KR20170123132A - Process for Preparing Treprostinil - Google Patents
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- KR20170123132A KR20170123132A KR1020160052391A KR20160052391A KR20170123132A KR 20170123132 A KR20170123132 A KR 20170123132A KR 1020160052391 A KR1020160052391 A KR 1020160052391A KR 20160052391 A KR20160052391 A KR 20160052391A KR 20170123132 A KR20170123132 A KR 20170123132A
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- 0 CCCCC[C@@](CC[C@@]([C@@](C1)O)[C@@](C2)[C@@]1Cc1c2cccc1OCC(*)=O)O Chemical compound CCCCC[C@@](CC[C@@]([C@@](C1)O)[C@@](C2)[C@@]1Cc1c2cccc1OCC(*)=O)O 0.000 description 1
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- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C07C35/22—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system
- C07C35/37—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring polycyclic, at least one hydroxy group bound to a condensed ring system with a hydroxy group on a condensed system having three rings
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Abstract
Description
본 발명은 트레프로스티닐 (Treprostinil)의 제조방법에 관한 것으로, 보다 상세하게는 고순도의 트레프로스티닐을 경제적이고 효율적으로 제조하는 방법에 관한 것이다.The present invention relates to a method for producing treprostinil, and more particularly, to a method for economically and efficiently preparing treprostinil in high purity.
하기 화학식 1의 화합물인 트레프로스티닐, 2-((1R,2R,3aS,9aS)-2-히드록시-1-((S)-3-히드록시옥틸)-2,3,3a,4,9,9a-헥사히드로-1H-시클로펜타[b]나프탈렌-5-일옥시)아세트산은 레모듈린 (RemodulinTM), 티바소 (TyvasoTM)와 오레니트람 (OrenitramTM)의 활성 성분이다. (S) -3,3-dihydroxy-1 - ((S) -3-hydroxyoctyl) -2,3,3a, 4 , 9,9a- hexahydro--1H- cyclopenta [b] naphthalene-5-yloxy) acetic acid is the active ingredient of the rail module Lin (Remodulin TM), tea Lancet (Tyvaso TM) and Toray knit Ram (Orenitram TM) .
[화학식 1] [Chemical Formula 1]
미국 특허 제4,306,075호에는 트레프로스티닐의 제조방법이 최초로 공개되어 있다. 또한, 문헌[Moriarty, et al., J. Org . Chem . 2004, 69, 1890-1902]에는 트레프로스티닐의 제조방법 및 에탄올과 물을 이용한 정제방법이 기재되어 있다. 아울러, 미국 특허 제8,497,393호에는 트레프로스티닐 디에탄올아민 염을 형성한 다음 산성화하여 트레프로스티닐을 제조하는 방법과 알코올성 용매와 물을 이용하는 정제방법이 기재되어 있다.U.S. Patent No. 4,306,075 discloses the first method for producing treprostinil. See also Moriarty, et al., J. Org . Chem . 2004, 69 , 1890-1902 discloses a process for preparing treprostinil and a purification process using ethanol and water. In addition, U.S. Patent No. 8,497,393 discloses a method for preparing treprostinil by forming a treprostyryl diethanolamine salt followed by acidification, and a purification method using an alcoholic solvent and water.
그러나, 종래의 제조방법에 따르면, 알코올성 용매와 물을 이용하여 정제함으로써 불순물인 트레프로스티닐 에스터가 생성되어 트레프로스티닐의 순도가 낮아지는 문제점이 있었다.However, according to the conventional preparation method, refining using an alcoholic solvent and water has a problem that a treprostinil ester, which is an impurity, is produced and the purity of treprostinil is lowered.
본 발명의 한 목적은 고순도의 트레프로스티닐을 경제적이고 효율적으로 제조하는 방법을 제공하는 것이다.It is an object of the present invention to provide a method for economically and efficiently preparing high purity treprostinil.
본 발명의 다른 목적은 상기 제조방법으로 제조된 고순도의 트레프로스티닐 결정형을 제공하는 것이다.Another object of the present invention is to provide a high-purity treprostinil crystal form prepared by the above process.
본 발명의 일 실시형태는 트레프로스티닐의 제조방법에 관한 것으로, 본 발명의 제조방법은 One embodiment of the present invention relates to a method for producing treprostinil,
(i) 하기 화학식 2의 화합물을 하기 화학식 3의 화합물과 알킬화 반응시켜 하기 화학식 4의 화합물을 수득하는 단계;(i) alkylating a compound of formula (2) with a compound of formula (3) to obtain a compound of formula (4);
(ii) 하기 화학식 4의 화합물의 에스터기를 가수분해 반응시켜 하기 화학식 1의 화합물을 수득하는 단계;(ii) hydrolyzing the ester group of the compound of formula (4) to obtain a compound of formula (1);
(iii) 하기 화학식 1의 화합물을 염기와 반응시켜 하기 화학식 5의 염 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계; 및(iii) reacting a compound of the formula (1) with a base to obtain a salt compound of the formula (5), and recrystallizing the salt by using acetonitrile and water; And
(iv) 하기 화학식 5의 염 화합물을 산과 반응시켜 하기 화학식 1의 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계를 포함한다.(iv) reacting a salt compound of the following formula (5) with an acid to obtain a compound of the formula (1), and recrystallizing it using acetonitrile and water.
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 1][Chemical Formula 1]
[화학식 5][Chemical Formula 5]
이하, 본 발명의 제조방법을 하기 반응식 1을 참조로 보다 상세히 설명한다. 하기 반응식 1에 기재된 방법은 대표적으로 사용된 방법을 예시한 것일 뿐 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다.Hereinafter, the production method of the present invention will be described in more detail with reference to Reaction Scheme 1 below. The method described in the following Reaction Scheme 1 exemplifies the representative method, but the reaction reagent, the reaction conditions, and the like may be changed as required.
[반응식 1][Reaction Scheme 1]
제1단계: 화학식 4의 화합물의 제조Step 1: Preparation of the compound of formula (4)
화학식 4의 화합물은 화학식 2의 화합물을 화학식 3의 화합물과 알킬화 반응시켜 제조할 수 있다.The compound of formula (4) can be prepared by alkylating a compound of formula (2) with a compound of formula (3).
상기 알킬화 반응은 염기의 존재 하에 수행될 수 있다. 상기 염기로는 소듐 하이드라이드, 세슘 카보네이트, 포타슘 카보네이트 등이 사용될 수 있고, 특히 포타슘 카보네이트가 바람직하다.The alkylation reaction may be carried out in the presence of a base. As the base, sodium hydride, cesium carbonate, potassium carbonate and the like can be used, and potassium carbonate is particularly preferable.
반응용매로는 디메틸포름아미드, 아세토니트릴, 테트라하이드로퓨란, 아세톤 등이 사용될 수 있고, 특히 아세톤이 바람직하다.As the reaction solvent, dimethylformamide, acetonitrile, tetrahydrofuran, acetone and the like can be used, and acetone is particularly preferable.
또한, 알킬화 반응의 온도는 약 50-60 ℃이 바람직하다.
In addition, the temperature of the alkylation reaction is preferably about 50-60 캜.
제2단계: 화학식 1의 화합물의 제조Step 2: Preparation of the compound of formula (1)
화학식 1의 화합물은 화학식 4의 화합물의 에스터기를 가수분해 반응시켜 제조할 수 있다. The compound of formula (1) can be prepared by hydrolysis of an ester group of the compound of formula (4).
상기 가수분해 반응은 염기의 존재 하에 수행될 수 있다. 상기 염기로는 리튬 하이드록사이드, 소듐 하이드록사이드, 포타슘 하이드록사이드 등이 사용될 수 있고, 특히 소듐 하이드록사이드가 바람직하다.The hydrolysis reaction may be carried out in the presence of a base. As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like may be used, and sodium hydroxide is particularly preferable.
반응용매로는 메탄올, 에탄올 또는 프로판올과 물이 사용될 수 있고, 특히 에탄올과 물이 바람직하다.
As the reaction solvent, methanol, ethanol or propanol and water may be used, and particularly ethanol and water are preferable.
제3단계: 화학식 5의 염 화합물의 제조Step 3: Preparation of Salt Compound of Chemical Formula 5
화학식 5의 염 화합물은 화학식 1의 화합물을 염기와 반응시켜 제조할 수 있다. The salt compound of formula (5) can be prepared by reacting the compound of formula (1) with a base.
상기 염기로는 소듐 하이드록사이드가 바람직하다.As the base, sodium hydroxide is preferable.
반응용매로는 메탄올, 에탄올 또는 프로판올과 물이 사용될 수 있고, 특히 에탄올과 물이 바람직하다. As the reaction solvent, methanol, ethanol or propanol and water may be used, and particularly ethanol and water are preferable.
또한, 반응온도는 약 -5~+5 ℃가 바람직하다.
The reaction temperature is preferably about -5 to + 5 ° C.
그런 다음, 생성된 화학식 5의 염 화합물을 아세토니트릴과 물을 이용하여 재결정하여 정제한다. 상기 재결정은 화학식 5의 염 화합물에 아세토니트릴과 물을 부가하여 실온에서 교반한 다음 -5 내지 5℃로 냉각하여 수행할 수 있다.
The resulting salt compound of formula (5) is then purified by recrystallization using acetonitrile and water. The recrystallization may be performed by adding acetonitrile and water to the salt compound of formula (5), stirring at room temperature, and cooling to -5 to 5 ° C.
제4단계: 고순도의 화학식 1의 화합물의 제조Step 4: Preparation of high purity compound of formula (I)
고순도의 화학식 1의 화합물은 화학식 5의 염 화합물을 산과 반응시켜 제조할 수 있다. The high purity compound of formula (1) can be prepared by reacting the salt compound of formula (5) with an acid.
상기 산으로는 염산, 황산 등이 사용될 수 있고, 특히 염산이 바람직하다. As the acid, hydrochloric acid, sulfuric acid and the like can be used, and hydrochloric acid is particularly preferable.
반응용매로는 메탄올, 에탄올, 프로판올, 물 등이 사용될 수 있고, 특히 물이 바람직하다.
As the reaction solvent, methanol, ethanol, propanol, water and the like can be used, and water is particularly preferable.
그런 다음, 생성된 화학식 1의 화합물을 아세토니트릴과 물을 이용하여 재결정하여 정제한다. 상기 재결정은 화학식 1의 화합물에 아세토니트릴과 물을 부가하여 실온에서 교반한 다음 -5 내지 5℃로 냉각하여 수행할 수 있다.
Then, the resulting compound of formula (I) is purified by recrystallization using acetonitrile and water. The recrystallization can be carried out by adding acetonitrile and water to the compound of formula (1), stirring at room temperature, and cooling to -5 to 5 ° C.
이와 같이 정제된 화학식 1의 화합물을 약 50-60 ℃에서 진공 건조하면 순도가 99.9% 이상인 트레프로스티닐 결정형 I이 생성된다.The thus purified compound of formula (I) is dried in vacuo at about 50-60 ° C. to yield a treprostinil crystal form I having a purity of 99.9% or higher.
상기 트레프로스티닐 결정형 I은 X-선 분말 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 10% 이상인 회절각(2θ)의 값이 6.59±0.2, 13.20±0.2, 20.82±0.2이다.In the X-ray powder diffraction analysis, the above-mentioned treprostinil crystal form I has a diffraction angle (2?) Of I / I 0 (I: intensity of peak at each diffraction angle, I 0 : intensity of largest peak) Values are 6.59 0.2, 13.20 0.2, and 20.82 0.2.
상기 트레프로스티닐 결정형 I은 시차주사열량 분석에서, 녹는점이 126.7 ℃의 값을 나타낸다.
In the differential scanning calorimetry, the melting point of the above-mentioned treprostinil crystal form I is 126.7 캜.
본 발명의 일 실시형태는 트레프로스티닐의 정제방법에 관한 것으로, 본 발명의 정제방법은 One embodiment of the present invention relates to a method for purifying treprostinil, wherein the purification method of the present invention comprises
(iii) 하기 화학식 1의 화합물을 염기와 반응시켜 하기 화학식 5의 염 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계; 및(iii) reacting a compound of the formula (1) with a base to obtain a salt compound of the formula (5), and recrystallizing the salt by using acetonitrile and water; And
(iv) 하기 화학식 5의 염 화합물을 산과 반응시켜 하기 화학식 1의 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계를 포함한다. (iv) reacting a salt compound of the following formula (5) with an acid to obtain a compound of the formula (1), and recrystallizing it using acetonitrile and water.
상기 단계 (iii) 및 (iv)에 대한 상세한 설명은 트레프로스티닐의 제조방법과 관련하여 상술한 제3단계 및 제4단계와 동일하므로, 중복을 피하기 위해 기재를 생략한다.The detailed description of the steps (iii) and (iv) is the same as the third and fourth steps described above with respect to the method for producing treprostinil, so that the description thereof is omitted in order to avoid duplication.
본 발명의 제조방법에 따르면, 99.9% 이상의 순도를 가지는 트레프로스티닐을 경제적이고 효율적으로 제조할 수 있다. According to the production method of the present invention, treprostinil having a purity of 99.9% or more can be produced economically and efficiently.
도 1은 실시예 4에서 수득한 트레프로스티닐 결정형 I의 X-선 분말 회절도이다.
도 2는 실시예 4에서 수득한 트레프로스티닐 결정형 I의 시차주사열량 분석도이다.1 is an X-ray powder diffraction chart of the treprostinil crystal form I obtained in Example 4. Fig.
Fig. 2 is a graph showing the differential scanning calorimetry of the treprostinil crystal form I obtained in Example 4. Fig.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It should be apparent to those skilled in the art that these embodiments are for illustrative purpose only and that the scope of the present invention is not limited to these embodiments.
실시예Example 1: 화학식 4의 화합물의 제조 1: Preparation of the compound of formula (4)
아세톤 (4.0 kg)에 용해한 화학식 2의 벤진덴 트리올 (440 g)에 포타슘 카보네이트 (549 g)과 화학식 3의 브로모메틸아세테이트 (405 g)을 가하였다. 반응용액을 50-60℃에서 10-16 시간 교반한 다음 HPLC로 반응 종결을 확인하였다. 15-25℃로 냉각 후 여과, 농축하였다. 에틸아세테이트 (4.5 kg)과 물 (5.0 kg)을 가하여 교반한 다음 유기층을 분리하였다. 황산나트륨 (1.0 kg)을 가하여 여과 및 농축하고 얻어진 잔류물을 n-헥산:초산에틸 (1:1)로 크로마토그라피하여 화학식 4 의 화합물(400 g, 74.8%)을 얻었다.Potassium carbonate (549 g) and bromomethyl acetate (405 g) of formula (3) were added to 440 g of benzidine ditriol of formula (2) dissolved in acetone (4.0 kg). The reaction solution was stirred at 50-60 ° C for 10-16 hours, and the reaction was terminated by HPLC. After cooling to 15-25 ° C, it was filtered and concentrated. Ethyl acetate (4.5 kg) and water (5.0 kg) were added and stirred, followed by separation of the organic layer. Sodium sulfate (1.0 kg) was added thereto, followed by filtration and concentration. The resulting residue was chromatographed with n-hexane: ethyl acetate (1: 1) to obtain the compound of Formula 4 (400 g, 74.8%).
1H NMR (300 MHz, CDCl3, δ ppm): 7.07 (t, J = 7.8, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.63 (s, 2H), 3.79 (s, 3H), 3.54-3.76 (m, 2H), 2.88 (dd, J = 14.7, 5.7 Hz, 1H), 2.76 (dd, J = 14.1, 6.0 Hz, 1H), 2.42-2.59 (m, 2H), 2.14-2.30 (m, 2H), 1.85-1.94 (m, 1H), 1.12-1.75 (m, 14H), 0.90 (t, J = 7.0 Hz, 3H). 1 H NMR (300 MHz, CDCl 3, δ ppm): 7.07 (t, J = 7.8, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 4.63 (s, 2H), 3.79 ( s, 3H), 3.54-3.76 (m, 2H), 2.88 (dd, J = 14.7, 5.7 Hz, 1H), 2.76 (dd, J = 14.1, 6.0 Hz, 1H), 2H), 2.14-2.30 (m, 2H), 1.85-1.94 (m, 1H), 1.12-1.75 (m, 14H), 0.90 (t, J = 7.0 Hz, 3H).
13C NMR (75 MHz, CDCl3, δ ppm): 169.72, 154.89, 141.06, 127.81, 126.14, 121.63, 109.69, 76.60, 72.58, 66.00, 52.31, 52.16, 41.44, 41.28, 37.45, 35.00, 33.74, 32.79, 31.91, 28.66, 25.98, 25.38, 22.65, 14.06.
13 C NMR (75 MHz, CDCl 3 ,? Ppm): 169.72,158.89,141.06,127.81,126.14,121.63,109.69,76.60,72.58,66.00,52.31,52.16,41.44,41.28,37.45,35.00,33.74,32.79, 31.91, 28.66, 25.98, 25.38, 22.65, 14.06.
실시예Example 2: 화학식 1의 화합물의 제조 2: Preparation of compound of formula (1)
에탄올 (2.0 kg)에 용해한 화학식 4의 화합물 (380 g)에 물 (2.0 kg)에 용해된 소듐 하이드록사이드 (75 g)을 가하고 3-5 시간 교반한 다음 반응 종결을 HPLC로 확인하였다. 반응용매를 농축한 다음, 물 (2.0 kg)을 가하여 교반하고, 물 (1820 g)에 용해된 염산 (210 g)을 가하여 pH 3-4로 산성화하였다. 초산에틸 (4.5 kg)을 가하고 20-30 분 교반한 다음 유기층을 분리하였다. 분리된 유기층에 물 (5.0 kg)을 가하고 20-30 분간 교반한 다음 유기층을 분리하였다. 분리된 유기층에 소금물 (5.0 kg)을 가하고 20-30 분간 교반한 다음 유기층을 분리하였다. 황산나트륨을 가하여 건조, 여과 및 농축하여 화학식 1의 화합물 (367 g, 100%)을 얻었다.Sodium hydroxide (75 g) dissolved in water (2.0 kg) was added to the compound of Formula 4 (380 g) dissolved in ethanol (2.0 kg) and stirred for 3-5 hours. The reaction was terminated by HPLC. After the reaction solvent was concentrated, water (2.0 kg) was added and stirred, and acidified to pH 3-4 by adding hydrochloric acid (210 g) dissolved in water (1820 g). Ethyl acetate (4.5 kg) was added, stirred for 20-30 minutes, and the organic layer was separated. Water (5.0 kg) was added to the separated organic layer, stirred for 20-30 minutes, and the organic layer was separated. Brine (5.0 kg) was added to the separated organic layer, stirred for 20-30 minutes, and the organic layer was separated. Sodium sulfate was added, followed by drying, filtration and concentration to obtain the compound of Formula 1 (367 g, 100%).
1H NMR (300 MHz, MeOD, δ ppm): 7.05 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 3.52-3.67 (m, 2H), 2.61-2.80 (m, 3H), 2.50 (dd, J = 14.4, 6.0 Hz, 1H), 2.21-2.34 (m, 1H), 1.86-2.12 (m, 2H), 1.05-1.76 (m, 14H), 0.92 (t, J = 7.0 Hz, 3H). 1 H NMR (300 MHz, MeOD , δ ppm): 7.05 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 3.52-3.67 (m, 2H), 2.61-2.80 (m, 3H), 2.50 (dd, J = 14.4, 6.0 Hz, (m, 2H), 1.05-1.76 (m, 14H), 0.92 (t, J = 7.0 Hz, 3H).
13C NMR (75 MHz, MeOD, δ ppm): 172.93, 156.52, 142.16, 128.69, 127.15, 122.42, 110.79, 77.61, 72.89, 66.56, 52.71, 498.83, 49.55, 49.26, 42.30, 42.01, 38.28, 36.04, 34.56, 34.06, 33.14, 29.60, 26.61, 26.48, 23.73, 14.41.
13 C NMR (75 MHz, MeOD,? Ppm): 172.93, 156.52, 142.16,128.69,127.15,122.42,110.79,77.61,72.89,66.56,52.71,498.83,49.55,49.26,42.30,42.01,38.28,36.04,34.56 , 34.06, 33.14, 29.60, 26.61, 26.48, 23.73, 14.41.
실시예Example 3: 화학식 5의 화합물의 제조 3: Preparation of the compound of formula (5)
에탄올 (1.6 kg)에 용해한 화학식 1 의 화합물 (350 g)을 -5~+5℃ 사이로 냉각한 후, 소듐 하이드록사이드 (36.2 g)을 물 (0.9 kg)에 녹여서 가하고 1~2 시간 교반하였다. 반응용매를 여과하고 농축하였다. 아세토니트릴 (1.8 kg)과 물 (800 g)을 가하여 용해하고 -5~+5℃ 사이로 냉각하여 4~6 시간 교반하였다. 생성된 고체를 여과하고 20~24 시간 동안 건조하여 화학식 5의 화합물 (310 g, 83.8%)을 얻었다. After cooling the compound of Formula 1 (350 g) dissolved in ethanol (1.6 kg) to -5 to + 5 ° C, sodium hydroxide (36.2 g) was dissolved in water (0.9 kg) and stirred for 1 to 2 hours . The reaction solvent was filtered and concentrated. Acetonitrile (1.8 kg) and water (800 g) were added to dissolve, cooled to -5 to + 5 ° C, and stirred for 4 to 6 hours. The resulting solid was filtered and dried for 20-24 hours to give the compound of formula 5 (310 g, 83.8%).
1H NMR (700 MHz, MeOD, δ ppm): 7.03 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 4.38 (s, 2H), 3.62-3.66 (m, 1H), 3.53-3.57 (m, 1H), 2.86 (dd, J = 14.7, 6.2 Hz, 1H), 2.75 (dd, J = 14.1, 6.2 Hz, 1H), 2.65 (dd, J = 14.7, 6.2 Hz, 1H), 2.50 (dd, J = 14.1, 6.3 Hz, 1H), 2.25-2.32 (m, 1H), 2.10-2.14 (m, 1H), 1.89-1.93 (m, 1H), 1.72-1.77 (m, 1H), 1.55-1.66 (m, 2H), 1.42-1.53 (m, 4H), 1.29-1.41 (m, 5H), 1.23-1.27 (m, 1H), 1.14-1.19 (m, 1H), 0.94 (t, J = 7.0 Hz, 3H). 1 H NMR (700 MHz, MeOD , δ ppm): 7.03 (t, J = 7.8 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 4.38 (s, 2H), 3.62-3.66 ( m, 1H), 3.53-3.57 (m, 1H), 2.86 (dd, J = 14.7, 6.2 Hz, 1H), 2.75 (dd, J = 14.1, 6.2 Hz, 1H ), 2.65 (dd, J = 14.7, 6.2 Hz, 1H), 2.50 (dd, J = 14.1, 6.3 Hz, 1H), 2.25-2.32 2H), 1.42-1.53 (m, 4H), 1.29-1.41 (m, 5H), 1.23-1.27 (m, 1H) ), 1.14-1.19 (m, 1H), 0.94 (t, J = 7.0 Hz, 3H).
13C NMR (176 MHz, MeOD, δ ppm): 175.73, 155.89, 140.42, 127.23, 125.60, 120.25, 109.76, 76.37, 71.52, 67.99, 51.42, 41.07, 40.75, 36.89, 34.71, 33.40, 32.77, 31.77, 28.29, 25.43, 25.11, 22.36, 13.04.
13 C NMR (176 MHz, MeOD , δ ppm): 175.73, 155.89, 140.42, 127.23, 125.60, 120.25, 109.76, 76.37, 71.52, 67.99, 51.42, 41.07, 40.75, 36.89, 34.71, 33.40, 32.77, 31.77, 28.29 , 25.43, 25.11, 22.36, 13.04.
실시예Example 4: 고순도의 화학식 1의 화합물의 제조 4: Preparation of high purity compound of formula (1)
물 (1.2 kg)에 용해한 화학식 5의 화합물 (310 g)에 2 N 염산을 천천히 가하여 pH 3-4로 산성화하였다. 초산에틸 (3.7 kg)을 가하고 교반한 다음 유기층을 분리하고 농축하였다. 아세토니트릴 (3.1 kg)과 물 (3.1 kg)을 가하여 용해하고 -5~+5℃ 사이로 냉각하여 4~6 시간 교반하였다. 생성된 고체를 여과하고 20~24 시간 동안 55℃에서 진공 건조하여 화학식 1의 화합물 (250 g, 85%)을 얻었다.2 N hydrochloric acid was slowly added to the compound of formula 5 (310 g) dissolved in water (1.2 kg) and acidified to pH 3-4. Ethyl acetate (3.7 kg) was added and stirred, and the organic layer was separated and concentrated. Acetonitrile (3.1 kg) and water (3.1 kg) were added to dissolve, cooled to -5 to + 5 ° C, and stirred for 4 to 6 hours. The resulting solid was filtered and vacuum dried at 55 ° C for 20-24 hours to give the compound of formula (1) (250 g, 85%).
수득한 화학식 1의 트레프로스티닐의 X-선 분말 회절도 및 시차주사열량 분석도를 측정하여 각각 도 1 및 도 2에 나타내었으며, 이를 트레프로스티닐 결정형 I이라 하였다. The X-ray powder diffraction chart and differential scanning calorimetry of the obtained treprostinil of formula (1) were measured and are shown in FIGS. 1 and 2, respectively, and they were referred to as treprostinil crystal form I.
도 1의 X-선 분말 회절도에 나타난 특징적인 피크(peak)를 하기 표 1에 나타내었으며, 여기서 2θ는 회절각을 의미한다.The characteristic peaks shown in the X-ray powder diffraction diagram of FIG. 1 are shown in the following Table 1, where 2? Denotes the diffraction angle.
융점 (시차주사열량법, DSC): 126.73 ℃Melting point (differential scanning calorimetry, DSC): 126.73 DEG C
1H NMR (300 MHz, MeOD, δ ppm): 7.05 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 3.52-3.67 (m, 2H), 2.61-2.80 (m, 3H), 2.50 (dd, J = 14.4, 6.0 Hz, 1H), 2.21-2.34 (m, 1H), 1.86-2.12 (m, 2H), 1.05-1.76 (m, 14H), 0.92 (t, J = 7.0 Hz, 3H). 1 H NMR (300 MHz, MeOD , δ ppm): 7.05 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 6.70 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 3.52-3.67 (m, 2H), 2.61-2.80 (m, 3H), 2.50 (dd, J = 14.4, 6.0 Hz, (m, 2H), 1.05-1.76 (m, 14H), 0.92 (t, J = 7.0 Hz, 3H).
13C NMR (75 MHz, MeOD, δ ppm): 172.93, 156.52, 142.16, 128.69, 127.15, 122.42, 110.79, 77.61, 72.89, 66.56, 52.71, 498.83, 49.55, 49.26, 42.30, 42.01, 38.28, 36.04, 34.56, 34.06, 33.14, 29.60, 26.61, 26.48, 23.73, 14.41.
13 C NMR (75 MHz, MeOD,? Ppm): 172.93, 156.52, 142.16,128.69,127.15,122.42,110.79,77.61,72.89,66.56,52.71,498.83,49.55,49.26,42.30,42.01,38.28,36.04,34.56 , 34.06, 33.14, 29.60, 26.61, 26.48, 23.73, 14.41.
상기에서 수득한 트레프로스티닐의 순도는 트레프로스티닐 2.5 mg을 이동상A:이동상B = 3:1 (25 mL)에 녹이고, 시료용액 20 ㎕에 대하여 하기와 같은 조작조건의 액체크로마토그래피로 각각의 피크 면적 백분율을 자동 적분법으로 측정하였다. 그 결과, 트레프로스티닐의 순도는 99.9%로 확인되었다.The purity of the treprostinil obtained above was 2.5 mg of treprostinil as mobile phase A: mobile phase B = 3: 1 (25 mL). To 20 μl of the sample solution, the percentage of each peak area was determined by an automatic integration method by liquid chromatography under the following operating conditions. As a result, the purity of the treprostinil was confirmed to be 99.9%.
(조작조건)(Operating conditions)
검출기: 자외부 흡광광도계 (측정파장 217nm)Detector: Ultraviolet absorptiometer (measuring wavelength 217 nm)
컬 럼: ODS column (5㎛, 250 X 4.6mm)Column: ODS column (5 탆, 250 X 4.6 mm)
컬럼온도: 25℃Column temperature: 25 ° C
유 량: 2.0 mL/min Flow rate: 2.0 mL / min
이동상A: 아세토니트릴 : 물 : 트리플루오로 초산 = 400 : 600 : 1Mobile phase A: Acetonitrile: Water: Trifluoroacetic acid = 400: 600: 1
이동상B: 아세토니트릴 : 물 : 트리플루오로 초산 = 780 : 220 : 1Mobile phase B: Acetonitrile: Water: Trifluoroacetic acid = 780: 220: 1
분석시간: 60분
Analysis time: 60 minutes
Claims (12)
(ii) 하기 화학식 4의 화합물의 에스터기를 가수분해 반응시켜 하기 화학식 1의 화합물을 수득하는 단계;
(iii) 하기 화학식 1의 화합물을 염기와 반응시켜 하기 화학식 5의 염 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계; 및
(iv) 하기 화학식 5의 염 화합물을 산과 반응시켜 하기 화학식 1의 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계를 포함하는 트레프로스티닐의 제조방법:
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 1]
[화학식 5]
(ii) hydrolyzing the ester group of the compound of formula (4) to obtain a compound of formula (1);
(iii) reacting a compound of the formula (1) with a base to obtain a salt compound of the formula (5), and recrystallizing the salt by using acetonitrile and water; And
(iv) reacting a salt compound of the following formula (5) with an acid to obtain a compound of the formula (1), and recrystallizing it using acetonitrile and water:
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 1]
[Chemical Formula 5]
(iv) 하기 화학식 5의 염 화합물을 산과 반응시켜 하기 화학식 1의 화합물을 수득하고, 이를 아세토니트릴과 물을 이용하여 재결정하는 단계를 포함하는 트레프로스티닐의 정제방법:
[화학식 1]
[화학식 5]
(iv) reacting a salt compound of the following formula (5) with an acid to obtain a compound of the formula (1), and recrystallizing it using acetonitrile and water:
[Chemical Formula 1]
[Chemical Formula 5]
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