¹H NMR(400MHz,DMSO-d₆)δ8.95(d,J＝2.0,1H),8.64(d,J＝2.0,1H),8.55(s,1H),8.11(s,1H), 7.91(d,J＝7.6,1H),7.53(d,J＝8.0,1H),4.06(3H,s),3.87(3H,s),2,59(s,3H).MS:M+H⁺＝350.1.

EXAMPLE 14 preparation of Compound 37

To a mixture of compound 4(2g) and anhydrous tetrahydrofuran (50mL) was added sodium hydride (329mg) at 20 ℃. The reaction mixture was stirred at 25 ℃ for 1 hour. Methyl iodide (1.95g) was added dropwise, and the reaction mixture was stirred at 20 ℃ for 17 hours and filtered to give a crude product. The crude product was slurried in tetrahydrofuran and filtered to provide compound 37.

¹H NMR(400MHz,DMSO-d₆)δ8.79(s,1H),8.52(s,2H),8.07(s,1H),7.88(d,J＝7.6,1H),7.51(d, J＝7.2,1H),4..22(3H,s),3.86(3H,s),2,50(s,3H).MS:M+H⁺＝306.2.

Example 15 preparation of Compound 38

To this was added potassium tert-butoxide (2.73 g). The reaction mixture was stirred at-66 ℃ to-70 ℃ for 3 hours. When the temperature was raised to room temperature, 1ml of water was added to stop the reaction. 20ml of 15% brine was added thereto and stirred for 1 hour. After separation of layers, the organic layer was washed twice with 15% brine. After separation, a yellow solution was obtained. After addition of 20ml of water, the mixture was concentrated to 30ml, to which 10ml of ethanol was added. After stirring for 1 hour, the mixture was filtered to obtain compound 38 as a white solid.

¹H NMR(400MHz,DMSO-d₆)δ13.9(br,2H),10.55(s,2H),8.74(s,2H),8.54(s,2H),8.21(m, 6H),8.11(d,J＝8.0,2H),7.93(t,J＝8.0,2H),7.83(d,J＝8.4,2H),7.53(d,J＝8.4,2H),3.87(4H,s),2.59(3H, s),2,53(s,3H).MS:M+H⁺＝882.4.

EXAMPLE 16 preparation of Compound 39

Sodium hydroxide (6.4g) was dissolved in 40ml of water, and Compound 3(5g) and 40ml of tetrahydrofuran were added. The reaction mixture was stirred at room temperature for 41 hours. After filtration, the filtrate was dried at 40 ℃ to obtain a white solid compound 39.

¹H NMR(400MHz,DMSO-d₆)δ13.9(br,1H),10.55(s,2H),8.73(s,1H),8.53(s,1H),8.21(s, 1H),8.06(d,J＝1.6,1H),7.85(m,1H),7.47(d,J＝8.0,2H),2.56(3H,s).

Example 17 preparation of Compound 40

Compound 40-1(294mg) was dissolved in tetrahydrofuran (7ml), and Compound 4(250mg) was added thereto, followed by cooling the reaction solution to-77 ℃. 520mg of potassium tert-butoxide were added and the reaction was stirred at-77 ℃ for 5 hours. The reaction solution was purified by column chromatography to give compound 40(60 mg).

¹H NMR(400MHz,DMSO-d₆)δ13.96(br,1H),10.57(s,1H),8.74(s,1H),8.54(s,1H),8.27(m,3H), 8.11(s,J＝8.0,1H),7.91(t,J＝8.0,1H),7.58(m,2H),7.36(d,J＝8.4,1H),6.79～6.84(m,3H),4.43(s,2H),3.60(s, 2H),2.16～2.67(m,14H).MS:M+H⁺＝706.3.

EXAMPLE 18 preparation of Compound 41

Preparation of Compound 41-1 20.00g of Compound 2, 158mL of NMP, 41.80g of trimethylsilylacetylene, and 2.35g of Pd (PPh)₃)₂Cl₂0.6380g CuI, 13.00g DIPEA. The reaction mixture was heated to 60-70 ℃ under nitrogen and stirred for 5 hours. After completion of the reaction, the reaction mixture was cooled to 5 ℃ and EtOAc and water were added. The mixture was stirred, separated, extracted, and the organic phases were combined, concentrated, and purified by column chromatography to provide 15.40g of compound 41-1 (yield: 72.8%).¹H NMR(400MHz, DMSO-d₆)δ8.74(d,J＝2.1Hz,1H),8.48(d,J＝2.1Hz,1H),8.43(s,1H),1.63(s,9H),0.27(s,9H).

Preparation of Compound 41 14.86g of Compound 41-1 and 150ml of methanol were added in this order, cooled to 0-5 ℃ and 9.76g of potassium carbonate were added in portions. Naturally heating to 10-15 deg.C after adding, reacting for 30-45min, slowly adding water to precipitate solid, maintaining for 30-45min, and filtering. The filter cake was washed with water to pH7 to 8 and dried to obtain 6.50g of Compound 41 as a solid powder (yield: 96.4%).

EXAMPLE 19 preparation of Compound 42

Compound 42-2 was prepared by adding compound 42-1(3.00g), carbon tetrachloride (50ml), NBS (2.89g), AIBN (356mg), and potassium carbonate (1.65g) in this order, heating to 60-70 ℃ overnight, and stirring for 15-19 hours. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated to dryness under reduced pressure, dissolved in ethyl acetate, washed with water, and concentrated to dryness under reduced pressure to give crude compound 42-2(4.35 g). MS: [ M + H]⁺＝356.9.

Compound 42-3 is prepared by sequentially adding compound 42-2(4.35g), sodium formate (3.17g), ethanol (180ml), and water (48ml), heating to 80-90 deg.C overnight, and stirring for 15-20 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added, stirred and separated. The organic phase was concentrated to dryness under reduced pressure to give a crude product of Compound 42-3 (3.52 g). Purifying the crude product with silica gel column to obtain compound 42-3 (1.20g) with yield of 33%. MS: [ M + H ]]⁺＝293.0.

Preparation of Compound 42-4 Compound 42-3(1.70g), Compound 41(833mg), Pd (PPh)₃)₂Cl₂(327mg), CuI (89mg), DIPEA (1.13g) and NMP (50ml), heated to 60-65 ℃ and stirred under nitrogen overnight for 10-15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 2-methyltetrahydrofuran and water were added and stirred. The layers were separated, the organic phase was washed with water, concentrated to dryness under reduced pressure, and purified by silica gel column to give 42-4(0.96g) in 54% yield. MS: [ M + H]⁺＝308.10.

¹H NMR(400MHz,DMSO-d₆)δ13.94(s,1H),8.74(q,J＝2.4,1.7Hz,1H),8.54(t,J＝1.7Hz, 1H),8.23(s,1H),8.07(s,1H),8.01(d,J＝8.0Hz,1H),7.74(d,J＝8.1Hz,1H),5.58(t,J＝5.6Hz,1H),4.84 (d,J＝5.4Hz,2H),3.88(s,3H).

Compound 4Preparation of 2 t-BuOK (1790mg) was dissolved in THF (14ml) for later use. Compound 42-4 (700mg), compound 5(623mg) and THF (30ml) were added, the temperature was reduced to-60 ℃ under nitrogen, and then a t-BuOK solution in THF was slowly added dropwise at-60 ℃. After the addition was complete, the temperature was maintained at-60 ℃ and stirring was continued for 1 hour. After the reaction, the temperature is raised to-10 ℃, water and ethyl acetate are added, and the mixture is stirred and layered. The organic phase was concentrated and dried under reduced pressure, purified by silica gel column to give crude 490 mg. The crude product and absolute ethanol were heated under reflux, stirred for 30 minutes, then cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was dried in a vacuum oven at 40 ℃ for 10-13 hours to give compound 42(270mg) as a white solid in 20% yield. MS: [ M + H]⁺＝549.10.

¹H NMR(400MHz,DMSO-d₆)δ13.95(s,1H),10.58(s,1H),8.74(t,J＝1.6Hz,1H),8.54(t,J＝ 1.6Hz,1H),8.27–8.16(m,3H),8.06(dd,J＝15.4,8.3Hz,2H),7.73(dd,J＝10.9,8.3Hz,2H),5.54(t,J＝ 5.7Hz,1H),4.86(d,J＝5.5Hz,2H),3.57(s,2H),2.37(d,J＝24.3Hz,8H),2.16(s,3H).

EXAMPLE 20 preparation of Compound 43

Preparation of Compound 43-2: under the protection of nitrogen, adding 30ml of concentrated sulfuric acid, cooling to 5-10 ℃, adding 10.00g of methyl 3-iodo-4-methylbenzoate (compound 42-1), stirring at 5-10 ℃ for 20min, and then dropwise adding a mixed solution of fuming nitric acid and concentrated sulfuric acid (4.57g of fuming nitric acid is dissolved in 10ml of concentrated sulfuric acid, and the temperature is controlled at 5-10 ℃). After the addition was complete, the reaction mixture was warmed to room temperature, poured into water, DCM was added, the layers were separated, the organic phase was collected and extracted. The combined organic phases were washed with water, concentrated to dryness and the crude product was purified by column chromatography to give 2.00g of compound 43-2 (yield: 17.2%)¹H NMR(400MHz,DMSO-d₆)δ8.57(d,J＝1.8Hz,1H), 8.32(d,J＝1.7Hz,1H),3.90(s,3H),2.56(s,3H).

Preparation of Compound 43-3 1.78g of Compound 43-2, 20ml of ethanol, 1.39g of iron powder, 0.3110g of ammonium chloride and 4.19g of aqueous solution were added in this order under a nitrogen atmosphere. The reaction mixture is stirred and heated to 80-90 ℃ for about 1-1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with DCM and added saturated aqueous sodium bicarbonate solution, the aqueous phase pH was about 8. Stirring the mixture, filtering, separating and extracting. The combined organic phases were washed with water and concentrated to give 1.60g of compound 43-3 (yield: 99.1%) which was used directly in the next step.

The compound 43-4 is prepared by adding 15ml of water under nitrogen protection, cooling to-5 deg.C to 5 deg.C, sequentially adding 1.37g of concentrated sulfuric acid, 1.00g of compound 43-3, and 15ml of ethanol. An aqueous solution of sodium nitrite (0.0618g sodium nitrite dissolved in 200ul water) was added slowly with stirring at 0-5 c and the temperature was maintained. Heating the reaction mixture to 80-90 ℃ for reflux and reacting for 30-45 min. After completion of the reaction, the reaction mixture was diluted by addition of DCM, layered and extracted. The combined organic phases were washed with alkali, water, concentrated and purified by column chromatography to give compound 43-4 (0.77g) as a solid.

Preparation of Compound 43-5 Compound 43-4(0.715g), NMP (20ml), Compound 41(0.876g), Pd (dppf) Cl were added in this order under nitrogen protection₂(0.358g), CuI (93mg) and DIPEA (3.16 g). The reaction mixture is heated to 90-95 ℃ and reacted for 5-7 hours. After completion of the reaction, the reaction mixture was cooled to 20 ℃, quenched with water, and extracted with 2-methyltetrahydrofuran. And combining organic phases, concentrating to dryness, and purifying by column chromatography to obtain a crude product. The crude product was washed with ethyl acetate, cooled to room temperature, n-heptane was added dropwise, stirred, filtered and dried to give compound 43-5(0.62g) in 83% purity and 82% yield.

Preparation of Compound 43-5(0.60g), Compound 5(0.53g) and THF (15ml) were added in this order under a nitrogen blanket. The temperature was reduced to-55 ℃ and a 1.0M solution of potassium tert-butoxide in THF (23.4ml) was slowly added dropwise. After the addition, the reaction is continued for 10 to 15 hours. After the reaction is finished, adding a 14% potassium dihydrogen phosphate solution to the pH value of 8-9, extracting by ethyl acetate, washing an organic phase by water, layering, washing the organic phase, and purifying by column chromatography to obtain a crude product. The crude product was stirred with THF (9ml), petroleum ether (15ml) was added dropwise, stirring continued for 20-30 minutes, filtered and dried to give compound 43(0.334g),purity 99% and yield 32%.¹H NMR(400MHz,DMSO-d₆) δ13.94(s,1H),10.50(s,1H),10.08(s,1H),8.72(d,J＝2.0Hz,1H),8.52(d,J＝1.9Hz,1H),8.25–8.18 (m,2H),8.07(dd,J＝8.6,2.1Hz,1H),7.75–7.67(m,2H),7.44(d,J＝1.7Hz,1H),3.58(s,2H),2.42(s, 10H),2.22(s,3H).MS:[M+H]⁺＝549.10.

Example 21 preparation of Compound 44 and Compound 45

Methyl 2-hydroxy-4-methylbenzoate (15.25g) and DCM (100ml) were added successively under nitrogen, cooled to 0-5 ℃ and NIS (19.82g) was added. After the addition is finished, the reaction mixture is heated to 20-25 ℃ and stirred for reaction for 20-22 hours. After completion of the reaction, water and DCM were added and the layers separated. The organic phase was washed with water, concentrated to dryness, and purified by column chromatography to give 15.10g of a product (a mixture of methyl 2-hydroxy-4-methylbenzoate, compound 44-1 and compound 45-1).

5.10g of the mixture of Compound 45-1, NMP (30ml), Compound 41(1.0g), PdCl were added successively₂(PPh₃)₂(0.39g), CuI (0.11g), and DIPEA (1.36 g). The reaction mixture is heated to 60-66 ℃ for reaction for 3-5 hours under the protection of nitrogen. After completion of the reaction, the reaction mixture was cooled to 20-25 ℃, poured into water, extracted with 2-methyltetrahydrofuran (200ml) and EtOAc (300ml), the organic phase was concentrated to dryness and purified by column chromatography to give 45-2(1.26g) in 59% yield.

Compound 45-2(0.6g) was dissolved in THF (8ml) to prepare a THF solution of compound 45-2 for later use. A mixture of Compound 5(0.56g) and 1.0M potassium tert-butoxide in THF (23.5ml) was cooled toA THF solution of compound 45-2 was added dropwise at-55 ℃. After the dropwise addition is finished, the reaction mixture is subjected to heat preservation reaction and stirred for 15-20 hours. The temperature was then raised to-30 ℃ and the reaction mixture was stirred for 4-5 hours. After completion of the reaction, water was added, 1M hydrochloric acid was added dropwise to a pH of 7-8, and extraction was performed with ethyl acetate. And combining organic phases, concentrating to dryness, and purifying by column chromatography to obtain a crude product. The crude product was refluxed with ethanol, cooled to room temperature, filtered and dried to give compound 45(70mg) with 78% purity and 6.5% yield. MS: [ M + H]⁺＝549.10

¹H NMR(400MHz,DMSO-d₆)δ13.88(s,1H),11.71(s,1H),8.67(d,J＝2.0Hz,1H),8.43(d,J ＝2.0Hz,1H),8.23–8.15(m,2H),8.13(s,1H),7.93(dd,J＝8.5,2.2Hz,1H),7.71(d,J＝8.5Hz,1H), 6.84(s,1H),3.60(s,2H),2.55(s,3H),2.46(s,7H),2.32(s,3H).

2.5g of the mixture of Compound 44-1, NMP (20ml), Compound 41(1.395g), Pd (dppf) Cl were added successively₂(1.424g), CuI (0.372g) and DIPEA (5.53 g). Under the protection of nitrogen, the reaction mixture is heated to 90-95 ℃ and reacted for 16-18 hours. After the reaction, the temperature was reduced to 20 ℃, water was added, and extraction was performed with 2-methyltetrahydrofuran. The organic phase was concentrated to dryness and purified by column chromatography to give compound 44-2(1.44g) with a purity of 86.8% and a yield of 55%.

Compound 44-2(0.50g) was dissolved in THF (8ml) to prepare a THF solution of compound 44-2 for later use. A mixture of compound 5(0.467g) and 1.0M potassium tert-butoxide in THF (19.5ml) was cooled to-55 deg.C and a solution of compound 44-2 in THF was slowly added dropwise. After the dropwise addition, stirring the reaction mixture, continuing the heat preservation reaction for 15-20 hours, after the reaction is finished, adding water, dropwise adding 1M hydrochloric acid until the pH value is 7-8, extracting with ethyl acetate, combining organic phases, concentrating to dryness, and purifying by column chromatography to obtain a crude productWashed with DCM, filtered and dried to provide compound 44(80mg) with 99% purity and 9% yield MS: [ M + H ]]⁺＝549.10.

¹H NMR(400MHz,DMSO-d₆)δ13.91(s,1H),10.62(s,1H),9.20(s,1H),8.74(s,1H),8.41– 8.18(m,2H),8.06(d,J＝8.5Hz,1H),7.89–7.73(m,2H),7.68(dd,J＝7.7,1.4Hz,1H),7.25(d,J＝7.7 Hz,1H),3.60(s,2H),2.62(s,3H),2.39(d,J＝26.4Hz,7H),2.17(d,J＝1.4Hz,3H).

Example 23 anti-proliferative Activity of selected Compounds in K562 cells

K562/Ku812/MEG-01 cells were seeded into 96-well plates and treated with different concentrations of the selected compounds for 72 hours. Cell viability was determined by CTG assay and IC 50 was calculated using GraphPad Prism 8, data points are shown as mean + SEM, and results are listed in the table below.

NA is not provided.

Claims

1. A process for preparing a compound of formula (Γ):

comprising reacting a compound of formula (II') with a compound of formula (III) in a solvent and in the presence of a base:

providing a compound of formula (I'):

wherein R is₁Is H, C₁-C₄Alkyl, or-C (═ O) O- (C)₁-C₄Alkyl groups);

R₂is or C₁-C₄An alkyl group;

R₃is that

-NH₂,-NHC(＝O)Me,

Or

R₇Is H or hydroxy;

R₈is H or hydroxy;

R₉is H or hydroxy;

R₁₀is H or hydroxy; and

with the proviso that the compound of formula (I') is not compound 6:

2. a process for preparing a compound of formula (I):

comprising reacting a compound of formula (II):

with a compound of formula (III):

providing a compound of formula (I) in a solvent and in the presence of a base,

wherein R is₁Is H, C₁-C₄Alkyl, or-C (═ O) O- (C)₁-C₄Alkyl), R₂Is H or C₁-C₄Alkyl, and R₃Is that

-NH₂,-NHC(＝O)Me,

Or

And with the proviso that the compound of formula (I) is not compound 6:

3. the method of claim 1 or 2, wherein the-CH 2-R3 group is para to the-NH-group.

4. The method of claim 3, wherein the compound of formula (I) is a compound of formula (I-A):

5. the method of claim 1 or 2, wherein the-CH 2-R3 group is para to the-CF 3 group.

6. The method of claim 5, wherein the compound of formula (I) is a compound of formula (I-B)

7. The method of any one of claims 1-6, wherein R₁Is H, tert-butyl, -C (═ O) OMe, or is methyl.

8. The method of any one of claims 1-7, wherein R₂Is H or methyl.

9. The method of claim 2, wherein the compound of formula (I) is a compound of formula (I-C)

10. The method of claim 1, wherein the compound of formula (I') is a compound of formula (I-D)

11. The process of any one of claims 1 to 10, wherein the compound of formula (II) is prepared by a process comprising reacting compound 1 with a compound of formula (IV) in a solvent and in the presence of a base, a catalyst and a catalyst ligand

12. The process of any one of claims 1 to 10, wherein the compound of formula (II') is prepared by a process comprising reacting a compound of formula (V) with a compound of formula (VI) in a solvent and in the presence of a base, a catalyst, and a catalyst ligand;

wherein X is a halogen atom or a halogen atom,

13. the process of claim 11 or 12, wherein the reaction between compound 1 and the compound of formula (IV) or the reaction between the compound of formula (V) and the compound of formula (VI) is carried out under nitrogen or inert gas;

and/or, the solvent comprises N-methylpyrrolidone, DMSO, DMF, N-dimethylacetamide, acetonitrile, toluene, dioxane, and THF;

and/or, the volume/mass ratio of solvent to compound of formula (IV) is (about 5 to about 10) mL:1 g;

and/or, the catalyst is a palladium catalyst;

and/or, the molar ratio of catalyst to compound of formula (IV) is (about 0.01 to about 0.05): 1;

and/or the catalyst ligand is a copper compound and/or triphenylphosphine;

and/or, the molar ratio of catalyst ligand to catalyst is (about 0.8 to about 1.2): 1;

and/or the base is an organic base and/or an inorganic base;

and/or, the molar ratio of base to compound of formula (IV) (about 1.0 to about 1.5): 1;

and/or, the molar ratio of compound 1 to compound of formula (IV) is (about 0.95 to about 2.0): 1;

and/or, the reaction temperature is from about 40 ℃ to about 80 ℃;

and/or, post-treatment of the reaction includes mixing with water and filtration.

14. The process of claim 13, wherein in the reaction of compound 1 with the compound of formula (IV) or the reaction of the compound of formula (V) with the compound of formula (VI), the solvent is N-methylpyrrolidone, DMSO, DMF, N-dimethylacetamide, or acetonitrile;

and/or, the volume/mass ratio of solvent to compound of formula (IV) is (about 7 to about 10) mL:1 g;

and/or, when the catalyst is a palladium catalyst, the palladium catalyst is selected from PdCl₂(PPh₃)₂、Pd(dppf)₂Cl₂、Pd(OAc)₂And palladium on carbon;

and/or, the molar ratio of catalyst to compound of formula (IV) is (about 0.01 to about 0.03): 1;

and/or, when the catalyst ligand comprises a copper compound, the copper compound is selected from the group consisting of CuI, CuBr, Cu₂O, CuO and copper acetate;

and/or the molar ratio of the catalyst ligand to the catalyst is 1: 1;

and/or, when the base comprises an organic base, the organic base comprises pyridine, C₁-C₄Alkali metal salts of alcohols or-N (R)₄)(R₅)(R₆) Wherein R is₄、R₅And R₆Each of which independently represents hydrogen or C₁-C₄An alkyl group;

and/or, when the base comprises an inorganic base, the inorganic base is an alkali metal carbonate and/or an alkali metal hydroxide;

and/or, the molar ratio of base to compound of formula (IV) is (about 1.2 to about 1.3): 1;

and/or, the molar ratio of compound 1 to compound of formula (IV) is (about 1.2 to about 1.5): 1;

and/or, the reaction temperature is about 60 ℃ to 75 ℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering, further comprising mixing with an amino acid compound prior to mixing with water;

and/or, when the post-reaction treatment comprises mixing with water and filtering, the mixing temperature in the mixing with water step is from about 20 ℃ to about 25 ℃;

and/or, when the post-reaction treatment comprises mixing with water and filtration, the filtration further comprises washing with water;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering, further comprises post-filtration pulping.

15. The process of claim 14, wherein in the reaction of compound 1 with the compound of formula (IV) or the reaction of the compound of formula (V) with the compound of formula (VI), the solvent is N-methylpyrrolidone, DMSO, DMF, or N, N-dimethylacetamide;

and/or, when the catalyst is a palladium catalyst, the palladium catalyst is PdCl2(PPh3)2 or pd (dppf)2Cl 2;

and/or, when the catalyst ligand comprises a copper compound, the copper compound is CuI or CuBr;

and/or, when the base comprises an organic base and the organic base comprises C₁-C₄Alkali metal salts of alcohols, C₁-C₄The alkali metal salt of the alcohol is potassium tert-butoxide and/or sodium tert-butoxide;

and/or, when the base comprises an organic base and the organic base comprises or-N (R)₄)(R₅)(R₆) When is, -N (R)₄)(R₅)(R₆) Including Et₃N、DIPEA、(i-Pr)₂NH and Bu₃N；

And/or, when the base comprises an inorganic base and the inorganic base comprises an alkali metal carbonate, the alkali metal carbonate is K₂CO₃And/or Cs₂CO₃；

And/or, when the base comprises an inorganic base, the inorganic base comprises an alkali metal hydroxide, the alkali metal hydroxide being NaOH and/or KOH;

and/or, the molar ratio of compound 1 to compound of formula (IV) is (about 1.2 to about 1.3): 1; and/or, the reaction temperature is from about 65 ℃ to about 70 ℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with an amino acid compound prior to mixing with water, the amino acid compound is selected from the group consisting of cysteine, N-acetyl-L-cysteine, ethylenediaminetetraacetic acid, sodium edetate and dithiocarbamate;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with an amino acid compound prior to mixing with water, the molar ratio of amino acid compound to compound of formula (IV) is (about 0.1 to about 0.5): 1;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with the amino acid compound prior to mixing with water, the mixing temperature when mixing with the amino acid compound is from 35 ℃ to about 45 ℃;

and/or, when the post-treatment of the reaction comprises mixing with water and filtering and further comprises mixing with the amino acid compound prior to mixing with water, the mixing time with the amino acid compound is about 4 to 5 hours;

and/or, when the post-reaction treatment comprises mixing with water, filtering and further comprises pulping immediately after filtering, the solvent used for pulping is a mixed solvent of ethyl acetate and n-heptane with a volume ratio of 1: 1;

and/or, when the post-treatment of the reaction comprises mixing with water, filtration and further comprises pulping immediately after filtration, the volume/mass ratio of solvent to coarse filter cake used for pulping is (about 5 to about 7) milliliters: 1 gram.

16. A compound which is:

17. a compound of formula (I-D):

wherein

R₇Is H or hydroxy;

R₈is H or hydroxy;

R₉is H or hydroxy;

R₁₀is H or hydroxy; and

or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17 which is:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of any one of claims 16 to 18 and a pharmaceutically acceptable excipient.

20. A method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 16 to 18 or a pharmaceutical composition of claim 19.