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CN113880812A - Preparation method of CSF-IR (CSF-IR) inhibitor - Google Patents

Preparation method of CSF-IR (CSF-IR) inhibitor Download PDF

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CN113880812A
CN113880812A CN202111358957.XA CN202111358957A CN113880812A CN 113880812 A CN113880812 A CN 113880812A CN 202111358957 A CN202111358957 A CN 202111358957A CN 113880812 A CN113880812 A CN 113880812A
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宗新杰
颜晓晨
李承铎
周治国
高强
郑保富
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Medchemexpress China Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

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Abstract

The invention relates to a preparation method of a CSF-IR inhibitor; the method takes the compound I as a raw material, further optimizes reaction conditions according to the characteristics of reactants and intermediate products, reduces side reactions, reduces the difficulty of post-treatment, reduces experimental operation steps of post-treatment, overcomes the defects of long route (eight steps), low yield and poor atom economy in the prior art, and can prepare a target product by using easily-obtained and cheap starting raw materials. The synthesis method has mild reaction conditions, is simple and convenient to operate, is suitable for small-amount preparation in a laboratory and is also suitable for industrial large-scale production.

Description

Preparation method of CSF-IR (CSF-IR) inhibitor
Technical Field
The invention relates to a preparation method of a CSF-IR inhibitor, belonging to the technical field of organic synthesis.
Background
Vimselitinib (DCC-3014, named 2- (isopropylamino) -3-methyl-5- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) pyrimidin-4 (3H) -one, CAS number 1628606-05-2, structure shown in formula below, is a dual inhibitor of c-FMS (CSF-IR) and c-Kit, has anticancer and antiproliferative activities, and IC50 values of <0.01 μ M and 0.1-1 μ M, respectively.
Figure BDA0003358302070000011
The synthesis of Vimseltinib is disclosed in patent WO2014145025a2, according to the disclosed technical scheme (shown in the following formula), eight steps of reaction are required to prepare Vimseltinib, the iodination reaction yield in step d is only 48%, and the substitution reaction in step e is less than 20% when the inventor repeats the prior art due to poor substrate activity.
Figure BDA0003358302070000012
For the preparation of the boron ester in step c, the subsequent Suzuki coupling reaction was carried out without any purification, with supposedly complete conversion, but at the same time with only 50% conversion of the crude product of other similar structures such as [2- (ethylamino) -4-methoxypyrimidin-5-yl ] boronic acid (example B1) and only 60% conversion of the crude product of N-isopropyl-4-methoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) pyrimidin-2-amine (example B3) in patent WO2014145025a2, the inventors found that the boron ester content in step 3 was very low when the prior art was repeated. The coupling yield of the two steps of step f and step g disclosed in patent WO2014145025A2 is low, and is only 67% and 34% respectively, the introduction of the isopropyl amine group in the last step needs to adopt a sealed tank for high-temperature reaction for 2 days, the yield is only 59%, and the preparation amount of the product in the patent is very small, and is only 88 mg. The total yield of the last three steps is only 13.4 percent. In conclusion, the preparation method disclosed in the prior art has very poor atom economy, high preparation period and cost, poor reproducibility and high requirements on equipment, and is obviously not suitable for industrial scale-up production. Therefore, the design and implementation of a synthetic method which is suitable for industrial production, simple and convenient to operate and high in yield is the key point of research and development of the technicians in the field.
Disclosure of Invention
The present invention is directed to a method for preparing a CSF-IR inhibitor, which solves the problems of the background art mentioned above, and more particularly, to a method for preparing 2- (substituted amino) -3-methyl-5- (6-methyl-5- ((2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl) oxy) pyridin-2-yl) pyrimidin-4 (3H) -one.
In order to solve the above-mentioned technical problems, a first aspect of the present invention provides a method for producing a compound VII, comprising the steps of:
and step 3: reacting the compound I with organic amine under the action of alkali to obtain a compound II;
and 4, step 4: demethylating and dearomatizing the compound II to obtain a compound III;
and 5: reacting the compound III with a methylating agent under an alkaline condition to obtain a compound IV;
step 6: reacting the compound IV with a borate compound to obtain a compound V;
and 7: carrying out coupling reaction on the compound V and the compound VI to obtain VII;
Figure BDA0003358302070000021
wherein R is1And R2Identically or differently selected from hydrogen, C1～6Saturated or unsaturated alkyl groups.
As a preferable technical scheme of the invention, R is1And R2Are respectively selected from hydrogen and isopropyl.
As a preferred embodiment of the present invention, the step 3 includes the steps of: mixing a compound I, organic amine and an organic solvent, adding alkali, heating and stirring at 40-60 ℃, monitoring the reaction process by TLC, cooling to room temperature after the reaction is finished, filtering, washing, drying and concentrating to obtain a compound II; and/or the reaction time is 8-16 h.
As a preferred embodiment of the present invention, the compound II prepared in step 3 can be directly used for demethylation without purification.
As a preferred embodiment of the present invention, the step 4 includes the steps of: and mixing the compound II with an organic solvent, adding a demethylating reagent, monitoring the reaction process by TLC, and processing after the reaction is finished to obtain a compound III.
As a preferred technical scheme of the invention, the compound III prepared in the step 4 can be directly used for methylation reaction without purification.
As a preferred embodiment of the present invention, the step 5 includes the steps of: mixing the compound III, alkali and an organic solvent, adding a methylation reagent, stirring overnight at room temperature, and after the reaction is finished, filtering, washing, drying, concentrating and purifying to obtain a compound IV; and/or the molar charge ratio of the compound III to the methylating agent is 1 (1.5-2.5).
As a preferred embodiment of the present invention, the step 6 includes the steps of: under the protection of inert gas, mixing a compound IV with an organic solvent, cooling to-60-78 ℃, dropwise adding a lithium reagent, stirring for reaction for 1-2 h, adding a borate compound, stirring for reaction for 2-3 h at-50-70 ℃, after TLC monitoring reaction is finished, quenching with the solvent at 0 ℃, and concentrating to obtain a compound V; and/or the molar charge ratio of the compound IV to the lithium reagent is 1 (2-3.5); and/or the organic solvent is selected from one or more of tetrahydrofuran, N-dimethylformamide, ethyl acetate and dichloromethane.
As a preferred embodiment of the present invention, the compound IV prepared in step 6 can be directly used in the coupling reaction without purification.
As a preferred embodiment of the present invention, the step 7 includes the steps of: under the protection of inert gas, mixing the compound V, alkali and the compound VI with an organic solvent, adding a catalyst, replacing with the inert gas again, and heating at 90-100 ℃ overnight; after the reaction is finished, filtering, washing, drying, concentrating and purifying to obtain a compound VIII; and/or the alkali is selected from one of potassium acetate, triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate and sodium hydroxide; and/or the catalyst is one selected from palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and allyl palladium (II) chloride dimer.
In a second aspect, the present invention provides a process for the preparation of compound VI, said process comprising the steps of:
step 1: carrying out coupling reaction on the compound VIII and the compound IX to prepare a compound X;
Figure BDA0003358302070000031
step 2: carrying out substitution reaction on the compound X and a compound XI to prepare a compound VI;
Figure BDA0003358302070000032
as a preferred embodiment of the present invention, the step 1 comprises the following steps: mixing the compound VIII, the compound IX, alkali and a solvent, adding a catalyst, replacing with inert gas, and heating and stirring overnight; after the reaction is finished, the compound X is obtained through post-treatment.
As a preferred embodiment of the present invention, the step 2 comprises the steps of mixing the compound X, the compound XI, the base and the organic solvent, and heating and stirring the mixture overnight; after the reaction is finished, the compound VI is obtained through post-treatment and purification.
As a preferable technical scheme, the molar charge ratio of the compound X to the compound XI is 1 (1-2); and/or the molar charge ratio of the compound X to the alkali is 1 (0.8-1.6).
Advantageous effects
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method of the CSF-IR inhibitor provided by the invention overcomes the defects of long route, low yield and poor atom economy in the prior art, and the target product can be prepared by using cheap and easily available raw materials through seven steps of reaction.
2. By specially selecting raw materials, reaction steps and reaction sequence, the method not only can effectively shorten the reaction steps, but also can reduce the reaction difficulty and effectively improve the reaction yield; particularly, 5-bromo-2-chloro-4-methoxypyrimidine is adopted as a raw material and is in butt joint with organic amine, so that the technical problems of difficulty in introduction of the organic amine, harsh conditions and low yield in the prior art are solved.
3. The compound VI is prepared by two-step reaction by taking the compound VIII as a substrate, so that the problem of low docking yield in the prior art is solved, and meanwhile, the problem of low reaction yield is also solved by applying the compound VI to the step 7.
4. The invention effectively solves the technical problem of low yield of the boric acid/boric ester compound in the prior art by optimizing reaction conditions, particularly adopting the synthesis method of the step 6.
5. The preparation method of the CSF-IR inhibitor provided by the invention can be used for carrying out multi-step continuous operation, effectively simplifying reaction post-treatment, shortening the synthesis period, reducing hazardous waste and improving the atom economy.
6. The preparation method of the CSF-IR inhibitor provided by the invention is simple and convenient in operation method, effectively overcomes the difficulty of synthesizing a target compound in the prior art through the synergistic effect of the steps, improves the reaction yield, and is not only suitable for small-amount preparation in a laboratory, but also suitable for industrial large-scale production.
Detailed Description
The disclosure may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples included therein. 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 invention belongs. In case of conflict, the present specification, including definitions, will control.
The term "prepared from …" as used herein is synonymous with "comprising". The terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," or any other variation thereof, as used herein, are intended to cover a non-exclusive inclusion. For example, a composition, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, process, method, article, or apparatus.
When an amount, concentration, or other value or parameter is expressed as a range, preferred range, or as a range of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. When a range of values is described herein, unless otherwise stated, the range is intended to include the endpoints thereof and all integers and fractions within the range.
The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. "optional" or "any" means that the subsequently described event or events may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Approximating language, as used herein throughout the specification and claims, is intended to modify a quantity, such that the invention is not limited to the specific quantity, but includes portions that are literally received for modification without substantial change in the basic function to which the invention is related. Accordingly, the use of "about" to modify a numerical value means that the invention is not limited to the precise value. In some instances, the approximating language may correspond to the precision of an instrument for measuring the value. In the present description and claims, range limitations may be combined and/or interchanged, including all sub-ranges contained therein if not otherwise stated.
In addition, the indefinite articles "a" and "an" preceding an element or component of the invention are not intended to limit the number requirement (i.e., the number of occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural unless the stated number clearly indicates that the singular form is intended.
In order to solve the above-mentioned technical problems, a first aspect of the present invention provides a method for producing a compound VII, comprising the steps of:
and step 3: reacting the compound I with organic amine under the action of alkali to obtain a compound II;
and 4, step 4: demethylating and dearomatizing the compound II to obtain a compound III;
and 5: reacting the compound III with a methylating agent under an alkaline condition to obtain a compound IV;
step 6: reacting the compound IV with a borate compound in the presence of a lithium reagent to obtain a compound V;
and 7: carrying out coupling reaction on the compound V and the compound VI to obtain VII;
Figure BDA0003358302070000051
wherein R is1And R2Identically or differently selected from hydrogen, C1～6Saturated or unsaturated alkyl groups.
In some preferred embodiments, R is1And R2Are respectively selected from hydrogen and isopropyl.
In some preferred embodiments, the lithium reagent is selected from one of n-butyllithium, t-butyllithium, methyllithium, phenyllithium.
Preferably, the lithium reagent is n-butyllithium.
In some preferred embodiments, the borate compound is isopropanol pinacol borate.
The CAS number of the isopropanol pinacol borate is 61676-62-8.
In some preferred embodiments, the molar charge ratio of the compound IV to the borate compound is 1 (1-3).
Preferably, the molar charge ratio of the compound IV to the borate compound is 1:2.
In some preferred embodiments, the molar charge ratio of the compound IV to the lithium reagent is 1 (2-3.5).
Preferably, the molar charge ratio of the compound IV to the lithium reagent is 1: 2.5.
In some preferred embodiments, the step 3 comprises the following steps: mixing a compound I, organic amine and an organic solvent, adding alkali, heating and stirring at 40-60 ℃, monitoring the reaction process by TLC, cooling to room temperature after the reaction is finished, filtering, washing, drying and concentrating to obtain a compound II; and/or the reaction time is 8-16 h.
Preferably, the compound II prepared in step 3 can be directly used for demethylation without purification.
In some preferred embodiments, the base is selected from one of potassium acetate, triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate, sodium hydroxide.
Preferably, the base is triethylamine.
In some preferred embodiments, the organic solvent is selected from one or more of tetrahydrofuran, dimethylsulfoxide, N-dimethylformamide, ethyl acetate, dichloromethane.
Preferably, the organic solvent is tetrahydrofuran.
In some preferred embodiments, the molar charge ratio of the compound I to the isopropylamine is 1 (4.5-7.3).
Preferably, the molar charge ratio of the compound I to the isopropylamine is 1: 6.
In some preferred embodiments, the step 4 comprises the following steps: and mixing the compound II with an organic solvent, adding a demethylating reagent, monitoring the reaction process by TLC, and processing after the reaction is finished to obtain a compound III.
Preferably, the demethylating agent is selected from one or more of aqueous hydrobromic acid solution, acetic acid hydrobromic acid solution and boron tribromide; the organic solvent is acetic acid.
Preferably, the compound III prepared in the step 4 can be directly used for methylation reaction without purification.
In some preferred embodiments, the step 5 comprises the following steps: and mixing the compound III, alkali and an organic solvent, adding a methylation reagent, stirring at room temperature overnight, and after the reaction is finished, filtering, washing, drying, concentrating and purifying to obtain a compound IV.
In some preferred embodiments, the base is selected from one of potassium acetate, triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate, sodium hydroxide.
Preferably, the base is potassium carbonate.
In some preferred embodiments, the methylating agent is selected from one of dimethyl sulfate, methyl iodide, methyl tosylate, methyl triflate.
Preferably, the methylating agent is methyl iodide.
In some preferred embodiments, the molar charge ratio of the compound III to the methylating agent is 1 (1.5-2.5).
Preferably, the molar charge ratio of the compound III to the methylating agent is 1: 1.9.
In some preferred embodiments, the step 6 comprises the following steps: under the protection of inert gas, mixing the compound IV with an organic solvent, cooling to-60-78 ℃, dropwise adding a lithium reagent, stirring for reacting for 1-2 h, adding a borate compound, stirring for reacting for 2-3 h at-50-70 ℃, after TLC monitoring reaction is finished, quenching with the solvent at 0 ℃, and concentrating to obtain a compound V.
Preferably, the molar charge ratio of the compound IV to the lithium reagent is 1 (2-3.5).
In some preferred embodiments, the organic solvent is selected from one or more of tetrahydrofuran, N-dimethylformamide, ethyl acetate, dichloromethane.
Preferably, the organic solvent is tetrahydrofuran.
Preferably, the compound IV prepared in step 6 can be directly used in the coupling reaction without purification.
In some preferred embodiments, the step 7 comprises the following steps: under the protection of inert gas, mixing the compound V, alkali and the compound VI with an organic solvent, adding a catalyst, replacing with the inert gas again, and heating at 90-100 ℃ overnight; and after the reaction is finished, filtering, washing, drying, concentrating and purifying to obtain the compound VIII.
In some preferred embodiments, the base is selected from one of potassium acetate, triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate, sodium hydroxide.
Preferably, the base is potassium carbonate.
In some preferred embodiments, the catalyst is selected from one of palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, allylpalladium (II) chloride dimer.
Preferably, the catalyst is [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (CAS number 95464-05-4).
In a second aspect, the present invention provides a process for the preparation of compound VI, said process comprising the steps of:
step 1: carrying out coupling reaction on the compound VIII and the compound IX to prepare a compound X;
Figure BDA0003358302070000071
step 2: carrying out substitution reaction on the compound X and a compound XI to prepare a compound VI;
Figure BDA0003358302070000081
in some preferred embodiments, the step 1 comprises the following steps: mixing the compound VIII, the compound IX, alkali and a solvent, adding a catalyst, replacing with inert gas, and heating and stirring overnight; after the reaction is finished, the compound X is obtained through post-treatment.
Preferably, the base is potassium carbonate.
In some preferred embodiments, the molar charge ratio of the compound VIII to the base is 1 (2-4).
Preferably, the molar charge ratio of the compound VIII to the base is 1: 3.
In some preferred embodiments, the molar charge ratio of the compound VIII to the compound IX is 1 (0.8-1.5).
Preferably, the molar charge ratio of the compound VIII to the compound IX is 1:1.
In some preferred embodiments, the catalyst is selected from one of palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex, [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium, allylpalladium (II) chloride dimer.
Preferably, the catalyst is tetrakis (triphenylphosphine) palladium (CAS number 14221-01-3).
In some preferred embodiments, the solvent is a mixture of dioxane and water, wherein the volume ratio of dioxane to water is (3-6): 1.
Preferably, the solvent is a mixture of dioxane and water, wherein the volume ratio of dioxane to water is 5: 1.
In some preferred embodiments, the step 2 comprises the steps of mixing the compound X, the compound XI, the base and the organic solvent, heating and stirring overnight; after the reaction is finished, the compound VI is obtained through post-treatment and purification.
In some preferred embodiments, the molar charge ratio of the compound X to the compound XI is 1 (1-2).
Preferably, the molar charge ratio of the compound X to the compound XI is 1: 1.5.
Preferably, the base is potassium carbonate.
In some preferred embodiments, the molar charge ratio of the compound X to the base is 1 (0.8-1.6).
Preferably, the molar charge ratio of the compound X to the base is 1:1.
Preferably, the organic solvent is N, N-dimethylaniline.
Examples
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, which are not specified under specific conditions, are generally carried out under conventional conditions.
The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.
The room temperature in the examples is 10-20 ℃. Unless otherwise indicated, the reagents were used without purification. All solvents were purchased from commercial suppliers, such as Aldrich (Aldrich), and used without treatment.
The reaction was analyzed by TLC and/or by LCMS, and termination of the reaction was judged by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, visualized with UV light (254nm) and/or iodine on silica gel, and/or heated with TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or ceric sulfate solution.
Abbreviations used in the present invention have the usual meaning in the art, such as: DMF for N, N-dimethylformamide, TEA for triethylamine, THF for tetrahydrofuran, EA for ethyl acetate, DMA for N, N-dimethylaniline, and AcOK for potassium acetate.
In the case of the example 1, the following examples are given,preparation of Compound VI
Figure BDA0003358302070000091
Mixing compound VIII (100g, 760mmol), compound IX (174g, 836mmol) and K2CO3(316g, 2280mmol) was mixed with dioxane/water (1.2L) in a volume ratio of 5:1, replaced with argon, and Pd (PPh) was added3)4(10g) Replacing with inert gas, and heating at 90 deg.C overnight; after the reaction, filtration was performed, water was added to the filtrate, EA (2L × 3) was used for extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the resulting crude product was purified by flash column chromatography (PE/EA ═ 2:1) to obtain pure compound X (122g, 90%).
Compounds XI (99g, 423mmol) and K2CO3(39g, 282.2mmol) was dispersed in DMA (500mL), stirred at room temperature for 30min, compound X (50g,282.2mmol), heating at 115 ℃ overnight; after the reaction is finished, cooling to room temperature, and adding H2O (1.5L) was extracted with EA (3L × 3), the organic phases were combined and washed with brine (3L), the solution was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 1:1 to 1:2) to obtain pure compound VI (106g, 95%).
1H NMR(400MHz,DMSO-<3/4):8.40(d,J＝5.6Hz,1H),8.30(s,1H),8.00(s,1H),7.77(d,J＝8.0Hz,1H),7.34(d,J＝8.4Hz,1H),7.26(d,J＝2.0Hz,1H),6.71(dd,J＝5.6,2.4Hz,1H),3.88(s,3H),2.35(s,3H)；MS(ESI)m/z 393.0(M+H+).
In the case of the example 2, the following examples are given,preparation of Compound VI
Figure BDA0003358302070000092
Mixing compound VIII (100g, 760mmol), compound IX (126.5g, 608mmol), K2CO3(210g, 1520mmol) was mixed with dioxane/water (1L) in a volume ratio of 5:1, replaced with argon, and Pd (PPh) was added3)4(8.2g), inert gas substitution, and heating at 90 ℃ overnight; after the reaction, filtration was performed, water was added to the filtrate, EA (2L × 3) was used for extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the resulting crude product was purified by flash column chromatography (PE/EA ═ 2:1) to obtain pure compound X (117g, 87%).
Compounds XI (66.3g, 282.2mmol) and K2CO3(31.2g, 225.76mmol) was dispersed in DMA (450mL), stirred at room temperature for 30min, compound X (50g, 282.2mmol) was added, and heated at 115 ℃ overnight; after the reaction is finished, cooling to room temperature, and adding H2O (1L) was extracted with EA (3L × 3), the organic phases were combined and washed with brine (2.5L), the solution was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 1:1 to 1:2) to obtain pure compound VI (100g, 91%).
In the case of the example 3, the following examples are given,preparation of Compound VI
Figure BDA0003358302070000101
Mixing compound VIII (100g, 760mmol), compound IX (237g, 1140mmol), and K2CO3(420g, 3040mmol) was mixed with dioxane/water (1.6L) in a volume ratio of 5:1, replaced with argon, and [1,1' -bis (diphenylphosphino) ferrocene ] was added]Palladium dichloride (12g), displaced with inert gas and heated at 90 ℃ overnight; after the reaction, filtration was performed, water was added to the filtrate, EA (2L × 3) was used for extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the resulting crude product was purified by flash column chromatography (PE/EA ═ 2:1) to obtain pure compound X (118g, 88%).
Compounds XI (132.6g, 564.4mmol) and K2CO3(62.4g, 451.52mmol) was dispersed in DMA (700mL), stirred at room temperature for 30min, compound X (50g, 282.2mmol) was added, and heated at 115 ℃ overnight; after the reaction is finished, cooling to room temperature, and adding H2O (2L) was extracted with EA (3L × 3), the combined organic phases were washed with brine (3L), separated, dried over anhydrous sodium sulfate added to the organic phase, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 1:1 to 1:2) to obtain pure compound VI (103g, 93%).
In the case of the example 4, the following examples are given,preparation of Compound VII
And step 3: preparation of Compound II
Figure BDA0003358302070000102
Compound I (100g, 447.5mmol), isopropylamine (264mL, 2685mmol) and THF (1L) were combined, TEA (125mL, 895mmol) was added and heated at 60 ℃ for 16 h; TLC monitoring reaction completion, cooling to room temperature, adding H2O (500mL), extracted with EA (2L × 3), the organic phases combined and washed with brine (2L), the layers separated, the organic phase dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give compound II (101.3g, 92%).
And 4, step 4: preparation of Compound III
Figure BDA0003358302070000111
Compound II (50g, 203.2mmol), HBr (250mL) and AcOH (400mL) were combined overnight at 100 deg.C, TLC monitored for reaction completion and concentrated to give crude compound III, which was used in the next reaction without purification.
And 5: preparation of Compound IV
Figure BDA0003358302070000112
The crude compound III obtained in the step 4 (wherein the content of the compound III is 40g, 172.36mmol) and K2CO3(23.82g, 172.36mmol) was mixed with DMF (500mL), iodomethane (48.93g, 334.71mmol) was added, the mixture was stirred at room temperature overnight, and after completion of the reaction, H was added2O (1.5L), EA (3 × 300mL), and the combined organic phases were washed with brine (300mL), separated, dried over anhydrous sodium sulfate added to the organic phase, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 2:1 to 1:1) to give pure compound IV (39g, 75%).
Step 6: preparation of Compound V
Figure BDA0003358302070000113
Dispersing compound IV (20g, 81.3mmol) in tetrahydrofuran (200mL), cooling to-70 ℃ under the protection of inert gas, adding n-BuLi (81.28mL, 203.25mmol), stirring at-70 ℃ for 1.5H, adding pyridinol isopropoxide borate (30.24g, 162.5mmol), stirring at-70 ℃ for 2.5H, monitoring by TLC after the reaction is completed, and using H at 0 DEG C2O (40mL) and MeOH (80mL) quench and concentrate to give crude compound V for the next reaction.
And 7: preparation of Compound VII
Figure BDA0003358302070000121
The crude compound V obtained in the step 6 (wherein the content of the compound V is 15.09g, 71.54mmol) and K2CO3(11.2g, 81.3mmol), Compound VI (31g, 80mmol) and 5:1 dioxane/water (240mL) in volume ratio were mixed, replaced with argon, Pd (dppf) Cl was added2After DCM (1.5g), argon replacement was again performed and heating was carried out at 95 ℃ overnight; TLC monitored the reaction was complete and the mixture was cooled to room temperature, water (200mL) was added, extracted with DCM (0.5L × 3), the organic phases combined and washed with brine (250mL), separated, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated and purified by column chromatography (EA/MeOH ═ 120:1 to 100:1) to give pure compound VII (27.47g, 89%).
1H NMR(400MHz,DMSO-<3/4):δ8.69(s,1H),8.37(d,J＝5.6Hz,1H),8.28(d,J＝8.8Hz,1H),8.26(s,1H),7.97(s,1H),7.53(d,J＝8.4Hz,1H),7.24(d,J＝2.4Hz,1H),7.06(d,J＝7.6Hz,1H),6.60(dd,J＝5.6,2.4Hz,1H),4.33(m,1H),3.86(s,3H),3.38(s,3H),2.36(s,3H),1.24(d,J＝6.8Hz,6H)；MS(ESI)m/z 432.2(M+H+).
Example 5Preparation of Compound VII
And step 3: preparation of Compound II
Figure BDA0003358302070000122
Compound I (100g, 447.5mmol), isopropylamine (198mL, 2013.7mmol) and THF (1L) were combined, TEA (94mL, 671.2mmol) was added, and heated at 60 ℃ for 16 h; TLC monitoring reaction completion, cooling to room temperature, adding H2O (500mL), extracted with EA (2L × 3), the organic phases combined and washed with brine (2L), the layers separated, the organic phase dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give compound II (99g, 90%).
And 4, step 4: preparation of Compound III
Figure BDA0003358302070000123
Compound II (50g, 203.2mmol), HBr (200mL) and AcOH (350mL) were combined overnight at 100 deg.C, TLC monitored for reaction completion and concentrated to give crude compound III, which was used in the next reaction without purification.
And 5: preparation of Compound IV
Figure BDA0003358302070000131
Crude compounds III and K obtained in the step 42CO3(18.2g, 131.68mmol) was mixed with DMF (450mL), iodomethane (35g, 246.9mmol) was added, the mixture was stirred at room temperature overnight, and after completion of the reaction, H was added2O (1.5L), EA (3 × 300mL), and the combined organic phases were washed with brine (300mL), separated, dried over anhydrous sodium sulfate added to the organic phase, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 2:1 to 1:1) to give pure compound IV (29.5g, 73%).
Step 6: preparation of Compound V
Figure BDA0003358302070000132
Dispersing compound IV (20g, 81.3mmol) in tetrahydrofuran (160mL), cooling to-70 ℃ under the protection of inert gas, adding n-BuLi (65mL, 162.6mmol), stirring at-70 ℃ for 1.5H, adding pyrazinyl isopropoxyborate (15.12g, 81.3mmol), stirring at-70 ℃ for 2.5H, monitoring by TLC, and reacting at 0 ℃ with H2O (40mL) and MeOH (80mL) quench and concentrate to give crude compound V for the next reaction.
And 7: preparation of Compound VII
Figure BDA0003358302070000133
Subjecting crude compound V, K obtained in step 6 to2CO3(8.3g, 60.1mmol), Compound VI (24g, 60mmol) and 5:1 dioxane by volume ratioMixing with water (240mL), argon substitution, and addition of Pd (dppf) Cl2After DCM (1.2g), argon replacement was again performed and heating was carried out at 95 ℃ overnight; TLC monitored the reaction was complete and the mixture was cooled to room temperature, water (200mL) was added, extracted with DCM (0.5L × 3), the organic phases combined and washed with brine (250mL), separated, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated and purified by column chromatography (EA/MeOH ═ 120:1 to 100:1) to give pure compound VII (27.47g, 89%).
In the case of the example 6, it is shown,preparation of Compound VIII
And step 3: preparation of Compound II
Figure BDA0003358302070000141
Compound I (100g, 447.5mmol), isopropylamine (321mL, 3266.75mmol) and THF (1.5L) were combined, TEA (156mL, 1118.75mmol) was added and heated at 60 ℃ for 16 h; TLC monitoring reaction completion, cooling to room temperature, adding H2O (500mL), extracted with EA (2L X3), the organic phases combined and washed with brine (2L), the layers separated, the organic phase dried over anhydrous sodium sulfate, filtered and the filtrate concentrated to give Compound II-1(98g, 89%).
And 4, step 4: preparation of Compound III
Figure BDA0003358302070000142
Compound II-1(50g, 203.2mmol), HBr (300mL) and AcOH (450mL) were combined and at 100 ℃ overnight, TLC monitored for reaction completion and concentrated to give crude compound III which was used in the next reaction without purification.
And 5: preparation of Compound IV
Figure BDA0003358302070000143
Crude compounds III and K obtained in the step 42CO3(34.5g, 249.93mmol) with DMF (500mL) was mixed, iodomethane (59g, 416.55mmol) was added thereto, the mixture was stirred at room temperature overnight, and after completion of the reaction, H was added thereto2O (1.5L), EA (300mL × 3), and the combined organic phases were washed with brine (300mL), separated, dried over anhydrous sodium sulfate added to the organic phase, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 2:1 to 1:1) to obtain pure compound IV (29.5g, 72%).
Step 6: preparation of Compound V
Figure BDA0003358302070000144
Dispersing compound IV (20g, 81.3mmol) in tetrahydrofuran (230mL), cooling to-70 ℃ under the protection of inert gas, adding n-BuLi (113.8mL, 284.55mmol), stirring at-70 ℃ for 1.5H, adding pyridoxine isopropoxyborate (30.24g, 162.5mmol), stirring at-70 ℃ for 2.5H, monitoring by TLC, and reacting at 0 ℃ with H2O (40mL) and MeOH (80mL) quench and concentrate to give crude compound V for the next reaction.
And 7: preparation of Compound VII
Figure BDA0003358302070000151
Subjecting crude compound V, K obtained in step 6 to2CO3(14.3g, 103.6mmol), Compound VI (39g, 100mmol) and 5:1 dioxane/water (260mL) in volume ratio were mixed, replaced with argon, Pd (dppf) Cl was added2After DCM (1.6g), argon replacement was again performed and heating was carried out at 95 ℃ overnight; TLC monitored the reaction was complete and the mixture was cooled to room temperature, water (200mL) was added, extracted with DCM (0.5L × 3), the organic phases were combined and washed with brine (250mL), separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated and purified by column chromatography (EA/MeOH ═ 120:1 to 100:1) to give pure compound VII (25.64g, 86%).
Example 7Preparation of Compound VI
Figure BDA0003358302070000152
Compounds XI (99g, 423mmol) and K2CO3(39g, 282.2mmol) in DMA (500mL), stirring at room temperature for 30min, adding Compound X (50g, 282.2mmol), and heating at 115 deg.C overnight; after the reaction is finished, cooling to room temperature, and adding H2O (1.5L) was extracted with EA (3L × 3), the organic phases were combined and washed with brine (3L), the solution was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 1:1 to 1:2) to obtain pure compound VI (41.5g, 75%).
In the case of the example 8, the following examples are given,preparation of Compound VI
Figure BDA0003358302070000161
Compounds XI (198g, 846.6mmol) and K2CO3(97.5g, 705.5mmol) was dispersed in DMA (600mL), stirred at room temperature for 30min, compound X (50g, 282.2mmol) was added, and heated at 115 ℃ overnight; after the reaction is finished, cooling to room temperature, and adding H2O (1.5L) was extracted with EA (3L × 3), the organic phases were combined and washed with brine (3L), the solution was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (PE/EA ═ 1:1 to 1:2) to obtain pure compound VI (86.3g, 78%).
In the case of the example 9, the following examples are given,preparation of Compound V
Figure BDA0003358302070000162
Dispersing compound IV (20g, 81.3mmol) in tetrahydrofuran (150mL), cooling to-70 ℃ under the protection of inert gas, adding n-BuLi (39.02mL, 97.56mmol), stirring at-70 ℃ for 1.5H, adding pirenoyl isopropoxyborate (9.07g, 48.78mmol), stirring at-70 ℃ for 2.5H, monitoring by TLC after the reaction is completed, and reacting with H at 0 DEG C2O(40mL) And MeOH (80mL) to give crude compound V, which was concentrated to give compound V (7.2g, 70%).
In the light of the above example 10,preparation of Compound V
Figure BDA0003358302070000163
Dispersing compound IV (20g, 81.3mmol) in tetrahydrofuran (450mL), cooling to-70 ℃ under the protection of inert gas, adding n-BuLi (130.08mL, 325.2mmol), stirring at-70 ℃ for 1.5H, adding pyridoxine isopropoxyborate (52.9g, 284.55mmol), stirring at-70 ℃ for 2.5H, monitoring by TLC, and reacting at 0 ℃ with H2O (40mL) and MeOH (80mL) were quenched and concentrated to give crude compound V, which gave compound V (11.67g, 68%).
In the case of the embodiment 11, the following examples are given,preparation of Compound V
Figure BDA0003358302070000171
Compound IV (1.04g, 4.25mmol), pinacol diboron (1.30g, 5.10mmol), AcOK (1.25g, 12.76mmol) were dissolved in dioxane (10mL), replaced with Ar, PdCl was added2(dppf) -DCM conjugate (0.17g, 0.21g), heated at 90 ℃ overnight; after the reaction was complete, it was cooled to room temperature, then brine (100mL), NaHCO3(100mL), extracted with EA (0.5 L.times.3), and Na2SO4Drying, concentration and purification gave compound V (0.3g, 40%).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A process for the preparation of compound VII, comprising the steps of:
and step 3: reacting the compound I with organic amine under the action of alkali to obtain a compound II;
and 4, step 4: demethylating and dearomatizing the compound II to obtain a compound III;
and 5: reacting the compound III with a methylating agent under an alkaline condition to obtain a compound IV;
step 6: reacting the compound IV with a borate compound to obtain a compound V;
and 7: carrying out coupling reaction on the compound V and the compound VI to obtain VII;
Figure FDA0003358302060000011
wherein R is1And R2Identically or differently selected from hydrogen, C1～6Saturated or unsaturated alkyl groups.
2. The method according to claim 1, wherein the step 3 comprises the steps of: mixing a compound I, organic amine and an organic solvent, adding alkali, reacting at 40-60 ℃, cooling to room temperature after the reaction is finished, filtering, washing, drying and concentrating to obtain a compound II; and/or the reaction time is 8-16 h.
3. The method according to claim 1, wherein the step 4 comprises the steps of: and mixing the compound II with an organic solvent, adding a demethylating reagent, monitoring the reaction process by TLC, and processing after the reaction is finished to obtain a compound III.
4. The method according to claim 1, wherein the step 5 comprises the steps of: mixing the compound III, alkali and an organic solvent, adding a methylation reagent, stirring overnight at room temperature, and after the reaction is finished, filtering, washing, drying, concentrating and purifying to obtain a compound IV; and/or the molar charge ratio of the compound III to the methylating agent is 1 (1.5-2.5).
5. The method according to claim 1, wherein the step 6 comprises the steps of: under the protection of inert gas, mixing a compound IV with an organic solvent, cooling to-60-78 ℃, dropwise adding a lithium reagent, stirring for reaction for 1-2 h, adding a borate compound, stirring for reaction for 2-3 h at-50-70 ℃, after TLC monitoring reaction is finished, quenching with the solvent at 0 ℃, and concentrating to obtain a compound V; and/or the molar charge ratio of the compound IV to the lithium reagent is 1 (2-3.5); and/or the organic solvent is selected from one or more of tetrahydrofuran, N-dimethylformamide, ethyl acetate and dichloromethane.
6. The method according to claim 1, wherein the step 7 comprises the steps of: under the protection of inert gas, mixing the compound V, alkali and the compound VI with an organic solvent, adding a catalyst, replacing with the inert gas again, and heating at 90-100 ℃ overnight; after the reaction is finished, filtering, washing, drying, concentrating and purifying to obtain a compound VIII; and/or the alkali is selected from one of potassium acetate, triethylamine, diisopropylethylamine, potassium phosphate, potassium carbonate and sodium hydroxide; and/or the catalyst is one selected from palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and allyl palladium (II) chloride dimer.
7. A process for the preparation of compound VI, comprising the steps of:
step 1: carrying out coupling reaction on the compound VIII and the compound IX to prepare a compound X;
Figure FDA0003358302060000021
step 2: carrying out substitution reaction on the compound X and a compound XI to prepare a compound VI;
Figure FDA0003358302060000022
8. the method according to claim 7, wherein the step 1 comprises the steps of: mixing the compound VIII, the compound IX, alkali and a solvent, adding a catalyst, replacing with inert gas, and heating and stirring overnight; after the reaction is finished, the compound X is obtained through post-treatment.
9. The method according to claim 7, wherein the step 2 comprises the steps of mixing the compound X, the compound XI, the base and the organic solvent, and heating and stirring the mixture overnight; after the reaction is finished, the compound VI is obtained through post-treatment and purification.
10. The preparation method according to claim 9, wherein the molar charge ratio of the compound X to the compound XI is 1 (1-2); and/or the molar charge ratio of the compound X to the alkali is 1 (0.8-1.6).
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12285430B2 (en) 2018-12-28 2025-04-29 Deciphera Pharmaceuticals, Llc Methods of treating disorders using CSF1R inhibitors
US12447149B2 (en) 2023-12-08 2025-10-21 Deciphera Pharmaceuticals, Llc Formulations of vimseltinib
US12509443B2 (en) 2025-08-14 2025-12-30 Deciphera Pharmaceuticals, Llc CSF-1R inhibitors and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014145023A1 (en) * 2013-03-15 2014-09-18 Deciphera Pharmaceuticals, Llc 1,2,4-triazol-5-ones and analogs exhibiting anti-cancer and anti-proliferative activities
CN105120864A (en) * 2013-03-15 2015-12-02 德西费拉制药有限责任公司 2-aminopyrimidin-6-ones and analogs exhibiting anticancer and antiproliferative activity
CN113453684A (en) * 2018-12-28 2021-09-28 德西费拉制药有限责任公司 CSF1R inhibitors for the treatment of cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014145023A1 (en) * 2013-03-15 2014-09-18 Deciphera Pharmaceuticals, Llc 1,2,4-triazol-5-ones and analogs exhibiting anti-cancer and anti-proliferative activities
CN105120864A (en) * 2013-03-15 2015-12-02 德西费拉制药有限责任公司 2-aminopyrimidin-6-ones and analogs exhibiting anticancer and antiproliferative activity
CN113453684A (en) * 2018-12-28 2021-09-28 德西费拉制药有限责任公司 CSF1R inhibitors for the treatment of cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRYA N D. SMITH等: "Vimseltinib: A Precision CSF1R Therapy for Tenosynovial Giant Cell Tumors and Diseases Promoted by Macrophages", 《MOLECULAR CANCER THERAPEUTICS》 *
KUN-HUNG LEE等: "Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12285430B2 (en) 2018-12-28 2025-04-29 Deciphera Pharmaceuticals, Llc Methods of treating disorders using CSF1R inhibitors
US12485120B2 (en) 2018-12-28 2025-12-02 Deciphera Pharmaceuticals, Llc Methods of treating disorders using CSF1R inhibitors
US12447149B2 (en) 2023-12-08 2025-10-21 Deciphera Pharmaceuticals, Llc Formulations of vimseltinib
US12509443B2 (en) 2025-08-14 2025-12-30 Deciphera Pharmaceuticals, Llc CSF-1R inhibitors and methods of use thereof

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