KR20180128201A - Crystalline Form of Nalfurafine and Process of Preparing the Same - Google Patents

Crystalline Form of Nalfurafine and Process of Preparing the Same Download PDF

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KR20180128201A
KR20180128201A KR1020170063416A KR20170063416A KR20180128201A KR 20180128201 A KR20180128201 A KR 20180128201A KR 1020170063416 A KR1020170063416 A KR 1020170063416A KR 20170063416 A KR20170063416 A KR 20170063416A KR 20180128201 A KR20180128201 A KR 20180128201A
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ethyl acetate
dichloromethane
nalfurafine
crystalline form
present
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문형욱
고은정
신현익
이기영
오창영
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연성정밀화학(주)
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    • C—CHEMISTRY; METALLURGY
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    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
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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
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Abstract

The present invention relates to the crystal form of nalfurafine and a method for efficiently preparing the crystal form of nalfurafine. According to an embodiment of the present invention, the method for preparing the high-purity nalfurafine crystal form includes a step of crystallizing the nalfurafine in a mixed solvent of dichloromethane and ethyl acetate. The crystallization reaction is executed in the process of dissolving the nalfurafine in the mixed solvent of dichloromethane and ethyl acetate and stirring the solution at room temperature.

Description

날퓨라핀 결정형 및 이의 제조방법 {Crystalline Form of Nalfurafine and Process of Preparing the Same}[0001] The present invention relates to a crystalline form of nalfurafine and a process for preparing the same,

본 발명은 날퓨라핀(Nalfurafine) 결정형 및 이의 제조방법에 관한 것이다. 보다 구체적으로, 본 발명은 고순도의 날퓨라핀 결정형 및 상기 날퓨라핀 결정형을 간단한 공정에 의해 제조하는 방법에 관한 것이다.The present invention relates to a Nalfurafine crystal form and a method for producing the same. More specifically, the present invention relates to a method for producing a high purity nalpurin crystal form and a nalpurin crystal form by a simple process.

하기 화학식 1로 표시되는 날퓨라핀 ((2E)-N-[5α,6β]-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-yl]-3-(3-furanyl)-N-methyl-2-propenamide)은 혈액투석환자를 위한 소양증 치료제인 레밋치(REMITCH®)의 활성 약학적 성분(API)인 날퓨라핀 염산염의 원료이다.To nalpyu Lapin ((2 E) represented by the formula 1 - N - [5α, 6β ] -17- (cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxymorphinan-6-yl] -3- (3- furanyl- N- methyl-2-propenamide is a raw material for napuracil hydrochloride, an active pharmaceutical ingredient (API) of REMITCH ® , a treatment for pruritus for hemodialysis patients.

[화학식 1] [Chemical Formula 1]

Figure pat00001
Figure pat00001

미국 특허 제6,277,859호에는 날퓨라핀을 에틸아세테이트를 이용하여 재결정화한 후 염산과 반응시켜 날퓨라핀 염산염을 제조하는 방법이 개시되어 있다.U.S. Patent No. 6,277,859 discloses a method for producing nalfurafine hydrochloride by recrystallizing nalfuraphine using ethyl acetate and reacting it with hydrochloric acid.

그러나, 상기 날퓨라핀의 결정화 방법은 날퓨라핀을 에틸아세테이트 조건 하에서 가열하여 완전히 용해시킨 후 에틸아세테이트를 일정량 감압 증류하고 결정화하는 복잡한 공정의 문제점이 있었다. 또한, 상기 제조방법에 따라 제조된 날퓨라핀은 순도가 낮은 문제점이 있었다. However, the method of crystallizing nalfurafine has a complicated process in which nafurafine is completely dissolved by heating under ethyl acetate conditions, and then a certain amount of ethyl acetate is distilled off under reduced pressure to crystallize. In addition, there is a problem that the purity of the furan powder produced according to the above-mentioned production method is low.

미국 특허 제6,277,859호U.S. Patent No. 6,277,859

본 발명의 한 목적은 고순도의 날퓨라핀 결정형을 제공하는 것이다.It is an object of the present invention to provide a high-purity fulleridine crystalline form.

본 발명의 다른 목적은 상기 날퓨라핀 결정형의 제조방법을 제공하는 것이다. Another object of the present invention is to provide a method for producing the nalpurin crystal form.

본 발명의 일 실시형태는 X선 분말 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 10% 이상인 회절각(2θ)의 값이 6.80±0.2, 9.11±0.2, 11.37±0.2, 13.25±0.2, 19.49±0.2 및 23.81±0.2인 하기 화학식 1로 표시되는 날퓨라핀 결정형에 관한 것이다.One embodiment of the present invention, I / I 0 in X-ray powder diffraction analysis, the value of not less than a 10% (I: intensity of the largest peak: each diffraction intensity of the peak in each, I 0) Diffraction angle (2θ) 6.80 ± 0.2, 9.11 ± 0.2, 11.37 ± 0.2, 13.25 ± 0.2, 19.49 ± 0.2 and 23.81 ± 0.2, respectively.

[화학식 1][Chemical Formula 1]

Figure pat00002
Figure pat00002

본 발명에 따른 날퓨라핀 결정형은 상기 X선 분말 회절피크 이외에 약한 강도로, 11.78±0.2, 16.39±0.2, 16.93±0.2, 18.04±0.2, 20.46±0.2, 21.34±0.2, 21.76±0.2, 22.42±0.2 및 22.81±0.2의 회절각(2θ)에서 X선 분말 회절피크를 추가로 가질 수 있다. 이때, "약한 강도"란 I/I0 (상대강도)가 10% 미만인 피크를 의미한다.The crystalline form of nalfuridine according to the present invention exhibits a weak intensity in addition to the above X-ray powder diffraction peaks at 11.78 ± 0.2, 16.39 ± 0.2, 16.93 ± 0.2, 18.04 ± 0.2, 20.46 ± 0.2, 21.34 ± 0.2, 21.76 ± 0.2 and 22.42 ± 0.2 And an X-ray powder diffraction peak at a diffraction angle (2?) Of 22.81 ± 0.2. At this time, "weak intensity" means a peak having I / I 0 (relative intensity) of less than 10%.

본 발명의 일 실시형태에 따른 날퓨라핀 결정형은 시차주사열량 분석에서, 첫번째 흡열점은 146.8 ℃, 두번째 흡열점은 162.0 ℃의 값을 나타낸다.In the case of the fullerfin crystalline form according to one embodiment of the present invention, in the differential scanning calorimetry, the first endothermic point is 146.8 캜 and the second endothermic point is 162.0 캜.

본 발명에 따른 날퓨라핀 결정형은 순도가 99.5% 이상, 특히 99.8% 이상이므로, 고순도의 날퓨라핀 염산염을 제조하는데 유용하게 사용될 수 있다. Since the crystal of the present invention has a purity of 99.5% or more, especially 99.8% or more, the present invention can be usefully used for producing highly pure pureulphane hydrochloride.

다른 한편으로, 본 발명은 날퓨라핀을 디클로로메탄과 에틸아세테이트의 혼합용매에서 결정화하는 단계를 포함하는 상기 날퓨라핀 결정형의 제조방법에 관한 것이다. On the other hand, the present invention relates to a process for the preparation of said nalpurin crystals comprising the step of crystallizing nalupapine in a mixed solvent of dichloromethane and ethyl acetate.

상기 디클로로메탄과 에틸아세테이트의 혼합 부피비는 1:1 내지 1:4일 수 있다. The mixing volume ratio of dichloromethane and ethyl acetate may be 1: 1 to 1: 4.

본 발명의 일 실시형태에서, 상기 결정화는 날퓨라핀을 디클로로메탄과 에틸아세테이트의 혼합용매에 용해시킨 다음 상온에서 교반하여 수행될 수 있다. 이때, 용해 시의 온도는 40 내지 60 ℃가 바람직하다. In one embodiment of the present invention, the crystallization can be performed by dissolving the fullerene in a mixed solvent of dichloromethane and ethyl acetate, followed by stirring at room temperature. At this time, the temperature at the time of dissolution is preferably 40 to 60 占 폚.

본 발명의 다른 실시형태에서, 상기 결정화는 날퓨라핀을 먼저 디클로로메탄에 용해시키고, 에틸아세테이트를 천천히 가한 다음 상온에서 교반하여 수행될 수 있다. 이때, 용해 시의 온도는 상온이 바람직하다.In another embodiment of the present invention, the crystallization can be performed by first dissolving the fullerin in dichloromethane, slowly adding ethyl acetate and stirring at room temperature. At this time, the temperature at the time of dissolution is preferably room temperature.

본 발명의 일 실시형태에 따른 날퓨라핀 결정형의 제조방법은 생성된 날퓨라핀 결정형을 여과하고 세척한 다음 건조하는 단계를 추가로 포함할 수 있다. The method for producing the fullerfin crystalline form according to an embodiment of the present invention may further include the step of filtering, washing, and then drying the resulting crystalline form of fulapine.

상기 결정화에 사용되는 날퓨라핀은 상업적으로 입수하거나 당해 기술분야에서 공지된 방법에 의해 용이하게 제조할 수 있다.The fulafilin used for the crystallization is commercially available or can be easily prepared by methods known in the art.

본 발명에 따른 날퓨라핀 결정형은 순도가 높아 고순도의 날퓨라핀 염산염을 제조하는데 유용하게 사용될 수 있다. 또한, 본 발명에 따른 날퓨라핀 결정형의 제조방법에 따르면, 날퓨라핀 결정형을 간단한 공정에 의해 제조할 수 있다. The crystalline form of nalfurafine according to the present invention has a high purity and can be usefully used for producing high purity nalfurate hydrochloride. Further, according to the preparation method of the fullerfin crystal according to the present invention, the crystal form of fuller's alpha can be produced by a simple process.

도 1은 실시예 1에서 수득한 날퓨라핀 결정형의 X선 분말 회절도이다.
도 2는 실시예 1에서 수득한 날퓨라핀 결정형의 시차주사열량 분석도이다.Fig. 1 is an X-ray powder diffraction chart of the crystalline form of nalfuridine obtained in Example 1. Fig.
Fig. 2 is a graph showing the differential scanning calorimetry of the crystalline form of nalfuridine obtained in Example 1. 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:  One: 날퓨라핀Napu raffin 결정형의 제조 Manufacture of crystal form

무정형의 날퓨라핀(1.0 g)을 40℃에서 디클로로메탄 : 에틸아세테이트 = 1 : 1 혼합용매(35 ml)에 녹인 후, 서서히 실온으로 낮추어 약 3시간 정도 교반하였다. 백색 고체가 생성되면 생성된 고체를 여과하고 디클로로메탄 : 에틸아세테이트 = 1 : 1 혼합용매(5 ml)로 세척하였다. 고체를 진공 중에 건조하여 날퓨라핀 결정형(0.70 g, 70%)를 수득하였다. 수득한 날퓨라핀 결정형의 순도는 99.882%였다.Amorphous nafugarupine (1.0 g) was dissolved in a mixed solvent of dichloromethane: ethyl acetate = 1: 1 (40 ml) at 40 ° C, and then slowly cooled to room temperature and stirred for about 3 hours. When a white solid was formed, the resulting solid was filtered and washed with dichloromethane: ethyl acetate = 1: 1 mixed solvent (5 ml). The solid was dried in vacuo to give crystalline fenraft phase (0.70 g, 70%). The purity of the obtained crystalline form of napulapine was 99.882%.

수득한 날퓨라핀 결정형의 X선 분말 회절분석 및 시차주사열량 분석을 수행하여, 그 결과를 각각 도 1 및 도 2에 나타내었다. The X-ray powder diffraction analysis and the differential scanning calorimetry of the obtained nafurafine crystal form were carried out, and the results are shown in Fig. 1 and Fig. 2, respectively.

도 1에서, 수득한 날퓨라핀 결정형이 X선 분말 회절분석에서 특징적인 결정형태를 갖는 것을 확인할 수 있었다. 도 1의 X선 분말 회절도에 나타난 특징적인 피크를 하기 표 1에 나타내었으며, 여기서 '2θ'는 회절각을, 'd'는 결정면 간의 거리를, 'I/I0'는 피크의 상대강도를 의미한다.In Fig. 1, it was confirmed that the obtained crystalline form of napulapine had a characteristic crystal form in the X-ray powder diffraction analysis. The characteristic peaks shown in the X-ray powder diffraction chart of FIG. 1 are shown in the following Table 1, where '2θ' is the diffraction angle, 'd' is the distance between the crystal faces, 'I / I 0 ' .

2θ2? dd I/I0 I / I 0 2θ2? dd I/I0 I / I 0 6.7966.796 12.9967112.99671 100100 19.49219,492 4.550384.55038 30.330.3 9.1149.114 9.695509.69550 57.157.1 20.45720.457 4.337814.33781 3.13.1 11.36911.369 7.777007.77700 13.413.4 21.33521.335 4.161244.16124 4.44.4 11.77611.776 7.508827.50882 9.19.1 21.75821.758 4.081444.08144 2.52.5 13.25013.250 6.676766.67676 29.229.2 22.42122.421 3.962153.96215 3.13.1 16.38816.388 5.404665.40466 4.54.5 22.81422.814 3.894873.89487 9.09.0 16.92516.925 5.234355.23435 4.24.2 23.80923.809 3.734243.73424 10.510.5 18.03518.035 4.914504.91450 9.19.1

X선 분말 회절분석X-ray powder diffraction analysis

상기 X선 분말 회절분석(XRD)은 분말 X선 회절기를 사용하여 5~40 °2θ의 범위에서 회절 패턴을 얻었다. 분말 X선 회절분석 조건은 다음과 같다.The X-ray powder diffraction analysis (XRD) used a powder X-ray diffractometer to obtain a diffraction pattern in the range of 5 to 40 degrees 2 ?. Powder X-ray diffraction analysis conditions are as follows.

- 기기: Bruker A26X1 D2 Phaser - Device: Bruker A26X1 D2 Phaser

- Time per step: 0.5 s- Time per step: 0.5 s

- 주사방식: Continuous PSD fast- Scanning method: Continuous PSD fast

- 검출기: Lynxeye (1D mode)- Detector: Lynxeye (1D mode)

시차주사열량 분석Differential scanning calorimetry

시차주사열량 분석(DSC)은 TA instrument의 Q2000 model을 사용하여 수행하였다. 약 2~3 mg의 시료를 알루미늄 팬에 넣고, 구멍 뚫린 뚜껑으로 덮어 DSC 실험에 필요한 시료를 준비하였다. 정확한 무게를 기록한 후, 질소 하에 10 ℃/min의 속도로 25 ~ 250 ℃까지 가열하였다.Differential scanning calorimetry (DSC) was performed using a TA instrument Q2000 model. About 2 ~ 3 mg of the sample was placed in an aluminum pan and covered with a perforated lid to prepare a sample required for DSC experiment. After recording the exact weight, it was heated to 25 to 250 DEG C at a rate of 10 DEG C / min under nitrogen.

실시예Example 2:  2: 날퓨라핀Napu raffin 결정형의 제조 Manufacture of crystal form

무정형의 날퓨라핀(1.0 g)을 실온에서 디클로로메탄(8 ml)에 1시간 내지 2시간 교반하여 완전히 용해하였다. 에틸아세테이트(8 ml)를 서서히 가한 뒤 실온에서 약 3시간 정도 교반하였다. 생성된 고체를 여과하고 에틸아세테이트(4 ml)로 세척하였다. 고체를 진공 중에 건조하여 날퓨라핀(0.72 g, 72%)를 수득하였다. 수득한 날퓨라핀 결정형의 순도는 99.807%였다.Amorphous nafurafine (1.0 g) was completely dissolved in dichloromethane (8 ml) at room temperature for 1 hour to 2 hours with stirring. Ethyl acetate (8 ml) was slowly added thereto, followed by stirring at room temperature for about 3 hours. The resulting solid was filtered and washed with ethyl acetate (4 ml). The solids were dried in vacuo to give nalurafine (0.72 g, 72%). The purity of the obtained nafurafine crystal form was 99.807%.

수득한 날퓨라핀 결정형의 X선 분말 회절분석 및 시차주사열량 분석을 수행하여, 실시예 1에서 얻은 결정형과 동일한 결정형임을 확인하였다.X-ray powder diffraction analysis and differential scanning calorimetry of the obtained nafurafine crystal type were carried out to confirm that the crystal form was the same as that of the crystalline form obtained in Example 1.

비교예Comparative Example 1:  One: 날퓨라핀Napu raffin 결정형의 제조 Manufacture of crystal form

무정형의 날퓨라핀(15.0 g)을 에틸아세테이트(630 ml)에 가열하면서 녹인 후, 에틸아세테이트(150 ml)를 증류 제거하였다. 서서히 상온으로 온도를 낮추어 날퓨라핀(9.03 g, 60%)을 수득하였다. 수득한 날퓨라핀의 순도는 99.282%였다.Amorphous nafurafine (15.0 g) was dissolved in ethyl acetate (630 ml) while heating, and then ethyl acetate (150 ml) was distilled off. The temperature was gradually lowered to room temperature to obtain nelfurypine (9.03 g, 60%). The purity of the obtained fugu raffin was 99.282%.

Claims (8)

X선 분말 회절분석에서 I/I0 (I: 각 회절각에서의 피크의 강도, I0: 가장 큰 피크의 강도)가 10% 이상인 회절각(2θ)의 값이 6.80±0.2, 9.11±0.2, 11.37±0.2, 13.25±0.2, 19.49±0.2 및 23.81±0.2인 날퓨라핀 결정형.In the X-ray powder diffraction analysis, the diffraction angles (2θ) of I / I 0 (I: intensity of peak at each diffraction angle, I 0 : intensity of largest peak) of 10% or more were 6.80 ± 0.2, 9.11 ± 0.2 , 11.37 ± 0.2, 13.25 ± 0.2, 19.49 ± 0.2 and 23.81 ± 0.2. 제1항에 있어서, 시차주사열량 분석에서 첫번째 흡열점은 146.8 ℃, 두번째 흡열점은 162.0 ℃의 값을 나타내는 날퓨라핀 결정형.The method according to claim 1, wherein the first endothermic point is 146.8 占 폚 in the differential scanning calorimetry and the second endothermic point is 162.0 占 폚. 제1항에 있어서, 99.8% 이상의 순도를 가지는 날퓨라핀 결정형.2. The crystalline form of fullerazine according to claim 1, having a purity of 99.8% or more. 날퓨라핀을 디클로로메탄과 에틸아세테이트의 혼합용매에서 결정화하는 단계를 포함하는 제1항에 따른 날퓨라핀 결정형의 제조방법.A process for producing a crystalline form of nalfuridine according to claim 1 comprising the step of crystallizing nalfurafine in a mixed solvent of dichloromethane and ethyl acetate. 제4항에 있어서, 상기 결정화는 날퓨라핀을 디클로로메탄과 에틸아세테이트의 혼합용매에 용해시킨 다음 상온에서 교반하여 수행되는 제조방법.5. The process according to claim 4, wherein the crystallization is carried out by dissolving the fullerene in a mixed solvent of dichloromethane and ethyl acetate, followed by stirring at room temperature. 제4항에 있어서, 상기 결정화는 날퓨라핀을 먼저 디클로로메탄에 용해시키고 에틸아세테이트를 천천히 가한 다음 상온에서 교반하여 수행되는 제조방법.5. The process according to claim 4, wherein the crystallization is carried out by first dissolving the fullerin in dichloromethane, slowly adding ethyl acetate and stirring at room temperature. 제4항에 있어서, 상기 디클로로메탄과 에틸아세테이트의 혼합 부피비는 1:1 내지 1:4인 제조방법.The process according to claim 4, wherein the mixing ratio of dichloromethane to ethyl acetate is 1: 1 to 1: 4. 제4항에 있어서, 생성된 날퓨라핀 결정형을 여과하고 세척한 다음 건조하는 단계를 추가로 포함하는 제조방법.5. The method according to claim 4, further comprising the step of filtering, washing, and then drying the resulting crystalline form of fulapain.
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