KR101102957B1 - Asymmetric synthetic method of preparing ?-dihydrotetrabenazine and tetrabenazine - Google Patents
Asymmetric synthetic method of preparing ?-dihydrotetrabenazine and tetrabenazine Download PDFInfo
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Abstract
본 발명은 알파-디하이드로테트라베나진 및 테트라베나진의 제조방법에 관한 것으로서, 본 발명의 제조방법에 의하여 알파-디하이드로테트라베나진 또는 테트라베나진을 직접적으로 제조할 수 있다. 본 발명의 제조방법에 의하여, 라세미체를 제조한 후 효소나 HPLC를 이용한 분리방법으로 한 쪽 이성질체를 제조하는 종래의 제조방법을 획기적으로 개선되어, 효과적으로 알파-디하이드로테트라베나진 또는 테트라베나진을 입체선택적으로 제조할 수 있다.The present invention relates to a method for preparing alpha-dihydrotetrabenazine and tetrabenazine, and it is possible to directly prepare alpha-dihydrotetrabenazine or tetrabenazine by the production method of the present invention. According to the preparation method of the present invention, a conventional preparation method for producing one isomer by a separation method using an enzyme or HPLC after preparing the racemate is greatly improved, and effectively alpha-dihydrotetrabenazine or tetrabena Genes can be stereoselectively prepared.
알파-디하이드로테트라베나진, 테트라베나진 Alpha-dihydrotetrabenazine, tetrabenazine
Description
본 발명은 알파-디하이드로테트라베나진 및 테트라베나진의 제조방법에 관한 것이다. 보다 구체적으로는 라세미체를 분리하는 것이 아니라 알파-디하이드로테트라베나진 또는 테트라베나진을 직접적으로 제조하는 방법으로서, 효과적으로 알파-디하이드로테트라베나진 또는 테트라베나진을 제조할 수 있다. The present invention relates to a process for preparing alpha-dihydrotetrabenazine and tetrabenazine. More specifically, as a method of directly preparing alpha-dihydrotetrabenazine or tetrabenazine without separating racemates, alpha-dihydrotetrabenazine or tetrabenazine can be effectively produced.
테트라베나진(Tetrabenazine, TBZ)은 하기 화학식 1과 같은 화학구조를 가지는 화합물로서, 1957년에 A. Pletscher 등에 의하여 최초로 개발된 화합물이다.Tetrabenazine (TBZ) is a compound having a chemical structure represented by the following Chemical Formula 1, and was first developed by A. Pletscher et al in 1957.
[화학식 1][Formula 1]
테트라베나진은 레세르핀(reserpine)의 진정효과를 개선하기 위해 구조적으로 레세르핀과 유사하면서 합성적으로 쉽게 만들 수 있는 이소퀴놀리지 딘(isoquinolizidine) 골격의 화합물로서, 당시 5-HT에 대한 방출효과가 레세르핀에 버금가는 활성을 보이는 물질로 알려지게 되었다 ((a) Pletscher, A. Science, 1957, 126, 507. (b) Brossi, A.; Chopard-dit-Jean, L. H.; Schnider, O. Helv. Chim. Acta 1958, 41, 1793. (c) Osbond, J. M. J. Chem. Soc., 1961, 4711.).Tetrabenazine is a compound of the isoquinolizidine skeleton that is structurally similar to reserpin and can be easily synthesized to improve the calming effect of reserpine. The release effect has been known to be comparable to reserpin ((a) Pletscher, A. Science , 1957, 126 , 507. (b) Brossi, A .; Chopard-dit-Jean, LH; Schnider , O. Helv. Chim.Acta 1958, 41 , 1793. (c) Osbond, JM J. Chem. Soc., 1961, 4711.).
1980년대 초반, VMAT(vesicular monoamine transporter, 소포 모노아민 운반체) 수송체(receptor)에 대해 테트라베나진이 선택적으로 결합하고 또한 이 결합이 가역적이라는 것이 알려지면서 테트라베나진에 대한 관심은 폭발적으로 증가하게 된다 ((a) Cooper, J. R.; Bloom, F. E.; Roth, R. H. The Biochemical Basis of Neuropharmacology 5th Ed, Oxford University Press, New York, 1986. (b) Neumeyer J. L. Weiner N. Pharmacological Basis of Therapeutics, New York, 1985.).Interest in tetrabenazine increased explosively in the early 1980s, when it was known that tetrabenazine selectively binds to the vesicular monoamine transporter (VMAT) receptor and that the binding is reversible. ((a) Cooper, JR; Bloom, FE; Roth, RH The Biochemical Basis of Neuropharmacology 5th Ed , Oxford University Press, New York, 1986. (b) Neumeyer JL Weiner N. Pharmacological Basis of Therapeutics , New York, 1985. ).
VMAT 수송체는 신경전달계 내의 도파민(dopamine), 세로토닌(serotonin), 노르에피네프린(norepinephrine)이 시냅스전(presynaptic) 뉴런의 소포(vesicle)내로 전달될 때 필수적인 수송체이다. VMAT 수송체는 이들 신경전달인자(neurotransmitter)를 ATP 의존적으로 소포내로 받아들이게 되는데 이렇게 해서 소포내로 들어간 신경전달인자들은 시냅스(synapse)로 옮겨져서 신경자극에 맞춰서 시냅스 틈(synaptic cleft)으로 방출된다. 시냅스 틈(synaptic cleft)으로 나온 신경전달인자들은 인접한 세포의 수용체를 자극하면서 신경신호를 전달 및 증폭하는 역할을 한다. 테트라베나진은 이러한 전달체계의 초기에 작용하는 VMAT 수송체를 선택적으로 억제하기 때문에 뇌신경학자들에게 각광을 받았던 것이다. 더구나 비슷 한 작용을 하는 천연물인 레세르핀에 비해 테트라베나진은 가역적으로 작용하기 때문에 부작용이 적다는 장점이 있다.VMAT transporters are essential transporters when dopamine, serotonin, and norepinephrine in the neurotransmitter are delivered into the vesicles of presynaptic neurons. The VMAT transporter accepts these neurotransmitters into the vesicles in an ATP-dependent manner, whereby the neurotransmitters that enter the vesicles are transported to the synapse and released into the synaptic cleft in response to the neurostimulation. Neurotransmitters that come out of the synaptic cleft stimulate the receptors of adjacent cells to transmit and amplify nerve signals. Tetrabenazine has been in the spotlight by neurologists because it selectively inhibits the VMAT transporter acting early in this delivery system. In addition, tetrabenazine is a reversible action compared to the natural product similar to the action of reserpine has the advantage of fewer side effects.
최근에는 테트라베나진이 미국 FDA에 의하여 희귀 유전성 질환인 헌팅턴 병(huntington's disease)의 치료약물로 승인되어, 테트라베나진에 대한 관심이 더욱 증가될 것으로 예상된다. 헌팅턴 병은 유전적 질환으로서 무도병(chorea)이라고도 불리는 증상을 보이는데, 4번 염색체에 위치하는 IT15라는 유전자의 결함이 원인으로 알려져 있다. 또한 1만 명당 1명의 비율로 발생하며 30대 초반에서 50대 사이에 주로 발생하며 대부분이 첫 번째 증상이 발현된 이후 15년을 넘기지 못하고 사망하는 질병으로 알려져 있다. 대표적인 증상은 근육의 경련적 동작이나 발작이고, 시간이 지나면서 기억력과 근육의 조절능력을 상실하게 되며, 혼란과 성격적인 문제가 나타나고 나중에는 운동, 사고, 의사소통의 기능을 상실하게 되며, 호흡곤란, 심부전, 감염등도 함께 수반될 수 있다. In recent years, tetrabenazine has been approved by the US FDA as a treatment for a rare hereditary disease, Huntington's disease, which is expected to further increase interest in tetrabenazine. Huntington's disease is a hereditary disease, also called chorea, which is known to be caused by a defect in the gene, IT15, located on chromosome 4. In addition, it occurs at a rate of 1 per 10,000 people, mainly between the early 30's and 50's, and most of them are known to die for less than 15 years after the first symptoms. Typical symptoms are muscle cramps or seizures, over time, loss of memory and muscle control, confusion and personality problems, later loss of exercise, thinking and communication, and breathing Difficulty, heart failure, and infection can be accompanied.
이에 테트라베나진은 임상시험 결과 69 ~ 80%의 환자에서 이러한 헌팅턴 병의 대표적인 증상인 무도증상(chorea)을 낮추는데 효과적이라는 것이 입증되어 미국 FDA의 승인을 받게 된 것이다. 다만, FDA에 의하여 승인된 테트라베나진은 라세미체로 승인을 받았다. Tetrabenazine has been clinically proven to be effective in lowering chorea, a major symptom of Huntington's disease, in 69-80% of patients. Tetrabenazine, approved by the FDA, has been approved for racemate.
알파-디하이드로테트라베나진(α-Dihydrotetrabenazine, DHTBZ)은 하기 화학식 2의 구조를 가지는 화합물로서, 테트라베나진이 체내에서 대사되어 생기는 물질로 1980년대 후반에 처음 보고되었으나 곧이어 테트라베나진보다도 VMAT 수용체에 더 선택적으로 결합하는 것이 밝혀졌다. 중요한 사실은, 라세미체를 분 리(resolution)하여 각각의 화합물에 대해 실험한 결과, 하기 구조를 가지는 알파-디하이드로테트라베나진이 이의 거울상 이성질체보다 VMAT 수용체에 보다 효과적으로 결합하는 것이 밝혀졌다 ((a) Kilbourn, M.; Lee, L.; Vander Borght, T.; Jewett, D.; Frey, K. Eur. J. Pharmacol. 1995, 278, 249-252. (b) Kilbourn, M. R.; Lee, L. C.; Heeg, M. J.; Jewett, D. M. Chirality 1997, 9, 59-62.).Alpha-Dihydrotetrabenazine (α-Dihydrotetrabenazine, DHTBZ) is a compound having the structure of Formula 2, which is a metabolite produced by tetrabenazine in the body, first reported in the late 1980s, but soon after the VMAT receptor than tetrabenazine It was found to bind more selectively. Importantly, the resolution of the racemate and the experiments for each compound revealed that alpha-dihydrotetrabenazine, which has the following structure, binds more effectively to the VMAT receptor than its enantiomer (( a) Kilbourn, M .; Lee, L .; Vander Borght, T .; Jewett, D .; Frey, K. Eur. J. Pharmacol . 1995, 278 , 249-252. (b) Kilbourn, MR; Lee, LC; Heeg, MJ; Jewett, DM Chirality 1997, 9 , 59-62.).
[화학식 2][Formula 2]
종래 Brossi 등은 하기 반응식에 기재된 바와 같이, 화합물 14에 4급 암모늄 염(15)을 가하여 이소퀴놀리지딘(isoquinolizidine, 16)을 한 번에 합성하였다. 여기에 팔라듐(palladium)을 이용한 환원반응으로 벤질보호기를 탈보호하고 메틸화 반응을 수행하여 테트라베나진(8)을 합성할 수 있었다. 이렇게 얻은 테트라베나진에 NaBH4를 이용한 환원반응을 수행하여 디하이드로테트라베나진(9)을 얻었으며 (Schwartz, D. E.; Bruderer, H.; Rieder, J.; Brossi, A. Biochem. Pharm. 1966, 15, 645.), 이 때의 입체선택성은 4 대 1 정도인 것으로 알려져 있다 (Lee, L.C.; Borght, T. V.; Sherman, P. S.; Frey, K. A.; Kilbourn, M. R. J. Med. Chem. 1996, 39, 191).Conventional Brossi et al. Synthesized isoquinolizidine (16) at once by adding a quaternary ammonium salt (15) to compound 14, as described in the following scheme. Here, the benzyl protecting group was deprotected by a reduction reaction using palladium, and methylation was performed to synthesize tetrabenazine (8). Thus obtained tetrabenazine was subjected to a reduction reaction with NaBH 4 to obtain dihydrotetrabenazine (9) (Schwartz, DE; Bruderer, H .; Rieder, J .; Brossi, A. Biochem. Pharm. 1966, 15 , 645.), the stereoselectivity at this time is known to be about 4 to 1 (Lee, LC; Borght, TV; Sherman, PS; Frey, KA; Kilbourn, MR J. Med. Chem . 1996, 39 , 191).
그러나 상기의 제조방법은 4급 암모늄 염(15)을 따로 만들어야 하는 단점과 그렇게 만든 암모늄 염과의 첫 번째 반응이 낮은 수율을 보인다는 단점이 있다. 그리고 마지막 환원반응시의 낮은 입체선택성도 극복해야할 점이다. 무엇보다도 이러한 경로로는 라세미체를 합성할 수 밖에 없으며 입체선택적인 합성을 위해서는 첫 번째 반응의 입체선택성을 연구해서 개선해야 하는데 이에 대한 연구는 거의 진행되지 않고 있다.However, the above production method has a disadvantage in that the quaternary ammonium salt (15) must be made separately and the first reaction with the ammonium salt thus made has a low yield. And low stereoselectivity in the last reduction reaction should be overcome. Above all, such a route can only synthesize racemates, and for stereoselective synthesis, the stereoselectivity of the first reaction should be studied and improved.
Kilbourn 등은 (+/-)-디하이드로테트라베나진을 chiral HPLC를 이용해서 분리하고자 하였다. 이 경우 두 차례 이상의 분리를 통해 광학적으로 순수한(optically pure) 이성질체를 확보할 수 있었는데, 한 번 분리시에 30 mg 이상을 주입(loading)할 수 없는 단점을 보였다 ((a) Kilbourn, M.; Lee, L.; Vander Borght, T.; Jewett, D.; Frey, K. Eur. J. Pharmacol. 1995, 278, 249. (b) Kilbourn, M. R.; Lee, L. C.; Heeg, M. J.; Jewett, D. M., Chirality, 1997, 9, 59.).Kilbourn et al. Attempted to separate (+/-)-dihydrotetrabenazine by chiral HPLC. In this case, it was possible to obtain optically pure isomer through two or more separations, which showed the disadvantage of not loading more than 30 mg in one separation ((a) Kilbourn, M .; Lee, L .; Vander Borght, T .; Jewett, D .; Frey, K. Eur. J. Pharmacol. 1995, 278 , 249. (b) Kilbourn, MR; Lee, LC; Heeg, MJ; Jewett, DM , Chirality , 1997, 9 , 59.).
이에 한 쪽 이성질체만 제조하는 방법이 요구되고 있으나, 이를 직접적으로 합성하는 비대칭합성법(asymmetric synthesis)은 아직 보고되지 않고 있으며, 통상적으로 라세미체를 제조한 후 효소나 HPLC를 이용하여 분리방법으로 한 쪽 이성질체를 제조하고 있는 실정이다. 그러나 효소를 이용한 분리 시에는 효소 분리를 위해 치환기를 수식해야 하고 또 반응 시에도 2주일 이상의 시간이 소요되며, HPLC를 이용한 방법은 대량 분리를 할 수 없다는 단점이 있다.There is a need for a method for preparing only one isomer, but asymmetric synthesis has not yet been reported to directly synthesize the isomer. It is the situation to manufacture the isomer. However, the separation using enzymes requires modification of the substituents for the separation of enzymes, and the reaction takes more than two weeks, and the method using HPLC does not have the disadvantage of mass separation.
본 발명의 목적은, 라세미체를 제조하여 분리하는 것이 아니라 알파-디하이드로테트라베나진 또는 테트라베나진을 직접적으로 제조하는 방법으로서, 효과적으로 알파-디하이드로테트라베나진 또는 테트라베나진을 제조하는 방법을 제공하는 것이다.An object of the present invention is to prepare alpha-dihydrotetrabenazine or tetrabenazine directly, not to prepare and separate racemates, and to effectively prepare alpha-dihydrotetrabenazine or tetrabenazine. To provide a way.
상기와 같은 목적을 달성하기 위하여, 본 발명은 반응식 1과 같이 알파-디하이드로테트라베나진의 제조방법을 제공한다. In order to achieve the above object, the present invention provides a method for preparing alpha-dihydrotetrabenazine as in Scheme 1.
또한 본 발명은 반응식 2와 같이 테트라베나진을 제조하는 방법을 제공한다.The present invention also provides a method for preparing tetrabenazine as in Scheme 2.
본 발명의 제조방법에 의하여 알파-디하이드로테트라베나진 및 테트라베나진을 제조를 하는 경우, 알파-디하이드로테트라베나진 및 테트라베나진의 한 쪽 이성질체만 효과적으로 제조할 수 있을 뿐만 아니라, 라세미체를 제조한 후 효소나 HPLC를 이용한 분리방법으로 한 쪽 이성질체를 제조하는 종래의 제조방법이 획기적으로 개선되므로, 알파-디하이드로테트라베나진 또는 테트라베나진을 효과적으로 제조할 수 있다. When alpha-dihydrotetrabenazine and tetrabenazine are prepared by the preparation method of the present invention, not only one isomer of alpha-dihydrotetrabenazine and tetrabenazine can be effectively produced, but also racemates Since the conventional manufacturing method for preparing one isomer by the separation method using enzyme or HPLC after the preparation is greatly improved, alpha-dihydrotetrabenazine or tetrabenazine can be effectively produced.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 반응식 1과 같이, The present invention is as shown in Scheme 1,
화학식 3으로 표시되는 화합물을 4-메틸발레인산과 아마이드화 반응으로 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1);Preparing a compound represented by Chemical Formula 4 by amidating 4-methylvaleric acid with an compound represented by Chemical Formula 3 (step 1);
단계 1에서 제조된 화학식 4로 표시되는 화합물을 말단 이중결합을 알데히드로 치환시키는 반응으로 화학식 5로 표시되는 화합물을 제조하는 단계(단계 2);Preparing a compound represented by Chemical Formula 5 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with an aldehyde substitution of a terminal double bond (Step 2);
단계 2에서 제조된 화학식 5로 표시되는 화합물에 t-부틸디메틸실릴 클로라이드(TBSCl)을 가한 후 1,8-디아자비시클로[5.4.0]운데트-7-엔(DBU)를 가하여 화학식 6으로 표시되는 화합물을 제조하는 단계(단계 3);T-Butyldimethylsilyl chloride (TBSCl) was added to the compound represented by Formula 5 prepared in Step 2, followed by addition of 1,8-diazabicyclo [5.4.0] undet-7-ene (DBU) to Formula 6 Preparing the compound to be displayed (step 3);
단계 3에서 제조된 화학식 6으로 표시되는 화합물을, 리튬 헥사디메틸디실라잔(LiHMDS); i-PrMgCl; 또는 t-butylMgCl과, 톨루엔 또는 벤젠하에 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계(단계 4);Compound represented by the formula (6) prepared in Step 3, Lithium hexadimethyldisilazane (LiHMDS); i-PrMgCl; Or reacting t-butylMgCl with toluene or benzene to produce a compound represented by Chemical Formula 7 (step 4);
단계 4에서 제조된 화학식 7로 표시되는 화합물을 벤젠 또는 테트라하이드로푸란(THF) 용매하에서, p-톨루엔설폰산(TsOH) 또는 요오드산(HI)를 가하여 화학식 8로 표시되는 화합물을 제조하는 단계(단계 5); 및Preparing a compound represented by Chemical Formula 8 by adding p-toluenesulfonic acid (TsOH) or iodic acid (HI) to a compound represented by Chemical Formula 7 prepared in step 4 in a benzene or tetrahydrofuran (THF) solvent ( Step 5); And
단계 5에서 제조된 화학식 8로 표시되는 화합물을 환원반응으로 화학식 2로 표시되는 화합물을 제조하는 단계(단계 6)Preparing a compound represented by Chemical Formula 2 by reducing the compound represented by Chemical Formula 8 prepared in Step 5 (Step 6)
를 포함하여 이루어지는 알파-디하이드로테트라베나진의 제조방법을 제공한다.It provides a method for producing alpha-dihydrotetrabenazine comprising a.
상기 반응식 1의 단계 1은 다음과 같이 수행될 수 있다. Step 1 of Scheme 1 may be performed as follows.
상기 단계 1은 아마이드화 반응(amidation)으로서, 화학식 3으로 표시되는 화합물을 4-메틸발레인산(4-methylvaleric acid)과 아마이드화 반응(amidation)을 수행하여 화학식 4로 표시되는 화합물을 제조할 수 있다. Step 1 is an amidation reaction, and the compound represented by Formula 4 may be prepared by amidation of 4-methylvaleric acid with 4-methylvaleric acid. have.
바람직하게는, 아마이드화 반응은 EDCI(1-(3-dimethylaminopropyl)-3-ethylcarboiimide)와 HOBt(1-hydoxybenzotriazole)의 혼합용매, Oxalyl Chloride, DCC (dicyclohexyl carbodiimide), HOAt (1-hydroxy-7-azabenzotriazole), HATU ((O-7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate), HBTU ((benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate), Pybop ((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate), Pybrop (bromotripyrrolidinophosphonium hexafluorophosphate), DEPC (diethylphosporyl cyanide) 또는 산성조건 (H+)에서 아마이드화를 시키는 것이 바람직하며, 보다 바람직하게는 EDCI(1-(3-dimethylaminopropyl)-3-ethylcarboiimide)와 HOBt(1-hydoxybenzotriazole)의 혼합용매하에 수행되는 것이 바람직하다.Preferably, the amidation reaction is a mixed solvent of EDCI (1- (3-dimethylaminopropyl) -3-ethylcarboiimide) and HOBt (1-hydoxybenzotriazole), Oxalyl Chloride, DCC (dicyclohexyl carbodiimide), HOAt (1-hydroxy-7- azabenzotriazole), HATU ((O-7-azabenzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate), HBTU ((benzotriazol-1-yl) -N, N, N, N-tetramethyluronium hexafluorophosphate) , Pybop ((benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate), Pybrop (bromotripyrrolidinophosphonium hexafluorophosphate), DEPC (diethylphosporyl cyanide) or amidation under acidic conditions (H +) is preferred, and more preferably EDCI (1- (3) -dimethylaminopropyl) -3-ethylcarboiimide) and HOBt (1-hydoxybenzotriazole) are preferably carried out under a mixed solvent.
상기 반응식 1의 단계 2는 다음과 같이 수행될 수 있다. Step 2 of Scheme 1 may be performed as follows.
상기 단계 2는 말단 이중결합을 알데히드로 치환시키는 반응으로서, 단계 1에서 제조된 화학식 4로 표시되는 화합물을 말단 이중결합을 알데히드로 치환시키는 반응으로 화학식 5로 표시되는 화합물을 제조할 수 있다.Step 2 is an aldehyde substitution of the terminal double bond, a compound represented by the formula (5) by the reaction of aldehyde substitution of the terminal double bond with the compound represented by Formula 4 prepared in step 1 can be prepared.
바람직하게는, 말단 이중결합을 알데히드로 치환시키는 반응은 Johnson-Lemieux protocol (Pappo, R.; Allen, Jr., D. S.; Lemieux, R. U.; Johnson, W. S. J. Org. Chem. 1956, 21, 478.)을 이용하여, dihydroxylation을 시키기 위하여 OsO4를 NMO(N-Methylmorpholine N-oxide) 존재 하에 반응시킨 후 얻어진 다이올(diol)에 NaIO4를 첨가하거나; Pd(OAc)4를 이용하거나; 또는 ozone(O3)을 이용한 ozonolysis가 바람직하며, 보다 바람직하게는 Johnson-Lemieux protocol을 이용하는 것이 바람직하다. Preferably, the reaction for aldehyde substitution of the terminal double bond is carried out in the Johnson-Lemieux protocol (Pappo, R .; Allen, Jr., DS; Lemieux, RU; Johnson, WS J. Org. Chem . 1956, 21 , 478. ) it was used and, after the reaction of OsO 4 in order to the dihydroxylation presence NMO (N-Methylmorpholine N-oxide ) was added NaIO 4 in the obtained diol (diol), or; Using Pd (OAc) 4 ; Or ozonolysis using ozone (O 3 ) is preferred, more preferably using the Johnson-Lemieux protocol.
상기 반응식 1의 단계 3은 다음과 같이 수행될 수 있다. Step 3 of Scheme 1 may be performed as follows.
상기 단계 3은 E-에놀 에테르(E-enol ether)를 선택적으로 제조하기 위한 방법으로서, 단계 2에서 제조된 화학식 5로 표시되는 화합물에 TBSCl(tert-Butyldimethylsilyl chloride)을 가한 후, DBU(1,8-Diazabicyclo[5.4.0]undec-7-ene)를 가하여 화학식 6으로 표시되는 화합물을 제조할 수 있다. Step 3 is a method for selectively preparing an E-enol ether. After adding TBSCl (tert-Butyldimethylsilyl chloride) to the compound represented by Formula 5 prepared in Step 2, DBU (1, 8-Diazabicyclo [5.4.0] undec-7-ene) may be added to prepare a compound represented by Chemical Formula 6.
바람직하게는, 단계 2에서 제조된 화학식 5로 표시되는 화합물을 CH2Cl2에 녹이고 t-부틸디메틸실릴 클로라이드(TBSCl)을 가하여 환류한 후, 여기에 1,8-디아자비시클로[5.4.0]운데트-7-엔(DBU)를 가하고 환류시켜 화학식 6으로 표시되는 화합물을 제조하는 것이 바람직하다. Preferably, the compound represented by Chemical Formula 5 prepared in Step 2 is dissolved in CH 2 Cl 2 and refluxed by adding t-butyldimethylsilyl chloride (TBSCl), followed by 1,8-diazabicyclo [5.4.0 ] Undec-7-ene (DBU) is added and refluxed to prepare the compound represented by the formula (6).
상기 반응은 대량 반응시에도 Z-에놀 에테르(Z-enol ether)를 거의 확인할 수 없을 정도로 좋은 선택성을 보이는데 이는 하기 반응식에 기재된 바와 같이 전위상태(transition state)의 1,3-diaxial interaction 때문인 것으로 판단된다.The reaction shows good selectivity such that Z-enol ether can hardly be identified even in a large amount of reaction, which may be due to the 1,3-diaxial interaction of the transition state as described in the following scheme. do.
상기 반응식 1의 단계 4는 다음과 같이 수행될 수 있다. Step 4 of Scheme 1 may be performed as follows.
상기 단계 4는 아자-클라이센 전위(aza-Claisen rearrangement) 반응으로서, 다양한 trapping reagent와 염기(base)를 사용하여 반응이 수행될 수 있다. 구체적으로, 단계 3에서 제조된 화학식 6으로 표시되는 화합물을, LiHMDS(Lithium Hexamethyldisilazide); i-PrMgCl(isopropylmagnesiumchloride); 또는 t-butylMgCl(tert-butylmagnesiumchloride)과 톨루엔 또는 벤젠하에 반응시켜 화학식 7로 표시되는 화합물을 제조할 수 있으며, 바람직하게는, 리튬 헥사디메틸디실라잔(LiHMDS); i-PrMgCl; 또는 t-butylMgCl를 화학식 6으로 표시되는 화합물에 대하여 1 내지 10 당량을 사용하는 것이 바람직하며, 보다 바람직하게는 1.2 내지 5 당량을 사용하는 것이 바람직하다. Step 4 is an aza-Claisen rearrangement reaction, and the reaction may be performed using various trapping reagents and bases. Specifically, the compound represented by Formula 6 prepared in Step 3, LiHMDS (Lithium Hexamethyldisilazide); i-PrMgCl (isopropylmagnesium chloride); Or reacting t-butylMgCl (tert-butylmagnesiumchloride) with toluene or benzene to produce a compound represented by Formula 7, preferably, lithium hexadimethyldisilazane (LiHMDS); i-PrMgCl; Or t-butylMgCl, preferably 1 to 10 equivalents, more preferably 1.2 to 5 equivalents, based on the compound represented by the formula (6).
상기 반응은 하기 반응식에 기재된 바와 같은 전위상태(transition state)를 통하여 반응이 진행되는 것으로 판단된다.It is determined that the reaction proceeds through a transition state as described in the following scheme.
하기 반응식에 기재된 바와 같은 부산물(화학식 7')의 생성을 최소화 한다는 관점에서, i-PrMgCl과 벤젠하에 반응시키는 것이 바람직하다.In view of minimizing the production of by-products (formula 7 ') as described in the following schemes, it is preferred to react i-PrMgCl with benzene.
상기 반응식 1의 단계 5는 다음과 같이 수행될 수 있다.Step 5 of Scheme 1 may be performed as follows.
상기 단계 5는 고리횡단반응(transannulation)으로서, 다양한 산조건과 용매를 이용하여 반응이 수행될 수 있다. 반응수율 및 입체선택성을 고려하여, 단계 4에서 제조된 화학식 7로 표시되는 화합물을 벤젠 또는 THF(tetrahydrofuran) 용매하에서, TsOH(p-Toluenesulfonic acid) 또는 요오드산(HI)를 가하여 화학식 8로 표시되는 화합물을 제조할 수 있으며, 하기 반응식에 기재된 바와 같은 부산물 (화학식 8')의 생성을 최소화 할 수 있다.Step 5 is a transannulation reaction, and the reaction may be performed using various acid conditions and a solvent. In consideration of reaction yield and stereoselectivity, the compound represented by Chemical Formula 7 prepared in Step 4 is added to the compound represented by Chemical Formula 8 by adding ps-toluenesulfonic acid (TsOH) or iodic acid (HI) in a benzene or THF (tetrahydrofuran) solvent. Compounds can be prepared and the production of by-products (formula 8 ') as described in the following schemes can be minimized.
바람직하게는, 단계 4에서 제조된 화학식 7로 표시되는 화합물을 벤젠 용매하에서 p-톨루엔설폰산(TsOH)를 가하여 화학식 8로 표시되는 화합물을 제조하는 것이 바람직하다.Preferably, p-toluenesulfonic acid (TsOH) is added to the compound represented by Formula 7 prepared in Step 4 in a benzene solvent to prepare a compound represented by Formula 8.
상기 반응식 1의 단계 6은 다음과 같이 수행될 수 있다.Step 6 of Scheme 1 may be performed as follows.
상기 단계 6은 환원반응으로서, 단계 5에서 제조된 화학식 8로 표시되는 화합물을 환원반응으로 화학식 2로 표시되는 화합물을 제조할 수 있다. Step 6 is a reduction reaction, the compound represented by the formula (8) prepared in step 5 may be prepared by the reduction reaction to the compound represented by the formula (2).
바람직하게는, 상기 환원반응은 AlH3, DIBAL(diisobutylaluminium hydride), Vitride(Red-Al, sodium bis(2-methoxyethoxy)aluminium hydride solution), 또는 LAH(lithium aluminium hydride)를 사용하는 것이 바람직하며, 보다 바람직하게는 LAH를 사용하는 것이 바람직하다.Preferably, the reduction reaction is preferably using AlH 3 , DIBAL (diisobutylaluminum hydride), Vitride (Red-Al, sodium bis (2-methoxyethoxy) aluminum hydride solution), or LAH (lithium aluminum hydride) Preferably, LAH is used.
또한, 본 발명은 하기 반응식 2와 같이, In addition, the present invention is as shown in Scheme 2,
화학식 3으로 표시되는 화합물을 4-메틸발레인산과 아마이드화 반응으로 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1);Preparing a compound represented by Chemical Formula 4 by amidating 4-methylvaleric acid with an compound represented by Chemical Formula 3 (step 1);
단계 1에서 제조된 화학식 4로 표시되는 화합물을 말단 이중결합을 알데히드로 치환시키는 반응으로 화학식 5로 표시되는 화합물을 제조하는 단계(단계 2);Preparing a compound represented by Chemical Formula 5 by reacting the compound represented by Chemical Formula 4 prepared in Step 1 with an aldehyde substitution of a terminal double bond (Step 2);
단계 2에서 제조된 화학식 5로 표시되는 화합물에 t-부틸디메틸실릴 클로라이드(TBSCl)을 가한 후 1,8-디아자비시클로[5.4.0]운데트-7-엔(DBU)를 가하여 화학식 6으로 표시되는 화합물을 제조하는 단계(단계 3);T-Butyldimethylsilyl chloride (TBSCl) was added to the compound represented by Formula 5 prepared in Step 2, followed by addition of 1,8-diazabicyclo [5.4.0] undet-7-ene (DBU) to Formula 6 Preparing the compound to be displayed (step 3);
단계 3에서 제조된 화학식 6으로 표시되는 화합물을, 리튬 헥사디메틸디실라잔(LiHMDS); i-PrMgCl; 또는 t-butylMgCl과, 톨루엔 또는 벤젠하에 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계(단계 4);Compound represented by the formula (6) prepared in Step 3, Lithium hexadimethyldisilazane (LiHMDS); i-PrMgCl; Or reacting t-butylMgCl with toluene or benzene to produce a compound represented by Chemical Formula 7 (step 4);
단계 4에서 제조된 화학식 7로 표시되는 화합물을 벤젠 또는 테트라하이드로푸란(THF) 용매하에서, p-톨루엔설폰산(TsOH) 또는 요오드산(HI)를 가하여 화학식 8로 표시되는 화합물을 제조하는 단계(단계 5); Preparing a compound represented by Chemical Formula 8 by adding p-toluenesulfonic acid (TsOH) or iodic acid (HI) to a compound represented by Chemical Formula 7 prepared in step 4 in a benzene or tetrahydrofuran (THF) solvent ( Step 5);
단계 5에서 제조된 화학식 8로 표시되는 화합물을 환원반응으로 화학식 2로 표시되는 화합물을 제조하는 단계(단계 6); 및Preparing a compound represented by Chemical Formula 2 by reducing the compound represented by Chemical Formula 8 prepared in Step 5 (Step 6); And
단계 6에서 제조된 화학식 2로 표시되는 화합물을 산화반응으로 화학식 1로 표시되는 화합물을 제조하는 단계 (단계 7)Preparing a compound represented by Chemical Formula 1 by oxidation of the compound represented by Chemical Formula 2 prepared in Step 6 (Step 7)
를 포함하여 이루어지는 테트라베나진의 제조방법을 제공한다.It provides a method for producing tetrabenazine comprising a.
상기 반응식 2의 단계 1 내지 6은 반응식 1의 단계 1 내지 6과 동일한 방법으로 수행될 수 있다. Steps 1 to 6 of Scheme 2 may be performed by the same method as steps 1 to 6 of Scheme 1.
상기 반응식 2의 단계 7은 다음과 같이 수행될 수 있다. Step 7 of Scheme 2 may be performed as follows.
상기 단계 7은 산화반응으로서, 단계 6에서 제조된 화학식 2로 표시되는 화합물을 산화반응으로 화학식 1로 표시되는 화합물을 제조할 수 있으며, 히드록시기를 케톤으로 변화시키는 방법이라면 어떤 방법이라도 제한되지 않으나, 바람직하게 는 TPAP(tetrapropyl ammonium perruthenate) 및 NMO(N-methylmorpholine N-Oxide)를 이용한 산화 방법으로 수행될 수 있다. Step 7 is an oxidation reaction, the compound represented by the formula (2) prepared in step 6 may be prepared by the oxidation reaction, and the compound represented by the formula (1), any method of changing the hydroxy group to ketone is not limited, Preferably it may be carried out by the oxidation method using TPAP (tetrapropyl ammonium perruthenate) and NMO (N-methylmorpholine N-Oxide).
이하, 본 발명을 더욱 상세하게 설명하기 위한 제조예 및 실시예를 제시한다. 그러나 하기의 제조예 및 실시예는 본 발명을 보다 쉽게 설명하기 위하여 제공되는 것일 뿐, 이에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preparation examples and examples for explaining the present invention in more detail. However, the following Preparation Examples and Examples are merely provided to more easily explain the present invention, thereby not limited to the content of the present invention.
[실시예 1] 알파-디하이드로테트라베나진의 제조Example 1 Preparation of Alpha-Dihydrotetrabenazine
[단계 1] 1-[(1R)-1-알릴-6, 7-디메톡시-3, 4-디하이드로-2(1 H)-이소퀴놀리닐]-4-메틸-1-펜타논의 제조 (화학식 4, 1-[(1R)-1-allyl-6, 7-dimethoxy-3, 4-dihydro-2(1 H)-isoquinolinyl]-4-methyl-1-pentanone)[Step 1] Preparation of 1-[(1R) -1-allyl-6, 7-dimethoxy-3, 4-dihydro-2 (1H) -isoquinolinyl] -4-methyl-1-pentanone (Formula 4, 1-[(1R) -1-allyl-6, 7-dimethoxy-3, 4-dihydro-2 (1H) -isoquinolinyl] -4-methyl-1-pentanone)
(R)-1-알릴-6,7-디메톡시-1,2,3,4-테트라하이드로이소퀴놀린(화학식 3, (R)-1-allyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1.2g)과 4-methylvaleric acid(0.89 mL, 7.0 mmol)의 CH2Cl2(20 mL) 용액에 EDCI(1.7 g, 8.8 mmol)와 HOBt(1.2 g, 8.8 mmol)를 실온에서 가하였다. 반응혼합물을 12시간동안 실온에서 교반한 후 포화 NH4Cl 용액을 가하여 반응을 종결하였다. CH2Cl2로 2회 추출하고 유층을 MgSO4로 건조 및 여과한 후 감압여과하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOAc: n-hexane: CH2Cl2 = 1: 4: 1 → 1: 2: 1)하여, 무색 oil의 표제화합물(1.2 g, 70 %)을 제조하였다.(R) -1-allyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Formula 3, (R) -1-allyl-6,7-dimethoxy-1,2,3 In a solution of CH 2 Cl 2 (20 mL) of 4-tetrahydroisoquinoline (1.2 g) and 4-methylvaleric acid (0.89 mL, 7.0 mmol), EDCI (1.7 g, 8.8 mmol) and HOBt (1.2 g, 8.8 mmol) were added to room temperature. Was added. The reaction mixture was stirred at room temperature for 12 hours and then saturated NH 4 Cl solution was added to terminate the reaction. Extraction was performed twice with CH 2 Cl 2 , the oil layer was dried over MgSO 4 , filtered and filtered under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc: n - hexane: CH 2 Cl 2 = 1: 4: 1-1: 2: 1) to give the title compound (1.2 g, 70%) as a colorless oil.
[α]D 20 -115.9 (c 1.9, MeOH); 1H-NMR (CD3OD, 300 MHz, mixture of rotamers) δ 6.79 (s), 6.74 (s, 1H), 6.69 (s, 1H), 5.95 - 5.74 (m, 1H), 5.54 (dd, 1H, J = 5.3, 8.8 Hz), 5.14 - 4.95 (m, 2H), 4.54 (dd, J = 3.5, 13.0 Hz), 3.91 (ddd, 1H, J= 2.9, 5.3, 13.5 Hz), 3.80 (s) 3.78 (s, 6H), 3.53 (ddd, J = 4.95, 10.0, 13.7 Hz), 3.10 (ddd, 1H, J= 4.95, 11.3, 12.9 Hz), 2.91 - 2.24 (m, 6H), 1.67 - 1.39 (m, 3H), 0.94 - 0.87 (m, 6H); 13C-NMR (CD3OD, 100 MHz, mixture of rotamers) δ 175.6, 175.4, 150.3, 150.1, 149.8, 137.2, 136.6, 130.9, 130.7, 128.4, 127.9, 119.6, 118.2, 113.9, 113.7, 112.6, 112.3, 58.2, 57.3, 57.2, 53.7, 43.0, 42.9, 41.9, 37.2, 36.5, 36.3, 33.4, 30.4, 29.8, 29.7, 29.3, 23.5; LRMS (EI) m/z 331 (M+); HR-MS (EI) Calcd for C20H29O3N (M+): 331.2147, Found 331.2135.[α] D 20 -115.9 (c 1.9, MeOH); 1 H-NMR (CD 3 OD, 300 MHz, mixture of rotamers) δ 6.79 (s), 6.74 (s, 1H), 6.69 (s, 1H), 5.95-5.74 (m, 1H), 5.54 (dd, 1H , J = 5.3, 8.8 Hz), 5.14-4.95 (m, 2H), 4.54 (dd, J = 3.5, 13.0 Hz), 3.91 (ddd, 1H, J = 2.9, 5.3, 13.5 Hz), 3.80 (s) 3.78 (s, 6H), 3.53 (ddd, J = 4.95, 10.0, 13.7 Hz), 3.10 (ddd, 1H, J = 4.95, 11.3, 12.9 Hz), 2.91-2.24 (m, 6H), 1.67-1.39 ( m, 3H), 0.94-0.87 (m, 6H); 13 C-NMR (CD 3 OD, 100 MHz, mixture of rotamers) δ 175.6, 175.4, 150.3, 150.1, 149.8, 137.2, 136.6, 130.9, 130.7, 128.4, 127.9, 119.6, 118.2, 113.9, 113.7, 112.6, 112.3 , 58.2, 57.3, 57.2, 53.7, 43.0, 42.9, 41.9, 37.2, 36.5, 36.3, 33.4, 30.4, 29.8, 29.7, 29.3, 23.5; LRMS (EI) m / z 331 (M + ); HR-MS (EI) Calcd for C 20 H 29 O 3 N (M + ): 331.2147, Found 331.2135.
[단계 2] 2-[(1R)-6,7-디메톡시-2-(4-메틸펜타노일)-1,2,3,4-테트라하이드로-1-이소퀴놀리닐]아세트알데하이드의 제조 (화학식 5, 2-[(1R)-6,7-dimethoxy-2-(4-methylpentanoyl)-1,2,3,4-tetrahydro-1-isoquinolinyl]acetaldehyde)[Step 2] Preparation of 2-[(1R) -6,7-dimethoxy-2- (4-methylpentanoyl) -1,2,3,4-tetrahydro-1-isoquinolinyl] acetaldehyde (Formula 5, 2-[(1R) -6,7-dimethoxy-2- (4-methylpentanoyl) -1,2,3,4-tetrahydro-1-isoquinolinyl] acetaldehyde)
N-메틸모르폴린 N-옥사이드(N-methylmorpholine N-oxide, 330 mg, 2.8 mmol)의 아세톤(2 mL)과 물(2 mL) 용액에 OsO4(0.05 M in toluene, 1.0 mL, 0.05 mmol)를 가하여 10분간 교반한 후, 단계 1에서 제조된 화합물(310 mg, 0.93 mmol)의 acetone(2 mL) 용액을 가하고 12시간동안 교반하였다. TLC(thin layer chromatography)로 반응이 다 간 것을 확인한 후에 반응용액에 NaIO4(590 mg, 2.8 mmol)를 가하고 30분간 교반하였다. 0 ℃ 에서 Na2SO3를 가하여 반응을 종결하고 반응혼합물을 감압여과하였다. 여액에 물을 가하고 EtOAc로 2회 추출하였다. 유층을 MgSO4를 이용하여 건조 및 여과하고 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOAc: n-hexane = 2: 1)하여, 무색결정형의 표제화합물(275 mg, 88%)을 제조하였다.OsO 4 (0.05 M in toluene, 1.0 mL, 0.05 mmol) in acetone (2 mL) and water (2 mL) solutions of N-methylmorpholine N-oxide (N - methylmorpholine N-oxide, 330 mg, 2.8 mmol) After stirring for 10 minutes, acetone (2 mL) solution of the compound (310 mg, 0.93 mmol) prepared in step 1 was added and stirred for 12 hours. After confirming that the reaction was completed by thin layer chromatography (TLC), NaIO 4 (590 mg, 2.8 mmol) was added to the reaction solution, which was stirred for 30 minutes. Na 2 SO 3 was added at 0 ° C. to terminate the reaction, and the reaction mixture was filtered under reduced pressure. Water was added to the filtrate and extracted twice with EtOAc. The oil layer was dried using MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc: n - hexane = 2: 1) to give the title compound (275 mg, 88%) as a colorless crystal.
[α]D 20 -114.0 (c 0.86, CHCl3); IR (KBr) νmax 2954, 1720, 1637, 1516, 1460, 1360, 1258, 1122 cm-1; 1H-NMR (CDCl3, 300 MHz, mixture of rotamers) δ 9.81 - 9.76 (m, 1H), 6.62 (s, 1H), 6.57 (s, 1H), 6.00 (q, 1H, J = 4.6 Hz), 3.91 - 3.76 (m, 1H), 3.81 (s, 6H), 3.47 (ddd, 1H, J = 4.5, 10.2, 13.3 Hz), 3.13 - 2.66 (m, 4H), 2.46 - 2.23 (m, 1H), 2.33 (q, 1H, J = 8.2 Hz), 1.61 - 1.44 (m, 2H), 0.88 (d, 3H, J = 2.4 Hz), 0.86 (d, 3H, J = 2.5 Hz); 13C-NMR (CDCl3, 100 MHz, mixture of rotamers) δ 200.0, 199.2, 172.5, 172.2, 148.2, 148.0, 147.9, 147.6, 127.8, 127.7, 126.4, 125.5, 111.6, 111.1, 109.6, 108.9, 55.9, 55.8, 51.8, 51.1, 49.9, 47.7, 40.1, 35.8, 34.0, 33.8, 33.5, 31.7, 31.6, 31.3, 28.6, 27.7, 27.5, 27.3, 22.4, 22.3, 22.2, 22.1; LRMS (EI) m/z 333 (M+); HRMS (EI) Calcd for C19H27O4N (M+): 333.1940, Found 333.1976.[α] D 20 -114.0 ( c 0.86, CHCl 3 ); IR (KBr) ν max 2954, 1720, 1637, 1516, 1460, 1360, 1258, 1122 cm −1 ; 1 H-NMR (CDCl 3 , 300 MHz, mixture of rotamers) δ 9.81-9.76 (m, 1H), 6.62 (s, 1H), 6.57 (s, 1H), 6.00 (q, 1H, J = 4.6 Hz) , 3.91-3.76 (m, 1H), 3.81 (s, 6H), 3.47 (ddd, 1H, J = 4.5, 10.2, 13.3 Hz), 3.13-2.66 (m, 4H), 2.46-2.23 (m, 1H) , 2.33 (q, 1H, J = 8.2 Hz), 1.61-1.44 (m, 2H), 0.88 (d, 3H, J = 2.4 Hz), 0.86 (d, 3H, J = 2.5 Hz); 13 C-NMR (CDCl 3 , 100 MHz, mixture of rotamers) δ 200.0, 199.2, 172.5, 172.2, 148.2, 148.0, 147.9, 147.6, 127.8, 127.7, 126.4, 125.5, 111.6, 111.1, 109.6, 108.9, 55.9, 55.8, 51.8, 51.1, 49.9, 47.7, 40.1, 35.8, 34.0, 33.8, 33.5, 31.7, 31.6, 31.3, 28.6, 27.7, 27.5, 27.3, 22.4, 22.3, 22.2, 22.1; LRMS (EI) m / z 333 (M + ); HRMS (EI) Calcd for C 19 H 27 O 4 N (M + ): 333.1940, Found 333.1976.
[단계 3] 1-[(1R)-1-((E)-2-[테트-부틸(디메틸)실릴]옥시에텐일)-6,7-디메톡시-3,4-디하이드로-2(1H)-이소퀴놀리닐]-4-메틸-1-펜타논의 제조 (화학식 6, 1-[(1R)-1-((E)-2-[tert-butyl(dimethyl)silyl]oxyethenyl)-6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]-4-methyl-1-pentanone)[Step 3] 1-[(1R) -1-((E) -2- [Tet-butyl (dimethyl) silyl] oxyethenyl) -6,7-dimethoxy-3,4-dihydro-2 ( Preparation of 1H) -isoquinolinyl] -4-methyl-1-pentanone (Formula 6, 1-[(1R) -1-((E) -2- [tert-butyl (dimethyl) silyl] oxyethenyl)- 6,7-dimethoxy-3,4-dihydro-2 (1H) -isoquinolinyl] -4-methyl-1-pentanone)
단계 2에서 제조된 화합물(82 mg, 0.25 mmol)과 t-부틸디메틸실릴 클로라이드(TBSCl)(70 mg, 0.46 mmol)의 CH2Cl2(10 mL) 용액에 1,8-디아자비시클로[5.4.0]운데트-7-엔(DBU)(50 μL, 0.40 mmol)를 가하고 5시간 동안 환류하였다. 반응용액을 실온으로 냉각하고 NaHCO3 수용액을 가하여 반응을 종결하였다. 반응용액을 CH2Cl2로 2회 추출한 후 유층을 Na2SO4로 건조 및 여과하고 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOAc: n-hexane: Et3N = 5: 15: 1)하여, 무색 oil의 표제화합물(103 mg, 94%)을 제조하였다.To a solution of the compound prepared in step 2 (82 mg, 0.25 mmol) and t-butyldimethylsilyl chloride (TBSCl) (70 mg, 0.46 mmol) in CH 2 Cl 2 (10 mL), 1,8-diazabicyclo [5.4 .0] undet-7-ene (DBU) (50 μL, 0.40 mmol) was added and refluxed for 5 hours. The reaction solution was cooled to room temperature and an aqueous NaHCO 3 solution was added to terminate the reaction. The reaction solution was extracted twice with CH 2 Cl 2, and the oil layer was dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc: n - hexane: Et 3 N = 5: 15: 1) to give the title compound (103 mg, 94%) as a colorless oil.
[α]D 20 -114.1 (c 1.46, MeOH); IR (KBr) νmax 2954, 1647, 1515, 1462, 1256, 1180, 1119 cm-1; 1H-NMR (CD3OD, 300 MHz, mixture of rotamers) δ 6.58 (s, 1H), 6.51 (s, 1H), 6.42 (d, J = 11.5 Hz), 6.34 (d, 1H, J = 11.7 Hz), 5.72 (d, J = 8.2 Hz), 5.25 (d, 1H, J = 7.6 Hz), 5.09 (dd, J = 7.6 Hz, 11.9 Hz), 4.98 (dd, 1H, J = 8.0 Hz, 11.7 Hz), 4.40 - 4.36 (m), 3.85 - 3.81 (m, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.39 - 3.29 (m), 2.97 - 2.87 (m, 1H), 2.79 - 2.52 (m, 2H), 2.38 - 2.24 (m, 2H), 1.50 - 1.34 (m, 3H), 0.79 - 0.77 (m, 15 H), 0.00 (m, 6H); 13C-NMR (CD3OD, 75 MHz, mixture of rotamers) δ 183.6, 175.2, 174.8, 150.4, 150.2, 149.9, 146.9, 145.9, 129.8, 128.5, 128.9, 128.2, 127.0, 113.6, 113.5, 113.4, 113.2, 113.0, 60.8, 59.3, 59.2, 56.9, 52.9, 44.7, 41.9, 38.1, 36.4, 36.3, 33.5, 33.2, 30.6, 29.8, 29.6, 27.1, 26.9, 23.6, 23.5, 20.2, -4.3; LRMS (EI) m/z 447 (M+); HRMS (EI) Calcd for C25H41O4NSi (M+): 447.2805, Found 447.2781.[α] D 20 -114.1 ( c 1.46, MeOH); IR (KBr) ν max 2954, 1647, 1515, 1462, 1256, 1180, 1119 cm −1 ; 1 H -NMR (CD 3 OD, 300 MHz, mixture of rotamers) δ 6.58 (s, 1H), 6.51 (s, 1H), 6.42 (d, J = 11.5 Hz), 6.34 (d, 1H, J = 11.7 Hz ), 5.72 (d, J = 8.2 Hz), 5.25 (d, 1H, J = 7.6 Hz), 5.09 (dd, J = 7.6 Hz, 11.9 Hz), 4.98 (dd, 1H, J = 8.0 Hz, 11.7 Hz ), 4.40-4.36 (m), 3.85-3.81 (m, 1H), 3.66 (s, 3H), 3.65 (s, 3H), 3.39-3.29 (m), 2.97-2.87 (m, 1H), 2.79- 2.52 (m, 2H), 2.38-2.24 (m, 2H), 1.50-1.34 (m, 3H), 0.79-0.77 (m, 15H), 0.00 (m, 6H); 13 C-NMR (CD 3 OD, 75 MHz, mixture of rotamers) δ 183.6, 175.2, 174.8, 150.4, 150.2, 149.9, 146.9, 145.9, 129.8, 128.5, 128.9, 128.2, 127.0, 113.6, 113.5, 113.4, 113.2 , 113.0, 60.8, 59.3, 59.2, 56.9, 52.9, 44.7, 41.9, 38.1, 36.4, 36.3, 33.5, 33.2, 30.6, 29.8, 29.6, 27.1, 26.9, 23.6, 23.5, 20.2, -4.3; LRMS (EI) m / z 447 (M + ); HRMS (EI) Calcd for C 25 H 41 O 4 NSi (M + ): 447.2805, Found 447.2781.
[단계 4] (5S,6R)-6-[테트-부틸(디메틸)실릴]옥시-5-이소부틸-10,11-디메톡시-2,3,5,6-테트라하이드로-3-벤즈아제신-4(1R)-온의 제조 (화학식 7, (5S,6R)-6-[tert-butyl(dimethyl)silyl]oxy-5-isobutyl-10,11-dimethoxy-2,3,5,6-tetrahydro-3-benzazecin-4(1R)-one)[Step 4] (5S, 6R) -6- [Tet-butyl (dimethyl) silyl] oxy-5-isobutyl-10,11-dimethoxy-2,3,5,6-tetrahydro-3-benzase Preparation of cin-4 (1R) -one (Formula 7, (5S, 6R) -6- [tert-butyl (dimethyl) silyl] oxy-5-isobutyl-10,11-dimethoxy-2,3,5,6 -tetrahydro-3-benzazecin-4 (1R) -one)
단계 3에서 제조된 화합물(230 mg, 0.51 mmol)과 다양한 trapping reagent와 다른 염기(base)를 사용하여 반응을 수행하였다. 하기 표 1에 나타난 trapping reagent와 다른 염기를 사용하여 반응을 수행하였다.The reaction was carried out using the compound prepared in step 3 (230 mg, 0.51 mmol), various trapping reagents and other bases. The reaction was performed using a trapping reagent and other bases shown in Table 1 below.
가장 바람직하게는, 벤젠 용매하에 i-PrMgCl을 사용하는 경우 목적화합물을 75%의 높은 수율로 얻을 수 있었으며, 원하지 않는 부산물은 5% 이하의 수율로 최소화 할 수 있었다. Most preferably, when i-PrMgCl was used in a benzene solvent, the target compound could be obtained in a high yield of 75%, and unwanted by-products could be minimized in a yield of 5% or less.
구체적으로, 단계 3에서 제조된 화합물(230 mg, 0.51 mmol)의 benzene(10 mL) 용액에 i-PrMgCl(0.51 mL of 2.0 M solution in THF, 1.0 mmol)를 80 ℃에서 가하고 5시간 동안 환류하였다. 반응용액에 물을 가하여 반응을 종결한 후 EtOAc로 2회 추출하였다. 유층을 MgSO4를 이용하여 건조 및 여과하고 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOAc: n-hexane: MeOH= 5: 15: 1)하여, 흰색 고체의 표제화합물(175 mg, 76%)을 제조하였다.Specifically, i-PrMgCl (0.51 mL of 2.0 M solution in THF, 1.0 mmol) was added to a benzene (10 mL) solution of the compound (230 mg, 0.51 mmol) prepared in step 3, and refluxed for 5 hours. . Water was added to the reaction solution to terminate the reaction and then extracted twice with EtOAc. The oil layer was dried using MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc: n-hexane: MeOH = 5: 15: 1) to give the title compound (175 mg, 76%) as a white solid.
[α]D 20 -171.1 (c 0.22, MeOH); IR (KBr) νmax 2924, 1631, 1458, 1257, 1099 cm-1; 1H-NMR (CD3OD, 300 MHz) δ 7.68 (t, 1H, J = 6.2 Hz), 6.67 (s, 1H), 6.61 (s, 1H), 6.34 (d, 1H, J = 16.2 Hz), 5.31 (dd, 1H, J = 8.2, 16.4 Hz), 3.98 (t, 1H, J = 8.8 Hz), 3.72 - 3.60 (m, 1H), 3.67 (s, 3H), 3.65 (s, 3H), 3.20 (dt, 1H, J = 3.5, 12.8 Hz), 2.64 (ddt, 1H, J = 2.5, 4.7, 10.8 Hz), 2.13 (td, 1H, J = 2.6, 11.3 Hz), 2.00 (dt, 1H, J = 2.1, 9.5 Hz), 1.59 (dd, 1H, J = 8.9, 11.3 Hz), 1.39 - 1.30 (m, 2H), 0.80 (s, 9H), 0.75 (d, 3H, J = 6.2 Hz), 0.68 (d, 3H, J = 6.0 Hz), 0.00 (s, 6H); 13C-NMR (CD3OD, 75 MHz) δ 178.3, 150.4, 150.1, 139.7, 134.4, 133.0, 131.6, 116.0, 111.7, 79.0, 57.4, 56.6, 45.1, 45.0, 38.4, 32.2, 28.8, 27.1, 25.0, 22.9, 19.8, -3.0, -3.8; LRMS (EI) m/z 447 (M+); HRMS (EI) Calcd for C25H41O4NSi (M+): 447.2805, Found 447.2825.[α] D 20 -171.1 ( c 0.22, MeOH); IR (KBr) ν max 2924, 1631, 1458, 1257, 1099 cm −1 ; 1 H-NMR (CD 3 OD, 300 MHz) δ 7.68 (t, 1H, J = 6.2 Hz), 6.67 (s, 1H), 6.61 (s, 1H), 6.34 (d, 1H, J = 16.2 Hz) , 5.31 (dd, 1H, J = 8.2, 16.4 Hz), 3.98 (t, 1H, J = 8.8 Hz), 3.72-3.60 (m, 1H), 3.67 (s, 3H), 3.65 (s, 3H), 3.20 (dt, 1H, J = 3.5, 12.8 Hz), 2.64 (ddt, 1H, J = 2.5, 4.7, 10.8 Hz), 2.13 (td, 1H, J = 2.6, 11.3 Hz), 2.00 (dt, 1H, J = 2.1, 9.5 Hz), 1.59 (dd, 1H, J = 8.9, 11.3 Hz), 1.39-1.30 (m, 2H), 0.80 (s, 9H), 0.75 (d, 3H, J = 6.2 Hz), 0.68 (d, 3H, J = 6.0 Hz), 0.00 (s, 6H); 13 C-NMR (CD 3 OD, 75 MHz) δ 178.3, 150.4, 150.1, 139.7, 134.4, 133.0, 131.6, 116.0, 111.7, 79.0, 57.4, 56.6, 45.1, 45.0, 38.4, 32.2, 28.8, 27.1, 25.0 , 22.9, 19.8, -3.0, -3.8; LRMS (EI) m / z 447 (M + ); HRMS (EI) Calcd for C 25 H 41 O 4 NSi (M + ): 447.2805, Found 447.2825.
[단계 5] (2R,3S,11bR)-2-하이드록시-3-이소부틸-9,10-디메톡시-1,2,3,6,7,11b-헥사하이드로-4H-피리도[2,1-a]이소퀴놀린-4-온 의 제조 (화학식 8, (2R,3S,11bR)-2-hydroxy-3-isobutyl-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrido[2,1-a]isoquinolin-4-one)[Step 5] (2R, 3S, 11bR) -2-Hydroxy-3-isobutyl-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrido [2 Preparation of isoquinolin-4-one (Formula 8, (2R, 3S, 11bR) -2-hydroxy-3-isobutyl-9,10-dimethoxy-1,2,3,6,7,11b -hexahydro-4H-pyrido [2,1-a] isoquinolin-4-one)
단계 4에서 제조된 화합물(40 mg, 89 μmol)을 사용하여 다양한 산조건과 용매하에 반응을 수행하였다. 하기 표 2에 나타난 산조건과 용매를 사용하여 반응을 수행하였다. The reaction was carried out under various acid conditions and solvents using the compound (40 mg, 89 μmol) prepared in step 4. The reaction was carried out using the acid conditions and the solvent shown in Table 2.
가장 바람직하게는 벤젠 용매하에 p-톨루엔설폰산(TsOH)를 사용하는 경우 목적화합물을 84%의 좋은 수율로 얻을 수 있었으며, 원하지 않는 부산물은 2% 내외의 수율로 최소화 할 수 있었다. Most preferably, when p-toluenesulfonic acid (TsOH) was used in a benzene solvent, the target compound could be obtained in a good yield of 84%, and unwanted by-products could be minimized in a yield of about 2%.
구체적으로, 단계 4에서 제조된 화합물(40 mg, 89 μmol)의 benzene(5 mL) 용액에 p-톨루엔설폰산(TsOH)·H2O(46 mg, 0.24 mmol)를 가하고, 반응용액을 실온에서 24시간 동안 교반한 후 반응용액에 물을 가하여 반응을 종결지었다. 반응용액을 EtOAc로 2회 추출하고 유층을 MgSO4를 이용하여 건조 및 여과하고 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOA: n-hexane: = 2: 1 → EtOAc)하여, 무색 오일의 표제화합물(25mg, 84%)을 제조하였다. Specifically, p-toluenesulfonic acid (TsOH) .H 2 O (46 mg, 0.24 mmol) was added to a benzene (5 mL) solution of the compound (40 mg, 89 μmol) prepared in step 4, and the reaction solution was allowed to come to room temperature. After stirring for 24 hours, water was added to the reaction solution to terminate the reaction. The reaction solution was extracted twice with EtOAc, and the oil layer was dried using MgSO 4 , filtered, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOA: n - hexane: = 2: 1-EtOAc) to give the title compound (25 mg, 84%) as a colorless oil.
[α]D 20 +101.8 (c 0.56, MeOH); IR (KBr) νmax 3396, 2923, 1617, 1515, 1458, 1257 cm-1; 1H-NMR (CDCl3, 500 MHz) δ 6.63 (s, 1H), 6.59 (s, 1H), 4.79 (m, 1H), 4.60 (dd, 1H, J = 3.9, 11.1 Hz), 3.91 (dt, 1H, J = 3.4, 9.4 Hz), 3.84 (s, 6H), 2.86 - 2.82 (m, 1H), 2.78 (dd, 1H, J = 2.6, 12.0 Hz), 2.70 (td, 1H, J = 3.9, 12.6 Hz), 2.60 (d, 1H, J = 15.3 Hz), 2.30 - 2.25 (m, 1H), 2.01 (dt, 1H, J = 6.6, 14.1 Hz), 1.87 (td, 1H, J = 6.5, 13.4 Hz), 1.74 (q, 1H, J = 11.4 Hz), 1.58 - 1.53 (m, 1H), 0.96 (d, 3H, J = 6.6 Hz), 0.90 (d, 3H, J = 6.6 Hz); 13C-NMR (CDCl3, 100 MHz) δ 171.0, 147.8, 147.7, 128.2, 127.2, 111.4, 107.9, 69.1, 56.0, 55.8, 53.3, 48.7, 39.9, 39.8, 38.8, 28.3, 26.6, 23.1, 22.4; LRMS (FAB) m/z 334 (M + H+); HRMS (FAB) Calcd for C19H28O4N (M + H+): 334.2018, Found 334.2022.[α] D 20 +101.8 ( c 0.56, MeOH); IR (KBr) ν max 3396, 2923, 1617, 1515, 1458, 1257 cm −1 ; 1 H-NMR (CDCl 3 , 500 MHz) δ 6.63 (s, 1H), 6.59 (s, 1H), 4.79 (m, 1H), 4.60 (dd, 1H, J = 3.9, 11.1 Hz), 3.91 (dt , 1H, J = 3.4, 9.4 Hz), 3.84 (s, 6H), 2.86-2.82 (m, 1H), 2.78 (dd, 1H, J = 2.6, 12.0 Hz), 2.70 (td, 1H, J = 3.9 , 12.6 Hz), 2.60 (d, 1H, J = 15.3 Hz), 2.30-2.25 (m, 1H), 2.01 (dt, 1H, J = 6.6, 14.1 Hz), 1.87 (td, 1H, J = 6.5, 13.4 Hz), 1.74 (q, 1H, J = 11.4 Hz), 1.58-1.53 (m, 1H), 0.96 (d, 3H, J = 6.6 Hz), 0.90 (d, 3H, J = 6.6 Hz); 13 C-NMR (CDCl 3 , 100 MHz) δ 171.0, 147.8, 147.7, 128.2, 127.2, 111.4, 107.9, 69.1, 56.0, 55.8, 53.3, 48.7, 39.9, 39.8, 38.8, 28.3, 26.6, 23.1, 22.4; LRMS (FAB) m / z 334 (M + H + ); HRMS (FAB) Calcd for C 19 H 28 O 4 N (M + H + ): 334.2018, Found 334.2022.
[단계 6] 알파-디하이드로테트라베나진의 제조 ((+)-α-Dihydrotetrabenazine , 화학식 2)[Step 6] Preparation of alpha-dihydrotetrabenazine ((+)-α-Dihydrotetrabenazine, Formula 2)
단계 5에서 제조된 화합물(13 mg, 39 μmol)의 테트라하이드로푸란(THF)(3 mL) 용액에 LAH(10 mg, 0.26 mmol)를 가한 후 12시간 동안 환류하였다. 반응용액을 실온으로 냉각한 후 15% aqueous sodium potassium tartrate(3 mL)을 가하여 반응을 종결하고 12시간동안 교반하여 층분리가 되는 것을 확인하였다. 반응혼합물을 EtOAc로 2회 추출하고 유층을 MgSO4를 이용하여 건조 및 여과하고 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOAc: MeOH = 20 : 1)하여, 흰색 고체의 표제화합물(9.5 mg, 76%)를 제조하였다.To a solution of compound (13 mg, 39 μmol) in tetrahydrofuran (THF) (3 mL) prepared in step 5 was added LAH (10 mg, 0.26 mmol) and refluxed for 12 hours. After the reaction solution was cooled to room temperature, 15% aqueous sodium potassium tartrate (3 mL) was added to terminate the reaction, followed by stirring for 12 hours. The reaction mixture was extracted twice with EtOAc, and the oil layer was dried using MgSO 4 , filtered and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (EtOAc: MeOH = 20: 1) to give the title compound (9.5 mg, 76%) as a white solid.
[α]D 20 +53.5 (c 1.60, MeOH); IR (KBr) νmax 3397, 2950, 1649, 1515, 1460, 1367, 1255 cm-1; 1H-NMR (CDCl3, 500 MHz) δ 6.65 (s, 1H), 6.55 (s, 1H), 3.82 (s, 6H), 3.37 (dt, 1H, J = 4.5, 10.5 Hz), 3.11 - 3.03 (m, 2H), 2.62 (d, 1H, J = 15.7 Hz), 2.57 (ddd, 1H, J = 2.4, 4.4, 12.3 Hz), 2.43 (dt, 1H, J = 3.9, 11.4 Hz), 1.95 (t, 1H, J = 11.3 Hz), 1.73 - 1.64 (m, 2H), 1.55 (ddd, 1H, J = 3.1, 10.2, 13.4 Hz), 1.49 (q, 1H, J = 11.4 Hz), 1.04 (ddd, 1H, J = 4.1, 9.9, 13.5 Hz), 0.91 (d, 3H, J = 6.5 Hz), 0.89 (d, 3H, J = 6.5 Hz); 13C-NMR (CDCl3, 75 MHz) δ 147.4, 147.2, 129.3, 126.3, 111.4, 107.8, 74.6, 60.8, 60.0, 55.9, 55.8, 51.9, 41.6, 40.5, 39.6, 29.1, 25.3, 24.1, 21.7; LRMS (FAB) m/z 320 (M + H+); HRMS (FAB) Calcd for C19H30O3N (M + H+): 320.2226, Found 320.2233.[α] D 20 +53.5 ( c 1.60, MeOH); IR (KBr) ν max 3397, 2950, 1649, 1515, 1460, 1367, 1255 cm −1 ; 1 H-NMR (CDCl 3 , 500 MHz) δ 6.65 (s, 1H), 6.55 (s, 1H), 3.82 (s, 6H), 3.37 (dt, 1H, J = 4.5, 10.5 Hz), 3.11-3.03 (m, 2H), 2.62 (d, 1H, J = 15.7 Hz), 2.57 (ddd, 1H, J = 2.4, 4.4, 12.3 Hz), 2.43 (dt, 1H, J = 3.9, 11.4 Hz), 1.95 ( t, 1H, J = 11.3 Hz), 1.73-1.64 (m, 2H), 1.55 (ddd, 1H, J = 3.1, 10.2, 13.4 Hz), 1.49 (q, 1H, J = 11.4 Hz), 1.04 (ddd , 1H, J = 4.1, 9.9, 13.5 Hz), 0.91 (d, 3H, J = 6.5 Hz), 0.89 (d, 3H, J = 6.5 Hz); 13 C-NMR (CDCl 3 , 75 MHz) δ 147.4, 147.2, 129.3, 126.3, 111.4, 107.8, 74.6, 60.8, 60.0, 55.9, 55.8, 51.9, 41.6, 40.5, 39.6, 29.1, 25.3, 24.1, 21.7; LRMS (FAB) m / z 320 (M + H + ); HRMS (FAB) Calcd for C 19 H 30 O 3 N (M + H + ): 320.2226, Found 320.2233.
[실시예 2] 테트라베나진의 제조Example 2 Preparation of Tetrabenazine
[단계 1] 알파-디하이드로테트라베나진의 제조 ((+)-α-Dihydrotetrabenazine , 화학식 2)[Step 1] Preparation of alpha-dihydrotetrabenazine ((+)-α-Dihydrotetrabenazine, Formula 2)
테트라베나진을 제조하기 위하여, 상기 실시예 1의 단계 1 내지 6과 동일한 방법으로 알파-디하이드로테트라베나진을 제조하였다.In order to prepare tetrabenazine, alpha-dihydrotetrabenazine was prepared in the same manner as in Steps 1 to 6 of Example 1.
[단계 2] 테트라베나진의 제조 (Tetrabenazine , 화학식 1)[Step 2] Preparation of tetrabenazine (Tetrabenazine, Formula 1)
단계 1에서 제조된 화합물(22 mg, 69 μmol)의 CH2Cl2(4 mL) 용액에 Molecular sieve(4A, 20 mg), N-메틸모르폴린 N-옥사이드(NMO)(12 mg, 103 μmol), TPAP(2.4 mg, 6.9 μmol)을 0 ℃에서 순서대로 가한 후 2시간 동안 교반하였다. 실리카겔을 이용하여 여과한 후 여액을 감압농축하였다. 얻어진 잔사를 컬럼 크로마토그래피(EtOAc: n-hexane = 1 : 1)하여, 흰색 고체의 표제화합물(14 mg, 64%)를 제조하였다.To a solution of the compound prepared in step 1 (22 mg, 69 μmol) in CH 2 Cl 2 (4 mL), Molecular sieve (4A, 20 mg), N-methylmorpholine N-oxide (NMO) (12 mg, 103 μmol) ), TPAP (2.4 mg, 6.9 μmol) was added sequentially at 0 ° C and stirred for 2 hours. The filtrate was concentrated under reduced pressure after filtration using silica gel. The obtained residue was subjected to column chromatography (EtOAc: n-hexane = 1: 1) to give the title compound (14 mg, 64%) as a white solid.
[α]D 20 +62.5 (c 0.180, MeOH); 1H-NMR (CDCl3, 400 MHz) δ 6.60 (s, 1H), 6.53 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.49 (d, 1H, J = 9.3 Hz), 3.27 (dd, 1H, J = 6.0, 11.6 Hz), 3.12 - 3.03 (m, 2H), 2.87 (dd, 1H, J = 2.8, 13.6 Hz), 2.76- 2.68 (m, 2H), 2.58 (dd, 1H, J = 10.0, 11.6 Hz), 2.52 (t, 1H, J = 12.8 Hz), 2.36-2.31 (m, 1H), 1.82-1.76 (m, 1H), 1.72-1.58 (m, 1H), 1.04-0.95 (m, 1H), 0.89 (d, 3H, J = 6.4 Hz), 0.88 (d, 3H, J = 6.5 Hz); 13C-NMR (CD3OD, 125 MHz) δ 211.8, 150.3, 149.8, 130.6, 128.2, 113.9, 110.7, 64.4, 62.9, 57.4, 57.2, 51.9, 48.6, 48.3, 37.0, 30.7, 27.4, 24.2, 23.3; IR (KBr) νmax 3397, 2950, 1649, 1515, 1460, 1367, 1255 cm-1; LRMS (FAB) m/z 318 (M + H+); HRMS (FAB) Calcd for C19H28O3N (M + H+): 318.2069, Found 318.2061. [α] D 20 +62.5 (c 0.180, MeOH); 1 H-NMR (CDCl 3 , 400 MHz) δ 6.60 (s, 1H), 6.53 (s, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.49 (d, 1H, J = 9.3 Hz ), 3.27 (dd, 1H, J = 6.0, 11.6 Hz), 3.12-3.03 (m, 2H), 2.87 (dd, 1H, J = 2.8, 13.6 Hz), 2.76-2.68 (m, 2H), 2.58 ( dd, 1H, J = 10.0, 11.6 Hz), 2.52 (t, 1H, J = 12.8 Hz), 2.36-2.31 (m, 1H), 1.82-1.76 (m, 1H), 1.72-1.58 (m, 1H) , 1.04-0.95 (m, 1H), 0.89 (d, 3H, J = 6.4 Hz), 0.88 (d, 3H, J = 6.5 Hz); 13 C-NMR (CD 3 OD, 125 MHz) δ 211.8, 150.3, 149.8, 130.6, 128.2, 113.9, 110.7, 64.4, 62.9, 57.4, 57.2, 51.9, 48.6, 48.3, 37.0, 30.7, 27.4, 24.2, 23.3 ; IR (KBr) ν max 3397, 2950, 1649, 1515, 1460, 1367, 1255 cm −1 ; LRMS (FAB) m / z 318 (M + H + ); HRMS (FAB) Calcd for C 19 H 28 O 3 N (M + H + ): 318.2069, Found 318.2061.
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