CN113402466A - Apaglucone intermediate and method for preparing apalone - Google Patents
Apaglucone intermediate and method for preparing apalone Download PDFInfo
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Abstract
The invention relates to an apaluridine intermediate and a method for preparing apaluridine, which adopts a compound shown as a formula (4)
The intermediate is used for preparing the apaluramine, in the formula (4), R is-COOR1Or CONH2，R1Is alkyl or aryl. The compound shown as the formula (4) is a compound shown as a formula (3)
Reacting with acylating reagent to generate acyl chloride
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to an apaluridine intermediate and a method for preparing apaluridine.
Background
Apaluamide (apaluamide) is an Androgen Receptor (AR) inhibitor developed by the university of california, usa, which was licensed to Aragon pharmaceutical in 2009. In month 2 2018, apalutamine was approved by the U.S. FDA for marketing for the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC), and was marketed in china in 2019.
Wherein the chemical name is 4- (7- (6-cyano-5- (trifluoromethyl) pyridine-3-yl) -8-oxo-6-sulfo-5, 7-diazaspiro [3.4] -octane-5-yl) -2-fluoro-N-methylbenzoyl, and the chemical structure is shown as the following structural formula:
the existing methods for synthesizing the apaluramine mainly comprise the following steps:
(1) document WO2007126765a2 first reports that compound 1 as a starting material is condensed with cyclobutanone and sodium cyanide to produce benzamide intermediate 2; reacting a compound 3 serving as a raw material with thiophosgene to obtain a thioisocyano pyridine intermediate 4; and finally preparing the apaluramine from the two intermediates under the microwave promotion. The route needs to use sodium cyanide and thiophosgene under acidic conditions, and the final cyclization reaction adopts microwaves, so that the industrial production is difficult.
(2) PCT patent WO2016100645 simplifies a new synthesis method of apaluramine, and utilizes a cyclobutanamide intermediate 2 obtained by a Strecker reaction of 3-fluoro-4-iodoaniline, cyclobutanone and cyanide and a 2-cyano-3-trifluoromethyl-5-aminopyridine compound 3 for condensation cyclization under the action of a thiocarbonyl compound, then completes a carbonyl insertion reaction under the catalysis of noble metal palladium to obtain a carboxylic ester intermediate or reacts with dry ice after Grignard exchange to obtain a carboxylic acid intermediate, and finally amidates to obtain the final product of apaluramine. Although the route has shorter steps, the cost of the palladium-catalyzed carbonyl insertion reaction or Grignard exchange reaction route is higher, the process production experimental conditions are harsher, and the method is not suitable for industrial production to synthesize the apaluramine.
(3) In patent CN104211683A, TMSCN is used to replace NaCN, so that the use of a highly toxic reagent is avoided, but in the final condensation reaction, the highly toxic reagent thiophosgene one-pot method is used to synthesize apaluramine, and the process production experimental conditions are harsh, and the method is not suitable for industrial production.
(4) In patent CN108383747A, N-methyl-2-fluoro-4-halo-benzamide compound 1 and cyclobutine hydrochloride 2 are used as starting materials to perform Ullman reaction under the catalysis of copper salt to obtain intermediate compound 3, the intermediate compound 3 is esterified to obtain intermediate compound 4, then the intermediate compound reacts with thiocyanide salt in the presence of alkali to cyclize to obtain compound 5, and then the intermediate compound and compound 6 are coupled and condensed in the presence of catalyst and alkali to obtain apaluramine, and the process route is as follows:
compared with other methods, the method adopts 1-aminocyclobutanecarboxylic acid hydrochloride as a raw material, has better crystallinity and stability, and avoids using virulent sodium cyanide in the original route. However, in the process of preparing the intermediate 5 from the intermediate 3, after the intermediate 4 is prepared from the intermediate 3, the intermediate 4 is separated and purified, so that the process is complicated, the reaction process for preparing the intermediate 5 from the intermediate 4 has poor stability and poor process repeatability, and the price of the N-methyl-2-fluoro-4-halo-benzamide compound 1 adopted in the reaction is high, so that the cost of the apaluramine is high. Therefore, this method is practically unsuitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of apaluramine suitable for industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
a compound represented by the formula (4),
in the formula (4), R is-COOR1Or CONH2，R1Is alkyl or aryl.
According to some embodiments of the invention, the R is1Selected from C1-C10 alkyl and C6-C18 aryl.
Preferably, said R is1Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, tolyl. More preferably, said R1Selected from methyl and ethyl.
The second technical scheme adopted by the invention is as follows: a process for producing a compound represented by the above formula (4), which comprises first reacting a compound represented by the above formula (3)
Acylation reaction is carried out with acylation reagent to generate acyl chloride
And (3) carrying out cyclization reaction on the acyl chloride and thiocyanide to generate the compound shown in the formula (4).
R in the formula (3)1Definition of (1)R in the same formula (4)1The definition of (1).
According to some embodiments of the invention, the thiocyanide is a combination of one or more of potassium thiocyanate, sodium thiocyanate, ammonium thiocyanate.
According to some embodiments of the invention, the acylating agent is one or a combination of more of thionyl chloride, oxalyl chloride.
In some embodiments, the compound represented by formula (3), the acylating agent and the thiocyanide are fed in a molar ratio of 1: 1.5-2.5: 2.5-3.5.
According to some embodiments of the invention, the acylation reaction is carried out in the presence of a solvent and under the protection of an inert gas at a temperature of 15-35 ℃; and/or the cyclization reaction is carried out at the temperature of 40-60 ℃ in the presence of a solvent and under the protection of inert gas. Preferably, the inert gas is nitrogen.
In some preferred and specific embodiments, in the step of generating the compound represented by formula (4), the compound represented by formula (3) is mixed with a solvent, the acylating agent is added dropwise under the protection of inert nitrogen gas, the temperature is controlled to cause the acylation reaction, then the thiocyanide compound is added, and the temperature is controlled to cause the cyclization reaction, wherein the temperature for performing the acylation reaction is controlled to be 15-35 ℃, and the temperature for performing the cyclization reaction is controlled to be 40-60 ℃.
Further, the solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile, tetrahydrofuran, toluene and 1, 4-dioxane.
In some preferred and specific embodiments, the method for preparing the compound represented by the formula (4) further comprises a step of post-treating the reaction solution after the reaction is finished, wherein the post-treatment comprises: filtering the reaction solution after the cyclization reaction is finished, concentrating the filtrate, adding a mixed solution of methanol and water, crystallizing, filtering, and drying to obtain the compound shown in the formula (4).
In some preferred and specific embodiments, the preparation method further comprises preparingA step of preparing a compound represented by the following formula (3): comprising reacting a compound represented by the formula (1)
And a compound represented by the formula (2)
Reacting in the presence of a catalyst and a base to generate the compound shown in the formula (3), wherein in the formula (1), X is halogen.
R in the formula (1) is as defined for R in the formula (4).
According to some embodiments of the invention, the X is F, Cl, Br or I. Preferably, the X is Br or Cl.
According to some embodiments of the present invention, in the step of preparing the compound represented by formula (3), the catalyst includes, but is not limited to, a chloride ion type compound of copper, preferably one or more of cuprous chloride, cuprous bromide, and cuprous iodide.
According to some embodiments of the present invention, in the step of preparing the compound represented by formula (3), the base used is not limited, and may be an organic base or an inorganic base, preferably, the base is one or more of triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate, and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
In some embodiments, the feeding molar ratio of the compound represented by the formula (1) to the compound represented by the formula (2) is 1: 1-1.5.
In some embodiments, the compound of formula (1), the catalyst, and the base are fed in a molar ratio of 1: 0.1-0.5: 2-3.
According to some embodiments of the present invention, in the step of preparing the compound represented by formula (3), the reaction is performed at 90 to 120 ℃ in the presence of an inert gas blanket and a solvent. Preferably, the inert gas is nitrogen.
According to some embodiments of the invention, in the step of preparing the compound represented by formula (3), the solvent is one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and dimethylsulfoxide.
The third technical scheme adopted by the invention is as follows: the application of the compound shown in the formula (4) in preparing the apaluridine.
The fourth technical scheme adopted by the invention is as follows: a process for producing a compound represented by the formula (6),
the preparation method comprises the steps of enabling the compound shown as the formula (4) and the compound shown as the formula (5) to react
A step of reacting in the presence of a catalyst and a base to produce the compound represented by the formula (6).
R in the formula (6) is as defined for R in the formula (4).
According to some embodiments of the present invention, in the step of generating the compound represented by formula (6), the catalyst includes, but is not limited to, a chloride ion type compound of copper, preferably one or more of cuprous chloride, cuprous bromide, and cuprous iodide.
According to some embodiments of the present invention, in the step of generating the compound represented by formula (6), the base used is not limited, and may be an organic base or an inorganic base, preferably, the base is one or more of triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate, and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).
According to some embodiments of the present invention, in the step of producing the compound represented by formula (6), the reaction is performed at a temperature of 70 to 100 ℃ in the presence of a solvent.
In some preferred and specific embodiments, in the step of generating the compound represented by formula (6), the reaction is further carried out in the presence of a catalyst promoter which is one or more of proline, N-dimethylglycine, 2-acetylcyclohexanone, N1, N2-bis (2, 6-dimethylphenyl) oxamide, N1, N2-bis (2-methylnaphthalen-1-yl) oxamide, N1, N2-bis (4-hydroxy-2, 6-dimethylphenyl) oxamide, N1-benzyl-N2- (2, 6-dimethylphenyl) oxamide, N1-benzyl-N2- (2-methylnaphthalen-1-yl) oxamide.
In some preferred and specific embodiments, the preparation method of the compound represented by the formula (6) comprises adding the compound represented by the formula (4), the compound represented by the formula (5), a solvent, a catalytic promoter, a base and a catalyst into a reaction kettle under the protection of nitrogen, and carrying out a reaction at 70-100 ℃ to generate the compound represented by the formula (6).
In some embodiments, the feeding molar ratio of the compound represented by the formula (4) to the compound represented by the formula (5) is 1: 0.5-1.5.
In some embodiments, the compound of formula (4), the catalyst, and the base are fed in a molar ratio of 1: 0.1-0.5: 2-3.
Preferably, the preparation method of the compound represented by the formula (6) further comprises a post-treatment step, wherein the post-treatment step is specifically implemented by adding a mixed solution of water and ethyl acetate into the reaction solution, standing for layering, washing the organic phase with saturated saline solution, layering, collecting the organic phase, concentrating, adding a mixed solution of methanol and water, crystallizing, filtering and drying to obtain the compound represented by the formula (6).
The fifth technical scheme adopted by the invention is as follows: a preparation method of apaluramine comprises the following steps:
s1: the compound shown in the formula (6) is prepared by the preparation method; and
s2: preparing the apaluramine from the compound shown in the formula (6).
According to some embodiments of the invention, in formula (6), R is-COOR1And step S2, reacting the compound shown in the formula (6) with methylamine at 20-30 ℃ to obtain the apaluramine.
In some embodiments, the feeding molar ratio of the compound shown in the formula (6) to methylamine is 1: 15-25.
According toIn still other embodiments of the present invention, formula (6), wherein R is CONH2In step S2, the compound represented by the formula (6) is reacted with N, N-dimethylformamide dimethyl acetal (DMF-DMA) in the presence of an alcohol to form an ester
And reacting the ester with methylamine at 20-30 ℃ to generate the apaluramine.
In some embodiments, the compound of formula (6) is fed to the N, N-dimethylformamide dimethyl acetal in a molar ratio of 1: 2.5 to 3.5.
The feeding molar ratio of the ester to the methylamine is 1: 15-25.
In the present invention, in the formula (6), R is-COOR1The yield of the synthetic route of the compound shown in the formula (6) is higher, and the yield of the whole synthetic route of the apaluramine is also higher.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the novel compound shown in the formula (4) is used as an intermediate to synthesize the apaluramine, a brand new process route for synthesizing the apaluramine is developed, and the process route is good in stability and repeatability and very suitable for industrial production.
The method for preparing the apalutam has high product purity, the yield can be obviously improved compared with the prior art, and simultaneously, no toxic substance is required to be adopted, and no expensive noble metal catalyst is required to be used, so that the method is obviously more suitable for industrial production compared with the prior art.
Detailed Description
The compound shown in the formula (1) and the compound shown in the formula (2) are subjected to coupling reaction under the action of a catalyst and alkali to generate the compound shown in the formula (3), so that highly toxic substances such as cyanide and the like are avoided, and the process operation is simple and convenient. Furthermore, the compound shown in the formula (3) reacts with an acylation reagent to generate acyl chloride, and then the acyl chloride reacts with thiocyanide to generate the compound shown in the formula (4), so that the method has the advantages of simple route, good stability of process route, good repeatability and high yield. Further, the compound shown in the formula (4) and the compound shown in the formula (5) are subjected to coupling reaction under the action of alkali and a catalyst to generate a compound shown in the formula (6), the compound shown in the formula (6) is reacted with methylamine to obtain the apaluramine, or the compound shown in the formula (6) is reacted with DMF-DMA in the presence of alcohol to generate an ester, and the ester is reacted with methylamine to obtain the apaluramine. The whole process route of the apaluamide has good stability and repeatability, is suitable for industrial production, adopts low-price raw materials, is simple and convenient to operate, greatly reduces the synthesis cost, and is as follows:
the invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications may be made by those skilled in the art after reading the disclosure of the present invention, and such equivalents may fall within the scope of the invention as defined by the appended claims.
Example 1
This example provides a method for the preparation of compound 3 a:
10g (43mmol) of 2-fluoro-4-bromo-methyl benzoate compound 1a, 5.99g (52mmol) of cyclobutylic acid and 50g of dimethyl sulfoxide are added into a three-neck flask, 1.64g (8.6mmol) of cuprous iodide and 15.1g (99mmol) of DBU are added under the protection of nitrogen, and after uniform stirring, the mixture is heated to 95-100 ℃ for reaction for 4 hours. And after the reaction is finished, adding 50mL of water and 50g of ethyl acetate, stirring and separating, adjusting the pH of the water phase to 2-3 by using hydrochloric acid, separating out a large amount of solids, filtering, and drying a filter cake to obtain a compound 3a, wherein the yield is 80%, and the purity is 97.78%.
Of Compound 3a1H-NMR(DMSO，400MHz):δppm12.70(s，1H)，7.61-7.65(t，1H)，7.51(s，1H)，6.25-6.27(d，1H)，6.01-6.04(d，1H)，3.74(s，3H)，2.59-2.65(m，2H)，2.16-2.21(t，2H)，1.95-2.01(m，2H)，m/z[M-1]-：266.2。
Example 2
This example provides a method for the preparation of compound 4 a:
10g (37.4mmol) of the compound 3a obtained in example 1 and 50g of THF are added into a three-neck flask, stirred uniformly, protected by nitrogen, 8.9g (74.8mmol) of thionyl chloride is added dropwise at room temperature, and the reaction is continued for 4.5h after the dropwise addition. 8.5g (112.3mmol) of ammonium thiocyanate are added in batches, and after the addition is finished, the temperature is raised to 40-50 ℃ for continuous reaction for 3 hours. After the reaction is finished, filtering, concentrating and drying the filtrate, adding 50g of methanol and 150g of water, crystallizing, filtering, and drying a filter cake to obtain the compound 4a with the yield of 85% and the purity of 99.19%.
Of Compound 4a1H-NMR(DMSO，400MHz):δppm12.28(s，1H)，8.03-8.07(t，1H)，7.54-7.57(m，1H)，7.37-7.40(m，1H)，3.90(s，3H)，2.35-2.46(m，2H)，2.27-2.33(m，2H)，1.87-1.99(m，1H)，1.47-1.54(m，1H)。m/z[M-1]-：307.1。
Example 3
This example provides a method for the preparation of compound 6 a:
10g (32mmol) of the intermediate 4a obtained in example 2, 9.6g (38mmol) of 5-bromo-2-cyano-3-trifluoromethylpyridine and 50g of dimethyl sulfoxide were charged into a three-necked flask, 1.2g (6.4mmol) of cuprous iodide, 9.8g (64mmol) of DBU and 2g (6.4mmol) of N1-benzyl-N2- (2-methylnaphthalen-1-yl) oxamide were added under nitrogen protection, and after stirring, the mixture was heated to 80 to 90 ℃ to react for 6 hours. After the reaction, 50mL of water and 50g of ethyl acetate are added, stirring and liquid separation are carried out, the organic phase is washed twice by saturated saline solution, standing and liquid separation are carried out, the organic phase is collected and concentrated to be dry, 50g of methanol and 150g of water are added, crystallization, filtration and filter cake drying are carried out, and the compound 6a is obtained, the yield is 80 percent, and the purity is 98.2 percent.
Of Compound 6a1H-NMR(DMSO，400MHz):δppm9.22(d，1H)，8.75(d，1H)，8.12-8.16(t，1H)，7.54-7.57(m，1H)，7.45-7.48(t，1H)，3.91(s，3H)，2.63-2.68(m，2H)，2.47-2.52(t，2H)，1.96-1.99(d，1H)，1.59-1.61(d，1H)。m/z[M+1]+：479.3。
Example 4
This example provides a method for the preparation of compound 3 b:
10g (46mmol) of 2-fluoro-4-bromo-benzamide 1b, 6.4g (55mmol) of cyclobutylic acid and 50g of dimethyl sulfoxide are added into a three-neck flask, 1.6g (9.2mmol) of cuprous iodide, 1.29g (9.2mmol) of 2-acetyl cyclohexanone and 16.2g (110mmol) of DBU are added under the protection of nitrogen, and after uniform stirring, the mixture is heated to 95-100 ℃ for reaction for 14 h. And after the reaction is finished, adding 50mL of water and 50g of ethyl acetate, stirring, separating liquid, collecting a water phase, filtering, adjusting the pH of the filtrate to 2-3 by using hydrochloric acid, separating out a large amount of solid, filtering, and drying a filter cake to obtain a compound 3b, wherein the yield is 80%, and the purity is 99.03%.
Of Compound 3b1H-NMR(DMSO，400MHz):δppm12.62(s，1H)，7.49-7.54(t，1H)，7.51(s，1H)，7.20-7.23(d，2H)，7.08(s，1H)，6.23-6.25(d，1H)，5.98-6.02(d，1H)，2.55-2.60(m，2H)，2.12-2.16(t，2H)，1.94-1.99(m，2H)。m/z[M-1]-：251.2。
Example 5
This example provides a method for the preparation of compound 4 b:
10g (37.4mmol) of the intermediate 3b prepared in the example 4 and 50g of THF are added into a three-neck flask, stirred uniformly, protected by nitrogen, 9.4g (79.3mmol) of thionyl chloride is added dropwise at room temperature, and the reaction is continued for 4-5 h after the addition of the thionyl chloride is finished. Adding 9.1g (118.9mmol) of ammonium thiocyanate in batches, heating to 40-50 ℃ after adding, and continuing to react for 2-4 h. After the reaction is finished, filtering, concentrating and drying the filtrate, adding 50g of methanol and 150g of water, crystallizing, filtering, and drying a filter cake to obtain the compound 4b with the yield of 85% and the purity of 98.87%.
Of Compound 4b1H-NMR(DMSO，400MHz):δppm12.24(s，1H)，7.91(s，1H)，7.56-7.80(m，2H)，7.44-7.47(m，1H)，7.29-7.31(m，1H)，2.40-2.46(m，2H)，2.26-2.34(m，2H)，1.90-1.95(t，1H)，1.48-1.51(m，1H)。m/z[M-1]-：292.1。
Example 6
This example provides a method for the preparation of compound 6 b:
10g (34mmol) of the intermediate 4b prepared in example 5, 10g (20mmol) of 5-bromo-2-cyano-3-trifluoromethylpyridine and 50g of dimethyl sulfoxide were charged into a three-necked flask, 1.3g (6.8mmol) of cuprous iodide, 9.8g (64mmol) of DBU and 2.2g (6.8mmol) of N1-benzyl-N2- (2-methylnaphthalen-1-yl) oxamide were added under nitrogen protection, and after stirring, the mixture was heated to 90 to 100 ℃ for reaction for 6 hours. After the reaction is finished, 50mL of water and 50g of ethyl acetate are added, stirring and standing for liquid separation are carried out, the organic phase is washed twice by saturated saline solution and is layered, the organic phase is collected and concentrated to be dried, 50g of methanol and 150g of water are added, crystallization, filtration and filter cake drying are carried out, and the compound 6b is obtained, the yield is 80 percent and the purity is 97.92 percent.
Of Compound 6b1H-NMR(DMSO，400MHz):δppm9.11(d，1H)，8.37-8.41(m，2H)，7.28-7.33(m，1H)，7.22-7.25(t，1H)，6.69-6.72(d，1H)，6.04(s，1H)，2.73-2.80(m，2H)，2.52-2.63(m，2H)，1.73-1.80(m，1H)，1.26-1.29(t，1H)。m/z[M+1]+：464.3。
Example 7
This example provides a method for the preparation of compound 6 a:
18g (38.8mmol) of the intermediate 6b obtained in example 6 and 276g of methanol were added to a three-necked flask at room temperature, stirred and heated to reflux, and 13.9g (117mmol) of DMF-DMA was added dropwise thereto, and after completion of the addition, the mixture was refluxed for 2.5 hours. After the reaction, the reaction solution was concentrated to remove most of the solvent, 20g of methanol and 60g of water were added, crystallization, filtration, and the filter cake was dried to obtain compound 6a with a yield of 80% and a purity of 98.32%.
Of Compound 6a1H-NMR(DMSO，400MHz):δppm9.22(d，1H)，8.75(d，1H)，8.12-8.16(t，1H)，7.54-7.57(m，1H)，7.45-7.48(t，1H)，3.91(s，3H)，2.63-2.68(m，2H)，2.47-2.52(t，2H)，1.96-1.99(d，1H)，1.59-1.61(d，1H)。m/z[M+1]+：479.3。
Example 8
This example provides a process for the preparation of apaluramine:
a three-necked flask was charged with 3g (6.3mmol) of the intermediate 6a obtained in example 7 and 12mL of 40% aqueous methylamine solution at room temperature, and the reaction mixture was stirred at 20 to 30 ℃ for 1 hour. After the reaction is finished, concentrating the reaction liquid to remove most of the solvent, adding 15g of methanol and 45g of water, crystallizing, filtering, and drying a filter cake to obtain the apaluramine with the yield of 90% and the purity of 99.38%.
Process for preparation of apaluramine1H-NMR(DMSO，400MHz):δppm9.22(d，1H)，8.75-8.76(d，1H)，8.48-8.49(d，1H)，7.82-7.86(t，1H)，7.46-7.49(m，1H)，7.38-7.40(m，1H)，2.81-2.83(d，3H)，2.63-2.69(m，2H)，2.46-2.54(m，2H)，1.98-2.00(d，1H)，1.58-1.61(d，1H)。m/z[M+1]+：478.3。
Comparative example 1
This comparative example provides a process for the preparation of compound 4a, which is carried out essentially under the conditions of examples 2 and 3 in patent CN108383747A, with the difference that compound 3a prepared in example 2 of the present application is used instead of compound 3 in patent CN108383747A, with the specific steps:
the method comprises the following steps: adding the compound 3a (100mmol) prepared in example 2 and methanol (133mL) into a three-neck flask, uniformly stirring, slowly adding thionyl chloride (150mmol), heating to 40-45 ℃ for reaction for 7 hours, removing part of methanol after the reaction is finished, slowly adding water (266mL), pulping, filtering, pulping a crude product by using a mixed solvent of methanol and petroleum ether, filtering and drying to obtain a compound with the following structural formula (yield is 90%)
Step two: and (3) uniformly stirring the compound (100mmol) prepared in the step one and having the structural formula and 75% methanol (280mL), adding potassium thiocyanate (120mmol) and diisopropylethylamine (200mmol), and after the addition, carrying out reflux reaction for 7 h. As a result of the control during sampling, the target compound 4a was not produced, and a large amount of the starting material remained, and mainly hydrolyzed impurity 3a was produced.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Claims (12)
1. A compound represented by the formula (4),
in the formula (4), R is-COOR1Or CONH2，R1Is alkyl or aryl.
2. The compound of formula (4) according to claim 1, wherein: the R is1Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, tolyl.
3. A process for producing a compound represented by the formula (4) as claimed in claim 1 or 2, characterized in that: the preparation method comprises the steps of firstly leading the compound shown as the formula (3)
Acylation reaction is carried out with acylation reagent to generate acyl chloride
The step of cyclizing the acyl chloride and the thiocyanide to generate the compound shown in the formula (4), wherein in the structural formulas of the formula (3) and the acyl chloride, R is defined as the same as the above claims.
4. The production method according to claim 3, characterized in that: the thiocyanide is selected from one or more of potassium thiocyanate, sodium thiocyanate and ammonium thiocyanate; and/or the acylating reagent is one or more of thionyl chloride and oxalyl chloride.
5. The production method according to claim 3, characterized in that: the acylation reaction is carried out at the temperature of 15-35 ℃ in the presence of a solvent and under the protection of inert gas; and/or the cyclization reaction is carried out at the temperature of 40-60 ℃ in the presence of a solvent and under the protection of inert gas.
6. The production method according to claim 3, characterized in that: in the step of generating the compound represented by the formula (4), the compound represented by the formula (3) is mixed with a solvent, then the acylating agent is dripped, the temperature is controlled to perform the acylation reaction, then the thiocyanide is added, and the temperature is controlled to perform the cyclization reaction, wherein the temperature is controlled to be 15-35 ℃ when the acylation reaction is performed, and the temperature is controlled to be 40-60 ℃ when the cyclization reaction is performed.
7. The production method according to claim 3, characterized in that: the preparation method further comprises the step of preparing the compound represented by the formula (3): comprising reacting a compound represented by the formula (1)
And a compound represented by the formula (2)
Reacting in the presence of a catalyst and a base to produce the compound represented by the formula (3), wherein in the formula (1), X is halogen, and R is as defined in the preceding claims.
8. The method of claim 7, wherein: the X is F, Cl, Br or I; and/or the catalyst is one or a combination of more of cuprous chloride, cuprous bromide and cuprous iodide; and/or the base is one or more of triethylamine, diisopropylethylamine, sodium acetate, potassium propionate, potassium carbonate, sodium carbonate, cesium carbonate and 1, 8-diazabicyclo [5.4.0] undec-7-ene.
9. Use of the compound of formula (4) as defined in claim 1 or 2 for the preparation of apaluridine.
10. A process for producing a compound represented by the formula (6),
the method is characterized in that: the preparation method comprises the step of mixing the compound shown as the formula (4) and the compound shown as the formula (5) in the claim 1 or 2
A step of reacting in the presence of a catalyst and a base to produce the compound represented by the formula (6).
11. A preparation method of apaluramine is characterized by comprising the following steps: the preparation method comprises the following steps:
s1: the compound shown as the formula (6) is prepared by the preparation method shown as the claim 10; and
s2: preparing the apaluramine from the compound shown in the formula (6).
12. A method of preparing apaluamide as claimed in claim 11, wherein: in the formula (6), R is-COOR1In step S2, reacting the compound shown in the formula (6) with methylamine at 20-30 ℃ to obtain the apaluramine; or the like, or, alternatively,
in the formula (6), R is CONH2In step S2, the compound represented by the formula (6) is reacted with N, N-dimethylformamide dimethyl acetal in the presence of an alcohol to form an ester
And reacting the ester with methylamine at 20-30 ℃ to generate the apaluramine.
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