CN115057824A - Quinazoline derivative and preparation method thereof - Google Patents
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Abstract
The invention relates to a preparation method of 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea, which comprises the following steps: is structured as
Carrying out amidation reaction on the compound III and cyclopropylamine to obtain a compound with the structure
And a compound II of the formula
The oxazoline derivative II is reacted to obtain the compound with the structure of
The quinazoline derivative I of (1). The preparation method has the advantages of easily available raw materials, simple operation, high total yield, less byproduct content, product purity higher than 99.5 percent and suitability for large-scale production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, relates to a quinazoline derivative and a preparation method thereof, and particularly relates to a preparation method of 1-cyclopropyl-3- (4- ((6, 7-dimethoxyquinazoline-4-yl) oxy) phenyl) urea.
Background
The vechicide is a quinazoline derivative with 4-substituted carbamidophenyl, is disclosed in patent document CN109776432A as a multi-target kinase inhibitor compound for the first time, can be used for treating related diseases which are regulated by multi-target kinase and are related to the abnormality of signal transduction pathways of the multi-target kinase, is a potential small-molecule anticancer drug, and is systematically named as 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea; molecular formula C 20 H 20 N 4 O 4 (ii) a The molecular weight is 380.403; CAS number 2378099-63-7; the chemical structure is as follows:
at present, few reports about the preparation method of the cercis-tinib exist, the total yield of the existing reported route is not high, and byproducts are easy to generate in the preparation process and are not beneficial to purification.
Therefore, a preparation method of the cercis-tinib with high total yield and low byproduct content is needed, and the preparation method is simple, easy to obtain raw materials, high in product purity and suitable for large-scale production.
Disclosure of Invention
The invention aims to provide a preparation method of a quinazoline derivative, which has high total yield and few byproducts and can be used for preparing the Vecis-tinib in a large scale.
The first aspect of the present invention provides a method for producing a quinazoline derivative, comprising the steps of:
preparation of compound ii: in the presence of a second base, the structure is
The compound III and cyclopropylamine are subjected to amidation reaction in a second solvent to obtain a compound with the structure of
The compound of (1); wherein R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted C1-C4 alkyl;
preparation of compound I: the compound II and the structure are
The quinazoline derivative II is reacted to obtain the compound with the structure of
The quinazoline derivative I of (a), which is the compound I; wherein X is selected from F, Cl, Br or I.
In some embodiments, in the method for producing the quinazoline derivative, in the step of producing the compound ii: the second base is selected from one or more of cyclopropylamine, triethylamine, N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and sodium ethoxide; and/or the presence of a catalyst in the reaction mixture,
in the compound III, R is substituted or unsubstituted phenyl; and/or the like, and/or,
the second solvent is selected from one or more of methanol, ethanol, isopropanol, butanol, acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide and N, N-dimethylformamide; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature of the amidation reaction is 20 to 60 ℃.
In some embodiments, in the method for producing the quinazoline derivative, in the step of producing the compound ii: the molar ratio of the compound III to the cyclopropylamine is 1 (1.0-2.5); and/or the presence of a catalyst in the reaction mixture,
the molar ratio of the second base to the compound III is (0.9-3.0): 1.
in some embodiments, the method for preparing the quinazoline derivative further comprises the step of separating and purifying the compound ii: after the amidation reaction, the temperature of the reaction is reduced to 10 +/-5 ℃, the reaction is stirred for 1 to 3 hours, and the reaction product is filtered, dried and recrystallized.
In some embodiments, in the method for producing a quinazoline derivative, the compound iii is obtained by a production method comprising the steps of: 4-aminophenol and chloroformate compounds are used as raw materials to carry out esterification reaction to prepare 4-hydroxybenzene carbamate compounds, namely the compound III.
In some embodiments, in the preparation method of the quinazoline derivative, the chloroformate compound is one or more selected from phenyl chloroformate, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, and butyl chloroformate.
In some embodiments, in the method for producing the quinazoline derivative, the step of producing the compound I includes: under the protection of inert gas and in the presence of a third base, dissolving the compound II in a third solvent, adding the quinazoline derivative II at 0-30 ℃, heating to 10-60 ℃, and reacting for 1-6 hours to obtain the quinazoline derivative I.
In some embodiments, in the method for producing a quinazoline derivative, in the step of producing the compound I, the third solvent is one or more selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and sulfolane.
In some embodiments, the method for preparing the quinazoline derivative further comprises the step of separating and purifying the compound I: and (3) reacting the compound II with the quinazoline derivative II, adding water, stirring at 15 +/-5 ℃ for 0.5-2 hours, filtering to obtain a filter cake, pulping the filter cake in a fourth solvent, filtering to obtain a solid, and drying.
The second aspect of the invention provides the use of a compound of formula (III) or 1-cyclopropyl-3- (4-hydroxyphenyl) urea of formula (II) for the preparation of Vecis-tinib;
wherein R is phenyl or substituted phenyl.
The preparation method of the quinazoline derivative provided by the invention is simple to operate, safe, environment-friendly, high in total yield, few in byproducts, easy in post-treatment and purification of the final product, easy for large-scale production and applicable to large-scale preparation of the Vecis-tinib.
The quinazoline derivative has high purity and does not contain impurities difficult to separate.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more fully understand the present application and the advantages thereof, the drawings that are required in the description of the embodiments will be briefly introduced below. It is obvious that the drawings in the following description are only some embodiments of the application, and that other drawings can be derived from these drawings by a person skilled in the art without inventive effort.
FIG. 1 is a liquid chromatography detection chart of a preparation solution of cercis-tinib in example 1 of the present invention;
fig. 2 is a liquid chromatography detection chart of a preparation solution of cercis nib in comparative example 1 of the present invention.
Detailed Description
The invention is further illustrated below with reference to embodiments, examples and figures. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, it should be understood that various changes and modifications can be made by those skilled in the art after reading the teaching of the present invention, and these equivalents also fall within the scope of the claims appended to the present application.
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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
Term(s) for
Unless otherwise stated or contradicted, terms or phrases used herein have the following meanings:
as used herein, "substituted or unsubstituted phenyl" includes unsubstituted phenyl, phenyl substituted with 1 to 4 halogen atoms, phenyl substituted with 1 to 4C 1 ～C 4 Alkyl-substituted phenyl. Wherein "C" is 1 ～C 4 Alkyl "means an alkyl group containing from 1 to 4 carbon atoms, which at each occurrence may be independently of each other C 1 Alkyl radical, C 2 Alkyl radical, C 3 Alkyl or C 4 An alkyl group.
As used herein, "halogen" or "halogen atom" are defined equivalently and refer to F, Cl, Br or I.
As used herein, the term "and/or", "and/or" is selected to encompass any of two or more of the associated listed items, as well as any and all combinations of the associated listed items, including any and all combinations of any two of the associated listed items, any more of the associated listed items, or all combinations of all of the associated listed items.
The present invention relates to "plural", etc., and indicates that it is 2 or more in number, unless otherwise specified. For example, "one or more" means one or two or more.
The terms "preferably", "better", and the like are used herein only to describe better embodiments or examples, and it should be understood that the scope of the present invention is not limited by these terms.
In the present invention, "further", "still further", "specifically" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of the present invention.
In the present invention, the technical features described in the open type include a closed technical solution composed of the listed features, and also include an open technical solution including the listed features.
In the present invention, where a range of values (i.e., a numerical range) is recited, unless otherwise specified, alternative distributions of values within the range are considered to be continuous, and include both the numerical endpoints of the range (i.e., the minimum and maximum values), and each numerical value between the numerical endpoints. Unless otherwise specified, when a numerical range refers to integers only within the numerical range, both endpoints of the numerical range are inclusive of the integers and each integer between the endpoints is inclusive of the integer. Further, when multiple range-describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, the ranges disclosed herein are to be understood to include any and all subranges subsumed therein.
The temperature parameter in the present invention is not particularly limited, and may be a constant temperature treatment or a variation within a certain temperature range. It will be appreciated that the described thermostatic process allows the temperature to fluctuate within the accuracy of the instrument control. Allowing fluctuations in the temperature ranges of. + -. 0.1 ℃ and. + -. 0.2 ℃ and. + -. 0.3 ℃ and. + -. 0.4 ℃ and. + -. 0.5 ℃.
In the present invention, "room temperature" means no temperature control operation, and mainly means 4 to 35 ℃, preferably 4 to 30 ℃, more preferably 20 ℃. + -. 0.5 ℃,20 ℃. + -. 1 ℃,20 ℃. + -. 2 ℃,20 ℃. + -. 3 ℃,20 ℃. + -. 4 ℃,20 ℃. + -. 5 ℃,20 ℃ to 30 ℃ and the like. Examples of "room temperature" in the present invention include 4 ℃,5 ℃, 6 ℃,7 ℃, 8 ℃, 9 ℃, 10 ℃, 11 ℃, 12 ℃, 13 ℃, 14 ℃, 15 ℃, 16 ℃, 17 ℃, 18 ℃, 19 ℃,20 ℃, 21 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃, 30 ℃, 31 ℃, 32 ℃, 33 ℃, 34 ℃, 35 ℃ and the like.
In the present invention, the compound II has the same meaning as that of the compound represented by the formula (II), and they are used interchangeably and have the structure
The chemical name of the compound is 1-cyclopropyl-3- (4-hydroxyphenyl) urea. The quinazoline derivative I, the compound I and the compound shown in the formula (I) have the same meanings, and the structures of the quinazoline derivative I and the compound I are
The chemical name of the compound is 1-cyclopropyl-3- (4- ((6, 7-dimethyl)Oxyquinazolin-4-yl) oxy) phenyl) urea. The compound III has the same meaning as that of the compound shown in the formula (III), and both refer to the general formula
The phenyl carbamate compound is shown.
The invention provides a preparation method of quinazoline derivatives, which has the advantages of easily obtained raw materials and simple and convenient steps: is structured as
Carrying out amidation reaction on the compound III and cyclopropylamine to obtain a compound with the structure
And a compound II of the formula
The quinazoline derivative II is reacted to obtain the compound with the structure of
The quinazoline derivative of (1) (quinazoline derivative I).
The reaction formula for preparing the compound I from the compound III is shown as the following formula:
first aspect of the invention
In a first aspect of the present invention, there is provided a process for the preparation of a quinazoline derivative, comprising the steps of:
s100: providing a compound represented by formula (III);
s200: carrying out amidation reaction on a compound shown as a formula (III) and cyclopropylamine to obtain a compound shown as a formula (II);
s300: the compound shown as the formula (II) has the structure
The quinazoline derivative II reacts to prepare the compound shown in the formula (I).
S100: to provide a compound represented by the formula (III)
In some embodiments, the compound of formula (iii) is obtained by a preparation method comprising the following preparation steps: 4-aminophenol and chloroformate compounds are used as raw materials to carry out esterification reaction to prepare 4-hydroxybenzene carbamate compounds, namely the compounds shown in the formula (III).
In some embodiments, R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted C1-C4 alkyl.
In some embodiments, R is selected from one or more of phenyl, ethyl, methyl, benzyl, isopropyl, and butyl.
In some embodiments, the chloroformate-based compound is selected from one or more of phenyl chloroformate, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, and butyl chloroformate.
In some embodiments, the second solvent is selected from one or more of ethyl acetate, isopropyl acetate, n-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, butanone, dichloromethane, and chloroform. Preferably, the second solvent is ethyl acetate.
In some embodiments, the temperature of the esterification reaction is 0 ℃ or higher, and further may be 20 ± 10 ℃.
In some embodiments, the esterification reaction occurs in the presence of a first base. In some embodiments, the first base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, cesium carbonate, sodium ethoxide, triethylamine, N-diisopropylethylamine, pyridine, and like inorganic or organic bases. Preferably, the first base is sodium bicarbonate.
In some embodiments, the molar ratio of the first base to the 4-aminophenol is (0.9 to 2.0): 1, further may be (0.9-1.5): 1.
in some embodiments, step S100 further includes a step of separating and purifying the compound represented by formula (iii) (first purification step) after the esterification reaction. In some embodiments, the first purification step comprises recrystallization. In some embodiments, the solvent system for recrystallization may be ethyl acetate/heptane, ethyl acetate/hexane, ethyl acetate/petroleum ether, and the like. Preferably, an ethyl acetate/heptane solvent system.
In the present invention, the specific operation of the esterification reaction in step S100 can also be referred to the common operation modes of esterification reaction in the art, such as [ Tetrahedron Letters,2014, vol.55, #9, p.1540-1543], [ Synlett,2006, #2, p.243-246], [ Journal of the Chemical Society of Pakistan,2013, vol.35, #2, p.385-390], and other literature reports.
S200: preparation of the Compound of formula (II)
In some embodiments, the compound of formula (III) and cyclopropylamine are subjected to an amidation reaction to produce a compound of formula (II).
In some embodiments, compound ii is prepared by amidation of compound iii and cyclopropylamine in a second solvent in the presence of a second base.
In some embodiments, the compound of formula (III) has the structure
In some embodiments, the second solvent is selected from one or more of methanol, ethanol, isopropanol, butanol, acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide, and N, N-dimethylformamide. Preferably, the second solvent is acetonitrile.
In some embodiments, the second base is selected from one or more of cyclopropylamine, triethylamine, N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and sodium ethoxide. Preferably, the second base is triethylamine.
In some embodiments, the reaction temperature of the amidation reaction in step S200 is 20 to 60 ℃, and further may be 55 ± 5 ℃.
In some embodiments, in step S200, the molar ratio of the compound represented by formula (III) to cyclopropylamine is 1 (1 to 2.5), and may further be 1 (1 to 1.5), for example, 1:1, 1:1.2, 1:1.5, 1:2, 1:2.3, 1:2.5, and the like.
In some embodiments, in step S200, the molar ratio of the second base to the compound of formula (iii) is (0.9-3.0): 1 may further be (1-2.5): 1, such as 0.9:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, and the like.
In some embodiments, in step S200, after the amidation reaction, a step of separating and purifying compound ii (second purification step) is further included. In some embodiments, the second purification step comprises: cooling to 10 +/-5 ℃, stirring for 1-3 h, filtering, drying and recrystallizing. In some embodiments, the solvent for recrystallization may be selected from the following organic solvents or a mixed solution thereof: acetonitrile, ethanol/heptane, ethanol/hexane, ethanol/petroleum ether, acetonitrile/1, 2-dichloroethane/heptane, methanol/hexane, and the like. Preferably, the solvent for recrystallization is acetonitrile.
S300: preparation of the Compound of formula (I)
In some embodiments, the compound of formula (II) and the structure are
The quinazoline derivative II reacts to prepare the compound shown in the formula (I).
In some embodiments, X of quinazoline derivative ii is selected from F, Cl, Br or I.
In some embodiments, the compound II is dissolved in a third solvent under the protection of inert gas and in the presence of a third base, the quinazoline derivative II is added at the temperature of 0-30 ℃, and then the temperature is increased to 10-60 ℃ for reaction for 1-6 hours, so as to obtain the compound shown in the formula (I).
In some embodiments, the third solvent is selected from one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and sulfolane. Preferably, the third solvent is dimethyl sulfoxide.
In some embodiments, the third base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, cesium carbonate, sodium ethoxide, and the like. Preferably, the third base is sodium hydroxide.
In some embodiments, the reaction temperature in step S300 is 10 ℃ to 60 ℃, more preferably 15 ℃ to 25 ℃.
In some embodiments, step S300 further comprises a step of isolating and purifying compound i (third purification step). In some embodiments, the third purification step comprises: adding water into the system, stirring for 0.5-2 hours at 15 +/-5 ℃, filtering to obtain a filter cake, pulping the filter cake in a fourth solvent, filtering to obtain a solid, and drying.
In some embodiments, the fourth solvent may be selected from a mixed solution of the following organic solvents: dimethyl sulfoxide/ethyl acetate, dimethyl sulfoxide/dichloromethane, dimethyl sulfoxide/ethanol, dimethyl sulfoxide/methanol, N-dimethylformamide/ethyl acetate, N-dimethylformamide/dichloromethane, N-dimethylformamide/ethanol, N-dimethylformamide/methanol, ethanol, methanol and other solvent systems. Preferably, the fourth solvent is a mixed solution of dimethyl sulfoxide/ethyl acetate.
In some embodiments, the third purification step comprises: adding water into the system, stirring for 0.5-2 hours at 15 +/-5 ℃, filtering to obtain a filter cake, mixing the filter cake with dimethyl sulfoxide, stirring for 30 minutes at 78 +/-5 ℃, adding ethyl acetate, continuously stirring for 0.5-2 hours, then stirring for 0.5-2 hours at 0-10 ℃, filtering and drying.
Second aspect of the invention
In a second aspect of the invention there is provided the use of a compound of formula (iii) or 1-cyclopropyl-3- (4-hydroxyphenyl) urea of formula (ii) in the preparation of cercis;
preferably, R is phenyl.
In the conventional preparation scheme, the compound is firstly prepared through ether bond
And
connecting to prepare a compound B
And then carrying out amidation reaction on the compound B serving as a raw material and cyclopropylamine to prepare the final product of the cercis-tinib. Herein, denotes a connection site.
Generally, the larger the molecular weight, the less the self-coupling phenomenon occurs due to steric hindrance between the molecules. Although the spontaneous coupling of the compound B occurs with a low probability, a part of the coupling by-product is present, and the structure is
The by-products of (a) are difficult to separate from the final product, and constitute about 1% of the total amount as major impurities.
The researchers of the invention unexpectedly discover that the compound shown in the formula (III) is prepared by esterification reaction of 4-aminophenol and chloroformate compounds serving as raw materials, the compound shown in the formula (III) and cyclopropylamine are subjected to amidation reaction under the conditions of proper temperature, alkali and solvent, a compound II (1-cyclopropyl-3- (4-hydroxyphenyl) urea) is obtained through proper purification steps, and finally the compound II is connected with a quinazoline part, so that the generation of self-coupling byproducts can be greatly reduced. The preparation scheme of the invention has extremely high total yield, extremely low content of self-coupling impurities (less than or equal to 0.15 percent), extremely high purity of the obtained intermediate and final product, and capability of meeting the requirement of medicinal production.
In some embodiments of the invention, the compound of formula (III) has a purity of 99.0% or more. In some preferred results, the purity is 99.0% to 99.9%, such as 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, etc.
In some embodiments of the invention, the purity of 1-cyclopropyl-3- (4-hydroxyphenyl) urea of formula (II) is 97.0% or greater. In some preferred results, the purity is 97.0% to 99.5%, such as 97.0%, 97.5%, 98.2%, 98.5%, 98.9%, 99.0%, 99.2%, 99.5%, etc.
In some embodiments of the invention, 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea of formula (I) has a purity of 99.0% or greater. In some preferred results, the purity is 99.0% to 99.9%, such as 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, etc.
Some specific examples are as follows.
Experimental parameters not described in the following specific examples are preferably referred to the guidelines given in the present application, and may be referred to experimental manuals in the art or other experimental methods known in the art, or to experimental conditions recommended by the manufacturer.
The starting materials and reagents mentioned in the following specific examples are commercially available or can be prepared by those skilled in the art according to known means.
In the following examples, the compound phenyl (4-hydroxyphenyl) carbamate was subjected to High Performance Liquid Chromatography (HPLC) using an apparatus of Shimadzu LC-2030C high performance liquid chromatograph, UV-visible light detector, SunAirEC 184.6X 150mm,5um column, column temperature: 30 ℃, detector wavelength: 210nm, mobile phase a: 0.1% phosphoric acid aqueous solution, mobile phase B: methanol, mobile phase flow rate: 1 mL/min.
In the following examples, the apparatus for High Performance Liquid Chromatography (HPLC) testing of compound 1-cyclopropyl-3- (4-hydroxyphenyl) urea (compound II) was Shimadzu LC-2030C HPLC, UV-visible detector, SunFieC 184.6X 150mm,5um column, column temperature: 30 ℃, detector wavelength: 210nm, mobile phase a: 10mmol/L aqueous dipotassium hydrogen phosphate solution, mobile phase B: methanol, mobile phase flow rate: 1 mL/min.
In the following examples, the instrument for performing High Performance Liquid Chromatography (HPLC) tests on vechicinib formula (1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea) (compound i) was shimadzu LC-2030C high performance liquid chromatograph, uv-visible light detector, sunfirmec 183.5 × 150mm,5um column, column temperature: 45 ℃, detector wavelength: 240nm, mobile phase a: monopotassium phosphate buffer (2.72 g of monopotassium phosphate was weighed, dissolved in water and diluted to 2000ml, pH adjusted to 3.0 ± 0.05) -methanol (9: 1) with phosphoric acid, mobile phase B: acetonitrile, mobile phase flow rate: 1 mL/min.
In the following examples, eq represents a molar equivalent. The room temperature is 4 ℃ to 35 ℃.
Example 1
1.1 preparation of phenyl (4-hydroxyphenyl) carbamate (compound III,
)
to the reaction flask were added ethyl acetate (390mL, 6mL/g), drinking water (260mL, 4mL/g), 4-aminophenol (65.00g, 1.0eq), and sodium bicarbonate (50.04g, 1.0 eq). The temperature was controlled at 15. + -. 5 ℃ and a mixture of ethyl acetate (195mL, 3mL/g) and phenyl chloroformate (93.26g, 1.0eq) was added to the above reaction mixture while controlling the internal temperature at not more than 30 ℃ during the addition. After the addition, the reaction solution is kept at the temperature of 20 +/-10 ℃ and stirred for reaction for 1 hour. The mixture was allowed to stand for liquid separation, the aqueous phase was extracted with ethyl acetate (195mL, 3mL/g), the organic phases were combined, and the solvent was evaporated under reduced pressure by the organic phase. Adding ethyl acetate (325mL, 5mL/g), heating to 75 +/-5 ℃, stirring until the materials are dissolved, adding n-heptane (650mL, 10mL/g), cooling to 15 +/-5 ℃, stirring for 1 hour, filtering, and drying a wet product at the temperature of 50 +/-10 ℃ in vacuum to obtain the phenyl (4-hydroxyphenyl) carbamate, wherein the yield is 93.5%, and the HPLC purity is 99.95%. 1 H NMR(400MHz,DMSO-d 6 ):δ9.90(s,1H),9.20(s,1H),7.44～7.39(m,2H),7.29(d,J＝8.8Hz,2H),7.27～7.22(m，1H),7.21～7.18(m，2H),6.75～6.71(m,2H)。
1.2 preparation of 1-cyclopropyl-3- (4-hydroxyphenyl) urea (Compound II)
Acetonitrile (460mL, 4mL/g) was added to a glass reaction flask, stirring was turned on, phenyl (4-hydroxyphenyl) carbamate (115.00g, 1.0eq), triethylamine (50.77g, 1.0eq) and cyclopropylamine (40.10g, 1.4eq) were added, the temperature was raised to 55. + -. 5 ℃ and the reaction was stirred for 1 hour. Cooling to 10 +/-5 ℃, and stirring for 2 hours. Filtering, drying the wet product at 50 +/-10 ℃ in vacuum to obtain the 1-cyclopropyl-3- (4-hydroxyphenyl) urea with the yield of 90.4 percent and the HPLC purity of 99.35 percent. 1 H NMR(400MHz,DMSO-d 6 )：δ8.94(s,1H),7.93(s,1H),7.17～7.13(m,2H),6.61～6.65(m,2H),6.21(d,J＝2.8Hz，1H),2.53～2.47(m,1H),0.63～0.38(m,4H)。
1.3 preparation of Vecis-tinib A formula (Compound I, 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea)
Adding 1-cyclopropyl-3- (4-hydroxyphenyl) urea (77.72g, 0.95eq), sodium hydroxide (18.94g, 1.4eq) and DMSO (700mL, 8mL/g) into a glass reaction bottle, starting stirring, cooling to below 20 ℃, adding 4-chloro-6, 7-dimethoxyquinazoline (70.00g, 1.0eq), controlling the temperature to be 15-25 ℃ under the protection of nitrogen, and stirring for reaction for 4 hours. Drinking water (1120mL, 15mL/g) was added, the temperature was reduced to 15. + -. 5 ℃ and the mixture was stirred for 1 hour. The mixture was filtered, and the filter cake was washed with purified water (1mL/g) and ethanol (1mL/g) in this order. Adding the filter cake into a reaction bottle, adding DMSO (245mL, 3.5mL/g), heating to 78 +/-5 ℃, stirring for 30 minutes, slowly adding ethyl acetate (1890mL, 27mL/g), controlling the temperature to 78 +/-5 ℃, stirring for 1 hour, cooling to 0-10 ℃, and stirring for 1 hour. Filtration was carried out, and the filter cake was washed with ethyl acetate (1 mL/g). The wet product was dried under vacuum at 50 + -10 deg.C to obtain 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea in 81.1% yield with 99.89% purity by HPLC assay (FIG. 1) with a self-coupling impurity content of 0.04%. 1 H NMR(400MHz,DMSO-d 6 ):δ8.53(s,1H)，8.39(s,1H),7.54(s,1H),7.49(m,2H),7.37(s,1H),7.16(m,2H),6.42(d,J＝2.8Hz,1H),3.98(s,3H),3.97(s,3H),2.56(m,1H),0.65～0.44(m,4H)。
TABLE 1 liquid-phase detection Peak Table corresponding to FIG. 1
In table 1, the substance with peak number 5 and retention time of 25.346min corresponds to the target product, viccininib, and the substance with peak number 9 and retention time of 31.127min corresponds to the self-coupling impurity.
Example 2
2.1 preparation of phenyl (4-hydroxyphenyl) carbamate (compound III,
)
tetrahydrofuran (120ml, 6ml/g) was added to a glass reaction flask, stirring was turned on, and purified water (60ml, 3ml/g), LSSM01(20.00g, 1.0eq), and sodium bicarbonate (17.86g, 1.1eq) were added. The temperature was controlled at 10-20 ℃ and a mixture of tetrahydrofuran (60ml, 3ml/g) and LSSM02(31.56g, 1.2eq) was slowly added to the reaction mixture. Keeping the temperature of the reaction liquid at 20 +/-10 ℃, and stirring for reaction for 30 minutes. Stirring was stopped, the aqueous phase was extracted with ethyl acetate (50mL, 2.5mL/g), the organic phase was vacuum evaporated to remove the solvent, ethyl acetate (200mL, 10mL/g) was added, the temperature was raised to 75 + -5 deg.C, stirring was carried out until the material was dissolved, and the wet product was dried under vacuum at 50 + -10 deg.C to give phenyl (4-hydroxyphenyl) carbamate in 84.5% yield and 99.93% HPLC purity.
2.2 preparation of 1-cyclopropyl-3- (4-hydroxyphenyl) urea (Compound II)
Ethanol (100ml, 3.3ml/g) was added to the glass reaction flask and stirring was turned on. LS01(30.00g, 1.0eq), triethylamine (13.30g, 1.0eq) and LSSM03(9.70g, 1.3eq) were added, the temperature was raised to 55. + -. 5 ℃ and the reaction was stirred for 2 hours. The temperature was reduced to 10. + -. 5 ℃ and n-heptane (400ml, 13.3ml/g) was added and stirred for 3 hours. Filtering, drying the wet product at 50 +/-10 ℃ in vacuum to obtain the 1-cyclopropyl-3- (4-hydroxyphenyl) urea with the yield of 92.5 percent and the HPLC purity of 97.03 percent.
2.3 preparation of Weicinini formula (Compound I)
Adding 4-chloro-6, 7-dimethoxyquinazoline (2.22g, 0.95eq), potassium hydroxide (0.73g, 1.3eq) and DMF (16mL, 8mL/g) into a glass reaction bottle, starting stirring, cooling to below 20-30 ℃, adding 1-cyclopropyl-3- (4-hydroxyphenyl) urea (2.00g, 1.0eq), controlling the temperature to be 20-30 ℃ under the protection of nitrogen, and stirring for reacting for 4 hours. Drinking water (32mL, 16mL/g) was added, the temperature was reduced to 25. + -. 5 ℃ and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with purified water (1mL/g) and ethanol (1mL/g) in this order. Adding the filter cake into a reaction bottle, adding DMSO (7mL, 3.5mL/g) and ethyl acetate (54mL, 27mL/g), controlling the temperature to 78 +/-5 ℃, stirring for 1 hour, cooling to 0-10 ℃, and stirring for 1 hour. Filtration was carried out, and the filter cake was washed with ethyl acetate (1 mL/g). The wet product was dried under vacuum at 50 + -10 deg.C to obtain 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea in 80.5% yield and 99.69% HPLC purity, with 0.03% self-coupling impurity content.
Example 3
Phenyl (4-hydroxyphenyl) carbamate (compound iii) and 1-cyclopropyl-3- (4-hydroxyphenyl) urea (compound ii) were prepared in the same preparation manner as in example 1;
the procedure for the preparation of compound I is as follows: adding 4-chloro-6, 7-dimethoxyquinazoline (1.11g, 0.95eq), sodium hydroxide (0.23g, 1.1eq), DMSO (8mL, 8mL/g) and 1-cyclopropyl-3- (4-hydroxyphenyl) urea (1.00g, 1.0eq) into a glass reaction flask at room temperature, controlling the temperature to be 40-50 ℃ under the protection of nitrogen, and stirring for reacting for 4 hours. Drinking water (16mL, 16mL/g) was added, the temperature was reduced to 25. + -. 5 ℃ and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with purified water (1mL/g) and ethanol (1mL/g) in this order. Adding the filter cake into a reaction bottle, adding DMSO (4mL, 4mL/g) and ethanol (16mL, 16mL/g), controlling the temperature to 78 +/-5 ℃, stirring for 1 hour, cooling to 0-10 ℃, and stirring for 1 hour. Filtration and washing of the filter cake with ethanol (1 mL/g). The wet product was dried under vacuum at 50 + -10 deg.C to obtain 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea in 82.1% yield and 99.26% HPLC purity, with 0.15% self-coupling impurity content.
Comparative example 1
Phenyl (4-hydroxyphenyl) carbamate (compound iii) and 1-cyclopropyl-3- (4-hydroxyphenyl) urea (compound ii) were prepared in the same preparation manner as in example 1;
the procedure for the preparation of compound I is as follows: adding 4-chloro-6, 7-dimethoxyquinazoline (5.60g, 0.95eq), sodium hydroxide (1.20g, 1.1eq), DMSO (40mL, 8mL/g) and 1-cyclopropyl-3- (4-hydroxyphenyl) urea (5.00g, 1.0eq) into a glass reaction bottle, and stirring for reaction for 1 hour under the protection of nitrogen and at the temperature of 70-80 ℃. Adding drinking water (80mL, 16mL/g), cooling to 20 + -5 deg.C, stirring for 1 hr, filtering, sequentially washing the filter cake with purified water (1mL/g) and ethanol (1mL/g), and drying the wet product at 50 + -10 deg.C under vacuum. DMSO (80mL, 16mL/g) and the dried material are added into a reaction bottle, the temperature is controlled to 40 +/-5 ℃, the mixture is stirred until the mixture is clear, the temperature is reduced to room temperature, water (140mL, 28mL/g) is added, the mixture is stirred for 1 hour, the temperature is reduced to 20 +/-5 ℃, the mixture is stirred for 1 hour, the mixture is filtered, and a filter cake is washed by ethanol (1 mL/g). Adding ethanol (110mL, 22mL/g) and the filter cake into a reaction bottle, controlling the temperature to 78 +/-5 ℃, stirring for 3 hours, cooling to 20 +/-5 ℃, and stirring for 1 hour. Filtration and washing of the filter cake with ethanol (1 mL/g). Adding ethanol (80mL, 16mL/g), DMSO (15mL, 3mL/g) and the filter cake into a reaction bottle, controlling the temperature to 78 +/-5 ℃, stirring for 3 hours, cooling to 20 +/-5 ℃, and stirring for 1 hour. Filtration and washing of the filter cake with ethanol (1 mL/g). Adding ethanol (80mL, 16mL/g) and filter cake into a reaction bottle, controlling the temperature to 78 +/-5 ℃, stirring for 3 hours, cooling to 20 +/-5 ℃, and stirring for 1 hour. Filtration and washing of the filter cake with ethanol (1 mL/g). The wet product was dried under vacuum at 50 + -10 deg.C to obtain 1-cyclopropyl-3- (4- ((6,7-dimethoxyquinazolin-4-yl) oxy) phenyl) urea in 71.0% yield with a purity of 94.69% by HPLC (FIG. 2), wherein the content of self-coupling impurities was 1.18%.
TABLE 2 liquid-phase detection peak table corresponding to FIG. 2
In table 2, the substance with peak number 7 and retention time of 25.262min corresponds to the target product, victorinib, and the substance with peak number 21 and retention time of 31.055min corresponds to the self-coupling impurity.
The preparation method provided by the invention is simple to operate, the content of self-coupling byproducts is less, the product purity is high, and the purity of partial better results is more than 99.5%; the yield of each step is higher than 80%, and the total yield is higher than 60%.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. The citation referred to herein is incorporated by reference in its entirety for all purposes unless otherwise in conflict with the present disclosure's objectives and/or technical solutions. Where a citation is referred to herein, the definition of a reference in the document, including features, terms, nouns, phrases, etc., that is relevant, is also incorporated by reference. In the present invention, when the citation is referred to, the cited examples and preferred embodiments of the related art features are also incorporated by reference into the present application, but the present invention is not limited to the embodiments. It should be understood that where the citation conflicts with the description herein, the application will control or be adapted in accordance with the description herein.
The technical features of the embodiments and examples described above can be combined in any suitable manner, and for the sake of brevity, all possible combinations of the technical features of the embodiments and examples described above are not described, but should be considered within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.
The above examples are only illustrative of several embodiments of the present invention, and should not be construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Furthermore, it should be understood that various changes or modifications can be made by those skilled in the art after reading the above teachings of the present invention, and equivalents obtained thereby also fall within the scope of the present invention. It should also be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the present invention as set forth in the appended claims. Therefore, the scope of the patent of the present invention is subject to the appended claims, and the description and drawings can be used to interpret the contents of the claims.
Claims (10)
1. A preparation method of a quinazoline derivative is characterized by comprising the following steps:
preparation of compound ii: in the presence of a second base, the structure is
The compound III and cyclopropylamine are subjected to amidation reaction in a second solvent to obtain a compound with the structure of
The compound of (1); wherein R is selected from substituted or unsubstituted phenyl, substituted or unsubstituted C1-C4 alkyl;
preparation of compound I: the compound II and the structure are
The quinazoline derivative II is reacted to obtain the compound with the structure of
The quinazoline derivative I of (a), which is the compound I; wherein X is selected from F, Cl, Br or I.
2. The process for producing a quinazoline derivative according to claim 1, wherein the step of producing the compound ii comprises: the second base is selected from one or more of cyclopropylamine, triethylamine, N-diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and sodium ethoxide; and/or the presence of a catalyst in the reaction mixture,
in the compound III, R is substituted or unsubstituted phenyl; and/or the presence of a catalyst in the reaction mixture,
the second solvent is selected from one or more of methanol, ethanol, isopropanol, butanol, acetonitrile, dichloromethane, chloroform, dimethyl sulfoxide and N, N-dimethylformamide; and/or the presence of a catalyst in the reaction mixture,
the reaction temperature of the amidation reaction is 20-60 ℃.
3. The process for producing a quinazoline derivative according to claim 2, wherein the step of producing the compound ii comprises: the molar ratio of the compound III to the cyclopropylamine is 1 (1.0-2.5); and/or the presence of a catalyst in the reaction mixture,
the molar ratio of the second base to the compound III is (0.9-3.0): 1.
4. a method for producing a quinazoline derivative according to claim 3, characterized in that the step of producing the compound ii further comprises a step of isolating and purifying the compound ii: after the amidation reaction, the temperature of the reaction is reduced to 10 +/-5 ℃, the reaction is stirred for 1 to 3 hours, and the reaction product is filtered, dried and recrystallized.
5. A method for producing a quinazoline derivative according to claim 1, characterized in that said compound iii is obtained by a production method comprising the steps of: 4-aminophenol and chloroformate compounds are used as raw materials to carry out esterification reaction to prepare 4-hydroxybenzene carbamate compounds, namely the compound III.
6. The method for preparing a quinazoline derivative according to claim 5, wherein the chloroformate compound is one or more selected from phenyl chloroformate, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, and butyl chloroformate.
7. The process for producing a quinazoline derivative according to claim 1, wherein the step of producing the compound I comprises: under the protection of inert gas and in the presence of a third base, dissolving the compound II in a third solvent, adding the quinazoline derivative II at 0-30 ℃, heating to 10-60 ℃, and reacting for 1-6 hours to obtain the quinazoline derivative I.
8. The method for producing a quinazoline derivative according to claim 7, wherein in the step of producing the compound I, the third solvent is one or more selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and sulfolane.
9. The process for producing a quinazoline derivative according to claim 8, wherein the step of producing the compound I further comprises the step of isolating and purifying the compound I: and (2) reacting the compound II with the quinazoline derivative II, adding water, stirring for 0.5-2 hours at 15 +/-5 ℃, filtering to obtain a filter cake, pulping the filter cake in a fourth solvent, filtering to obtain a solid, and drying.
10. The application of a compound shown as a formula (III) or 1-cyclopropyl-3- (4-hydroxyphenyl) urea shown as a formula (II) in preparing Vecistinib;
wherein R is phenyl or substituted phenyl.
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