KR101294702B1 - process for preparing S-(-)-amlodipine.HCl - Google Patents

process for preparing S-(-)-amlodipine.HCl Download PDF

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KR101294702B1
KR101294702B1 KR1020060101163A KR20060101163A KR101294702B1 KR 101294702 B1 KR101294702 B1 KR 101294702B1 KR 1020060101163 A KR1020060101163 A KR 1020060101163A KR 20060101163 A KR20060101163 A KR 20060101163A KR 101294702 B1 KR101294702 B1 KR 101294702B1
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김준섭
김종민
최재구
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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Abstract

본 발명은 S-(-)-암로디핀 염산염(화학식 7)의 개량된 제조방법에 관한 것으로, 하기 화학식 3을 2-클로로 벤즈알데히드와 손잡이성을 갖는 화학식 4를 반응시켜 화학식 5를 제조하고, 계속해서 화학식 6, 7을 제조하는 것을 특징으로 한다.The present invention relates to an improved process for the preparation of S-(-)-amlodipine hydrochloride (Formula 7), wherein the formula (3) is reacted with 2-chlorobenzaldehyde and formula (4) having a handleability to produce formula (5), and then It is characterized in that the formula 6, 7.

Figure 112006075007931-pat00001
Figure 112006075007931-pat00001

암로디핀, 암로디핀 염산염, 트리아존 화합물, (S)-(+)-2-메톡시-2-페닐에틸-3-아미노이소크로토네이트, S-(-)-암로디핀  Amlodipine, Amlodipine Hydrochloride, Triazone Compound, (S)-(+)-2-methoxy-2-phenylethyl-3-aminoisocrotonate, S-(-)-amlodipine

Description

Ｓ-(-)-암로디핀입체이성질체의 제조방법 {process for preparing S-(-)-amlodipine.HCl}Process for preparing S-(-)-amlodipine isomer {process for preparing S-(-)-amlodipine.HCl}

본 발명은 고혈압 치료제로서 유용한 암로디핀의 새롭고 개량된 제조방법에 관한 것이다. 화학식 10의 암로디핀은 여러 종류의 염이나 Pro Drug의 제조를 위해 아주 유용하나, 보통 합성된 암로디핀은 2개의 좌우대칭 이성질체로 존재하는데 각각 다른 약리적인 효능을 가진다. 즉, S-(-)-이성질체는 칼슘채널 차단제로서 매우 효능이 크며, R-(+)-이성질체는 동맥경화의 치료와 예방에 효능을 나타낸다.The present invention relates to a new and improved method for preparing amlodipine useful as a therapeutic agent for hypertension. Amlodipine of Formula 10 is very useful for the preparation of various types of salts or Pro Drugs, but usually synthesized amlodipine exists as two bilaterally symmetric isomers, each having different pharmacological effects. That is, the S-(-)-isomer is very effective as a calcium channel blocker, and the R-(+)-isomer is effective in the treatment and prevention of atherosclerosis.

E. Wehinger 등은 DOS 2935451(1981)에서 키랄 아미노 에스테르를 사용하여 순수한 키랄 에스테르를 가지는 1,4-디히드로피리딘 유도체 화학식 8(a)를 합성하였다. J. E. Arrosmith 등은 J. Med . Chem. (1986) 29 1696 에서 부분입체 이성질 아지드 에스테르 화학식 8(b)를 분리함으로써 2개의 암로디핀 좌우대칭 이성질체를 제조하였음을 보고하였다.E. Wehinger et al. Synthesized a 1,4-dihydropyridine derivative having the pure chiral ester Formula 8 (a) using chiral amino ester in DOS 2935451 (1981). JE Arrosmith et al . J. Med . Chem . (1986) 29 It was reported that two amlodipine bilaterally symmetric isomers were prepared by separating diastereomeric azide ester Formula 8 (b) at 1696.

Roman Davis 등은 JACS (1988) 110 7873 에서 키랄 술폭시드를 이용하여 순수한 1,4-디히드로피리딘 유도체 화학식 8(c)를 합성하였다. S. Goldman 등은 J. Med. Chem. (1992) 35 3341 에서 부분입체 이성질체인 화학식 7의 탈염화된 base form을 크로마토그래피를 이용하여 분리.제조하였다. 또한 Angew . Chem . Int . Edn.(Engl.) (1991) 30 1559에서 치환된 타르타르산을 이용하여 여러 종류의 용매에서 순수한 좌우대칭 이성질체 화학식 8(d)를 얻었음을 기술하였다.Roman Davis et al. Synthesized pure 1,4-dihydropyridine derivative Formula 8 (c) using chiral sulfoxide in JACS (1988) 110 7873. S. Goldman et al . J. Med. Chem . (1992) 35 3341, a desaltated base form of the formula (7), which is a diastereomer, was isolated and prepared by chromatography. Also Angew . Chem . Int . Edn. (Engl.) (1991) 30 It was described that substituted tartaric acid in 1559 yielded the pure left-right symmetric isomer Formula 8 (d) in various solvents.

Figure 112006075007931-pat00002
Figure 112006075007931-pat00002

그러나 위에서 기술한 방법은 수율과 좌우대칭 이성질체의 순도가 만족할 만한 결과를 주지 못하고 있다. 이와 같은 종래의 방법을 고려할 때 부분입체 암로디핀 이성체에서 순수한 화학식 10을 제조하는 과정에서 반응단계를 줄이고 부반응을 억제하여 공정 수율을 극대화 할 수 있는 제조 방법이 요구되고 있다.However, the method described above does not yield satisfactory yield and purity of the symmetric isomer. In consideration of such a conventional method, there is a demand for a method of preparing a pure formula (10) in diastereomeric amlodipine isomer to reduce the reaction step and inhibit side reactions to maximize the process yield.

또한 암로디핀 물질 자체는 이미 공지되어 있으며, 아미노기의 전구체에서 아미노기를 제조하는 여러가지 방법들이 소개되어 있다. 먼저, 대한민국 특허공고 제87-809호에는 화학식 10을 제조하는 여러가지 방법들이 개시되어 있다. 예를 들어, 반응식 1에서 볼 수 있는 바와 같이 화학식 9의 아지드 화합물을 트리페닐포스핀이나 아연 및 염산, 또는 Pd/H2 등으로 환원시켜 화학식 10의 암로디핀을 제조한다. 그러나 아지드 화합물을 사용하는 종래의 방법들은 아지드 화합물류의 폭발성(Chemical Abstract, 105, 11321t)으로 인하여 상당한 위험성이 내포되어 있다. Also, the amlodipine material itself is already known, and various methods of preparing amino groups from precursors of amino groups are introduced. First, Korean Patent Publication No. 87-809 discloses various methods of preparing Chemical Formula 10. For example, as shown in Scheme 1, the azide compound of Formula 9 is reduced with triphenylphosphine or zinc and hydrochloric acid, or Pd / H 2 to prepare Amlodipine of Formula 10. However, conventional methods using an azide compound pose significant risks due to the explosive nature of the azide compounds ( Chemical Abstract , 105, 11321t).

Figure 112006075007931-pat00003
Figure 112006075007931-pat00003

반응식 2에서 화학식 11의 프탈이미드 화합물로부터 프탈이미드기를 제거하여 화학식 10의 암로디핀을 제조한다. 그러나 히드라진과 같은 염기를 사용(J. Org . Chem., 60, 4536, (1995)) 함으로서 에스테르기가 아미드가 되는 부반응이 일어날 수 있는 문제점이 있다.Amlodipine of Formula 10 is prepared by removing a phthalimide group from the phthalimide compound of Formula 11 in Scheme 2. However, by using a base such as hydrazine ( J. Org . Chem ., 60 , 4536, (1995)), there is a problem that a side reaction in which the ester group becomes an amide may occur.

Figure 112006075007931-pat00004
Figure 112006075007931-pat00004

한편, 미합중국 특허 제5,389,654호에는 하기 반응식 3에서 볼 수 있는 바와 같이 암로디핀의 아미노기를 트리틸기로 보호한 화학식 12를 벤젠술폰산으로 처리한 후 트리틸기를 제거함으로써 화학식 13을 제조하는 방법이 개시되어 있다. 그러 나 이러한 방법에서도 정제공정이 까다롭고 복잡하며, 수율도 저조한 문제점이 있다.On the other hand, US Patent No. 5,389,654 discloses a process for preparing Formula 13 by treating Formula 12 in which the amino group of amlodipine is protected by a trityl group with benzenesulfonic acid and then removing the trityl group as shown in Scheme 3 below. . However, even in this method, the purification process is difficult and complicated, and the yield is also low.

Figure 112006075007931-pat00005
Figure 112006075007931-pat00005

이에 본 발명에서는 종래의 기술이 가지고 있는 문제점을 해결하고자, 새로운 중간체 화합물인 화학식 4와 5를 사용함으로써 반응공정이 위험하지 않으며, 순수한 S-(-)-암로디핀 입체이성질체의 제조방법을 제공하고자 한다.In the present invention, to solve the problems of the prior art, by using the new intermediate compounds of formula (4) and 5 is not dangerous reaction process, to provide a method for producing pure S-(-)-amlodipine stereoisomers .

상기 목적을 달성하기 위하여 본 발명은 중요한 중간체인 화학식 3화합물로 부터 적당한 유기산, 알데히드, 그리고 키랄 엔아민을 사용하여 화학식 5화합물을 얻고, 이를 염기와 산을 이용하여 S-(-)-암로디핀 염산염(화학식 7)을 얻는 제조방법에 관한 것이다.In order to achieve the above object, the present invention obtains the compound of formula (5) using a suitable organic acid, aldehyde, and chiral enamine from the compound of formula (3), which is an important intermediate, and uses S-(-)-amlodipine hydrochloride using base and acid. It relates to a production method for obtaining the general formula (7).

이하 본 발명을 대략 설명하면 아래와 같다.Hereinafter, the present invention will be described below.

본 발명의 화학식 7은 반응식 4에 의해 제조할 수 있다. 1차 아미노기를 보호하는 공정은 이미 알려진 공정으로, J. Org . Chem., 57, 6239, (1992)와 유사한 공정에 의해 제조하였다.Formula 7 of the present invention may be prepared by Scheme 4. The process of protecting primary amino groups is a known process, J. Org . Prepared by a process similar to Chem ., 57 , 6239, (1992).

화학식 5의 트리아존 화합물은 일반적인 한츠(Hantzsch) 합성법, J. Org . Chem., 16, 1259, (1951)에 의해 합성하였고, 화학식 5를 염기와 산을 사용하여 S-(-)-암로디핀 염산염(화학식 7)을 제조 제조할 수 있다.Triazone compounds of formula (5) are conventional Hanzsch synthesis, J. Org . It was synthesized by Chem ., 16 , 1259, (1951), and the formula (5) can be prepared using the base and acid to prepare S-(-)-amlodipine hydrochloride (Formula 7).

Figure 112006075007931-pat00006
Figure 112006075007931-pat00006

본 발명의 화학식 7의 (S)-(-)-암로디핀 염산염의 제조방법은 다음 단계로 이루어 진다.The preparation method of (S)-(-)-amlodipine hydrochloride of the formula (7) of the present invention consists of the following steps.

화학식 1의 2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에탄 올을 유기용매에 녹이고, 염기 존재하에 메탈 할로아세테이트와 반응시켜 화학식 2의 2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시 아세트산을 제조하는 단계 1; 2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethanol of formula 1 was dissolved in an organic solvent and reacted with metal haloacetate in the presence of a base to Step 1 to prepare 2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy acetic acid of 2;

화학식 2의 화합물, Im2CO(CDI, 카르보닐다이이미다졸) 와 2,2,-다이메틸-1,3-다이옥산-4,6-다이온을 유기용매에 녹이고, 유기염기 존재하에 에탄올을 가하여 화학식 3의 에틸-4-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-3-옥소-아세테이트를 제조하는 단계 2;Compound 2, Im 2 CO (CDI, carbonyldiimidazole) and 2,2, -dimethyl-1,3-dioxane-4,6-dione are dissolved in an organic solvent, and ethanol is dissolved in the presence of an organic base. Was added ethyl-4- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-3-oxo-acetate of formula (3). Manufacturing step 2;

화학식 3의 화합물과 2-클로로 벤즈알데하이드를 유기용매에 녹이고 화학식 4의 (S)-(+)-2-메톡시-2-페닐에틸-3-아미노 아이소크로토네이트를 가하여 화학식 5의 2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-5-[(S)-(+)-2-메톡시-2-페닐에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘을 제조하는 단계 3;2-chloro benzaldehyde and the compound of formula 3 were dissolved in an organic solvent, and (S)-(+)-2-methoxy-2-phenylethyl-3-amino isocrotonate of formula 4 was added to [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-4- (2-chlorophenyl) -3-ethoxy carbox Step 3 to prepare carbonyl-5-[(S)-(+)-2-methoxy-2-phenylethoxy carbonyl-6-methyl] -1,4-dihydro pyridine;

화학식 5의 화합물을 유기용매에 녹이고, 염기를 가하여 화학식 6의 2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시카르보닐-6-메틸]-1,4-다이하이드로 피리딘을 제조하는 단계 4;The compound of formula 5 was dissolved in an organic solvent, and a base was added to the compound to give 2- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy of formula 6 ] -Methyl-4- (2-chlorophenyl) -3-ethoxycarbonyl-6-methyl] -1,4-dihydro pyridine;

화학식 6의 화합물을 유기용매에 녹이고 무수 산을 가하여 화학식 7의 2-(2-아미노 에톡시메틸)-4-(2-클로로페닐)-6-메틸-1,4-다이하이드로피리딘-3,5-다이카르본산-3-에틸에스테르-5-메틸에스테르 염산염을 제조하는 단계 5를 포함하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The compound of formula 6 was dissolved in an organic solvent, and anhydrous acid was added to the compound to give 2- (2-amino ethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3, A process for preparing S-(-)-amlodipine hydrochloride of Formula 7 comprising step 5 of preparing 5-dicarboxylic acid-3-ethylester-5-methylester hydrochloride.

단계 1에서 반응온도는 0 내지 80oC 이고, 사용되는 유기용매는 테트라히드로퓨란(THF), 다이옥산의 단일 또는 혼합용매가 사용된다. 또한 사용되는 메탈 할로아세테이트는 메탈로 칼륨(K) 또는 나트륨(Na), 할로겐으로서는 브로모 또는 클로로가 사용되며, 염기는 수소화나트륨(NaH)이 바람직하다.In step 1, the reaction temperature is 0 to 80 ° C., and the organic solvent used is a single or mixed solvent of tetrahydrofuran (THF), dioxane. In addition, as the metal halo acetate used, metallo potassium (K) or sodium (Na), bromo or chloro is used as the halogen, and sodium hydride (NaH) is preferable as the base.

단계 2에서 반응온도는 20 내지 100oC 이고, 사용되는 유기용매는 디클로로메탄(DCM), 테트라히드로퓨란(THF), 다이옥산의 단일 또는 혼합용매가 사용된다. 또한 사용되는 유기염기는 피리딘, 트리에틸아민(Et3N) 등이 사용된다.In step 2, the reaction temperature is 20 to 100 o C, and the organic solvent used is a single or mixed solvent of dichloromethane (DCM), tetrahydrofuran (THF), dioxane. As the organic base used, pyridine, triethylamine (Et 3 N), and the like are used.

단계 3에서 반응온도는 70 내지 100oC 이고, 사용되는 유기용매는 에탄올, 다이옥산의 단일 또는 혼합용매가 사용된다.In step 3, the reaction temperature is 70 to 100 o C, the organic solvent used is a single or mixed solvent of ethanol, dioxane.

단계 4에서 반응온도는 60 내지 100oC 이고, 사용되는 염기는 NaOMe(메톡시화 나트륨) 또는 메톡시화 칼륨(KOMe)이고, 사용되는 유기용매는 메탄올,다이옥산 또는 다이글라임의 혼합용매가 사용된다.In step 4, the reaction temperature is 60 to 100 o C, the base used is NaOMe (sodium methoxylated) or potassium methoxylated (KOMe), and the organic solvent used is a mixed solvent of methanol, dioxane or diglyme. .

단계 5에서 반응온도는 70 내지 100oC 이고, 사용되는 산으로는 무수 염산이나 무수황산이고, 사용되는 유기용매는 에탄올, 아이소프로판올의 단일 또는 혼합용매가 사용된다.In step 5, the reaction temperature is 70 to 100 o C, and the acid used is hydrochloric anhydride or sulfuric anhydride, and the organic solvent used is a single or mixed solvent of ethanol or isopropanol.

이하, 바람직한 실시예를 통하여 본 발명에 따른 제조 방법을 구체적으로 설명한다. 단, 이들 실시예는 본 발명의 예시일 뿐, 본 발명의 범위가 이들 만으로 한정되는 것은 아니다.Hereinafter, the manufacturing method according to the present invention will be described in detail through preferred embodiments. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited to these.

실시예 1 : 2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시 아세트산(화학식 2)의 제조 Example 1 Preparation of 2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy acetic acid (Formula 2)

2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에탄올(121.3g, 0.7mol)을 무수 THF(테트라히드로퓨란)(400mL)에 녹이고, 0oC에서 60% NaH(수소화나트륨)(28g, 0.7mol)을 가한 현탁 용액을 무수 THF(400mL)에 나트륨 클로로아세테이트(48.5g, 0.42mol)과 n-Bu4NI(테트라부틸암모늄 아이오다이드)(10g, 0.027mol)를 현탁시킨 용액에 가하고 24시간 동안 가열.환류한다. 반응 혼합물을 냉각시킨 후, 물(50mL)을 가한다. 혼합용액을 감압.증류하여 THF를 제거하고, 물(300mL)을 가한다. 1N 염산 수용액을 사용하여 pH=4로 산성화한 후, 포화소금물과 DCM(디클로로메탄)을 이용하여 추출한다. 추출된 유기용액을 무수 MgSO4(황산마그네슘)(40g)로 건조, 여과하고, 감압.증류하여 화학식 2의 화합물 45.7g을 얻는다(수율 : 47%).2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethanol (121.3 g, 0.7 mol) was dissolved in anhydrous THF (tetrahydrofuran) (400 mL) , Suspension solution with 60% NaH (28 g, 0.7 mol) at 0 o C was added to dry THF (400 mL) with sodium chloroacetate (48.5 g, 0.42 mol) and n- Bu 4 NI (tetrabutylammonium eye). ) (10 g, 0.027 mol) is added to the suspended solution and heated and refluxed for 24 hours. After cooling the reaction mixture, water (50 mL) is added. The mixed solution is distilled under reduced pressure, distilled to remove THF, and water (300 mL) is added. Acidify to pH = 4 with 1N aqueous hydrochloric acid solution, and then extract with saturated brine and DCM (dichloromethane). The extracted organic solution was dried over anhydrous MgSO 4 (magnesium sulfate) (40 g), filtered, and distilled under reduced pressure to obtain 45.7 g of the compound of formula 2 (yield: 47%).

1H NMR (CDCl3) δ 2.90(s, 6H), 3.05(t, 2H), 3.67(t, 2H), 4.21(s, 4H), 4.31(s, 2H) 1 H NMR (CDCl 3 ) δ 2.90 (s, 6H), 3.05 (t, 2H), 3.67 (t, 2H), 4.21 (s, 4H), 4.31 (s, 2H)

실시예 2 : 에틸-4-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-3-옥소-아세테이트(화학식 3)의 제조 Example 2 ethyl-4- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-3-oxo-acetate ( Preparation of Formula 3)

카르보닐다이이미다졸(13.75g, 84mmol)과 2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시 아세트산(18.5g, 80mmol)을 질소기체 하에서 DCM(150mL)에 녹이고 실온에서 1시간 동안 교반한다. DCM(50mL)에 피리딘(6.1g, 77.1mmol)과 2,2-다이메틸-1,3-다이옥산-4,6-다이온(11g, 84mmol)을 녹인 용액을 혼합용액에 적가하고 실온에서 12시간 동안 교반한다. 2N HCl(2 * 50mL)으로 세척 후, MgSO4로 건조, 여과하고, 감압.농축한다. 농축물을 에탄올(75mL)에 녹이고, 70oC에서 3시간 동안 가열.교반한다. 반응 혼합물을 냉각시킨 후, DCM(75mL)로 희석시키고 물(3 * 50mL)로 세척한다. 세척된 유기용액을 MgSO4로 건조, 여과하고, 감압.농축한다. 농축된 생성물을 칼람크로마토그라피를 이용하여 화학식 3의 화합물 11.57g을 얻는다(수율 : 48%).Carbonyldiimidazole (13.75 g, 84 mmol) and 2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy acetic acid (18.5 g, 80 mmol) Is dissolved in DCM (150 mL) under nitrogen gas and stirred at room temperature for 1 hour. A solution of pyridine (6.1 g, 77.1 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (11 g, 84 mmol) in DCM (50 mL) was added dropwise to the mixed solution. Stir for hours. After washing with 2N HCl (2 * 50mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The concentrate is taken up in ethanol (75 mL) and heated and stirred at 70 ° C. for 3 hours. After cooling the reaction mixture is diluted with DCM (75 mL) and washed with water (3 * 50 mL). The washed organic solution is dried over MgSO 4 , filtered, and concentrated under reduced pressure. The concentrated product is obtained by column chromatography to obtain 11.57 g of a compound of formula 3 (yield: 48%).

1H NMR (CDCl3) δ 1.18(t, 3H), 2.90(s, 6H), 3.05(t, 2H), 3.41(s, 2H), 3.67(t, 2H), 4.05(q, 2H), 4.21(s, 4H), 4.53(s, 2H) 1 H NMR (CDCl 3 ) δ 1.18 (t, 3H), 2.90 (s, 6H), 3.05 (t, 2H), 3.41 (s, 2H), 3.67 (t, 2H), 4.05 (q, 2H), 4.21 (s, 4H), 4.53 (s, 2H)

실시예 3 : 2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-5-[(S)-(+)-2-메톡시-2-페닐에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘(화학식 5)의 제조 Example 3: 2- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-4- (2-chlorophenyl) Preparation of 3-Ethoxycarbonyl-5-[(S)-(+)-2-methoxy-2-phenylethoxy carbonyl-6-methyl] -1,4-dihydro pyridine (Formula 5)

에틸-4-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-3-옥소-아세테이트(12.05g, 40mmol), 2-클로로 벤즈알데하이드(4.2g, 30mmol) 그리고 화학식 4의 (S)-(+)-2-메톡시-2-페닐에틸-3-아미노 아이소크로토네이트(7.6g, 30mmol)를 에탄올(100mL)에 녹이고 2시간 동안 가열.환류한다. 반응 후, 반응 혼합물을 냉각시키고 얻어진 결정을 여과, 세척 그리고 건조시켜 화학식 5의 화합물 7.9g을 얻는다(수율 : 41%).Ethyl-4- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-3-oxo-acetate (12.05 g, 40 mmol ), 2-chloro benzaldehyde (4.2 g, 30 mmol) and (S)-(+)-2-methoxy-2-phenylethyl-3-amino isocrotonate (7.6 g, 30 mmol) Dissolve in (100 mL) and heat and reflux for 2 hours. After the reaction, the reaction mixture is cooled and the crystals obtained are filtered, washed and dried to give 7.9 g of the compound of formula 5 (yield: 41%).

1H NMR (CDCl3) δ 1.18(t, 3H), 2.30(s, 3H), 2.90(s, 6H), 3.05(t, 2H), 3.24(s, 3H), 3.67(t, 2H), 4.05(q, 2H), 4.21(s, 4H), 4.46(d, 2H), 4.72(t, 1H), 4.76(s, 2H), 5.40(s, 1H), 7.05-7.44(m, 9H) 1 H NMR (CDCl 3 ) δ 1.18 (t, 3H), 2.30 (s, 3H), 2.90 (s, 6H), 3.05 (t, 2H), 3.24 (s, 3H), 3.67 (t, 2H), 4.05 (q, 2H), 4.21 (s, 4H), 4.46 (d, 2H), 4.72 (t, 1H), 4.76 (s, 2H), 5.40 (s, 1H), 7.05-7.44 (m, 9H)

실시예 4 : 2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘(화학식 6)의 제조 Example 4: 2- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-4- (2-chlorophenyl) Preparation of 3-Ethoxycarbonyl-6-methyl] -1,4-dihydropyridine (Formula 6)

2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-5-[(S)-(+)-2-메톡시-2-페닐에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘(436mg, 0.68mmol)을 메탄올(5mL)과 다이글라임(5mL)의 혼합용매에 NaOMe(31mg)을 녹인 용액에 가하고 1시간 동안 가열.환류한다. 반응 후, 반응 혼합물을 냉각시키고 물로 희석시킨 후, DCM으로 추출한다. 추출된 유기용액을 MgSO4로 건조, 여과하고, 감압.농축한다. 농축된 생성물을 칼람크로마토그라피를 이용하여 화학식 6의 화합물 267mg을 얻는다(수율 : 75.4%).2- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-4- (2-chlorophenyl) -3- Toxycarbonyl-5-[(S)-(+)-2-methoxy-2-phenylethoxy carbonyl-6-methyl] -1,4-dihydropyridine (436 mg, 0.68 mmol) in methanol (5 mL ) And diglyme (5 mL) are added to a solution of NaOMe (31 mg) dissolved in a mixed solvent and heated and refluxed for 1 hour. After the reaction, the reaction mixture is cooled down and diluted with water and then extracted with DCM. The extracted organic solution is dried over MgSO 4 , filtered, and concentrated under reduced pressure. The concentrated product is purified by column chromatography to obtain 267 mg of the compound of formula 6 (yield: 75.4%).

1H NMR (CDCl3) δ 1.18(t, 3H), 2.30(s, 3H), 2.90(s, 6H), 3.05(t, 2H), 3.61(s, 3H), 3.67(t, 2H), 4.05(q, 2H), 4.21(s, 4H), 4.76(s, 2H), 5.40(s, 1H), 7.05-7.44(m, 4H) 1 H NMR (CDCl 3 ) δ 1.18 (t, 3H), 2.30 (s, 3H), 2.90 (s, 6H), 3.05 (t, 2H), 3.61 (s, 3H), 3.67 (t, 2H), 4.05 (q, 2H), 4.21 (s, 4H), 4.76 (s, 2H), 5.40 (s, 1H), 7.05-7.44 (m, 4H)

실시예 5 : 2-(2-아미노 에톡시메틸)-4-(2-클로로페닐)-6-메틸-1,4-다이하이드로피리딘-3,5-다이카르본산-3-에틸에스테르-5-메틸에스테르 염산염의 제조 Example 5: 2- (2-amino ethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5 Preparation of Methyl Ester Hydrochloride

2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘(5g, 9.6mmol)을 아이소프로판올(30mL)에 용해시킨 후, 무수 염산을 이소프로판올(20mL)에 용해시킨 용액에 적가하고 1시간 동안 가열.환류한다. 반응 후, 반응 혼합물을 냉각시키고 감압.농축한다. 농축된 생성물에 에틸아세테이트(50mL)를 가하고 실온에서 1시간 동안 교반한다. 이 혼합물에 물(10mL)을 가하여 실온에서 3시간 동안 교반하여 생성되는 고체를 감압.건조, 여과시킨다.2- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-4- (2-chlorophenyl) -3- Toxyl carbonyl-6-methyl] -1,4-dihydropyridine (5 g, 9.6 mmol) was dissolved in isopropanol (30 mL), and then anhydrous hydrochloric acid was added dropwise to a solution dissolved in isopropanol (20 mL) for 1 hour. Heat and reflux. After the reaction, the reaction mixture is cooled and concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the concentrated product and stirred at room temperature for 1 hour. Water (10 mL) was added to the mixture, and the resultant solid was stirred at room temperature for 3 hours, and the resulting solid was dried under reduced pressure, and filtered.

건조된 생성물을 메탄올에서 재결정, 감압.건조하여 화학식 7의 S-(-)-암로디핀 염산염 3.89g을 얻는다(수율 : 91%).The dried product was recrystallized in methanol, depressurized and dried to obtain 3.89 g of S-(-)-amlodipine hydrochloride of formula 7 (yield: 91%).

1H NMR (CDCl3) δ 1.17(t, 3H), 2.10(s, 3H), 3.50(t, 2H), 3.56(s, 3H), 3.63(t, 2H), 4.03(q, 2H), 4.63(s, 2H), 5.33(s, 1H), 7.05-7.44(m, 4H), 8.01(br s, 3H) 1 H NMR (CDCl 3 ) δ 1.17 (t, 3H), 2.10 (s, 3H), 3.50 (t, 2H), 3.56 (s, 3H), 3.63 (t, 2H), 4.03 (q, 2H), 4.63 (s, 2H), 5.33 (s, 1H), 7.05-7.44 (m, 4H), 8.01 (br s, 3H)

본 발명은 중간체나 최종 라셈화물의 분리와 아민의 보호 전구체인 아지도화물의 수소화 반응 등을 이용하지 않는 S-(-)-암로디핀 염산염(화학식 7)의 개량된 제조방법에 관한 것으로, 화학식 3을 2-클로로 벤즈알데히드와 손잡이성을 갖는 화학식 4를 반응시켜 화학식 5를 제조하고, 계속해서 화학식 6, 7을 제조하고, 이어서 S-(-)-암로디핀의 페길화를 통해 물에 대한 용해도를 높인 친수화된 프로드러그를 제공한다.The present invention relates to an improved process for the preparation of S-(-)-amlodipine hydrochloride (Formula 7), which does not utilize the separation of intermediates or final lasimides and the hydrogenation of azidodes, which are protective precursors of amines. Was prepared by reacting 2-chlorobenzaldehyde with formula (4) having handleability to prepare formula (5), followed by formulas (6) and (7), and then increasing the solubility in water through PEGylation of S-(-)-amlodipine. Provide hydrophilic prodrugs.

Claims (15)

화학식 1의 2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에탄올을 유기용매에 녹이고, 염기 존재하에 메탈 할로아세테이트와 반응시켜 화학식 2의 2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시 아세트산을 제조하는 단계 1;2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethanol of Formula 1 was dissolved in an organic solvent and reacted with a metal haloacetate in the presence of a base to Step 1 to prepare 2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy acetic acid; 화학식 2의 화합물, Im2CO(CDI, 카르보닐다이이미다졸) 와 2,2,-다이메틸-1,3-다이옥산-4,6-다이온을 유기용매에 녹이고, 유기염기 존재하에 에탄올을 가하여 화학식 3의 에틸-4-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-3-옥소-아세테이트를 제조하는 단계 2;Compound 2, Im 2 CO (CDI, carbonyldiimidazole) and 2,2, -dimethyl-1,3-dioxane-4,6-dione are dissolved in an organic solvent, and ethanol is dissolved in the presence of an organic base. Was added ethyl-4- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-3-oxo-acetate of formula (3). Manufacturing step 2; 화학식 3의 화합물과 2-클로로 벤즈알데하이드를 유기용매에 녹이고 화학식 4의 (S)-(+)-2-메톡시-2-페닐에틸-3-아미노 아이소크로토네이트를 가하여 화학식 5의 2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-5-[(S)-(+)-2-메톡시-2-페닐에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘을 제조하는 단계 3;2-chloro benzaldehyde and the compound of formula 3 were dissolved in an organic solvent, and (S)-(+)-2-methoxy-2-phenylethyl-3-amino isocrotonate of formula 4 was added to [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy] -methyl-4- (2-chlorophenyl) -3-ethoxy carbox Step 3 to prepare carbonyl-5-[(S)-(+)-2-methoxy-2-phenylethoxy carbonyl-6-methyl] -1,4-dihydro pyridine; 화학식 5의 화합물을 유기용매에 녹이고, 염기를 가하여 화학식 6의 2-[2-(1,3-다이메틸헥사하이드로-2-옥소-1,3,5-트리아진-5-일)에톡시]-메틸-4-(2-클로로페닐)-3-에톡시 카르보닐-6-메틸]-1,4-다이하이드로 피리딘을 제조하는 단계 4;The compound of formula 5 was dissolved in an organic solvent, and a base was added to the compound to give 2- [2- (1,3-dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl) ethoxy of formula 6 ] -Methyl-4- (2-chlorophenyl) -3-ethoxy carbonyl-6-methyl] -1,4-dihydro pyridine; 화학식 6의 화합물을 유기용매에 녹이고 무수 산을 가하여 화학식 7의 2-(2- 아미노 에톡시메틸)-4-(2-클로로페닐)-6-메틸-1,4-다이하이드로피리딘-3,5-다이카르본산-3-에틸에스테르-5-메틸에스테르 염산염을 제조하는 단계 5를 포함하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The compound of formula 6 was dissolved in an organic solvent, and anhydrous acid was added to the compound to give 2- (2-amino ethoxymethyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydropyridine-3, A process for preparing S-(-)-amlodipine hydrochloride of Formula 7 comprising step 5 of preparing 5-dicarboxylic acid-3-ethylester-5-methylester hydrochloride.
Figure 112006075007931-pat00007
Figure 112006075007931-pat00007
 제1항에 있어서, 단계 1에서 화학식 1의 에테르화 반응으로 에톡사이드를 만들고, 이어서 메탈할로아세테이트와 반응시켜 화학식 2의 화합물을 제조하는 것을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The S-(-)-amlodipine of Formula 7 according to claim 1, wherein the ethoxide is prepared by the etherification reaction of Formula 1 in Step 1, and then reacted with a metal haloacetate to prepare a compound of Formula 2. Method for preparing hydrochloride. 제1항 또는 제2항에 있어서, 단계 1에서 화학식 1의 에테르화 반응 온도는 0 내지 80oC 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The process for preparing S-(-)-amlodipine hydrochloride of Formula 7 according to claim 1 or 2, wherein the etherification temperature of the formula (1) in step 1 is 0 to 80 o C. 제1항 또는 제2항에 있어서, 단계 1에서 반응 용매는 THF(테트라히드로퓨란), 다이옥산의 단일 또는 혼합용매임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method of claim 1 or 2, wherein the reaction solvent in step 1 is a single or mixed solvent of THF (tetrahydrofuran), dioxane, S-(-)-amlodipine hydrochloride of the formula (7). 제1항 또는 제2항에 있어서, 단계 1에서 화학식 1의 에테르화 반응에서 사용되는 메탈 할로아세테이트는, 메탈은 K(칼륨) 또는 Na(나트륨)이고, 할로겐은 브로모 또는 클로로임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법. The metal halo acetate used in the etherification reaction of Formula 1 in step 1 is characterized in that the metal is K (potassium) or Na (sodium) and the halogen is bromo or chloro. A process for preparing S-(-)-amlodipine hydrochloride of formula (7). 제1항에 있어서, 단계 2에서 반응 온도는 20 내지 100oC 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method of claim 1, wherein the reaction temperature in step 2 is 20 to 100 ° C. A process for preparing S-(-)-amlodipine hydrochloride of formula 7 제1항에 있어서, 단계 2에서 반응 용매는 디클로로메탄, THF(테트라히드로퓨란) 또는 다이옥산 중에서 선택되는 1종 이상 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method of claim 1, wherein the reaction solvent in step 2 is at least one selected from dichloromethane, THF (tetrahydrofuran) or dioxane. 제1항에 있어서, 단계 2에서 사용되는 유기염기는 피리딘 또는 트리에틸아민임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법. The method according to claim 1, wherein the organic base used in step 2 is pyridine or triethylamine. 제1항에 있어서, 단계 3에서 화학식 3의 고리화 반응시 반응온도는 70 내지 100oC 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method for preparing S-(-)-amlodipine hydrochloride of Formula 7 according to claim 1, wherein the reaction temperature in the cyclization reaction of Chemical Formula 3 in step 3 is 70 to 100 ° C. 제1항에 있어서, 단계 3에서 화학식 3의 고리화 반응시 용매는 에탄올, 다이옥산의 단일 또는 혼합용매임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법. The method for preparing S-(-)-amlodipine hydrochloride of Formula 7 according to claim 1, wherein the solvent is a single or mixed solvent of ethanol and dioxane. 제1항에 있어서, 단계 4에서 화학식 5의 트랜스에스테르화 반응에 사용되는 염기는 NaOMe(메톡시화 나트륨) 또는 KOMe(메톡시화 칼륨) 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method of claim 1, wherein the base used in the transesterification reaction of formula (5) in step 4 is NaOMe (sodium methoxylated) or KOMe (potassium methoxylated) of S-(-)-amlodipine hydrochloride of formula 7 Manufacturing method. 제1항에 있어서, 단계 4에서 화학식 5의 트랜스에스테르화 반응에 사용되는 용매는 메탄올, 다이클라임 또는 다이옥산 중에서 선택되는 1종 이상 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The S-(-)-amlodipine hydrochloride of Formula 7 according to claim 1, wherein the solvent used in the transesterification reaction of Formula 5 in step 4 is at least one selected from methanol, diclime or dioxane. Manufacturing method. 제1항에 있어서, 단계 5에서 화학식 6의 아민의 탈보호화 반응시 반응온도는 70 내지 100oC 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method for preparing S-(-)-amlodipine hydrochloride of Formula 7 according to claim 1, wherein the reaction temperature in the deprotection reaction of the amine of formula 6 in step 5 is 70 to 100 ° C. 제1항에 있어서, 단계 5에서 화학식 6의 아민의 탈보호화 반응 용매는 에탄올 또는 이소프로판올의 단일 또는 혼합용매 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The process for preparing S-(-)-amlodipine hydrochloride of Formula 7 according to claim 1, wherein the solvent for deprotecting the amine of formula 6 in step 5 is a single or mixed solvent of ethanol or isopropanol. 제1항에 있어서, 단계 5에서 화학식 6의 아민의 탈보호화 반응에 사용되는 유기산은 무수 황산 또는 무수 염산 임을 특징으로 하는 화학식 7의 S-(-)-암로디핀 염산염의 제조방법.The method of claim 1, wherein the organic acid used in the deprotection reaction of the amine of formula (6) in step 5 is anhydrous sulfuric acid or anhydrous hydrochloric acid.
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US4798840A (en) * 1985-12-13 1989-01-17 Bayer Aktiengesellschaft Coronary-active fluorine-containing 1,4-dihydropyridines
JPH01113398A (en) * 1987-10-28 1989-05-02 Nissan Chem Ind Ltd Optically active dihydropyridine-5-phosphonic acid ester
JPH0211592A (en) * 1988-06-29 1990-01-16 Nissan Chem Ind Ltd Optically active dihydropyridinephosphonic ester
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