KR101134021B1 - Manufacturing method of pitavastatin hemicalcium using novel intermediates - Google Patents

Manufacturing method of pitavastatin hemicalcium using novel intermediates Download PDF

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KR101134021B1
KR101134021B1 KR1020100016680A KR20100016680A KR101134021B1 KR 101134021 B1 KR101134021 B1 KR 101134021B1 KR 1020100016680 A KR1020100016680 A KR 1020100016680A KR 20100016680 A KR20100016680 A KR 20100016680A KR 101134021 B1 KR101134021 B1 KR 101134021B1
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조동옥
김승기
조현숙
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주식회사 메디켐코리아
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

본 발명은 HMG-Co A 환원 효소 억제제(HMG-Co A reductase inhibitor)로 유용하며, 고지혈증의 치료제로 사용되는 피타바스타틴 헤미칼슘의 신규한 제조방법에 관한 것으로서, 특히 새로운 중간체를 이용하는 피타바스타틴 헤미칼슘의 신규한 제조방법에 관한 것이며, 피타바스타틴을 제조하기 위한 신규한 중간체를 이용, 피타바스타틴의 효율적인 제조방법을 제공하고, 또한 신규한 중간체 중 알콜보호기는 산 촉매하에서 온화한 반응조건으로 1 내지 2시간 이내에 쉽게 디알콜을 보호화할 뿐 만 아니라, 디알콜의 탈보호화 반응 시 0 내지 25℃의 매우 온화한 반응조건하에서 30분 내지 1시간 이내에 반응이 완결되므로, 이성질체의 생성을 최대한 낮추었다는 점들이 본 발명의 장점이라 할 수 있다. 또한, 본 발명은 탈보호화 반응 후, 가수분해반응과 피타바스타틴 헤미칼슘 반응을 단리반응 없이 연속적으로 수행함에도 불구하고 고순도의 피타바스타틴 헤미칼슘을 고수율로 수득할 수 있다는 점이 본 발명의 장점이라 할 수 있다.The present invention relates to a novel method for preparing pitavastatin hemicalcium, which is useful as an HMG-Co A reductase inhibitor and is used as a therapeutic agent for hyperlipidemia, and in particular, pitavastatin using a new intermediate. The present invention relates to a novel process for preparing hemicalcium, and provides an efficient process for preparing pitavastatin using a novel intermediate for preparing pitavastatin, and an alcohol protecting group in the novel intermediate under mild reaction conditions under an acid catalyst. In addition to easily protecting the dialcohol within 1 to 2 hours, the reaction was completed within 30 minutes to 1 hour under very mild reaction conditions of 0 to 25 ° C during the deprotection of dialcohol, resulting in the lowest possible production of isomers. This is an advantage of the present invention. In addition, the present invention is an advantage of the present invention that high purity pitavastatin hemicalcium can be obtained in high yield even after the deprotection reaction is carried out without hydrolysis and pitavastatin hemicalcium reaction without isolation reaction. This can be called.

Description

새로운 중간체를 이용하는 피타바스타틴 헤미칼슘의 신규한 제조방법 {Manufacturing method of pitavastatin hemicalcium using novel intermediates}Novel manufacturing method of pitavastatin hemicalcium using new intermediates {Manufacturing method of pitavastatin hemicalcium using novel intermediates}

본 발명은 HMG-Co A 환원 효소 억제제(HMG-Co A reductase inhibitor)로 유용하며, 고지혈증의 치료제로 사용되는 피타바스타틴 헤미칼슘의 신규한 제조방법에 관한 것이다. 특히 본 발명은 새로운 중간체를 이용하는 피타바스타틴 헤미칼슘의 신규한 제조방법 및 그의 결정형에 관한 것이다.The present invention is useful as a HMG-Co A reductase inhibitor, and relates to a novel method for preparing pitavastatin hemicalcium used as a therapeutic agent for hyperlipidemia. In particular, the present invention relates to a novel process for the production of pitavastatin hemicalcium using the new intermediates and to their crystalline forms.

하기 화학식 1로 표시되는 피타바스타틴헤미칼슘(Pitavastatin hemicalcium)은 닛산케미칼 (Nissan Chemical industry)에 의하여 상품명 리발로(LIVALO)판매되고 있는 심혈관 질환의 발병위험이 있는 환자의 혈류중 저밀도지단백(LDL) 농도를 낮추며 고지혈증에 유용한 약물(참고문헌; Cardiovasc Drug Rev 2003;21:199~215. J Clin Pract 2005;59: 239~252)이다.Pitavastatin hemicalcium represented by Formula 1 is low density lipoprotein (LDL) in the bloodstream of a patient at risk of developing cardiovascular disease, which is sold by Nissan Chemical industry under the trade name LIVALO. Drugs that are low in concentration and useful for hyperlipidemia (Ref. Cardiovasc Drug Rev 2003; 21: 199-215. J Clin Pract 2005; 59: 239-252).

Figure 112010012115746-pat00001
Figure 112010012115746-pat00001

상기 화학식 1의 피타바스타틴 헤미칼슘은 일본특허 제 207224호(1987년), 일본특허 제15585호(1988년), 동 제193606호(1988년), 동 제93/01551호, 국제특허 제95/ 11898호, 미국특허 제5856336호, 동 제4739073호, 유럽특허 제11402호, 한국특허 제1996-0000852호, 논문 Bioorganic &Medicinal Chemistry Letters 9 (1999)2977~2982, 논문 Bioorg. Med. Chem 9(2001)2727~2743 등에 공지되어 있으며 공지내용을 요약하면 하기 반응식 1로 표현된다.The pitavastatin hemicalcium of Formula 1 is Japanese Patent No. 207224 (1987), Japanese Patent No. 15585 (1988), Japanese Patent No. 193606 (1988), Japanese Patent No. 93/01551, International Patent No. 95 / 11898, U.S. Pat.No.5856336, U.S. Pat.No.4739073, European Patent No.11402, Korean Patent No.1996-0000852, Paper Bioorganic & Medical Chemistry Letters 9 (1999) 2977 ~ 2982, Paper Bioorg. Med. Chem 9 (2001) 2727-2743 and the like are summarized in the following Reaction Scheme 1.

[반응식 1]Scheme 1

Figure 112010012115746-pat00002
Figure 112010012115746-pat00002

상기 반응식 1은 화학식(2)의 벤질알콜 화합물을 디메틸설폭사이드(DMSO)와 산화제하에서 산화반응에 의하여 벤질알콜기를 벤즈알데히드기로 전환된 화확식(3)으로 합성한 후, 디에틸시아노메틸포스페이트 화합물과 에몬스-호너 커플링반응(Emmons- Horner coupling)하고, 다시 강력한 환원제인 디이소부틸알루미늄하이드라이드(DIBAH)로 환원반응에 의하여 화학식(4)의 프로페날 화합물로 합성한다. 상기 화학식(4)의 프로페날 화합물을 n-부틸리튬(n-BuLi)의 강력한 염기 하에 에틸아세테이트와 알돌 축합반응(Aldol condensation)에 의하여 β-케토-δ-히드록시에스터(β-keto-δ-hydroxy ethyl ester)를 라세믹(Racemic)의 화학식(5)로 합성한다. 상기 화학식(5)의 라세믹 화합물을 강력한 환원제인 소듐보로하이드라이드(NaBH4)로 환원반응시켜 에난티오머(Enantiomer)(화학식(6))로 합성한 후, 가수분해 및 칼슘반응을 통하여 상기 화학식 1의 피타바스타틴 헤미칼슘을 합성하였다.Scheme 1 is a diethylcyanomethyl phosphate compound after the benzyl alcohol compound of formula (2) is synthesized by converting the benzyl alcohol group to benzaldehyde group by oxidation reaction under dimethyl sulfoxide (DMSO) and oxidizing agent And the Emmons-Honer coupling reaction, and is then synthesized into a propenal compound of the formula (4) by reduction with diisobutyl aluminum hydride (DIBAH), a powerful reducing agent. Propane compound of formula (4) was subjected to beta-keto-δ-hydroxyester (β-keto-δ) by aldol condensation with ethyl acetate under a strong base of n-butyllithium (n-BuLi). -hydroxy ethyl ester) is synthesized by racemic formula (5). The racemic compound of Formula (5) is reduced with sodium borohydride (NaBH 4 ), a powerful reducing agent, to synthesize Enantiomer (Formula (6)), followed by hydrolysis and calcium reaction. Pitavastatin hemicalcium of Formula 1 was synthesized.

피타바스타틴의 합성과정의 상기 반응식 1은 화학식(4), 화학식(5) 및 화학식(6)들의 합성 시, 이성질체도 동시에 합성되어지는 단점과 또한 디이소부틸알루미늄하이드라이드, n-부틸리튬, 소듐보로하이드라이드 등과 같이 수분 및 공기 접촉에 매우 민감하여 폭발의 위험성이 있는 산업적으로 매우 불리한 환원제 및 염기 등을 사용하여야 한다는 단점이 있다.Scheme 1 of the synthesis process of pitavastatin has the disadvantage that isomers are simultaneously synthesized in the synthesis of formula (4), formula (5) and formula (6), and also isobutyl aluminum hydride, n-butyl lithium, It is disadvantageous in that industrially disadvantageous reducing agents and bases, such as sodium borohydride, which are very sensitive to contact with moisture and air, have a risk of explosion, must be used.

상기 반응식 1을 더욱 자세히 살펴보면 다음과 같다.Looking at the reaction scheme 1 in more detail as follows.

첫째 ; 상기 반응식 1의 화학식(3)의 벤즈알데히드(Benzaldehyde)를 디에틸시아노메틸포스포네이트(diethy(cyanomethyl)phosphonate)를 이용하여 에몬스-호너 커플링 반응을 통하여 상기 화학식(4)의 트랜스-프로페날(trans-Propenal)로 합성하는 경우, 불순물인 지-폼(Z-form)의 이성질체도 동시에 생성되며, 생성된 이성질체 화합물(Z-propenal)의 제거 또한 용이하지 않다. first ; Benzaldehyde of formula (3) of Scheme 1 is trans-propenal of formula (4) through an emons-Honner coupling reaction using dithycyanomethyl phosphonate In the case of synthesizing (trans-Propenal), isomers of Z-form as impurities are generated at the same time, and the removal of the resulting isomeric compound (Z-propenal) is not easy.

둘째 ; 이성질체를 제거하기 위해 정제과정을 수행해야하는 단점이 있을 뿐만 아니라, 상기 화학식(5)의 β-케토-δ-히드록시에스터(β-keto-δ-hydroxy ethyl ester) 합성 시, 수분과 공기에 매우 폭발성이 강한 n-부틸리튬(n-BuLi)의 염기를 사용함이 단점이라 할 수 있다. 또한 상기 화학식(4)의 불순물인 Z-프로페날 화합물의 알데히드기가 2차알콜로 변환될 때 입체화학적 성질이 상이한 라세믹의 혼합물이 생성됨이 단점이라 할 수가 있다. 이는 상기 화학식(4)의 합성 시 생성된 이-폼(E-form), 지-폼 혼합물에 상기 화학식(5)를 합성할 때 생성되는 라세믹 혼합물까지 매우 순도가 낮은 단점이 있다.second ; In addition to the disadvantage of having to perform the purification process to remove the isomers, the synthesis of β-keto-δ-hydroxy ester of formula (5) is very resistant to moisture and air. The disadvantage of using a highly explosive base of n-butyllithium (n-BuLi). In addition, when the aldehyde group of the Z-propenal compound, which is an impurity of the formula (4), is converted to a secondary alcohol, a disadvantage is that a mixture of racemic substances having different stereochemical properties is produced. This has the disadvantage of having a very low purity up to the racemic mixture produced when synthesizing the formula (5) to the E-form, G-form mixture produced during the synthesis of the formula (4).

셋째 ; 상기 화학식(6)을 합성하기 위하여 상기 화학식(5)의 β-케토기를 선택적 환원반응시킨 후, 상기 화학식(6)이 서로 상이한 입체화학적 구조의 (R,R),(S,S)의 에난티오머(Enantiomer)의 혼합물로 생성된다는 것이 매우 큰 단점이다.third ; After selectively reducing the β-keto group of the formula (5) to synthesize the formula (6), the formula (6) of (R, R), (S, S) of the stereochemical structure different from each other A major disadvantage is that it is produced as a mixture of enantiomers.

상기 반응식 1의 개선된 방법으로 하기 반응식 2로 표현되는 제조방법이 제안되었다.As an improved method of Scheme 1, a preparation method represented by Scheme 2 was proposed.

[반응식 2]Scheme 2

Figure 112010012115746-pat00003
Figure 112010012115746-pat00003

상기 반응식 2는 화학식(D)를 합성한 후, 화학식(G)와 커플링반응을 한 후, 다시 디올의 보호기를 탈보호화한 후, 락톤화합물인 화학식(J)를 합성한다. 상기 화학식(J)의 락톤을 가수분해시켜 피타바스타틴을 합성한다.Reaction Scheme 2 synthesizes Formula (D), performs a coupling reaction with Formula (G), deprotects the protecting group of the diol, and then synthesizes Formula (J), which is a lactone compound. The lactone of formula (J) is hydrolyzed to synthesize pitavastatin.

상기 반응식 2는 상기 반응식 1에 비해 피타바스타틴의 개선된 제조방법이나, 다음과 같은 단점이 있다.Scheme 2 is an improved method of preparing pitavastatin compared to Scheme 1, but has the following disadvantages.

첫째 ; 화학식(G)와 화학식(D)의 커플링 반응을 통하여 화학식(H)를 합성하는 경우, 상당량의 불순물인 화학식(I)의 이성질체가 생성되며, 또한 분리 정제하기 매우 어려운 불순물인 상기 화학식(I)의 이성질체를 분리 정제해야하는 단점이 있다.first ; In the case of synthesizing the formula (H) through the coupling reaction of the formula (G) and the formula (D), a considerable amount of isomers of the formula (I) are produced, and the impurities of the formula (I) which are very difficult to separate and purify There is a disadvantage in that the isomer of) must be separated and purified.

둘째 ; 상기 화학식(H)의 화학식(J)로의 합성 시 디올의 보호기를 탈보호화 해야 하는데 탈보호화 반응 시, 강산인 삼불화아세트산(TFA ; Trifluoroacetic acid)을 사용해야 하며, 또한 24시간 이상의 매우 긴 반응시간이 단점이며, 긴 반응시간으로 인한 불순물인 이성질체(Z-form)가 생성됨이 단점이다.second ; In the synthesis of Formula (H) to Formula (J), the protecting group of the diol should be deprotected. In the deprotection reaction, a strong acid, trifluoroacetic acid (TFA), must be used, and a very long reaction time of 24 hours or more is required. It is a disadvantage, and the disadvantage is that an isomer (Z-form) is generated due to a long reaction time.

셋째 ; 상기 화학식(J)를 합성하기 위하여 강산과 24시간의 긴 반응시간으로 탈보호화한 후, 다시 화학식(J)의 락톤 화합물을 합성해야 한다. 하지만 이때 상당량의 이성질체(Z-form)가 생성되며, 또한 이성체를 제거하기 위한 공정을 수행하여야 하므로 수율이 저하되는 문제점을 가지고 있다. third ; In order to synthesize the above formula (J), after deprotection with a strong reaction with a strong acid for 24 hours, the lactone compound of the formula (J) should be synthesized again. However, at this time, a considerable amount of isomers (Z-form) are generated, and also has a problem in that the yield is reduced because a process for removing the isomers must be performed.

이와 같이, 상기의 반응식 1과 상기의 반응식 2 등의 기존의 방법들은 반응 시 필연적으로 생성되는 불순물인 이성질체로 인한 순도 저하와 이성질체를 제거하기 위한 매우 복잡한 정제공정을 거쳐야 함은 물론 수율 저하 뿐 만 아니라, 순도의 저하의 원인이 될 수 있다.As described above, the existing methods such as Scheme 1 and Scheme 2 have to go through a very complicated purification process to remove the isomer and the purity due to the isomer that is inevitably generated during the reaction. It may be a cause of lowering of purity.

본 발명은 피타바스타틴 제조에 있어서, 상기에서 기술한 종래의 단점을 보완한 제조방법을 제공하는 것을 목적으로 하며, 이는 산업적으로 매우 유용한 피타바스타틴의 제조방법이라 할 수 있다. An object of the present invention is to provide a method for preparing pitavastatin, which supplements the above-mentioned disadvantages, and is an industrially useful method for preparing pitavastatin.

본 발명자들이 오랜 기간 동안 체계적이면서도 집중적으로 연구개발한 피타바스타틴의 제조방법은 산업적으로 매우 유용한 제조공정이다. 이는 피타바스타틴 제조에 있어서 산업적으로 매우 유용한 원료 및 시약을 사용할 뿐 만 아니라, 피타바스타틴의 제조를 단순화하여 대량생산에 적합한 공정으로, 종래의 문제점를 극복한 발전된 피타바스타틴의 제조방법이라 할 수 있다.The method of producing pitavastatin, which the inventors have systematically and intensively researched for a long time, is an industrially very useful manufacturing process. This not only uses industrially useful raw materials and reagents for the production of pitavastatin, but also simplifies the production of pitavastatin and is suitable for mass production. have.

상기한 바와 같은 목적을 달성하기 위한 본 발명은, 피타바스타틴 헤미칼슘 제조를 위한 하기 반응식 3으로 표현된 바와 같이 총 7단계로 구성됨을 특징으로 한다.The present invention for achieving the object as described above, characterized in that composed of a total of seven steps as represented by the following Scheme 3 for the production of pitavastatin hemicalcium.

[반응식 3]Scheme 3

Figure 112010012115746-pat00004
Figure 112010012115746-pat00004

본 발명은 HMG-Co A 환원 효소 억제제(HMG-Co A reductase inhibitor)로 유용하며, 고지혈증의 치료제로 사용되는 피타바스타틴 헤미칼슘의 신규한 제조방법을 제공하며, 본 발명에 따르면, 새로운 중간체를 이용하는 피타바스타틴 헤미칼슘의 신규한 제조방법을 제공함으로써 산업적으로 매우 유용한 원료 및 시약을 사용할 뿐 만 아니라, 피타바스타틴의 제조를 단순화하여 대량생산에 적합하여 대량생산 등을 가능하게 하는 효과가 있다.The present invention provides a novel method for preparing pitavastatin hemicalcium, which is useful as an HMG-Co A reductase inhibitor, and is used as a therapeutic agent for hyperlipidemia. By providing a novel method for preparing pitavastatin hemicalcium, it not only uses industrially useful raw materials and reagents, but also simplifies the production of pitavastatin, making it suitable for mass production and enabling mass production. .

도 1은 피타바스타틴 헤미칼슘의 X선분말 회절도이다. 1 is an X-ray powder diffractogram of pitavastatin hemicalcium.

이하, 본 발명의 구체적인 실시예를 첨부한 도면을 참조하여 상세히 설명한다.Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings.

본 발명자들은 피타바스타틴 헤미칼슘의 제조방법을 조직적이면서 끈질기게 연구한 결과, 제조공정을 매우 단순화 하였을 뿐 만 아니라, 이로 인한 산업적으로 대량생산이 가능한 피타바스타틴의 제조방법을 완성하였다.The present inventors have systematically and persistently studied the manufacturing method of pitavastatin hemicalcium, and not only greatly simplified the manufacturing process but also completed the manufacturing method of pitavastatin which can be industrially mass-produced.

본 발명의 특징 중 하나는 피타바스타틴을 제조하기 위한 신규한 중간체를 이용, 피타바스타틴의 효율적인 제조방법을 제공하고, 또한 신규한 중간체 중 알콜보호기는 산 촉매하에서 온화한 반응조건으로 1 내지 2시간 이내에 쉽게 디알콜을 보호화할 뿐 만 아니라, 디알콜의 탈보호화 반응 시 0 내지 25℃의 매우 온화한 반응조건하에서 30분 내지 1시간 이내에 반응이 완결되므로, 이성질체의 생성을 최대한 낮추었다는 점들이 본 발명의 장점이라 할 수 있다.One of the features of the present invention provides an efficient process for the preparation of pitavastatin using a novel intermediate for preparing pitavastatin, and the alcohol protecting group in the novel intermediate is 1 to 2 hours under mild reaction conditions under acid catalyst. In addition to easily protecting the dial within the alcohol, the reaction was completed within 30 minutes to 1 hour under very mild reaction conditions of 0 to 25 ° C. during the deprotection of the dialcohol, thus reducing the formation of isomers as much as possible. This can be said to be an advantage.

또한, 본 발명은 탈보호화 반응 후, 가수분해반응과 피타바스타틴 헤미칼슘 반응을 단리반응 없이 연속적으로 수행함에도 불구하고 고순도의 피타바스타틴 헤미칼슘을 고수율로 수득할 수 있다는 점이 본 발명의 장점이라 할 수 있다.In addition, the present invention is an advantage of the present invention that high purity pitavastatin hemicalcium can be obtained in high yield even after the deprotection reaction is carried out without hydrolysis and pitavastatin hemicalcium reaction without isolation reaction. This can be called.

본 발명은 피타바스타틴 헤미칼슘 제조를 위한 하기 반응식 3으로 표현된 바와 같이 총 7단계로 구성된다. The present invention consists of a total of seven steps as represented by Scheme 3 below for the preparation of pitavastatin hemicalcium.

[반응식 3]Scheme 3

Figure 112010012115746-pat00005
Figure 112010012115746-pat00005

이하에서 본 발명을 단계별로 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail step by step.

본 발명에 따른 새로운 중간체를 이용하는 피타바스타틴 헤미칼슘의 신규한 제조방법은 총 7단계의 단계적인 공정들로 이루어지며, 이하에서 이를 구분하여 설명한다.
The novel method for preparing pitavastatin hemicalcium using the new intermediate according to the present invention consists of a total of seven step processes, which will be described separately below.

제 1 단계 : 3차-부틸2-((4R,6S)-6-(히드록시메틸)-2-알콕시-1,3-디옥산-4-일)아세테이트(화학식(9))의 합성단계First step: synthesis of tert-butyl2-((4R, 6S) -6- (hydroxymethyl) -2-alkoxy-1,3-dioxan-4-yl) acetate (Formula (9))

상기 반응식 3의 피타바스타틴(화학식(1))의 측쇄(Side chain)를 구성하는 3차-부틸2-((4R,6S)-6-포밀-2-알콕시-1,3-디옥산-4-일)아세테이트(화학식(10))를 합성하기 위한 전구물질로서의 3차-부틸2-((4R,6S)-6(히드록시메틸)-2-알콕시-1,3-디옥산-4-일)아세테이트(화학식(9))를 합성하는 단계이다.Tert-butyl2-((4R, 6S) -6-formyl-2-alkoxy-1,3-dioxane- constituting the side chain of pitavastatin (Formula 1) of Scheme 3 Tert-butyl2-((4R, 6S) -6 (hydroxymethyl) -2-alkoxy-1,3-dioxane-4 as a precursor to synthesize 4-yl) acetate (Formula 10) -Yl) acetate (Formula 9).

출발물질인 (3R,5S)-3차-부틸-3,5,6-트리히드록시헥사노에이트(화학식(8))를 테트라히드로퓨란(THF), 디클로로메탄, 아세토니트릴, 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 용매에 용해시킨 후, 트리에틸아민, 트리메틸아민, 피리딘, N,N-디메틸아닐린 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 염기촉매를 가한 후, -10 내지 25℃ 범위의 반응온도의 조건 하에서 아세틸클로라이드와 반응시켜 6번 위치의 1차알콜기를 보호화 한다.Starting material (3R, 5S) -tert-butyl-3,5,6-trihydroxyhexanoate (Formula 8) was converted to tetrahydrofuran (THF), dichloromethane, acetonitrile, dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), acetone or a solvent consisting of two or more mixtures thereof, and then from a group consisting of triethylamine, trimethylamine, pyridine, N, N-dimethylaniline or a mixture of two or more thereof After adding the selected base catalyst, the primary alcohol group at position 6 is protected by reacting with acetyl chloride under conditions of a reaction temperature in the range of -10 to 25 ° C.

상기에서 수득되는 반응액을 정제수와 포화소금물로 세척하고, 황산마그네슘을 투입하여 잔류수분을 제거한 후, 여과한다.The reaction solution obtained above is washed with purified water and saturated brine, and magnesium sulfate is added to remove residual moisture, followed by filtration.

여과액을 -10 내지 25℃, 바람직하게는 0 내지 5℃로 냉각시킨 후, 다시 테트라히드로퓨란, 디클로로메탄, 아세토니트릴, 디메틸포름아미드, 디메틸설폭사이드, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 용매에 용해시킨 후, 황산, 초산, 파라-톨루엔술폰산, 메탄술폰산 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 산촉매를 가한 후, 10 내지 30분간 교반한 후, 트리에틸오르토포메이트(Triethyl orthoformate), 트리메틸오르토포메이트(Trimethyl orthoformate), 트리페닐오르도포메디트(triphenyl orthoformate)들로 이루어지는 그룹 중에서 선택되는 어느 하나의 화합물을 가한 후, 상기 온도을 유지하면서 30분 내지 2시간 동안 교반시켜 3, 5번 위치의 2차알콜기들을 보호화 한다. The filtrate is cooled to -10 to 25 DEG C, preferably 0 to 5 DEG C, and then again made of tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide, acetone or a solvent composed of two or more thereof. After dissolving in, an acid catalyst selected from the group consisting of sulfuric acid, acetic acid, para-toluenesulfonic acid, methanesulfonic acid or a mixture of two or more thereof is added, followed by stirring for 10 to 30 minutes, followed by triethyl orthoformate. , Trimethyl orthoformate, triphenyl orthoformate and any one compound selected from the group consisting of, and then stirred for 30 minutes to 2 hours while maintaining the temperature 3, 5 times Protect secondary alcohols in position.

그 후, 반응액 중의 산촉매를 중화에 의해 제거한 후, 3차-부틸2-((4R,6S)-6-(히드록시메틸)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(9))를 95% 이상의 고수율로 라세미체의 형태로 수득할 수 있다. Thereafter, the acid catalyst in the reaction solution was removed by neutralization, and then tert-butyl2-((4R, 6S) -6- (hydroxymethyl) -2-methoxy-1,3-dioxan-4-yl Acetate (Formula 9) can be obtained in the form of a racemate in high yield of at least 95%.

계속해서, 상기 화학식(9)의 라세미체를 테트라히드로퓨란, 디클로로메탄, 아세토니트릴, 디메틸포름아미드, 디메틸설폭사이드, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 용매에 용해시킨다. 별도의 반응용기에 2,2,6,6-테트라메틸피페리딘-1-옥실(TEMPO), 브롬화칼륨(KBr) 또는 브롬화리튬(LiBr)의 촉매 하에서 포타슘카보네이트(Potasium carbonate) 또는 소듐바이카보네이트(NaHCO3) 등과 같은 약염기의 촉매를 가하고, 교반한 후, -5 내지 5℃로 냉각시키고, 계속해서 상기 화학식(9)의 용액을 서서히 적가하고, NaOCl, NaHCO3을 더 가한 후, 실온에서 4 내지 10시간 교반시킨다. 교반에 의하여 상기와 같은 약염기 하에서 6번 위치의 1차알콜기를 탈보호화 하여 황색오일로서 97% 이상의 수율로 3차-부틸2-((4R,6S)-6-(히드록시메틸)-2-알콕시-1,3-디옥산-4-일)아세테이트(화학식(9))가 합성된다.Subsequently, the racemate of formula (9) is dissolved in a solvent consisting of tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethylsulfoxide, acetone or a mixture of two or more thereof. Potassium carbonate or sodium bicarbonate under a catalyst of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), potassium bromide (KBr) or lithium bromide (LiBr) in a separate reaction vessel After adding a weak base catalyst such as (NaHCO 3 ) and stirring, cooling to -5 to 5 ° C., and then slowly adding the solution of formula (9) dropwise, further adding NaOCl and NaHCO 3 , and then at room temperature Stir for 4-10 hours. Deprotection of the primary alcohol group at position 6 under the weak base by stirring to give tert-butyl2-((4R, 6S) -6- (hydroxymethyl) -2- in a yield of at least 97% as a yellow oil. Alkoxy-1,3-dioxan-4-yl) acetate (Formula (9)) is synthesized.

본 발명에서는 디히드록시기의 보호화제로서 CH(OR)3로 표시되는 트리알킬오르토포르메이트를 선택 사용하는데 그 특징이 있다.
In the present invention, a trialkylorthoformate represented by CH (OR) 3 is selected and used as a protecting agent for the dihydroxy group.

제 2 단계 : 3차-부틸2-((4R,6S)-5-포밀-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(10))의 합성단계Second Step: Synthesis of tert-Butyl2-((4R, 6S) -5-formyl-2-methoxy-1,3-dioxan-4-yl) acetate (Formula 10)

상기 제 1 단계에서 수득되는 상기 화학식(9)의 1차알콜기를 이산화망간(MnO2), 과산화수소(H2O2), 퍼아세트산(CH3CO3H), 소듐하이포클로리트(NaOCl) 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 산화제를 이용하는 산화반응을 통하여 1차알콜기를 알데히드기로 변환시키는 단계이다. 상기 화학식(9)의 6번 위치의 1차알콜기를 알데히드로 산화시켜 3차-부틸2-((4R,6S)-6-포밀-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(10))가 합성된다.The primary alcohol group of formula (9) obtained in the first step is manganese dioxide (MnO 2 ), hydrogen peroxide (H 2 O 2 ), peracetic acid (CH 3 CO 3 H), sodium hypochlorite (NaOCl) or these Converting the primary alcohol group to an aldehyde group through an oxidation reaction using an oxidizing agent selected from the group consisting of two or more mixtures. Tertiary-butyl2-((4R, 6S) -6-formyl-2-methoxy-1,3-dioxan-4-yl by aldehyde oxidation of the primary alcohol group at position 6 of formula (9) Acetate (Formula 10) is synthesized.

상기 산화반응은 단일 또는 혼합촉매 하에 산화제를 이용한 선택된 용매를 사용하여 0℃ 내지 실온의 반응온도, 바람직하게는 0 내지 25℃의 온도범위의 온화한 반응조건에서 말단기의 히드록시메틸기를 알데히드기로 산화시켜 상기 화학식(10)을 고수율(90%이상)로 수득할 수 있다. 촉매제로는 TEMPO(2,2,6,6-테트라메틸피페리딘 1-옥실)의 단독 또는 KBr(포타슘브로미드)와의 혼합촉매로 사용할 수 있으며, 혼합촉매가 더 효과적이다. 상기 산화반응에서는 테트라히드로퓨란, 디메틸포름아미드, 디메틸설폭사이드, 디에틸에테르, 벤젠, 디클로로메탄, 아세토니트릴, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택되는 용매를 사용할 수 있다. 더욱 상세히 설명하면, 반응용기에 소듐바이카보네이트(NaHCO3)의 염기 하에 무게비로 0.005%의 TEMPO촉매, 무게비로 0.005%의 KBr을 디클로로메탄에 투입하고, 0℃에서 현탁시킨 후, 상기 화학식(9)를 디클로로메탄에 용해시킨 용액을 적가하고, 상온에서 교반하는 것으로 수행된다.
The oxidation reaction is carried out using a selected solvent using an oxidizing agent under a single or mixed catalyst, oxidizing the hydroxymethyl group of the terminal group to an aldehyde group under mild reaction conditions ranging from 0 ° C to room temperature, preferably 0 to 25 ° C. Formula (10) can be obtained in high yield (90% or more). As a catalyst, TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) can be used alone or as a mixed catalyst with KBr (potassium bromide), and a mixed catalyst is more effective. In the oxidation reaction, a solvent selected from the group consisting of tetrahydrofuran, dimethylformamide, dimethylsulfoxide, diethyl ether, benzene, dichloromethane, acetonitrile, acetone or a mixture of two or more thereof can be used. In more detail, in a reaction vessel under a base of sodium bicarbonate (NaHCO 3), 0.005% of TEMPO catalyst by weight and 0.005% of KBr by weight were added to dichloromethane and suspended at 0 ° C., followed by the above formula (9). The solution dissolved in dichloromethane is added dropwise, and stirred at room temperature.

제 3 단계 : 3-(브로모메틸)-2-사이클로프로필-4-(4-플루오로페닐)퀴놀린(화학식(12)의 합성단계Third Step: Synthesis of 3- (Bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline (Formula 12)

상기 반응식 3의 피타바스타틴(화학식(1))의 주요골격(skeleton structure)을 구성하는 퀴놀린(Quinoline) 구조에 상기 측쇄(Side chain)를 구성하는 3차-부틸2-((4R,6S)-6-포밀-2-알콕시-1,3-디옥산-4-일)아세테이트(화학식(10))를 도입하기 위한 단계이다.Tert-butyl2-((4R, 6S) constituting the side chain in a quinoline structure constituting the skeleton structure of pitavastatin (Formula (1)) -6-formyl-2-alkoxy-1,3-dioxan-4-yl) acetate (Formula 10).

출발물질로서 (2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)메탄올(화학식(11))의 메틸알콜기를 할로겐화물로 전환하여 3-(브로모메틸)-2-사이클로프로필-4-(4-플루오로페닐)퀴놀린(화학식(12))을 합성하는 단계이다.Methyl alcohol group of (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) methanol (Formula 11) as a starting material was converted to a halide to give 3- (bromomethyl) -2- Synthesis of cyclopropyl-4- (4-fluorophenyl) quinoline (Formula 12).

할로겐화물로 전환시키기 위한 할라이드화제로는 브롬(Br2), 염소(Cl2), 펜타클로로포스틴(PCl5), 트리브로모포스핀(PBr3) 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택되는 할라이드화제를 톨루엔, 벤젠, 자일렌, 테트라히드로퓨란, 디메틸포름아미드, 디메틸설폭사이드, 디에틸에테르, 디클로로메탄, 아세토니트릴, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 용매 속에서 0 내지 25℃의 온화한 반응온도 하에서 상기 화학식(12)로 표시되는 할로겐기가 도입된 화합물을 수득하게 된다. 더욱 상세히 설명하면, 상기 화학식(11)을 실온에서 톨루엔/디클로로메탄의 혼합용매로 녹인 후, 상기 할로겐화제를 가한다. 반응물을 0℃로 냉각한 후, 서서히 소듐바이카보네이트를 적가하여 반응을 완성시킨다.
The halide agent for converting to a halide is selected from the group consisting of bromine (Br 2 ), chlorine (Cl 2 ), pentachloropostin (PCl 5 ), tribromophosphine (PBr 3 ) or mixtures of two or more thereof The halide agent is 0 in a solvent selected from the group consisting of toluene, benzene, xylene, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, diethyl ether, dichloromethane, acetonitrile, acetone or mixtures of two or more thereof. Under a mild reaction temperature of 25 ° C., a compound having a halogen group represented by Formula 12 was introduced. In more detail, after dissolving the formula (11) in a mixed solvent of toluene / dichloromethane at room temperature, the halogenating agent is added. After the reaction was cooled to 0 ° C., sodium bicarbonate was slowly added dropwise to complete the reaction.

제 4 단계 : 트리페닐(2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로미드염(화학식(13))의 합성단계Fourth Step: Synthesis of Triphenyl (2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide salt (Formula 13)

상기 화학식(12)을 P(R1)3로 표시되는 트리알킬포스핀 또는 트리아릴포스핀 화합물을 이용하여 트리페닐(2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드(화학식(13))를 합성하는 단계이다.Formula (12) using trialkylphosphine or triarylphosphine compound represented by P (R 1 ) 3 triphenyl (2-cyclopropyl-4- (4-fluorophenyl) -quinoline-3- Monomethyl) -phosphonium) bromide (Formula 13).

상기 화학식(12)인 할라이드 화합물을 벤젠, 톨루엔, 자일렌, 디메틸설폭사이드, 디메틸포름아미드 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택되는 용매에 용해시킨 후, 트리알킬포스핀 또는 트리아릴포스핀을 가한 후, 1 내지 5시간 동안 가열하여 트리페닐(2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드(화학식(13))를 수득한다. The halide compound of formula (12) is dissolved in a solvent selected from the group consisting of benzene, toluene, xylene, dimethyl sulfoxide, dimethylformamide or a mixture of two or more thereof, and then trialkylphosphine or triarylphosphine After addition, the mixture was heated for 1 to 5 hours to obtain triphenyl (2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13). .

더욱 상세히 설명하면, 톨루엔에 상기 화학식(12)과 트리알킬포스핀 또는 트리아릴포스핀을 넣고, 실온에서 30분간 교반 후, 3시간 가열한다. 반응이 종결되면 반응액 중에서 상기 화학식(13)이 생성되며, 실온으로 냉각한 후, 여과하는 것으로 상기 단계가 수행된다.
In more detail, the above formula (12) and trialkylphosphine or triarylphosphine are added to toluene, stirred at room temperature for 30 minutes, and then heated for 3 hours. When the reaction is complete, the above formula (13) is produced in the reaction solution, and the step is performed by cooling to room temperature and then filtering.

제 5 단계 : 3차-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(14))의 합성단계Fifth step: tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Synthesis step of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

상기 화학식(13)과 상기 화학식(10)을 포타슘카보네이트(K2CO3), 소듐바이카보네이트(NaHCO3), 포타슘3차-부톡사이드(t-BuOK), 수산화칼륨(KOH), 수산화나트륨(NaOH) 등과 같은 무기염기 또는 아닐린, 치환된 아닐린, 피리딘, 치환된 피리딘 등과 같은 유기염기들 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 염기 하에서의 커플링반응을 통하여 3차-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(14))를 합성하는 단계이다. 반응용매로는 벤젠, 톨루엔, 자일렌, 디메틸설폭사이드, 디메틸포름아미드 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 용매가 사용될 수 있으며, 상기 반응용매로 반응물을 용해시킨 후, 50 내지 150℃로 가열시켜 커플링반응을 통하여 상기 화학식(14)를 수득하게 된다. 더욱 상세히 설명하면 디메틸설폭사이드 용매에 상기 화학식(13), 상기 화학식(10) 및 소듐카보네이트을 용해시킨 후, 70℃에서 4시간 정도 가열교반 한다. 반응액을 실온으로 냉각 후 감압농축하여 반응용매를 제거하고 반응액을 톨루엔으로 녹인후 정제수로 세척하고 황산 마그네슘으로 잔류 수분을 제거한다. 여과하여 불용물을 제거하고 톨루엔을 감압농축후, 크로마토그래피로 분리하여 백색고체로서 3차-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(14))를 수득한다.
The formula (13) and the formula (10) is potassium carbonate (K 2 CO 3 ), sodium bicarbonate (NaHCO 3 ), potassium tert-butoxide (t-BuOK), potassium hydroxide (KOH), sodium hydroxide ( Tert-butyl2-(() through a coupling reaction under an inorganic base such as NaOH) or a base selected from the group consisting of organic bases such as aniline, substituted aniline, pyridine, substituted pyridine and the like, or a mixture of two or more thereof. 4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) -2-methoxy-1,3-dioxane- 4-yl) acetate (Formula 14) is synthesized. As the reaction solvent, a solvent selected from the group consisting of benzene, toluene, xylene, dimethyl sulfoxide, dimethylformamide or a mixture of two or more thereof may be used, and after dissolving the reactants with the reaction solvent, 50 to 150 ° C The compound of formula (14) is obtained by coupling to a coupling reaction. In more detail, after dissolving the formula (13), the formula (10) and sodium carbonate in a dimethyl sulfoxide solvent, the mixture is heated and stirred at 70 ° C. for about 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the reaction solvent. The reaction solution was dissolved in toluene, washed with purified water, and residual moisture was removed with magnesium sulfate. The insoluble matter was removed by filtration, and toluene was concentrated under reduced pressure, and then separated by chromatography to obtain tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4) as a white solid. -(4-fluorophenyl) quinolin-3-yl) vinyl) -2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14) is obtained.

제 6 단계 : (E,3R,5S)-3차-부틸7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵-6-테노에이트(화학식(15))의 합성단계Sixth Step: (E, 3R, 5S) -tert-butyl7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhep-6 Synthesis step of tenoate (Formula 15)

상기 화학식(14)의 2-메톡시디옥산기의 산촉매로서 염산,황산,초산,메탄술폰산등을 정제수에 희석한 희석산 하에서 탈보호화 공정을 통하여 (E,3R,5S)-3차-부틸 7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵-6-테노에이트(화학식(15))를 제조하는 공정이다.(E, 3R, 5S) -tert-butyl 7 as an acid catalyst of the 2-methoxydioxane group of the formula (14) through a deprotection process under dilute acid diluted hydrochloric acid, sulfuric acid, acetic acid, methanesulfonic acid and the like in purified water -(2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhep-6-tenoate (Formula 15).

상기 화학식(14)를 메탄올, 에탄올, 프로판올, 이소프로판올, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 용매 속에서 희석산 수용액을가한 후, 0 내지 25℃의 온화한 반응온도 하에서 1시간 이내에 탈보호화 반응을 수행한다. 더욱 상세히 설명하면 디히드록시기가 보호된 상기 화학식(14)를 메탄올의 용매에 녹인 후, 0 내지 5℃ 반응온도 하에서 2N-염산을 가한 후, 10 내지 30분간 교반하여 상기 화학식(14)를 정량적으로 제조한다. 디올이 탈보호화된 상기 화학식(15)를 단리 또는 연속공정으로 수행할 수 있으나, 순도면에서는 단리공정이 유리하다.
The formula (14) was added to a dilute acid solution in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone or a mixture of two or more thereof, followed by degassing within 1 hour under a mild reaction temperature of 0 to 25 ° C. Perform the gelatinization reaction. In more detail, after dissolving the formula (14) in which the dihydroxy group is protected in a solvent of methanol, 2N hydrochloric acid is added under a reaction temperature of 0 to 5 ° C, and then stirred for 10 to 30 minutes to quantitatively formulate the formula (14). Manufacture. The formula (15) in which the diol is deprotected may be carried out in an isolated or continuous process, but in isolation, the isolation process is advantageous.

제 7 단계 : 피타바스타틴(1)의 합성단계Step 7: Synthesis of Pitavastatin (1)

상기 화학식(15)를 가수분해하여 상기 화학식 1의 피타바스타틴산을 제조하는 공정이다.Hydrolysis of the formula (15) is a process for producing pitavastatin acid of the formula (1).

상기 화학식(15)인 (E,3R,5S)-3차-부틸7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵테-6-노에이트를 수산화나트륨, 수산화칼륨, 포타슘3차-부톡사이드 등과 같은 무기염기를 이용하여 수용액 상에서 가수분해하여 상기 화학식 1로 표시되는 피타바스타틴금속염을 제조하는 후 연속반응으로 피타바스타틴 헤미칼슘을 수득하게 된다.(E, 3R, 5S) -tert-butyl7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhepte of formula (15) -6-noate was hydrolyzed in an aqueous solution using an inorganic base such as sodium hydroxide, potassium hydroxide, potassium tert-butoxide and the like to prepare a pitavastatin metal salt represented by Formula 1, followed by pitavastatin in a continuous reaction. Hemicalcium is obtained.

상기 공정은 단리공정 또는 연속공정으로 가능하며, 연속공정은 수용액 상에서 가수분해 공정 후, 염화칼슘(CaCl2), 아세트산칼슘(Ca(OAc)2)의 칼슘화제를 연속적으로 가하여 피타바스타틴 헤미칼슘의 신규한 결정을 제조한다. 피타바스타틴 헤미칼슘 제조공정 중 단리공정 또는 연속공정의 수율 또는 순도의 차이는 미미하므로 연속공정이 유리하다.The process can be carried out in isolation or in a continuous process, after which the hydrolysis process in aqueous solution, calcium chloride (CaCl 2 ), calcium acetate (Ca (OAc) 2 ) is added continuously to the calcination of pitavastatin hemicalcium New crystals are prepared. Since the difference in yield or purity of the isolation process or the continuous process is small in the pitavastatin hemicalcium manufacturing process, the continuous process is advantageous.

보다 상세하게 설명하면, 상기 화학식(15)인 (E,3R,5S)-tert-부틸7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵테-6-노에이트를 0 내지 25℃의 온화한 반응온도 하에서 메탄올, 에탄올, 프로판올, 이소프로판올, 아세톤, 아세토니트릴 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 용매 중에서 수산화나트륨, 수산화칼륨, 포타슘3차-부톡사이드 등과 같은 무기염기를 이용하여 수용액 상에서 1 내지 2시간 동안 가수분해시켜 상기 화학식 1로 표시되는 피타바스타틴산을 제조한다. 상기 화학식 1의 피타바스타틴산을 단리 또는 연속공정으로 피타바스타틴 헤미칼슘으로 제조할 수 있으며, 단리공정이 수율면에서 유리하다. 그러나, 단리공정과 연속공정의 차이가 순도의 차이로 이어지는 것은 아니다. 가수분해로 생성된 피타바스타틴 나트륨염 반응용액에 칼슘클로리드(CaCl2) 또는 칼슘아세테이트(Ca(OAc)2)를 가하여 0 내지 25℃에서 5 내지 8시간 동안 교반하여 고수율(91%이상), 고순도(99.6% HPLC Area %)로 아래와 같이 피타바스타틴헤미칼슘의 신규한 결정형을 제조한다.In more detail, (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5 of formula (15) Sodium hydroxide, hydroxide in dihydroxyhepte-6-noate in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, acetone, acetonitrile or a mixture of two or more thereof under a mild reaction temperature of 0 to 25 ° C. By using an inorganic base such as potassium, potassium tert-butoxide, etc., hydrolysis is carried out in an aqueous solution for 1 to 2 hours to prepare pitavastatin acid represented by Chemical Formula 1. The pitavastatin acid of Formula 1 may be prepared by pitavastatin hemicalcium in an isolated or continuous process, and the isolation process is advantageous in terms of yield. However, the difference between the isolation process and the continuous process does not lead to a difference in purity. Calcium chloride (CaCl 2 ) or calcium acetate (Ca (OAc) 2 ) was added to the phytavastatin sodium salt reaction solution produced by hydrolysis, and the mixture was stirred at 0 to 25 ° C. for 5 to 8 hours to obtain high yield (more than 91%). ), A new crystalline form of pitavastatin hemicalcium is prepared in high purity (99.6% HPLC Area%) as follows.

하기 표 1은 2θ, d-스페이싱 및 2분간 분쇄후, CuKα 조사에 의한 회절기(Bruker D8 advance)상에서 측정된 >20%의 상대강도를 가지는 상대강도의 용어로 표현되는 아래의 X선분말 회절양상으로 피타바스타틴헤미칼슘 및 그의 수화물을 특징으로 한다.Table 1 below shows the following X-ray powder diffraction expressed in terms of relative intensity having a relative intensity of> 20% measured on a diffracter (Bruker D8 advance) by CuKα irradiation after 2θ, d-spacing and grinding for 2 minutes. Aspects are characterized by pitavastatin hemicalcium and its hydrates.

2θ2θ d-값(Å)d-value 2분간 분쇄후 상대적 강도(>20%)Relative strength after grinding for 2 minutes (> 20%) 3.8543.854 22.9076222.90762 100100 5.4125.412 16.3171316.31713 69.769.7 7.7417.741 11.3115611.31156 49.949.9 11.29711.297 7.826327.82632 46.746.7 15.45715.457 5.728015.72801 35.235.2 17.80717.807 4.977054.97705 46.246.2 19.32319.323 4.589794.58979 54.554.5

도 1은 피타바스타틴 헤미칼슘의 X선분말 회절도이다. 1 is an X-ray powder diffractogram of pitavastatin hemicalcium.

본 발명에 따라 수득되는 피타바스타틴 헤미칼슘 중 수분(Moisture)은 상기 화학식 1의 화합물에 흡수된(Absorbed)상태와 상기 화학식 1의 화합물과 1 내지 3개의 물분자가 수화된(Hydrate) 상태로 존재한다.Moisture in pitavastatin hemicalcium obtained according to the present invention is absorbed in the compound of Formula 1, and the compound of Formula 1 and 1 to 3 water molecules are hydrated. exist.

상기 피타바스타틴 헤미칼슘에 흡수된 수분은 50 내지 60℃의 건조기 속에서 대략 10시간 동안 건조시킴으로써 흡수 수분을 제거할 수 있다. 상기 피타바스타틴 헤미칼슘 수화물의 확인은 피타바스타틴 헤미칼슘 결정을 60℃의 건조기 속에서 10시간 건조하여 인습된 수분을 제거한 후, 수분 측정기(Karl-Fisher) 및 열중량분석기(Thermogravimetric Analysis, TGA) 측정에 의하여 확인할 수 있다. The water absorbed by the pitavastatin hemicalcium may be removed by drying for about 10 hours in a dryer of 50 to 60 ℃. The pitavastatin hemicalcium hydrate was confirmed by drying the pitavastatin hemicalcium crystals in a drier at 60 ° C. for 10 hours to remove the moisture, followed by a water meter (Karl-Fisher) and a thermogravimetric analysis (TGA). ) Can be confirmed by measurement.

상기 반응식 3에서 R은 수소, 메틸, 에틸, C1~C6인 알킬기 또는 C6~C18인 아릴기를 나타내고, R1은 C1~C6 알킬기 또는 알콕시기, 페닐기, 치환된 페닐기, 비치환된 페닐기를 나타내고, X는 할로겐원자를 나타낸다.In Scheme 3, R represents hydrogen, methyl, ethyl, C 1 ~ C 6 alkyl group or C 6 ~ C 18 aryl group, R 1 is C 1 ~ C 6 alkyl group or alkoxy group, phenyl group, substituted phenyl group, non- The substituted phenyl group is represented and X represents a halogen atom.

또한, 상기 반응식 3에 따른 일련의 제조과정을 수행하는 과정에서 반응중간체로 합성되는 상기 화학식(9), 상기 화학식(10) 및 상기 화학식(14)로 표시되는 화합물들 각각은 신규한 중간체 화합물들로서 본 발명에 따른 피타바스타틴의 합성에 유용하다.In addition, each of the compounds represented by Chemical Formula (9), Chemical Formula (10) and Chemical Formula (14) synthesized as a reaction intermediate in the course of carrying out a series of preparation processes according to Scheme 3 are novel intermediate compounds. It is useful for the synthesis of pitavastatin according to the invention.

본 발명에 따르면, 상기 화학식 1로 표시되는 피타바스타틴의 제조방법에서는 하기와 같은 효과를 얻고 있다.According to the present invention, in the method for preparing pitavastatin represented by Chemical Formula 1, the following effects are obtained.

첫째 ; 제 1 단계부터 제 7 단계까지의 공정들을 각각 분리함으로써 고순도의 중간체(99.6%이상 고성능액체크로마토그래피(HPLC) 면적%)를 통한 피타바스타틴 헤미칼슘을 고수율로 제조하는 효과를 얻고 있다.first ; By separating the processes from the first to the seventh step, it is possible to obtain a high yield of pitavastatin hemicalcium through high-purity intermediates (more than 99.6% high performance liquid chromatography (HPLC) area%).

둘째 ; 디히드록시기가 보호화된 광학활성 디올중간체를 반응 초기단계에 합성하여 퀴놀린유도체와의 커플링 반응을 통하여 피타바스타틴을 제조하므로 고순도의 광학활성 및 입체화학적 화합물을 수득하는 효과가 있다.second ; Synthesis of a dihydroxy group protected optically active diol intermediate in the initial stage of the reaction to prepare pitavastatin through a coupling reaction with a quinoline derivative, there is an effect of obtaining a high purity optical activity and stereochemical compounds.

셋째 ; 디히드록시기의 보호화제로서 트리알킬오르토포르메이트를 선택사용함으로 인하여 전체 7 단계의 공정들 중 4개의 공정들이 산업적으로 매우 용이한 실온 이하의 반응온도 조건에서 30분 내지 3시간 이내에 목적화합물들이 정량적으로 수득되는 효과를 얻고 있다.third ; By using trialkylorthoformate as a protecting agent for the dihydroxy group, four of the seven steps are quantitatively quantitatively prepared within 30 minutes to 3 hours at reaction temperature conditions below room temperature, which is industrially very easy. The effect obtained is obtained.

넷째 ; 디히드록시기의 보호화제로서 트리알킬오르토포르메이트를 선택사용하여 0℃ 내지 실온조건에서도 보호화 반응이 가능하고, 탈보호화 반응과 가수분해 반응을 연속적으로 수행할 수 있을 뿐 만 아니라 피타바스타틴 염을 분리없이 연속적으로 피타바스타 틴헤미칼슘의 연속반응으로 수행할 수 있어 목적하는 피타바스타틴 헤미칼슘을 높은 수율과 높은 순도(99.6%이상 고성능액체크로마토그래피 면적%)로 수득하는 효과를 얻고 있다.fourth ; By using trialkyl orthoformate as the protecting agent of the dihydroxy group, the protection reaction can be performed even at 0 ° C to room temperature, and the deprotection reaction and the hydrolysis reaction can be carried out continuously, as well as the pitavastatin salt. It can be carried out by the continuous reaction of pitavastatin hemicalcium without separation to obtain the effect of obtaining the desired pitavastatin hemicalcium in high yield and high purity (99.6% or more high performance liquid chromatography area%).

이상에서 설명한 바와 같은 본 발명의 제조방법은 그 제조과정이 비교적 간단하고, 반응조건이 온화하면서도 제조수율 및 순도가 높아서 고지혈증치료제로 유효한 의약품인 피타바스타틴 헤미칼슘을 공업적 생산방법으로 적용하기에 매우 적합하다.As described above, the manufacturing method of the present invention has a relatively simple manufacturing process, mild reaction conditions, and high production yield and purity, so that phytavastatin hemicalcium, which is an effective drug for treating hyperlipidemia, can be applied as an industrial production method. Very suitable.

이러한 본 발명은 다음의 실시예에 의거하여 더욱 상세히 설명하겠는바 본 발명이 다음의 실시예에 의해 한정되는 것은 결코 아니다.
The present invention will be described in more detail based on the following examples, which should not be construed as limiting the invention thereto.

실시예 1. 3차-부틸 2-((4R,6S)-6-(히드록시메틸)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식(9))의 제조Example 1 Preparation of Tert-Butyl 2-((4R, 6S) -6- (hydroxymethyl) -2-methoxy-1,3-dioxan-4-yl) acetate (Formula (9))

질소로 충진된 반응용기에 (3R,5S)-3차-부틸 3,5,6-트리히드록시헥사노에이트 30g(0.136몰(mol))을 넣고 테트라히드로퓨란 270㎖로 용해시켰다. 반응용기를 0℃로 냉각한 후, 트리에틸아민 6.3㎖(0.136몰)을 가한 후, 10분간 교반시켰다. 아세틸클로라이드 10.6㎖(0.149몰)을 테트라히드로퓨란 20㎖로 희석한 후, 30분 동안 서서히 가하고, 온도를 유지하면서 30분에서 1시간 교반시켰다. 박막크로마토그래피(TLC)를 통하여 반응이 완결된 것을 확인한 후, 반응용매를 감압농축하여 제거하였다. 농축액을 에틸아세테이트 300㎖에 가하여 용해시키고, 정제수 200㎖를 가하여 반응물을 2회 반복 세척하였다. 유기용매를 층분리한 후, 소금물로 세척하고, 황산마그네슘으로 잔류수분을 제거하였다. 여과 후, 여과액을 감압농축한 후, 테트라히드로퓨란 270㎖로 용해시켰다. 질소로 충진 후, 0℃로 냉각하고, 메탄술폰산 0.1g을 가하였다. 상기 온도를 유지하면서 10분간 교반 후, 트리메틸오르토포르메이트 17.9㎖(0.163몰)를 30분간에 걸쳐 첨가하였다. 반응액 온도를 유지하면서 1시간 동안 교반시켰다. 반응액을 트리에틸아민으로 중화한 후, 반응용매를 감압농축시켰다. 농축액을 메탄올로 용해시킨 후, 0℃로 냉각하고 수산화나트륨 5.4g(0.136몰)을 정제수 50㎖에 용해시킨 용액을 상기 반응액에 서서히 가한 후, 20분간 교반시켰다. 상기 반응액에 디클로로메탄 450㎖와 정제수 100㎖를 가하여 층분리시켰다. 유기층을 다시 정제수 300㎖, 소금물로 순차적으로 세척하고, 황산마그네슘으로 잔류용매를 제거하고 여과하였다. 상기 여과액을 감압농축하여 무색오일로서 표제의 에피머(Epimer) 33.5g(93.2%)를 수득하였다.30 g (0.136 mol (mol)) of (3R, 5S) -tert-butyl 3,5,6-trihydroxyhexanoate was added to a reaction vessel filled with nitrogen and dissolved in 270 ml of tetrahydrofuran. After cooling the reaction vessel to 0 ° C., 6.3 ml (0.136 mol) of triethylamine was added, followed by stirring for 10 minutes. After diluting 10.6 ml (0.149 mol) of acetyl chloride with 20 ml of tetrahydrofuran, the mixture was slowly added for 30 minutes and stirred at 30 minutes for 1 hour while maintaining the temperature. After confirming that the reaction was completed through thin layer chromatography (TLC), the reaction solvent was removed by concentration under reduced pressure. The concentrated solution was added to 300 ml of ethyl acetate and dissolved, and 200 ml of purified water was added to wash the reaction twice. The organic solvent was separated and then washed with brine, and residual moisture was removed with magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and dissolved in 270 ml of tetrahydrofuran. After filling with nitrogen, it was cooled to 0 ° C and 0.1 g of methanesulfonic acid was added. After stirring for 10 minutes while maintaining the temperature, 17.9 ml (0.163 mol) of trimethylorthoformate was added over 30 minutes. The reaction solution was stirred for 1 hour while maintaining the temperature. After neutralizing the reaction solution with triethylamine, the reaction solvent was concentrated under reduced pressure. The concentrated solution was dissolved in methanol, cooled to 0 ° C., and a solution obtained by dissolving 5.4 g (0.136 mol) of sodium hydroxide in 50 mL of purified water was slowly added to the reaction solution, followed by stirring for 20 minutes. 450 ml of dichloromethane and 100 ml of purified water were added to the reaction solution, and the layers were separated. The organic layer was washed again with 300 ml of purified water and brine sequentially, and the residual solvent was removed with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 33.5 g (93.2%) of the title Epimer as colorless oil.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 1.32(s, 9H), δ 1.5~1.8(m, 2H), δ 2.2~2.5(m, 2H), δ 3.32(s, 3H), δ 3.5~3.9(m, 3H), δ 4.41(m, 1H), 5.89(s, 1H).
Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H NMR (CDCl 3 )) Data: δ 1.32 (s, 9H), δ 1.5 ~ 1.8 (m, 2H), δ 2.2 ~ 2.5 (m, 2H), δ 3.32 (s, 3H), δ 3.5-3.9 (m, 3H), δ 4.41 (m, 1H), 5.89 (s, 1H).

실시예 2 : 3차-부틸 2-((4R,6S)-5-포밀-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식 10)의 제조Example 2 Preparation of Tert-Butyl 2-((4R, 6S) -5-formyl-2-methoxy-1,3-dioxan-4-yl) acetate (Formula 10)

질소로 충진된 2구 반응용기에 소듐바이카보네이트(NaHCO3) 45.2g(0.538몰), 브롬화칼륨(KBr) 4.8g(0.04몰), TEMPO 100㎎을 넣고, 디클로로메탄 300㎖을 넣어 현탁시켰다. 반응물을 0℃로 냉각한 후, 30분간 교반시켰다. 별도의 질소로 충진된 반응용기에 3차-부틸 2-((4R,6S)-6-(히드록시메틸)-2-메톡시-1,3-디옥산-4-일)아세테이트 50g(0.19몰)을 디클로로메탄 200㎖에 녹인 후, 반응액에 첨가하였다.In a two-necked reaction vessel filled with nitrogen, 45.2 g (0.538 mol) of sodium bicarbonate (NaHCO 3 ), 4.8 g (0.04 mol) of potassium bromide (KBr), and 100 mg of TEMPO were added and suspended in 300 ml of dichloromethane. The reaction was cooled to 0 ° C. and then stirred for 30 minutes. 50 g (0.19) of tert-butyl 2-((4R, 6S) -6- (hydroxymethyl) -2-methoxy-1,3-dioxan-4-yl) acetate in a separate nitrogen-filled reaction vessel Mole) was dissolved in 200 ml of dichloromethane and added to the reaction solution.

0℃로 온도를 유지하면서 10% 소듐하이포클로리트(NaOCl) 80㎖을 서서히 가한 후, 20분간 교반시켰다. 다시 반응액에 소듐바이카보네이트 48.3g(.0576몰)을 가한 후, 다시 20분간 교반시켰다. 10% 소듐하이포클로리트 27㎖을 가한 후, 상온으로 승온하여 4시간 교반시켰다.80 ml of 10% sodium hypochlorite (NaOCl) was slowly added while maintaining the temperature at 0 ° C, followed by stirring for 20 minutes. 48.3 g (.0576 mol) of sodium bicarbonate was further added to the reaction solution, followed by further stirring for 20 minutes. After adding 27 ml of 10% sodium hypochlorite, the mixture was heated to room temperature and stirred for 4 hours.

반응액을 세라이트(celite)로 충진된 여과기 하에 여과 후, 여과액을 10% 소듐티오설페이트(Na2S2O3) 용액으로 세척하였다. 여과액을 황산마그네슘(MgSO4)으로 잔류수분을 제거한 후, 여과 농축하여 연노랑색 오일로서 표제의 화합물 44.8g( 90.3%)을 수득하였다.The reaction solution was filtered under a filter filled with celite, and then the filtrate was washed with 10% sodium thiosulfate (Na 2 S 2 O 3 ) solution. The filtrate was removed with residual water with magnesium sulfate (MgSO 4 ) and then filtered and concentrated to give 44.8 g (90.3%) of the title compound as a pale yellow oil.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 1.38(s, 9H), δ 1.8~2.6(m, 4H), δ 4.4~4.7(m, 2H), δ 3.33(s, 3H), δ 5.88(s, 1H), δ 9.48(s, 1H).
Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H NMR (CDCl 3 )) Data: δ 1.38 (s, 9H), δ 1.8 ~ 2.6 (m, 4H), δ 4.4 ~ 4.7 (m, 2H), δ 3.33 (s, 3H), δ 5.88 (s, 1H), δ 9.48 (s, 1H).

실시예 3 : 3-(브로모메틸)-2-사이클로프로필-4-(4-플루오로페닐)퀴놀린(화학식 12)의 제조Example 3: Preparation of 3- (Bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline (Formula 12)

질소로 충진된 3구 반응용기에 (2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)메탄올 50g(0.170몰)을 톨루엔 340㎖와 디클로로메탄 170㎖의 혼합용매에 용해시켰다.Dissolve 50 g (0.170 mole) of (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) methanol in a mixed solvent of 340 ml of toluene and 170 ml of dichloromethane in a three-necked reaction vessel filled with nitrogen. I was.

반응액에 삼브롬화인(PBr3) 32.8㎖(0.348몰)을 상온에서 서서히 가한 후, 2시간 동안 교반시켰다. 반응액을 0℃로 냉각한 후, 냉각된 소듐바이카보네이트 용액을 서서히 가한 후, 에틸아세테이트 400㎖로 2회 반복 추출하였다. 유기층을 황산마그네슘으로 건조시킨 후, 여과하고, 여과액을 감압 농축하여 백색고체로서 표제화합물 53.3g(87.8%)을 수득했다.32.8 mL (0.348 mol) of phosphorus tribromide (PBr 3 ) was slowly added to the reaction mixture at room temperature, followed by stirring for 2 hours. After cooling the reaction solution to 0 ° C., the cooled sodium bicarbonate solution was slowly added, followed by extraction twice with 400 ml of ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 53.3 g (87.8%) of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.86(d, 1H), δ 7.65(t, 1H), δ 7.4~7.3(m, 5H), δ 7.23(d, 1H), δ 5.66(s, 2H), δ 2.75~2.70(m, 1H), δ 1.2~1.1(m, 2H), δ 1.07~1.03(m, 2H).
Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H NMR (CDCl 3 )) Data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.4 ~ 7.3 (m, 5H), δ 7.23 (d, 1H) , δ 5.66 (s, 2H), δ 2.75 ~ 2.70 (m, 1H), δ 1.2 ~ 1.1 (m, 2H), δ 1.07 ~ 1.03 (m, 2H).

실시예 4 : 트리페닐((2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드(화학식 13)의 제조Example 4 Preparation of Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13)

질소로 충진된 반응용기에 3-(브로모메틸)-2-사이클로프로필-4-(4-플루오로페닐)퀴놀린 30g(0.0845몰), PPh3 23.3g(0.0887몰)을 넣고 실온에서 톨루엔 420㎖로 용해시켰다. 온도를 서서히 상승시켜 3시간 동안 가열 환류시켰다. 반응이 종결되면, 상온으로 냉각하여 생성된 고체를 여과하였다. 여과물을 건조시켜 백색고체로서 표제화합물 50.4g(96.4%)을 수득했다.30 g (0.0845 mole) of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline and 23.3 g (0.0887 mole) of PPh 3 were added to a reaction vessel filled with nitrogen and toluene 420 at room temperature. Dissolved in ml. The temperature was slowly raised to reflux for 3 hours. After the reaction was completed, the resulting solid was filtered by cooling to room temperature. The filtrate was dried to give 50.4 g (96.4%) of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.8~7.9(m, 5H), δ 7.6~7.7(m, 8H), δ 7.4~7.2(m, 10H), δ 5.21(bs, 2H), δ 2.0~1.99(m, 1H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H NMR (CDCl 3 )) Data: δ 7.8 ~ 7.9 (m, 5H), δ 7.6 ~ 7.7 (m, 8H), δ 7.4 ~ 7.2 (m, 10H), δ 5.21 ( bs, 2H), δ 2.0-1.99 (m, 1H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 5 : 트리에틸((2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드(화학식 13)의 제조Example 5 Preparation of Triethyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13)

질소로 충진된 반응용기에 3-(브로모메틸)-2-사이클로프로필-4-(4-플루오로페닐)퀴놀린 30g(0.0845몰), 트리에틸포스파인(triethylphosphine) 9.6g(0.0887몰)을 넣고 실온에서 톨루엔 420㎖로 용해시켰다. 온도를 서서히 상승시켜 3시간 동안 가열 환류시켰다. 반응이 종결되면, 상온으로 냉각하여 생성된 고체를 여과하였다. 여과물을 건조시켜 백색고체로서 표제화합물 42g을 수득했다.30 g (0.0845 mole) of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline and 9.6 g (0.0887 mole) of triethylphosphine were added to a reaction vessel filled with nitrogen. The solution was dissolved in 420 ml of toluene at room temperature. The temperature was slowly raised to reflux for 3 hours. After the reaction was completed, the resulting solid was filtered by cooling to room temperature. The filtrate was dried to give 42 g of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.8~7.9(m, 5H), δ 7.6~7.7(m, 8H), δ 7.4~7.2(m, 10H), δ 2.61(bs, 2H), δ 1.3~1.4(m, 6H), δ 0.91~0.93(m, 9H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H NMR (CDCl 3 )) Data: δ 7.8 ~ 7.9 (m, 5H), δ 7.6 ~ 7.7 (m, 8H), δ 7.4 ~ 7.2 (m, 10H), δ 2.61 ( bs, 2H), δ 1.3-1.4 (m, 6H), δ 0.91-0.93 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 6 : 트리에톡시((2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드(화학식 13)의 제조Example 6 Preparation of Triethoxy ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide (Formula 13)

질소로 충진된 반응용기에 3-(브로모메틸)-2-사이클로프로필-4-(4-플루오로페닐)퀴놀린 30g(0.0845몰), 포타슘에톡사이드(P(OEt)3) 14.8g(0.0887몰)을 넣고, 실온에서 톨루엔 420㎖에 용해시켰다. 온도를 서서히 상승시켜 3시간 동안 가열 환류시켰다. 반응이 종결되면, 상온으로 냉각하여 생성된 고체를 여과하였다. 여과물을 건조시켜 백색고체로서 표제화합물 29.3g을 수득했다.30 g (0.0845 mol) of 3- (bromomethyl) -2-cyclopropyl-4- (4-fluorophenyl) quinoline, 14.8 g of potassium ethoxide (P (OEt) 3 ) in a reaction vessel filled with nitrogen 0.0887 mol) was dissolved in 420 ml of toluene at room temperature. The temperature was slowly raised to reflux for 3 hours. After the reaction was completed, the resulting solid was filtered by cooling to room temperature. The filtrate was dried to give 29.3 g of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.8~7.9(m, 5H), δ 7.6~7.7(m, 8H), δ 7.4~7.2(m, 10H), δ 3.4~3.6(m, 6H) δ 2.63(bs, 2H), δ 0.90~1.1(m, 9H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H NMR (CDCl 3 )) Data: δ 7.8 ~ 7.9 (m, 5H), δ 7.6 ~ 7.7 (m, 8H), δ 7.4 ~ 7.2 (m, 10H), δ 3.4 ~ 3.6 (m, 6H) δ 2.63 (bs, 2H), δ 0.90 to 1.1 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 7 : 3차t-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식 14)의 제조Example 7: tertiary t-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) Preparation of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

질소로 충진된 2구 반응용기에 트리페닐((2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드 46g(0.074몰), 탄산칼륨 30.8g(0.223몰)을 넣고, 디메틸설폭사이드 460㎖로 용해시켰다. 반응물을 70℃에서 4시간 동안 가열 환류시켰다.Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide 46g (0.074mol), potassium carbonate 30.8g (0.223 mol) was added and dissolved in 460 ml of dimethyl sulfoxide. The reaction was heated to reflux at 70 ° C. for 4 hours.

반응물을 실온으로 냉각한 후, 정제수 460㎖을 가하고, 톨루엔 350㎖로 2회 추출하였다. 유기층을 정제수 500㎖로 2회 반복 세척한 후, 황산마그네슘으로 건조시킨 후, 여과하고, 여과액을 감압농축하여 조생성물을 고체로 수득하였다.After the reaction was cooled to room temperature, 460 ml of purified water was added, followed by extraction twice with 350 ml of toluene. The organic layer was washed twice with 500 ml of purified water twice, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product as a solid.

상기 조생성물을 크로마토그래피로 분리하여 백색고체로서 표제화합물 29.6g(76.7%)을 수득했다.The crude product was separated by chromatography to give 29.6 g (76.7%) of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.86(d, 1H), δ 7.65(t, 1H), δ 7.43(t, 1H), δ 7.3~7.2(m, 5H), δ 6.54(d, 1H), δ 5.99(s, 1H), δ 5.49(dd, 1H), δ 4.3~4.5(m, 2H), δ 3.26(s, 3H), δ 2.5~2.2(m, 2H), δ 1.7~1.5(m, 3H), δ 1.3~1.4(m, 9H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton nuclear magnetic resonance spectroscopy ( 1 H NMR (CDCl 3 )) data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H) , δ 6.54 (d, 1H), δ 5.99 (s, 1H), δ 5.49 (dd, 1H), δ 4.3 ~ 4.5 (m, 2H), δ 3.26 (s, 3H), δ 2.5 ~ 2.2 (m, 2H), δ 1.7-1.5 (m, 3H), δ 1.3-1.4 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 8 : 3차-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식 14)의 제조Example 8 tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Preparation of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

질소로 충진된 2구 반응용기에 트리페닐((2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드 46g(0.074몰), 소듐바이카보네이트 18.7g(0.223몰)을 넣고, 디메틸설폭사이드 460㎖로 용해시켰다. 반응물을 70℃에서 9시간 가열 환류시켰다.Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide 46g (0.074mol), sodium bicarbonate 18.7 g (0.223 mol) was added and dissolved in 460 ml of dimethyl sulfoxide. The reaction was heated to reflux at 70 ° C. for 9 hours.

반응물을 실온으로 냉각한 후, 정제수 460㎖을 가하고, 톨루엔 350㎖로 2회 추출하였다. 유기층을 정제수 500㎖로 2회 반복 세척한 후, 황산마그네슘으로 건조시킨 후, 여과하고, 여과액을 감압농축시켜 조생성물을 고체로 수득하였다.After the reaction was cooled to room temperature, 460 ml of purified water was added, followed by extraction twice with 350 ml of toluene. The organic layer was washed twice with 500 ml of purified water, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product as a solid.

상기 조생성물을 크로마토그래피로 분리하여 백색고체로서 표제화합물 17.9g(46.5%)을 수득했다.The crude product was separated by chromatography to give 17.9 g (46.5%) of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.86(d, 1H), δ 7.65(t, 1H), δ 7.43(t, 1H), δ 7.3~7.2(m, 5H), δ 6.54(d, 1H), δ 5.99(s, 1H), δ 5.49(dd, 1H), δ 4.3~4.5(m, 2H), δ 3.26(s, 3H), δ 2.5~2.2(m, 2H), δ 1.7~1.5(m, 3H), δ 1.3~1.4(m, 9H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton nuclear magnetic resonance spectroscopy ( 1 H NMR (CDCl 3 )) data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H) , δ 6.54 (d, 1H), δ 5.99 (s, 1H), δ 5.49 (dd, 1H), δ 4.3 ~ 4.5 (m, 2H), δ 3.26 (s, 3H), δ 2.5 ~ 2.2 (m, 2H), δ 1.7-1.5 (m, 3H), δ 1.3-1.4 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 9 : 3차-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트(화학식 14)의 제조Example 9: tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl)- Preparation of 2-methoxy-1,3-dioxan-4-yl) acetate (Formula 14)

질소로 충진된 2구 반응용기에 트리페닐((2-사이클로프로필-4-(4-플루오로페닐)-퀴놀린-3-일메틸)-포스포늄)브로마이드 46g(0.074몰), 디메틸아미노피리딘(DMAP) 27.2g(0.223몰)을 넣고, 디메틸설폭사이드 460㎖로 용해시켰다. 반응물을 70℃에서 6시간 가열 환류시켰다.Triphenyl ((2-cyclopropyl-4- (4-fluorophenyl) -quinolin-3-ylmethyl) -phosphonium) bromide 46g (0.074mol), dimethylaminopyridine 27.2 g (0.223 mol) of DMAP) were added and dissolved in 460 ml of dimethyl sulfoxide. The reaction was heated to reflux at 70 ° C. for 6 hours.

반응물을 실온으로 냉각한 후, 정제수 460㎖을 가하고, 톨루엔 350㎖로 2회 추출하였다. 유기층을 정제수 500㎖로 2회 반복 세척한 후, 황산마그네슘으로 건조시키고, 여과한 후, 여과액을 감압농축시켜 조생성물을 고체로 수득하였다.After the reaction was cooled to room temperature, 460 ml of purified water was added, followed by extraction twice with 350 ml of toluene. The organic layer was washed twice with 500 ml of purified water, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product as a solid.

상기 조생성물을 크로마토그래피로 분리하여 백색고체로서 표제화합물 21.2g(55.0%)을 수득했다.The crude product was separated by chromatography to give 21.2 g (55.0%) of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.86(d, 1H), δ 7.65(t, 1H), δ 7.43(t, 1H), δ 7.3~7.2(m, 5H), δ 6.54(d, 1H), δ 5.99(s, 1H), δ 5.49(dd, 1H), δ 4.3~4.5(m, 2H), δ 3.26(s, 3H), δ 2.5~2.2(m, 2H), δ 1.7~1.5(m, 3H), δ 1.3~1.4(m, 9H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton nuclear magnetic resonance spectroscopy ( 1 H NMR (CDCl 3 )) data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H) , δ 6.54 (d, 1H), δ 5.99 (s, 1H), δ 5.49 (dd, 1H), δ 4.3 ~ 4.5 (m, 2H), δ 3.26 (s, 3H), δ 2.5 ~ 2.2 (m, 2H), δ 1.7-1.5 (m, 3H), δ 1.3-1.4 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 10 : (E,3R,5S)-3차-부틸 7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵테-6-노에이트(화학식 15)의 제조Example 10 (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhepte-6 Preparation of Noate (Formula 15)

반응기에 순도 99.4%의 t-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트 20g을 넣고, 메탄올 140㎖로 용해시켰다. 반응물에 2N 염산 28㎖를 가한 후, 30분 내지 1시간 동안 교반시켰다. 반응이 완결되면, 반응액에 정제수 100㎖와 디클로로메탄 200㎖를 가하여 추출하였다. 수층을 디클로로메탄으로 재추출한 후, 유기층을 모두 합하고, 정제수 150㎖, 포화소금물로 연속 세척하였다. 유기층을 황산나트륨(Na2SO4)로 건조시킨 후, 여과하고, 여과액을 감압농축시켰다. 농축액을 디클로로메탄으로 용해시킨 후, 0℃로 냉각하고, 헥산을 서서히 가하여 백색고체로서 표제화합물 17.7g(96.4%; 순도 99.6% 고성능액체크로마토그래피 면적%)을 수득하였다.T-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) with 99.4% purity in the reactor) 20 g of -2-methoxy-1,3-dioxan-4-yl) acetate were added and dissolved in 140 ml of methanol. 28 mL of 2N hydrochloric acid was added to the reaction, followed by stirring for 30 minutes to 1 hour. When the reaction was completed, 100 ml of purified water and 200 ml of dichloromethane were added to the reaction solution. After re-extracting the aqueous layer with dichloromethane, all the organic layers were combined and washed successively with 150 ml of purified water and saturated brine. The organic layer was dried over sodium sulfate (Na 2 SO 4 ), filtered, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane, cooled to 0 ° C., and hexane was added slowly to give 17.7 g (96.4%; purity 99.6% high performance liquid chromatography area%) of the title compound as a white solid.

양성자 핵자기공명분광분석(1H NMR(CDCl3)) 데이터 : δ 7.86(d, 1H), δ 7.65(t, 1H), δ 7.43(t, 1H), δ 7.3~7.2(m, 5H), δ 6.54(d, 1H), δ 5.49(dd, 1H), δ 4.3~4.5(m, 2H), δ 2.5~2.2(m, 2H), δ 1.7~1.5(m, 3H), δ 1.3~1.4(m, 9H), δ 0.85(bs, 2H), δ 0.50(bs, 2H).
Proton nuclear magnetic resonance spectroscopy ( 1 H NMR (CDCl 3 )) data: δ 7.86 (d, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H) , δ 6.54 (d, 1H), δ 5.49 (dd, 1H), δ 4.3 ~ 4.5 (m, 2H), δ 2.5 ~ 2.2 (m, 2H), δ 1.7 ~ 1.5 (m, 3H), δ 1.3 ~ 1.4 (m, 9H), δ 0.85 (bs, 2H), δ 0.50 (bs, 2H).

실시예 11 : (E,3R,5S)-3차-부틸 7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵테-6-노에이트(화학식 15)의 제조Example 11 (E, 3R, 5S) -tert-butyl 7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhepte-6 Preparation of Noate (Formula 15)

반응기에 순도 99.4%의 3차-부틸2-((4R,6S)-6-((E)-2-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)바이닐)-2-메톡시-1,3-디옥산-4-일)아세테이트 20g을 넣고 메탄올 140㎖로 용해시켰다. 반응물에 2N 염산 28㎖를 가한 후, 30분 내지 1시간 동안 교반시켰다. 반응이 완결되면, 반응액에 정제수 100㎖와 디클로로메탄 200㎖를 가하여 추출하였다. 수층을 디클로로메탄으로 재추출한 후, 유기층을 모두 합하고 정제수 150㎖, 포화소금물로 연속 세척하였다. 유기층을 황산나트륨(Na2SO4)로 건조시킨 후, 여과하고, 여과액을 감압농축하였다. 농축액을 더 이상의 반응후공정 없이 바로 다음 반응을 진행하였다.
Tert-butyl2-((4R, 6S) -6-((E) -2- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) vinyl) of 99.4% purity in the reactor 20 g of) -2-methoxy-1,3-dioxan-4-yl) acetate was added and dissolved in 140 ml of methanol. 28 mL of 2N hydrochloric acid was added to the reaction, followed by stirring for 30 minutes to 1 hour. When the reaction was completed, 100 ml of purified water and 200 ml of dichloromethane were added to the reaction solution. After re-extracting the aqueous layer with dichloromethane, all the organic layers were combined and washed successively with 150 mL of purified water and saturated brine. The organic layer was dried over sodium sulfate (Na 2 SO 4 ), filtered, and the filtrate was concentrated under reduced pressure. The concentrated solution proceeded to the next reaction immediately without any further reaction.

실시예 12 : (E)-7-(2-사이클로프로필-4-(4-플루오로페닐)퀴놀린-3-일)-3,5-디히드록시헵-6-테노익 나트륨염(화학식 1)의 제조Example 12: (E) -7- (2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl) -3,5-dihydroxyhep-6-tenoic sodium salt (Formula 1) Manufacturing

상기 실시예 11에서 수득된 농축액 화합물을 실온에서 메탄올 140㎖로 용해시켰다. 수산화나트륨 2.3g(0.057몰)을 정제수 20㎖에 용해시킨 용액을 서서히 가하였다. 실온에서 2시간 동안 교반시켜 반응을 완결시켰다. 더 이상의 정제과정 없이 다음 반응을 진행하였다.
The concentrated compound obtained in Example 11 was dissolved in 140 ml of methanol at room temperature. A solution of 2.3 g (0.057 mol) of sodium hydroxide dissolved in 20 ml of purified water was slowly added. The reaction was completed by stirring at room temperature for 2 hours. The following reaction proceeded without further purification.

실시예 13 : 피타바스타틴 헤미칼슘의 제조Example 13 Preparation of Pitavastatin Hemicalcium

염화칼슘(CaCl2) 4.2g(0.037몰)을 정제수 10㎖에 용해시킨 용액을 0℃로 냉각된 상기 실시예 12의 반응물에 서서히 가하였다. 30분간 교반한 후, 불용물을 여과하여 제거한 후, 여과액을 실온으로 승온시켜 8시간 동안 교반하였다.A solution of 4.2 g (0.037 mol) of calcium chloride (CaCl 2 ) dissolved in 10 ml of purified water was slowly added to the reaction product of Example 12 cooled to 0 ° C. After stirring for 30 minutes, the insolubles were filtered off, and then the filtrate was raised to room temperature and stirred for 8 hours.

반응물을 0℃로 냉각시킨 후, 정제수 280㎖을 서서히 가하여 결정을 석출시켰다.After the reaction was cooled to 0 ° C., 280 ml of purified water was slowly added to precipitate crystals.

결정을 여과한 후, 진공건조시켜 백색고체로서 피타바스타틴 헤미칼슘을 12.3g 수득하였다.The crystals were filtered and dried in vacuo to yield 12.3 g of pitavastatin hemicalcium as a white solid.

양성자 핵자기공명분광분석(1H NMR(DMSO-d6)) 데이터 : δ 11.2(s, 1H), δ 7.65(t, 1H), δ 7.43(t, 1H), δ 7.3~7.2(m, 5H), δ 6.64(d, 1H), δ 6.25(dd, 1H), δ 3.91(m, 2H), δ 3.56(m, 1H), δ 2.5~2.2(m, 2H), δ 1.6~1.5(m, 3H), δ 0.6~0.3(m, 4H).
Proton nuclear magnetic resonance spectroscopy ( 1 H NMR (DMSO-d6)) data: δ 11.2 (s, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H ), δ 6.64 (d, 1H), δ 6.25 (dd, 1H), δ 3.91 (m, 2H), δ 3.56 (m, 1H), δ 2.5 to 2.2 (m, 2H), δ 1.6 to 1.5 (m , 3H), δ 0.6-0.3 (m, 4H).

실시예 14 : 피타바스타틴 헤미칼슘의 제조Example 14 Preparation of Pitavastatin Hemicalcium

아세트산칼슘(Ca(OAc)2) 5.8g(0.037몰)을 정제수 10㎖에 용해시킨 용액을 0℃로 냉각된 상기 실시예 12의 반응물에 서서히 가하였다. 30분간 교반한 후, 불용물을 여과하여 제거한 후, 여과액을 실온으로 승온시켜 8시간 동안 교반시켰다. A solution in which 5.8 g (0.037 mol) of calcium acetate (Ca (OAc) 2 ) was dissolved in 10 mL of purified water was slowly added to the reaction product of Example 12 cooled to 0 ° C. After stirring for 30 minutes, the insolubles were filtered off, and then the filtrate was raised to room temperature and stirred for 8 hours.

반응물을 0℃로 냉각 후, 정제수 280㎖을 서서히 가하여 결정을 석출시켰다.After the reaction was cooled to 0 ° C., 280 ml of purified water was slowly added to precipitate crystals.

결정을 여과한 후, 진공건조시켜 백색고체로서 피타바스타틴 헤미칼슘을 12.7g 수득하였다.The crystals were filtered and dried in vacuo to yield 12.7 g of pitavastatin hemicalcium as a white solid.

양성자 핵자기공명분광분석(1H NMR(DMSO-d6)) 데이터 : δ 11.2(s, 1H), δ 7.65(t, 1H), δ 7.43(t, 1H), δ 7.3~7.2(m, 5H), δ 6.64(d, 1H), δ 6.25(dd, 1H), δ 3.91(m, 2H), δ 3.56(m, 1H), δ 2.5~2.2(m, 2H), δ 1.6~1.5(m, 3H), δ 0.6~0.3(m, 4H).Proton nuclear magnetic resonance spectroscopy ( 1 H NMR (DMSO-d6)) data: δ 11.2 (s, 1H), δ 7.65 (t, 1H), δ 7.43 (t, 1H), δ 7.3 ~ 7.2 (m, 5H ), δ 6.64 (d, 1H), δ 6.25 (dd, 1H), δ 3.91 (m, 2H), δ 3.56 (m, 1H), δ 2.5 to 2.2 (m, 2H), δ 1.6 to 1.5 (m , 3H), δ 0.6-0.3 (m, 4H).

이상에서 설명한 바와 같이 본 발명은 피타바스타틴 헤미칼슘(Pitavastatin hemicalcium)의 제조에 있어서 특정 작용기를 도입하기 위하여 불필요한 제조과정이 없을 뿐 더러 본 발명은 7단계 모든 과정이 비교적 온화한 반응조건 하에서 짧은 반응시간으로 피타바스타틴을 높은 수율로 수득할 수 있어, 산업적으로 유효하한 신규한 피타바스타틴을 제조하는 데 이용될 수 있다.As described above, the present invention has no unnecessary manufacturing process in order to introduce a specific functional group in the production of Pitavastatin hemicalcium, and the present invention has a short reaction time under relatively mild reaction conditions in all seven steps. Thus, pitavastatin can be obtained in high yield, and can be used to prepare novel pitavastatin which is industrially effective.

이상에서 본 발명은 기재된 구체예에 대해서만 상세히 설명되었지만 본 발명의 기술사상 범위 내에서 다양한 변형 및 수정이 가능함은 당업자에게 있어서 명백한 것이며, 이러한 변형 및 수정이 첨부된 특허청구범위에 속함은 당연한 것이다.
Although the present invention has been described in detail only with respect to the described embodiments, it will be apparent to those skilled in the art that various modifications and variations are possible within the technical scope of the present invention, and such modifications and modifications are within the scope of the appended claims.

Claims (12)

피타바스타틴 헤미칼슘의 제조에 있어서,
i) 하기 반응식 4의 화학식(8)로 표시되는 화합물을 산촉매하에서 CH(OR)3로 표시되는 화합물과 보호화 반응시켜 하기 반응식 4의 화학식(9)로 표시되는 화합물을 제조하는 제 1 단계;
[반응식 4]
Figure 112011081105191-pat00017

상기 반응식 4에서 R은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기임,
ii) 하기 반응식 5의 화학식(9)로 표시되는 화합물을 2,2,6,6-테트라메틸피페리딘-1-옥실(TEMPO), 브롬화칼륨(KBr) 또는 브롬화리튬(LiBr)의 존재 하에서 산화제로서 이산화망간(MnO2), 과산화수소(H2O2), 퍼아세트산(CH3CO3H), 소듐하이포클로리트(NaOCl) 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 산화제로 산화반응시켜 하기 반응식 5의 화학식(10)으로 표시되는 화합물을 제조하는 제 2 단계;
[반응식 5]
Figure 112011081105191-pat00018

상기 반응식 5에서 R은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기임,
iii) 하기 반응식 6의 화학식(11)로 표시되는 화합물을 할로겐화제로서 브롬(Br2), 브롬화인(PBr3), 염소(Cl2), 염화인(PCl5)들로 이루어지는 그룹으로부터 선택되는 할로겐화제를 이용하여 하기 반응식 6의 화학식(12)로 표시되는 화합물을 제조하는 제 3 단계;
[반응식 6]
Figure 112011081105191-pat00019

상기 반응식 6에서, X는 할로겐원자임,
iv) 하기 반응식 7의 화학식(12)로 표시되는 화합물을 하기 반응식 7의 화학식(13)으로 표시되는 화합물로 제조하는 제 4 단계;
[반응식 7]
Figure 112011081105191-pat00020

상기 반응식 7에서, R1은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기이고, X는 할로겐원자임,
v) 하기 반응식 8의 화학식(13)으로 표시되는 화합물과 하기 반응식 8의 화학식(10)으로 표시되는 화합물을 커플링 반응시켜 하기 반응식 8의 화학식(14)로 표시되는 화합물을 제조하는 제 5 단계;
[반응식 8]
Figure 112011081105191-pat00021

상기 반응식 8에서 R 및 R1은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기이고, X는 할로겐원자임,
vi) 하기 반응식 9의 화학식(14)로 표시되는 화합물을 수용액 상에서 황산, 염산, 초산 또는 메탄술폰산을 정제수 또는 유기용매로 희석시킨 희석산으로 탈보호화 반응시켜 하기 반응식 9의 화학식(15)로 표시되는 화합물을 제조하는 제 6 단계;
[반응식 9]
Figure 112011081105191-pat00022

상기 반응식 9에서, R 및 R1은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기임,
vii) 하기 반응식 10의 화학식(15)로 표시되는 화합물을 가수분해화제로서 수산화나트륨, 수산화칼륨, 포타슘3차-부톡사이드, 수산화리튬 또는 이들 중 2이상의 혼합물로 이루어지는 그룹으로부터 선택되는 가수분해화제를 이용하는 가수분해 반응 후, 칼슘화제로서 염화칼슘 또는 아세트산칼슘을 사용하는 연속반응으로 하기 반응식 10의 화학식(1)인 피타바스타틴 헤미칼슘을 제조하는 제 7 단계;
[반응식 10]
Figure 112011081105191-pat00023

를 포함하여 이루어짐을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.In the preparation of pitavastatin hemicalcium,
i) protecting the compound represented by formula (8) of Scheme 4 with a compound represented by CH (OR) 3 under an acid catalyst to prepare a compound represented by formula (9) of Scheme 4 below;
[Reaction Scheme 4]
Figure 112011081105191-pat00017

In Scheme 4, R is hydrogen, C 1 ~ C 6 Alkyl group, C 6 ~ C 12 It is a substituted or unsubstituted aryl group,
ii) the compound represented by the formula (9) of Scheme 5 in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), potassium bromide (KBr) or lithium bromide (LiBr); Oxidizing with an oxidizing agent selected from the group consisting of manganese dioxide (MnO 2 ), hydrogen peroxide (H 2 O 2 ), peracetic acid (CH 3 CO 3 H), sodium hypochlorite (NaOCl) or a mixture of two or more thereof A second step of preparing a compound represented by the formula (10) of Scheme 5;
Scheme 5
Figure 112011081105191-pat00018

In Scheme 5, R is hydrogen, an alkyl group of C 1 ~ C 6 , a substituted or unsubstituted aryl group of C 6 ~ C 12 ,
iii) The compound represented by the formula (11) of Scheme 6 is selected from the group consisting of bromine (Br 2 ), phosphorus bromide (PBr 3 ), chlorine (Cl 2 ), phosphorus chloride (PCl 5 ) as the halogenating agent; A third step of preparing a compound represented by Chemical Formula 12 using Scheme Halogen;
Scheme 6
Figure 112011081105191-pat00019

In Scheme 6, X is a halogen atom,
iv) a fourth step of preparing a compound represented by formula (12) of Scheme 7 below with a compound represented by formula (13):
[Reaction Scheme 7]
Figure 112011081105191-pat00020

In Scheme 7, R1 is hydrogen, an alkyl group of C 1 ~ C 6 , a substituted or unsubstituted aryl group of C 6 ~ C 12 , X is a halogen atom,
v) a fifth step of preparing a compound represented by the formula (14) of Scheme 8 by coupling-reacting the compound represented by the formula (13) of Scheme 8 and the compound represented by the formula (10) ;
Scheme 8
Figure 112011081105191-pat00021

In Scheme 8, R and R1 are hydrogen, an alkyl group of C 1 ~ C 6 , a substituted or unsubstituted aryl group of C 6 ~ C 12 , X is a halogen atom,
vi) Deprotection reaction of the compound represented by the formula (14) of Scheme 9 with dilute acid diluted with purified water or organic solvent of sulfuric acid, hydrochloric acid, acetic acid or methanesulfonic acid in an aqueous solution is represented by the formula (15) A sixth step of preparing the compound;
Scheme 9
Figure 112011081105191-pat00022

In Scheme 9, R and R1 are hydrogen, C 1 ~ C 6 Alkyl group, C 6 ~ C 12 It is a substituted or unsubstituted aryl group,
vii) A hydrolysis agent selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, lithium hydroxide or a mixture of two or more thereof as the hydrolysis agent A seventh step of preparing pitavastatin hemicalcium represented by the formula (1) below in a continuous reaction using calcium chloride or calcium acetate as the calcium agent after the hydrolysis reaction to be used;
Scheme 10
Figure 112011081105191-pat00023

Method for producing pitavastatin hemicalcium, characterized in that comprises a. 제 1 항에 있어서,
상기 보호화 반응은 테트라히드로퓨란(THF), 디메틸에테르, 디메틸포름아미드(DMF), 디메틸설폭사이드(DMSO), 벤젠, 디클로로메탄, 아세토니트릴, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택된 용매를 사용하는 조건에서 수행하는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
The protection reaction is a solvent selected from the group consisting of tetrahydrofuran (THF), dimethyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzene, dichloromethane, acetonitrile, acetone or mixtures of two or more thereof. Method for producing pitavastatin hemicalcium, characterized in that carried out under the conditions using. 제 1 항에 있어서,
상기 보호화 반응은 황산, 염산, 아세트산, 메탄설폰산, 파라-톨루엔설폰산 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택된 산촉매를 사용하는 조건에서 수행하는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
The protection reaction is carried out under the conditions using an acid catalyst selected from the group consisting of sulfuric acid, hydrochloric acid, acetic acid, methanesulfonic acid, para-toluenesulfonic acid or a mixture of two or more thereof, phytavastatin hemicalcium Way. 제 1 항에 있어서,
상기 산화반응은 디클로로메탄 용매 하에서 촉매제로 KBr, LiBr과 TEMPO 혼합촉매제를 사용하는 조건에서 수행하는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
The oxidation reaction is a method of producing pitavastatin hemicalcium, characterized in that carried out under the conditions using a mixed catalyst KBr, LiBr and TEMPO as a catalyst in a dichloromethane solvent. 제 1 항에 있어서,
상기 커플링반응은 테트라히드로퓨란(THF), 디메틸에테르, 디메틸포름아미드(DMF),디메틸설폭사이드(DMSO), 벤젠, 톨루엔, 자일렌, 디클로로메탄, 아세토니트릴, 아세톤 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택되는 용매와 NaHCO3, NaH, K2CO3 들로 이루어지는 그룹 중에서 선택된 염기를 사용하는 조건에서 수행되는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
The coupling reaction is tetrahydrofuran (THF), dimethyl ether, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), benzene, toluene, xylene, dichloromethane, acetonitrile, acetone or a mixture of two or more thereof. Method for producing pitavastatin hemicalcium, characterized in that carried out under conditions using a solvent selected from the group consisting of a base selected from the group consisting of NaHCO 3 , NaH, K 2 CO 3 . 제 1 항에 있어서,
상기 탈보호화반응은 용매로서 메탄올, 아세톤, 아세토니트릴, DMSO, DMF, THF 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택되는 용매 및 탈보호화제로서 황산, 염산, 아세트산, 메탄설폰산, 파라-톨루엔설폰산 또는 이들 중 2이상의 혼합물로 이루어지는 그룹 중에서 선택되는 희석산을 사용하는 조건에서 수행되는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
The deprotection reaction is a solvent selected from the group consisting of methanol, acetone, acetonitrile, DMSO, DMF, THF or a mixture of two or more thereof as a solvent and sulfuric acid, hydrochloric acid, acetic acid, methanesulfonic acid, para-toluene as a deprotection agent. A process for producing pitavastatin hemicalcium, characterized in that it is carried out under conditions using a dilute acid selected from the group consisting of sulfonic acid or a mixture of two or more thereof. 제 1 항에 있어서,
상기 가수분해 반응 후, 피타바스타틴 헤미칼슘을 연속반응으로 수행하는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
After the hydrolysis reaction, the method of producing pitavastatin hemicalcium, characterized in that the pitavastatin hemicalcium is carried out in a continuous reaction. 제 1 항에 있어서,
상기 칼슘화제로 염화칼슘 또는 아세트산칼슘을 이용한 연속반응으로 수행하는 것을 특징으로 하는 피타바스타틴 헤미칼슘의 제조방법.The method of claim 1,
Method for producing pitavastatin hemicalcium, characterized in that carried out in a continuous reaction using calcium chloride or calcium acetate as the calcium agent. 하기 화학식 9로 표시되는 화합물:
[화학식 9]
Figure 112011081105191-pat00024

상기 화학식 9에서 R은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기임.Compound represented by the following formula (9):
[Formula 9]
Figure 112011081105191-pat00024

R in Formula 9 is hydrogen, an alkyl group of C 1 ~ C 6 , C 6 ~ C 12 It is a substituted or unsubstituted aryl group. 하기 화학식 10으로 표시되는 화합물:
[화학식 10]
Figure 112011081105191-pat00025

상기 화학식 10에서 R은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기임.Compound represented by the following formula (10):
[Formula 10]
Figure 112011081105191-pat00025

R in Formula 10 is hydrogen, an alkyl group of C 1 ~ C 6 , C 6 ~ C 12 It is a substituted or unsubstituted aryl group. 하기 화학식 14로 표시되는 화합물:
[화학식 14]
Figure 112011081105191-pat00026

상기 화학식 14에서 R은 수소, C1~C6의 알킬기, C6~C12의 치환 또는 비치환된 아릴기임.
Compound represented by the following formula (14):
[Formula 14]
Figure 112011081105191-pat00026

In Formula 14, R is hydrogen, an alkyl group of C 1 ~ C 6 , a substituted or unsubstituted aryl group of C 6 ~ C 12 .
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