CN107674072B - Process for producing dihydropyrimidine derivative and acid adduct thereof - Google Patents
Process for producing dihydropyrimidine derivative and acid adduct thereof Download PDFInfo
- Publication number
- CN107674072B CN107674072B CN201710637253.3A CN201710637253A CN107674072B CN 107674072 B CN107674072 B CN 107674072B CN 201710637253 A CN201710637253 A CN 201710637253A CN 107674072 B CN107674072 B CN 107674072B
- Authority
- CN
- China
- Prior art keywords
- formula
- solvent
- compound represented
- iia
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a preparation method of optically pure dihydropyrimidine derivatives shown as a general formula (I) or a tautomer thereof shown as a formula (Ia), and also relates to a preparation method of L-tartaric acid compounds of dihydropyrimidine derivatives shown as a general formula (I) or a tautomer thereof shown as a formula (Ia), wherein variables are defined as the specification.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a preparation method of an optically pure dihydropyrimidine derivative or tautomer thereof or an acid adduct thereof.
Background
WO 2014029193 discloses a series of dihydropyrimidine compounds and their use in medicine, especially as medicines for treating and preventing hepatitis B. Wherein the active compound is a racemic compound. The applicant carries out resolution on the active compound in subsequent researches to obtain four stereoisomers, the four stereoisomers are respectively measured for pharmacological activity, and the experimental results show that pharmacokinetic parameters and liver microsome stability between isomers are also obviously different. The difference in activity between the different isomers is described in patent WO2015144093, and it is therefore of great value to prepare active compounds of high optical purity. In industrial production, the racemic product is directly resolved by using preparative chromatography, which has high requirements on experimental instruments and cannot be used for large-scale production. Therefore, the development of an efficient and simple method for preparing the optically pure dihydropyrimidine derivative is of great significance.
The present invention has been made mainly in view of the above-mentioned problems, and an object of the present invention is to provide a process for producing an optically pure dihydropyrimidine derivative (I) or its tautomer (Ia) or its acid adduct from a diastereomer compound (II) or (IIa) as a starting material, which enables to efficiently resolve optical isomers even when the diastereomer compound (II) or (IIa) is dissolved in a suitable solvent, and which enables to efficiently resolve optical isomers even when the diastereomer compound (II) or (IIa) is dissolved in a different acid to form an acid adduct under specific conditions. The product obtained by the method is the optically pure compound (I) or (Ia) or the acid addition product thereof, the compounds or the acid addition product thereof can be directly used for production without increasing production steps, the operation is simple, the optical purity of the product is high, the yield is high, the post-treatment is simple, the large-scale production is facilitated, and the method has important application value in industrial production.
Disclosure of Invention
In one aspect, the present invention relates to a process for preparing a compound represented by formula (I) or (Ia) or a solvate thereof from a compound represented by formula (II) or (IIa) or a solvate thereof,
wherein each R is1Independently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Each R4Independently hydrogen, methyl or isopropyl;
n is 1,2 or 3;
m is 0, 1 or 2;
which comprises the following steps: stirring the compound represented by the formula (II) or (IIa) in a suitable solvent, filtering to remove solids, and then concentrating the filtrate to obtain the compound represented by the formula (I) or (Ia).
According to the preparation method of the present invention, in some embodiments, the present invention relates to a preparation method for preparing a compound represented by formula (I-a) or (Ia-a) or a solvate thereof from a compound represented by formula (II-a) or (IIa-a) or a solvate thereof,
wherein each R is1And R1aIndependently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Which comprises the following steps: stirring the compound represented by the formula (II-a) or (IIa-a) in a suitable solvent, filtering to remove solids, and then concentrating the filtrate to obtain the compound represented by the formula (I-a) or (Ia-a).
The preparation method according to the present invention, in some embodiments, wherein the stirring time is 2 to 7 hours, in some embodiments, 3 to 6 hours; in some embodiments, the stirring time is 4 hours.
According to the preparation method of the present invention, the compound represented by formula (II) or (IIa) is stirred at a suitable temperature, in some embodiments, wherein the suitable temperature shown is 10 ℃ to 40 ℃; in some embodiments, suitable temperatures are from 20 ℃ to 35 ℃; in still other embodiments, a suitable temperature is from 25 ℃ to 30 ℃.
According to the preparation method of the present invention, the compound represented by formula (II-a) or (IIa-a) is stirred at a suitable temperature, in some embodiments, wherein the suitable temperature is 10 ℃ to 40 ℃; in some embodiments, suitable temperatures are from 20 ℃ to 35 ℃; in still other embodiments, a suitable temperature is from 25 ℃ to 30 ℃.
The preparation method according to the present invention, wherein the suitable solvent is C in some embodiments1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4A halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent thereof; in other embodiments, wherein the suitable solvent is C1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4The solvent comprises a halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent of two solvents of the halogenated alkane solvent, the toluene, the tetrahydrofuran and the water, wherein the volume ratio of the two solvents in the mixed solvent is 1/1-1/20.
According to the preparation method of the present invention, in some embodiments, the suitable solvent is methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methylene chloride, tetrahydrofuran, acetonitrile, water or a mixed solvent thereof, and preferably the solvent is ethanol, methanol, n-propanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, methyl tert-butyl ether, acetone, methyl ethyl ketone, acetonitrile or a mixed solvent of ethyl acetate and ethanol; in other embodiments, the suitable solvent is methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water or a mixed solvent of two solvents thereof, wherein the volume ratio of the two solvents in the mixed solvent is 1/1 to 1/20, and preferably the solvent is ethanol, methanol, n-propanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, methyl tert-butyl ether, acetone, methyl ethyl ketone, acetonitrile or a mixed solvent of ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate to ethanol is 10/1 to 1/10.
According to the preparation method of the present invention, in some embodiments, the suitable solvent is used in an amount of 2-12 mL per gram of the compound represented by formula (II) or (IIa); in other embodiments, the suitable solvent is used in an amount of 3 to 6mL per gram of the compound of formula (II) or (IIa).
According to the preparation method of the present invention, in some embodiments, the suitable solvent is used in an amount of 2-12 mL per gram of the compound represented by formula (II-a) or (IIa-a); in other embodiments, where a suitable solvent is used in an amount of 3 to 6mL of the suitable solvent per gram of a compound of formula (II-a) or (IIa-a), the solvent is preferably used in a solvent-free amount.
In another aspect, the present invention relates to a process for preparing an acid adduct of a compound represented by formula (I) or (Ia) from a compound represented by formula (II) or (IIa),
wherein each R is1Independently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Each R4Independently is hydrogen, methyl orIsopropyl group;
n is 1,2 or 3;
m is 0, 1 or 2;
which comprises the following steps:
a step (1) in which a compound represented by the formula (II) or (IIa) and a suitable acid are reacted in a suitable solvent to form an acid adduct of the compound represented by the formula (I) or (Ia);
cooling and precipitating an acid adduct of the compound represented by the formula (I) or (Ia);
and (3) isolating the acid adduct of the compound represented by formula (I) or (Ia).
The production process according to the present invention, wherein the compound represented by the formula (II) or (IIa), the compound represented by the formula (I) or (Ia), may comprise a solvate thereof.
The production method according to the present invention is a method for producing an acid adduct comprising adding L-valine, L-alanine, L-glutamic acid, L-tartaric acid, D- (+) -DTTA, L- (+) -DTTA, D-DBTA, (+) -CSA, (S) - (+) -1,1 '-dinaphthyl-2-2' -bisphosphate, or (R) - (-) -1,1 '-dinaphthyl-2-2' -bisphosphate.
According to the preparation process of the present invention, in some embodiments, the present invention relates to a preparation process of an acid adduct of a compound represented by formula (I-a) or (Ia-a) from a compound represented by formula (II-a) or (IIa-a),
wherein each R is1And R1aIndependently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Which comprises the following steps:
a step (1) in which a compound represented by the formula (II-a) or (IIa-a) is reacted with an appropriate acid in an appropriate solvent to form an acid adduct of the compound represented by the formula (I-a) or (Ia-a);
cooling and precipitating an acid adduct of the compound represented by the formula (I-a) or (Ia-a);
and (3) isolating the acid adduct of the compound represented by the formula (I-a) or (Ia-a).
The production process according to the present invention, wherein the compound represented by the formula (II-a) or (IIa-a), the compound represented by the formula (I-a) or (Ia-a) may comprise a solvate thereof.
The production method according to the present invention is a method for producing an acid adduct comprising adding L-valine, L-alanine, L-glutamic acid, L-tartaric acid, D- (+) -DTTA, L- (+) -DTTA, D-DBTA, (+) -CSA, (S) - (+) -1,1 '-dinaphthyl-2-2' -bisphosphate, or (R) - (-) -1,1 '-dinaphthyl-2-2' -bisphosphate.
The preparation method according to the present invention, in some embodiments, wherein the step (1) is specifically performed as: stirring the compound represented by the formula (II) or (IIa) in a suitable solvent, filtering to remove solids, and stirring the obtained filtrate in a suitable acid at a suitable temperature to form an acid adduct of the compound represented by the formula (I) or (Ia). In other embodiments, wherein step (1) is practiced as: directly stirring the compound shown in the formula (II) or (IIa) with a proper acid in a proper solvent at a proper temperature to form an acid adduct of the compound shown in the formula (I) or (Ia).
The preparation method according to the present invention, in some embodiments, wherein the step (1) is specifically performed as: stirring the compound represented by the formula (II-a) or (IIa-a) in a suitable solvent, filtering to remove solids, and stirring the obtained filtrate in a suitable acid at a suitable temperature to form an acid adduct of the compound represented by the formula (I-a) or (Ia-a). In other embodiments, wherein step (1) is practiced as: directly stirring the compound shown in the formula (II-a) or (IIa-a) with a suitable acid in a suitable solvent at a suitable temperature to form an acid adduct of the compound shown in the formula (I-a) or (Ia-a).
According to the preparation method of the present invention, in some embodiments, wherein suitable acids in step (1) are L-valine, L-alanine, L-glutamic acid, L-tartaric acid, D- (+) -DTTA, L- (+) -DTTA, D-DBTA, (+) -CSA, (S) - (+) -1,1 '-dinaphthyl-2-2' -bisphosphate or (R) - (-) -1,1 '-dinaphthyl-2-2' -bisphosphate.
The preparation method according to the present invention, wherein the suitable solvent in step (1) is C in some embodiments1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4A halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent thereof; in other embodiments, wherein the suitable solvent of step (1) is C1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4The solvent comprises a halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent of two solvents of the halogenated alkane solvent, the toluene, the tetrahydrofuran and the water, wherein the volume ratio of the two solvents in the mixed solvent is 1/1-1/20.
According to the preparation method of the present invention, in some embodiments, wherein the suitable solvent in step (1) is methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water or a mixed solvent thereof, the preferred solvent is absolute ethanol, methanol, n-propanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, ethyl formate or methyl acetate; in other embodiments, the suitable solvent in step (1) is methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, acetone, butanone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water or a mixed solvent of two solvents thereof, wherein the ratio of the two solvents in the mixed solvent is 1/1-1/20, and the preferred solvent is absolute ethanol, methanol, n-propanol, isopropanol, acetone, butanone, ethyl acetate, acetonitrile, ethyl formate or methyl acetate.
According to the production method of the present invention, in some embodiments, the compound represented by formula (II) or (IIa) and a suitable acid are separately dissolved in a suitable solvent, and then the two solutions are mixed; in other embodiments, the compound of formula (II) or (IIa) is mixed with a suitable acid and then dissolved in a suitable solvent; in yet another example, the compound of formula (II) or (IIa) is stirred in a suitable solvent, the solid is removed by filtration, and the filtrate is combined with a suitable acid.
According to the production method of the present invention, in some embodiments, the compound represented by the formula (II-a) or (IIa-a) and an appropriate acid are separately dissolved in an appropriate solvent, and then the two solutions are mixed; in other embodiments, the compound of formula (II-a) or (IIa-a) is first mixed with a suitable acid and then dissolved in a suitable solvent; in still another example, a compound represented by the formula (II-a) or (IIa-a) is stirred in a suitable solvent, the solid is removed by filtration, and the filtrate is mixed with a suitable acid.
According to the preparation method of the present invention, in some embodiments, the amount of the suitable solvent required in step (1) is 2 to 40mL per gram of the compound represented by formula (II) or (IIa); in other embodiments, the amount of solvent required is 2 to 30mL of suitable solvent per gram of compound of formula (II) or (IIa); in still other embodiments, the amount of solvent required is 2 to 15mL of suitable solvent per gram of compound of formula (II) or (IIa).
According to the preparation method of the present invention, in some embodiments, the amount of the suitable solvent required in the step (1) is 2 to 40mL of the suitable solvent per gram of the compound represented by the formula (II-a) or (IIa-a); in other embodiments, the amount of solvent required is 2-30 mL of suitable solvent per gram of compound of formula (II-a) or (IIa-a); in still other embodiments, the amount of solvent required is 2-15 mL of suitable solvent per gram of a compound of formula (II-a) or (IIa-a).
According to the preparation method of the present invention, in some embodiments, the process of obtaining an acid adduct of a compound represented by formula (I) or (Ia) is suitably carried out at a temperature of 20 ℃ to 160 ℃; in other embodiments, suitable temperatures are from 25 ℃ to 98 ℃; in yet other embodiments, a suitable temperature is from 25 ℃ to 80 ℃.
According to the preparation method of the present invention, in some embodiments, the acid adduct of the compound represented by formula (I-a) or (Ia-a) is obtained at a suitable temperature of 20 ℃ to 160 ℃; in other embodiments, suitable temperatures are from 25 ℃ to 98 ℃; in yet other embodiments, a suitable temperature is from 25 ℃ to 80 ℃.
According to the preparation method of the present invention, in some embodiments, the ratio of the molar amount of a suitable acid to the compound represented by formula (II) or (IIa) in step (1) is 0.3/1 to 3/1; in some embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II) or (IIa) in step (1) is from 0.45/1 to 1.5/1; in still other embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II) or (IIa) in step (1) is from 0.5/1 to 1/1.
According to the preparation method of the present invention, in some embodiments, the ratio of the molar amount of a suitable acid to the compound represented by formula (II-a) or (IIa-a) in step (1) is 0.3/1 to 3/1; in some embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II-a) or (IIa-a) in step (1) is from 0.45/1 to 1.5/1; in still other embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II-a) or (IIa-a) in step (1) is from 0.5/1 to 1/1.
According to the production method of the present invention, in some embodiments, wherein the formation of the acid adduct of step (1) and the precipitation of the acid adduct of step (2) may be performed during stirring.
According to the preparation method of the present invention, in some embodiments, wherein in the step (2) of cooling to precipitate the solid, the temperature is reduced to-20 ℃ to 50 ℃; in other embodiments, the reduced temperature is from-10 ℃ to 45 ℃; in still other embodiments, the reduced temperature is from 0 ℃ to 40 ℃.
In some embodiments, wherein step (2) is precipitating solids under stirring, wherein the stirring time is 10 to 22 hours, in other embodiments, 15 to 18 hours; in still other embodiments, the stirring time is 16 hours.
According to the production method of the present invention, in some embodiments, wherein the step (3) is specifically vacuum filtration or centrifugal separation of the obtained solid; in other embodiments, the filter cake obtained by filtration is washed with a suitable solvent; in some embodiments, the washing solvent is cooled or normal temperature methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water, or a mixed solvent thereof.
According to the preparation method of the present invention, in some embodiments, the acid adduct solid may be obtained and then subjected to further recrystallization purification to improve the purity of the product. In some embodiments, the recrystallization solvent may be methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water, or a mixed solvent thereof, or other suitable recrystallization solvent. The recrystallization may be carried out at a dissolution temperature ranging from 20 ℃ to the boiling temperature of the solvent, e.g., from 20 ℃ to 90 ℃, and at a cooling crystallization temperature ranging from the boiling temperature of the solvent to about-20 ℃, e.g., from 40 ℃ to-20 ℃.
Detailed description of the invention
Definitions and general terms
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
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. All patents and publications referred to herein are incorporated by reference in their entirety.
Unless otherwise expressly indicated, the recitation "… … independently" as used herein is intended to be broadly interpreted as referring to the fact that particular items expressed between the same symbols in different groups do not affect each other, or the recitation of particular items expressed between the same symbols in the same groups does not affect each other. For example, as in formula a, the specific options of n are not affected by each other, and R's are multiple1Are not affected by each other.
The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. Wherein, the solvent can be alcohols, alcohol aqueous solution, ethers, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, trifluoroethanol, DMF, NMP or the combination thereof. Such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 50:50(v: v) aqueous ethanol, trifluoroethanol, t-butanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, isopropyl ether, DMF, tetrahydrofuran, diethyl ether, dioxane, methyl t-butyl ether, dimethoxyethane, NMP, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, ethyl acetate, isopropyl acetate, acetone, butanone, benzene, toluene, xylene, or combinations thereof.
The "acid adduct" as used herein refers to a salt, a cocrystal or a complex of a compound and a compound having a carboxyl group and an acidic hydrogen.
"co-crystals" are compounds in which the active ingredient and a suitable co-crystal former (also called a ligand) form a specific crystal structure by molecular recognition through intermolecular forces such as hydrogen bonding, halogen bonding, pi stacking, van der waals forces, etc., without breaking the chemical bonds of the active ingredient itself. There is a fixed stoichiometric ratio between the components in the co-crystal. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate. For pharmaceutical active ingredients, the crystalline form may affect a number of physicochemical properties which have a direct effect on their ability to be processed and/or prepared into pharmaceutical and corresponding final dosage forms, for example, co-crystals may improve the solubility, hygroscopicity, stability of a drug substance and its manufacturing (e.g. compressibility, flowability, filterability) and also drug stability, dissolution and bioavailability. The co-crystals can affect the quality, safety and efficacy of the drug.
The "solvate" as referred to herein means a compound having a solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice, which may be methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, butanone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, isobutanol, trifluoroethanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, dioxane, dimethoxyethane, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-dichloroethane, chloroform, benzene, xylene, water, a mixture thereof and the like. A specific example of a solvate is a hydrate, wherein the solvent on the surface, in the crystal lattice or on the surface and in the crystal lattice is water. The hydrates may or may not have other solvents than water on the surface of the substance, in the crystal lattice or both.
"room temperature" in the present invention means a temperature of from about 10 ℃ to about 40 ℃. In some embodiments, "room temperature" refers to a temperature of from about 20 ℃ to about 30 ℃; in other embodiments, "room temperature" refers to a temperature of from about 25 ℃ to about 30 ℃.
Any reaction temperature suitable for forming the acid adduct is encompassed by the present invention. Further, many similar modifications, equivalents, or equivalents of the temperatures and temperature ranges recited in this disclosure are deemed to be within the scope of the present disclosure. In certain embodiments, the temperature at which the acid adduct is formed ranges from room temperature to 160 ℃. The reaction at the beginning or beginning is carried out at a relatively low temperature, and after the temperature is increased, the reaction is carried out at a relatively high temperature, which may be from about 20 ℃ to the boiling point of the solvent, from about 30 ℃ to the boiling point of the solvent, from about 25 ℃ to 160 ℃, from about 30 ℃ to 160 ℃.
Any suitable cooling temperature after the reaction to form the acid adduct is contemplated by the present invention. Further, many similar modifications, equivalents, or equivalents of the temperatures and temperature ranges recited in this disclosure are deemed to be within the scope of the present disclosure. In certain embodiments, the cooling temperature is generally from about-80 ℃ to about 60 ℃. After the reaction for forming the acid adduct is completed, cooling the reaction solution at a higher temperature from the boiling point of the solvent to 60 ℃, from the boiling point of the solvent to 40 ℃, from the boiling point of the solvent to 30 ℃, from the boiling point of the solvent to 25 ℃, from the boiling point of the solvent to 0 ℃, from the boiling point of the solvent to-10 ℃, from the boiling point of the solvent to-15 ℃, from the boiling point of the solvent to-20 ℃, from the boiling point of the solvent to-40 ℃, from the boiling point of the solvent to-50 ℃ or from the boiling point of the solvent to-80 ℃; may be from about 60 ℃ to-20 ℃, from about 50 ℃ to-20 ℃, from about 40 ℃ to 10 ℃, from about 30 ℃ to 10 ℃ or from about room temperature (typically 25 ℃) to 10 ℃. The post-cooling is conducted at a relatively low temperature, which may be from about-80 ℃ to about 10 ℃, from about-60 ℃ to about 10 ℃, from about-40 ℃ to about 10 ℃, from about-20 ℃ to about 10 ℃, from about-10 ℃ to about 10 ℃ or from about 0 ℃ to about 10 ℃.
The recrystallization solvent used in the present invention is not particularly limited, and any solvent capable of dissolving the crude product to some extent and precipitating crystals under certain conditions is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention. Wherein, the solvent can be alcohols, alcohol aqueous solution, ethers, alkanes, halogenated hydrocarbons, esters, ketones, aromatic hydrocarbons, acetonitrile, DMF, NMP or the combination thereof. For example, methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, butanone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, methylene chloride, tetrahydrofuran, acetonitrile, isobutanol, t-butanol, trifluoroethanol, petroleum ether, n-pentane, n-hexane, n-heptane, cyclohexane, DMF, dioxane, dimethoxyethane, NMP, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-dichloroethane, chloroform, benzene, xylene, water or a mixed solvent thereof.
Any suitable holding temperature for recrystallization is encompassed by the present invention. Further, many similar modifications, equivalents, or equivalents of the temperatures and temperature ranges recited in this disclosure are deemed to be within the scope of the present disclosure. In certain embodiments, the recrystallization incubation temperature is generally from about-80 ℃ to about 60 ℃. After the crude product is completely dissolved, the heat preservation reaction is carried out under the condition of higher temperature, which can be from the boiling point of the solvent to 60 ℃, from the boiling point of the solvent to 50 ℃, from the boiling point of the solvent to 40 ℃, from the boiling point of the solvent to 30 ℃, from the boiling point of the solvent to 25 ℃, from the boiling point of the solvent to 0 ℃, from the boiling point of the solvent to-10 ℃, from the boiling point of the solvent to-15 ℃, from the boiling point of the solvent to-20 ℃, from the boiling point of the solvent to-30 ℃, from the boiling point of the solvent to-40 ℃, from the boiling point of the solvent to-50 ℃ or from the boiling point; may be from about 60 ℃ to-20 ℃, from about 50 ℃ to-20 ℃, from about 40 ℃ to 10 ℃, from about 30 ℃ to 10 ℃ or from about room temperature (typically 25 ℃) to 10 ℃. The post incubation is conducted at a relatively low temperature, which may be from about-80 ℃ to about 10 ℃, from about-60 ℃ to about 10 ℃, from about-40 ℃ to about 10 ℃, from about-20 ℃ to about 10 ℃, from about-10 ℃ to about 10 ℃ or from about 0 ℃ to about 10 ℃.
The reaction solvent used in each reaction step of the present invention is not particularly limited, and the content of water in the solvent is not particularly limited. Any amount of solvent that can be used to some extent in the present invention is considered a solvent as described herein. Such as less than about 0.05%, less than 0.1%, less than 0.2%, less than 0.5%, less than 5%, less than 10%, less than 25%, less than 30%, or 0% moisture in the solvent.
Unless otherwise indicated, the formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformers) thereof are within the scope of the present invention.
The definitions and rules of stereochemistry used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "stereoschemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994. All stereoisomeric forms of the compounds of the present invention include, but are in no way limited to: diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to designate the rotation of plane polarized light by the compound, (-) or l indicates that the compound is left-handed, and the prefix (+) or d indicates that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer is an enantiomer, and mixtures of such isomers are commonly referred to as enantiomeric mixtures. 50 of enantiomer: 50 mixtures are referred to as racemic mixtures or racemates, which can occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion by recombination of some of the bonding electrons, for example, (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid and (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid are tautomers of each other. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Description of the preparation Process of the invention
In one aspect, the present invention relates to a process for preparing a compound represented by formula (I) or (Ia) or a solvate thereof from a compound represented by formula (II) or (IIa) or a solvate thereof,
wherein each R is1Independently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Each R4Independently hydrogen, methyl or isopropyl;
n is 1,2 or 3;
m is 0, 1 or 2;
which comprises the following steps: stirring the compound represented by the formula (II) or (IIa) in a suitable solvent, filtering to remove solids, and then concentrating the filtrate to obtain the compound represented by the formula (I) or (Ia).
According to the preparation method of the present invention, in some embodiments, the present invention relates to a preparation method for preparing a compound represented by formula (I-a) or (Ia-a) or a solvate thereof from a compound represented by formula (II-a) or (IIa-a) or a solvate thereof,
wherein each R is1And R1aIndependently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Which comprises the following steps: stirring the compound represented by the formula (II-a) or (IIa-a) in a suitable solvent, filtering to remove solids, and then concentrating the filtrate to obtain the compound represented by the formula (I-a) or (Ia-a).
The preparation method according to the present invention, in some embodiments, wherein the stirring time is 2 to 7 hours, in some embodiments, 3 to 6 hours; in some embodiments, the stirring time is 4 hours.
According to the preparation method of the present invention, the compound represented by formula (II) or (IIa) is stirred at a suitable temperature, in some embodiments, wherein the suitable temperature shown is 10 ℃ to 40 ℃; in some embodiments, suitable temperatures are from 20 ℃ to 35 ℃; in still other embodiments, a suitable temperature is from 25 ℃ to 30 ℃.
According to the preparation method of the present invention, the compound represented by formula (II-a) or (IIa-a) is stirred at a suitable temperature, in some embodiments, wherein the suitable temperature is 10 ℃ to 40 ℃; in some embodiments, suitable temperatures are from 20 ℃ to 35 ℃; in still other embodiments, a suitable temperature is from 25 ℃ to 30 ℃.
The preparation method according to the present invention, wherein the suitable solvent is C in some embodiments1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4A halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent thereof; in other embodiments, wherein the suitable solvent is C1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4The solvent comprises a halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent of two solvents of the halogenated alkane solvent, the toluene, the tetrahydrofuran and the water, wherein the volume ratio of the two solvents in the mixed solvent is 1/1-1/20.
According to the preparation method of the present invention, in some embodiments, the suitable solvent is methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, methylene chloride, tetrahydrofuran, acetonitrile, water or a mixed solvent thereof, and preferably the solvent is ethanol, methanol, n-propanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, methyl tert-butyl ether, acetone, methyl ethyl ketone, acetonitrile or a mixed solvent of ethyl acetate and ethanol; in other embodiments, the suitable solvent is methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water or a mixed solvent of two solvents thereof, wherein the volume ratio of the two solvents in the mixed solvent is 1/1 to 1/20, and preferably the solvent is ethanol, methanol, n-propanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, methyl tert-butyl ether, acetone, methyl ethyl ketone, acetonitrile or a mixed solvent of ethyl acetate and ethanol, wherein the volume ratio of ethyl acetate to ethanol is 10/1 to 1/10.
According to the preparation method of the present invention, in some embodiments, the suitable solvent is used in an amount of 2-12 mL per gram of the compound represented by formula (II) or (IIa); in other embodiments, the suitable solvent is used in an amount of 3 to 6mL per gram of the compound of formula (II) or (IIa).
According to the preparation method of the present invention, in some embodiments, the suitable solvent is used in an amount of 2-12 mL per gram of the compound represented by formula (II-a) or (IIa-a); in other embodiments, where a suitable solvent is used in an amount of 3 to 6mL of the suitable solvent per gram of a compound of formula (II-a) or (IIa-a), the solvent is preferably used in a solvent-free amount.
In another aspect, the present invention relates to a process for preparing an acid adduct of a compound represented by formula (I) or (Ia) from a compound represented by formula (II) or (IIa),
wherein each R is1Independently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Each R4Independently hydrogen, methyl or isopropyl;
n is 1,2 or 3;
m is 0, 1 or 2;
which comprises the following steps:
a step (1) in which a compound represented by the formula (II) or (IIa) and a suitable acid are reacted in a suitable solvent to form an acid adduct of the compound represented by the formula (I) or (Ia);
cooling and precipitating an acid adduct of the compound represented by the formula (I) or (Ia);
and (3) isolating the acid adduct of the compound represented by formula (I) or (Ia).
The production process according to the present invention, wherein the compound represented by the formula (II) or (IIa), the compound represented by the formula (I) or (Ia), may comprise a solvate thereof.
The production method according to the present invention is a method for producing an acid adduct comprising adding L-valine, L-alanine, L-glutamic acid, L-tartaric acid, D- (+) -DTTA, L- (+) -DTTA, D-DBTA, (+) -CSA, (S) - (+) -1,1 '-dinaphthyl-2-2' -bisphosphate, or (R) - (-) -1,1 '-dinaphthyl-2-2' -bisphosphate.
According to the preparation process of the present invention, in some embodiments, the present invention relates to a preparation process of an acid adduct of a compound represented by formula (I-a) or (Ia-a) from a compound represented by formula (II-a) or (IIa-a),
wherein each R is1And R1aIndependently hydrogen, fluoro, chloro, bromo, iodo, nitro, trifluoromethyl or cyano;
each R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
each R3Is composed of
Which comprises the following steps:
a step (1) in which a compound represented by the formula (II-a) or (IIa-a) is reacted with an appropriate acid in an appropriate solvent to form an acid adduct of the compound represented by the formula (I-a) or (Ia-a);
cooling and precipitating an acid adduct of the compound represented by the formula (I-a) or (Ia-a);
and (3) isolating the acid adduct of the compound represented by the formula (I-a) or (Ia-a).
The production process according to the present invention, wherein the compound represented by the formula (II-a) or (IIa-a), the compound represented by the formula (I-a) or (Ia-a) may comprise a solvate thereof.
The production method according to the present invention is a method for producing an acid adduct comprising adding L-valine, L-alanine, L-glutamic acid, L-tartaric acid, D- (+) -DTTA, L- (+) -DTTA, D-DBTA, (+) -CSA, (S) - (+) -1,1 '-dinaphthyl-2-2' -bisphosphate, or (R) - (-) -1,1 '-dinaphthyl-2-2' -bisphosphate.
The preparation method according to the present invention, in some embodiments, wherein the step (1) is specifically performed as: stirring the compound represented by the formula (II) or (IIa) in a suitable solvent, filtering to remove solids, and stirring the obtained filtrate in a suitable acid at a suitable temperature to form an acid adduct of the compound represented by the formula (I) or (Ia). In other embodiments, wherein step (1) is practiced as: directly stirring the compound shown in the formula (II) or (IIa) with a proper acid in a proper solvent at a proper temperature to form an acid adduct of the compound shown in the formula (I) or (Ia).
The preparation method according to the present invention, in some embodiments, wherein the step (1) is specifically performed as: stirring the compound represented by the formula (II-a) or (IIa-a) in a suitable solvent, filtering to remove solids, and stirring the obtained filtrate in a suitable acid at a suitable temperature to form an acid adduct of the compound represented by the formula (I-a) or (Ia-a). In other embodiments, wherein step (1) is practiced as: directly stirring the compound shown in the formula (II-a) or (IIa-a) with a suitable acid in a suitable solvent at a suitable temperature to form an acid adduct of the compound shown in the formula (I-a) or (Ia-a).
According to the preparation method of the present invention, in some embodiments, wherein suitable acids in step (1) are L-valine, L-alanine, L-glutamic acid, L-tartaric acid, D- (+) -DTTA, L- (+) -DTTA, D-DBTA, (+) -CSA, (S) - (+) -1,1 '-dinaphthyl-2-2' -bisphosphate or (R) - (-) -1,1 '-dinaphthyl-2-2' -bisphosphate.
According to the bookThe preparation method of the invention, in some embodiments, wherein the suitable solvent described in step (1) is C1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4A halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent thereof; in other embodiments, wherein the suitable solvent of step (1) is C1-4Alcohol solvent, C2-6Ester solvent, C2-6Ether solvent, C3-8Ketone solvent, acetonitrile, C1-4The solvent comprises a halogenated alkane solvent, toluene, tetrahydrofuran, water or a mixed solvent of two solvents of the halogenated alkane solvent, the toluene, the tetrahydrofuran and the water, wherein the volume ratio of the two solvents in the mixed solvent is 1/1-1/20.
According to the preparation method of the present invention, in some embodiments, wherein the suitable solvent in step (1) is methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water or a mixed solvent thereof, the preferred solvent is absolute ethanol, methanol, n-propanol, isopropanol, acetone, methyl ethyl ketone, acetonitrile, ethyl acetate, ethyl formate or methyl acetate; in other embodiments, the suitable solvent in step (1) is methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, acetone, butanone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water or a mixed solvent of two solvents thereof, wherein the ratio of the two solvents in the mixed solvent is 1/1-1/20, and the preferred solvent is absolute ethanol, methanol, n-propanol, isopropanol, acetone, butanone, ethyl acetate, acetonitrile, ethyl formate or methyl acetate.
According to the production method of the present invention, in some embodiments, the compound represented by formula (II) or (IIa) and a suitable acid are separately dissolved in a suitable solvent, and then the two solutions are mixed; in other embodiments, the compound of formula (II) or (IIa) is mixed with a suitable acid and then dissolved in a suitable solvent; in yet another example, the compound of formula (II) or (IIa) is stirred in a suitable solvent, the solid is removed by filtration, and the filtrate is combined with a suitable acid.
According to the production method of the present invention, in some embodiments, the compound represented by the formula (II-a) or (IIa-a) and an appropriate acid are separately dissolved in an appropriate solvent, and then the two solutions are mixed; in other embodiments, the compound of formula (II-a) or (IIa-a) is first mixed with a suitable acid and then dissolved in a suitable solvent; in still another example, a compound represented by the formula (II-a) or (IIa-a) is stirred in a suitable solvent, the solid is removed by filtration, and the filtrate is mixed with a suitable acid.
According to the preparation method of the present invention, in some embodiments, the amount of the suitable solvent required in step (1) is 2 to 40mL per gram of the compound represented by formula (II) or (IIa); in other embodiments, the amount of solvent required is 2 to 30mL of suitable solvent per gram of compound of formula (II) or (IIa); in still other embodiments, the amount of solvent required is 2 to 15mL of suitable solvent per gram of compound of formula (II) or (IIa).
According to the preparation method of the present invention, in some embodiments, the amount of the suitable solvent required in the step (1) is 2 to 40mL of the suitable solvent per gram of the compound represented by the formula (II-a) or (IIa-a); in other embodiments, the amount of solvent required is 2-30 mL of suitable solvent per gram of compound of formula (II-a) or (IIa-a); in still other embodiments, the amount of solvent required is 2-15 mL of suitable solvent per gram of a compound of formula (II-a) or (IIa-a).
According to the preparation method of the present invention, in some embodiments, the process of obtaining an acid adduct of a compound represented by formula (I) or (Ia) is suitably carried out at a temperature of 20 ℃ to 160 ℃; in other embodiments, suitable temperatures are from 25 ℃ to 98 ℃; in yet other embodiments, a suitable temperature is from 25 ℃ to 80 ℃.
According to the preparation method of the present invention, in some embodiments, the acid adduct of the compound represented by formula (I-a) or (Ia-a) is obtained at a suitable temperature of 20 ℃ to 160 ℃; in other embodiments, suitable temperatures are from 25 ℃ to 98 ℃; in yet other embodiments, a suitable temperature is from 25 ℃ to 80 ℃.
According to the preparation method of the present invention, in some embodiments, the ratio of the molar amount of a suitable acid to the compound represented by formula (II) or (IIa) in step (1) is 0.3/1 to 3/1; in some embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II) or (IIa) in step (1) is from 0.45/1 to 1.5/1; in still other embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II) or (IIa) in step (1) is from 0.5/1 to 1/1.
According to the preparation method of the present invention, in some embodiments, the ratio of the molar amount of a suitable acid to the compound represented by formula (II-a) or (IIa-a) in step (1) is 0.3/1 to 3/1; in some embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II-a) or (IIa-a) in step (1) is from 0.45/1 to 1.5/1; in still other embodiments, the ratio of suitable acids to the molar amount of compounds of formula (II-a) or (IIa-a) in step (1) is from 0.5/1 to 1/1.
According to the production method of the present invention, in some embodiments, wherein the formation of the acid adduct of step (1) and the precipitation of the acid adduct of step (2) may be performed during stirring.
According to the preparation method of the present invention, in some embodiments, wherein in the step (2) of cooling to precipitate the solid, the temperature is reduced to-20 ℃ to 50 ℃; in other embodiments, the reduced temperature is from-10 ℃ to 45 ℃; in still other embodiments, the reduced temperature is from 0 ℃ to 40 ℃.
In some embodiments, wherein step (2) is precipitating solids under stirring, wherein the stirring time is 10 to 22 hours, in other embodiments, 15 to 18 hours; in still other embodiments, the stirring time is 16 hours.
According to the production method of the present invention, in some embodiments, wherein the step (3) is specifically vacuum filtration or centrifugal separation of the obtained solid; in other embodiments, the filter cake obtained by filtration is washed with a suitable solvent; in some embodiments, the washing solvent is cooled or normal temperature methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water, or a mixed solvent thereof.
According to the preparation method of the present invention, in some embodiments, the acid adduct solid may be obtained and then subjected to further recrystallization purification to improve the purity of the product. In some embodiments, the recrystallization solvent may be methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, ethyl formate, ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, diethyl ether, isopropyl ether, methyl t-butyl ether, dichloromethane, tetrahydrofuran, acetonitrile, water, or a mixed solvent thereof, or other suitable recrystallization solvent. The recrystallization may be carried out at a dissolution temperature ranging from 20 ℃ to the boiling temperature of the solvent, e.g., from 20 ℃ to 90 ℃, and at a cooling crystallization temperature ranging from the boiling temperature of the solvent to about-20 ℃, e.g., from 40 ℃ to-20 ℃.
Drawings
FIG. 1 is a unit cell diagram of the L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid.
General synthetic methods
Those skilled in the art will recognize that: the preparation examples described herein can be used to suitably resolve a number of other acid adducts described herein.
NMR spectral data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, CDC13,DMSO-d6,CD3OD or d6Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton, singlet), d (doublet ), t (triplet, triplet), m (multiplet ), br (broad, doublet), dd (doublet of doublets, doublet), ddd (doublet of doublets), dt (doublet of triplets ), ddt (doublet of doublets, doublet of triplets), td (triplet of doublets, triplet). Coupling constants are expressed in hertz (Hz).
The X-ray single crystal diffraction research and analysis method comprises the following steps: irradiation with Cu Kalpha on an Agilent Technologies Gemini A Ultra diffractometer
Data collection, indexing and processing of measured intensity data using the CrysAlis PRO program, cell parameters were determined by pre-experiment, and data collection strategies were developed based on cell parameters for data collection. The structural analysis and Refinement were carried out by direct analysis using the Program SHELX-97 (Shell drag, G.M. SHELXTL-97, Program for Crystal Structure Solution and reference; University of Gottingen: Gottingen, Germany, 1997). The derived atomic parameters (coordinates and temperature factors) are corrected by a full matrix least squares method. Function sigma minimized in the modificationw(|Fo|-|Fc|)2. R is defined as | | | Fo|-|Fc||/∑|FoL, and Rw＝[∑w(|Fo|-|Fc|)2/∑w|Fo|2]1/2Where w is a suitable weighting function based on the error in the observed intensity. The difference map is checked at all stages of the correction. The positions of the hydrogen atoms are determined by theoretical calculation, except that the positions of the hydrogen atoms on the nitrogen atom and the oxygen atom are determined by a difference Fourier mapAnd (4) obtaining. The simulated powder X-ray pattern was calculated using Mercury software. Single crystals measured 0.4 × 0.38 × 0.23 mm were picked for single crystal diffraction analysis. Selected crystals were fixed to fine glass fibers with a small amount of petrolatum and measured by mounting on an Agilent Technologies Gemini a Ultra diffractometer.
The examples described below, unless otherwise indicated, all temperatures are in degrees Celsius (. degree. C.). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu chemical Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaihua factory.
The solubility of the invention was measured using an Aglient 1200 high performance liquid chromatograph VWD detector with a column model Waters Xbridge-C18 (4.6X 150mm, 5 μm). The detection wavelength was 250nm, the flow rate was 1.0mL/min, the column temperature was 35 ℃, and the mobile phase was acetonitrile-water (v/v-40/60).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:
table 1: gradient elution conditions for low resolution mass spectrometry mobile phase
| Time (min) | A(CH3CN,0.1％HCOOH) | B(H2O,0.1％HCOOH) |
| 0-3 | 5-100 | 95-0 |
| 3-6 | 100 | 0 |
| 6-6.1 | 100-5 | 0-95 |
| 6.1-8 | 5 | 95 |
The purity of the compounds was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
DTTA (-) -di-p-toluoyl-L-tartaric acid
DBTA D- (+) -dibenzoyl tartaric acid monohydrate
CSA D (+) -10-camphorsulfonic acid
EA, EtOAc ethyl acetate
DMF N, N-dimethylformamide
THF tetrahydrofuran
NMP N-methylpyrrolidone
MeCN,CH3CN acetonitrile
DCM,CH2Cl2Methylene dichloride
CHCl3Chloroform, chloroform
PE Petroleum Ether
CH3OH, MeOH methanol
MTBE formic acid tert-butyl ether
rt Room temperature
g
c concentration
mol mole of
mmol millimole
h hours
min for
mL of
v/v, v: v, volume ratio
DMSO dimethyl sulfoxide
e.q. equivalent
Detailed Description
The embodiment of the invention discloses a method for preparing an acid addition product of an optically pure dihydropyrimidine derivative. The skilled person can use the contents to modify the experimental conditions appropriately to achieve the purpose. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included in the invention. While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods described herein, or appropriate variations and combinations thereof, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
For a further understanding of the present invention, reference will now be made in detail to the following examples.
First, referring to the test method described in patent WO 2014029193, the compound (3S) -4- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid (a) can be obtained
Example 1: preparation of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid
(3S) -4- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid (1g) and ethanol (5mL) were added sequentially in a 25mL single-necked flask, the mixture was stirred at room temperature for 4 hours, filtered, the filtrate was concentrated under reduced pressure, and the solvent was removed to give (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid as a yellow foamy solid (0.46g, 92%) chiral purity 95%.
MS(ESI,pos.ion)m/z:494.9[M+H]+；
1H NMR(400MHz,DMSO-d6):12.52(br,1H),9.86(s,1H),8.03(d,1H),7.94(d,1H),7.43-7.38(m,2H),7.16(td,1H),6.04(s,1H),4.24(d,1H),4.06-3.97(m,2H),3.84(dd,1H),3.73-3.66(m,2H),3.64-3.59(m,1H),3.51(s,3H),3.10-3.06(m,1H),2.43-2.39(m,1H).
(S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid can also be prepared according to the experimental conditions listed in Table 2 below, with specific operating methods according to the methods described in example 1
TABLE 2 Experimental conditions
And (4) conclusion: as can be seen from the experimental results of table 2, higher yields and higher optical purity of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid can be obtained with appropriate changes in experimental conditions.
Example 2: preparation of L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid (method one)
(3S) -4- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid (7g,14.14mmol), ethanol (45mL) and L-tartaric acid (1.2g,8mmol) were added sequentially in a 100mL three-necked flask, and the resulting mixture was warmed to 55 degrees and stirred for 30min with constant temperature. Then the heating is closed, the temperature is reduced to 25 ℃, and the stirring is continued for 16 hours under the condition of heat preservation. After the reaction was complete, filtration was carried out and the filter cake was washed with ethanol (10mL) and then dried under vacuum at 65 ℃ for 8 hours to give the L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid as a yellow solid (3.56g, 78%) with a chiral purity of 96.7%.
1H NMR(400MHz,DMSO-d6)(ppm):9.86(s,1H),8.02(d,J＝3.1Hz,1H),7.93(d,J＝3.1Hz,1H),7.40(dt,J＝9.0,4.6Hz,2H),7.15(td,J＝8.5,2.6Hz,1H),6.04(s,1H),4.31(s,2H),4.24(d,J＝17.6Hz,1H),4.10-3.91(m,2H),3.83(dd,J＝11.1,3.1Hz,1H),3.74-3.64(m,2H),3.61(t,J＝3.6Hz,1H),3.51(s,3H),3.08(t,J＝8.5Hz,1H),2.40(d,J＝12.0Hz,1H).
Single crystal X-ray study:
the L-tartaric acid complex was grown into a single crystal, which was characterized by the unit cell parameters listed in table 3, and diffracted by an X-ray single crystal. The unit cell parameters were measured at a temperature of about 150(2) K.
Table 3: unit cell parameters of L-tartaric acid complex
The result of the structural analysis is that the unit cell has two molecular formula units (formula units) and the structure is a monoclinic space group P21. Single crystal atomic coordinate parameter (× 10)4) As shown in Table 4, the unit cell structure of the L-tartaric acid complex single crystal is shown in FIG. 1.
TABLE 4 atomic coordinate parameters (. times.10) of single crystals of complexes of the compound of formula (Ia) and L-tartaric acid4)
The experimental results show that: (1) the molar ratio of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid in the L-tartaric acid complex was 1: 1.
The complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid and L-tartaric acid can also be prepared according to the conditions listed in table 5 below, with specific operating methods according to the method described in example 2.
TABLE 5 Experimental conditions
And (4) conclusion: as can be seen from the experimental results of table 5, with appropriate changes in experimental conditions, higher yields and higher optical purity of the L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid can be obtained.
Example 3: preparation of L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid (c) (method two)
(3S) -4- ((6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid (7g,14.14mmol) and ethanol (45mL) were added sequentially in a 100mL three-necked flask, and the mixture was stirred at room temperature for 4 hours and filtered. The resulting filtrate was transferred to a single-neck flask (100mL), then warmed to 55 deg.C, L-tartaric acid (1.2g,8mmol) was added and the resulting mixture was stirred for 30 minutes with incubation. Then the heating is closed, the temperature is reduced (7 ℃/hour), and after the temperature is reduced to 25 ℃, the heat preservation and the stirring are continued for 16 hours. Filtration, washing with ethanol (10mL), followed by vacuum drying at 65 ℃ for 8 hours gave the L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid as a yellow solid (3.42g, 75%) with a chiral purity of 99.2%.
The complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -1, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid and L-tartaric acid can also be prepared according to the conditions listed in table 6 below, with specific operating methods according to the method described in example 3.
TABLE 6 Experimental conditions
And (4) conclusion: as can be seen from the experimental results of table 6, with appropriate changes in experimental conditions, higher yields and higher optical purity of the L-tartaric acid complex of (S) -4- (((R) -6- (2-chloro-4-fluorophenyl) -5- (methoxycarbonyl) -2- (thiazol-2-yl) -3, 6-dihydropyrimidin-4-yl) methyl) morpholine-3-carboxylic acid can be obtained.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (13)
1. A process for producing a compound represented by the formula (I) or (Ia) from a compound represented by the formula (II) or (IIa),
wherein each R is1Independently hydrogen, fluorine, chlorine or bromine;
R2is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
R3is composed of
Each R4Independently is hydrogen;
n is 2;
m is 0, 1 or 2;
which comprises the following steps: stirring the compound represented by the formula (II) or (IIa) in a suitable solvent, filtering to remove solids, and then concentrating the filtrate to obtain the compound represented by the formula (I) or (Ia);
wherein the suitable solvent is ethanol, methanol, n-propanol, isopropanol, ethyl formate, methyl acetate, ethyl acetate, methyl tert-butyl ether, acetone, butanone, acetonitrile or a mixed solvent of ethyl acetate and ethanol.
2. The method according to claim 1, wherein the suitable solvent is used in an amount of 3 to 6mL per gram of the compound represented by formula (II) or (IIa).
3. A process for producing an acid adduct of a compound represented by the formula (I) or (Ia) from a compound represented by the formula (II) or (IIa),
wherein each R is1Independently hydrogen, fluorine, chlorine or bromine;
R2is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl;
R3is composed of
Each R4Independently is hydrogen;
n is 2;
m is 0, 1 or 2;
which comprises the following steps:
a step (1) in which a compound represented by the formula (II) or (IIa) and a suitable acid are reacted in a suitable solvent to form an acid adduct of the compound represented by the formula (I) or (Ia);
cooling and precipitating an acid adduct of the compound represented by the formula (I) or (Ia);
separating the acid adduct of the compound represented by the formula (I) or (Ia);
wherein a suitable acid in step (1) is L-tartaric acid;
the suitable solvent in the step (1) is ethanol, methanol, n-propanol, isopropanol, acetone, butanone or ethyl acetate.
4. The method of claim 3, wherein step (1) is practiced by: stirring a compound represented by formula (II) or (IIa) in a suitable solvent, filtering to remove solids, and stirring the obtained filtrate in a suitable acid at a suitable temperature to form an acid adduct of the compound represented by formula (I) or (Ia); or
The step (1) is implemented specifically as follows: directly stirring the compound shown in the formula (II) or (IIa) with a proper acid in a proper solvent at a proper temperature to form an acid adduct of the compound shown in the formula (I) or (Ia).
5. The method according to claim 3 or 4, wherein the solvent is used in an amount of 2 to 40mL per gram of the compound represented by formula (II) or (IIa).
6. The method according to claim 3 or 4, wherein the solvent is used in an amount of 2 to 15mL per gram of the compound represented by formula (II) or (IIa).
7. The production method according to claim 3 or 4, wherein the acid adduct of step (1) is formed at a suitable temperature of 20 to 160 ℃.
8. The production method according to claim 3 or 4, wherein the acid adduct of step (1) is formed at a suitable temperature of 25 to 80 ℃.
9. The process according to claim 3 or 4, wherein the ratio of the molar amount of a suitable acid to the compound represented by formula (II) or (IIa) in step (1) is 0.45/1 to 1.5/1.
10. The process according to claim 3 or 4, wherein the ratio of the molar amount of a suitable acid to the compound of formula (II) or (IIa) in step (1) is from 0.5/1 to 1/1.
11. The method according to claim 3, wherein the temperature in the step (2) of precipitating the acid adduct is suitably from-10 to 45 ℃.
12. The production method according to claim 3, wherein the temperature in the step (2) of precipitating the acid adduct is suitably 0 to 40 ℃.
13. The process according to claim 3, wherein the step (3) is carried out by suction filtration under reduced pressure or centrifugation to separate the acid adduct of the compound represented by formula (I) or (Ia).
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610627164 | 2016-08-01 | ||
| CN2016106271646 | 2016-08-01 | ||
| CN201610841058 | 2016-09-22 | ||
| CN2016108410588 | 2016-09-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107674072A CN107674072A (en) | 2018-02-09 |
| CN107674072B true CN107674072B (en) | 2020-11-24 |
Family
ID=61133166
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710637253.3A Active CN107674072B (en) | 2016-08-01 | 2017-07-31 | Process for producing dihydropyrimidine derivative and acid adduct thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107674072B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626752A (en) * | 2012-08-24 | 2014-03-12 | 广东东阳光药业有限公司 | Dihydropyrimidine compounds and application of same in drugs |
| CN104672222A (en) * | 2013-11-27 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative |
| CN104945395A (en) * | 2014-03-28 | 2015-09-30 | 广东东阳光药业有限公司 | Dihydropyrimidine compound and application thereof in medicaments |
-
2017
- 2017-07-31 CN CN201710637253.3A patent/CN107674072B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626752A (en) * | 2012-08-24 | 2014-03-12 | 广东东阳光药业有限公司 | Dihydropyrimidine compounds and application of same in drugs |
| CN104672222A (en) * | 2013-11-27 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative |
| CN104672223A (en) * | 2013-11-27 | 2015-06-03 | 广东东阳光药业有限公司 | Preparation method of dihydropyrimidine derivative and intermediate of dihydropyrimidine derivative |
| CN104945395A (en) * | 2014-03-28 | 2015-09-30 | 广东东阳光药业有限公司 | Dihydropyrimidine compound and application thereof in medicaments |
Non-Patent Citations (1)
| Title |
|---|
| 结晶法拆分非对映异构体;赵临襄;《化学制药工艺学》;20150831;第126页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107674072A (en) | 2018-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2018244451B2 (en) | Crystal form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3) pyridazine-3-carboxamide | |
| EP3174855B1 (en) | Coformer salts of (2s,3s)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1h-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and methods of preparing them | |
| AU2017219189A1 (en) | Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-carboxylic acid | |
| US20070270590A1 (en) | Methods for preparing eszopiclone crystalline form a, substantially pure eszopiclone and optically enriched eszopiclone | |
| WO2011060213A2 (en) | Preparation of sitagliptin and salts thereof | |
| WO2010002777A2 (en) | Process for the preparation of benzoimidazol-2-yl pyrimidine derivatives | |
| CN111039937B (en) | Preparation method of rivaroxaban intermediate | |
| EP2279186A1 (en) | CONVERSION OF TRYPTOPHAN INTO ß-CARBOLINE DERIVATIVES | |
| CN107674072B (en) | Process for producing dihydropyrimidine derivative and acid adduct thereof | |
| WO2017202357A1 (en) | Method for preparing trifluoromethyl-substituted pyran derivative | |
| JP2013527239A (en) | Ixabepilone solid form | |
| JP2019535742A (en) | Chemical methods for preparing imidazopyrrolidinone derivatives and intermediates thereof | |
| CN112424149B (en) | Synthesis of tipifanib | |
| WO2022092247A1 (en) | Method of producing 3-methyl-4-halo-indole derivative | |
| EA042764B1 (en) | METHODS FOR OBTAINING (R)-(+)-TIPIFARNIBA | |
| WO2018159734A1 (en) | Production method for crystal of 5-cyclopropyl-2-((1-(3-fluorobenzyl)-1h-indol-5-yl)-amino)nicotinic acid | |
| WO2024084227A1 (en) | Substituted bicyclic dienes | |
| WO2014208586A1 (en) | Method for producing tricyclic heterocyclic compound | |
| WO2007066512A1 (en) | Triazasumanene and method for producing same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd. |