WO2013180403A1 - Process for preparing gefitinib and an intermediate used for preparing thereof - Google Patents

Process for preparing gefitinib and an intermediate used for preparing thereof Download PDF

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WO2013180403A1
WO2013180403A1 PCT/KR2013/004024 KR2013004024W WO2013180403A1 WO 2013180403 A1 WO2013180403 A1 WO 2013180403A1 KR 2013004024 W KR2013004024 W KR 2013004024W WO 2013180403 A1 WO2013180403 A1 WO 2013180403A1
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chemical formula
gefitinib
compound represented
chloro
quinazoline
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PCT/KR2013/004024
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French (fr)
Inventor
Seung Uk Lee
Dae Koo WOO
Sung Kwon Kang
Dong Jin Kim
Dae Jong Park
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Chong Kun Dang Pharmaceutical Corp.
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Publication of WO2013180403A1 publication Critical patent/WO2013180403A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage

Definitions

  • the present invention relates to a method of preparing gefitinib and an intermediate used in the preparation of gefitinib.
  • gefitinib N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) represented by Chemical Formula 1 below is a quinazoline derivative useful in treatment of non-small cell lung cancer.
  • the structure of gefitinib is shown in the following Chemical Formula 1.
  • WO 96/33980 discloses the gefitinib synthesis method as represented in Scheme 1 below.
  • gefitinib thus synthesized contains an excess of an N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine in the final step, the impurity should be separated via column chromatography, undesirably lowering the yield and making it difficult to achieve commercial production.
  • WO 2004/024703 discloses a method of synthesizing gefitinib from a start material of 3-hydroxy-4-methoxy benzonitrile as shown in Scheme 2 below.
  • a morpholinopropyl group is introduced before forming a quinazoline ring, thus suppressing the production of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine which is the N-alkylated impurity.
  • reduction of a nitro compound, formation of a quinazoline ring, and chlorination of the quinazoline ring in the final step to carry out condensation with chlorofluoroaniline are performed in the presence of the morpholinopropyl group, undesirably complicating the reaction process and lengthening the reaction time.
  • WO 2008/125867 discloses a method of synthesizing gefitinib from a start material of isovanilin as shown in Scheme 3 below.
  • WO 2005/023783 discloses a method of synthesizing gefitinib from imine via a rearrangement reaction
  • WO 2005/070909 discloses a method of synthesizing gefitinib by performing nitrilization of oxime and then forming a quinazoline ring.
  • the preparation methods mentioned in the prior techniques produce an excess of impurity or include other routes to suppress the formation of the impurity, undesirably increasing the number of preparation steps and thus resulting in complicated processes and a long synthesis time, and thereby these methods are unsuitable for commercial production.
  • gefitinib which may minimize the production of an impurity and be suitable for use in industrial production.
  • Patent Document 1 WO 96/33980
  • Patent Document 2 WO 2004/024703
  • Patent Document 3 WO 2008/125867
  • Patent Document 4 WO 2005/070909
  • the present invention is to provide a method of preparing gefitinib, which minimizes the production of an impurity and enables the mass production of gefitinib having very high purity.
  • the present invention is to provide an intermediate, which enables the minimal production of an impurity and the mass production of gefitinib.
  • One Aspect of the present invention provides a method of preparing a compound represented by Chemical Formula 1, comprising a) reacting a compound represented by Chemical Formula 3 with a compound represented by Chemical Formula A to prepare a compound represented by Chemical Formula 4, and b) reacting the compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 5 to prepare a compound represented by Chemical Formula 6.
  • the generation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine which is the N-alkylated impurity of gefitinib, as represented by Chemical Formula 2, may be minimized, thus increasing the yield of gefitinib and, efficiently obtaining gefitinib having high purity, without chromatography.
  • the reaction may be completed within a short period of time, and thus the method of the invention may be effectively applied to commercial production of gefitinib.
  • the compound represented by Chemical Formula 3 may be prepared by reacting a compound represented by Chemical Formula 7 with a metal hydroxide.
  • the compound represented by Chemical Formula 7 is reacted with the metal hydroxide.
  • the reaction is carried out at room temperature ranging from about 10°C to about 30°C it is completed within a short period of time, thus obtaining the compound represented by Chemical Formula 3 at high yield.
  • the metal hydroxide may be lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or mixtures thereof.
  • the metal hydroxide may be lithium hydroxide.
  • the reaction between the compound represented by Chemical Formula 7 and the metal hydroxide to prepare the compound represented by Chemical Formula 3 may be performed using a solvent such as water, methanol, ethanol, isopropylalcohol or mixtures thereof, and preferably using a mixture of methanol and water as the solvent.
  • a solvent such as water, methanol, ethanol, isopropylalcohol or mixtures thereof, and preferably using a mixture of methanol and water as the solvent.
  • a) may be performed in the presence of a base.
  • the base may be potassium carbonate, sodium carbonate, calcium carbonate or a mixture thereof, and may be preferably potassium carbonate.
  • a) may be performed in the presence of a catalyst, and the catalyst may be N,N-dimethylaminopyridine.
  • a) and b) may be performed using a solvent such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, or mixtures thereof, and preferably using N,N-dimethylacetamide as the solvent.
  • a solvent such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, or mixtures thereof, and preferably using N,N-dimethylacetamide as the solvent.
  • a) and b) may be performed in situ using a single reactor.
  • the compound represented by Chemical Formula 5 may be added to the solution containing the compound represented by Chemical Formula 4, which is prepared by the reaction of a), without separating the compound represented by Chemical Formula 4, thereby preparing the compound represented by Chemical Formula 6.
  • protection and deprotection may be carried out using a single reactor without separating the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 6, thus simplifying the preparation process of gefitinib and remarkably increasing the reaction efficiency.
  • the method of the invention may further include c) eliminating a trimethylsilyl group from the compound represented by Chemical Formula 6.
  • the trimethylsilyl group which functions as an amine protecting group is eliminated from the compound represented by Chemical Formula 6, so that the amine group is exposed, thereby obtaining gefitinib represented by Chemical Formula 1.
  • the trimethylsilyl group of the compound represented by Chemical Formula 6 is substituted with -H, yielding gefitinib.
  • the elimination of the trimethylsilyl group may be performed by adding water to the solution containing the compound represented by Chemical Formula 6.
  • the trimethylsilyl group may be eliminated from Chemical Formula 6, so that the gefitinib may be directly obtained as a solid.
  • the production of the N-alkylated impurity is low and a simple process involving the addition of water is performed without an additional process for separating the compound represented by Chemical Formula 6, the preparation and separation of gefitinib may occur simultaneously, thereby simplifying the preparation process of gefitinib.
  • the method of the invention may be effectively applied to mass production of gefitinib.
  • the production of the N-alkylated impurity may be inherently inhibited and gefitinib having high purity of 99.9% or more may be obtained at high yield without a complicated process such as chromatography.
  • the present invention provides a compound represented by Chemical Formula 4 or 6 and salts thereof.
  • the compound represented by Chemical Formula 4 or 6 may be used as an intermediate in the preparation of gefitinib.
  • the production of the impurity that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine, may be inherently suppressed. Also, complicated multi-steps need not be performed in order to suppress the production of the N-alkylated impurity, and a process such as chromatography need not be conducted in order to eliminate the N-alkylated impurity.
  • the compound represented by Chemical Formula 6 is produced via the reaction between the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5, and then only water is added to the solution containing the compound represented by Chemical Formula 6 without the need for separation and purification, whereby the trimethylsilyl group is eliminated, and gefitinib in a solid is produced.
  • the compound represented by Chemical Formula 6 is produced via the reaction between the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5, and then only water is added to the solution containing the compound represented by Chemical Formula 6 without the need for separation and purification, whereby the trimethylsilyl group is eliminated, and gefitinib in a solid is produced.
  • gefitinib is deposited in a solid in the solution at the same time of being produced, only a filtration process is performed without the additional need for a separation process, yielding gefitinib.
  • gefitinib having very high purity may be easily produced with high efficiency via a simple process.
  • the salts of the compound represented by Chemical Formula 4 or 6 may be pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salts indicate salts typically used in the pharmaceutical industry, and examples thereof include metal ion salts prepared using calcium, potassium, sodium, magnesium, etc., inorganic acid salts prepared using hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc., organic acid salts prepared using acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanilic acid, hydroiodic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid
  • gefitinib In the method of preparing gefitinib according to the present invention, production of an N-alkylated impurity can be inhibited via a simple process, and gefitinib can be obtained via filtration, etc., without the need for a complicated separation process such as chromatography, thus enabling the effective mass production of gefitinib having very high purity with high efficiency.
  • HPLC conditions used in the present invention were as follows, and HPLC was used to measure the purity of gefitinib and the amount of the N-alkyl impurity, in the reaction mixture after reaction.
  • UV spectrophotometer (measurement wavelength: 250 nm)
  • test sample 25 mg/mobile phase 50 mL
  • Example 3-1 About 154.7 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine obtained in Example 3-1 was suspended with stirring in about 2320.0 mL of toluene and about 1160.0 mL of anhydrous ethanol, and then heated to about 40°C so as to be thoroughly dissolved. About 37.0 g of neutral activated carbon was added in the resulting solution, stirred for about 1 hr, and filtered to thus remove the activated carbon. The filtrate was concentrated to about 1400 mL, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 246.0 mL of toluene, and dried at about 40°C for about 3 hr, thus obtaining about 135.3 g of white gefitinib.
  • the purified gefitinib was added to about 2340.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75°C so that gefitinib was thoroughly dissolved, and then further stirred for about 1 hr.
  • the solution was gradually cooled to about 20°C and the produced solid was stirred for about 30 min and then further stirred at about 5°C for about 1 hr.
  • HPLC purity 99.91% (without N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine)
  • Example 3-2 About 8.6 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine obtained in Example 3-2 was suspended with stirring in about 129.0 mL of toluene and about 65.0 mL of anhydrous ethanol, and heated to about 40°C so as to be thoroughly dissolved. About 1.9 g of neutral activated carbon was added into the resulting solution, stirred for about 1 hr, and filtered to thus remove the activated carbon. The filtrate was concentrated to about 90 mL, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 20.0 mL of toluene, and dried at about 40°C for about 3 hr, thus obtaining about 7.3 g of white gefitinib.
  • the purified gefitinib was added to about 125.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75°C so that gefitinib was thoroughly dissolved, and then further stirred for about 1 hr.
  • the solution was gradually cooled to about 20°C and the produced solid was stirred for about 30 min and then further stirred at about 5°C for about 1 hr.
  • HPLC purity 99.89% (without N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine)
  • HPLC purity 88% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 10.0%)
  • the purified gefitinib was added to about 207.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75°C so that the gefitinib was thoroughly dissolved, and then further stirred for about 1 hr.
  • the solution was gradually cooled to about 20°C, and the produced solid was stirred for about 30 min and then additionally stirred at about 5°C for about 1 hr.
  • HPLC purity 96% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 3.0%)
  • Example 2 Under test conditions in Example 2 and Comparative Example 1, the reaction time required to terminate the reaction and the amount of unreacted 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate in the reaction solution mixture were measured using HPLC. The results are summarized in Table 1 below.
  • the amount of the N-alkylated impurity was only 1% or less before purification, and after purification, the N-alkylated impurity was not detected or was detected in a very small amount corresponding to 1/100 ⁇ 1/30 of those of the comparative examples.
  • the preparation method according to the present invention can be seen to minimize the production of the impurity.
  • gefitinib In the method of preparing gefitinib according to the present invention, production of an N-alkylated impurity can be inhibited via a simple process, and gefitinib can be obtained via filtration, etc., without the need for a complicated separation process such as chromatography, thus enabling the effective mass production of gefitinib having very high purity with high efficiency.

Abstract

This invention relates to a method of preparing gefitinib and an intermediate used therein. In the method of preparing gefitinib, the production of an N-alkylated impurity can be suppressed via a simple process, and thus, gefitinib having high purity can be obtained with high efficiency without a complicated separation process such as chromatography, thereby enabling the effective mass production of gefitinib.

Description

PROCESS FOR PREPARING GEFITINIB AND AN INTERMEDIATE USED FOR PREPARING THEREOF
The present invention relates to a method of preparing gefitinib and an intermediate used in the preparation of gefitinib.
N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) represented by Chemical Formula 1 below is a quinazoline derivative useful in treatment of non-small cell lung cancer. The structure of gefitinib is shown in the following Chemical Formula 1.
[Chemical Formula 1]
Figure PCTKR2013004024-appb-I000001
WO 96/33980 discloses the gefitinib synthesis method as represented in Scheme 1 below.
[Scheme 1]
Figure PCTKR2013004024-appb-I000002
According to the synthesis method of Scheme 1, 6,7-dimethoxy quinazolin-4-one as a starting material is subjected to selective demethylation, condensation with chlorofluoroaniline and then etherification with 4-(3-morpholinopropyl)chloride, thereby synthesizing gefitinib. Because gefitinib thus synthesized contains an excess of an N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine in the final step, the impurity should be separated via column chromatography, undesirably lowering the yield and making it difficult to achieve commercial production.
To solve such problems, WO 2004/024703 discloses a method of synthesizing gefitinib from a start material of 3-hydroxy-4-methoxy benzonitrile as shown in Scheme 2 below.
[Scheme 2]
Figure PCTKR2013004024-appb-I000003
In the synthesis method of Scheme 2, a morpholinopropyl group is introduced before forming a quinazoline ring, thus suppressing the production of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine which is the N-alkylated impurity. However, reduction of a nitro compound, formation of a quinazoline ring, and chlorination of the quinazoline ring in the final step to carry out condensation with chlorofluoroaniline are performed in the presence of the morpholinopropyl group, undesirably complicating the reaction process and lengthening the reaction time.
WO 2008/125867 discloses a method of synthesizing gefitinib from a start material of isovanilin as shown in Scheme 3 below.
[Scheme 3]
Figure PCTKR2013004024-appb-I000004
In the synthesis method of Scheme 3, propoxychloride is introduced before forming the quinazoline ring, thus suppressing the production of the N-alkylated impurity. After a quinazoline ring is formed and a morpholine group is introduced, chlorofluoroaniline is introduced, thus synthesizing gefitinib. However, a chloropropyl group and a morpholine group are separately introduced, instead of the morpholinopropyl group, thus increasing the number of synthesis steps, and also, the nitro reduction and the quinazoline ring reaction are performed in the presence of the chloropropyl group, undesirably causing the production of an impurity.
Additionally, WO 2005/023783 discloses a method of synthesizing gefitinib from imine via a rearrangement reaction, and WO 2005/070909 discloses a method of synthesizing gefitinib by performing nitrilization of oxime and then forming a quinazoline ring.
However, the preparation methods mentioned in the prior techniques produce an excess of impurity or include other routes to suppress the formation of the impurity, undesirably increasing the number of preparation steps and thus resulting in complicated processes and a long synthesis time, and thereby these methods are unsuitable for commercial production.
Therefore, there is required a method of efficiently and simply preparing gefitinib, which may minimize the production of an impurity and be suitable for use in industrial production.
[Citation List]
[Patent Literature]
(Patent Document 1) WO 96/33980
(Patent Document 2) WO 2004/024703
(Patent Document 3) WO 2008/125867
(Patent Document 4) WO 2005/070909
Accordingly, the present invention is to provide a method of preparing gefitinib, which minimizes the production of an impurity and enables the mass production of gefitinib having very high purity.
The present invention is to provide an intermediate, which enables the minimal production of an impurity and the mass production of gefitinib.
One Aspect of the present invention provides a method of preparing a compound represented by Chemical Formula 1, comprising a) reacting a compound represented by Chemical Formula 3 with a compound represented by Chemical Formula A to prepare a compound represented by Chemical Formula 4, and b) reacting the compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 5 to prepare a compound represented by Chemical Formula 6.
[Chemical Formula 3]
Figure PCTKR2013004024-appb-I000005
[Chemical Formula 4]
Figure PCTKR2013004024-appb-I000006
[Chemical Formula 5]
Figure PCTKR2013004024-appb-I000007
In Chemical Formula 5, wherein X is -Cl, -Br or -I.
[Chemical Formula 6]
Figure PCTKR2013004024-appb-I000008
[Chemical Formula 1]
Figure PCTKR2013004024-appb-I000009
[Chemical Formula A]
Figure PCTKR2013004024-appb-I000010
In Chemical Formula A, wherein X is -Cl, -Br or -I.
According to the method of the invention, the generation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine, which is the N-alkylated impurity of gefitinib, as represented by Chemical Formula 2, may be minimized, thus increasing the yield of gefitinib and, efficiently obtaining gefitinib having high purity, without chromatography.
[Chemical Formula 2]
Figure PCTKR2013004024-appb-I000011
Also, according to the present invention, the reaction may be completed within a short period of time, and thus the method of the invention may be effectively applied to commercial production of gefitinib.
In the present invention, the compound represented by Chemical Formula 3 may be prepared by reacting a compound represented by Chemical Formula 7 with a metal hydroxide.
[Chemical Formula 7]
Figure PCTKR2013004024-appb-I000012
The compound represented by Chemical Formula 7 is reacted with the metal hydroxide. Thus, even when the reaction is carried out at room temperature ranging from about 10℃ to about 30℃ it is completed within a short period of time, thus obtaining the compound represented by Chemical Formula 3 at high yield.
However, in the case where an organic base such as ammonia is reacted with the compound represented by Chemical Formula 7, the reaction time is lengthened and the reaction efficiency is decreased, thus increasing the unreacted proportion of the compound represented by Chemical Formula 7, resulting in decreased yield of the compound represented by Chemical Formula 3. When a portion of the reactant is left behind in this way, the reactant may function as an impurity in the subsequent process, and also, an additional purification process should be performed to separate the reactant from the product, undesirably complicating the preparation process and making it difficult to achieve mass production.
The metal hydroxide may be lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, or mixtures thereof. Preferably, the metal hydroxide may be lithium hydroxide.
The reaction between the compound represented by Chemical Formula 7 and the metal hydroxide to prepare the compound represented by Chemical Formula 3 may be performed using a solvent such as water, methanol, ethanol, isopropylalcohol or mixtures thereof, and preferably using a mixture of methanol and water as the solvent.
In the method of the invention, a) may be performed in the presence of a base. The base may be potassium carbonate, sodium carbonate, calcium carbonate or a mixture thereof, and may be preferably potassium carbonate.
Also, a) may be performed in the presence of a catalyst, and the catalyst may be N,N-dimethylaminopyridine.
In the present invention, a) and b) may be performed using a solvent such as dimethylsulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, or mixtures thereof, and preferably using N,N-dimethylacetamide as the solvent.
According to the present invention, a) and b) may be performed in situ using a single reactor. Particularly, the compound represented by Chemical Formula 5 may be added to the solution containing the compound represented by Chemical Formula 4, which is prepared by the reaction of a), without separating the compound represented by Chemical Formula 4, thereby preparing the compound represented by Chemical Formula 6. Thus, protection and deprotection may be carried out using a single reactor without separating the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 6, thus simplifying the preparation process of gefitinib and remarkably increasing the reaction efficiency.
The method of the invention may further include c) eliminating a trimethylsilyl group from the compound represented by Chemical Formula 6.
In the present invention, the trimethylsilyl group which functions as an amine protecting group is eliminated from the compound represented by Chemical Formula 6, so that the amine group is exposed, thereby obtaining gefitinib represented by Chemical Formula 1. Briefly, the trimethylsilyl group of the compound represented by Chemical Formula 6 is substituted with -H, yielding gefitinib.
The elimination of the trimethylsilyl group may be performed by adding water to the solution containing the compound represented by Chemical Formula 6.
When water is added to the solution containing the compound represented by Chemical Formula 6, the trimethylsilyl group may be eliminated from Chemical Formula 6, so that the gefitinib may be directly obtained as a solid. Thus, according to the present invention, because the production of the N-alkylated impurity is low and a simple process involving the addition of water is performed without an additional process for separating the compound represented by Chemical Formula 6, the preparation and separation of gefitinib may occur simultaneously, thereby simplifying the preparation process of gefitinib. Ultimately, the method of the invention may be effectively applied to mass production of gefitinib.
In the method of preparing gefitinib according to the present invention, the production of the N-alkylated impurity may be inherently inhibited and gefitinib having high purity of 99.9% or more may be obtained at high yield without a complicated process such as chromatography.
The present invention provides a compound represented by Chemical Formula 4 or 6 and salts thereof.
[Chemical Formula 4]
Figure PCTKR2013004024-appb-I000013
[Chemical Formula 6]
Figure PCTKR2013004024-appb-I000014
The compound represented by Chemical Formula 4 or 6 may be used as an intermediate in the preparation of gefitinib.
In the case where the compound represented by Chemical Formula 4 is reacted with the compound represented by Chemical Formula 5, the compound represented by Chemical Formula 5 does not react with N of the amine group of quinazoline but selectively reacts with the -OH group of quinazoline, thus effectively preparing the compound represented by Chemical Formula 6.
[Chemical Formula 5]
Figure PCTKR2013004024-appb-I000015
Thus, the production of the impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine, may be inherently suppressed. Also, complicated multi-steps need not be performed in order to suppress the production of the N-alkylated impurity, and a process such as chromatography need not be conducted in order to eliminate the N-alkylated impurity.
Also, the compound represented by Chemical Formula 6 is produced via the reaction between the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 5, and then only water is added to the solution containing the compound represented by Chemical Formula 6 without the need for separation and purification, whereby the trimethylsilyl group is eliminated, and gefitinib in a solid is produced. Briefly, because gefitinib is deposited in a solid in the solution at the same time of being produced, only a filtration process is performed without the additional need for a separation process, yielding gefitinib.
Accordingly, when the compound represented by Chemical Formula 4 and the compound represented by Chemical Formula 6 are used as intermediates for preparing gefitinib, gefitinib having very high purity may be easily produced with high efficiency via a simple process.
The salts of the compound represented by Chemical Formula 4 or 6 may be pharmaceutically acceptable salts. The pharmaceutically acceptable salts indicate salts typically used in the pharmaceutical industry, and examples thereof include metal ion salts prepared using calcium, potassium, sodium, magnesium, etc., inorganic acid salts prepared using hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc., organic acid salts prepared using acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanilic acid, hydroiodic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, etc., sulfonic acid salts prepared using methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or naphthalenesulfonic acid, amino acid salts prepared using glycine, arginine, lysine, etc., and amine salts prepared using trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the kinds of salts used in the present invention are not limited by the salts listed as above.
In the method of preparing gefitinib according to the present invention, production of an N-alkylated impurity can be inhibited via a simple process, and gefitinib can be obtained via filtration, etc., without the need for a complicated separation process such as chromatography, thus enabling the effective mass production of gefitinib having very high purity with high efficiency.
A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention.
Unless otherwise stated, reagents and solvents mentioned below were those available from Sigma-Aldrich Korea and Merck, HPLC was 1200 Series available from Agilent Technologies, and 1H NMR data was measured using 400 UltraShield NMR Spectrometer available from Bruker.
The HPLC conditions used in the present invention were as follows, and HPLC was used to measure the purity of gefitinib and the amount of the N-alkyl impurity, in the reaction mixture after reaction.
Detector: UV spectrophotometer (measurement wavelength: 250 nm)
Column: Hypersil C18 (4.6 mm X 250 mm, 5 ㎛)
Mobile phase: mixture of 5 mol% ammonium acetate aqueous solution and acetonitrile (60:40)
Flow rate: 1.0 mL/min
Sample: test sample 25 mg/mobile phase 50 mL
Injected amount: 20 ㎕
<Example 1> Preparation of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride
About 100.0 g of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate and about 1100.0 mL of toluene were placed in a flask and then stirred at about 20℃. About 90.0 mL of triethylamine and about 59.9 mL of phosphorylchloride were placed in the flask and then stirred at about 60℃ for about 5 hr. The reaction mixture was cooled to about 20℃ and then about 600.0 mL of isopropylalcohol was slowly added while paying attention to heat generation. Subsequently, a solution of about 62.1 g of 3-chloro-4-fluoroaniline dissolved in about 100.0 mL of isopropylalcohol was slowly added in droplets, and the resulting mixture was heated to about 65℃ and stirred for about 2 hr. The termination of the reaction was confirmed using HPLC and TLC. The temperature of the flask was decreased to about 20℃, stirring was performed for about 1 hr, and the produced solid was filtered. The solid was washed with about 800.0 mL of isopropylalcohol and then dried at about 40℃ for about 2 hr, thus obtaining about 180.0 g of the title compound 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride as yellow powder.
1H NMR (400MHz, DMSO-d6): 2.3 (s,3H), 4.0 (s,3H), 7.5 (t,1H), 7.6 (s,1H), 7.7 (m,1H), 8.0 (m,1H), 8.8 (s,1H), 8.9 (s,1H), 11.5 (broad s, 1H)
<Example 2> Preparation of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol
About 180.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride, about 1000.0 mL of methanol and about 1000.0 mL of water were slowly placed in a flask while paying attention to heat generation. The resulting mixture was suspended at about 20℃ with stirring, added with about 30.7 g of lithium hydroxide, and vigorously stirred for about 30 min. The termination of the reaction was confirmed using HPLC and TLC. The reaction product was cooled to about 20℃, and then neutralized to pH 7.0 using about 200.0 mL of about 20% (v/v%) acetic acid. This solution was stirred at about 20℃ for about 1 hr, and the produced solid was filtered. The solid was washed with about 200.0 mL of methanol and then dried in a vacuum at about 40℃ for about 3 hr, thus obtaining about 123.0 g of the title compound 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol as pale yellow powder.
1H NMR (400MHz, DMSO-d6): 4.0 (s, 3H), 7.4 (s, 1H), 7.8 (s, 1H), 7.85 (m,1H), 8.2 (m, 1H), 8.5 (s, 1H), 9.45 (s, 1H), 9.65 (s, 1H)
<Example 3-1> Preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)
About 123.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and about 1100.0 mL of N,N-dimethylformamide were placed in a flask. The resulting mixture was suspended with stirring while about 186.0 g of potassium carbonate and about 4.7 g of N,N-dimethylaminopyridine were added. The reaction mixture was cooled to about -10℃, slowly added with about 77.0 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15℃ for about 1 hr. Then about 75.5 g of 4-(3-chloropropyl)morpholine was diluted with about 130.0 mL of N,N-dimethylformamide and then slowly added. The reaction mixture was heated to about 80℃ and stirred for about 2 hr. The termination of the reaction was confirmed using HPLC and TLC. The reaction product was cooled to about 20℃, slowly added with 2460.0 mL of purified water, and stirred for 30 min, and the produced solid was filtered. The obtained solid was washed with about 490.0 mL of purified water and then dried in a vacuum at about 50℃ for about 3 hr, yielding about 154.7 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder.
HPLC purity: 99.21% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.3%)
1H-NMR (400MHz, DMSO-d6): 2.0 (m,2H), 2.4 (m,6H), 3.7 (m,4H), 3.9 (s,3H), 4.2 (t,2H), 7.2 (s,1H), 7.4 (t,1H), 7.8 (m,2H), 8.2 (m,1H), 8.5 (s,1H), 9.6 (s,1H)
<Example 3-2> Preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)
About 7.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and about 63.0 mL of N,N-dimethylacetamide were placed in a flask. The mixture was suspended with stirring while about 10.6 g of potassium carbonate and 0.3 g of N,N-dimethylaminopyridine were added. The reaction mixture was cooled to about -10℃, slowly added with 4.4 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15℃ for about 1 hr. About 4.3 g of 4-(3-chloropropyl)morpholine was diluted with about 8.0 mL of N,N-dimethylformamide and then slowly added. The reaction mixture was heated to about 80℃, and stirred for about 2 hr. The termination of the reaction was confirmed using HPLC and TLC. The reaction product was cooled to about 20℃, slowly added with about 140.0 mL of purified water, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 20.0 mL of purified water and then dried in a vacuum at about 50℃ for about 3 hr, yielding about 8.6 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder.
HPLC purity: 99.20% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.3%)
<Example 3-3> Preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)
About 8.3 g of the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder was obtained in the same manner as in Example 3-2, with the exception that dimethylsulfoxide (DMSO) was used as the solvent, instead of N,N-dimethylacetamide (DMAC).
HPLC purity: 98.89% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.7%)
<Example 3-4> Confirmation of 4-((3-chloro-4-fluorophenyl)(trimethylsilyl)amino)-7-methoxyquinazolin-6-ol (Reaction intermediate represented by Chemical Formula 4)
About 0.5 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and 5.0 mL of N,N-dimethylformamide-d7 were placed in a flask. This mixture was suspended with stirring while about 0.462 g of potassium carbonate was added. The reaction mixture was cooled to about -10℃, slowly added with about 0.22 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15℃ for about 1 hr. About 1 mL of the reaction sample was subjected to NMR analysis, and thereby the title compound 4-((3-chloro-4-fluorophenyl)(trimethylsilyl)amino)-7-methoxyquinazolin-6-ol was confirmed to be synthesized.
1H NMR (400MHz, DMF-d7): 0.3 (s,9H), 3.9 (s,3H), 7.2 (s,1H), 7.4 (m,1H), 7.8 (m,2H), 8.2 (m,1H), 8.6 (s,1H), 9.93 (s,1H)
<Example 3-5> Confirmation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(trimethylsilyl)-quinazoline-4-amine (Reaction intermediate represented by Chemical Formula 6)
About 0.5 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol and about 5.0 mL of N,N-dimethylformamide-d7 were placed in a flask. This mixture was suspended with stirring while about 0.462 g of potassium carbonate and about 0.013 g of N,N-dimethylaminopyridine were added. The reaction mixture was cooled to about -10℃, slowly added with about 0.22 g of iodotrimethylsilane while paying attention to heat generation, and stirred at about 15℃ for about 1 hr. About 0.222 g of 4-(3-chloropropyl)morpholine was diluted with about 1.0 mL of N,N-dimethylformamide and then slowly added. The reaction mixture was heated to about 80℃ and stirred for about 2 hr. About 1 mL of the reaction sample was subjected to NMR analysis, and thereby the title compound N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(trimethylsilyl)-quinazoline-4-amine was confirmed to be synthesized.
1H-NMR (400MHz, DMF-d7): 0.2 (s,9H), 1.9 (m,2H), 2.3 (br,4H), 2.4 (m,2H), 3.6 (m,4H), 3.9 (s,3H), 4.2 (t,2H), 7.2 (s,1H), 7.4 (t,1H), 7.8 (m,2H), 8.1 (m,1H), 8.5 (s,1H), 9.6 (s,1H)
<Example 4-1> Purification of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)
About 154.7 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine obtained in Example 3-1 was suspended with stirring in about 2320.0 mL of toluene and about 1160.0 mL of anhydrous ethanol, and then heated to about 40℃ so as to be thoroughly dissolved. About 37.0 g of neutral activated carbon was added in the resulting solution, stirred for about 1 hr, and filtered to thus remove the activated carbon. The filtrate was concentrated to about 1400 mL, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 246.0 mL of toluene, and dried at about 40℃ for about 3 hr, thus obtaining about 135.3 g of white gefitinib.
The purified gefitinib was added to about 2340.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75℃ so that gefitinib was thoroughly dissolved, and then further stirred for about 1 hr. The solution was gradually cooled to about 20℃ and the produced solid was stirred for about 30 min and then further stirred at about 5℃ for about 1 hr. The obtained solid was filtered, washed with about 123.0 mL of anhydrous ethanol, and dried in a vacuum at about 45℃ for about 5 hr, yielding about 128.5 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib).
HPLC purity: 99.91% (without N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine)
<Example 4-2> Purification of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)
About 8.6 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine obtained in Example 3-2 was suspended with stirring in about 129.0 mL of toluene and about 65.0 mL of anhydrous ethanol, and heated to about 40℃ so as to be thoroughly dissolved. About 1.9 g of neutral activated carbon was added into the resulting solution, stirred for about 1 hr, and filtered to thus remove the activated carbon. The filtrate was concentrated to about 90 mL, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 20.0 mL of toluene, and dried at about 40℃ for about 3 hr, thus obtaining about 7.3 g of white gefitinib.
The purified gefitinib was added to about 125.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75℃ so that gefitinib was thoroughly dissolved, and then further stirred for about 1 hr. The solution was gradually cooled to about 20℃ and the produced solid was stirred for about 30 min and then further stirred at about 5℃ for about 1 hr. The obtained solid was filtered, washed with about 7.0 mL of anhydrous ethanol, and dried in a vacuum at about 45℃ for about 5 hr, yielding about 6.5 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib).
HPLC purity: 99.89% (without N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine)
<Example 4-3> Purification of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib)
About 6.2 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) was obtained in the same manner as in Example 4-1, with the exception that the gefitinib prepared in Example 3-3 was used.
HPLC purity: 99.87% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 0.03%)
<Comparative Example 1> Synthesis of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol
About 30.0 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate hydrochloride and about 1050 mL of methanol were placed in a flask, suspended with stirring, and then slowly added with about 37.6 mL of 30% (w/w%) aqueous ammonia. The mixture was stirred at room temperature for about 15 hr, heated to about 65℃ and refluxed with stirring for about 2 hr. The termination of the reaction was confirmed using TLC. The reaction product was cooled to about 20℃ and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 150 mL of methanol and dried in a vacuum at about 40℃, yielding about 22.6 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol as pale yellow powder.
<Comparative Example 2-1>
About 22.6 g of 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol obtained in Comparative Example 1 and about 339 mL of N,N-dimethylformamide were placed in a flask, suspended with stirring, and about 34.2 g of potassium carbonate and about 13.9 g of 4-(3-chloropropyl)morpholine were slowly added. The reaction mixture was heated to about 80℃ and stirred for about 5 hr. The termination of the reaction was confirmed using TLC. The reaction product was cooled to about 20℃, slowly added with about 678.0 mL of purified water, and stirred for about 1 hr, and the produced solid was filtered. The obtained solid was washed with about 150.0 mL of purified water, dried at about 40℃ for about 3 hr, and further dried in a vacuum at about 50℃, yielding about 23.0 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) as pale yellow powder.
HPLC purity: 65% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 30%)
<Comparative Example 2-2>
About 23.7 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) was obtained in the same manner as in Comparative Example 2-1, with the exception that, upon addition of potassium carbonate, about 0.9 g of N,N-dimethylaminopyridine was added together.
HPLC purity: 88% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 10.0%)
<Comparative Example 3-1>
About 23.0 g of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine obtained in Comparative Example 2-1 was suspended with stirring in about 345.0 mL of toluene and about 173.0 mL of anhydrous ethanol, and then heated to about 40℃ so as to be thoroughly dissolved. About 5.8 g of neutral activated carbon was added in the resulting solution, stirred for about 1 hr, and filtered to remove the activated carbon. The filtrate was concentrated to about 25 mL, and stirred for about 30 min, and the produced solid was filtered. The obtained solid was washed with about 50.0 mL of toluene, and dried at about 40℃ for about 3 hr, yielding about 11.5 g of white gefitinib.
The purified gefitinib was added to about 207.0 mL of anhydrous ethanol to prepare a suspension, which was then refluxed with stirring at about 75℃ so that the gefitinib was thoroughly dissolved, and then further stirred for about 1 hr. The solution was gradually cooled to about 20℃, and the produced solid was stirred for about 30 min and then additionally stirred at about 5℃ for about 1 hr. The obtained solid was filtered, washed with about 11.0 mL of anhydrous ethanol, and dried in a vacuum at about 45℃ for about 5 hr, yielding 10.1 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib).
HPLC purity: 96% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 3.0%)
<Comparative Example 3-2>
About 14.5 g of purified white N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib) was obtained in the same manner as in Comparative Example 3-1, with the exception that the gefitinib prepared in Comparative Example 2-2 was used.
HPLC purity: 98% (N-alkylated impurity, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine: 1.0%)
<Test Example 1> Analysis of unreacted residue according to the method of preparing 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol
Under test conditions in Example 2 and Comparative Example 1, the reaction time required to terminate the reaction and the amount of unreacted 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate in the reaction solution mixture were measured using HPLC. The results are summarized in Table 1 below.
[Table 1]
Figure PCTKR2013004024-appb-I000016
In the case where 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol was prepared using aqueous ammonia in Comparative Example 1, the reaction at room temperature for 18 hr and reflux with stirring at increased temperature were performed, resulting in about 2% of the unreacted residue. Such an unreacted residue is regarded as an impurity, and thus may negatively affect the quality of finally obtained gefitinib in the subsequent reaction.
However, in the case where 4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol was prepared using the method of Example 2 according to the present invention, the reaction time was very short, resulting in 0.1% or less of the unreacted residue. Thus, it is confirmed that the reaction efficiency is greatly increased.
Therefore, it is confirmed that the preparation method according to the present invention remarkably increase the reaction efficiency.
<Test Example 2> Analysis of N-alkylated impurity according to the method of preparing N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine
In the preparation of N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine of Examples 3-1 to 3-3 and 4-1 to 4-3 and Comparative Examples 2-1, 2-2, 3-1, 3-2, the reaction mixture was analyzed using HPLC, and the amount of the N-alkylated impurity in the reaction mixture was measured. The results are summarized in Table 2 below.
[Table 2]
Figure PCTKR2013004024-appb-I000017
As is apparent from Table 2, in the case where the reaction was carried out without the addition of a silyl protecting group (Comparative Examples 2-1 and 2-2), the impurity having alkyl introduced to the amino group, that is, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)quinazoline-4-amine, was produced in a large amount. Also, as in Comparative Examples 3-1 and 3-2, such an impurity was left behind in a large amount in the final gefitinib even after the additional purification process.
However, in the examples according to the invention, the amount of the N-alkylated impurity was only 1% or less before purification, and after purification, the N-alkylated impurity was not detected or was detected in a very small amount corresponding to 1/100 ~ 1/30 of those of the comparative examples.
Therefore, the preparation method according to the present invention can be seen to minimize the production of the impurity.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.
In the method of preparing gefitinib according to the present invention, production of an N-alkylated impurity can be inhibited via a simple process, and gefitinib can be obtained via filtration, etc., without the need for a complicated separation process such as chromatography, thus enabling the effective mass production of gefitinib having very high purity with high efficiency.

Claims (13)

  1. A method of preparing a compound represented by Chemical Formula 1, comprising:
    a) reacting a compound represented by Chemical Formula 3 with a compound represented by Chemical Formula A, to prepare a compound represented by Chemical Formula 4; and
    b) reacting the compound represented by Chemical Formula 4 with a compound represented by Chemical Formula 5 to prepare a compound represented by Chemical Formula 6:
    [Chemical Formula 3]
    Figure PCTKR2013004024-appb-I000018
    [Chemical Formula 4]
    Figure PCTKR2013004024-appb-I000019
    [Chemical Formula 5]
    Figure PCTKR2013004024-appb-I000020
    in chemical Formula 5, wherein X is -Cl, -Br or -I.
    [Chemical Formula 6]
    Figure PCTKR2013004024-appb-I000021
    [Chemical Formula 1]
    Figure PCTKR2013004024-appb-I000022
    [Chemical Formula A]
    Figure PCTKR2013004024-appb-I000023
    in the chemical formula A, wherein X is -Cl, -Br or -I.
  2. The method of claim 1, wherein the compound represented by Chemical Formula 3 is prepared by reacting a compound represented by Chemical Formula 7 with a metal hydroxide.
    [Chemical Formula 7]
    Figure PCTKR2013004024-appb-I000024
  3. The method of claim 2, wherein the metal hydroxide is at least one selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide.
  4. The method of claim 1, further comprising c) substituting a trimethylsilyl group of the compound represented by Chemical Formula 6 with -H.
  5. The method of claim 4, wherein c) is performed by adding water.
  6. The method of claim 5, wherein the compound represented by Chemical Formula 1 is obtained as a solid by adding water.
  7. The method of claim 1, wherein a) is performed using a catalyst.
  8. The method of claim 7, wherein the catalyst is N,N-dimethylaminopyridine.
  9. The method of claim 1, wherein a) and b) are performed using at least one selected from the group consisting of dimethylsulfoxide, N,N-dimethylacetamide and N,N-dimethylformamide, as a solvent.
  10. The method of claim 1, wherein a) is performed using at least one base selected from the group consisting of potassium carbonate, sodium carbonate, and calcium carbonate.
  11. The method of claim 1, wherein a) and b) are performed using N,N-dimethylformamide as a solvent.
  12. A compound represented by Chemical Formula 4 or salts thereof.
    [Chemical Formula 4]
    Figure PCTKR2013004024-appb-I000025
  13. A compound represented by Chemical Formula 6 or salts thereof.
    [Chemical Formula 6]
    Figure PCTKR2013004024-appb-I000026
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CN104817506A (en) * 2015-05-06 2015-08-05 山东新时代药业有限公司 Quinazoline nitrogen oxide
CN111533703A (en) * 2020-05-07 2020-08-14 山东安弘制药有限公司 Gefitinib purification process

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