KR101102957B1 - Asymmetric synthetic method of preparing ?-dihydrotetrabenazine and tetrabenazine - Google Patents

Abstract

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.

Alpha-dihydrotetrabenazine, tetrabenazine

Description

Asymmetric synthesis of alpha-dihydrotetrabenazine and tetrabenazine {ASYMMETRIC SYNTHETIC®METHOD OF PREPARING α-DIHYDROTETRABENAZINE AND TETRABENAZINE}

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.

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.

[Formula 1]

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.).

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 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.

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.

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.

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.).

[Formula 2]

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).

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 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.).

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.

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.

In order to achieve the above object, the present invention provides a method for preparing alpha-dihydrotetrabenazine as in Scheme 1.

The present invention also provides a method for preparing tetrabenazine as in Scheme 2.

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.

Hereinafter, the present invention will be described in detail.

The present invention is as shown in Scheme 1,

Preparing a compound represented by Chemical Formula 4 by amidating 4-methylvaleric acid with an compound represented by Chemical Formula 3 (step 1);

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);

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);

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);

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); And

Preparing a compound represented by Chemical Formula 2 by reducing the compound represented by Chemical Formula 8 prepared in Step 5 (Step 6)

It provides a method for producing alpha-dihydrotetrabenazine comprising a.

Step 1 of Scheme 1 may be performed as follows.

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.

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.

Step 2 of Scheme 1 may be performed as follows.

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.

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.

Step 3 of Scheme 1 may be performed as follows.

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.

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).

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.

Step 4 of Scheme 1 may be performed as follows.

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).

It is determined that the reaction proceeds through a transition state as described in the following scheme.

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.

Step 5 of Scheme 1 may be performed as follows.

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.

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.

Step 6 of Scheme 1 may be performed as follows.

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).

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.

In addition, the present invention is as shown in Scheme 2,

Preparing a compound represented by Chemical Formula 4 by amidating 4-methylvaleric acid with an compound represented by Chemical Formula 3 (step 1);

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);

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);

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);

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);

Preparing a compound represented by Chemical Formula 2 by reducing the compound represented by Chemical Formula 8 prepared in Step 5 (Step 6); And

Preparing a compound represented by Chemical Formula 1 by oxidation of the compound represented by Chemical Formula 2 prepared in Step 6 (Step 7)

It provides a method for producing tetrabenazine comprising a.

Steps 1 to 6 of Scheme 2 may be performed by the same method as steps 1 to 6 of Scheme 1.

Step 7 of Scheme 2 may be performed as follows.

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).

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.

Example 1 Preparation of Alpha-Dihydrotetrabenazine

[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-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); 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.

[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)

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, 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.

[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)

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) 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.

[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)

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.

Solvent Reactant Temperature product toluene 2eq, LiMHDS -78 ℃ to 120 ℃ 7 (<10%) toluene 2eq, LiMHDS rt to 120 ℃ 7 (<10%) toluene 3eq, LiMHDS 120 ℃ 7 (25%), 7 '(> 40%) toluene 5eq, i-PrMgCl rt to 120 ℃ 7 (33%), 7 '(50%) benzene 2eq, i-PrMgCl 90 ℃ 7 (76%), 7 '(<5%) benzene 1.2eq, i-PrMgCl 90 ℃ 7 (75%), 7 '(<5%) benzene 2eq, t-butylMgCl 90 ℃ 7 (33%), 7 '(> 40%)

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.

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) 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.

[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)

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.

Solvent Reactant Temperature product benzene HI rt 8 (40%), 8 '(13%) benzene TsOH rt 8 (75%), 8 '(20%) THF TsOH rt to reflux 8 (50%), 8 '(<5%) benzene TsOH rt to reflux 8 (84%), 8 '(2.3%)

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%.

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) 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.

[Step 6] Preparation of alpha-dihydrotetrabenazine ((+)-α-Dihydrotetrabenazine, Formula 2)

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) 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.

Example 2 Preparation of Tetrabenazine

[Step 1] Preparation of alpha-dihydrotetrabenazine ((+)-α-Dihydrotetrabenazine, Formula 2)

In order to prepare tetrabenazine, alpha-dihydrotetrabenazine was prepared in the same manner as in Steps 1 to 6 of Example 1.

[Step 2] Preparation of tetrabenazine (Tetrabenazine, Formula 1)

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); 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.

Claims (11)

As in Scheme 1, Preparing a compound represented by Chemical Formula 4 by amidating 4-methylvaleric acid with an compound represented by Chemical Formula 3 (step 1); 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); 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); 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); 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); And Preparing a compound represented by Chemical Formula 2 by reducing the compound represented by Chemical Formula 8 prepared in Step 5 (Step 6) Alpha-dihydrotetrabenazine production method comprising a. Scheme 1

The method according to claim 1, wherein the amidation reaction is carried out in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBt) solvent. The method for producing alpha-dihydrotetrabenazine. In the first paragraph the second step, a substitution reaction of the terminal double bond to the aldehydes is osmium tetroxide (OsO ₄₎ the N- methylmorpholine N- oxide (NMO) the addition of NaIO ₄ was reacted in the presence Method for producing alpha-dihydrotetrabenazine, characterized in that. Step 3 of claim 1, wherein the compound represented by the formula (5) prepared in step 2 is dissolved in CH ₂ Cl ₂ and refluxed by the addition of t-butyldimethylsilyl chloride (TBSCl), 1,8- diazabi A process for producing alpha-dihydrotetrabenazine, characterized by adding cyclo [5.4.0] undet-7-ene (DBU) and refluxing to produce a compound represented by the formula (6). The method of claim 1, wherein the lithium hexadimethyldisilazane (LiHMDS); i-PrMgCl or t-butylMgCl is a method for producing alpha-dihydrotetrabenazine, characterized in that 1 to 10 equivalents to the compound represented by the formula (6). The method of claim 5, wherein the lithium hexadimethyldisilazane (LiHMDS); i-PrMgCl; Or t-butylMgCl is used in the preparation of alpha-dihydrotetrabenazine, wherein 1.2 to 5 equivalents is used relative to the compound represented by Chemical Formula 6. The step 4 of claim 1, wherein the compound represented by the formula (6) prepared in step 3 is reacted with i-PrMgCl under benzene to prepare a compound represented by the formula (7) characterized in that the preparation of alpha-dihydrotetrabenazine Way. In the step 5 of claim 1, the compound represented by the formula (7) prepared in step 4 is added to p-toluenesulfonic acid (TsOH) in a benzene solvent to prepare a compound represented by the formula (8) Method for producing tetrabenazine. The method of claim 6, wherein the reduction reaction using AlH ₃ , diisobutyl aluminum hydride (DIBAL), sodium bis (2-methoxyethoxy) aluminum hydride or lithium aluminum hydride (LAH) Method for producing alpha-dihydrotetrabenazine, characterized in that. As shown in Scheme 2, Preparing a compound represented by Chemical Formula 4 by amidating 4-methylvaleric acid with an compound represented by Chemical Formula 3 (step 1); 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); 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); Compound represented by the formula (6) prepared in Step 3, LiHMDS; i-PrMgCl; Or reacting t-butylMgCl with toluene or benzene to produce a compound represented by Chemical Formula 7 (step 4); 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); Preparing a compound represented by Chemical Formula 2 by reducing the compound represented by Chemical Formula 8 prepared in Step 5 (Step 6); And Preparing a compound represented by Chemical Formula 1 by oxidation of the compound represented by Chemical Formula 2 prepared in Step 6 (Step 7) Method for producing tetrabenazine comprising a. Scheme 2

The method of claim 10, wherein the oxidation reaction is carried out by adding tetra-n-propyl ammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO) Method of making gin.