KR100475244B1 - Preparation of an intermediate for the synthesis of atorvastatin - Google Patents

Preparation of an intermediate for the synthesis of atorvastatin Download PDF

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KR100475244B1
KR100475244B1 KR10-2002-0036636A KR20020036636A KR100475244B1 KR 100475244 B1 KR100475244 B1 KR 100475244B1 KR 20020036636 A KR20020036636 A KR 20020036636A KR 100475244 B1 KR100475244 B1 KR 100475244B1
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formula
fluorophenyl
phenone
reaction
oxo
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KR20040001435A (en
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김문환
심영기
이광재
이수헌
류의상
안승호
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한국화학연구원
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    • E—FIXED CONSTRUCTIONS
    • E03—WATER SUPPLY; SEWERAGE
    • E03C—DOMESTIC PLUMBING INSTALLATIONS FOR FRESH WATER OR WASTE WATER; SINKS
    • E03C1/00—Domestic plumbing installations for fresh water or waste water; Sinks
    • E03C1/12—Plumbing installations for waste water; Basins or fountains connected thereto; Sinks
    • E03C1/28—Odour seals
    • E—FIXED CONSTRUCTIONS
    • E03—WATER SUPPLY; SEWERAGE
    • E03C—DOMESTIC PLUMBING INSTALLATIONS FOR FRESH WATER OR WASTE WATER; SINKS
    • E03C1/00—Domestic plumbing installations for fresh water or waste water; Sinks
    • E03C1/12—Plumbing installations for waste water; Basins or fountains connected thereto; Sinks
    • E03C1/28—Odour seals
    • E03C1/298—Odour seals consisting only of non-return valve

Abstract

본 발명은 아토르바스타틴(상품명:리피토)을 제조하기 위한 핵심 중간체인, 4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티르아미드의 효율적인 제조방법에 관한 것으로서, 4-메틸-3-옥소-N-페닐펜타미드와 2-할로-1-(4-플루오르페닐)-2-페논 또는 2,2-디할로-1-(4-플루오르페닐)-2-페논을 염기 존재 하에서 친핵성 치환반응시키는 본 발명에 따르면 온화한 조건에서 높은 수율로 아트로바스타틴 제조용 중간체를 수득할 수 있다.The present invention provides an efficient preparation of 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo- N -phenyl-butyramide, which is a key intermediate for preparing atorvastatin (trade name: Lipitor). Process relates to 4-methyl-3-oxo- N -phenylpentamide and 2-halo-1- (4-fluorophenyl) -2-phenone or 2,2-dihalo-1- (4-fluorophenyl According to the present invention in which nucleophilic substitution of the 2--2-phenone in the presence of a base, an intermediate for producing atorvastatin can be obtained in high yield under mild conditions.

Description

아토르바스타틴 합성 중간체의 제조방법{PREPARATION OF AN INTERMEDIATE FOR THE SYNTHESIS OF ATORVASTATIN}Preparation method of atorvastatin synthetic intermediate {PREPARATION OF AN INTERMEDIATE FOR THE SYNTHESIS OF ATORVASTATIN}

본 발명은 고지혈증 치료제인 아토르바스타틴(상품명: 리피토)을 제조하기 위한 핵심 중간체인 4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티르아미드의 효율적인 제조방법에 관한 것이다.The present invention relates to the preparation of 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo- N -phenyl-butyramide, which is a key intermediate for preparing atorvastatin (trade name: Lipitor), which is a therapeutic agent for hyperlipidemia. It relates to an efficient manufacturing method.

하기 화학식 1로 표시되는 아토르바스타틴은 워너램버트제약사에서 개발되고 화이자제약사에서 시판되고 있는 고지혈증 치료제로서 HMG-CoA 환원효소 억제제, ACAT 억제제의 작용을 가지며 화학명은 (3R,5R)-7-[2-(4-플루오르페닐)-5-이소프로필-3-페닐-4-(페닐카보오닐)피롤-1-일]-3,5-디하이드록시헵타노익산 칼슘 염이다.Atorvastatin represented by the following Chemical Formula 1 is an antihyperlipidemic drug developed by Warner Lambert and marketed by Pfizer Pharmaceuticals, and has the action of an HMG-CoA reductase inhibitor and an ACAT inhibitor. The chemical name is (3R, 5R) -7- [2- ( 4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbononyl) pyrrol-1-yl] -3,5-dihydroxyheptanoic acid calcium salt.

아토르바스타틴을 제조하기 위해서는 통상 중간체로서 하기 화학식 2의 4-(4-플루오르페닐)-2-이소부티릴-4-옥소-N-페닐부티르아미드의 합성이 필수적이다.In order to prepare atorvastatin, synthesis of 4- (4-fluorophenyl) -2-isobutyryl-4-oxo- N -phenylbutyramide of the following general formula (2) is usually necessary as an intermediate.

상기 화학식 2의 중간체의 합성을 위한 방법이 여러 문헌에 소개되어 있다. 예를 들어 워너램버트제약사에서 개발된 방법을 보면 (참고문헌: US 5,124,482, US 5,097,045, US 5,216,174, 한국특허공고 97-11579, 한국특허공고 97-11462, 한국특허공고 91-2794, 한국특허공고 90-700478, 한국특허공고 97-11578), 하기 반응식 1에 나타낸 바와 같이 알킬이소부티릴아세테이트와 아닐린을 반응시켜 4-메틸-3-옥소-N-페닐펜타아미드(화학식 3)를 60% 수율로 합성한 후(제1 단계), 이를 벤즈알데히드와 축합반응시켜 75% 수율로 2-이소부티릴-3,N-디페닐아크릴아미드를 E,Z 혼합물로 합성한 다음 (제2 단계), 4-플루오르벤즈알데히드와 촉매존재하에 반응시켜 70% 수율로 원하는 화학식 2의 화합물을 얻는(제3 단계) 공정을 개시하였다.Methods for the synthesis of intermediates of the above formula (2) have been introduced in several documents. For example, the method developed by Warner Lambert, Inc. (Ref .: US 5,124,482, US 5,097,045, US 5,216,174, Korean Patent Publication 97-11579, Korean Patent Publication 97-11462, Korean Patent Publication 91-2794, Korean Patent Publication 90 -700478, Korean Patent Publication No. 97-11578), and alkylisobutyryl acetate and aniline were reacted as shown in Scheme 1 to give 4-methyl-3-oxo- N -phenylpentaamide (Formula 3) in 60% yield. After synthesis (first step), it was condensed with benzaldehyde to synthesize 2-isobutyryl-3, N -diphenylacrylamide in E , Z mixture in 75% yield (second step), 4- A process of reacting fluorbenzaldehyde in the presence of a catalyst to obtain the desired compound of formula (2) in 70% yield (3rd step) was initiated.

그러나, 상기 워너램버트의 합성 방법은 제1 단계 반응이 수율이 낮고 부생성물이 많으며, 제3 단계 반응이 고도의 무수 조건하의 반응으로 약간의 수분이 존재해도 생성화합물이 깨어져 벤즈알데히드가 유리되어 4-플루오르 벤즈알데히드와 경쟁반응이 일어나서 부생성물이 생성되므로, 원하는 화학식 2의 화합물의 수율이 현격히 저하된다는 단점이 있으며 (참고문헌 J. Labelled Cpd. Radiopharm. 42, pp 121-127, 1999(수율 43-62%, 부생성물 증대), J. Labelled Cpd. Radiopharm. 43, pp 261-270, 2000(수율 22-25%, 부생성물 증대), 또한 정제 공정이 까다롭고 복잡하며 수율이 저조하고 편차가 크며 고가의 촉매를 사용하여야 하는 단점이 있다.However, the method of synthesizing Warner Lambert has low yield and high by-products in the first stage reaction, and even though some moisture is present in the third stage reaction under highly anhydrous conditions, the product compound is broken and benzaldehyde is released. As a byproduct is produced by competition with fluorine benzaldehyde, there is a disadvantage that the yield of the desired compound of formula (II) is significantly lowered (see J. Labeled Cpd. Radiopharm. 42 , pp 121-127, 1999 (yield 43-62). %, Increased by-products), J. Labeled Cpd.Radiopharm. 43 , pp 261-270, 2000 (yield 22-25%, increased by-products), and also has a difficult and complex purification process, low yields, large deviations and high prices There is a disadvantage to use a catalyst of.

이에 본 발명자들은 종래 기술이 가지는 문제점을 해결하고자 예의 연구한 결과, 기존의 중간체인 4-메틸-3-옥소-N-페닐펜타아미드(화학식 3)을 할로페논 화합물과 반응시킴으로써 종래의 합성방법보다 간편한 1단계 공정으로 고수율의 아토르바스타틴의 핵심 중간체(화학식 2)를 합성할 수 있음을 알고 본 발명을 완성하게 되었다.Accordingly, the present inventors have diligently studied to solve the problems of the prior art, and thus, by reacting the existing intermediate 4-methyl-3-oxo- N -phenylpentaamide (Formula 3) with a halophenone compound, The present invention has been accomplished by knowing that a simple one-step process can synthesize a high yield of the core intermediate of atorvastatin (Formula 2).

따라서, 본 발명의 목적은 아토르바스타틴 중간체의 보다 효율적인 제조방법을 제공하는 것이다. It is therefore an object of the present invention to provide a more efficient method for preparing atorvastatin intermediates.

상기 목적을 달성하기 위하여, 본 발명에서는 하기 화학식 3의 4-메틸-3-옥소-N-페닐펜타미드와 하기 화학식 4의 2-할로-1-(4-플루오르페닐)-2-페논 또는 하기 화학식 5의 2,2-디할로-1-(4-플루오르페닐)-2-페논 또는 이들의 혼합물을 염기 존재하에서 친핵성 치환반응시킴을 포함하는, 하기 화학식 2의 4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티르아미드의 제조 방법을 제공한다:In order to achieve the above object, in the present invention, 4-methyl-3-oxo- N -phenylpentamide of the following formula (3) and 2-halo-1- (4-fluorophenyl) -2-phenone of the following formula (4) or 4- (4-fluorophenyl) of Formula 2, comprising nucleophilic substitution of 2,2-dihalo-1- (4-fluorophenyl) -2-phenone of Formula 5 or a mixture thereof in the presence of a base ) -2-Isobutyryl-3-phenyl-4-oxo- N -phenyl-butyramide is provided:

화학식 2Formula 2

상기 식에서,Where

X는 Cl, Br 또는 I이다.X is Cl, Br or I.

이하 본 발명에 대하여 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.

구체적으로, 본 발명에 따른 방법은 하기 반응식 2에서와 같이 수행된다.Specifically, the process according to the invention is carried out as in Scheme 2 below.

상기 반응에 있어서, 출발물질로 사용된 상기 화학식 3의 4-메틸-3-옥소-N-페닐펜타미드는, 5-이소부틸-2,2-디메틸-[1,3]디옥산-4,6-디온 (참고문헌 J. Org. Chem. 43, pp 2087-2088, 1978; Synthesis, pp 1213-1214, 1992; Chem. Pharm. Bull. 35, pp 1860-1870, 1987; Synth. Commun. 10, pp 221-224, 1980 에 나타난 방법에 따라 합성)을 출발물질로 하여 제조된 알킬이소부티릴 아세테이트와 아닐린(H2NPh)을 반응시켜 제조할 수 있다(참고문헌 미국 특허 제5,124,482호).In the above reaction, 4-methyl-3-oxo- N -phenylpentamide of the general formula (3) used as starting material is 5-isobutyl-2,2-dimethyl- [1,3] dioxane-4, 6-dione (Ref. J. Org. Chem. 43 , pp 2087-2088, 1978; Synthesis , pp 1213-1214, 1992; Chem. Pharm. Bull. 35 , pp 1860-1870, 1987; Synth. Commun. 10 , pp 221-224, 1980) can be prepared by reacting an alkyl isobutyryl acetate prepared with aniline (H 2 NPh) prepared as a starting material (see US Patent No. 5,124,482).

또한, 출발물질로 사용된 상기 화학식 4의 2-할로-(4-플루오르페닐)-2-페논 및 상기 화학식 5의 2,2-디할로-(4-플루오르페닐)-2-페논은, 통상의 방법에 따라 2-(4-플루오르페닐)페논에 할로겐화(halogenation) 시약을 대략 0.5 내지 1 몰당량의 양으로 -10oC 내지 상온 범위의 온도에서 반응시켜 약 70-80%의 높은 수율로 얻을 수 있다(미국 특허 제4,824,081호). 이때, 상기 2-(4-플루오르페닐)페논은 4-플루오르벤즈알데히드와 벤질할라이드를 그리냐드반응이나 금속 촉매 존재 하에 반응시켜 2차 알코올을 얻은 후 이를 산화 반응시켜 높은 수율로 얻을 수 있다(참고문헌 Tetrahedron Letter 39, pp 9393-9396, 1998).In addition, 2-halo- (4-fluorophenyl) -2-phenone of Chemical Formula 4 and 2,2-dihalo- (4-fluorophenyl) -2-phenone of Chemical Formula 5 used as starting materials are usually The halogenated reagent is reacted with 2- (4-fluorophenyl) phenone in an amount of approximately 0.5 to 1 molar equivalents at a temperature ranging from -10 o C to room temperature in a high yield of about 70-80%. Obtainable (US Pat. No. 4,824,081). In this case, the 2- (4-fluorophenyl) phenone may be reacted with 4-fluorbenzaldehyde and benzyl halide in a Grignard reaction or in the presence of a metal catalyst to obtain a secondary alcohol, followed by oxidation to obtain a high yield (Reference) Tetrahedron Letter 39 , pp 9393-9396, 1998).

본 발명에 따른 상기 친핵성 치환 반응은 불활성 극성 또는 비극성용매 중에서 0 내지 100oC 온도 범위, 바람직하게는 상온 내지 82oC 온도범위에서 수행할 수 있으며, 상기 용매로는 테트라히드로푸란, 아세토나이트릴, 디메틸포름아미드, 디에틸에테르, 에틸아세테이트, 아세톤, 클로로포름 등을 사용할 수 있다.The nucleophilic substitution reaction according to the present invention may be carried out in an inert polar or nonpolar solvent in a temperature range of 0 to 100 o C, preferably in a room temperature to 82 o C temperature, the solvent is tetrahydrofuran, acetonite Reel, dimethylformamide, diethyl ether, ethyl acetate, acetone, chloroform and the like can be used.

또한, 본 발명의 방법에 사용될 수 있는 염기로는 탄산칼륨, 탄산칼슘, 나트륨, 수소화나트륨, 3급부톡시화칼륨, 메톡시화칼륨 등의 무기염기류와 트리에틸아민, 디이소프로필에틸아민, 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU) 등의 유기염기류가 있다.Further, bases that can be used in the method of the present invention include inorganic bases such as potassium carbonate, calcium carbonate, sodium, sodium hydride, potassium tert-butoxide and potassium methoxy hydride, triethylamine, diisopropylethylamine, 1, Organic bases such as 8-diazabicyclo [5.4.0] -7-undecene (DBU).

상기 본 발명에 따른 친핵성 치환 반응에 있어서, 출발물질은 화학식 3의 화합물: 화학식 4, 5 또는 이의 혼합물을 9:1 내지 2:1의 몰비로 사용하는 것이 바람직하다. 혼합물 사용시 화학식 4의 모노할로 화합물과 화학식 5의 디할로화합물의 혼합몰비는 9:1 내지 2:1 범위일 수 있다.In the nucleophilic substitution reaction according to the present invention, it is preferable that the starting material is a compound of the formula 3: Formula 4, 5 or a mixture thereof in a molar ratio of 9: 1 to 2: 1. When the mixture is used, the mixing molar ratio of the monohalo compound of Formula 4 and the dihalo compound of Formula 5 may range from 9: 1 to 2: 1.

본 발명의 방법은 기지의 방법보다 온화한 반응조건에서 짧은 시간내에 간단히 고순도, 고수율로 아토르바스타틴의 핵심 중간체인 4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티르아미드(화학식 2)를 얻을 수 있다.The method of the present invention is 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo- which is a key intermediate of atorvastatin in high purity and high yield in a short time under milder reaction conditions than known methods. N -phenyl-butyramide (Formula 2) can be obtained.

이하 본 발명을 실시예에 의거하여 자세히 설명하기로 하며, 이들 실시예는 본 발명을 예시하는 것일 뿐 본 발명이 이들 실시예로 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, and these Examples are merely illustrative of the present invention, and the present invention is not limited to these Examples.

제조예 1: 4-메틸-3-옥소-N-페닐펜타미드(화학식 3의 화합물)의 제조Preparation Example 1 Preparation of 4-Methyl-3-oxo- N -phenylpentamide (Compound 3)

단계 1) 2,2-디메틸-[1,3]-디옥산-4,6-디온(화학식 9의 화합물; 멜드럼산)의 제조Step 1) Preparation of 2,2-Dimethyl- [1,3] -dioxane-4,6-dione (Compound 9; Meldmic Acid)

말론산 500 g(4.8 mole)를 무수 아세트산 580 mL(5.76 mole)에 첨가한 후 여기에 0oC에서 진한 황산 15 mL을 천천히 가한 후 1시간동안 교반하였다. 생성물에 동일온도에서 아세톤 530 mL(5.28 mole)을 천천히 적가한 후 상온에서 1시간동안 교반하고 혼합물을 9시간동안 냉장 보관하였다. 생성된 흰색고체를 여과하고 찬 증류수 300 mL로 여러 번 씻어준 후 감압건조하여 흰색고체의 목적 화합물 390 g을 얻었다.500 g (4.8 mole) of malonic acid was added to 580 mL (5.76 mole) of acetic anhydride, and 15 mL of concentrated sulfuric acid was slowly added thereto at 0 ° C., followed by stirring for 1 hour. Acetone 530 mL (5.28 mole) was slowly added dropwise to the product at room temperature, stirred at room temperature for 1 hour, and the mixture was refrigerated for 9 hours. The resulting white solid was filtered, washed several times with 300 mL of cold distilled water, and dried under reduced pressure to obtain 390 g of the target compound as a white solid.

TLC 헥산/에틸아세테이트=1/1, R f 0.5.TLC hexanes / ethyl acetate = 1/1, R f 0.5.

단계 2) 5-이소부틸-2,2-디메틸-[1,3]디옥산-4,6-디온(아실멜드럼산)의 제조Step 2) Preparation of 5-isobutyl-2,2-dimethyl- [1,3] dioxane-4,6-dione (acylmeldrumic acid)

상기 단계 1에서 얻은 멜드럼산 340 g(2.36 mole)을 메틸렌클로라이드 200 mL에 녹인 후 생성용액을 0oC로 냉각하고, 여기에 피리딘 390 mL(4.72 mole)을 서서히 적가한 후 30분간 교반하였다. 생성혼합물에 동일온도에서 이소부티릴 클로라이드 298 mL(2.83 mole)을 1시간동안 적가한 후 상온에서 3시간동안 교반하였다. 반응이 완결되면 1N HCl 약 300 mL를 적가 후 유기층을 추출 분리하였고 다시 물층을 메틸렌클로라이드 100 mL로 추출한 후 얻어진 유기층을 무수 황산마그네슘으로 건조 시킨 후 감압농축하여 표제화합물 430 g(85%)을 얻었다.Melt 340 g (2.36 mole) of the medulric acid obtained in step 1 was dissolved in 200 mL of methylene chloride, the resulting solution was cooled to 0 o C, and pyridine 390 mL (4.72 mole) was slowly added dropwise thereto, followed by stirring for 30 minutes. . 298 mL (2.83 mole) of isobutyryl chloride was added dropwise to the resultant mixture at the same temperature for 1 hour, followed by stirring at room temperature for 3 hours. After completion of the reaction, 300 mL of 1N HCl was added dropwise, and the organic layer was extracted and separated. Then, the aqueous layer was extracted with 100 mL of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 430 g (85%) of the title compound. .

1H NMR(CD3OD) : δ1.06(d, 6H), 1.64(s, 6H), 3.85(m, 1H) 1 H NMR (CD 3 OD): δ1.06 (d, 6H), 1.64 (s, 6H), 3.85 (m, 1H)

단계 3) 에틸이소부티릴 아세테이트의 제조Step 3) Preparation of ethylisobutyryl acetate

상기 단계 2에서 얻은 아실 멜드럼산 150 g(0.7 mole)을 상온에서 에탄올 100 mL에 녹인 후 p-톨루엔 설포닉산 26.7 g(0.14 mole)을 첨가하고 1시간 동안 가열 환류시켰다. TLC로 반응의 완결됨을 확인한 후 반응생성물을 감압 농축하여 용매를 제거하고 잔사를 감압증류(82-85oC/40 mmHg)하여 표제화합물을 무색오일 75 g(72%)로 얻었다.After dissolving 150 g (0.7 mole) of the acyl meldrumic acid obtained in step 2 in 100 mL of ethanol at room temperature, 26.7 g (0.14 mole) of p -toluene sulfonic acid was added and heated to reflux for 1 hour. After confirming the completion of the reaction by TLC the reaction product was concentrated under reduced pressure to remove the solvent and the residue was distilled under reduced pressure (82-85 o C / 40 mmHg) to give the title compound as a colorless oil 75 g (72%).

1H NMR(CDCl3) : δ1.14(d, 6H), 1.25(t, 3H), 2.73(m, 1H), 3.47(s, 1H), 4.2(q, 2H) 1 H NMR (CDCl 3 ): δ 1.14 (d, 6H), 1.25 (t, 3H), 2.73 (m, 1H), 3.47 (s, 1H), 4.2 (q, 2H)

단계 4) 4-메틸-3-옥소-N-페닐펜타미드(화학식 3의 화합물)의 제조Step 4) Preparation of 4-methyl-3-oxo- N -phenylpentamide (Compound of Formula 3)

상기 단계 3에서 얻은 에틸이소부티릴 아세테이트 176 g(0.82 mole)을 상온에서 톨루엔 150 mL에 녹인 후 생성용액에 아닐린 83 mL(0.90 mloe)을 첨가하고 1시간동안 가열 환류시켰다. 반응이 완결된 후 반응 혼합물에 1N HCl 200 mL를 가한 후 유기층을 추출 분리하여 여분의 아닐린을 제거하였고 얻어진 유기층을 건조시킨 후 감압농축하였다. 얻어진 갈색 오일을 물 200 mL에 넣고 격렬히 교반한 후 여과하여 얻어진 갈색 고체를 물 100 mL와 핵산 100 mL로 씻어준 후 감압농축하여 원하는 표제화합물을 갈색고체 155 g(93%)로 얻었다. 176 g (0.82 mole) of ethyl isobutyryl acetate obtained in step 3 was dissolved in 150 mL of toluene at room temperature, and 83 mL (0.90 mloe) of aniline was added to the resulting solution, followed by heating to reflux for 1 hour. After the reaction was completed, 200 mL of 1N HCl was added to the reaction mixture, and the organic layer was extracted and separated to remove excess aniline. The organic layer was dried and concentrated under reduced pressure. The obtained brown oil was poured into 200 mL of water, stirred vigorously, filtered, and the obtained brown solid was washed with 100 mL of water and 100 mL of nucleic acid and concentrated under reduced pressure to give the title compound as the brown solid 155 g (93%).

1H NMR(CDCl3) : δ1.16(d, 6H), 2.73(m, 1H), 3.60(s, 2H), 7.13(m, 1H), 7.26-7.36(m, 2H), 7.55(d, 2H), 9.21(b, 1H) 1 H NMR (CDCl 3 ): δ 1.16 (d, 6H), 2.73 (m, 1H), 3.60 (s, 2H), 7.13 (m, 1H), 7.26-7.36 (m, 2H), 7.55 (d , 2H), 9.21 (b, 1H)

제조예 2: 2-브로모-1-(4-플루오르페닐)-2-페논과 2,2-디브로모-1-(4-플루오르페닐)-2-페논(화학식 4 및 5의 화합물)의 제조Preparation Example 2 2-Bromo-1- (4-fluorophenyl) -2-phenone and 2,2-dibromo-1- (4-fluorophenyl) -2-phenone (Compounds 4 and 5) Manufacture

단계 1) 1-하이드록시-2-페닐-4-플루오르벤젠의 제조Step 1) Preparation of 1-hydroxy-2-phenyl-4-fluorobenzene

디에틸에테르 150 mL에 Mg 조각 5.9 g(0.242 mole)을 넣고 교반하면서 가열하였다. 에테르가 환류되면 브로모에탄 5 mL을 첨가한 후 반응이 격렬하게 시작되면 얼음용기하에서 벤질브로마이드 38.3 mL(0.322 mole)을 천천히 적가하였다. 반응이 종결되면 0oC에서 4-플루오르벤즈알데히드 8.6 mL(0.08 mole)을 천천히 적가하였다. 반응이 종결되면 1N HCl 100 mL로 씻고 물로 세척한 후 건조농축시켜 원하는 표제화합물 13.9 g(93%)을 얻었다.5.9 g (0.242 mole) of Mg pieces were added to 150 mL of diethyl ether and heated with stirring. When the ether was refluxed, 5 mL of bromoethane was added, and when the reaction started vigorously, 38.3 mL (0.322 mole) of benzylbromide was slowly added dropwise under an ice container. At the end of the reaction, 8.6 mL (0.08 mole) of 4-fluorbenzaldehyde was slowly added dropwise at 0 ° C. After the reaction was completed, washed with 100 mL of 1N HCl, washed with water and concentrated to dryness to give the desired title compound 13.9 g (93%).

1H NMR(CDCl3) : δ2.90(d, 2H), 4.90(t, 1H), 7.01-7.30(m, 9H) 1 H NMR (CDCl 3 ): δ 2.90 (d, 2H), 4.90 (t, 1H), 7.01-7.30 (m, 9H)

단계 2) 2-(4-플루오르페닐)페논의 제조Step 2) Preparation of 2- (4-fluorophenyl) phenone

아세톤 150 mL가 들어있는 플라스크에 상기 단계 1)에서 얻은 1-하이드록시-2-페닐-4-플루오르벤젠 10 g(0.046 mole)을 넣고 교반시키면서 0oC에서 존스시약을 서서히 첨가하였다. 반응용액이 적색으로 변하면 반응을 종결시킨 후 반응용액을 염기로 중화시킨 후 아세톤을 증류한 후 에틸아세테이트 100 mL에 녹였다. 1N HCl 50 mL, 포화 탄산수소나트륨용액 50 mL, 소금물 50 mL로 씻어준 후 감압증류하여 원하는 표제화합물 8.91 g(90%)을 얻었다.10 g (0.046 mole) of 1-hydroxy-2-phenyl-4-fluorobenzene obtained in step 1) was added to a flask containing 150 mL of acetone, and the Jones reagent was slowly added at 0 ° C. while stirring. When the reaction solution turned red, the reaction was terminated, the reaction solution was neutralized with a base, acetone was distilled off, and dissolved in 100 mL of ethyl acetate. After washing with 50 mL of 1N HCl, 50 mL of saturated sodium bicarbonate solution, and 50 mL of brine, distillation under reduced pressure afforded 8.91 g (90%) of the title compound.

1H NMR(CDCl3) : δ4.20(s, 2H),7.01-7.40(m, 7H), 8.02(q, 2H) 1 H NMR (CDCl 3 ): δ 4.20 (s, 2H), 7.01-7.40 (m, 7H), 8.02 (q, 2H)

단계 3) 2-브로모-1-(4-플루오르페닐)-2-페논과 2,2-디브로모-1-(4-플루오르페닐)-2-페논의 제조Step 3) Preparation of 2-bromo-1- (4-fluorophenyl) -2-phenone and 2,2-dibromo-1- (4-fluorophenyl) -2-phenone

상기 단계 2)에서 얻은 2-(4-플루오르페닐)페논 10.47 g(0.049 mole)을 에틸에테르 100 mL에 넣고 녹인 후 브롬 7.5 g(0.047 mole)을 상온에서 적가한 후 상온에서 2일 동안 교반시켰다. 물 50 mL과 포화탄산수소나트륨용액 50 mL, 소금물 50 mL로 씻어준 후 유기층을 건조 후 감압농축 시켰다. 얻어진 잔사를 일반적인 실리카겔 컬럼크로마토그래피를 통해 모노브로모 표제화합물을 노란색 오일 7 g로 얻고 디브로모 표제화합물을 흰색 고체 6 g로 얻었다. 10.47 g (0.049 mole) of 2- (4-fluorophenyl) phenone obtained in step 2) was dissolved in 100 mL of ethyl ether, and 7.5 g (0.047 mole) of bromine was added dropwise at room temperature, followed by stirring at room temperature for 2 days. . After washing with 50 mL of water, 50 mL of saturated sodium bicarbonate solution and 50 mL of brine, the organic layer was dried and concentrated under reduced pressure. The obtained residue was subjected to general silica gel column chromatography to give 7 g of a monobromo title compound as a yellow oil and 6 g of a white solid as a dibromo title compound.

모노브로모 표제화합물 Monobromo title compound

Mass(EI+) : 293, 1H NMR(CDCl3) : δ6.32(s, 1H), 7.01-7.54(m, 7H), 8.02(q, 2H)Mass (EI + ): 293, 1 H NMR (CDCl 3 ): δ6.32 (s, 1H), 7.01-7.54 (m, 7H), 8.02 (q, 2H)

디브로모 표제화합물Dibromo Title Compound

Mass(EI+) : 372, 1H NMR(CDCl3) : δ6.80-7.01(m, 2H), 7.30-7.84(m, 7H)Mass (EI + ): 372, 1 H NMR (CDCl 3 ): δ6.80-7.01 (m, 2H), 7.30-7.84 (m, 7H)

제조예 3: 2-클로로-1-(4-플루오르페닐)-2-페논 및 2,2-디클로로-1-(4-플루오르페닐)-2-페논(화학식 4 및 5의 화합물)의 제조Preparation Example 3 Preparation of 2-chloro-1- (4-fluorophenyl) -2-phenone and 2,2-dichloro-1- (4-fluorophenyl) -2-phenone (compounds of Formulas 4 and 5)

상기 제조예 2의 단계 2)에서 얻은 2-(4-플루오르페닐)페논 30 g(0.14 mole)을 클로로포름 300 mL에 넣고 녹인 후 디메틸포름아미드 5 mL를 가하였다. 염소가스를 주입하면서 반응을 TLC로 체크하였다. 약 2일 후 반응을 종결한 다음, 물 150 mL로 세척하고 클로로포름 150 mL로 추출하였다. 실리카겔 컬럼크로마토그래피를 통해 분리하여 모노클로로 표제화합물을 노란색 오일 32 g로 얻었고, 디클로로 표제화합물을 무색 오일 3 g로 얻었다.30 g (0.14 mole) of 2- (4-fluorophenyl) phenone obtained in Step 2) of Preparation Example 2 was dissolved in 300 mL of chloroform, and 5 mL of dimethylformamide was added thereto. The reaction was checked by TLC while injecting chlorine gas. After about 2 days the reaction was terminated, washed with 150 mL of water and extracted with 150 mL of chloroform. Separation via silica gel column chromatography gave the monochloro title compound as 32 g of a yellow oil, and the dichloro title compound as a colorless oil (3 g).

모노클로로 표제화합물 Monochloro title compound

Mass(EI+) : 248, 1H NMR(CDCl3) : δ6.32(s, 1H), 7.10(q, 2H), 7.30-7.41(m, 3H), 7.50(q, 2H), 8.02(q, 2H)Mass (EI + ): 248, 1 H NMR (CDCl 3 ): δ6.32 (s, 1H), 7.10 (q, 2H), 7.30-7.41 (m, 3H), 7.50 (q, 2H), 8.02 ( q, 2H)

디클로로 표제화합물Dichloro Title Compound

Mass(EI+) : 283, 1H NMR(CDCl3) : δ6.90(q, 2H), 7.30(m, 3H), 7.62(q, 2H), 7.81(q, 2H)Mass (EI + ): 283, 1 H NMR (CDCl 3 ): δ6.90 (q, 2H), 7.30 (m, 3H), 7.62 (q, 2H), 7.81 (q, 2H)

4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-4- (4-Fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo- NN -페닐-부티르아미드(화학식 2의 화합물)의 제조Preparation of -phenyl-butyramide (Compound of Formula 2)

실시예 1Example 1

둥근 플라스크에 아세토니트릴 250mL를 넣고 제조예 1에서 얻은 4-메틸-3-옥소-N-페닐펜타미드 10 g(0.049 mole)과 제조예 2에서 얻은 2-브로모-1-(4-플루오르페닐)-2-페논 15.75 g(0.053 mole), 탄산칼륨 6.7 g(0.048 mole)을 넣고 6시간동안 가열 환류하였다. 1N HCl 수용액으로 중화시킨 후 용매를 감압증류하였다. 잔사를 에틸아세테이트 50 mL에 녹인 후 물과 소금물로 씻은 후 용매를 건조후 감압증류 한 후 실리카겔 컬럼크로마토그래피를 통해 분리하여, 순수한 표제화합물 16.27 g(80%)을 흰색고체로 얻었다.250 mL of acetonitrile was placed in a round flask, and 10 g (0.049 mole) of 4-methyl-3-oxo- N -phenylpentamide obtained in Preparation Example 1 and 2-bromo-1- (4-fluorophenyl) obtained in Preparation Example 2 15.75 g (0.053 mole) of -2--2-phenone and 6.7 g (0.048 mole) of potassium carbonate were added thereto, followed by heating to reflux for 6 hours. After neutralizing with 1N aqueous HCl solution, the solvent was distilled under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate, washed with water and brine, and the solvent was dried under reduced pressure and distilled under reduced pressure. Then, silica gel column chromatography was used to obtain 16.27 g (80%) of the title compound as a white solid.

Mass(EI+) : 417Mass (EI + ): 417

1H NMR(CDCl3) : δ1.10(d, 3H), 1.20(d, 2H), 2.91(m, 1H), 4.51(d, 1H), 5.30(d, 1H), 7.01(t, 2H), 7.10(q, 3H), 7.20(m, 5H), 7.30(d, 2H), 7.70(s, 1H), 8.01(q. 2H) 1 H NMR (CDCl 3 ): δ 1.10 (d, 3H), 1.20 (d, 2H), 2.91 (m, 1H), 4.51 (d, 1H), 5.30 (d, 1H), 7.01 (t, 2H ), 7.10 (q, 3H), 7.20 (m, 5H), 7.30 (d, 2H), 7.70 (s, 1H), 8.01 (q. 2H)

실시예 1-1Example 1-1

실시예 1에서 출발물질로서의 제조예 2의 브로모페논 화합물 대신에 제조예 3에서 얻은 2-클로로-1-(4-플루오르페닐)-2-페논을 사용하여 동일한 조건으로 반응을 수행하여 동일한 결과를 수득하였다.Instead of the bromophenone compound of Preparation Example 2 as starting material in Example 1, the reaction was carried out under the same conditions using 2-chloro-1- (4-fluorophenyl) -2-phenone obtained in Preparation Example 3 to obtain the same result. Obtained.

실시예 2Example 2

둥근 플라스크에 아세토니트릴 25mL를 넣고 제조예 1에서 얻은 4-메틸-3-옥소-N-페닐펜타미드 2.0 g(0.0097 mole)와 제조예 2에서 얻은 2,2-디브로모-1-(4-플루오르페닐)-2-페논 3.9 g(0.0104 mole), 및 탄산칼륨 1.4 g(0.0101 mole)을 넣고 6시간동안 가열 환류하였다. 1N HCl 수용액으로 중화시킨 후 용매를 감압증류하였다. 잔사를 에틸아세테이트 10 mL에 녹인 후 물과 소금물로 씻은 후 용매를 건조후 감압증류 한후 실리카겔 컬럼크로마토그래피를 통해 분리하여, 순수한 표제화합물 2.44 g(60%)을 흰색고체로 얻었다.25 mL of acetonitrile was added to a round flask and 2.0 g (0.0097 mole) of 4-methyl-3-oxo- N -phenylpentamide obtained in Preparation Example 1 and 2,2-dibromo-1- (4) obtained in Preparation Example 2 were prepared. 3.9 g (0.0104 mole) of -fluorophenyl) -2-phenone and 1.4 g (0.0101 mole) of potassium carbonate were added thereto, and the mixture was heated to reflux for 6 hours. After neutralizing with 1N aqueous HCl solution, the solvent was distilled under reduced pressure. The residue was dissolved in 10 mL of ethyl acetate, washed with water and brine, and the solvent was dried under reduced pressure and distilled under reduced pressure. Then, silica gel column chromatography was used to obtain 2.44 g (60%) of the title compound as a white solid.

Mass(EI+) : 417Mass (EI + ): 417

1H NMR(CDCl3) : δ1.10(d, 3H), 1.20(d, 2H), 2.91(m, 1H), 4.51(d, 1H), 5.30(d, 1H), 7.01(t, 2H), 7.10(q, 3H), 7.20(m, 5H), 7.30(d, 2H), 7.70(s, 1H), 8.01(q. 2H) 1 H NMR (CDCl 3 ): δ 1.10 (d, 3H), 1.20 (d, 2H), 2.91 (m, 1H), 4.51 (d, 1H), 5.30 (d, 1H), 7.01 (t, 2H ), 7.10 (q, 3H), 7.20 (m, 5H), 7.30 (d, 2H), 7.70 (s, 1H), 8.01 (q. 2H)

실시예 2-1Example 2-1

실시예 2에서, 출발물질로서의 제조예 2의 브로모페논 화합물 대신에 제조예 3에서 얻은 2,2-디클로로-1-(4-플루오르페닐)-2-페논을 사용하여 동일한 조건으로 반응을 수행하여 동일한 결과를 수득하였다.In Example 2, the reaction was carried out under the same conditions using 2,2-dichloro-1- (4-fluorophenyl) -2-phenone obtained in Preparation Example 3 instead of the bromophenone compound of Preparation Example 2 as starting material. The same result was obtained.

실시예 3Example 3

둥근 플라스크에 아세토니트릴 25 mL를 넣고 제조예 1에서 얻은 4-메틸-3-옥소-N-페닐펜타미드 2.0 g(0.0097 mole)와 제조예 2에서 얻은 2-브로모-1-(4-플루오르페닐)-2-페논과 2,2-디브로모-1-(4-플루오르페닐)-2-페논 혼합물(2:1 몰비) 4 g, 그리고 탄산칼륨 1.4 g(0.0101 mole)을 넣고 실시예 1 또는 2와 동일한 방법으로 반응시켜 원하는 순수한 표제화합물 2.64 g(65%)을 흰색고체로 얻었다.25 mL of acetonitrile was added to a round flask and 2.0 g (0.0097 mole) of 4-methyl-3-oxo- N -phenylpentamide obtained in Preparation Example 1 and 2-bromo-1- (4-fluorine obtained in Preparation Example 2) were obtained. 4 g of a mixture of phenyl) -2-phenone and 2,2-dibromo-1- (4-fluorophenyl) -2-phenone (2: 1 molar ratio), and 1.4 g (0.0101 mole) of potassium carbonate were added thereto. The reaction was carried out in the same manner as 1 or 2, to obtain 2.64 g (65%) of the desired pure title compound as a white solid.

Mass(EI+) : 417Mass (EI + ): 417

1H NMR(CDCl3) : δ1.10(d, 3H), 1.20(d, 2H), 2.91(m, 1H), 4.51(d, 1H), 5.30(d, 1H), 7.01(t, 2H), 7.10(q, 3H), 7.20(m, 5H), 7.30(d, 2H), 7.70(s, 1H), 8.01(q. 2H) 1 H NMR (CDCl 3 ): δ 1.10 (d, 3H), 1.20 (d, 2H), 2.91 (m, 1H), 4.51 (d, 1H), 5.30 (d, 1H), 7.01 (t, 2H ), 7.10 (q, 3H), 7.20 (m, 5H), 7.30 (d, 2H), 7.70 (s, 1H), 8.01 (q. 2H)

본 발명에 따르면, 4-메틸-3-옥소-N-페닐펜타미드를 2-할로-1-(4-플루오르페닐)-2-페논 또는 2,2-디할로-1-(4-플루오르페닐)-2-페논 또는 이의 혼합물과 염기존재하에서 친핵성 치환 반응시킴으로써, 기지의 방법보다 온화한 반응조건에서 짧은 시간내에 간단히 고순도, 고수율로 아토르바스타틴의 핵심 중간체인 4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티르아미드를 얻을 수 있다.According to the present invention, 4-methyl-3-oxo- N -phenylpentamide is converted to 2-halo-1- (4-fluorophenyl) -2-phenone or 2,2-dihalo-1- (4-fluorophenyl). 4- (4-fluorophenyl) -2, which is a key intermediate of atorvastatin, in high purity and high yield in a short time under mild reaction conditions milder than known methods, by nucleophilic substitution reaction in the presence of a base))-2-phenone or a mixture thereof. -Isobutyryl-3-phenyl-4-oxo- N -phenyl-butyrylamide can be obtained.

Claims (7)

하기 화학식 3의 4-메틸-3-옥소-N-페닐펜타미드와 하기 화학식 4의 2-할로-1-(4-플루오르페닐)-2-페논 또는 하기 화학식 5의 2,2-디할로-1-(4-플루오르페닐)-2-페논 또는 이들의 혼합물을 염기 존재하에서 친핵성 치환반응시킴을 포함하는, 하기 화학식 2의 4-(4-플루오르페닐)-2-이소부티릴-3-페닐-4-옥소-N-페닐-부티르아미드의 제조 방법:4-Methyl-3-oxo- N -phenylpentamide of Formula 3 and 2-halo-1- (4-fluorophenyl) -2-phenone of Formula 4 or 2,2-dihalo- of Formula 5 4- (4-fluorophenyl) -2-isobutyryl-3- of formula (2) comprising nucleophilic substitution of 1- (4-fluorophenyl) -2-phenone or mixtures thereof in the presence of a base Process for preparing Phenyl-4-oxo- N -phenyl-butyramide: 화학식 2Formula 2 화학식 3Formula 3 화학식 4Formula 4 화학식 5Formula 5 상기 식에서,Where X는 Cl, Br 또는 I이다.X is Cl, Br or I. 제 1 항에 있어서,The method of claim 1, 염기가 탄산칼륨, 탄산칼슘, 나트륨, 수소화나트륨, 3급부톡시화칼륨 및 메톡시화칼륨로 이루어진 군 중에서 선택된 1종 이상의 무기염기이거나 트리에틸아민, 디이소프로필 에틸아민 및 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU)로 이루어진 군 중에서 선택된 1종 이상의 유기염기임을 특징으로 하는 방법.The base is one or more inorganic bases selected from the group consisting of potassium carbonate, calcium carbonate, sodium, sodium hydride, potassium tert-butoxide and potassium methoxide, or triethylamine, diisopropyl ethylamine and 1,8-diazabicyclo [5.4.0] -7-Undecene (DBU) A method characterized in that at least one organic base selected from the group consisting of. 제 1 항에 있어서,The method of claim 1, 화학식 3의 화합물과 화학식 4 또는 5 또는 이들의 혼합물을 9:1 내지 2:1의 몰비로 사용함을 특징으로 하는 방법.The compound of formula 3 and formula 4 or 5 or a mixture thereof may be prepared in a range of 9: 1 to 2: 1 Characterized in that used in molar ratio. 제 1 항에 있어서,The method of claim 1, 극성 또는 비극성용매 중에서 0 내지 100oC 온도범위에서 반응을 수행하는 것을 특징으로 하는 방법.The reaction is carried out in a polar or nonpolar solvent in the temperature range of 0 to 100 ° C. 제 4 항에 있어서,The method of claim 4, wherein 반응온도가 상온 내지 82oC 범위임을 특징으로 하는 방법.The reaction temperature ranges from room temperature to 82 o C. 제 4 항에 있어서,The method of claim 4, wherein 용매가 테트라히드로푸란, 아세토나이트릴, 디메틸포름아미드, 디에틸에테르, 에틸아세테이트, 아세톤 및 클로로포름으로 이루어진 군 중에서 선택된 1종 이상임을 특징으로 하는 방법.The solvent is characterized in that at least one selected from the group consisting of tetrahydrofuran, acetonitrile, dimethylformamide, diethyl ether, ethyl acetate, acetone and chloroform. 제 1 항에 있어서,The method of claim 1, 화학식 4의 2-할로-(4-플루오르페닐)-2-페논 또는 화학식 5의 2,2-디할로-(4-플루오르페닐)-2-페논이, 4-플루오르벤즈알데히드와 벤질할라이드를 그리냐드 반응이나 금속 촉매 존재 하에 반응시켜 2차 알코올을 얻고 이를 산화 반응시켜 2-(4-플루오르페닐)페논을 얻은 다음 이를 할로겐화(halogenation) 시약과 반응시키는 것을 포함하는 공정에 의해 수득된 것임을 특징으로 하는 방법.2-halo- (4-fluorophenyl) -2-phenone of formula (4) or 2,2-dihalo- (4-fluorophenyl) -2-phenone of formula (5) gives 4-fluorbenzaldehyde and benzyl halide Reacting in the presence of a reaction or metal catalyst to obtain a secondary alcohol and oxidizing it to obtain 2- (4-fluorophenyl) phenone followed by reaction with a halogenation reagent. Way.
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