KR102004422B1 - A preparation method of bosentan monohydrate, novel intermediate useful for the preparation of bosentan monohydrate, and the preparation method thereof - Google Patents
A preparation method of bosentan monohydrate, novel intermediate useful for the preparation of bosentan monohydrate, and the preparation method thereof Download PDFInfo
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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
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Abstract
본 발명은 보센탄 일수화물의 제조방법, 이에 사용되는 신규 중간체 화합물 및 이의 제조방법을 제공한다.
본 발명의 신규 중간체 화합물은 고수율 및 고순도로 제조되며, 이를 이용하여 고순도의 보센탄 일수화물을 고수율로 경제적으로 대량생산할 수 있다. The present invention provides a process for preparing bosentan monohydrate, a novel intermediate compound used therefor and a process for producing the same.
The novel intermediate compound of the present invention is produced at a high yield and a high purity, and can be economically mass produced in high yield at a high yield using high purity bosentan monohydrate.
Description
본 발명은 보센탄 일수화물의 제조방법, 이에 사용되는 신규 중간체 및 이의 제조방법에 관한 것이다.The present invention relates to a process for producing boscanner monohydrate, novel intermediates used therefor and a process for producing the same.
하기 [화학식 1]로 표시되는 보센탄은 엔도쎄린(endothelin) 저해 활성을 가짐으로써 고혈압, 허혈, 혈관경련 및 협심증과 같은 심혈관 질환의 치료에 유용한 설폰아미드계 화합물이다.Bosentan, represented by the following formula (1), is a sulfonamide compound useful for the treatment of cardiovascular diseases such as hypertension, ischemia, vasospasm and angina pectoris by having endothelin inhibitory activity.
[화학식 1][Chemical Formula 1]
특히, 약 3 ~ 5%의 수분함량을 가지는 보센탄 일수화물은 악텔리온 파마슈티컬즈(Actelion Pharmaceuticals)에 의해 상품명 Tracleer®판매되고 있다.In particular, the bosentan monohydrate with a moisture content of about 3 to 5% is sold under the trade name Tracleer ® by Actelion Pharmaceuticals.
상기 보센탄은 미국등록특허 제5,292,740호에서 처음으로 개시되었다. 미국등록특허 제5,292,740호는 하기 [반응식 1]에 나타낸 바와 같이, 1) 화합물 2의 4,6-디클로로비피리미딘 화합물에 화합물 3의 설폰아미드 칼륨염을 반응시켜 화합물 4의 모노클로로 화합물을 만들고, 2) 화합물 4의 모노클로로 화합물을 에틸렌글리콜 및 나트륨으로 반응시켜 화합물 6의 보센탄을 제조하는 방법을 개시하였다. The bosentan was first disclosed in U.S. Patent No. 5,292,740. U.S. Patent No. 5,292,740 discloses a process for preparing a compound of formula (I) as shown in
[반응식 1][Reaction Scheme 1]
그러나, 상기 [반응식 1]의 반응에서 2분자의 화합물 4의 모노클로로 화합물이 1분자의 에틸렌글리콜과 커플링함으로써 하기 [화학식 2]의 2량체 불순물들 (dimeric impurities)과 같은 원치 않는 불순물이 생성되며, 이로 인하여 최종 수득되는 보센탄의 순도가 낮아지는 문제점이 발생한다. 이들 불순물들의 양을 낮추기 위해서는 다단계의 결정화와 정제방법이 요구되며, 정제시 수율이 낮아지는 문제점이 존재한다.However, in the reaction of the
[화학식 2](2)
또한, 상기 [반응식 1]의 반응은 나트륨을 사용하는 것을 특징으로 한다. 그러나, 나트륨은 수분과 접촉시 폭발위험이 있어 산업적으로 사용하기 어려운 제약이 있다. The reaction of [Reaction Scheme 1] is characterized in that sodium is used. However, there is a risk that sodium is explosive in contact with moisture and is difficult to use industrially.
한편, 미국등록특허 제6,136,971호는 불순물 생성을 방지하기 위하여 하기 [반응식 2]와 같이 한쪽 수산화기가 보호된 화합물 9을 사용하여 순도가 높은 보센탄 일수화물 1을 합성하는 방법을 개시하고 있다. On the other hand, US Patent No. 6,136,971 discloses a method for synthesizing
[반응식 2][Reaction Scheme 2]
상기 [반응식 2]의 제조방법은 치환된 피리미딘 모노할라이드 유도체를 에틸렌글리콜 모노 t-부틸에테르와 수산화나트륨 존재 하에서 톨루엔 중에서 반응시켜 t-부틸 에테르 유도체를 얻고, 이를 포름산을 사용하여 톨루엔 중에서 탈보호화하여 2-(포르밀옥시)에톡시 유도체를 얻는 것을 포함한다. 최종적으로, 수성 수산화나트륨을 사용하여 상기 포르밀 기를 제거함으로써 보센탄 일수화물을 얻는다.In the above process, the substituted pyrimidine monohalide derivative is reacted with toluene in the presence of ethylene glycol mono-t-butyl ether in the presence of sodium hydroxide to obtain a t-butyl ether derivative, which is then deprotected in toluene using formic acid To obtain a 2- (formyloxy) ethoxy derivative. Finally, the aqueous formic acid sodium hydroxide is used to remove the formyl group to obtain the boscentine monohydrate.
그러나, 상기 제조방법은 에틸렌글리콜의 보호화 단계 및 탈보호화 단계를 거쳐야 하며, 이로 인하여 추가적인 노동력, 시간, 비용을 발생시키는 문제점이 존재한다. 따라서, 상기 제조방법은 산업스케일로는 적절하지 못하다.However, the above-mentioned preparation method requires a step of protecting and degreasing ethylene glycol, which causes additional labor, time, and cost. Therefore, the above manufacturing method is not suitable for an industrial scale.
보센탄 일수화물을 제조하는 또 다른 문헌인 국제공개특허 WO 2009-083739호을 살펴보면, 하기 [반응식 3]과 같이, 모노클로로 화합물 8에 에틸렌글리콜과 수산화바륨을 사용하여 보센탄 바륨염을 제조하고, 묽은 염산으로 산처리해 보센탄 바륨염을 제거하고 보센탄 일수화물을 제조하는 방법이 개시되어 있다. 상기 특허문헌에는 강염기인 수산화나트륨 대신에 약염기인 수산화바륨을 사용함으로써 원하지 않는 불순물의 생성을 줄일 수 있어 최종 보센탄의 순도를 향상시킬 수 있다고 기재되어 있다. As disclosed in International Patent Publication No. WO 2009-083739, which is another reference for producing boscentan monohydrate, the bosentan barium salt is prepared by using ethylene glycol and barium hydroxide in the
[반응식 3][Reaction Scheme 3]
그러나, 상기 [반응식 3]의 제조방법은 고가인 수산화바륨을 사용하고 있어 고비용이 요구되어 산업스케일로는 부적합하고, 바륨염 형태만으로 보센탄을 고순도로 얻기에는 무리가 있다.However, the production method of [Reaction Scheme 3] requires expensive barium hydroxide because it is expensive and is not suitable for industrial scale, and it is difficult to obtain bosentan with high purity only in barium salt form.
따라서, 복잡한 공정 없이 경제적으로 고순도의 보센탄을 고수율로 제조할 수 있는 개선된 제조방법의 필요성이 대두되고 있다.Therefore, there is a need for an improved manufacturing method which can economically produce high purity bosentan at a high yield without a complicated process.
본 발명의 목적은 고순도의 보센탄 일수화물을 고수율 및 경제적으로 대량생산할 수 있는 제조방법을 제공하는데 있다. It is an object of the present invention to provide a production method capable of mass-producing high purity bosentan monohydrate in high yield and economical.
본 발명의 다른 목적은 보센탄 일수화물을 고수율 및 고순도로 제조하는데 유용한 벤젠설폰아미드 나트륨염 이수화물 중간체 화합물 및 그 제조방법을 제공하는데 있다.Another object of the present invention is to provide a benzenesulfonamide sodium salt dihydrate intermediate compound useful for producing bosentan monohydrate in high yield and high purity and a process for preparing the same.
보센탄Boscentan 일수화물의Monohydrate 제조방법 Manufacturing method
본 발명은 보센탄 일수화물의 제조방법을 제공한다.The present invention provides a process for producing boscanner monohydrate.
본 발명에 따른 보센탄 일수화물의 제조방법은 1) 하기 [반응식 I]에 의하여, 유기용매에서 제1염기 존재 하에 4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘과 4-(tert-부틸)벤젠설폰아미드을 반응시켜, 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 알칼리 금속염을 제조하는 제1단계;The process for the preparation of boscentan monohydrate according to the present invention comprises the steps of: 1) reacting 4,6-dichloro-5- (2-methoxyphenoxy) -2,2 '- bipyridinium limiter Dean and 4- (tert- butyl) benzene sulfonamide by reaction ahmideueul, 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2, 2' - bipyrimidin) -4-yl] benzenesulfonamide alkali metal salt;
[반응식 I][Reaction Scheme I]
{상기 M은 리튬, 나트륨, 칼륨이다}{M is lithium, sodium, potassium}
2) 하기 [반응식 II]에 의하여, 유기용매에서 제2염기 존재 하에 제1단계에서 제조된 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 알칼리 금속염을 에틸렌글리콜과 반응시켜 조(crude)-보센탄을 제조한 후, 산을 가하여 보센탄 산부가염을 제조하는 제2단계; 및2) by the [Reaction Scheme II], prepared in the first step under the second presence of a base in an organic solvent 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyrimidin) -4-yl] benzenesulfonamide was reacted with ethylene glycol to prepare crude-butocene, and then acid was added thereto to prepare a bis step; And
[반응식 II][Reaction Scheme II]
3) 하기 [반응식 III]에 의하여, 제2단계에서 제조된 보센탄 산부가염을 수용성 용매에서 보센탄 일수화물로 전환하는 제3단계;3) a third step of converting the bis-pentanoic acid addition salt prepared in the second step into a boscentan monohydrate in a water-soluble solvent according to the following Reaction Scheme III;
[반응식 III][Reaction Scheme III]
를 포함할 수 있다.. ≪ / RTI >
본 발명에 따른 보센탄 일수화물의 제조방법에 사용되는 상기 유기용매는 디메틸설폭시드, 테트라하이드로퓨란, 아세토니트릴, 디메틸포름아미드, 디메틸아세트아미드, 자일렌, 톨루엔, 1,4-디옥산 및 이들의 혼합용매로 이루어진 군으로부터 선택될 수 있으며, 바람직하게는 디메틸설폭시드를 사용할 수 있다. The organic solvent used in the method for preparing the boscanner monohydrate according to the present invention may be selected from dimethylsulfoxide, , And dimethyl sulfoxide may be preferably used.
본 발명에 따른 보센탄 일수화물의 제조방법의 제1단계에서 사용되는 상기 제1염기는 수산화리튬, 수산화나트륨, 수산화칼륨, 탄산리튬, 탄산나트륨 및 탄산칼륨로 이루어진 군으로부터 선택될 수 있으며, 바람직하게는 탄산나트륨를 사용할 수 있다. The first base used in the first step of the method for producing the bentene monohydrate according to the present invention may be selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate, May be sodium carbonate.
또한, 상기 제1단계의 반응은 60 내지 120℃에서 2 내지 10시간 동안 수행될 수 있다.Also, the reaction of the first step may be performed at 60 to 120 ° C for 2 to 10 hours.
본 발명에 따른 제1단계에서 제조되는 상기 알칼리 금속염은 이수화물일 수 있으며, 바람직하게는 하기 [화학식 I] 구조의 나트륨염 이수화물일 수 있다. The alkali metal salt prepared in the first step according to the present invention may be a dihydrate, and preferably it may be a sodium salt dihydrate having a structure of the following formula (I).
[화학식 I](I)
본 발명에 따른 상기 알칼리 금속염 이수화물은 제1단계의 반응 후 정제수를 가하여 얻어질 수 있다. The alkali metal salt dihydrate according to the present invention can be obtained by adding purified water after the reaction of the first step.
본 발명에 따른 보센탄 일수화물의 제조방법의 제2단계에서 사용되는 상기 제2염기는 수산화리튬, 수산화나트륨 및 수산화칼륨로 이루어진 군으로부터 선택될 수 있으며, 바람직하게는 수산화나트륨를 사용할 수 있다. 따라서, 본 발명에서는 제2 염기로서 종래기술과 달리 나트륨을 사용하지 않으므로 폭발위험을 해소할 수 있다.The second base used in the second step of the method for producing boscanner monohydrate according to the present invention may be selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide. Therefore, in the present invention, since sodium is not used as the second base unlike the prior art, the risk of explosion can be solved.
또한, 상기 제2단계에서 조(crude)-보센탄 제조는 40 내지 80℃에서 2 내지 8시간 동안 수행되는 것이 바람직하다. 상기 반응은 고온에서 진행되지 않으므로 부반응에 의한 불순물 생성을 줄일 수 있다.In addition, in the second step, the preparation of crude-butocene is preferably carried out at 40 to 80 ° C for 2 to 8 hours. Since the reaction does not proceed at a high temperature, the generation of impurities due to side reactions can be reduced.
본 발명에 따른 제2단계에서 제조되는 보센탄 산부가염은 안정한 고체상(결정형 또는 무정형)으로 분리되어 정제에 유용하며, 제2단계에서 사용되는 상기 산(acid)은 pKa가 3 미만인 경우 보센탄 산부가염을 고수율 및 고순도로 제조할 수 있다. The acid of the bosentanic acid salt prepared in the second step according to the present invention is separated into a stable solid (crystalline or amorphous) and is useful for purification. When the pKa of the acid used in the second step is less than 3, The salt can be produced in high yield and high purity.
따라서, 상기 제2단계에서 사용되는 산은 염산(hydrochloric acid), 브롬화수소(hydrobromic acid), 메탄설폰산(methane sulfonic acid), 벤젠설폰산(benzenesulfonic acid), 황산(sulfuric acid), p-톨루엔설폰산(p-toluenesulfonic acid), 옥살산(oxalic acid) 및 말레산(maleic acid)으로 이루어진 군으로부터 선택될 수 있다.Accordingly, the acid used in the second step may be selected from the group consisting of hydrochloric acid, hydrobromic acid, methane sulfonic acid, benzenesulfonic acid, sulfuric acid, p -toluenesulfonic acid, P- toluenesulfonic acid, oxalic acid, and maleic acid.
또한, 본 발명에 따른 보센탄 산부가염은 p-톨루엔설폰산(p-toluenesulfonic acid)을 가하여 제조된 하기 [화학식 II] 구조의 보센탄 p-톨루엔설폰산염인 것이 가장 바람직하다.Further, the beam ambrisentan acid addition salts according to the invention are p-toluene sulfonate is most preferred that the-toluenesulfonic acid (p -toluenesulfonic acid) and the mixture to the prepared [formula II] of the structural beam ambrisentan p.
[화학식 II]≪ RTI ID = 0.0 &
제3단계에서 사용되는 상기 수용성 용매는 물, 아세톤, 알코올 또는 이들의 혼합물을 사용할 수 있으며, 상기 알코올은 C1 ~ C4알코올이 바람직하다.The water-soluble solvent used in the third step may be water, acetone, alcohol or a mixture thereof, and the alcohol is preferably a C1-C4 alcohol.
본 발명의 제조방법에 따라 제조된 보센탄 일수화물은 간단한 제조공정을 통하여 고수율 및 고순도로 제조되므로, 본 발명의 제조방법은 보센탄 일수화물 제조에 매우 적합하다.Since the boscanner monohydrate produced according to the process of the present invention is produced at a high yield and a high purity through a simple production process, the production process of the present invention is suitable for producing boscanner monohydrate.
보센탄Boscentan 일수화물Monohydrate 제조에 유용한 신규 중간체 화합물 A novel intermediate compound
본 발명은 보세탄 일수화물 제조에 유용하게 사용되는 하기 [화학식 I] 구조의 벤젠설폰아미드 나트륨염 이수화물을 제공한다.The present invention provides a benzenesulfonamide sodium salt dihydrate of the following structural formula (I) useful for the preparation of bonded tent monohydrate.
[화학식 I](I)
상기 벤젠설폰아미드 나트륨염 이수화물 화합물은 신규한 화합물로서, 간단한 제조공정을 통하여 고수율 및 고순도로 제조될 수 있다. 또한, 고순도로 제조된 벤젠설폰아미드 나트륨염 이수화물 중간체를 후속단계의 반응물질로 사용함으로써 보센탄 산부가염 및 보센탄 일수화물을 간단한 제조공정을 통하여 고순도 및 고수율로 제조할 수 있다. The benzenesulfonamide sodium salt dihydrate compound is a novel compound and can be prepared in high yield and high purity through a simple production process. In addition, by using a benzenesulfonamide sodium salt dihydrate intermediate prepared in high purity as a reaction material in a subsequent stage, the bosentanic acid addition salt and the bosentan monohydrate can be produced at a high purity and a high yield through a simple production process.
신규 중간체의 제조방법Method for producing novel intermediates
본 발명은 보센탄 일수화물 제조에 유용하게 사용되는 벤젠설폰아미드 나트륨염 이수화물의 제조방법을 제공한다. The present invention provides a process for preparing a benzenesulfonamide sodium salt dihydrate useful for the preparation of boscentanel monohydrate.
상기 벤젠설폰아미드 나트륨염 이수화물은 하기 [반응식 I-1]에 의하여, 유기용매에서 염기 존재 하에 4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘과 4-(tert-부틸)벤젠설폰아미드를 반응시키고 정제수를 가함으로써 제조될 수 있다.The benzenesulfonamide sodium salt dihydrate is reacted with 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine With 4- (tert-butyl) benzenesulfonamide and adding purified water.
[반응식 I-1] [Reaction Scheme I-1]
상기 반응식 [I-1]에서 사용되는 유기용매는 디메틸설폭시드, 테트라하이드로퓨란, 아세토니트릴, 디메틸포름아미드, 디메틸아세트아미드, 자일렌, 톨루엔, 1,4-디옥산 및 이들의 혼합용매로 이루어진 군으로부터 선택될 수 있으며, 상기 염기는 수산화나트륨 또는 탄산나트륨이 사용될 수 있다.The organic solvent used in the above reaction formula [I-1] is preferably an organic solvent selected from the group consisting of dimethylsulfoxide, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, xylene, toluene, , And the base may be sodium hydroxide or sodium carbonate.
또한, 상기 [반응식 I-1]의 반응은 60 내지 120℃에서 2 내지 10시간 동안 수행되는 것이 바람직하다.The reaction of [Scheme I-1] is preferably carried out at 60 to 120 ° C for 2 to 10 hours.
상기 반응을 통하여 제조된 벤젠설폰아미드 나트륨염 이수화물은 고수율 및 고순도로 제조될 수 있다.The benzenesulfonamide sodium salt dihydrate prepared through the above reaction can be produced with high yield and high purity.
본 발명의 제조방법은 고순도의 보센탄 일수화물을 고수율로 경제적으로 대량생산할 수 있는 작용효과를 나타낸다.The production method of the present invention exhibits an action effect of economically mass-producing high-purity bosentan monohydrate at a high yield.
또한, 본 발명의 벤젠설폰아미드 나트륨염 이수화물 중간체는 고수율 및 고순도로 쉽게 제조되어 보센탄 일수화물을 고수율 및 고순도로 제조할 수 있는 작용효과를 나타낸다.In addition, the benzenesulfonamide sodium salt dihydrate intermediate of the present invention can be easily produced at a high yield and at a high purity, and exhibits the action and effect of producing boscanner monohydrate with high yield and high purity.
도 1은 실시예 1 에서 얻어진 벤젠설폰아미드 나트륨염 이수화물의 DSC 그래프이다.
도 2는 실시예 1 에서 얻어진 벤젠설폰아미드 나트륨염 이수화물의 MS 그래프이다.1 is a DSC graph of the benzenesulfonamide sodium salt dihydrate obtained in Example 1. Fig.
2 is a MS graph of the benzenesulfonamide sodium salt dihydrate obtained in Example 1. Fig.
이하에서는 본 발명을 다음 실시예에 의하여 더욱 상세히 설명하겠으나, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by way of the following examples, but the present invention is not limited thereto.
실시예Example 1 내지 5 : 1 to 5: 벤젠설폰아미드Benzenesulfonamide 알칼리 금속염의 제조 Preparation of alkali metal salts
실시예Example 1: One: 벤젠설폰아미드Benzenesulfonamide 나트륨염 이수화물의 제조 Preparation of sodium salt dihydrate
4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘 43.2 g, 디메틸설폭 시드 204 mL, 4-(tert-부틸)벤젠설폰아미드 30.8 g, 탄산나트륨 24.4 g을 반응기에 투입하였다. 70~80℃로 10시간 동안 교반하였다. 상온으로 냉각하고 정제수 344 mL를 적가하였다. 30분 동안 교반한 후 여과하였다. 정제수 172 mL, 에틸아세테이트 172 mL로 연속 세척하였다. 50~60℃에서 진공 건조시켜 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 68.8 g (95.0%)을 얻었다.43.2 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 204 mL of dimethylsulfoxide, 30.8 g of 4- (tert- butyl) benzenesulfonamide, 24.4 g Were introduced into the reactor. And the mixture was stirred at 70 to 80 ° C for 10 hours. The mixture was cooled to room temperature and 344 mL of purified water was added dropwise. The mixture was stirred for 30 minutes and then filtered. 172 mL of purified water, and 172 mL of ethyl acetate. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 68.8 g (95.0%) of a sulfonamide sodium salt dihydrate was obtained.
1H NMR (400 MHz, DMSO-d6): δ 1.22 (s, 9H), 3.79 (s, 3H), 6.41~6.43 (d, 1H), 6.75~6.78 (t, 1H), 6.95~6.99 (t, 1H), 7.05~7.07 (d, 1H), 7.27~7.30 (d, 2H), 7.60~7.63 (t, 1H), 7.68~7.70 (d, 2H), 8.95~8.96 (d, 2H) 1 H NMR (400 MHz, DMSO -d 6): δ 1.22 (s, 9H), 3.79 (s, 3H), 6.41 ~ 6.43 (d, 1H), 6.75 ~ 6.78 (t, 1H), 6.95 ~ 6.99 ( 2H), 7.60-7.63 (t, 1H), 7.68-7.70 (d, 2H), 8.95-8.96 (d, 2H)
MS(EI) m/z 548 [M+Na]+ MS (EI) m / z 548 [M + Na] < + &
순도(HPLC): 99.90% Purity (HPLC): 99.90%
수분(칼피셔법): 7.1%Moisture (Karl Fischer method): 7.1%
또한, 상기 화합물의 DSC 측정 결과, 도 1에 나타난 바와 같이, 물 탈리 온도는 116.56℃이며, 녹는점은 233.41℃로 측정되었다.As a result of DSC measurement of the above compound, as shown in Fig. 1, the water desorption temperature was 116.56 占 폚, and the melting point was 233.41 占 폚.
실시예Example 2: 2: 벤젠설폰아미드Benzenesulfonamide 나트륨염 이수화물의 제조 Preparation of sodium salt dihydrate
4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘 20.0 g, 디메틸포름아미드 65 mL, 4-(tert-부틸)벤젠설폰아미드 15.4 g, 수산화나트륨 7.0 g을 반응기에 투입하였다. 90~100℃로 6시간 동안 교반하였다. 상온으로 냉각하고 정제수 200 mL를 적가하였다. 30분 동안 교반한 후 여과하였다. 정제수 43 mL, 에틸아세테이트 43 mL로 연속 세척하였다. 50~60℃에서 진공 건조시켜 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 23.7 g (70.8%)을 얻었다.20.0 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 65 mL of dimethylformamide, 15.4 g of 4- (tert- butyl) benzenesulfonamide, g was added to the reactor. The mixture was stirred at 90 to 100 DEG C for 6 hours. The solution was cooled to room temperature and 200 mL of purified water was added dropwise. The mixture was stirred for 30 minutes and then filtered. And successively washed with 43 mL of purified water and 43 mL of ethyl acetate. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 23.7 g (70.8%) of a sulfonamide sodium salt dihydrate was obtained.
순도(HPLC): 99.87%Purity (HPLC): 99.87%
수분(칼피셔법): 6.9%Water (Karl Fischer method): 6.9%
1H NMR, MS, DSC 측정결과는 실시예 1과 동일함. The results of 1 H NMR, MS and DSC measurements are the same as in Example 1.
실시예Example 3: 3: 벤젠설폰아미드Benzenesulfonamide 나트륨염 이수화물의 제조 Preparation of sodium salt dihydrate
4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘 5.0 g, 디메틸포름아미드 10 mL, 4-(tert-부틸)벤젠설폰아미드 3.7 g, 탄산나트륨 2.0 g을 반응기에 투입하였다. 90~100℃로 5시간 동안 교반하였다. 상온으로 냉각하고 정제수 45 mL를 적가하였다. 30분 동안 교반한 후 여과하였다. 정제수 43 mL, 에틸아세테이트 43 mL로 연속 세척하였다. 50~60℃에서 진공 건조시켜 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 6.7 g (80.1%)을 얻었다.5.0 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 10 mL of dimethylformamide, 3.7 g of 4- (tert- butyl) benzenesulfonamide, 2.0 g Were introduced into the reactor. And the mixture was stirred at 90 to 100 DEG C for 5 hours. The mixture was cooled to room temperature and 45 mL of purified water was added dropwise. The mixture was stirred for 30 minutes and then filtered. And successively washed with 43 mL of purified water and 43 mL of ethyl acetate. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 6.7 g (80.1%) of a sulfonamide sodium salt dihydrate was obtained.
순도(HPLC): 99.72% Purity (HPLC): 99.72%
수분(칼피셔법): 7.1%Moisture (Karl Fischer method): 7.1%
1H NMR, MS, DSC 측정결과는 실시예 1과 동일함. The results of 1 H NMR, MS and DSC measurements are the same as in Example 1.
실시예Example 4: 4: 벤젠설폰아미드Benzenesulfonamide 나트륨염 이수화물의 제조 Preparation of sodium salt dihydrate
4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘 20.0 g, 자일렌 195 mL, 4-(tert-부틸)벤젠설폰아미드 15.4 g, 수산화나트륨 7.0 g을 반응기에 투입하였다. 90~100℃로 6시간 동안 교반하였다. 상온으로 냉각해 30분 동안 교반한 후 여과하였다. 에틸아세테이트 43 mL, 정제수 43 mL 로 연속 세척하였다. 여과한 고체를 정제수 150 mL에서 1시간 동안 교반한 후, 여과하고 정제수와 에틸아세테이트로 연속 세척하였다. 50~60℃에서 진공 건조시켜 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 26.0 g (77.7%)을 얻었다.20.0 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 195 mL of xylene, 15.4 g of 4- (tert- butyl) benzenesulfonamide, 7.0 g Were introduced into the reactor. The mixture was stirred at 90 to 100 DEG C for 6 hours. The mixture was cooled to room temperature, stirred for 30 minutes, and then filtered. Ethyl acetate (43 mL), and purified water (43 mL). The filtered solid was stirred in 150 mL of purified water for 1 hour, then filtered and washed successively with purified water and ethyl acetate. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 26.0 g (77.7%) of a sulfonamide sodium salt dihydrate was obtained.
순도(HPLC): 99.57% Purity (HPLC): 99.57%
수분(칼피셔법): 6.7%Moisture (Karl Fischer method): 6.7%
1H NMR, MS, DSC 측정결과는 실시예 1과 동일함. The results of 1 H NMR, MS and DSC measurements are the same as in Example 1.
실시예Example 5: 5: 벤젠설폰아미드Benzenesulfonamide 칼륨염의 제조 Manufacture of potassium salts
4,6-디클로로-5-(2-메톡시페녹시)-2,2'-비피리미딘 12.5 g, 톨루엔 180 mL, 4-(tert-부틸)벤젠설폰아미드 9.0 g, 탄산칼륨 11.0 g, 테트라부틸암모늄 브로마이드 2.6 g을 반응기에 투입하였다. 반응용액을 환류하면서10시간 동안 교반하였다. 상온으로 냉각하고 여과하였다. 톨루엔 73 mL로 세척하였다. 여과한 고체를 정제수 200 mL에서 1시간 동안 교반한 후, 여과하고 정제수와 아세토니트릴로 연속 세척하였다. 50~60℃에서 진공 건조시켜 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 칼륨염 17.7 g (87.7%)을 얻었다.12.5 g of 4,6-dichloro-5- (2-methoxyphenoxy) -2,2'-bipyrimidine, 180 mL of toluene, 9.0 g of 4- (tert- butyl) benzenesulfonamide, 2.6 g of tetrabutylammonium bromide was charged into the reactor. The reaction solution was stirred for 10 hours while refluxing. Cooled to room temperature and filtered. And washed with 73 mL of toluene. The filtered solid was stirred at 200 mL of purified water for 1 hour, filtered, and washed successively with purified water and acetonitrile. Vacuum drying at 50 ~ 60 ℃ 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) -4-yl] benzene 17.7 g (87.7%) of potassium salt of sulfonamide was obtained.
1H NMR (400 MHz, DMSO-d6): δ 1.21 (s, 9H), 3.83 (s, 3H), 6.43~6.45 (d, 1H), 6.77~6.81 (t, 1H), 6.95~6.99 (t, 1H), 7.07~7.09 (d, 1H), 7.26~7.29 (d, 2H), 7.59~7.61 (t, 1H), 7.80~7.83 (d, 2H), 8.98~8.99 (d, 2H) 1 H NMR (400 MHz, DMSO -d 6): δ 1.21 (s, 9H), 3.83 (s, 3H), 6.43 ~ 6.45 (d, 1H), 6.77 ~ 6.81 (t, 1H), 6.95 ~ 6.99 ( 2H), 7.59-7.61 (t, 1H), 7.80-7.83 (d, 2H), 8.98-8.99 (d, 2H)
순도(HPLC): 98.57% Purity (HPLC): 98.57%
실시예Example 6 내지 10 : 6 to 10: 보센탄Boscentan 산부가염의Acidophilic 제조 Produce
실시예Example 6 : 6: 보센탄Boscentan pp -- 톨루엔설폰산염의Of toluene sulfonate 제조 Produce
수산화나트륨 5.1 g, 에틸렌글리콜 80 mL를 반응기에 투입하고 45~50℃ 에서 30분 동안 교반한다. 실시예 1에서 얻은 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 15.0 g과 디메틸설폭시드 34 mL를 투입하고 40~50℃에서 4시간 동안 교반하였다. 20~25℃로 냉각하고 디메틸클로라이드 86 mL, 묽은 염산 86 mL (35% 염산 9 mL + 정제수 77 mL)를 첨가하였다. 35% 염산 7 mL를 가하여 pH 4~5로 조절하였다. 층분리하여 유기층을 취하고 물층은 다시 디메틸클로라이드로 재추출하였다. 얻어진 유기층을 정제수 86 mL, 20% 염화나트륨 86 mL로 연속 세척하였다. 무수황산마그네슘으로 탈수 후, 여과하고 디메틸클로라이드 17 mL로 세척하였다. 여액을 감압 농축하였다. 잔사에 아세토니트릴 258 mL와 메탄올 58 mL를 가하고 p-톨루엔설폰산수화물 5.4 g을 첨가하였다. 1시간 동안 교반하고 석출된 결정을 여과한 후, 아세토니트릴 52 mL로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 p-톨루엔설폰산염 13.0 g (70.0%)을 얻었다.5.1 g of sodium hydroxide and 80 mL of ethylene glycol are put into the reactor and stirred at 45 to 50 DEG C for 30 minutes. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 15.0 g of a salt dihydrate and 34 mL of dimethyl sulfoxide were added and stirred at 40 to 50 ° C for 4 hours. Cool to 20-25 ° C, add 86 mL of dimethyl chloride, 86 mL of dilute hydrochloric acid (9 mL of 35% hydrochloric acid + 77 mL of purified water). The pH was adjusted to 4 to 5 by adding 7 mL of 35% hydrochloric acid. The organic layer was separated by layer separation and the water layer was re-extracted with dimethyl chloride. The obtained organic layer was successively washed with 86 mL of purified water and 86 mL of 20% sodium chloride. Dehydrated with anhydrous magnesium sulfate, filtered and washed with 17 mL of dimethyl chloride. The filtrate was concentrated under reduced pressure. To the residue were added 258 mL of acetonitrile and 58 mL of methanol, and 5.4 g of p -toluenesulfonic acid hydrate was added. After stirring for 1 hour, the precipitated crystals were filtered and washed with 52 mL of acetonitrile. Followed by vacuum drying at 50 to 60 ° C to obtain 13.0 g (70.0%) of bosentan p -toluenesulfonate.
1H NMR (400 MHz, DMSO-d6): δ 1.26 (s, 9H), 2.29 (s, 3H), 3.48~3.50 (t, 2H), 3.79 (s, 3H), 4.34~4.37 (t, 2H), 6.70~6.72 (d, 1H), 6.78~6.82 (t, 1H), 7.01~7.05 (t, 1H), 7.07~7.09 (d, 1H), 7.12~7.14 (d, 2H), 7.48~7.51 (d, 2H), 7.53~7.56 (d, 2H), 7.68~7.71 (t, 1H), 8.21~8.23 (d, 2H), 9.10~9.11 (d, 2H) 1 H NMR (400 MHz, DMSO -d 6): δ 1.26 (s, 9H), 2.29 (s, 3H), 3.48 ~ 3.50 (t, 2H), 3.79 (s, 3H), 4.34 ~ 4.37 (t, 2H), 6.70-6.72 (d, 1H), 6.78-6.82 (t, 1H), 7.01-7.05 (t, 2H), 7.51 (d, 2H), 7.53-7.56 (d, 2H), 7.68-7.71
순도(HPLC): 99.90%Purity (HPLC): 99.90%
실시예Example 7: 7: 보센탄Boscentan pp -- 톨루엔설폰산염의Of toluene sulfonate 제조 Produce
수산화나트륨 3.7 g, 에틸렌글리콜 50 mL를 반응기에 투입하고 50~60℃ 로 가열하였다. 실시예 1에서 얻은 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 10.0 g과 1,4-디옥산 20 mL를 투입하고 50~60℃에서 6시간 동안 교반하였다. 20~25℃로 냉각하고 디메틸클로라이드 50 mL, 묽은 염산 50 mL (35% 염산 5 mL + 정제수 45 mL)를 첨가하였다. 35% 염산를 가하여 pH 4~5로 조절하였다. 층분리하여 유기층을 취하고 물층은 다시 디메틸클로라이드로 재추출하였다. 얻어진 유기층을 정제수 76 mL, 20% 염화나트륨 76 mL로 연속 세척하였다. 무수황산마그네슘으로 탈수 후, 여과하고 디메틸클로라이드로 세척하였다. 여액을 감압 농축하였다. 잔사를 아세토니트릴 100 mL에 녹이고 p-톨루엔설폰산수화물 3.8 g을 투입하였다. 1시간 동안 교반하여 석출된 결정을 여과하고 아세토니트릴 52 mL로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 p-톨루엔설폰산염 8.5 g (69.0%)을 얻었다.3.7 g of sodium hydroxide and 50 mL of ethylene glycol were charged into the reactor and heated to 50 to 60 ° C. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 10.0 g of a salt dihydrate and 20 mL of 1,4-dioxane were added thereto, and the mixture was stirred at 50 to 60 DEG C for 6 hours. Cool to 20-25 ° C and add 50 mL of dimethyl chloride and 50 mL of diluted hydrochloric acid (5 mL of 35% hydrochloric acid + 45 mL of purified water). 35% hydrochloric acid was added to adjust pH to 4 ~ 5. The organic layer was separated by layer separation and the water layer was re-extracted with dimethyl chloride. The obtained organic layer was successively washed with 76 mL of purified water and 76 mL of 20% sodium chloride. Dehydrated with anhydrous magnesium sulfate, filtered and washed with dimethylchloride. The filtrate was concentrated under reduced pressure. The residue was dissolved in 100 mL of acetonitrile, and 3.8 g of p -toluenesulfonic acid hydrate was added. The mixture was stirred for 1 hour, and the precipitated crystals were filtered and washed with 52 mL of acetonitrile. Vacuum drying was performed at 50 to 60 ° C to obtain 8.5 g (69.0%) of bosentan p -toluenesulfonate.
순도(HPLC): 99.87% Purity (HPLC): 99.87%
1H NMR 데이터는 실시예 6과 동일함. & Lt; 1 > H NMR data are the same as in Example 6.
실시예Example 8: 8: 보센탄Boscentan pp -- 톨루엔설폰산염의Of toluene sulfonate 제조 Produce
수산화나트륨 1.7 g, 에틸렌글리콜 30 mL를 반응기에 투입하고 45~50℃ 에서 30분 동안 교반한다. 실시예 1에서 얻은 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 5.0 g과 디메틸아세트아미드 11 mL를 투입하고 40~50℃에서 5시간 동안 교반하였다. 20~25℃로 냉각하고 디메틸클로라이드 29 mL, 묽은 염산 29 mL (35% 염산 3 mL + 정제수 27 mL)를 첨가하였다. 35% 염산 2.3 mL를 가하여 pH 4~5로 조절하였다. 층분리하여 유기층을 취하고 물층은 다시 디메틸클로라이드로 재추출하였다. 얻어진 유기층을 정제수 29 mL, 20% 염화나트륨 29 mL로 연속 세척하였다. 무수황산마그네슘으로 탈수 후, 여과하고 디메틸클로라이드 5 mL로 세척하였다. 여액을 감압 농축하였다. 잔사에 아세토니트릴 85 mL와 메탄올 18 mL를 가하고 p-톨루엔설폰산수화물 1.8 g을 첨가하였다. 1시간 동안 교반하고 석출된 결정을 여과한 후, 아세토니트릴 52 mL로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 p-톨루엔설폰산염 4.4 g (71.0%)을 얻었다.1.7 g of sodium hydroxide and 30 mL of ethylene glycol are put into the reactor and stirred at 45 to 50 DEG C for 30 minutes. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 5.0 g of a salt dihydrate and 11 mL of dimethylacetamide were added and stirred at 40 to 50 ° C for 5 hours. Cool to 20-25 ° C and add 29 mL of dimethyl chloride and 29 mL of dilute hydrochloric acid (3 mL of 35% hydrochloric acid + 27 mL of purified water). The pH was adjusted to 4 to 5 by adding 2.3 mL of 35% hydrochloric acid. The organic layer was separated by layer separation and the water layer was re-extracted with dimethyl chloride. The obtained organic layer was successively washed with 29 mL of purified water and 29 mL of 20% sodium chloride. Dehydrated with anhydrous magnesium sulfate, filtered and washed with 5 mL of dimethyl chloride. The filtrate was concentrated under reduced pressure. To the residue were added 85 mL of acetonitrile and 18 mL of methanol, and 1.8 g of p -toluenesulfonic acid hydrate was added. After stirring for 1 hour, the precipitated crystals were filtered and washed with 52 mL of acetonitrile. Vacuum drying was performed at 50 to 60 ° C to obtain 4.4 g (71.0%) of p -toluenesulfonate of bosentan.
순도(HPLC): 99.88% Purity (HPLC): 99.88%
1H NMR 데이터는 실시예 6과 동일함. & Lt; 1 > H NMR data are the same as in Example 6.
실시예Example 9: 9: 보센탄Boscentan 염산염의 제조 Preparation of hydrochloride
수산화나트륨 1.7 g, 에틸렌글리콜 30 mL를 반응기에 투입하고 45~50℃ 에서 30분 동안 교반한다. 실시예 1에서 얻은 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 5.0 g과 디메틸설폭시드 11 mL를 투입하고 40~50℃에서 4시간 동안 교반하였다. 20~25℃로 냉각하고 디메틸클로라이드 29 mL, 묽은 염산 29 mL (35% 염산 3 mL + 정제수 27 mL)를 첨가하였다. 35% 염산 2.3 mL를 가하여 pH 4~5로 조절하였다. 층분리하여 유기층을 취하고 물층은 다시 디메틸클로라이드로 재추출하였다. 얻어진 유기층을 정제수 29 mL, 20% 염화나트륨 29 mL로 연속 세척하였다. 무수황산마그네슘으로 탈수 후, 여과하고 디메틸클로라이드 5 mL로 세척하였다. 여액을 감압 농축하였다. 잔사에 2-프로판올 55 mL를 가하고 50~60℃로 가열하였다. 2-프로판올성 5M 염산 1.88 mL 를 서서히 적가하고, 20~30℃로 냉각하여 4시간 동안 교반하였다. 다시 0~10℃로 냉각하여 1시간 더 교반하고 석출된 결정을 여과한 후, 차가운 2-프로판올 10 mL로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 염산염 3.27 g (65.0%)을 얻었다.1.7 g of sodium hydroxide and 30 mL of ethylene glycol are put into the reactor and stirred at 45 to 50 DEG C for 30 minutes. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 5.0 g of a salt dihydrate and 11 mL of dimethyl sulfoxide were added and stirred at 40 to 50 ° C for 4 hours. Cool to 20-25 ° C and add 29 mL of dimethyl chloride and 29 mL of dilute hydrochloric acid (3 mL of 35% hydrochloric acid + 27 mL of purified water). The pH was adjusted to 4 to 5 by adding 2.3 mL of 35% hydrochloric acid. The organic layer was separated by layer separation and the water layer was re-extracted with dimethyl chloride. The obtained organic layer was successively washed with 29 mL of purified water and 29 mL of 20% sodium chloride. Dehydrated with anhydrous magnesium sulfate, filtered and washed with 5 mL of dimethyl chloride. The filtrate was concentrated under reduced pressure. 55 mL of 2-propanol was added to the residue, and the mixture was heated to 50 to 60 ° C. 1.88 mL of 2-propanolic 5M hydrochloric acid was slowly added dropwise, cooled to 20-30 째 C, and stirred for 4 hours. The mixture was further cooled to 0 to 10 ° C and stirred for 1 hour. The precipitated crystals were filtered and washed with 10 mL of cold 2-propanol. Vacuum drying was performed at 50 to 60 ° C to obtain 3.27 g (65.0%) of bosentan hydrochloride.
1H NMR (400 MHz, DMSO-d6): δ 1.26 (s, 9H), 3.48~3.50 (t, 2H), 3.79 (s, 3H), 4.34~4.37 (t, 2H), 6.70~6.72 (d, 1H), 6.77~6.82 (t, 1H), 7.01~7.09 (m, 2H), 7.53~7.55 (d, 2H), 7.68~7.70 (t, 1H), 8.22 (br s, 2H), 9.09~9.11 (d, 2H) 1 H NMR (400 MHz, DMSO -d 6): δ 1.26 (s, 9H), 3.48 ~ 3.50 (t, 2H), 3.79 (s, 3H), 4.34 ~ 4.37 (t, 2H), 6.70 ~ 6.72 ( 2H), 7.52 (d, IH), 6.77-6.82 (t, IH), 7.01-7.09 (m, 2H), 7.53-7.55 ~9.11 (d, 2H)
순도(HPLC): 99.82%Purity (HPLC): 99.82%
실시예Example 10: 10: 보센탄Boscentan 황산염의 제조 Production of sulfate
수산화나트륨 1.7 g, 에틸렌글리콜 30 mL를 반응기에 투입하고 45~50℃ 에서 30분 동안 교반한다. 실시예 1에서 얻은 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 나트륨염 이수화물 5.0 g과 디메틸설폭시드 11 mL를 투입하고 40~50℃에서 4시간 동안 교반하였다. 20~25℃로 냉각하고 디메틸클로라이드 29 mL, 묽은 염산 29 mL (35% 염산 3 mL + 정제수 27 mL)를 첨가하였다. 35% 염산 2.3 mL를 가하여 pH 4~5로 조절하였다. 층분리하여 유기층을 취하고 물층은 다시 디메틸클로라이드로 재추출하였다. 얻어진 유기층을 정제수 29 mL, 20% 염화나트륨 29 mL로 연속 세척하였다. 무수황산마그네슘으로 탈수 후, 여과하고 디메틸클로라이드 5 mL로 세척하였다. 여액을 감압 농축하였다. 잔사에 아세토니트릴 60 mL를 가하고 98% 황산 0.53 mL 를 적가하였다. 3시간 동안 교반하고, 다시0~10℃로 냉각하여 1시간 더 교반하였다. 석출된 결정을 여과한 후, 차가운 아세토니트릴10 mL로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 황산염 3.78 g (68.0%)을 얻었다.1.7 g of sodium hydroxide and 30 mL of ethylene glycol are put into the reactor and stirred at 45 to 50 DEG C for 30 minutes. N - - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyridinium limiter Dean) 4-yl] benzenesulfonamide sodium Example 1 4- (tert- butyl) obtained in 5.0 g of a salt dihydrate and 11 mL of dimethyl sulfoxide were added and stirred at 40 to 50 ° C for 4 hours. Cool to 20-25 ° C and add 29 mL of dimethyl chloride and 29 mL of dilute hydrochloric acid (3 mL of 35% hydrochloric acid + 27 mL of purified water). The pH was adjusted to 4 to 5 by adding 2.3 mL of 35% hydrochloric acid. The organic layer was separated by layer separation and the water layer was re-extracted with dimethyl chloride. The obtained organic layer was successively washed with 29 mL of purified water and 29 mL of 20% sodium chloride. Dehydrated with anhydrous magnesium sulfate, filtered and washed with 5 mL of dimethyl chloride. The filtrate was concentrated under reduced pressure. 60 mL of acetonitrile was added to the residue, and 0.53 mL of 98% sulfuric acid was added dropwise. The mixture was stirred for 3 hours, cooled again to 0 to 10 ° C, and further stirred for 1 hour. The precipitated crystals were filtered off and washed with 10 mL of cold acetonitrile. Followed by vacuum drying at 50 to 60 ° C to obtain 3.78 g (68.0%) of bosentan sulfate.
1H NMR (400 MHz, DMSO-d6): δ 1.26 (s, 9H), 3.47~3.50 (t, 2H), 3.79 (s, 3H), 4.34~4.37 (t, 2H), 6.69~6.72 (d, 1H), 6.77~6.81 (t, 1H), 7.01~7.09 (m, 2H), 7.53~7.55 (d, 2H), 7.68~7.71 (t, 1H), 8.21~8.22 (d, 2H), 9.10~9.11 (d, 2H) 1 H NMR (400 MHz, DMSO -d 6): δ 1.26 (s, 9H), 3.47 ~ 3.50 (t, 2H), 3.79 (s, 3H), 4.34 ~ 4.37 (t, 2H), 6.69 ~ 6.72 ( 2H), 7.53-7.55 (d, 2H), 7.68-7.71 (t, 1H), 8.21-8.22 (d, 2H) 9.10 ~ 9.11 (d, 2H)
순도(HPLC): 99.85%Purity (HPLC): 99.85%
실시예Example 11 및 12 : 11 and 12: 보세탄Bose Tan 일수화물의Monohydrate 제조 Produce
실시예Example 11: 11: 보센탄Boscentan 일수화물의Monohydrate 제조 Produce
실시예 6에서 얻은 보센탄 p-톨루엔설폰산염 11.5 g과 무수에탄올 44 mL, 정제수 62 mL를 반응기에 투입한 후, 탄산수소나트륨 1.5 g을 적가하였다. 20~25℃에서 1시간 동안 교반하고 여과한 후, 무수에탄올 14 mL와 정제수 20 mL 혼합액으로 세척하였다. 여과한 조 보센탄수화물을 반응기에 투입하고 무수에탄올 49 mL, 아세톤 24 mL를 가하였다. 40~45℃로 가온해 녹이고 여과하여 불순물을 제거하였다. 무수에탄올 10 mL와 아세톤 5 mL 혼합액으로 세척하였다. 여액에 정제수 122 mL를 적가하고, 20~25℃ 에서 1시간 동안 교반하였다. 석출된 결정을 여과하고 무수에탄올와 정제수 혼합액으로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 일수화물 8.4 g (93.0%)을 얻었다.11.5 g of bosentan p -toluenesulfonate obtained in Example 6, 44 mL of anhydrous ethanol and 62 mL of purified water were charged into a reactor, and 1.5 g of sodium hydrogencarbonate was added dropwise. The mixture was stirred at 20 to 25 ° C for 1 hour, filtered, and washed with a mixture of 14 mL of anhydrous ethanol and 20 mL of purified water. Filtered crude borane carbohydrate was added to the reactor, and 49 mL of absolute ethanol and 24 mL of acetone were added. The solution was heated at 40 to 45 DEG C to dissolve and remove impurities by filtration. And washed with a mixture of 10 mL of anhydrous ethanol and 5 mL of acetone. 122 mL of purified water was added dropwise to the filtrate, and the mixture was stirred at 20 to 25 ° C for 1 hour. The precipitated crystals were filtered and washed with a mixture of absolute ethanol and purified water. Followed by vacuum drying at 50 to 60 DEG C to obtain 8.4 g (93.0%) of boscentan monohydrate.
1H NMR (400 MHz, DMSO-d6): δ 1.24(s,9H), 3.46(s,2H), 3.78(s,3H), 4.32(s,2H), 6.68 ~ 6.79(m,2H), 7.02 ~ 7.08(m,2H), 7.52 ~ 7.54(d,2H), 7.65(s,1H), 8.28 ~ 8.30(d,2H), 11.31 (s,1H) 1 H NMR (400 MHz, DMSO -d 6): δ 1.24 (s, 9H), 3.46 (s, 2H), 3.78 (s, 3H), 4.32 (s, 2H), 6.68 ~ 6.79 (m, 2H) , 7.02-7.08 (m, 2H), 7.52-7.54 (d, 2H), 7.65
MS(EI) m/z 552 [M-H2O+H]+ MS (EI) m / z 552 [MH 2 O + H] +
순도(HPLC): 99.97%Purity (HPLC): 99.97%
수분 (칼피셔법): 3.0%Water (Karl Fischer method): 3.0%
실시예Example 12: 12: 보센탄Boscentan 일수화물의Monohydrate 제조 Produce
실시예 7에서 얻은 보센탄 p-톨루엔설폰산염 5.0 g과 무수에탄올 16 mL, 정제수 25 mL를 반응기에 투입한 후, 탄산수소나트륨 0.7 g을 적가하였다. 20~25℃에서 1시간 동안 교반하고 여과한 후, 무수에탄올 5 mL와 정제수 11 mL 혼합액으로 세척하였다. 여과한 조 보센탄수화물을 반응기에 투입하고 무수에탄올 21 mL, 아세톤 11 mL를 가하였다. 40~45℃로 가온해 녹이고 여과하여 불순물을 제거하였다. 무수에탄올 5 mL와 아세톤 3 mL 혼합액으로 세척하였다. 여액에 정제수 61 mL를 적가하고, 20~25℃ 에서 1시간 동안 교반하였다. 석출된 결정을 여과하고 무수에탄올와 정제수 혼합액으로 세척하였다. 50~60℃에서 진공 건조시켜 보센탄 일수화물 3.6 g (92.8%)을 얻었다.5.0 g of bosentan p -toluenesulfonate obtained in Example 7, 16 mL of anhydrous ethanol and 25 mL of purified water were added to the reactor, and 0.7 g of sodium hydrogencarbonate was added dropwise. The mixture was stirred at 20 to 25 ° C for 1 hour, filtered, and then washed with a mixture of 5 mL of anhydrous ethanol and 11 mL of purified water. Filtered crude borane carbohydrate was added to the reactor, and 21 mL of absolute ethanol and 11 mL of acetone were added. The solution was heated at 40 to 45 DEG C to dissolve and remove impurities by filtration. Washed with a mixture of 5 mL of anhydrous ethanol and 3 mL of acetone. 61 mL of purified water was added dropwise to the filtrate, and the mixture was stirred at 20 to 25 ° C for 1 hour. The precipitated crystals were filtered and washed with a mixture of absolute ethanol and purified water. And vacuum-dried at 50 to 60 ° C to obtain 3.6 g (92.8%) of boscentan monohydrate.
순도(HPLC): 99.95% Purity (HPLC): 99.95%
수분(칼피셔법): 3.1%Water (Karl Fischer method): 3.1%
1H-NMR 및 MS 측정결과는 실시예 11과 동일함. The results of 1 H-NMR and MS measurements are the same as in Example 11. [
측정방법 How to measure
1) One) 1One H-H- NMRNMR (핵자기공명스펙트럼) (Nuclear magnetic resonance spectrum)
- 제조사: Varian- Manufacturer: Varian
- 기기명: Mercury Plus 400 MHz NMR- Instrument name:
2) 2) MSMS (질량스펙트럼) (Mass spectrum)
- 제조사: AB SCIEX- Manufacturer: AB SCIEX
- 기기명: API-2000- Device name: API-2000
3) 3) HPLCHPLC (고성능 액체크로마토그래피) (High performance liquid chromatography)
- 제조사: Agilent Technologies- Manufacturer: Agilent Technologies
- 기기명: SYS-LC-1200 series- Device name: SYS-LC-1200 series
- Column: Zorbax RX-C8(4.6×250mm, 5 ㎛, 80Å) 또는 이와 동등품Column: Zorbax RX-C8 (4.6 × 250 mm, 5 μm, 80 Å) or equivalent
- 이동상A: 인산이수소칼륨 1.36 g 을 정제수 750 mL에 녹이고 인산으로 pH 2.5가 되도록 한 다음 아세토니트릴 250 mL와 혼합한다.- Mobile phase A: 1.36 g of potassium dihydrogenphosphate is dissolved in 750 mL of purified water, adjusted to pH 2.5 with phosphoric acid, and mixed with 250 mL of acetonitrile.
- 이동상B: 인산이수소칼륨 1.36 g 을 정제수 300 mL에 녹이고 인산으로 pH 2.5가 되도록 한 다음 아세토니트릴 700 mL와 혼합한다.- Mobile phase B: Dissolve 1.36 g of potassium dihydrogenphosphate in 300 mL of purified water, adjust to pH 2.5 with phosphoric acid, and mix with 700 mL of acetonitrile.
- 유속: 1.5ml/분- Flow rate: 1.5 ml / min
- 검출기 파장: 220nm- Detector wavelength: 220 nm
- 이동상 구배:- mobile phase gradient:
4) 4) DSCDSC (시차주사열량계) (Differential scanning calorimeter)
- 제조사: TA instrument Inc.,U.S.A.- Manufacturer: TA instrument Inc., U.S.A.
- 모델명: DSC 1000 (Differential Scanning Calorimeter)- Model name: DSC 1000 (Differential Scanning Calorimeter)
- 승온속도: 10℃/min으로 300℃까지 승온시킴- Temperature increase rate: Up to 300 ℃ at 10 ℃ / min
5) 5) KarlKarl -- FisherFisher 수분 측정 Moisture measurement
- 제조사: Metrohm- Manufacturer: Metrohm
- 모델명: 787 KF Titrino- Model: 787 KF Titrino
- 사용용매: 메탄올- Solvent used: methanol
Claims (22)
[반응식 I]
{상기 M은 나트륨이다}
2) 하기 [반응식 II]에 의하여, 유기용매에서 제2염기 존재 하에 제1단계에서 제조된 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 알칼리 금속염을 에틸렌글리콜과 반응시켜 조(crude)-보센탄을 제조한 후, 산을 가하여 보센탄 산부가염을 제조하는 제2단계; 및
[반응식 II]
3) 하기 [반응식 III]에 의하여, 제2단계에서 제조된 보센탄 산부가염을 수용성 용매에서 보센탄 일수화물로 전환하는 제3단계;
[반응식 III]
를 포함하고,
상기 반응식 I 및 II에서 4-(tert-부틸)-N-[6-클로로-5-(2-메톡시페녹시)-(2,2'-비피리미딘)-4-일]벤젠설폰아미드 알칼리 금속염은 하기 [화학식 I] 구조의 나트륨염 이수화물인 것인 보센탄 일수화물의 제조방법.
[화학식 I]
[Reaction Scheme I]
{The above M is sodium}
2) by the [Reaction Scheme II], prepared in the first step under the second presence of a base in an organic solvent 4- (tert- butyl) - N - [6- chloro-5- (2-methoxyphenoxy) - (2,2'-bipyrimidin) -4-yl] benzenesulfonamide was reacted with ethylene glycol to prepare crude-butocene, and then acid was added thereto to prepare a bis step; And
[Reaction Scheme II]
3) a third step of converting the bis-pentanoic acid addition salt prepared in the second step into a boscentan monohydrate in a water-soluble solvent according to the following Reaction Scheme III;
[Reaction Scheme III]
Lt; / RTI >
In the above schemes I and II, 4- (tert-butyl) -N- [6-chloro-5- (2-methoxyphenoxy) - (2,2'-bipyrimidin) -4-yl] benzenesulfonamide Wherein the alkali metal salt is a sodium salt dihydrate having a structure represented by the following formula (I).
(I)
[화학식 II]
≪ RTI ID = 0.0 &
[화학식 I]
(I)
[반응식 I-1]
[Reaction Scheme I-1]
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