KR20070119276A - Process for preparing lercanidipine hydrochloride - Google Patents

Process for preparing lercanidipine hydrochloride Download PDF

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KR20070119276A
KR20070119276A KR1020060053681A KR20060053681A KR20070119276A KR 20070119276 A KR20070119276 A KR 20070119276A KR 1020060053681 A KR1020060053681 A KR 1020060053681A KR 20060053681 A KR20060053681 A KR 20060053681A KR 20070119276 A KR20070119276 A KR 20070119276A
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lercanidipine hydrochloride
dimethyl
dichloromethylmethylether
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조대진
김홍엽
이공열
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일양약품주식회사
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    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

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Abstract

A method for preparing lercanidipine hydrochloride is provided to shorten the process by using a coupling agent of a,a-dichloromethylmethylether, mass-produce the lercanidipine hydrochloride due to a shortened process, decrease of the toxic gas generation and a simple purifying step and easily remove a by-product of methyl formate through concentration under reduced pressure. A method for preparing lercanidipine hydrochloride represented by the formula(1) comprises a step of reacting 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid represented by the formula(2) with 2,N-dimethyl-N-(3,3-diphenylpropyl)-1-amino-2-propanol represented by the formula(3) in the presence of a coupling reagent of a,a-dichloromethylmethylether represented by the formula(5) and solvent such as ethylacetate, dichloromethane, methanol, N,N-dimethylformamide and 1,4-dioxane at a reaction temperature of 10-60 deg.C.

Description

염산레르카니디핀의 새로운 제조방법{Process for Preparing Lercanidipine Hydrochloride}Process for Preparing Lercanidipine Hydrochloride

본 발명은 고혈압치료제로 유용한 하기 화학식1인 염산레르카니디핀 (Lercanidipine Hydrochloride)의 새로운 제조방법에 관한 것이다. 하기 화학식 1로 표시되는 염산레르카니디핀은 하기 화학식4로 표시되는 레르카니디핀(Lercanidipine)의 염산염의 화학명으로써, 장기간에 걸쳐 활성을 나타내는 칼슘채널차단제(Calcium channel blocker)이다. The present invention relates to a novel method for preparing lercanidipine hydrochloride of Formula 1, which is useful as a therapeutic agent for hypertension. The lercanidipine hydrochloride represented by the following formula (1) is a chemical name of the hydrochloride salt of lercanidipine represented by the following formula (4), and is a calcium channel blocker that shows activity over a long period of time.

[화학식1][Formula 1]

Figure 112006041762257-PAT00005
Figure 112006041762257-PAT00005

[화학식4][Formula 4]

Figure 112006041762257-PAT00006
Figure 112006041762257-PAT00006

염산레르카니디핀 물질자체는 이미 공지되어있으며, 여러가지 제조방법들이 소개되어있다. The lercanidipine hydrochloride material itself is already known and various preparation methods have been introduced.

먼저, 미국특허 제 4705797호에는 화학식4의 레르카니디핀을 제조할 수 있는 방법이 개시되어 있는데, 이것은 하기 반응식 1과 같다.First, US Patent No. 4705797 discloses a method for preparing lercanidipine of Formula 4, which is shown in Scheme 1 below.

[반응식1][Scheme 1]

Figure 112006041762257-PAT00007
Figure 112006041762257-PAT00007

이 방법은 중간체 (3)을 합성하는 단계에서 반응시간이 매우 길고(3~4일), 중간체(2)를 합성하는 단계와 최종합성단계에서 부산물의 제거를 위해 칼럼크로마토그래피와 같은 정제 단계가 필요하므로 대규모 생산에는 적용하기 어려운 단점이 있다.This method has a very long reaction time (3-4 days) in the synthesis of the intermediate (3), and the purification step such as column chromatography for the synthesis of the intermediate (2) and removal of by-products in the final synthesis step. There is a disadvantage that it is difficult to apply to large scale production.

또한, 최종단계의 수율이 매우 낮고(약 36%) 위 공정에 의해 수득된 생성물 은 흡습성질이 있어 안정성이 떨어지는 단점이 있다.(대한민국 공개특허 특1999-008378). 그리고 대한민국 특허공고 제 99-8378호에는 하기 반응식2와 같이 개량된 제조방법이 개시되어있다.In addition, the yield of the final step is very low (about 36%) and the product obtained by the above process has a hygroscopic property has a disadvantage of poor stability (Korean Patent Laid-Open Patent No. 1999-008378). In addition, Korean Patent Publication No. 99-8378 discloses an improved manufacturing method as in Scheme 2 below.

[반응식2][Scheme 2]

Figure 112006041762257-PAT00008
Figure 112006041762257-PAT00008

이 방법은 비교적 높은 수율로 제조할 수 있는 장점이 있으나 반응공정에 사용되는 티오닐클로라이드(SOCl2)는 반응 중에 산성의 황화물 및 유독한 염산가스를 발생시킬 뿐만 아니라 생성된 아실클로라이드 중간체가 공기중의 수분에 민감하여 수율저하의 원인이 되므로 대량생산에는 적용하기 어려운 단점이 있다. 따라서, 상기에서 알 수 있듯이 기존의 방법으로서 염산레르카니디핀을 제조하는 방법에는 낮은 수율, 복잡하고 까다로운 정제공정 및 유독가스 발생 등의 여러가지 문제점이 있어왔다.This method has advantages in that it can be produced in a relatively high yield, but the thionyl chloride (SOCl 2 ) used in the reaction process not only generates acidic sulfides and toxic hydrochloric acid gases during the reaction, but also the resulting acyl chloride intermediates in the air. Because it is sensitive to the moisture of the cause of yield decreases, there is a disadvantage that is difficult to apply to mass production. Accordingly, as can be seen from the above, there have been various problems in the conventional method for preparing lercanidipine hydrochloride, such as low yield, complicated and difficult purification process, and generation of toxic gas.

이에 본 발명은 앞서 설명한 바와 같은 종래기술의 문제점을 더욱 효율적으로 해결하기 위하여 제공된 것으로써, 본 발명의 목적은 하기 화학식2인 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피 리딘-3-카르복실산과 하기 화학식 3인 2,N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로판올을 커플링시약 (coupling reagent)인 하기 화학식5인 a,a-디클로로메틸메틸에테르를 사용하여 간단한 정제과정과 선택적인 반응을 통하여 높은 수율과 생산단가를 낮출 수 있는 특징이 있는 하기 화학식1인 염산레르카니디핀의 제조방법에 관한 것이다.Accordingly, the present invention has been provided to more efficiently solve the problems of the prior art as described above, the object of the present invention is 2,6-dimethyl-5-methoxycarbonyl-4- (3- Coupling nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid with 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol of the formula Lercanidipine hydrochloride (Formula 1) is characterized by a high purification rate and low production cost through a simple purification process and selective reaction using a, a-dichloromethylmethyl ether of formula (5) as a reagent (coupling reagent) It relates to a manufacturing method of.

[화학식1][Formula 1]

Figure 112006041762257-PAT00009
Figure 112006041762257-PAT00009

[화학식2][Formula 2]

Figure 112006041762257-PAT00010
Figure 112006041762257-PAT00010

[화학식3][Formula 3]

Figure 112006041762257-PAT00011
Figure 112006041762257-PAT00011

[화학식5][Formula 5]

Figure 112006041762257-PAT00012
Figure 112006041762257-PAT00012

상기한 목적을 달성하기 위하여, 본 발명에 따른 고혈압치료제인 염산레르카니디핀의 제조방법은 개선된 커플링시약(coupling reagent)을 사용하여 염산레르카니디핀을 합성하는 방법으로써, 하기 화학식 2의 화합물인 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피 리딘-3-카르복실산과 하기 화학식 3의 화합물인 2,N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로판올을 커플링시약 (coupling reagent)인 하기 화학식5인 a,a-디클로로메틸메틸에테르와 반응하여 하기 화학식 1의 화합물인 염산레르카니디핀을 제조할 수 있다. In order to achieve the above object, a method of preparing lercanidipine hydrochloride, a therapeutic agent for hypertension according to the present invention, is a method of synthesizing lercanidipine hydrochloride using an improved coupling reagent, a compound of formula 2 Phosphorous 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid and 2, N-dimethyl-N which is a compound of formula -Herric acid hydrochloride, a compound of formula 1, by reacting-(3,3-diphenylpropyl) -1-amino-2-propanol with a, a-dichloromethylmethylether of formula 5 as a coupling reagent Canidipine can be prepared.

[화학식1][Formula 1]

Figure 112006041762257-PAT00013
Figure 112006041762257-PAT00013

[화학식2][Formula 2]

Figure 112006041762257-PAT00014
Figure 112006041762257-PAT00014

[화학식3][Formula 3]

Figure 112006041762257-PAT00015
Figure 112006041762257-PAT00015

[화학식5][Formula 5]

Figure 112006041762257-PAT00016
Figure 112006041762257-PAT00016

상기 용매가 에틸아세테이트, 디클로로메탄, 메탄올, N,N-디메틸포름아미드, 또는 1,4-디옥산으로 이루어진 군에서 선택된 용매일 수 있다.The solvent may be a solvent selected from the group consisting of ethyl acetate, dichloromethane, methanol, N, N-dimethylformamide, or 1,4-dioxane.

상기 반응에서, 반응 온도가 10 내지 60℃일 수 있다.In the reaction, the reaction temperature may be 10 to 60 ℃.

상기 화학식5인 a,a-디클로로메틸메틸에테르는 화학식2인 화합물 1몰당 0.5 내지 1.5당량 사용할 수 있다.The a, a-dichloromethylmethyl ether of Formula 5 may be used in an amount of 0.5 to 1.5 equivalents per mole of the compound of Formula 2.

이하 본 발명에 대하여 상세히 설명하면 다음과 같다. Hereinafter, the present invention will be described in detail.

본 발명의 합성에 사용되는 화학식2의 화합물인 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페 닐)-1,4-디히드로피리딘-3-카르복실산은 이미 공지된 물질(독일특허 제 284737호)이며, 또한 화학식 3의 화합물인 2,N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로판올도 이미 공지된 물질(미국특허 제 4705797호)로써, 상기 화합물인 화학식 2와 화학식 3을 새로운 형태의 커플링시약(coupling reagent)인 a,a-디클로로메틸메틸에테르(화학식5)와 반응시켜 화학식 1인 염산레르카니디핀을 합성한다. 커플링시약(coupling reagent)인 a,a-디클로로메틸메틸에테르를 사용하는 공정은 이미 알려진 공정으로, Org. Syn . Coll, vol 7, p467(1990) 및 Tetrahedron Letters, p3037(1979)과 유사한 공정에 의해 제조되었다. 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitropenyl) -1,4-dihydropyridine-3-carboxylic acid, a compound of formula 2 used in the synthesis of the present invention, is already known. 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol, which is a compound of formula 3, is also known as 4705797), wherein the compounds of formula (2) and (3) are reacted with a, a-dichloromethylmethylether (formula 5), a new type of coupling reagent, to synthesize lercanidipine hydrochloride (Formula 1). do. The process using a, a-dichloromethylmethylether, a coupling reagent, is a known process . Syn . Prepared by a process similar to Coll , vol 7, p467 (1990) and Tetrahedron Letters , p3037 (1979).

반면 화학식2와 화학식3은 커플링시약인 화학식5와 반응시켜 간단한 정제과정과 놀픈 수율의 화학식1인 염산레르카니디핀을 합성한 것은 지금까지 밝혀지지 않은 신규한 것이며, 본원 발명의 발명자들에 연구에 의해 최초로 시도되어 그 우수함을 입증한 것이라 할 수 있다.On the other hand, Chemical Formula 2 and Chemical Formula 3 reacted with Chemical Formula 5, a coupling reagent, to synthesize lercanidipine hydrochloride, which is a simple purification procedure and a surprising yield, was not known. It was the first attempt by the company to prove its excellence.

[반응식3]Scheme 3

Figure 112006041762257-PAT00017
Figure 112006041762257-PAT00017

본 발명의 방법에서는 상기 반응식 3에서 화학식 5인 a,a-디클로로 메틸메틸에테르는 화학식 2인 화합물 1몰당 0.5~1.5당량이 적당하며, 바람직하게 1당량이 최적이다.In the method of the present invention, the a, a-dichloro methylmethyl ether represented by the formula (5) in Scheme 3 is suitable 0.5 to 1.5 equivalents per mole of the compound represented by the formula (2), preferably one equivalent.

따라서 반응에 사용되는 화학식2, 화학식3, 화학식 5인 화합물들의 최적의 반응 당량비는 1: 1: 1 이다.Therefore, the optimum reaction equivalent ratio of the compounds of the formulas (2), (3) and (5) used in the reaction is 1: 1: 1.

0.5당량 이하 사용할 경우에는 반응이 수율이 낮아지고, 1.5당량 이상 사용하는 경우에는 부반응이 생성되어 전체 수율이 낮아진다If the amount is 0.5 equivalent or less, the yield is lower, and if it is used more than 1.5 equivalent, side reactions are generated and the overall yield is lowered.

또한, 용매로는 에틸아세테이트, 디클로로메탄, 메탄올, N,N-디메틸포름아미드, 1,4-디옥산으로 이루어진 군으로부터 선택되며, 바람직하게는 에틸아세테이트이다. 이때 반응온도는 10~60℃가 적당하며, 바람직하게는 25~50℃이다. Further, the solvent is selected from the group consisting of ethyl acetate, dichloromethane, methanol, N, N-dimethylformamide, 1,4-dioxane, and preferably ethyl acetate. At this time, the reaction temperature is suitable 10 ~ 60 ℃, preferably 25 ~ 50 ℃.

반응온도가 10℃ 미만인 경우에는 반응 수율이 낮아지고, 60℃를 초과한 경우에는 부반응이 형성되어 전체 수율이 낮아진다.When the reaction temperature is less than 10 ° C, the reaction yield is low, when it exceeds 60 ° C side reactions are formed, the overall yield is lowered.

본 발명의 중요한 특징은 커플링시약으로 a,a-디클로로메틸메틸에테르를 사용함으로써 종래의 합성방법에 비해 안전하고 간단한 정제과정, 짧은 반응시간으로 인해 월등히 높은 수율로 대량생산이 가능하며 반응시 생성되는 부산물인 메틸포메이트(HCOOCH3)는 끓는점이 32~33℃로 매우 낮아서 감압농축으로 쉽게 제거됨으로써 최적의 반응조건으로 화학식 1인 염산레르카니디핀을 제조할 수 있다.An important feature of the present invention is the use of a, a-dichloromethylmethylether as a coupling reagent, which is safer and simpler than conventional synthetic methods, and can be mass-produced in a very high yield due to a short reaction time. As a byproduct, methylformate (HCOOCH 3 ) has a low boiling point of 32-33 ° C., so that it can be easily removed under reduced pressure, thereby preparing lercanidipine hydrochloride (I) as an optimum reaction condition.

이하 본 발명은 하기 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by the following examples.

단 하기 실시예는 본 발명을 예시하는 것일뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

[실시예1]Example 1

1,4- 디히드로 -2,6-디메틸-4-(3- 니트로페닐 )-3,5- 피리딘디카르복실산 -2-[(3, 3-디 페닐프로 필) 메틸아미노 ]-1,1-디메틸에틸 메틸에스터 염산염 ( 염산레르 카니디핀 )의 제조. 1,4 -dihydro -2,6-dimethyl-4- (3 -nitrophenyl ) -3,5- pyridinedicarboxylic acid- 2-[(3,3- diphenylpropyl ) methylamino ] -1 , 1-dimethylethyl methyl ester hydrochloride ( leric acid hydrochloride Preparation of candipine ) .

에틸아세테이트 100ml에 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산(화학식2) 10g(29.7mmol)을 넣고 상온에서 a,a-디클로로메틸메틸에테르(화학식5) 2.69ml(29.7mmol)을 천천히 적가한 후 상온에서 30분간 교반하고 50℃에서 30분간 교반한다.10 g (29.7 mmol) of 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3-carboxylic acid (Formula 2) was added to 100 ml of ethyl acetate. 2.69ml (29.7mmol) of a, a-dichloromethylmethylether (Formula 5) was slowly added dropwise at room temperature, followed by stirring at room temperature for 30 minutes and stirring at 50 ° C for 30 minutes.

다시 상온으로 냉각 후 2,N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로판올(화학식3) 8.83g(29.7mmol)을 천천히 적가한다. 상온에서 8~10시간 교반시킨 다음, 물 50ml를 가하고 유기층을 감압농축하여 목적물인 염산레르카니디핀(화학식1) 17.92g(수율 : 93%)을 수득하였다After cooling to room temperature again, 8.83 g (29.7 mmol) of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol (Formula 3) was slowly added dropwise. After stirring at room temperature for 8-10 hours, 50 ml of water was added and the organic layer was concentrated under reduced pressure to obtain 17.92 g (yield: 93%) of lercanidipine hydrochloride (Formula 1).

1H-NMR(DMSO-d6) : d 1,47(s, 6H), 2.57(s, 3H), 2.65~3.25(m, 13H), 3.35~4.20(m, 6H), 5.10(s, 1H), 7.25~7.60(m, 10H), 7.67~7.88(m, 2H), 8.10~8.35(m, 2H), 9.50(bs, 1H), 9.55~10.85(bb, 1H) 1 H-NMR (DMSO-d 6 ): d 1,47 (s, 6H), 2.57 (s, 3H), 2.65 ~ 3.25 (m, 13H), 3.35 ~ 4.20 (m, 6H), 5.10 (s, 1H), 7.25-7.70 (m, 10H), 7.67-7.88 (m, 2H), 8.10-8.35 (m, 2H), 9.50 (bs, 1H), 9.55-10.85 (bb, 1H)

융점 : 186~189℃Melting Point: 186 ~ 189 ℃

본 발명에 따른 염산레르카니디핀의 제조방법은 커플링시약인 a,a-디클로로메틸메틸에테르를 사용하여 합성하므로 공정이 단축되고 합성공정상의 유독가스 발생의 감소 및 간단한 정제과정으로 인하여 높은수율로 대량생산이 가능하며 반응시 생성되는 부산물인 메틸포메이트(HCOOCH3)는 끓는점이 32~33℃로 매우 낮아서 감압 농축으로 쉽게 제거됨으로써 최적의 반응조건으로 염산레르카니디핀을 제조할 수 있다. The method for preparing lercanidipine hydrochloride according to the present invention is synthesized using a coupling reagent, a, a-dichloromethylmethyl ether, which shortens the process and reduces the generation of toxic gases in the synthesis process and results in high yield. Methyl formate (HCOOCH3), which is a by-product produced during the reaction, can be mass-produced, and its boiling point is very low at 32-33 ° C., so that it can be easily removed by concentration under reduced pressure, thereby producing lercanidipine hydrochloride as an optimal reaction condition.

Claims (4)

고혈압치료제인 염산레르카니디핀의 제조에 있어서, 하기 반응식3과 같이 하기 화학식2의 화합물인 2,6-디메틸-5-메톡시카르보닐-4-(3-니트로페닐)-1,4-디히드로피리딘-3-카르복실산과 하기 화학식3의 화합물인 2,N-디메틸-N-(3,3-디페닐프로필)-1-아미노-2-프로판올을 커플링 시약인 하기 화학식5의 화합물인 a,a-디클로로메틸메틸에테르와 용매 중에서 반응시켜 하기 화학식1의 화합물을 제조하는 것을 특징으로 하는 고혈압치료제인 염산레르카니디핀의 제조방법. In the preparation of lercanidipine hydrochloride, a therapeutic agent for hypertension, 2,6-dimethyl-5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-di which is a compound represented by the following formula (2) Hydropyridine-3-carboxylic acid and 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol, which are compounds of Formula 3, are compounds of Formula 5 A method for preparing lercanidipine hydrochloride, which is a hypertension therapeutic agent, by reacting a, a-dichloromethylmethylether in a solvent to produce a compound of formula (1). [화학식1][Formula 1]
Figure 112006041762257-PAT00018
Figure 112006041762257-PAT00018
 [화학식2][Formula 2]
Figure 112006041762257-PAT00019
Figure 112006041762257-PAT00019
 [화학식3][Formula 3]
Figure 112006041762257-PAT00020
Figure 112006041762257-PAT00020
 [화학식5][Formula 5]
Figure 112006041762257-PAT00021
Figure 112006041762257-PAT00021
 [반응식3]Scheme 3
Figure 112006041762257-PAT00022
Figure 112006041762257-PAT00022
 제1항에 있어서, The method of claim 1, 상기 용매가 에틸아세테이트, 디클로로메탄, 메탄올, N,N-디메틸포름아미드, 또는 1,4-디옥산으로 이루어진 군에서 선택된 용매를 사용하는 것을 특징으로 하는 고혈압치료제인 염산레르카니디핀의 제조방법. The solvent is a method of producing lercanidipine hydrochloride therapeutic agent, characterized in that using a solvent selected from the group consisting of ethyl acetate, dichloromethane, methanol, N, N- dimethylformamide, or 1,4-dioxane. 제 1항에 있어서,The method of claim 1, 상기 반응시 반응 온도가 10 내지 60℃인 것을 특징으로 하는 고혈압치료제 인 염산레르카니디핀의 제조방법. Method of producing lercanidipine hydrochloride is a hypertension, characterized in that the reaction temperature is 10 to 60 ℃ during the reaction. 제 1항에 있어서, 상기 화학식5인 a,a-디클로로메틸메틸에테르가 화학식2인 화합물 1몰당 0.5 내지 1.5 당량 사용되는 것을 특징으로 하는 고혈압치료제인 염산레르카니디핀의 제조방법. The method of claim 1, wherein 0.5 to 1.5 equivalents of a, a-dichloromethylmethylether of Formula 5 is used per mole of the compound of Formula 2.
KR1020060053681A 2006-06-15 2006-06-15 Process for preparing lercanidipine hydrochloride KR20070119276A (en)

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