KR101457453B1 - 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 PDFInfo
- Publication number
- KR101457453B1 KR101457453B1 KR1020120057883A KR20120057883A KR101457453B1 KR 101457453 B1 KR101457453 B1 KR 101457453B1 KR 1020120057883 A KR1020120057883 A KR 1020120057883A KR 20120057883 A KR20120057883 A KR 20120057883A KR 101457453 B1 KR101457453 B1 KR 101457453B1
- Authority
- KR
- South Korea
- Prior art keywords
- gefitinib
- formula
- compound represented
- chloro
- reaction
- Prior art date
Links
Classifications
-
- 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
Abstract
본 발명은 게피티닙 제조방법 및 상기 제조방법에 사용되는 중간체를 제공한다. 본 발명의 게피티닙 제조방법에 따르면, 간단한 공정으로 N-알킬화된 불순물의 생성을 억제할 수 있다. 따라서, 크로마토그래피와 같은 복잡합 분리 공정을 거치지 않고 고효율로 고순도의 게피티닙을 수득할 있어 게피티닙을 효과적으로 대량생산 할 수 있다. The present invention provides a process for producing gefitinib and intermediates used in the process. According to the gefitinib production method of the present invention, the production of N-alkylated impurities can be suppressed by a simple process. Thus, it is possible to obtain high-purity gefitinib with high efficiency and high efficiency without performing a complex separation and separation step such as chromatography, thereby enabling mass production of gefitinib effectively.
Description
본 발명은 게피티닙의 제조방법 및 상기 게피티닙의 제조에 사용되는 중간체에 관한 것이다. The present invention relates to a process for the preparation of gefitinib and intermediates used in the preparation of said gefitinib.
하기 화학식 1로 표시되는 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민(게피티닙)은 비소세포폐암의 치료에 유용한 퀴나졸린 유도체이다. 게피티닙의 구조는 아래 화학식 1과 같다.(3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib) represented by the following formula ≪ / RTI > The structure of gefitinib is shown in the following chemical formula 1.
[화학식 1][Chemical Formula 1]
WO 96/33980에 하기 반응식 1과 같이 게피티닙의 합성법을 개시하고 있다. WO 96/33980 discloses a method for synthesizing gefitinib as shown in Reaction Scheme 1 below.
[반응식 1][Reaction Scheme 1]
상기 반응식 1의 제조방법에 따르면, 6,7-디메톡시 퀴나졸린-4-온을 출발물질로 하여 선택적인 디메틸화 반응을 거쳐 생성된 화합물을 클로로플루오로아닐린과 축합반응시킨 후, 4-(3-몰포리노프로필)클로라이드와 에테르화 반응을 거쳐 게피티닙이 합성된다. 이렇게 합성된 게피티닙은 최종단계에서 N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민이 과량 포함되어 있기 때문에 불순물을 컬럼크로마토그래피에 의해 분리하여야만 하고 이로 인해 수율이 저조하고 상업적인 생산이 어렵다. According to the process of Reaction Scheme 1, a compound produced through optional dimetization reaction using 6,7-dimethoxyquinazolin-4-one as a starting material is condensed with chlorofluoroaniline, 3-morpholinopropyl) chloride and etherified to synthesize gefitinib. The thus synthesized gefitinib is reacted with an N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) -Morpholinopropyl) quinazolin-4-amine, the impurities must be separated by column chromatography, which results in poor yield and difficult commercial production.
이와 같은 문제점을 해결하기 위하여 WO 2004/024703에는 3-하이드록시-4-메톡시 벤조니트릴을 출발물질로 하여 하기 반응식 2와 같이 게피티닙을 합성하는 방법을 기재하고 있다. In order to solve such a problem, WO 2004/024703 describes a method for synthesizing gefitinib using 3-hydroxy-4-methoxybenzonitrile as a starting material as shown in Reaction Scheme 2 below.
[반응식 2][Reaction Scheme 2]
상기 반응식 2의 제조방법에서는 퀴나졸린 고리화합물을 합성하기 이전에 몰포리노프로필기를 먼저 도입하여 N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민의 생성을 억제하였으나 몰포리노프로필기가 도입된 상태에서 나이트로 화합물의 환원, 퀴나졸린 고리의 형성, 최종단계에서 퀴나졸린 고리의 클로로화를 통한 클로로플루오로아닐린과의 축합반응을 수행하여 반응 공정이 복잡해지고 반응시간이 길어지는 문제점이 있다. In the method of the above reaction formula 2, the morpholinopropyl group is first introduced before the synthesis of the quinazoline ring compound to obtain N- (3-chloro-4-fluorophenyl) -7-methoxy- (3-morpholinopropoxy) -N- (3-morpholinopropyl) quinazolin-4-amine, the reduction of the nitro compound, formation of the quinazoline ring, The condensation reaction with chlorofluoroaniline through the chlorination of the quinazoline ring is performed to complicate the reaction process and increase the reaction time.
WO 2008/125867의 이소바닐린을 출발물질로 하여 게피티닙을 합성하는 제조방법은 하기 반응식 3과 같이 표시 될 수 있다.A preparation method of synthesizing gefitinib using isovanillin of WO 2008/125867 as a starting material can be represented by the following reaction formula (3).
[반응식 3][Reaction Scheme 3]
상기 반응식 3의 제조방법 역시 퀴나졸린 고리화합물을 합성하기 이전에 프로폭시클로라이드를 도입하여 N-알킬화된 불순물의 생성을 억제하고 있으며, 퀴나졸린 고리를 형성하고 몰포린기를 도입한 후 클로로플루오로아닐린을 도입함으로써 게피티닙을 합성한다. 그러나 몰포리노프로필기 대신 클로로프로필기와 몰포린기로 나누어 도입함으로써 합성 단계가 증가하고 클로로프로필기가 도입된 상태에서 나이트로 환원반응, 퀴나졸린 고리화 반응을 수행함으로써 불순물의 생성을 야기할 수 있다. The preparation method of the above Reaction Scheme 3 also inhibits the formation of N-alkylated impurities by introducing propoxy chloride prior to the synthesis of the quinazoline ring compound, forming a quinazoline ring, introducing a morpholine group and then introducing chlorofluoroaniline To synthesize gefitinib. However, by introducing a chloropropyl group and a morpholine group in place of the morpholino propyl group, the synthesis step is increased, and in the state where the chloropropyl group is introduced, a reduction reaction with a nitro group or a quinazoline cyclization reaction can be carried out to generate impurities.
이 밖에 WO 2005/023783에서 이민형태로부터 재배열반응을 거쳐 게피티닙을 합성하는 방법과, WO 2005/070909에서는 옥심을 니트릴화한 후 퀴나졸린고리화합물을 합성하는 경로를 거쳐 게피티닙을 합성하는 방법을 개시하고 있다.Further, WO 2005/023783 discloses a method for synthesizing gefitinib through rearrangement reaction from an imine form, and WO 2005/070909 discloses a method for synthesizing gefitinib through nitrile oxime and a route for synthesizing a quinazoline ring compound A method is disclosed.
그러나 상기 선행기술들에서 언급되어진 제조방법 역시, 과량의 불순물이 생성되거나 이를 억제하기 위하여 다른 경로로 합성되어지기 때문에 다단계를 필요로 하여 공정이 복잡해지고 합성에 많은 시간이 소요되며 그 결과 대규모의 상업적 생산에 적합하지 않다.However, the manufacturing methods mentioned in the above prior arts also require a multistage process because the excess impurities are produced or synthesized by other routes in order to inhibit them, which complicates the process and takes a long time for the synthesis. As a result, Not suitable for production.
따라서 불순물의 생성을 최소화하고 효율적이고 간단한 방법으로 대규모의 산업적인 생산에 적합한 게피티닙 제조 방법이 요구된다. Therefore, there is a need for a method for producing gefitinib that is suitable for large-scale industrial production in an efficient and simple manner with minimal generation of impurities.
본 발명의 목적은 불순물의 생성을 최소화하고 고순도의 게피티닙을 대량으로 생산할 수 있는 게피티닙의 제조 방법을 제공하는 것이다. It is an object of the present invention to provide a method for producing gefitinib which can minimize the production of impurities and can produce a large amount of high purity gefitinib.
본 발명의 다른 목적은 불순물의 생성을 최소화하고 게피티닙의 대량생산을 가능하게 하는 중간체를 제공하는 것이다. Another object of the present invention is to provide an intermediate which minimizes the production of impurities and enables the mass production of gefitinib.
본 발명은 a) 하기 화학식 3으로 표시되는 화합물을 클로로트리메틸실란, 브로모트리메틸실란 및 아이오도트리메틸실란 중에서 선택된 하나의 화합물과 반응시켜 하기 화학식 4로 표시되는 화합물을 제조하는 단계 및 b) 상기 화학식 4로 표시되는 화합물을 하기 화학식 5로 표시되는 화합물과 반응시켜 하기 화학식 6으로 표시되는 화합물을 제조하는 단계를 포함하는 하기 화학식 1로 표시되는 화합물을 제조하는 방법을 제공한다. The present invention relates to a process for the preparation of a compound of formula (I), comprising the steps of: a) reacting a compound represented by the formula (3) with one compound selected from chlorotrimethylsilane, bromotrimethylsilane and iodotrimethylsilane, and b) 4 is reacted with a compound represented by the following formula (5) to prepare a compound represented by the following formula (6).
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
상기 화학식 5에서 X는 -Cl, -Br 또는 -I이다.In Formula 5, X is -Cl, -Br, or -I.
[화학식 6][Chemical Formula 6]
[화학식 1][Chemical Formula 1]
삭제delete
삭제delete
삭제delete
본 발명의 방법에 따르면, 하기 화학식 2로 표시되는 게피티닙의 N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민의 발생을 최소화할 수 있어 게피티닙의 수율을 향상시킬 수 있으며, 크로마토그래피 공정 없이 간단하게 고순도의 게피티닙을 수득할 수 있다. According to the process of the present invention there is provided a process for the preparation of N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopro (3-morpholinopropyl) quinazolin-4-amine can be minimized and the yield of gefitinib can be improved and a high purity gefitinib can be obtained without a chromatographic process .
[화학식 2](2)
또한, 본 발명에 따르면, 짧은 시간에 반응을 완료할 수 있어 게피티닙의 상업적 대량생산에 효과적으로 적용될 수 있다. Further, according to the present invention, the reaction can be completed in a short time and can be effectively applied to the commercial mass production of gefitinib.
본 발명에 있어서, 상기 화학식 3으로 표시되는 화합물은 하기 화학식 7로 표시되는 화합물을 금속 수산화물과 반응시켜 제조될 수 있다. In the present invention, the compound represented by Formula 3 may be prepared by reacting a compound represented by Formula 7 with a metal hydroxide.
[화학식 7](7)
상기 화학식 7로 표시되는 화합물을 금속 수산화물과 반응시킴으로써 10 내지 30℃와 같은 상온에서 반응을 진행하여도 짧은 시간 안에 반응이 완료되어 화학식 3으로 표시되는 화합물을 높은 수율로 수득할 수 있다. By reacting the compound represented by the formula (7) with a metal hydroxide, the reaction is completed in a short time even if the reaction is carried out at room temperature such as 10 to 30 ° C, and the compound represented by the formula (3) can be obtained in a high yield.
그러나 암모니아와 같은 유기 염기와 상기 화학식 7로 표시되는 화합물을 반응시키는 경우, 반응시간이 길어지고 반응 효율이 저하되어 화학식 7로 표시되는 화합물의 미반응 비율이 증가하고 그 결과 화학식 3으로 표시되는 화합물의 수율이 다소 저하될 수 있다. 이와 같이 반응 물질 중 일부가 잔류하는 경우 상기 반응 물질이 후속 공정에서 불순물로 작용할 수 있으며 또한 상기 반응 물질을 생성 물질과 분리하기 위하여 추가적인 정제 공정을 수행해야 하므로 공정이 복잡해져 대량 생산에 적용하기 부적합하다.However, when an organic base such as ammonia is reacted with the compound represented by the above formula (7), the reaction time is lengthened and the reaction efficiency is lowered to increase the unreacted ratio of the compound represented by the formula (7) May be somewhat lowered. In the case where a part of the reactants is left as such, the reactant may act as an impurity in a subsequent process, and further purification process must be performed in order to separate the reactant from the product, which complicates the process and is unsuitable for mass production .
상기 금속 수산화물은 리튬히드록사이드, 소듐히드록사이드, 포타슘히드록사이드, 칼슘히드록사이드 또는 이들의 혼합물일 수 있으며 바람직하게는 리튬히드록사이드일 수 있다.The metal hydroxide may be lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or a mixture thereof, preferably lithium hydroxide.
상기 화학식 7으로 표시되는 화합물을 금속 수산화물과 반응시켜 상기 화학식 3로 표시되는 화합물을 제조하는 단계는 물, 메탄올, 에탄올, 이소프로필알콜 또는 이들의 혼합물을 용매로 사용하여 수행될 수 있으며, 바람직하게는 메탄올과 물의 혼합물을 용매로 사용하여 수행될 수 있다. The step of reacting the compound represented by the formula (7) with a metal hydroxide to produce the compound represented by the formula (3) can be carried out using water, methanol, ethanol, isopropyl alcohol or a mixture thereof as a solvent, Can be carried out using a mixture of methanol and water as a solvent.
상기 a) 단계는 염기 존재 하에 수행될 수 있으며, 상기 염기는 탄산칼륨, 탄산나트륨, 탄산칼슘일 수 있으며, 바람직하게는 탄산칼륨일 수 있다. The step a) may be carried out in the presence of a base, and the base may be potassium carbonate, sodium carbonate or calcium carbonate, preferably potassium carbonate.
상기 a) 단계는 촉매 존재 하에서 수행될 수 있으며, 상기 촉매는 N,N-디메틸아미노피리딘 일 수 있다. The step a) may be carried out in the presence of a catalyst, and the catalyst may be N, N-dimethylaminopyridine.
본 발명에 있어 상기 a) 단계 및 상기 b) 단계는 디메틸설폭시드, N,N-디메틸아세트아미드, N,N-디메틸포름아미드 또는 이들의 혼합물을 용매로 사용하여 수행될 수 있으며, 바람직하게는 N,N-디메틸아세트아미드를 용매로 사용하여 수행될 수 있다. In the present invention, steps a) and b) may be carried out using a solvent such as dimethylsulfoxide, N, N-dimethylacetamide, N, N-dimethylformamide or a mixture thereof, N, N-dimethylacetamide as a solvent.
본 발명에 따르면, 상기 a) 단계 및 단계 b)는 하나의 반응기 내에서 인 시츄(in situ)로 수행될 수 있다. 즉, a) 단계의 반응을 수행하여 제조된 화학식 4로 표시되는 화합물을 분리하지 않고 상기 화학식 4로 표시되는 화합물을 포함하는 용액에 화학식 5로 표시되는 화합물을 투입하여 화학식 6으로 표시되는 화합물을 제조할 수 있다. 따라서, 상기 화학식 4로 표시되는 화합물 및 화학식 6으로 표시되는 화합물의 분리 공정을 거칠 필요가 없이 하나의 반응기 내에서 protection 및 deprotection 반응을 진행할 수 있어 게피티닙의 제조 공정을 단순화하고 반응 효율을 현저히 높일 수 있다. According to the present invention, steps a) and b) may be carried out in situ in one reactor. That is, the compound represented by the formula (5) is added to a solution containing the compound represented by the formula (4) without separating the compound represented by the formula (4) by carrying out the reaction of the step a) Can be manufactured. Therefore, it is possible to carry out the protection and deprotection reaction in one reactor without having to go through the separation step of the compound represented by the formula 4 and the compound represented by the formula 6, thereby simplifying the process of producing gefitinib, .
본 발명은 c)상기 화학식 6으로 표시되는 화합물에서 트리메틸실릴기를 이탈시키는 단계를 더 포함할 수 있다. The present invention can further include a step c) of removing the trimethylsilyl group from the compound represented by the above formula (6).
본 발명에 있어서 상기 화학식 6으로 표시되는 화합물에서 아민보호기로 작용하는 트리메틸실릴기를 이탈시켜 아민기를 노출시킴으로써 상기 화학식 1로 표시되는 게피티닙이 제조된다. 즉, 상기 화학식 6으로 표시되는 화합물의 트리메틸실릴기를 -H로 치환하여 게피티닙이 제조된다. In the present invention, the trimethylsilyl group acting as an amine protecting group is removed from the compound represented by Chemical Formula 6 to expose the amine group, thereby producing the gefitinib represented by Chemical Formula 1 above. That is, gefitinib is prepared by replacing the trimethylsilyl group of the compound represented by Formula 6 with -H.
상기 트릴메틸실릴기의 이탈은 상기 화학식 6으로 표시되는 화합물을 포함하는 용액에 물을 첨가함으로써 수행될 수 있다. The elimination of the trimethylsilyl group can be carried out by adding water to a solution containing the compound represented by the formula (6).
상기 화학식 6으로 표시되는 화합물을 포함하는 용액에 물을 첨가하면 트리메틸실릴기가 상기 화학식 6으로부터 이탈되어 제조된 게피티닙이 바로 고체로 수득될 수 있다. 따라서, 본 발명의 제조방법에 따르면, N-알킬화된 불순물의 생성이 적을 뿐만 아니라 화학식 6으로 표시되는 화합물을 분리하는 별도의 공정 없이 물을 첨가하는 단순한 공정을 통해 게피티닙의 제조와 분리가 동시에 수행될 수 있어 게피티닙 제조 공정을 단순화할 수 있으며 그 결과 게피티닙의 대량 생산에 효과적으로 적용될 수 있다. When water is added to a solution containing the compound represented by the above formula (6), the gefitinib prepared by separating the trimethylsilyl group from the above formula (6) can be directly obtained as a solid. Therefore, according to the production method of the present invention, the production and separation of gefitinib can be achieved through a simple process in which water is added without any separate process for separating the compound represented by the formula (6) Can be performed at the same time, simplifying the process of producing gefitinib, and as a result, can be effectively applied to the mass production of gefitinib.
본 발명의 게피티닙 제조방법에 따르면, N-알킬화된 불순물의 생성을 원천적으로 막을 수 있으며 크로마토그래피와 같은 복잡한 공정 없이 99.9% 이상의 높은 순도를 가지는 게피티닙을 높은 수율로 얻을 수 있다. According to the method of the present invention for producing gefitinib, it is possible to prevent generation of N-alkylated impurities and to obtain gefitinib having a high purity of 99.9% or more without complicated processes such as chromatography.
본 발명은 하기 화학식 4 또는 하기 화학식 6으로 표시되는 화합물 및 이들의 염을 제공한다. The present invention provides a compound represented by the following formula (4) or (6) and salts thereof.
[화학식 4][Chemical Formula 4]
[화학식 6][Chemical Formula 6]
상기 화학식 4 또는 화학식 6으로 표시되는 화합물은 게피티닙 제조의 중간체로 사용될 수 있다. The compound represented by Formula 4 or Formula 6 may be used as an intermediate for the production of gefitinib.
상기 화학식 4로 표시되는 화합물을 하기 화학식 5로 표시되는 화합물과 반응시키는 경우, 상기 화학식 5로 표시되는 화합물이 퀴나졸린에 결합된 아민기의 N과 반응하지 않고 퀴나졸린에 결합된 -OH기와 선택적으로 반응하여 상기 화학식 6으로 표시되는 화합물이 효과적으로 제조될 수 있다. When the compound represented by the general formula (4) is reacted with a compound represented by the following general formula (5), the compound represented by the general formula (5) reacts with the -OH group bonded to the quinazoline without reacting with N of the amine group bonded to the quinazoline, The compound represented by Formula 6 can be effectively prepared.
[화학식 5][Chemical Formula 5]
따라서, 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민의 생성을 원천적으로 억제할 수 있다. 또한, N-알킬화된 불순물의 생성을 억제하기 위하여 복잡한 다단계 공정을 거칠 필요가 없으며, N-알킬화된 불순물을 분리하기 위하여 크로마토그래피와 공정을 거칠 필요가 없다. Thus, the use of the impurity of N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) -N- (3-morpholinopropyl) quinazolin- Generation can be suppressed originally. Also, there is no need to go through a complex multi-step process to inhibit the formation of N-alkylated impurities, and there is no need to undergo chromatography and processing to separate the N-alkylated impurities.
또한, 상기 화학식 6으로 표시되는 화합물은 상기 화학식 4로 표시되는 화합물과 상기 화학식 5로 표시되는 화합물의 반응에 의해 생성된 후 따로 분리 및 정제 공정을 거칠 필요 없이, 상기 화학식 6으로 표시되는 화합물을 포함하는 용액에 물만을 첨가하면 트리메틸실릴기가 이탈되며, 고체 게피티닙이 생성된다. 즉, 게피티닙의 생성과 동시에 용액 속에서 고체로 석출되기 때문에 번거로운 분리 공정을 거칠 필요 없이 단순한 여과 공정만을 수행하여 게피티닙을 수득할 수 있다. The compound represented by Formula 6 may be prepared by reacting the compound represented by Formula 4 with the compound represented by Formula 5 without any separate separation and purification steps, Addition of water only to the contained solution releases the trimethylsilyl group, resulting in solid gefitti nips. In other words, since it precipitates as a solid in a solution at the same time as the generation of gefitinib, it is possible to obtain gefitinib by performing only a simple filtration process without having to go through a troublesome separation process.
따라서, 상기 화학식 4로 표시되는 화합물 및 상기 화학식 6으로 표시되는 화합물을 게피티닙 제조의 중간체로 사용하면 간단한 공정을 통해 용이하게 고효율로 고순도의 게피티닙을 생산할 수 있다. Therefore, when the compound represented by the formula (4) and the compound represented by the formula (6) are used as intermediates in the production of gefitinib, it is possible to easily produce high purity gefitti nips through a simple process.
상기 화학식 4 또는 화학식 6으로 표시되는 화합물의 염은 약제학적으로 허용 가능한 염일 수 있다. 상기 약제학적으로 허용 가능한 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 및 황산 등으로 제조된 무기산염, 아세트산, 트리플루오로아세트산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산, 만델산, 뮤크산, 파모산, 판토텐산, 숙신산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 캄포르설폰산, 또는 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트리메틸아민, 트리에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다.The salt of the compound represented by Chemical Formula 4 or Chemical Formula 6 may be a pharmaceutically acceptable salt. The pharmaceutically acceptable salt means a salt commonly used in the medical industry. Examples of the salt include inorganic ion salts such as calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, Acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid An organic acid salt prepared from an organic acid such as hydrochloric acid, hydrobromic acid, citric acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, Sulfonic acid salts prepared by sulfonic acid, sulfonic acid, sulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid or naphthalenesulfonic acid; amino acid salts prepared by glycine, arginine, And amine salts prepared by using trimethylamine, triethylamine, ammonia, pyridine, picoline, and the like. However, the types of salts defined in the present invention are not limited by the listed salts.
본 발명의 게피티닙 제조방법에 따르면, 간단한 공정으로 N-알킬화된 불순물의 생성을 막을 수 있으며, 크로마토그래피와 같은 복잡한 분리 공정 없이 여과 등을 통해 게피티닙을 수득할 수 있어 고효율로 고순도의 게피티닙을 효과적으로 대량생산 할 수 있다. According to the method of the present invention for producing gefitinib, it is possible to prevent generation of N-alkylated impurities by a simple process, and it is possible to obtain gefitinib through filtration without a complicated separation process such as chromatography, It is possible to effectively mass-produce gefitinib.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.
또한, 이하에서 언급된 시약 및 용매는 특별한 언급이 없는 한 Sigma-Aldrich Korea 및 Merck사로부터 구입한 것이며, HPLC는 Agilent Technoliges 사의 1200 Series를 사용하였고, 1H NMR 데이터는 Bruker(브루커)사의 400 UltraShield NMR Spectrometer 를 사용하여 측정하였다. Unless otherwise noted, the reagents and solvents mentioned below were purchased from Sigma-Aldrich Korea and Merck, HPLC was a 1200 series from Agilent Technologies, 1 H NMR data was obtained from Bruker 400 UltraShield NMR Spectrometer.
본 발명에서 사용된 HPLC 조건은 다음과 같으며, HPLC는 반응 후 반응혼합물중의 게피티닙 순도 및 N-알킬 불순물을 측정하였다.The HPLC conditions used in the present invention are as follows. HPLC determined the purity of gelatin and the N-alkyl impurity in the reaction mixture after the reaction.
검출기: 자외부흡광광도계 (측정파장 : 250 nm) Detector: Ultraviolet absorptiometer (measuring wavelength: 250 nm)
칼 럼: Hypersil C18 (4.6 mm X 250 mm, 5 μm)Column: Hypersil C18 (4.6 mm x 250 mm, 5 m)
이동상: 5 몰% 암모늄아세테이트 수용액과 아세토니트릴의 혼합액 (60:40)Mobile phase: a mixture of aqueous solution of 5 mol% ammonium acetate and acetonitrile (60:40)
유 량: 1.0 mL/minFlow rate: 1.0 mL / min
시 료: 검체시료 25mg/이동상 50mLSample: 25 mg sample / 50 mL mobile phase
주입량: 20㎕Injection amount: 20 μl
<< 실시예Example 1> 4-(3- 1 > 4- (3- 클로로Chloro -4--4- 플루오로페닐아미노Fluorophenylamino )-7-) -7- 메톡시퀴나졸린Methoxyquinazoline -6-일 아세테이트 염산염의 제조-6-yl acetate hydrochloride
플라스크에 7-메톡시-4-옥소-3,4-디히드로퀴나졸린-6-일 아세테이트 100.0 g과 톨루엔 1100.0 ㎖를 주입하고 20℃에서 교반하였다. 상기 플라스크에 트리에틸아민 90.0㎖와 포스포릴클로라이드 59.9㎖를 투입하고 60℃에서 5시간 교반하였다. 반응물의 온도를 20℃로 냉각한 후 이소프로필알콜 600.0㎖를 발열에 주의하면서 서서히 주입하였다. 이 후, 3-클로로-4-플루오로 아닐린 62.1g을 이소프로필알콜 100.0 ㎖에 용해하여 서서히 적가한 후 65℃로 승온시킨 후 2시간 교반하고 HPLC 및 TLC를 사용하여 반응 종료를 확인하였다. 상기 플라스크의 온도를 20℃으로 냉각하여 1시간 교반하고 생성된 고체를 여과하였다. 상기 고체를 이소프로필알콜 800.0㎖로 세척한 후 40℃에서 2시간 건조하여 황색의 분말인 표제화합물 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일 아세테이트 염산염 180.0g을 수득하였다.100.0 g of 7-methoxy-4-oxo-3,4-dihydroquinazolin-6-yl acetate and 1100.0 ml of toluene were placed in a flask and stirred at 20 占 폚. 90.0 ml of triethylamine and 59.9 ml of phosphoryl chloride were added to the flask, and the mixture was stirred at 60 ° C for 5 hours. After the temperature of the reaction product was cooled to 20 ° C, 600.0 ml of isopropyl alcohol was gradually added while paying attention to heat generation. Thereafter, 62.1 g of 3-chloro-4-fluoroaniline was dissolved in 100.0 ml of isopropyl alcohol, and the solution was slowly added dropwise. After the temperature was raised to 65 ° C, stirring was continued for 2 hours and HPLC and TLC were used to confirm the completion of the reaction. The temperature of the flask was cooled to 20 DEG C and stirred for 1 hour, and the resulting solid was filtered. The solid was washed with 800.0 ml of isopropyl alcohol and dried at 40 ° C for 2 hours to obtain the title compound 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6- Acetate hydrochloride (180.0 g).
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) 1 H NMR (400MHz, DMSO- d 6): 2.3 (s, 3H), 4.0 (s, 3H), 7.5 (t, 1H), 7.6 (s, 1H), 7.7 (m, 1H), 8.0 (m , 8.8 (s, 1 H), 8.9 (s, 1 H), 11.5 (broad s,
<< 실시예Example 2> 4-(3- 2 > 4- (3- 클로로Chloro -4--4- 플루오로페닐아미노Fluorophenylamino )-7-) -7- 메톡시퀴나졸린Methoxyquinazoline -6-올의 제조-6-ol
플라스크에 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일 아세테이트 염산염 180.0g과 메탄올 1000.0 ㎖, 물 1000.0 ㎖을 발열에 주의하면서 서서히 주입하였다. 상기 혼합물을 20℃에서 현탁 교반하면서 리튬히드록사이드 30.7g을 투입하고 강하게 30분간 교반 후 HPLC 및 TLC를 사용하여 반응 종료를 확인하였다. 반응물을 20℃로 냉각한 후 20%(v/v%) 아세트산 200.0 ㎖를 주입하여 pH 7.0으로 중화하였다. 상기 용액을 20℃에서 1시간 동안 교반하여 생성된 고체를 여과하였다. 상기 고체를 메탄올 200.0 ㎖로 세척한 후 40℃에서 3시간 진공건조하여 미황색의 분말로 표제화합물인 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 123.0g을 수득하였다. 180.0 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-yl acetate hydrochloride, 1000.0 ml of methanol and 1000.0 ml of water were slowly added to the flask while paying attention to heat generation. 30.7 g of lithium hydroxide was added thereto while stirring and stirring at 20 ° C, and the mixture was stirred for 30 minutes. After completion of the reaction, HPLC and TLC were used to confirm completion of the reaction. After the reaction was cooled to 20 ° C, 200.0 ml of 20% (v / v%) acetic acid was added to neutralize the solution to pH 7.0. The solution was stirred at 20 < 0 > C for 1 hour and the resulting solid was filtered. The solid was washed with 200.0 ml of methanol and then vacuum-dried at 40 ° C for 3 hours to give 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin- 123.0 g was obtained.
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) 1 H NMR (400 MHz, DMSO-d 6 ): 4.0 (s, 3H), 7.4 (s, IH), 7.8 , 9.45 (s, 1 H), 9.65 (s, 1 H)
<< 실시예Example 3-1> N-(3- 3-1 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭Morpholino pro-width 시)city) 퀴나졸린Quinazoline -4-아민 (-4-amine ( 게피티닙Gefitinib )의 제조)
플라스크에 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 123.0g과 N,N-디메틸포름아미드 1100.0㎖를 주입하였다. 상기 혼합물을 현탁 교반하면서 탄산칼륨 186.0g 과 N,N-디메틸아미노피리딘 4.7g을 투입하였다. 반응물을 -10℃로 냉각한 후 아이오도트리메틸실란 77.0g을 발열에 주의하면서 서서히 주입하고 15℃에서 1시간 교반한 다음 4-(3-클로로프로필)몰포린 75.5g을 N,N-디메틸포름아미드 130.0㎖에 희석하여 서서히 주입하고 반응 혼합물을 80℃로 승온하여 2시간 교반 후 HPLC 및 TLC를 사용하여 반응종료를 확인하였다. 반응물을 20℃로 냉각한 후 정제수 2460.0㎖를 서서히 주입하고 30분간 교반한 후 생성된 고체를 여과하였다. 상기 수득된 고체를 정제수 490.0㎖로 세척한 후 50℃에서 3시간 진공건조하여 미황색의 분말인 표제화합물 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민(게피티닙) 154.7 g을 수득하였다. 123.0 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol and 1100.0 ml of N, N-dimethylformamide were introduced into the flask. 186.0 g of potassium carbonate and 4.7 g of N, N-dimethylaminopyridine were added while suspending and stirring the mixture. After cooling the reaction mixture to -10 DEG C, 77.0 g of iodotrimethylsilane was slowly added with caution to exothermic reaction, stirred at 15 DEG C for 1 hour, and then 75.5 g of 4- (3-chloropropyl) Amide and gradually added thereto. The reaction mixture was heated to 80 DEG C and stirred for 2 hours, and the completion of the reaction was confirmed by HPLC and TLC. After the reaction was cooled to 20 ° C, 2460.0 ml of purified water was slowly added thereto, stirred for 30 minutes, and the resulting solid was filtered. The obtained solid was washed with 490.0 ml of purified water and then vacuum-dried at 50 ° C for 3 hours to obtain the title compound N- (3-chloro-4-fluorophenyl) -7-methoxy- (Morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 99.21% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민: 0.3%)HPLC purity: 99.21% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-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) 1 H-NMR (400MHz, DMSO -d 6): 2.0 (m, 2H), 2.4 (m, 6H), 3.7 (m, 4H), 3.9 (s, 3H), 4.2 (t, 2H), 7.2 ( 1H), 7.4 (t, 1H), 7.8 (m, 2H), 8.2 (m,
<< 실시예Example 3-2> N-(3- 3-2 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭Morpholino pro-width 시)city) 퀴나졸린Quinazoline -4-아민 (-4-amine ( 게피티닙Gefitinib )의 제조)
플라스크에 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 7.0g과 N,N-디메틸아세트아미드 63.0㎖를 주입하였다. 상기 혼합물을 현탁 교반하면서 탄산칼륨 10.6g 과 N,N-디메틸아미노피리딘 0.3g을 투입하였다. 반응물을 -10℃로 냉각한 후 아이오도트리메틸실란 4.4g을 발열에 주의하면서 서서히 주입하고 15℃에서 1시간 교반한 다음 4-(3-클로로프로필)몰포린 4.3g을 N,N-디메틸포름아미드 8.0㎖에 희석하여 서서히 주입하고 반응 혼합물을 80℃로 승온하여 2시간 교반 후 HPLC 및 TLC를 사용하여 반응종료를 확인하였다. 반응물을 20℃로 냉각한 후 정제수 140.0㎖를 서서히 주입하고 30분간 교반한 후 생성된 고체를 여과하였다. 상기 수득된 고체를 정제수 20.0㎖로 세척한 후 50℃에서 3시간 진공건조하여 미황색의 분말인 표제화합물 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민(게피티닙) 8.6 g을 수득하였다. 7.0 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol and 63.0 ml of N, N-dimethylacetamide were introduced into a flask. While stirring the mixture, 10.6 g of potassium carbonate and 0.3 g of N, N-dimethylaminopyridine were added. After the reaction mixture was cooled to -10 ° C, 4.4 g of iodotrimethylsilane was slowly added with caution to exothermic reaction and stirred at 15 ° C for 1 hour. Then, 4.3 g of 4- (3-chloropropyl) Amide. The reaction mixture was heated to 80 DEG C and stirred for 2 hours. HPLC and TLC were used to confirm the completion of the reaction. The reaction mixture was cooled to 20 ° C, 140.0 ml of purified water was gradually added thereto, stirred for 30 minutes, and the resulting solid was filtered. The resulting solid was washed with 20.0 ml of purified water and vacuum-dried at 50 ° C for 3 hours to obtain the title compound N- (3-chloro-4-fluorophenyl) -7-methoxy- 8.6 g of morpholinopropoxy) quinazolin-4-amine (gefitinib) was obtained.
HPLC 순도 : 99.20% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 0.3%)HPLC purity: 99.20% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 0.3%
<< 실시예Example 3-3> N-(3- 3-3 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭Morpholino pro-width 시)city) 퀴나졸린Quinazoline -4-아민 (-4-amine ( 게피티닙Gefitinib )의 제조)
용매로 N,N-디메틸아세트아미드(DMAC) 대신 디메틸설폭사이드(DMSO) 사용한 점을 제외하고 실시예 3-2와 동일한 방법으로 미황색의 분말인 표제화합물 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민(게피티닙) 8.3g을 수득하였다. The title compound N- (3-chloro-4-fluoro-pyridin-2-ylamine) was obtained in the same manner as in Example 3-2, except that dimethyl sulfoxide (DMSO) was used instead of N, N-dimethylacetamide (DMAC) Phenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 98.89% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 0.7%)HPLC purity: 98.89% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 0.7%
<< 실시예Example 3-4> 4-((3- 3-4 > 4 - ((3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )() ( 트리메틸실릴Trimethylsilyl )아미노)-7-) Amino) -7- 메톡시퀴나졸린Methoxyquinazoline -6-올 (6-ol ( 화학식4로(4) 표시되는 반응 중간체)의 확인 Identification of the indicated reaction intermediates)
플라스크에 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 0.5g과 N,N-디메틸포름아미드-d7 5.0㎖를 주입하였다. 상기 혼합물을 현탁 교반하면서 탄산칼륨 0.462g을 투입하였다. 반응물을 -10℃로 냉각한 후 아이오도트리메틸실란 0.22g을 발열에 주의하면서 서서히 주입하고 15℃에서 1시간 교반한 후, 반응 시료 1㎖을 취하여 NMR 분석을 하여 상기 표제의 4-((3-클로로-4-플루오로페닐)(트리메틸실릴)아미노)-7-메톡시퀴나졸린-6-올이 합성되었음을 확인하였다.0.5 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol and 5.0 ml of N, N-dimethylformamide-d 7 were introduced into a flask. 0.462 g of potassium carbonate was added while suspending and stirring the mixture. After the reaction mixture was cooled to -10 ° C, 0.22 g of iodotrimethylsilane was gradually added with caution to exotherm and the mixture was stirred at 15 ° C for 1 hour. Then, 1 ml of the reaction sample was taken and subjected to NMR analysis to obtain 4 - -Chloro-4-fluorophenyl) (trimethylsilyl) amino) -7-methoxyquinazolin-6-ol was 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)1H NMR (400MHz, DMF-d 7 ): 0.3 (s, 9H), 3.9 (s, 3H), 7.2 1H), 8.6 (s, IH), 9.93 (s, IH)
<< 실시예Example 3-5> N-(3- 3-5 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭시Morpholino propoxy )-N-() -N- ( 트리메틸실릴Trimethylsilyl )-) - 퀴나졸린Quinazoline -4--4- 아민(화학식6으로 표시되는 반응 중간체)의Amine (the reaction intermediate represented by the formula (6)) 확인 Confirm
플라스크에 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 0.5g과 N,N-디메틸포름아미드-d7 5.0㎖을 주입하였다. 상기 혼합물을 현탁 교반하면서 탄산칼륨 0.462g 과 N,N-디메틸아미노피리딘 0.013g을 투입하였다. 반응물을 -10℃로 냉각한 후 아이오도트리메틸실란 0.22g을 발열에 주의하면서 서서히 주입하고 15℃에서 1시간 교반한 다음 4-(3-클로로프로필)몰포린 0.222g을 N,N-디메틸포름아미드 1.0㎖에 희석하여 서서히 주입하였다. 반응 혼합물을 80℃로 승온하여 2시간 교반 후 반응 시료 1㎖을 취해 NMR 분석을 수행하여 표제의 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(트리메틸실릴)-퀴나졸린-4-아민이 합성되었음을 확인하였다.0.5 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol and 5.0 ml of N, N-dimethylformamide-d 7 were introduced into a flask. 0.462 g of potassium carbonate and 0.013 g of N, N-dimethylaminopyridine were added while suspending and stirring the mixture. After cooling the reaction mixture to -10 ° C, 0.22 g of iodotrimethylsilane was slowly added with caution to exothermic reaction, stirred at 15 ° C for 1 hour, and then 0.222 g of 4- (3-chloropropyl) Amide and slowly injected. The reaction mixture was heated to 80 DEG C and stirred for 2 hours, and 1 mL of the reaction sample was taken and subjected to NMR analysis to obtain the title compound, N- (3-chloro-4-fluorophenyl) -7-methoxy- Linopropoxy) -N- (trimethylsilyl) -quinazolin-4-amine was 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) 1 H-NMR (400MHz, DMF -d 7): 0.2 (s, 9H), 1.9 (m, 2H), 2.3 (br, 4H), 2.4 (m, 2H), 3.6 (m, 4H), 3.9 ( 1H), 8.5 (s, 1H), 9.6 (s, 1H), 7.2 (s, , 1H)
<< 실시예Example 4-1> N-(3- 4-1 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭Morpholino pro-width 시)city) 퀴나졸린Quinazoline -4-아민 (-4-amine ( 게피티닙Gefitinib )의 정제) Tablets
실시예 3-1에서 수득된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 154.7g을 톨루엔 2320.0㎖과 무수에탄올 1160.0 ㎖에 현탁 교반한 다음 40℃로 승온하여 완전히 용해시켰다. 이 후 중성 활성탄 37.0g을 첨가하고 1시간 교반한 후 여과하여 활성탄을 제거하였다. 여과액을 1400㎖까지 농축하고 30분간 교반 한 후 생성된 고체를 여과하였다. 수득된 고체를 톨루엔 246.0㎖로 세척하고 40℃에서 3시간 건조하여 백색의 게피티닙 135.3 g을 수득하였다.154.7 g of N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine obtained in Example 3-1 was dissolved in 2320.0 ml Suspended in 1160.0 ml of anhydrous ethanol, and then heated to 40 ° C to dissolve completely. Thereafter, 37.0 g of neutral activated carbon was added, stirred for 1 hour, and then filtered to remove activated carbon. The filtrate was concentrated to 1400 ml, stirred for 30 minutes, and the resulting solid was filtered. The obtained solid was washed with 246.0 ml of toluene and dried at 40 占 폚 for 3 hours to obtain 135.3 g of white gepitti nip.
정제하여 수득된 게피티닙을 무수 에탄올 2340.0 ㎖에 첨가하여 현탁액을 제조하고 상기 현탁액을 75℃에서 환류교반하여 게피티닙을 완전히 용해시킨 후 1시간 더 교반하였다. 상기 용액을 서서히 20℃로 냉각하고 생성된 고체를 30분간 교반한 다음 5℃에서 1시간 더 교반하였다. 수득된 고체를 여과한 후 무수 에탄올 123.0 ㎖로 세척하고 45℃에서 5시간 진공건조하여 백색의 정제된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 128.5g을 수득하였다.The resulting gepitinib was added to 2340.0 ml of anhydrous ethanol to prepare a suspension. The suspension was refluxed and stirred at 75 캜 to completely dissolve gefitinib, and then stirred for 1 hour. The solution was slowly cooled to 20 < 0 > C and the resulting solid was stirred for 30 minutes and then at 5 < 0 > C for an additional hour. The obtained solid was filtered, washed with 123.0 ml of absolute ethanol and vacuum-dried at 45 ° C for 5 hours to obtain white purified N- (3-chloro-4-fluorophenyl) -7-methoxy- (Morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 99.91% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 없음)HPLC purity: 99.91% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI >
<< 실시예Example 4-2> N-(3- 4-2 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭Morpholino pro-width 시)city) 퀴나졸린Quinazoline -4-아민 (-4-amine ( 게피티닙Gefitinib )의 정제) Tablets
실시예 3-2에서 수득된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 8.6g을 톨루엔 129.0㎖과 무수에탄올 65.0 ㎖에 현탁 교반한 다음 40℃로 승온하여 완전히 용해시켰다. 이 후 중성 활성탄 1.9g을 첨가하고 1시간 교반한 후 여과하여 활성탄을 제거하였다. 여과액을 90㎖까지 농축하고 30분간 교반 한 후 생성된 고체를 여과하였다. 수득된 고체를 톨루엔 20.0㎖로 세척하고 40℃에서 3시간 건조하여 백색의 게피티닙 7.3 g을 수득하였다. 8.6 g of N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine obtained in Example 3-2 was dissolved in 129.0 ml Suspended in 65.0 ml of anhydrous ethanol, and then heated to 40 ° C to dissolve completely. After that, 1.9 g of neutral activated carbon was added, stirred for 1 hour, and then filtered to remove activated carbon. The filtrate was concentrated to 90 ml and stirred for 30 minutes, and the resulting solid was filtered. The obtained solid was washed with 20.0 ml of toluene and dried at 40 占 폚 for 3 hours to obtain 7.3 g of white goitti nip.
정제하여 수득된 게피티닙을 무수 에탄올 125.0 ㎖에 첨가하여 현탁액을 제조하고 상기 현탁액을 75℃에서 환류교반하여 게피티닙을 완전히 용해시킨 후 1시간 더 교반하였다. 상기 용액을 서서히 20℃로 냉각하고 생성된 고체를 30분간 교반한 다음 5℃에서 1시간 더 교반하였다. 수득된 고체를 여과한 후 무수 에탄올 7.0 ㎖로 세척하고 45℃에서 5시간 진공건조하여 백색의 정제된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 6.5g을 수득하였다.Gapitinib obtained by the purification was added to 125.0 ml of anhydrous ethanol to prepare a suspension, and the suspension was refluxed and stirred at 75 DEG C to completely dissolve gefitinib, and then stirred for 1 hour. The solution was slowly cooled to 20 < 0 > C and the resulting solid was stirred for 30 minutes and then at 5 < 0 > C for an additional hour. The resulting solid was filtered, washed with absolute ethanol (7.0 ml), and dried in vacuo at 45 캜 for 5 hours to obtain white purified N- (3-chloro-4-fluorophenyl) -7-methoxy- Morpholinopropoxy) quinazolin-4-amine (gefitinib) was obtained.
HPLC 순도 : 99.89% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 없음)HPLC purity: 99.89% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI >
<< 실시예Example 4-3> N-(3- 4-3 > N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭시Morpholino propoxy )) 퀴나졸린Quinazoline -4-아민 (-4-amine ( 게피티닙Gefitinib )의 정제) Tablets
실시예 3-3에서 제조된 게피티닙을 사용한 점을 제외하고 실시예 4-1과 동일한 방법으로 백색의 정제된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 6.2g을 수득하였다.(3-chloro-4-fluorophenyl) -7-methoxy-6-quinolinecarboxamide was obtained in the same manner as in Example 4-1, except that gefitinib prepared in Example 3-3 was used. - (3-morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 99.87% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 0.03%)HPLC purity: 99.87% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 0.03%
< 비교예1 > 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올의 합성 <Comparative Example 1> Synthesis of 4- (3-chloro-4-fluoro-phenylamino) -7-methoxy-quinazolin-6-ol Synthesis of
플라스크에 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일 아세테이트 염산염 30.0g과 메탄올 1050㎖을 첨가하고 현탁 교반한 후 30%(w/w%)암모니아수 37.6㎖ 을 천천히 주입하였다. 상기 혼합물을 상온에서 15시간 교반하고 65℃로 승온하여 2시간동안 환류교반한 후 TLC를 사용하여 반응 종료를 확인하였다. 상기 반응물을 20℃로 냉각하고 30분간 교반한 후 생성된 고체를 여과하였다. 수득된 고체를 메탄올 150㎖로 세척하고 40℃에서 진공건조하여 미황색분말인 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 22.6 g을 수득하였다.To the flask, 30.0 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-yl acetate hydrochloride and 1050 ml of methanol were added, 37.6 ml of ammonia water was slowly injected. The mixture was stirred at room temperature for 15 hours, heated to 65 ° C, refluxed for 2 hours, and then terminated by TLC. The reaction was cooled to 20 < 0 > C and stirred for 30 minutes, and the resulting solid was filtered. The obtained solid was washed with 150 ml of methanol and vacuum dried at 40 占 폚 to obtain 22.6 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol as a light yellow powder.
<< 비교예Comparative Example 2-1> 2-1>
플라스크에 상기 비교예 1에서 수득된 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올 22.6g과 N,N-디메틸포름아미드 339㎖을 첨가하고 현탁교반한 후, 탄산칼륨 34.2g과 4-(3-클로로프로필)몰포린 13.9 g을 서서히 주입하였다. 이 후 상기 반응 혼합물을 80℃로 승온하여 5시간 교반 후 TLC를 사용하여 반응종료를 확인하였다. 반응물을 20℃으로 냉각한 후 정제수 678.0㎖를 서서히 주입하고 1시간 교반하여 생성된 고체를 여과하였다. 수득된 고체를 정제수 150.0 ㎖로 세척한 후 40℃에서 3시간 간이건조하고 50℃에서 진공건조하여 미황색의 분말인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 23.0 g을 수득하였다.22.6 g of 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol obtained in the above Comparative Example 1 and 339 ml of N, N-dimethylformamide were added to a flask, After stirring, 34.2 g of potassium carbonate and 13.9 g of 4- (3-chloropropyl) morpholine were slowly added. Then, the reaction mixture was heated to 80 ° C and stirred for 5 hours. TLC was used to confirm the completion of the reaction. The reaction mixture was cooled to 20 ° C, and 678.0 ml of purified water was slowly added thereto. The resulting mixture was stirred for 1 hour and filtered. The obtained solid was washed with 150.0 ml of purified water, dried at 40 ° C for 3 hours, and vacuum-dried at 50 ° C to obtain a pale yellow powder of N- (3-chloro-4-fluorophenyl) (3-morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 65% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 30%)HPLC purity: 65% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 30%
<< 비교예Comparative Example 2-2> 2-2>
탄산칼륨 첨가시 N,N-디메틸아미노피리딘 0.9g을 함께 첨가한 점을 제외하고 비교예 2-1과 동일한 방법으로 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 23.7g을 수득하였다.(3-chloro-4-fluorophenyl) -7-methoxy-6-phenyl-isoxazole was prepared in the same manner as in Comparative Example 2-1, except that 0.9 g of N, N-dimethylaminopyridine was added together with potassium carbonate. - (3-morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 88% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 10.0%)HPLC purity: 88% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 10.0%
<< 비교예Comparative Example 3-1> 3-1>
비교예 2-1에서 수득된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 23.0g을 톨루엔 345.0㎖과 무수에탄올 173.0 ㎖에 현탁 교반한 다음 40℃로 승온하여 완전히 용해시켰다. 이 후 중성 활성탄 5.8g을 첨가하고 1시간 교반한 후 여과하여 활성탄을 제거하였다. 여과액을 25㎖까지 농축하고 30분간 교반 한 후 생성된 고체를 여과하였다. 수득된 고체를 톨루엔 50.0㎖로 세척하고 40℃에서 3시간 건조하여 백색의 게피티닙 11.5 g을 수득하였다. 23.0 g of N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine obtained in Comparative Example 2-1 was dissolved in 345.0 ml The suspension was stirred in 173.0 ml of anhydrous ethanol and then heated to 40 ° C to dissolve completely. After that, 5.8 g of neutral activated carbon was added, stirred for 1 hour, and then filtered to remove activated carbon. The filtrate was concentrated to 25 ml and stirred for 30 minutes, and the resulting solid was filtered. The obtained solid was washed with 50.0 ml of toluene and dried at 40 占 폚 for 3 hours to obtain 11.5 g of white gepitti nip.
정제하여 수득된 게피티닙을 무수 에탄올 207.0 ㎖에 첨가하여 현탁액을 제조하고 상기 현탁액을 75℃에서 환류교반하여 게피티닙을 완전히 용해시킨 후 1시간 더 교반하였다. 상기 용액을 서서히 20℃로 냉각하고 생성된 고체를 30분간 교반한 다음 5℃에서 1시간 더 교반하였다. 수득된 고체를 여과한 후 무수 에탄올 11.0 ㎖로 세척하고 45℃에서 5시간 진공건조하여 백색의 정제된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 10.1g을 수득하였다.The resulting gepitinib was dissolved in 207.0 ml of anhydrous ethanol to prepare a suspension. The suspension was refluxed and stirred at 75 캜 to completely dissolve gefitinib, and then stirred for 1 hour. The solution was slowly cooled to 20 < 0 > C and the resulting solid was stirred for 30 minutes and then at 5 < 0 > C for an additional hour. The resulting solid was filtered and washed with 11.0 ml of absolute ethanol and vacuum dried at 45 ° C for 5 hours to obtain a white, purified N- (3-chloro-4-fluorophenyl) -7-methoxy- Morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 96% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 3.0%)HPLC purity: 96% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 3.0%
<< 비교예Comparative Example 3-2> 3-2>
비교예 2-2에서 제조된 게피티닙을 사용한 점을 제외하고 비교예 3-1과 동일한 방법으로 백색의 정제된 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민 (게피티닙) 14.5g을 수득하였다.(3-chloro-4-fluorophenyl) -7-methoxy-6-quinolinecarboxamide was obtained in the same manner as in Comparative Example 3-1, except that gefitinib prepared in Comparative Example 2-2 was used. - (3-morpholinopropoxy) quinazolin-4-amine (gefitinib).
HPLC 순도 : 98% (N-알킬화된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민 1.0%)HPLC purity: 98% (N-alkylated impurity N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3- morpholinopropoxy) ) Quinazolin-4-amine < / RTI > 1.0%
<< 실험예1Experimental Example 1 > 4-(3-> 4- (3- 클로로Chloro -4--4- 플루오로페닐아미노Fluorophenylamino )-7-) -7- 메톡시퀴나졸린Methoxyquinazoline -6-올의 제조방법에 따른 잔류 6-ol < / RTI > 미반응물Unreacted material 분석 analysis
실시예 2 및 비교예 1의 실험조건별 반응 종료시점까지의 반응시간과 반응 혼합 용액 중 반응하지 않은 미반응물인 7-메톡시-4-옥소-3,4-디히드로퀴나졸린-6-일 아세테이트을 HPLC 분석을 통해 그 함량을 확인하고 측정한 값을 하기 [표 1]에 정리하였다.The reaction time up to the end of the reaction according to the experimental conditions of Example 2 and Comparative Example 1 and the reaction time of the unreacted unreacted product 7-methoxy-4-oxo-3,4-dihydroquinazolin- Acetate was confirmed by HPLC analysis and the measured values were summarized in Table 1 below.
[표 1][Table 1]
비교예1과 같이 암모니아수를 사용하여 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올을 제조하는 경우 18시간 동안 상온에서 반응시키고 승온하여 환류교반을 진행했음에도 미반응물이 2% 가량 잔류하였다. 이와 같은 미반응물을 불순물이며, 따라서, 이와 같은 미반응물은 이후 반응에서 최종적으로 수득되는 게피티닙의 품질에 영향을 줄 수 있다. In the case of preparing 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol using ammonia water as in Comparative Example 1, the reaction was carried out at room temperature for 18 hours, And 2% of the unreacted material remained. Such unreacted materials are impurities, and thus such unreacted materials can affect the quality of the finally obtained gatifti nip in subsequent reactions.
그러나 본원발명의 실시예 2의 방법에 따라 4-(3-클로로-4-플루오로페닐아미노)-7-메톡시퀴나졸린-6-올을 제조하는 경우, 매우 짧은 반응시간에도 미반응물이 0.1% 이하로 잔류하는 바, 반응의 효율성이 크게 향상되었음을 알 수 있었다.However, when 4- (3-chloro-4-fluorophenylamino) -7-methoxyquinazolin-6-ol was prepared according to the method of Example 2 of the present invention, %, It was found that the efficiency of the reaction was greatly improved.
따라서, 본원발명의 제조방법은 반응 효율을 현저하게 증가시킴을 알 수 있었다.Therefore, it was found that the production method of the present invention remarkably increases the reaction efficiency.
<< 실험예2Experimental Example 2 > N-(3-> N- (3- 클로로Chloro -4--4- 플루오로페닐Fluorophenyl )-7-) -7- 메톡시Methoxy -6-(3--6- (3- 몰포리노프로폭시Morpholino propoxy )) 퀴The 나졸린-4-Nazolin-4- 아민의Amine 제조방법에 따른 N-알킬화 불순물의 분석 Analysis of N-alkylated impurities according to manufacturing method
실시예 3-1 내지 3-3, 실시예 4-1 내지 4-3, 비교예 2-1, 2-2 및 비교예 3-1, 3-2의 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)퀴나졸린-4-아민의 제조에 있어 반응혼합물을 HPLC를 사용하여 분석하였고, 반응혼합물 중의 N-알킬화된 불순물을 측정한 값을 하기 [표 2]로 정리하였다.(3-Chloro-4-fluoro-4-fluoropyridine) of Examples 3-1 to 3-3, Examples 4-1 to 4-3, Comparative Examples 2-1 and 2-2 and Comparative Examples 3-1 and 3-2 (3-morpholinopropoxy) quinazolin-4-amine, the reaction mixture was analyzed using HPLC and the N-alkylated impurities in the reaction mixture were measured The values are summarized in Table 2 below.
[표 2][Table 2]
상기 표 2에서 볼 수 있는 바와 같이, 실릴 보호기를 도입하지 않고 반응을 진행하는 경우(비교예 2-1 및 비교예 2-2), 아미노기에 알킬이 도입된 불순물인 N-(3-클로로-4-플루오로페닐)-7-메톡시-6-(3-몰포리노프로폭시)-N-(3-몰포리노프로필)퀴나졸린-4-아민이 다량 생성되었다. 또한 이와 같은 불순물은 비교예 3-1 및 비교예 3-2에서 알 수 있는 바와 같이 정제 공정을 추가적으로 수행하여도 최종적으로 수득된 게피티닙에서도 다량으로 잔류함을 알 수 있었다.As can be seen from Table 2, when the reaction proceeded without introduction of a silyl protecting group (Comparative Example 2-1 and Comparative Example 2-2), N- (3-chloro- 4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) -N- (3-morpholinopropyl) quinazolin-4-amine. Also, as shown in Comparative Example 3-1 and Comparative Example 3-2, it was found that such impurities remained in a large amount even in the finally obtained gefitinib even after the purification process was further performed.
그러나 본원발명의 실시예들에 따르면, 정제 전에 N-알킬화된 불순물의 함량이 1%이하에 불과하였으며, 정제 후에는 N-알킬화된 불순물이 전혀 검출되지 않거나 비교예들의 1/100 내지 1/30의 아주 미량으로 검출되었다.However, according to the embodiments of the present invention, the content of the N-alkylated impurities before purification was no more than 1%, no N-alkylated impurities were detected after purification, or 1/100 to 1/30 In a very small amount.
따라서, 본원발명의 제조방법은 불순물의 생성을 최소화할 수 있음을 알 수 있었다. Therefore, it was found that the production method of the present invention can minimize the generation of impurities.
Claims (13)
b) 상기 화학식 4로 표시되는 화합물을 하기 화학식 5로 표시되는 화합물과 반응시켜 하기 화학식 6으로 표시되는 화합물을 제조하는 단계를 포함하는 하기 화학식 1로 표시되는 화합물을 제조하는 방법.
[화학식 3]
[화학식 4]
[화학식 5]
상기 화학식 5에서 X는 -Cl, -Br 또는 -I이다.
[화학식 6]
[화학식 1]
b) reacting a compound represented by the formula (4) with a compound represented by the following formula (5) to prepare a compound represented by the following formula (6).
(3)
[Chemical Formula 4]
[Chemical Formula 5]
In Formula 5, X is -Cl, -Br, or -I.
[Chemical Formula 6]
[Chemical Formula 1]
[화학식 7]
(7)
c) 상기 화학식 6으로 표시되는 화합물의 트리메틸실릴기를 -H로 치환하는 단계를 더 포함하는 것인 화학식 1로 표시되는 화합물을 제조하는 방법.The method according to claim 1,
c) replacing the trimethylsilyl group of the compound represented by Formula 6 with -H.
[화학식 4]
[Chemical Formula 4]
[화학식 6]
[Chemical Formula 6]
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020120057883A KR101457453B1 (en) | 2012-05-31 | 2012-05-31 | Process for preparing gefitinib and an intermediate used for preparing thereof |
| PCT/KR2013/004024 WO2013180403A1 (en) | 2012-05-31 | 2013-05-08 | Process for preparing gefitinib and an intermediate used for preparing thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020120057883A KR101457453B1 (en) | 2012-05-31 | 2012-05-31 | Process for preparing gefitinib and an intermediate used for preparing thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20130134407A KR20130134407A (en) | 2013-12-10 |
| KR101457453B1 true KR101457453B1 (en) | 2014-11-04 |
Family
ID=49673552
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020120057883A KR101457453B1 (en) | 2012-05-31 | 2012-05-31 | Process for preparing gefitinib and an intermediate used for preparing thereof |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101457453B1 (en) |
| WO (1) | WO2013180403A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104817506A (en) * | 2015-05-06 | 2015-08-05 | 山东新时代药业有限公司 | Quinazoline nitrogen oxide |
| CN111533703B (en) * | 2020-05-07 | 2021-06-08 | 山东安弘制药有限公司 | Gefitinib purification process |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996033980A1 (en) * | 1995-04-27 | 1996-10-31 | Zeneca Limited | Quinazoline derivatives |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0221245D0 (en) * | 2002-09-13 | 2002-10-23 | Astrazeneca Ab | Chemical process |
| GB0320793D0 (en) * | 2003-09-05 | 2003-10-08 | Astrazeneca Ab | Chemical process |
| WO2005070909A1 (en) * | 2004-01-22 | 2005-08-04 | Natco Pharma Limited | An improved process for the preparation of gefitinib |
| JP2010524909A (en) * | 2007-04-16 | 2010-07-22 | シプラ・リミテッド | Method for producing gefitinib |
-
2012
- 2012-05-31 KR KR1020120057883A patent/KR101457453B1/en not_active IP Right Cessation
-
2013
- 2013-05-08 WO PCT/KR2013/004024 patent/WO2013180403A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996033980A1 (en) * | 1995-04-27 | 1996-10-31 | Zeneca Limited | Quinazoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20130134407A (en) | 2013-12-10 |
| WO2013180403A1 (en) | 2013-12-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102356063B (en) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof | |
| KR101472686B1 (en) | Method for preparation of benzimidazole derivatives | |
| WO2014135096A1 (en) | Ivacaftor preparation method and intermediate thereof | |
| KR101457453B1 (en) | Process for preparing gefitinib and an intermediate used for preparing thereof | |
| KR100686695B1 (en) | A process for preparing pranlukast or its hydrate and a synthetic intermediate thereof | |
| US9206133B2 (en) | Process for the synthesis of 7-chloro-4-(piperazin-1-yl)-quinoline | |
| JP7205059B2 (en) | Method for producing evodiamine | |
| US20200354368A1 (en) | Processes to produce acalabrutinib | |
| IL132593A (en) | Synthesis of acridine derivative multidrug-resistant inhibitors | |
| JP2022511948A (en) | Method for preparing 1-[(3R, 4S) -4-cyanotetrahydropyran-3-yl] -3-[(2-fluoro-6-methoxy-4-pyridyl) amino] pyrazole-4-carboxamide | |
| KR101635724B1 (en) | An improved process for the preparation of gefitinib | |
| CN111943979B (en) | Ifosfamide intermediate, preparation method and application thereof | |
| CN114621220B (en) | Indolo [3,2-c ] quinoline compound and synthesis method thereof | |
| JP2006001882A (en) | Method for producing o-substituted tyrosine compound | |
| CN109153652A (en) | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone | |
| JP5279449B2 (en) | Process for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride | |
| CN110204490B (en) | Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib | |
| KR100566317B1 (en) | A process for preparing carbazolone derivatives | |
| WO2023100110A1 (en) | Process for preparing brivaracetam | |
| KR100566319B1 (en) | A process for preparing carbazolone derivatives | |
| KR20170050453A (en) | Novel process for preparing thienopyrimidine compound and intermediates used therein | |
| CN117486878A (en) | Preparation method of ennafilat | |
| KR100566318B1 (en) | A process for preparing carbazolone derivatives | |
| Stefani et al. | Synthesis of trifluoroacetylketene O, N-acetals in water | |
| JPWO2002085880A1 (en) | Method for producing nitrile compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| N231 | Notification of change of applicant | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| LAPS | Lapse due to unpaid annual fee |