CN114805220A - Preparation method of quinazolinone compound - Google Patents
Preparation method of quinazolinone compound Download PDFInfo
- Publication number
- CN114805220A CN114805220A CN202210058949.1A CN202210058949A CN114805220A CN 114805220 A CN114805220 A CN 114805220A CN 202210058949 A CN202210058949 A CN 202210058949A CN 114805220 A CN114805220 A CN 114805220A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- solvent
- carbon
- salt
- 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.)
- Pending
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of quinazolinone compounds. The invention provides a preparation method of a compound 4, which comprises the following steps: in a solvent, organic amine and the compound 3 are subjected to salt forming reaction and then separated to obtain a salt of a compound 4; and (3) carrying out an acidification reaction on the salt of the compound 4 and acid to obtain the compound 4, wherein the organic amine is S-sparteine and/or S-phenylethylamine. The compound 4 can be used for synthesizing other quinazolinone compounds. In the preparation method for synthesizing the quinazolinone compound, an SFC (small form factor C) resolution technology is not used in the whole process of synthesizing the target molecule, compared with the target compound obtained by the prior art, the method has the advantages of lower cost, higher speed and larger batch in one time, and the quinazolinone compound is prepared by 99.5% ee value.
Description
Technical Field
The invention relates to a preparation method of quinazolinone compounds.
Background
Patent WO2019091476a1 of roxacin biotechnology limited discloses compounds of the formula which are PI3K α inhibitors and reports a synthetic route in the patent which allows the synthesis of such compounds on the milligram scale.
Rocoxin pharmaceutical industry has published in ACS med. chem. lett.2020,11,1463-1469 on a class of PI3K α active compounds as 3- (4-oxoquinazolin-3 (4 hydro) yl) -N-methylpropanamide, several synthetic routes to prepare this class of compounds on a gram scale of 1-5g are reported.
The preparation route shown in patent WO2019091476A1 discloses that the alkyl chain substituted WX087-02 compound is obtained by connecting ethyl ester segment with 2-amino-5-bromobenzoic acid BB2-4 and then closing quinazoline ring with formic acid. Obtaining a racemic WX089-2 compound through methylamine amidation and aryl sulfonyl chloride, and finally obtaining a medicinal active molecule WX089 or WX090 containing chirality through SFC resolution.
Three preparation routes of quinazolinone compounds reported in ACS Med.chem.Lett.2020,11,1463-1469 are:
route one: the method comprises the steps of carrying out substitution reaction on 6-bromoquinazoline-4 (3H) -ketone and 3-bromo-2-methyl propionate to obtain a quinazoline compound with an alkyl side chain substituted, carrying out Suzuki coupling, hydrolysis reaction and amide condensation reaction to obtain a racemic compound 10 in a patent, and finally carrying out SFC resolution to obtain the compound 10 in a chiral medicinal active molecule patent.
And a second route: according to the method, 5-bromo-2-chloro-3-nitropyridine is used as a starting material, 5-bromo-2-ethoxypyridine-3-amine is obtained through sodium ethoxide substitution and zinc powder reduction, sulfonyl-substituted pyridine borate is obtained through bis (pinacol) borate and arylsulfonyl chloride, the sulfonyl-substituted pyridine borate reacts with an alkyl side chain-substituted quinazoline compound, and the compound 27 in the patent is obtained through SFC resolution.
And a third route: in the route, an amide derivative is formed by aminolysis of an alkyl side chain substituted quinazoline compound, then a racemic compound 42 in a patent is obtained by Suzuki coupling and sulfonyl chloride substitution, and finally a chiral compound 42 is obtained by SFC.
The above-described method has the following disadvantages (1) that the route disclosed in WO2019091476A1, the synthesis of the bromoquinazoline fragment proceeds through a four-step reaction, the route is long, and a highly toxic methyl iodide reagent is used. (2) The first route, reported by ACS med.chem.lett, is the same as the claimed route in the basic route, but the racemic final compound is synthesized and then resolved. (3) In the above 5 routes reported in WO2019091476A1 or ACS Med. chem.Lett.2020,11,1463-1469, the chiral compound is obtained by synthesizing the racemic compound of interest and then resolving it by SFC technique, and both documents report that the final chiral compound is obtained in the order of hundreds of milligrams to several grams. The SFC resolution needs a supercritical fluid chromatograph, a specific chromatographic solvent, a specific chiral column and other expensive consumables. The SFC technology has long resolving process time, small batch in single sample injection, time consumption in the resolving process of repeated sample injection in multiple batches and low yield generally. The separation of compounds with high ee values by SFC separation techniques usually requires repeated resolution to increase the ee value, which is usually only suitable for obtaining target compounds in the order of milligrams to grams due to cost and time consuming disadvantages, but is not suitable for industrial mass production.
Disclosure of Invention
The technical problem to be solved by the invention is the defects that the existing method for preparing the quinazolinone compound is low in efficiency and not suitable for industrialization, therefore, the invention provides the method for preparing the quinazolinone compound, and the method is lower in cost, higher in efficiency and capable of realizing large-scale production.
The invention provides a preparation method of a compound 4, which comprises the following steps: in a solvent, organic amine and the compound 3 are subjected to salt forming reaction and then separated to obtain a salt of a compound 4;
the salt of the compound 4 and acid are carried out acidification reaction to obtain the compound 4, and the organic amine is S-sparteine
And/or S-phenylethylamine
In the salt-forming reaction, preferably, the organic amine is S-phenylethylamine.
In the salt formation reaction, the molar ratio of the organic amine to the compound 3 is preferably (0.8-1.5): 1; for example, 1.03: 1.
in the salt formation reaction, the solvent is preferably selected from one or more of ketone solvents, alcohol solvents and nitrile solvents. More preferably, the solvent is a ketone solvent.
In the salt forming reaction, the ketone solvent may be a ketone solvent conventional in the art, and preferably, the ketone solvent is acetone.
In the salt-forming reaction, the alcohol solvent may be an alcohol solvent conventional in the art, such as methanol and/or ethanol, and further such as ethanol.
In the salt-forming reaction, the nitrile solvent may be a nitrile solvent conventional in the art, such as acetonitrile.
In the salification reaction, the volume-to-mass ratio of the solvent to the compound 3 is 10mL/g to 40mL/g, such as 20mL/g, 25mL/g or 30mL/g, preferably 20mL/g to 30 mL/g.
In the present invention, the temperature of the salt-forming reaction may be a reaction temperature conventional in the art, for example, 50 to 60 ℃.
In the present invention, the acidification reaction includes the steps of adding an acid to the aqueous solution of the salt of the compound 4 to precipitate a solid, and collecting the solid to obtain the compound 4.
In the present invention, the acid in the acidification reaction is an acid conventional in the art, such as hydrochloric acid, more preferably 2M hydrochloric acid.
In the present invention, the acidification reaction is preferably carried out by adjusting the pH to dissociate the compound 4 with an acid, for example, to pH 2.
In the present invention, the separation can be conventional in the art, and preferably, the separation comprises the following steps: filtering the reaction liquid obtained by the salt forming reaction, cooling and crystallizing, and recrystallizing to obtain the pure compound 4 salt.
In the invention, preferably, the recrystallization time is 1-4 times; preferably 3 times.
In the invention, the method and conditions for cooling crystallization can be selected by referring to the routine in the field, preferably, the temperature of the reaction liquid obtained by the filtered salt-forming reaction is adjusted to 50-60 ℃, and the temperature is reduced to 28-35 ℃ to precipitate solids, so as to obtain the crude product of the compound 4.
In the cooling crystallization, the cooling is followed by heat preservation, the heat preservation time is related to the scale of recrystallization, and preferably, the amount of the compound 3 used in the salt formation reaction is 280kg, and the heat preservation time is 4 hours.
In the recrystallization, the solvent for recrystallization may be conventional in the art, preferably, for example, a ketone solvent, and further, for example, acetone.
In the recrystallization, the amount of the solvent for recrystallization can be conventional in the art, and preferably, the volume-to-mass ratio of the solvent for recrystallization to the crude product is 10mL/g to 40mL/g, such as 20mL/g, 25mL/g or 30 mL/g.
In the recrystallization, the dissolving temperature of the recrystallization is preferably 50 to 60 ℃.
In the recrystallization, the temperature of the recrystallization is preferably reduced to 25 ℃.
In the invention, the compound 3 can be prepared by the following method: in a solvent, carrying out hydrolysis reaction on the compound 2 and alkali to obtain a compound 3;
in the hydrolysis reaction, the solvent can be conventional in the art, and preferably, the solvent is a mixed solution of an organic solvent and water; more preferably, the organic solvent is tetrahydrofuran; preferably, the solvent is tetrahydrofuran water solution with the mass fraction of 70%.
In the hydrolysis reaction, preferably, the base may be a base conventional in the art, preferably lithium hydroxide, more preferably lithium hydroxide monohydrate.
In the hydrolysis reaction, the amount of the base is the amount conventionally used in the art, and preferably, the mass ratio of the base to the compound 1 is 2.1: 1.
in the hydrolysis reaction, the hydrolysis reaction time is related to the reaction scale, and when the dosage of the compound 1 is 160.7Kg, the reaction time is 1-3 h; preferably 1 h.
In the hydrolysis reaction, the reaction temperature of the hydrolysis reaction is 15-25 ℃.
In the invention, the compound 2 can be prepared by the following method: in a solvent, under the action of alkali and BHT (dibutyl hydroxy toluene), the compound 1 and methyl methacrylate are subjected to addition reaction to obtain the compound 2:
in the addition reaction, the solvent is ester solvent which is conventional in the field, such as ethyl acetate.
In the addition reaction, the base may be a base conventional in the art, such as DBU (1, 8-diazabicycloundecen-7-ene).
In the addition reaction, the amount of the base is the amount which is conventional in the art, and preferably, the molar ratio of the base to the compound 1 is (0.8-1.5): 1, e.g. 0.8: 1.
in the addition reaction, the reaction temperature of the addition reaction is 60-70 ℃.
In the addition reaction, the addition reaction time is related to the reaction scale, and when the using amount of the compound 1 is 187.1Kg, the reaction time is 16 h.
In the addition reaction, the molar ratio of the methyl methacrylate to the compound 1 is (1.5-4.0): 1, e.g. 2: 1.
in the addition reaction, the molar ratio of the BHT to the compound 1 is (0.2-1.0): 1, e.g. 0.7: 1.
in the invention, the compound 1 can be prepared by the following method, which comprises the following steps: in a solvent, 2-amino-5-bromobenzoic acid and formamidine acetate carry out cyclization reaction as shown in the following formula to obtain a compound 1;
in the cyclization reaction, the solvent may be a solvent conventional in the art, and the solvent may be one or more selected from Tetrahydrofuran (THF), ethanol and DMF.
In the cyclization reaction, the solvent is preferably tetrahydrofuran, ethanol or DMF.
In the cyclization reaction, the reaction temperature of the cyclization reaction can be the reaction temperature which is conventional in the field, and the reaction temperature of the cyclization reaction is 60-70 ℃.
In the cyclization reaction, the cyclization reaction time is related to the reaction scale, and when the amount of the 2-amino-5-bromobenzoic acid is 180.0Kg, the reaction time is 16 h.
In the cyclization reaction, the molar ratio of formamidine acetate to 2-amino-5-bromobenzoic acid is preferably (1.5-5.0): 1, e.g. 2.0: 1. 2.5: 1 or 3.0: 1; preferably (2.0-3.0): 1.
the invention also provides a preparation method of the quinazolinone compound shown as the formula I, which comprises the following steps:
(1) in a solvent, organic amine and the compound 3 are subjected to salt forming reaction and then separated to obtain a salt of a compound 4; carrying out an acidification reaction on the salt of the compound 4 and acid to obtain a compound 4, wherein the organic amine is S-sparteine and/or S-phenylethylamine;
(2) subjecting the compound 4 to amidation reaction shown as the following formula to obtain a compound 5, subjecting the compound 5 and the compound 6 to carbon-carbon coupling reaction shown as the following formula to obtain a compound 7, and subjecting the compound 7 and the compound 8 to sulphonation reaction shown as the following formula to prepare a quinazolinone compound shown as a formula I;
in the step (1), the reaction conditions and operations are as described in any of the above.
In the amidation reaction, the amidation reaction conditions are those conventional in the art, and preferably, the amidation reaction comprises the following steps: in a solvent, in the presence of DMF, carrying out esterification reaction on the compound 4 and oxalyl chloride, and then carrying out amidation reaction on the compound and methylamine organic solution to prepare a compound 5.
In the esterification reaction, the solvent may be a solvent conventional in the art, for example, tetrahydrofuran.
In the esterification reaction, the mole ratio of the oxalyl chloride to the compound 4 is (1.1-2.0): 1, e.g. 1.5: 1.
in the esterification reaction, the temperature of adding oxalyl chloride in the esterification reaction is 10-20 ℃.
In the esterification reaction, the reaction temperature of the esterification reaction is a reaction temperature conventional in the art, for example, 20 to 30 ℃.
In the esterification reaction, preferably, the esterification reaction is carried out under the protection of gas; the protective gas is nitrogen.
In the esterification reaction, the methylamine organic solution is a methylamine tetrahydrofuran solution, preferably a 2M methylamine tetrahydrofuran solution.
In the carbon-carbon coupling reaction, the carbon-carbon coupling reaction conditions may be those conventional in the art, and preferably, the carbon-carbon coupling reaction comprises the following steps: and in a solvent, carrying out carbon-carbon coupling reaction on the compound 5 and the compound 6 in the presence of alkali and a catalyst to prepare a compound 7.
In the carbon-carbon coupling reaction, the solvent may be a solvent conventional in the art, such as 1, 4-dioxane.
In the carbon-carbon coupling reaction, the base can be a base conventional in the art, such as potassium acetate; also for example anhydrous potassium acetate.
In the carbon-carbon coupling reaction, the amount of the base is the amount which is conventional in the art, and preferably, the molar ratio of the base to the compound 5 is 3.0: 1.
in the carbon-carbon coupling reaction, the molar ratio of the compound 6 to the compound 5 is (0.8-1.5): 1, e.g. 1.2: 1.
in the carbon-carbon coupling reaction, the catalyst is 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride.
In the carbon-carbon coupling reaction, the molar ratio of the catalyst to the compound 5 is (0.01-0.2): 1, e.g. 0.03: 1.
in the carbon-carbon coupling reaction, the reaction temperature of the carbon-carbon coupling reaction is 85-95 ℃.
In the present invention, the sulphation reaction conditions are conventional sulphation reaction conditions in the art, and preferably, the sulphation reaction comprises the following steps: in a solvent, the compound 7 and the compound 8 are subjected to a sulfation reaction in the presence of alkali to prepare the quinazolinone compound shown in the formula I.
In the sulphonylation reaction, the solvent may be a solvent conventional in the art, such as dichloromethane.
In the sulphonylation reaction, the base may be a base conventional in the art, such as pyridine.
In the sulphation reaction, the amount of the base is the amount of the base which is conventional in the art, for example, the molar ratio of the base to the compound 5 is (2.0-6.0): 1, e.g. 4.6: 1.
in the sulphation reaction, the molar ratio of the compound 8 to the compound 7 is (0.8-1.5): 1, e.g. 1.2: 1.
in the sulfation reaction, the amount of the solvent is the amount of the solvent which is conventional in the art, for example, the mass ratio of the solvent to the compound 7 is 5.3: 1.
in the sulphation reaction, the reaction temperature of the sulphation reaction is 20-25 ℃.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
in the preparation method of the quinazolinone compound shown in the formula I, an SFC resolution technology is not used in the whole process of synthesizing the target molecule, compared with the target compound obtained by the prior art, the target compound is lower in cost, higher in speed and larger in batch at one time, and the quinazolinone compound shown in the formula I is prepared by using an ee value of 99.5%. In addition, the compound 4 preparation method provided by the invention can realize single-step resolution yield of more than 64%. Meanwhile, the ee value of the key fragment compound 4 is continuously improved through repeated recrystallization, the ee value of the finally obtained compound 4 is 99.5%, and the recrystallization operation is commonly used in industrial production, so that the industrial scale-up production of the chiral compound 4 becomes possible.
Drawings
FIG. 1 is a liquid phase diagram of Compound 5;
FIG. 2 is a chiral purity diagram of Compound 5;
FIG. 3 is a diagram showing the effect of peak separation of racemate of Compound 5;
FIG. 4 is a NMR spectrum of a compound of formula I;
FIG. 5 is a chiral purity diagram of a compound of formula I.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The route of the preparation method of the quinazolinone compound shown in the formula I is shown as the following formula:
example 1
The method comprises the following steps:
ethanol (2124.0Kg) was added to a 3000L enamel reactor under vacuum and stirred at room temperature. 2-amino-5-bromobenzoic acid (180.0Kg, 833mol), formamidine acetate (216.0Kg, 2077mol, 2.5eq) were added in sequence. After the addition, the temperature is raised to 80 plus or minus 5 ℃, reflux reaction is carried out, and the reaction is carried out for 16 hours under the condition of heat preservation. After the reaction, the sample was taken and HPLC was controlled to < 2% for 2-amino-5-bromobenzoic acid. The reaction is continued for 4 hours at 80 + -5 deg.C. The temperature of the reaction liquid is reduced to 50 ℃, and the reaction liquid is transferred to a concentration kettle. Concentrating under reduced pressure at 45 + -5 deg.C to remove half of ethanol. The residue was cooled to 25. + -. 5 ℃ and the mixture was filtered through a filter cell. 204.5Kg of wet product of the compound 1 is obtained. Drying at 50 + -5 deg.C for 14 hr to constant weight to obtain 187.1Kg solid with yield of 99.8% and water content of less than 0.5%.
The central control analysis method comprises the following steps: HPLC
The type of the chromatographic column: InertSustain C185 um Specification: 4.6 x 150mm
Flow rate: 1.0000mL/min column temperature: 40 deg.C
Mobile phase: a H 2 O-0.1％H 3 PO 4
Step two:
the 2000L reactor was started and vacuum was applied to draw in ethyl acetate (830.0Kg) and the stirring was turned on. Compound 1(187.1Kg, 831mol), methyl methacrylate (166.5Kg, 1665mol, 2.0eq), DBU (126.0Kg), BHT (1.87Kg, 573mol, 0.7eq) (dibutylhydroxytoluene) were added successively. After the addition, the system is heated to 65 plus or minus 5 ℃ and the reaction is carried out for 16 hours under the condition of heat preservation. After the reaction, sampling, performing HPLC (high performance liquid chromatography) control, reacting until the compound is less than 1% and less than 30%, and cooling the reaction liquid to 25 +/-5 ℃. The reaction solution was poured into a liquid separation pot containing 1M hydrochloric acid. Filtration gave 211.0Kg of compound 2 as a wet product. Blowing and drying at 50 ℃ for 14 hours to obtain 160.7Kg of compound 2 product, 494mol, and the yield is 59.4%.
The central control analysis method comprises the following steps: HPLC (absorption wavelength)
The type of the chromatographic column: InertSustain C185 um Specification: 4.6 x 150mm
Flow rate: 1.0000mL/min column temperature: 40 deg.C
Mobile phase: a H 2 O-0.1％H 3 PO 4
Step three:
tetrahydrofuran (697.0Kg) was added to a 3000L reactor under vacuum with agitation turned on. Water (465.0Kg), Compound 2(160.7Kg, 494mol) was added. The temperature is controlled at 10 +/-5 ℃, and the prepared lithium hydroxide monohydrate aqueous solution (332.8Kg) is added into the reaction liquid dropwise. Reacting at 20 +/-5 ℃ for 1 hour, controlling the compound to be less than 1 percent in HPLC, and adding water (774.0Kg) into the reaction solution for dilution. Extracted three times with ethyl acetate (700 Kg. times.3). Stirred for 10 minutes and kept stand for 20 minutes for liquid separation. Hydrochloric acid (329.0Kg) was added dropwise to the aqueous phase to adjust the pH to about 2, and a large amount of white solid was precipitated. Filtration gave 272.0Kg of the wet product of Compound 3. And (3) drying the wet product in a drying oven at 70 ℃ for 10h in vacuum until the weight is constant, so as to obtain a white solid compound 3: 148.3Kg, 476mol, yield 96.5%.
The central control analysis method comprises the following steps: TLC
The central control analysis method comprises the following steps: HPLC
The type of the chromatographic column: InertSustain C185 um Specification: 4.6 x 150mm
Flow rate: 1.0000mL/min column temperature: 40 deg.C
Mobile phase: a H 2 O-0.1％H 3 PO 4
Step four:
acetone (5529Kg) was added to the kettle and the stirring was started. Compound 3(280.0Kg, 900mol), S-phenethylamine (112.2Kg, 927mol, 1.03eq) was added, completing the addition. Heating to 55 plus or minus 5 ℃, keeping the temperature and stirring for 1 hour, and filtering. Transferring the filtrate to a crystallization kettle, heating to 55 +/-5 ℃, and stirring until the filtrate is clear. Slowly cooling to 28-35 ℃ and preserving the temperature for 4 hours. Centrifuging and filtering to obtain a crude product of the first resolution, and detecting an ee value by using chiral HPLC: 78.4 percent. Acetone (1290.0Kg) was added to the crystallization kettle, the stirring was turned on, and the first crude resolution product was added. Heating to 55 + -5 deg.C, stirring to dissolve, and filtering. The temperature of the filtrate is slowly reduced to 28-35 ℃, and the temperature is kept for 4 hours. Centrifuging and filtering to obtain a second crude product, sampling, and detecting ee value by chiral HPLC (high performance liquid chromatography) to be 97.9%. Adding acetone (1240.0Kg) into the crystallization kettle, starting stirring, adding the crude product of the second resolution, heating to 55 +/-5 ℃, and stirring until the crude product is clear. Slowly cooling to about 25 ℃, and preserving heat for 3 hours. Centrifuging and filtering to obtain a third crude product, sampling chiral HPLC to detect ee value: 99.17 percent. Adding acetone (690.0Kg) into a crystallization kettle, starting stirring, adding the crude product of the third resolution, heating to 55 +/-5 ℃, and stirring until the crude product is clear. Stopping stirring, slowly cooling to about 15-20 ℃, and keeping the temperature for 3 hours. And (4) performing centrifugal filtration to obtain 68.3Kg of crude products of the fourth resolution, and sampling to detect an ee value of 99.63 percent by HPLC. Water (1025Kg) was added to the crystallization kettle, and 68.3Kg of the resulting salt was added. Stirring for 10 min, adding 2M hydrochloric acid dropwise to adjust pH to 2, and precipitating a solid. Filtering, and leaching a filter cake by using water (60.0Kg) to obtain 101.5Kg of a wet product of the compound 4. The wet sample was taken out, and the ee value of compound 4 was 99.5% by chiral HPLC. The wet product is dried for 48 hours at 65 +/-5 ℃ in a drying oven to constant weight, and 48.61Kg of compound 4 white solid and 155mol are obtained, with the yield of 17.4 percent.
The central control analysis method comprises the following steps: chiral HPLC
The type of the chromatographic column: OX-H specification: 4.6 mm 5um
Flow rate: 1.00mL/min column temperature: 35 deg.C
Mobile phase: n-hexane/ethanol/trifluoroacetic acid 92:8:0.1
The gradient method is as follows:
gradient operation for 30min.
Step five:
tetrahydrofuran (553Kg) was added to the 1500L reactor and the stirring was turned on. Compound 4(41.45Kg, 133mol), DMF (0.04Kg) was added. And introducing nitrogen into the reaction kettle for protection after the addition is finished. Oxalyl chloride (25.5Kg, 201mol, 1.5eq) was added dropwise, and the temperature was controlled at 15. + -. 5 ℃. After the addition, the temperature is raised to 25 plus or minus 5 ℃, and the stirring and the heat preservation are carried out for 4 hours. And (4) performing HPLC (HPLC, performing methyl chloride esterification to obtain a medium, and taking a sample of methanol to quench to generate methyl ester) on the methyl ester derivative of which the concentration is less than 5%, and continuously keeping the temperature at 25 +/-5 ℃ for reacting for 4 hours. The reaction solution is decompressed and concentrated at 45 +/-5 ℃ until no liquid is discharged. 2M methylamine in tetrahydrofuran (289.0Kg, 578mol, 4.3eq) was added dropwise over 4 hours. After the addition, the temperature is raised to 25 plus or minus 5 ℃ and the mixture is stirred for 4 hours. The reaction was transferred to a concentration kettle with sampling HPLC with methyl ester derivative < 5%. Water (1105.0Kg), ethyl acetate (540.0Kg) were added. Stirred for 20 minutes and left to stand for 40 minutes. The solution was separated, dried by adding anhydrous sodium sulfate (15.0K g), stirred for 20 minutes, and allowed to stand for 1 hour. Separating the liquid, and concentrating the filtrate to one volume under reduced pressure at 40 +/-5 ℃. Filtering to obtain 47.0Kg of wet product, and vacuum drying at 60 ℃ for 24h to constant weight to obtain 29.8Kg of compound 5 as white solid, 92mol, and 69% yield. As shown in FIG. 1, the liquid phase purity of compound 5 was 99.59%, and the retention time was 12.47 min. As shown in fig. 2, the chiral purity of compound 5 is 99.68%, the retention time is 20.68min, and the mobile phase is n-hexane: ethanol: trifluoroacetic acid 92:8: 0.1. the racemate separation effect of the compound 5 is shown in figure 3, the retention time is 20.95min and 25.24min respectively, and the mobile phase is n-hexane: ethanol: trifluoroacetic acid 92:8:0.1 (the racemate of Compound 5 is from Shanghai Mingkudde New drug development Co., Ltd., Material code LX-00000086-BP-04, batch No. TH 06556-077-P1.) it can be seen from FIGS. 2 and 3 that Compound 5 prepared by the present application has a different individual retention time from its enantiomer.
FIG. 1 Central control analysis method: HPLC
The type of the chromatographic column: InertSustain C185 um Specification: 4.6 x 150mm
Flow rate: 1.0000mL/min column temperature: 40 deg.C
Mobile phase: a H 2 O-0.1％H 3 PO 4
The central control analysis method in fig. 2 and 3: chiral HPLC
The central control analysis method comprises the following steps: chiral HPLC
The type of the chromatographic column: OX-H specification: 4.6 mm 5um
Flow rate: 1.00mL/min column temperature: 35 deg.C
Mobile phase: n-hexane/ethanol/trifluoroacetic acid 92:8:0.1
The gradient method is as follows: gradient operation for 30min.
Step six:
1, 4-dioxane (202.3kg) was added to kettle 1 at 20-25 deg.C and the stirring was started. To kettle 1 was added compound 5(19.6kg, 60mol), purified water (20.0kg), compound 6(18.36kg, 73mol, 1.2eq) and anhydrous potassium acetate (18.1kg, 185mol, 3.0eq) with stirring turned on. To pot 1 was added 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride (1.4kg, 1.9mol, 0.03eq), 1, 4-dioxane (3.5 kg). Heating the system to 85-95 ℃ for reaction, and starting sampling and tracking after 2 hours until the compound 5 is less than or equal to 1.0%. And cooling the system to 20-25 ℃, filtering and concentrating until the residue of the 1, 4-dioxane is less than or equal to 10%, stopping concentrating, and adding purified water (337.5 kg). Ethyl acetate (101.3kg) was added to the system and the organic phases were extracted with stirring twice. The organic phase is concentrated to the remaining 20-40L and filtered. Drying the solid at the temperature of less than or equal to 45 ℃ until the weight is constant, and discharging to obtain an off-white powder compound 7: 14.9Kg, 40mol (98.5% purity, 98.66% content, 66.2% yield).
The reaction and product analysis were followed as in table 1:
TABLE 1
Step seven:
dichloromethane (74.7kg), compound 7(14.1kg, 38mol) was added to kettle 1 at 20-25 deg.C, and the stirring was started. Pyridine (13.9kg, 176mol, 4.6eq) was added to the kettle 1, and then compound 8(9.6kg, 45mol, 1.2eq) was added dropwise at a reference dropping rate of 3-5 kg/h. After finishing the dripping, the system in the kettle 1 reacts at 20-25 ℃, sampling is started after 3 hours, and the compound is tracked until the temperature is less than or equal to 7.5 percent. And cooling the system to 0-5 ℃. Keeping the temperature at 0-5 ℃ and stirring for 1-2 h. The system was filtered with a filter drier. Controlling the temperature T to be less than or equal to 45 ℃ and drying the material until the weight is constant. The solids were weighed into a pharmaceutical grade antistatic plastic bag. Obtaining the quality of a target product: 11.4kg, 21mol total impurities: 0.2%, content: 99.5%, yield: 59.6%, appearance: a white-like powder. The nuclear magnetization of the compound of formula I is shown in FIG. 4. The liquid phase purity of the compound of formula I was 99.5%. The chiral purity of the compound of formula I is shown in figure 5, and the purity is 100%. The compound of formula I has a purity of 100% by LCMS detection; m +1 ═ 544.2).
The analytical methods for the liquid trace reaction of the compounds of formula I are shown in table 2:
TABLE 2
The isomer detection analysis of the product is shown in table 3:
TABLE 3
Example 2, the reaction conditions and operation were the same as in step one of example 1, except that the reaction solvents were DMF and THF, respectively, and the reaction results are shown in table 4:
TABLE 4
| Kind of solvent | Purity of reaction solution | Yield of | Others |
| DMF | 95％ | 92％ | Difficult filtration of material precipitation |
| THF | 85％ | 87％ | Good material particle and easy filtration |
Example 3, the reaction conditions and operation were the same as in step one of example 1, except that, for the formamidine acetate equivalent, the reaction results are shown in table 5:
TABLE 5
Example 4, the reaction conditions and operation and example 1 step four the same, the difference, organic base or solvent type, the reaction results are shown in Table 6:
TABLE 6
Example 5, the reaction conditions and operation were the same as in step four of example 1 except that the solvent volume was different (here, the solvent amount V is the mass ratio of the solvent volume at the time of recrystallization from the reaction to the starting material in mL/g), and the reaction results are as follows:
TABLE 7
| Amount of acetone used | Yield of | ee value |
| 20V | 82％ | 65％ |
| 30V | 70％ | 72％ |
。
Claims (10)
1. A process for the preparation of compound 4, characterized in that it comprises the following steps: in a solvent, organic amine and the compound 3 are subjected to salt forming reaction and then separated to obtain a salt of a compound 4;
carrying out an acidification reaction on the salt of the compound 4 and acid to obtain a compound 4, wherein the organic amine is S-sparteine and/or S-phenylethylamine;
2. the method of claim 1, wherein the organic amine is S-phenylethylamine;
and/or, in the salt forming reaction, the mol ratio of the organic amine to the compound 3 is (0.8-1.5): 1; for example, 1.03: 1;
and/or in the salt forming reaction, the solvent is selected from one or more of ketone solvents, alcohol solvents and nitrile solvents; the ketone solvent is preferably acetone; the alcohol solvent is preferably methanol and/or ethanol, such as ethanol; the nitrile solvent is preferably acetonitrile; preferably, the solvent is a ketone solvent;
and/or, in the salt forming reaction, the volume-to-mass ratio of the solvent to the compound 3 is 10mL/g to 40mL/g, such as 20mL/g, 25mL/g or 30mL/g, preferably 20mL/g to 30 mL/g;
and/or, in the salt-forming reaction, the temperature of the salt-forming reaction is 50-60 ℃;
and/or, in the acidification reaction, the hydrochloric acid, such as 2M hydrochloric acid;
and/or, in the acidification reaction, the pH is adjusted to dissociate compound 4 with an acid, e.g. to 2;
and/or the acidification reaction comprises the following steps of adding acid into the aqueous solution of the salt of the compound 4, precipitating solid, and collecting the solid to obtain the compound 4.
3. A process for the preparation of compound 4 according to claim 1, wherein said isolation comprises the steps of: filtering the reaction liquid obtained by the salt forming reaction, cooling and crystallizing, and recrystallizing to obtain the pure compound 4 salt.
4. The method for preparing compound 4 according to claim 3, wherein the temperature-reduced crystallization further comprises an incubation, the incubation time is related to the scale of recrystallization, preferably, the amount of compound 3 used in the salt-forming reaction is 280kg, and the incubation time is 4 h;
and/or the recrystallization time is 1-4; preferably 3 times;
and/or, in the recrystallization, the solvent for recrystallization is a ketone solvent, such as acetone;
and/or the volume-to-mass ratio of the recrystallized solvent to the crude product is 10mL/g to 40mL/g, such as 20mL/g, 25mL/g, or 30 mL/g;
and/or the dissolving temperature of recrystallization is 50-60 ℃;
and/or, the temperature of recrystallization is reduced to 25 ℃;
and/or, the method and the condition for cooling crystallization are that the temperature of reaction liquid obtained by the filtered salt forming reaction is adjusted to 50-60 ℃, and the temperature is reduced to 28-35 ℃ to precipitate solid, so as to obtain the crude product of the compound 4.
5. The process for the preparation of compound 4 according to any one of claims 1 to 4, wherein compound 3 is prepared by: in a solvent, carrying out hydrolysis reaction on the compound 2 and alkali to obtain a compound 3;
preferably, in the hydrolysis reaction, the solvent is a mixed solution of an organic solvent and water; more preferably, the organic solvent is tetrahydrofuran; preferably, the solvent is tetrahydrofuran water solution with the mass fraction of 70%;
preferably, in the hydrolysis reaction, the alkali is lithium hydroxide, preferably lithium hydroxide monohydrate;
preferably, in the hydrolysis reaction, the mass ratio of the base to the compound 1 is 2.1: 1;
preferably, in the hydrolysis reaction, when the amount of the compound 1 is 160.7Kg, the reaction time is 1-3 h; preferably 1 h;
preferably, in the hydrolysis reaction, the reaction temperature of the hydrolysis reaction is 15-25 ℃.
6. The method of claim 5, wherein compound 2 is prepared by: in a solvent, under the action of alkali and BHT, performing addition reaction on the compound 1 and methyl methacrylate to obtain a compound 2:
preferably, in the addition reaction, the solvent is ethyl acetate;
preferably, in the addition reaction, the base is DBU;
preferably, in the addition reaction, the molar ratio of the base to the compound 1 is (0.8-1.5): 1, e.g. 0.8: 1;
preferably, in the addition reaction, the reaction temperature of the addition reaction is 60-70 ℃;
preferably, in the addition reaction, when the amount of the compound 1 is 187.1Kg, the reaction time is 16 h;
preferably, in the addition reaction, the molar ratio of the methyl methacrylate to the compound 1 is (1.5-4.0): 1, e.g. 2: 1;
preferably, in the addition reaction, the molar ratio of the BHT to the compound 1 is (0.2-1.0): 1, e.g. 0.7: 1.
7. the process for preparing compound 4 according to claim 6, wherein compound 1 is prepared by the following process comprising the steps of: in a solvent, 2-amino-5-bromobenzoic acid and formamidine acetate are subjected to cyclization reaction as shown in the following formula to obtain a compound 1;
preferably, in the cyclization reaction, the solvent is one or more selected from tetrahydrofuran, ethanol and DMF; more preferably, in the cyclization reaction, the solvent is tetrahydrofuran, ethanol or DMF;
preferably, in the cyclization reaction, the reaction temperature of the cyclization reaction is 60-70 ℃;
preferably, in the cyclization reaction, when the using amount of the 2-amino-5-bromobenzoic acid is 180.0Kg, the reaction time is 16 h;
preferably, in said cyclization, the molar ratio of formamidine acetate to 2-amino-5-bromobenzoic acid is (1.5-5.0): 1, e.g. 2.0: 1. 2.5: 1 or 3.0: 1; preferably (2.0-3.0): 1.
8. a preparation method of quinazolinone compounds shown in formula I is characterized by comprising the following steps:
(1) in a solvent, organic amine and the compound 3 are subjected to salt forming reaction and then separated to obtain a salt of a compound 4; carrying out an acidification reaction on the salt of the compound 4 and acid to obtain a compound 4, wherein the organic amine is S-sparteine and/or S-phenylethylamine;
(2) subjecting the compound 4 to amidation reaction shown as the following formula to obtain a compound 5, subjecting the compound 5 and the compound 6 to carbon-carbon coupling reaction shown as the following formula to obtain a compound 7, and subjecting the compound 7 and the compound 8 to sulphonation reaction shown as the following formula to prepare a quinazolinone compound shown as a formula I;
in step (1), the reaction conditions and operations are as defined in any one of claims 1 to 7.
9. The method for preparing quinazolinone compounds of formula I according to claim 8, wherein said amidation reaction comprises the following steps: in a solvent, in the presence of DMF, carrying out esterification reaction on the compound 4 and oxalyl chloride, and then carrying out amidation reaction on the compound and methylamine organic solution to prepare a compound 5;
the carbon-carbon coupling reaction comprises the following steps: in a solvent, carrying out carbon-carbon coupling reaction on the compound 5 and the compound 6 in the presence of alkali and a catalyst to prepare a compound 7;
the sulphation reaction comprises the following steps: in a solvent, the compound 7 and the compound 8 are subjected to a sulfation reaction in the presence of alkali to prepare the quinazolinone compound shown in the formula I.
10. The method for preparing quinazolinone compounds of formula I according to claim 9, wherein in the esterification reaction, the solvent is tetrahydrofuran;
and/or, in the esterification reaction, the mole ratio of the oxalyl chloride to the compound 4 is (1.1-2.0): 1, e.g. 1.5: 1;
and/or, in the esterification reaction, the temperature of adding oxalyl chloride in the esterification reaction is 10-20 ℃;
and/or in the esterification reaction, the reaction temperature of the esterification reaction is 20-30 ℃;
and/or, in the esterification reaction, the esterification reaction is carried out under the protection of gas; preferably, the protective gas is nitrogen;
and/or in the esterification reaction, the methylamine organic solution is a methylamine tetrahydrofuran solution, preferably a 2M methylamine tetrahydrofuran solution;
and/or, in the carbon-carbon coupling reaction, the solvent is 1, 4-dioxane;
and/or, in the carbon-carbon coupling reaction, the alkali is potassium acetate; such as anhydrous potassium acetate;
and/or, in the carbon-carbon coupling reaction, the molar ratio of the alkali to the compound 5 is 3.0: 1;
and/or, in the carbon-carbon coupling reaction, the molar ratio of the compound 6 to the compound 5 is (0.8-1.5): 1, e.g. 1.2: 1;
and/or in the carbon-carbon coupling reaction, the catalyst is 1, 1-bis (diphenylphosphino) ferrocene palladium dichloride;
and/or, in the carbon-carbon coupling reaction, the molar ratio of the catalyst to the compound 5 is (0.01-0.2): 1, e.g. 0.03: 1;
and/or in the carbon-carbon coupling reaction, the reaction temperature of the carbon-carbon coupling reaction is 85-95 ℃;
and/or in the sulphation reaction, the solvent is dichloromethane;
and/or, in the sulphation reaction, the alkali is pyridine;
and/or, in the sulphation reaction, the molar ratio of the base to the compound 5 is (2.0-6.0): 1, e.g. 4.6: 1;
and/or, in the sulphation reaction, the molar ratio of the compound 8 to the compound 7 is (0.8-1.5): 1, e.g. 1.2: 1;
and/or in the sulphation reaction, the mass ratio of the solvent to the compound 7 is 5.3: 1;
and/or in the sulphation reaction, the reaction temperature of the sulphation reaction is 20-25 ℃.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2021100741263 | 2021-01-20 | ||
| CN202110074126 | 2021-01-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114805220A true CN114805220A (en) | 2022-07-29 |
Family
ID=82527966
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210058949.1A Pending CN114805220A (en) | 2021-01-20 | 2022-01-17 | Preparation method of quinazolinone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114805220A (en) |
-
2022
- 2022-01-17 CN CN202210058949.1A patent/CN114805220A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| CN109867673B (en) | Method for synthesizing palbociclib | |
| CN113214320A (en) | Preparation method of Reidesciclovir compound | |
| CN114957101A (en) | Synthesis method of 3-aryl substituted dipiperidinone and nilapali | |
| CN112679498B (en) | Quaternary ammonium sulfonate compound and preparation method and application thereof | |
| CN110183445A (en) | The synthetic method of Moxifloxacin and its derivative | |
| CN107674062B (en) | Anti-hepatitis C drug intermediate, preparation method and application | |
| CN113416150A (en) | Novel synthesis method of lobaplatin intermediate | |
| CN112778303A (en) | Preparation method of CDK4/6 kinase inhibitor SHR6390 | |
| CN111675653A (en) | Preparation method and application of impurities of 4-aminoquinoline compound | |
| CN116120393A (en) | Oxidized glutathione and preparation method of crystal forms and impurities thereof | |
| CN111349045A (en) | Synthetic method of lenvatinib and novel intermediate | |
| CN114805220A (en) | Preparation method of quinazolinone compound | |
| CN115960059A (en) | Method for synthesizing furosemide impurity D with high yield and high purity | |
| CN111072660A (en) | Simple preparation method of rilibatan | |
| CN115697968B (en) | Preparation method of (S) -2-amino-3- (4- (2, 3-dimethylpyridine-4-yl) phenylpropionic acid methyl ester and salt thereof | |
| CN107868033B (en) | Preparation method of phenylalanine compound | |
| CN113072514B (en) | Preparation method of Xuanjinning and intermediate thereof | |
| WO2006009374A1 (en) | Process for preparing levofloxacin or its hydrate | |
| EP3356372B1 (en) | Novel process for preparing thienopyrimidine compound and intermediates used therein | |
| CN113354551A (en) | Preparation method of amide compound | |
| CN111440173B (en) | Preparation method of PI3K inhibitor | |
| CN105017287B (en) | A kind of preparation method of cephamycin intermediate | |
| CN110818676A (en) | Crystal form of cyclohexane derivative | |
| CN111808040B (en) | Synthesis method of multi-configuration 2-oxo-oxazolidine-4-carboxylic acid compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |