CN113501758B - Preparation method of biphenyl compound - Google Patents
Preparation method of biphenyl compound Download PDFInfo
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- CN113501758B CN113501758B CN202111060699.7A CN202111060699A CN113501758B CN 113501758 B CN113501758 B CN 113501758B CN 202111060699 A CN202111060699 A CN 202111060699A CN 113501758 B CN113501758 B CN 113501758B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/94—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
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Abstract
The preparation method of the biphenyl compound shown as the formula IV has the advantages of high yield, simple process and no generation of impurities which are difficult to remove, and the biphenyl compound shown as the formula IV prepared by the method has high purity and yield and is suitable for industrial mass production.
Description
Technical Field
The invention relates to the fields of pharmaceutical chemistry and organic synthesis, in particular to a preparation method of a biphenyl compound.
Background
On day 4/10.2019, trofarotene (triflorotene) cream from Galderma corporation (high delm corporation) was approved by the U.S. Food and Drug Administration (FDA) for topical treatment of acne. Trafagotine is a selective gamma Retinoic Acid Receptor (RAR) agonist and keratolytic agent useful in the treatment of facial acne and acne in the trunk.
The chemical name of the trefarotene is: 3'' -tert-butyl-4 '- (2-hydroxyethoxy) -4' '-pyrrolidin-1-yl [1,1';3', 1']Terphenyl-4-carboxylic acid, CAS number 895542-09-3, molecular formula C29H33NO4The corresponding molecular weight is 459.58. It is a white to off-white or yellowish powder and has the following formula:
at present, a biphenyl compound IV is a key intermediate of trefaritine, the synthetic methods of trefaritine and the biphenyl compound IV disclosed in the prior art are few, or the preparation method provided in the prior art introduces more impurities, is complex to operate and is not suitable for industrial production.
Due to the safety of drug administration, prior to commercialization of products of pharmaceutical active ingredients, both domestic and international drug regulatory agencies established very low limits for quality control of unknown impurities. The quality control limit for known impurities is typically 0.15%, but the quality control limit for unknown impurities is typically less than 0.10%.
As is well known, impurities in the raw material medicines may come from the preparation process of the raw material medicines and the self-degradation of the raw material medicines, so that the control of the preparation process of the raw material medicines and the introduction of the impurities as little as possible are important aspects of controlling the content of the impurities.
Aiming at the process defects of the existing biphenyl compound IV preparation method, the method for preparing the biphenyl compound IV, which has the advantages of simple reaction, high yield and high purity and can be suitable for industrial production, needs to be found, and the technical problem to be solved at present is urgent.
Disclosure of Invention
The invention aims to provide a large-scale safe and effective method for preparing a compound shown in a formula IV. The preparation method of the compound shown in the formula IV has the advantages of high yield and mild reaction conditions, and the prepared compound shown in the formula IV has the advantages of few impurities, high purity and convenience in post-treatment, and is more suitable for industrial mass production.
In addition, the invention also aims to provide a compound shown in the formula IIIA and a preparation method thereof.
The purpose of the invention is achieved by the following technical scheme:
in a first aspect, the present invention provides a process for the preparation of a compound of formula iv:
the method comprises the following steps:
(a) contacting a compound of formula II with a compound of formula I under reaction conditions sufficient to produce a compound of formula III:
(b) further reacting the compound of formula iii under reaction conditions sufficient to produce a compound of formula iv:
wherein R is1Is alkyl, R2Is a protecting group and X is halogen.
In some embodiments of the above method of making a compound of formula iv, wherein said alkyl refers to a saturated monovalent hydrocarbon radical having 1 to 10 carbon atoms, further refers to a saturated monovalent hydrocarbon radical having 1 to 5 carbon atoms, and further refers to a saturated monovalent hydrocarbon radical having 1 to 3 carbon atoms. In some embodiments, the alkyl group is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl; preferably, the alkyl group is selected from one of methyl and ethyl.
In some embodiments of the above method for preparing a compound of formula iv, wherein said protecting group is selected from the group consisting of acetyl, benzoyl, formyl, benzyloxycarbonyl, t-butyloxycarbonyl, fluorenylmethyloxycarbonyl, and trimethylsilyl. In some embodiments, the protecting group is one of acetyl, benzoyl, t-butyloxycarbonyl, fluorenylmethyloxycarbonyl, and trimethylsilyl.
In some embodiments of the above methods for preparing a compound of formula iv, wherein said halogen is a halogen comprising fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At). In some embodiments, the halogen is selected from one of fluorine, chlorine, bromine, iodine. In a specific embodiment, the halogen is bromine.
In some embodiments of the above methods for preparing a compound of formula iv, step (a), wherein the reaction conditions comprise an inorganic base. In some embodiments, the inorganic base is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydride, potassium phosphate, sodium phosphate. In some embodiments, the inorganic base is one of potassium carbonate, sodium carbonate, cesium carbonate. In certain embodiments, the inorganic base is used in an amount of 1.0 to 3.0 molar equivalents. In certain specific embodiments, the inorganic base is used in an amount of 1.5 to 2.5 molar equivalents.
In some embodiments of the above process for preparing a compound of formula IV, in step (a), wherein the compound of formula II is used in an amount of 1.0 to 3.0 molar equivalents. In some embodiments, the compound of formula II is used in an amount of 1.5 to 2.5 molar equivalents.
In some embodiments of the above process for preparing a compound of formula iv, step (a), wherein the reaction is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is selected from one or two of DMF, acetonitrile, tetrahydrofuran, acetone. In certain embodiments, the solvent is one of DMF, tetrahydrofuran.
In some embodiments of the above process for preparing a compound of formula iv, in step (b), wherein the reaction conditions comprise N-bromosuccinimide and thiourea. In various embodiments, 1.05 to 2.0 molar equivalents of the N-bromosuccinimide and 0.01 to 0.2 molar equivalents of the thiourea may be used. In some embodiments, 1.2 to 1.7 molar equivalents of the N-bromosuccinimide and 0.03 to 0.08 molar equivalent of the thiourea may be used.
In some embodiments of the above process for preparing a compound of formula iv, step (b), wherein the reaction is carried out in a solvent. In some embodiments, the solvent is selected from one or two of DMF, dichloromethane, tetrahydrofuran, ethanol, acetonitrile, acetone. In certain embodiments, the solvent is one or two of dichloromethane, acetonitrile, DMF. In a specific embodiment, the solvent is a combination of acetonitrile, DMF.
In a specific embodiment, the present invention also provides a process for preparing a compound of formula iva:
the method comprises the following steps:
(a) contacting a compound of formula ia with a compound of formula iia under reaction conditions sufficient to produce a compound of formula iiia, to form a compound of formula iiia:
(b) further reacting the compound of formula IIIA under reaction conditions sufficient to produce a compound of formula IVA:
in some embodiments of the above methods of making a compound of formula iva, in step (a), wherein the reaction conditions comprise an inorganic base. In some embodiments, the inorganic base is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydride, potassium phosphate, sodium phosphate. In some embodiments, the inorganic base is one of potassium carbonate, sodium carbonate, cesium carbonate. In certain embodiments, the inorganic base is used in an amount of 1.0 to 3.0 molar equivalents. In certain specific embodiments, the inorganic base is used in an amount of 1.5 to 2.5 molar equivalents.
In some embodiments of the above process for preparing a compound of formula IVA, step (a), wherein the compound of formula IIA is used in an amount of 1.0 to 3.0 molar equivalents. In some embodiments, the compound of formula IIA is used in an amount of 1.5 to 2.5 molar equivalents.
In some embodiments of the above process for preparing a compound of formula iva, step (a), wherein the reaction is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is selected from one or two of DMF, acetonitrile, tetrahydrofuran, acetone. In certain embodiments, the solvent is one of DMF, tetrahydrofuran.
In some embodiments of the above process for preparing a compound of formula iva, in step (b), wherein the reaction conditions comprise N-bromosuccinimide and thiourea. In various embodiments, 1.05 to 2.0 molar equivalents of the N-bromosuccinimide and 0.01 to 0.2 molar equivalents of the thiourea may be used. In some embodiments, 1.2 to 1.7 molar equivalents of the N-bromosuccinimide and 0.03 to 0.08 molar equivalent of the thiourea may be used.
In some embodiments of the above process for preparing a compound of formula iva, step (b), wherein the reaction is carried out in a solvent. In some embodiments, the solvent is selected from one or two of DMF, dichloromethane, tetrahydrofuran, ethanol, acetonitrile, acetone. In certain embodiments, the solvent is one or two of dichloromethane, acetonitrile, DMF. In a specific embodiment, the solvent is a combination of acetonitrile, DMF.
In a second aspect, the present invention provides a process for preparing a compound of formula iii:
the method comprises the following steps: contacting a compound of formula II with a compound of formula I under reaction conditions sufficient to produce a compound of formula III:
wherein R is1Is alkyl, R2Is a protecting group and X is halogen.
In some embodiments of the above method of preparing a compound of formula iii, wherein said alkyl refers to a saturated monovalent hydrocarbon group having 1 to 10 carbon atoms, further refers to a saturated monovalent hydrocarbon group having 1 to 5 carbon atoms, and further refers to a saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. In some embodiments, the alkyl group is one of methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl; preferably, the alkyl group is selected from one of methyl and ethyl.
In some embodiments of the above method for preparing a compound of formula iii, wherein the protecting group is selected from one of acetyl, benzoyl, formyl, benzyloxycarbonyl, t-butoxycarbonyl, fluorenylmethoxycarbonyl, and trimethylsilyl. In some embodiments, the protecting group is one of acetyl, benzoyl, t-butyloxycarbonyl, fluorenylmethyloxycarbonyl, and trimethylsilyl.
In some embodiments of the above methods of preparing a compound of formula iii, wherein said halogen is a halogen element comprising fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At). In some embodiments, the halogen is selected from one of fluorine, chlorine, bromine, iodine. In a specific embodiment, the halogen is bromine.
In some embodiments of the above methods of preparing a compound of formula iii, wherein the reaction conditions comprise an inorganic base selected from one of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydride, potassium phosphate, and sodium phosphate. In some embodiments, the inorganic base is one of potassium carbonate, sodium carbonate, cesium carbonate. In certain embodiments, the inorganic base is used in an amount of 1.0 to 3.0 molar equivalents. In certain specific embodiments, the inorganic base is used in an amount of 1.5 to 2.5 molar equivalents.
In some embodiments of the above methods for preparing a compound of formula III, wherein the compound of formula II is used in an amount of 1.0 to 3.0 molar equivalents. In some embodiments, the compound of formula II is used in an amount of 1.5 to 2.5 molar equivalents.
In some embodiments of the above methods of preparing a compound of formula iii, wherein the reaction is carried out in a polar aprotic solvent. In some embodiments, the polar aprotic solvent is selected from one or two of DMF, acetonitrile, tetrahydrofuran, acetone. In certain embodiments, the solvent is one of DMF, tetrahydrofuran.
In a third aspect, the present invention provides an intermediate compound of formula IIIA:
the preparation method has the advantages that: the preparation method of the compound shown in the formula IV and the preparation method of the compound shown in the formula III provided by the invention have the advantages of high yield, simple preparation process, no introduction of dibromo impurities and no need of using chromatographic methods (such as column chromatography and liquid phase preparation) for separation. The compound of the formula IV and the compound of the formula III prepared by the preparation method have high yield and high purity, do not contain dibromo impurities, have simple production process and are suitable for industrial mass production. The invention also provides a compound of formula IIIA, which has the advantages of high yield, high purity, simple and convenient post-treatment, simple production process and capability of effectively synthesizing the compound of formula IVA.
Detailed Description
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be considered as ambiguous or unclear without special definition, but rather construed in a generic sense. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
In the present invention, the term "alkyl group" means a saturated monovalent hydrocarbon group having 1 to 10 carbon atoms, further means a saturated monovalent hydrocarbon group having 1 to 5 carbon atoms, and further means a saturated monovalent hydrocarbon group having 1 to 3 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, and the like are all specific examples of the term "alkyl".
In the present invention, the term "protecting group" refers to a protecting group for hydroxyl group as known to those skilled in the art, such as benzoyl, acetyl, t-butyloxycarbonyl, etc. Some protecting groups are commonly used in the art to mimic undesirable reactions of certain functional groups. Suitable protecting groups for the various functional groups and suitable conditions for protecting and deprotecting the particular functional group are well known in the art. For example, many Protecting Groups are described in t.w. green (t.w. greene) and g.m. wood (g.m.wuts), Protecting Groups in Organic Synthesis (Protecting Groups in Organic Synthesis), 3 rd edition, Wiley press (Wiley), new york, 1999 and references cited therein.
In the invention, the terms "acid", "peroxide" and "base" can be added directly to the reaction system, or can be diluted or prepared into a solution according to the operation habit of a person skilled in the art, and the amounts of the active ingredient substances are the same; the term "metal hydroxide" may be added in the form of containing no water of crystallization or containing water of crystallization during the reaction if it may contain water of crystallization, based on the same amount of the substance.
In the present invention, the term "base" is intended to mean a chemical substance which is a proton acceptor. Suitable bases for use in the present invention are inorganic bases. Examples of inorganic bases include, but are not limited to, potassium hydroxide (KOH), potassium carbonate (K)2CO3) Sodium carbonate (Na)2CO3) Cesium carbonate (Cs)2CO3) Sodium hydride (NaH), potassium phosphate (K)3PO4) Sodium phosphate (Na)3PO4) And the like.
The term "reaction conditions" is meant to indicate physical and/or environmental conditions under which a chemical reaction is carried out, including, but not limited to, one or more of the following: reaction temperature, solvent, pH, pressure, reaction time, molar ratio of reactants (expressed as molar equivalents), acid or base, presence or absence of catalyst, type of catalyst, and the like. Reaction conditions may be named after the particular chemical reaction in which the conditions are used, e.g., coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, deuteration conditions, and the like.
The reaction route of the preparation method of the compound shown in the formula IV provided by the invention is as follows:
wherein R is1Is alkyl, R2X is halogen, and the reaction conditions are as defined above.
The invention also specifically provides a reaction route of the preparation method of the compound IV A, which comprises the following steps:
wherein each reaction condition is as defined above.
The inventor of the invention finds that the preparation method does not introduce brominated impurities, and the obtained product has high yield and good purity. The inventors of the present invention also tried the following preparation method in the experimental process, and found that it is very easy to introduce bromine atoms at both ortho-positions of the phenolic hydroxyl group to generate dibromo impurity compound 5a, and the specific reaction route is as follows.
Through experiments, the inventors of the present invention found that the attempted preparation method not only produces the target compound 5, but also produces the dibromo impurity 5 a. No matter how the reaction temperature, the molar equivalent of NBS and the feeding mode are adjusted, dibromo-substituted impurity 5a is generated, and the content of the dibromo-substituted impurity 5a in the reaction solution is about 9% of the total amount of the product. The physicochemical property of the dibromo-impurity 5a is similar to that of the target compound 5, and the dibromo-impurity is difficult to remove by conventional means such as recrystallization, and the conventional reliable method is chromatographic column or preparative liquid phase purification, but the yield is low, and the purity can only reach about 97%. Although the dibromo-impurity 5a and the compound of the formula IIA do not react further to generate corresponding impurities, the dibromo-impurity 5a still exists in the product of the second step reaction, and conventional recrystallization is difficult to remove, so that the purification difficulty is high.
The intermediate compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present invention.
The chemical reactions of the embodiments of the present invention are carried out in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
The skilled person can also select suitable work-up means to obtain the desired product, including extraction, distillation under reduced pressure, recrystallization, column chromatography, etc., and the art can also select suitable reagents to neutralize or destroy excess reagents in the reaction.
The present invention will be specifically described below by way of examples, which are not intended to limit the present invention in any way.
All solvents used in the present invention are commercially available and can be used without further purification.
The invention employs the following abbreviations: r.t. represents room temperature; aq represents an aqueous solution; DCM represents dichloromethane; THF represents tetrahydrofuran; DMF represents N, N-dimethylformamide; EtoAc stands for ethyl acetate; MeOH represents methanol; THF represents tetrahydrofuran; EtOH stands for ethanol; h2O represents water; IPA stands for isopropanol; acetone represents Acetone; CAN represents acetonitrile; NBS represents N-bromosuccinimide; AIBN stands for azobisisobutyronitrile; AIBME stands for dimethyl azodiisobutyrate; BPO stands for dibenzoyl peroxide; MTBE represents methyl tert-butyl ether; cbz represents benzyloxycarbonyl; boc represents tert-butyloxycarbonyl; fmoc represents fluorenylmethyloxycarbonyl; PMB represents p-methoxybenzyl; bn represents a benzyl group; trt represents trityl; teoc represents trimethylsiloxyethyl carbonyl; f represents fluorine; cl represents chlorine; br represents bromine; i represents iodine; at represents astatine; eq represents molar equivalent.
The compounds were named manually or by ChemDraw software and the commercially available compounds were given the supplier catalog name.
The test method comprises the following steps:
high Performance Liquid Chromatography (HPLC) analytical methods:
the instrument used was Waters e2695 HPLC; a chromatographic column: GL Science ODS-3V, 4.6X 150mm, 5 μm;
the measurement conditions were as follows:
sample introduction volume: 10 mu l of the mixture;
flow rate: 1.0 ml/min;
detection wavelength: 295 nm;
sample concentration: 1.0 mg/ml;
diluting liquid: acetonitrile;
column temperature: 35 ℃;
mobile phase A: 10mM ammonium formate solution;
mobile phase B: acetonitrile;
the elution gradient is shown in table 1:
TABLE 1
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The present application is further illustrated with reference to 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 application.
The test methods in the following examples, in which specific conditions are not specified, may be carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is familiar to those skilled in the art.
Preparation of Compound IIIA
Example 1
Into a 2L three necked round bottom flask was charged 50.00 g of Compound IA (206.38mmol, 1.00eq), 67.24g of Cs were added2CO3(206.38mmol, 1.00eq), 500ml THF, stirring, heating under reflux, and addition of 34.46g of Compound IIA (206.38mmol, 1.00eq) for reaction. After the reaction is completed, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solids, stirring for 0.5-2 hours at room temperature after the dropwise addition is completed, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 64.67g of a compound IIIA, wherein the yield is 95.42%, and the purity is as follows: 99.53 percent.
1H NMR (400 MHz, CDCl3) δ 8.09（d, J=8.8Hz, 2H）; 7.59（m, 4H）; 7.00（d, J=8.8Hz, 2H）; 4.45（t, J=9.2Hz, 2H）; 4.39（dd, J=7.2Hz, 7.2Hz, 2H）; 4.22（t, J=9.6Hz, 2H）; 2.11（s, 3H）; 1.41（t, J=14.4Hz, 3H）. MS m/z：329.4 [M+H]+。
Example 2
A2L three-necked round-bottomed flask was charged with 50.00 g of Compound IA (206.38mmol, 1.00eq), 7.43g of NaH (309.57mmol, 1.5eq) and 500ml of DMF, stirred, heated to 80-85 ℃ and reacted with 51.7 g of Compound IIA (309.57mmol, 1.5 eq). After the reaction is completed, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solids, stirring at room temperature for 0.5-2 hours after the dropwise addition is completed, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 64.56g of a compound IIIA, wherein the yield is 95.26%, and the purity is as follows: 98.65 percent.
Example 3
Into a 2L three necked round bottom flask was added 50.00 g of Compound IA (206.38mmol, 1.00eq), 57.05g K was added2CO3(412.76 mmol, 2.0eq), 500ml DMF, magnetic stirring, heating to a temperature of 80-85 ℃ and adding 86.16g of compound IIA(515.95 mmol, 2.5 eq). After the reaction is completed, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solids, stirring at room temperature for 0.5-2 hours after the dropwise addition is completed, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 65.32g of a compound IIIA, wherein the yield is 96.38%, and the purity is as follows: 99.59 percent.
Example 4
Into a 2L three-necked round-bottomed flask, 50.00 g of Compound IA (206.38mmol, 1.00eq) was charged, and 54.69g of Na was added2CO3(515.95 mmol, 2.5eq), 500ml acetonitrile, stirred, heated to reflux, and 68.93g of compound IIA (412.76 mmol, 2.0eq) added to react. After the reaction is completed, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solid, stirring at room temperature for 0.5-2 hours after the dropwise addition is completed, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 64.96g of a compound IIIA, wherein the yield is 95.85%, and the purity is as follows: 99.26 percent.
Example 5
To a 2L three-necked round-bottomed flask, 50.00 g of Compound IA (206.38mmol, 1.00eq), 34.74g of potassium hydroxide (619.14 mmol, 3.0eq), and 500ml of acetone were added, followed by stirring, heating under reflux, and addition of 103.38g of Compound IIA (619.14 mmol, 3.0eq) to react. After the reaction is completed, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solids, stirring for 0.5-2 hours at room temperature after the dropwise addition is completed, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 64.91g of a compound IIIA, wherein the yield is 95.78%, and the purity is: 98.54 percent.
Example 6
50.00 g of Compound IA (206.38mmol, 1.00eq) was added to a 2L three-necked round-bottomed flask, 84.58g of sodium phosphate (515.95 mmol, 2.5eq) and 500ml of DMF were added, the mixture was stirred, heated to 80 to 85 ℃ and 50.58g of Compound IIB (412.76 mmol, 2.0eq) was added to react. After the reaction is completed, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solid, stirring at room temperature for 0.5-2 hours after the dropwise addition is completed, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 65.25g of a compound IIIA, wherein the yield is 96.28%, and the purity is as follows: 99.39 percent.
Example 7
50.00 g of Compound IA (206.38mmol, 1.00eq), 87.61g of potassium phosphate (412.76 mmol, 2.0eq), and 500ml of DMF were added to a 2L three-necked round-bottomed flask, magnetically stirred, heated to a temperature of 80-85 ℃ and reacted with 88.33g of Compound IIC (412.76 mmol, 2.0 eq). After the reaction is finished, filtering, adding 500ml of water into the filtrate, precipitating a large amount of solids, stirring for 0.5-2 hours at room temperature after the dropwise addition is finished, filtering, washing the filter cake twice by using 50ml of ethanol/water (1: 1) solution, draining, and drying to obtain 64.60g of a compound IIIA, wherein the yield is 95.32%, and the purity is: 99.16 percent.
Preparation of Compound IVA
Example 8
50.00 g of compound IIIA (152.27mmol, 1.00eq) was added to a 2L three-necked round-bottomed flask, 0.12 g of thiourea (1.52mmol, 0.01eq) and 500ml of dichloromethane were added, magnetic stirring was performed, 28.46 g N-bromosuccinimide (159.88mmol, 1.05eq) was added at room temperature, the color of the system was reddish brown, and the reaction was completed at 40 to 45 ℃. Cooling to 15-30 ℃, adding an aqueous solution containing 3.83g of sodium sulfite (30.4 mmol, 0.20eq) to dilute the system color and separate out a large amount of solids, adding 450ml of water, stirring at room temperature for 0.5-2 hours after the dropwise addition is completed, filtering, washing a filter cake twice by using 100ml of acetonitrile/water (1: 1.2) solution, draining, drying to obtain 59.27g of a compound IVA, wherein the yield is 95.58%, and the purity is as follows: 99.43 percent.
1H NMR (400 MHz, CDCl3) δ 8.09（d, J=12.4Hz, 2H）; 7.83（s, 1H）; 7.59（d, J=12.4Hz, 2H）; 7.52（d, J=10.8Hz, 1H）; 6.99（d, J=8.4Hz, 1H）; 4.50（t, J=10.0Hz, 2H）; 4.40（dd, J=7.2Hz, 7.2Hz, 2H）; 4.29（t, J=9.6Hz, 2H）; 2.13（s, 3H）; 1.41（t, J=14.4Hz, 3H）. MS m/z：408.3 [M+H]+。
Example 9
50.00 g of compound IIIA (152.27mmol, 1.00eq) was added to a 2L three-necked round-bottomed flask, 0.58g of thiourea (7.6 mmol, 0.05eq) and 600 mL of THF were added, the mixture was stirred, 32.52 g N-bromosuccinimide (182.72 mmol, 1.20eq) was added at room temperature, the color of the system was reddish brown, and the reaction was completed at 40-45 ℃. After the reaction is finished, cooling the system to 15-30 ℃, adding an aqueous solution containing 3.83g of sodium sulfite (30.4 mmol, 0.20eq) to dilute the system color and separate out a large amount of solids, continuously dropping 450ml of water, stirring at room temperature for 0.5-2 hours, filtering, washing the filter cake twice by using 100ml of acetonitrile/water (1: 1.2) solution, draining, and drying to obtain 59.52g of a compound IVA with yield of 95.98%, purity: 99.56 percent.
Example 10
To a 2L three-necked round-bottomed flask, 50.00 g of Compound IIIA (152.27mmol, 1.00eq), 1.16 g of thiourea (15.22 mmol, 0.10eq), 500ml of acetonitrile, 100ml of N, N-dimethylformamide (2.0V) were added, and magnetic stirring was carried out, and 40.65 g N-bromosuccinimide (228.40mmol, 1.50eq) was added at room temperature to turn the system into reddish brown, 40 to 45 ℃. After the reaction is finished, cooling to 15-30 ℃, adding an aqueous solution containing 3.83g of sodium sulfite (30.4 mmol, 0.20eq) into the system, lightening the color of the system, separating out a large amount of solids, continuously dropwise adding 450ml of water, stirring at room temperature for 0.5-2 hours after the dropwise adding is finished, filtering, washing the filter cake twice by using 100ml of acetonitrile/water (1: 1.2) solution, draining, and drying to obtain 60.04g of a compound IVA, wherein the yield is 96.83%, and the purity: 99.52 percent.
Example 11
50.00 g of compound IIIA (152.27mmol, 1.00eq) was added to a 2L three-necked round-bottomed flask, 1.74 g of thiourea (22.80 mmol, 0.15eq) and 500ml of N, N-dimethylformamide were added, magnetic stirring was performed, 46.07g N-bromosuccinimide (258.86 mmol, 1.70eq) was added at room temperature, the color of the system was reddish brown, and the reaction was completed at 40-45 ℃. After the reaction is finished, cooling to 15-30 ℃, dropwise adding an aqueous solution containing 3.83g of sodium sulfite (30.4 mmol, 0.20eq) to dilute the system color and separate out a large amount of solids, continuously dropwise adding 500ml of water, stirring at room temperature for 0.5-2 hours, filtering, washing a filter cake twice by using 100ml of acetonitrile/water (1: 1.2) solution, draining, and drying to obtain 59.44g of a compound IVA, wherein the yield is 95.85%, and the purity: 99.48 percent.
Example 12
50.00 g of compound IIIA (152.27mmol, 1.00eq) was added to a 2L three-necked round-bottomed flask, 2.32 g of thiourea (30.45mmol, 0.20eq) and 600 ml of ethanol were added, magnetic stirring was performed, 54.20g N-bromosuccinimide (304.54 mmol, 2.00eq) was added at room temperature, the color of the system was reddish brown, and the reaction was completed at 40-45 ℃. After the reaction is finished, cooling the system to 15-30 ℃, adding an aqueous solution containing 3.83g of sodium sulfite (30.4 mmol, 0.20eq) into the system, lightening the color of the system, separating out a large amount of solids, adding 450ml of water, stirring at room temperature for 0.5-2 hours after the dropwise addition is finished, filtering, washing a filter cake twice by using 100ml of acetonitrile/water (1: 1.2) solution, draining the filter cake, and drying to obtain 59.2g of a compound IVA, wherein the yield is 95.5%, and the purity: 99.53 percent.
Example 13
50.00 g of Compound IIIA (152.27mmol, 1.00eq) was added to a 2L three-necked round-bottomed flask, 1.16 g of thiourea (15.22 mmol, 0.05eq) and 500ml of acetone were added, magnetic stirring was performed, 37.94g N-bromosuccinimide (213.18mmol, 1.40eq) was added at room temperature, and the color of the system was reddish brown, 40-45 ℃. After the reaction is finished, cooling to 15-30 ℃, adding an aqueous solution containing 3.83g of sodium sulfite (30.4 mmol, 0.20eq) into the system, lightening the color of the system, separating out a large amount of solids, continuously dropwise adding 450ml of water, stirring at room temperature for 0.5-2 hours after the dropwise adding is finished, filtering, washing the filter cake twice by using 100ml of acetonitrile/water (1: 1.2) solution, draining, and drying to obtain 59.73g of a compound IVA, wherein the yield is 96.32%, and the purity: 99.46 percent.
EXAMPLE 12 stability Studies of Compounds of formula IIIA
The compound of formula IIIA obtained by the experiment and the compound 5 (prepared by comparative example 1) were left open and laid flat, and the stability test of the samples was performed under the conditions of high temperature (60 ℃), high humidity (RH 92.5%), and light (4500. + -. 500 Lux), and the contents of each substance and related impurities in the samples at different sampling times (0 day, 6 days, 54 days) were measured, as shown in Table 2.
TABLE 2 stability test of Compounds of formula IIIA, Compound 5
The crude compound 5 prepared in comparative example 1 was purified by column chromatography to obtain compound 5 used in this experiment, wherein the purity of compound 5 was 97.67%.
Analysis of the results in table 2 above shows that the compound of formula iiia is compared to compound 5: under the conditions of high temperature, high humidity and illumination, the compound shown in the formula IIIA has better stability, is convenient to store and is more suitable for industrial mass production.
Comparative example 1 preparation of Compound IVA
Step (1) Synthesis of Compound 5
To a 250ml three-necked round bottom flask, 10.00 g of compound IA (41.2 mmol, 1.00eq), 0.71 g of p-toluenesulfonic acid (4.1 mmol, 0.1eq), 100ml of ethanol (10.0V) were added, magnetic stirring was performed, 7.71 g N-bromosuccinimide (43.3 mmol, 1.05eq) was added at room temperature, and reaction was completed at 20-25 ℃. The reaction mixture, Compound 5a, was taken as 8.83% (area normalization). After the reaction is finished, adding 100ml of water, precipitating a large amount of solid, stirring for 0.5-2 hours at room temperature, filtering, washing the filter cake twice by using 20 ml of ethanol/water (1: 1.2) solution, draining, and drying to obtain 10.89g of a crude compound 5 product, wherein the yield is as follows: 82.13%, purity: 89.3 percent. The crude product was found to contain 8.83% of impurity 5a by HPLC.
Step (2) Synthesis of Compound IVA
To a 250ml three-necked round-bottomed flask, the crude compound 5 (about 33.91 mmol, 1.00eq) obtained in step (1) was added, 1.22g of NaH (50.86 mmol, 1.5eq) and 110 ml of DMF (10.0V) were added, magnetic stirring was performed, 6.79 g of Compound IIA (40.69 mmol, 1.2eq) was added at room temperature, and the reaction was completed at 40-45 ℃. And after the reaction is finished, filtering, adding 100ml of water into the filtrate, precipitating a large amount of solids, stirring at room temperature for 0.5-2 hours, filtering, washing the filter cake twice by using 40 ml of ethanol/water (1: 1) solution, draining, and drying to obtain 10.82g of a crude compound IVA product, wherein the total yield of the two-step reaction is 64.48%. The purity of the crude compound IVA was 86.44% by HPLC and the crude product contained 8.63% of impurity 5 a.
Claims (6)
1. A process for preparing a compound of formula iv:
the method comprises the following steps:
(a) reacting a compound of formula ii with a compound of formula i in the presence of an inorganic base to form a compound of formula iii:
(b) further reacting the compound of formula iii in the presence of N-bromosuccinimide and thiourea to produce a compound of formula iv:
wherein R is1Is alkyl, R2Is a protective group,X is halogen.
2. The method of claim 1, wherein the alkyl group refers to a saturated monovalent hydrocarbon group having 1 to 5 carbon atoms; the protective group is selected from one of acetyl, benzoyl, formyl, benzyloxycarbonyl, tert-butoxycarbonyl, fluorenylmethoxycarbonyl and trimethylsilyl; the halogen is selected from one of fluorine, chlorine, bromine and iodine.
3. The method according to claim 1, wherein the alkyl is selected from one of methyl and ethyl; the protective group is selected from one of acetyl, benzoyl, tert-butyloxycarbonyl, fluorenylmethyloxycarbonyl and trimethylsilyl; the halogen is bromine.
4. The method according to claim 1, wherein in step (a), the inorganic base is selected from one of potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydride, potassium phosphate and sodium phosphate, the amount of the inorganic base is 1.0-3.0 molar equivalents, and the amount of the compound of formula II is 1.0-3.0 molar equivalents; in the step (b), the dosage of the N-bromosuccinimide is 1.05-2.0 molar equivalent, and the dosage of the thiourea is 0.01-0.2 molar equivalent.
5. The method of claim 4, wherein in step (a), the inorganic base is one of potassium carbonate, sodium carbonate and cesium carbonate, the amount of the inorganic base is 1.5-2.5 molar equivalents, and the amount of the compound of formula II is 1.5-2.5 molar equivalents; in the step (b), the dosage of the N-bromosuccinimide is 1.2-1.7 molar equivalent, and the dosage of the thiourea is 0.03-0.08 molar equivalent.
6. A compound of the formula IIIA,
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