Hydroxyl tetrabenazine intermediate and preparation method thereof

Abstract

The invention discloses a hydroxyl tetrabenazine intermediate and a preparation method thereof, and provides novel intermediate compounds such as a compound shown in a formula V and a compound shown in a formula IV in a hydroxyl tetrabenazine preparation route, and the preparation method is short in overall route, short in production period, high in yield and high in yield. Each step of reaction can achieve the effects of high yield, short reaction time, simple post-treatment operation and the like, and industrial expansion of the production scale is facilitated. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a preparation method of hydroxytetrabenazine, and specifically provides two hydroxytetrabenazine intermediates and preparation methods thereof. Background Art

[0002] Hydroxytetrabenazine (HTBZ or DHTBZ, structural formula shown below) is the carbonyl reduction product of tetrabenazine (TBZ) and also its metabolite. Both are benzisoquinoline derivatives. As a clinical vesicular monoamine transporter-2 (VMAT-2) inhibitor, it exerts its pharmacological effects by binding to and inhibiting VMAT-2, thereby reducing the level of monoamine neurotransmitters in the brain.

[0003]

[0004] In the central nervous system, VMAT-2 is responsible for the storage and subsequent release of monoamines such as dopamine, serotonin, norepinephrine, epinephrine and histamine from the cytoplasm into vesicles. Functional disorders of VMAT-2 will lead to many neurological and psychiatric diseases, including Parkinson's disease (PD), Huntington's disease (HD), schizophrenia, psychostimulant addiction and depression. For drug development, VMAT-2 is considered to be an effective target for the treatment of the above diseases. In 1957, tetrabenazine (TBZ) racemate was first found to be used to regulate 5-hydroxytryptamine levels, and was later found to be a clinical VMAT-2 inhibitor. In 1971, it was approved in Europe for the treatment of Huntington's disease (HD). In 2008, it was approved by the US FDA for the treatment of excitatory movement disorders caused by dopamine hyperfunction, such as Huntington's disease and Tourette syndrome, becoming the first drug approved in the United States for the treatment of HD.

[0005] Hydroxytetrabenazine (α-HTBZ) is a metabolite of tetrabenazine, which can act highly selectively on VMAT-2 in the central nervous system. Studies have shown that TBZ (racemic form) is actually a prodrug, and it is α-HTBZ that actually works in the human body. Since TBZ will produce multiple stereoisomers during metabolism in the body, only one of the enantiomers shows excellent therapeutic effects. On this basis, valbenazine has developed into a new prodrug and has become a new drug approved by the US FDA for the treatment of tardive dyskinesia (TD) and HD.

[0006] At present, many research teams have completed the racemic and asymmetric synthesis of tetrabenazine and hydroxytetrabenazine. In 1958, Hoffmann et al. first reported the synthesis method of TBZ and issued a related patent (US2830993.1958-04-15), using 6,7-dimethoxy-3,4-dihydroisoquinoline and 3-isobutyl-3-butene-2-one as starting materials, and the Mannich reaction was used to form a ring. In 1965, Whittaker et al. used the precursor trimethyl quaternary ammonium salt of enone and 6,7-dimethoxy-3,4-dihydroisoquinoline to synthesize TBZ (GB 999095.1965-07-21). On this basis, in 2010, Grant et al. made further improvements to the reaction (WO 2010044981.2010-04-22). They used 5-methyl-2-hexanone as a raw material for the reaction of quaternary ammonium iodide with 6,7-dimethoxy-3,4-dihydroisoquinoline to obtain the target product. In 2012, Chen et al. improved the experimental scheme (Mol. Cryst. Liq. Cryst. 2012, 557, 39). Son et al. reported a method for synthesizing tetrabenazine by intramolecular aza-Prins cyclization with a total of 12 steps (Org. Lett. 2011, 13, 6500). In 2015, Orgren et al. reported a method for synthesizing tetrabenazine racemate by four steps from 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride as a raw material (J. Org. Chem. 2015, 80, 12635). In 2019, Wu et al. used propargyl alcohol and 6,7-dimethoxy-3,4-dihydroisoquinoline as raw materials via Diels-Alder reaction to synthesize the target product TBZ in 6 steps (Org. Biomol. Chem. 2019, 17, 8827), and hydroxytetrabenazine can ultimately be obtained from the synthesized tetrabenazine by reduction with sodium borohydride.

[0007] There are also reports on the asymmetric synthesis of hydroxytetrabenazine. Kilbourn et al. used the method of enzyme-catalyzed hydrolysis kinetic resolution in 1997 (Chirality 1997, 9, 59) to obtain enantiomerically pure (+)-α-HTBZ. In 2009, Rehder et al. used p-methylbenzoyl-(L)-tartaric acid to convert the racemic α-HTBZ mixture into its separable (+)-α-HTBZ-(L)-tartrate (Synth. Commun. 2009, 39, 3574). In 2009, Rishel et al. used organometallic palladium catalysis to achieve the first chemical asymmetric synthesis (J. Org. Chem. 2009, 74, 4001). Suh et al. reported the second asymmetric synthesis of (+)-TBZ in 2010 (J. Org. Chem. 2017, 82, 1464). In 2012, Johannes et al. introduced chiral auxiliary groups for asymmetric synthesis (Org. Lett. 2012, 14, 3752). In the same year, Reddy et al. applied chiral sulfonamide to the asymmetric synthesis of (-)-α-HTBZ (Tetrahedron Lett. 2012, 53, 6916), with a total of 11 transformation steps.

[0008] Most of the publicly reported synthetic routes focus on the synthesis of tetrabenazine (TBZ), and use NaBH4 to reduce the carbonyl group, resulting in the production of multiple isomers, which brings cumbersome operations to the subsequent separation; in addition, the method of asymmetric control of hydroxyl chirality has a long synthetic route, limited construction of chiral centers, and some chemical reactions have poor stereoselectivity and require multiple column chromatography separation and purification, use of expensive transition metal catalysts, and use of toxic reagents that are harmful to the environment. Therefore, it is still urgent and necessary to design a highly stereoselective synthetic method to prepare hydroxytetrabenazine and improve the efficiency of chiral drug synthesis. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the defects of the prior art, such as the long preparation path of hydroxytetrabenazine, low yield, and difficulty in separating stereoisomers, and to provide a new route for preparing compound VI using a new intermediate. New compound V and compound IV are used as intermediates, and compound III is used as a raw material. Compound VI can be prepared in only three steps. The whole route directly avoids the generation of stereoisomers. Not only is the yield high and the reaction time short, but the intermediates are all easily crystallized solids, which are conducive to separation and purification and large-scale production. The experimental operation is convenient and is conducive to the application of industrial production.

[0010] The present invention solves the above technical problems through the following technical solutions.

[0011] The present invention provides a method for preparing a compound as shown in Formula VI, which comprises the following steps:

[0012] In an organic solvent, in the presence of a metallized alkaline reagent and an activating reagent, an alkylation reaction is carried out between the compound represented by formula V and isobutyl iodide to obtain a compound represented by formula VI;

[0013]

[0014] The metallized alkaline agent is LDA.

[0015] In the alkylation reaction, the molar ratio of the metallized alkaline reagent to the compound represented by formula V is (3.5-5.5):1, preferably (3.6-4):1, for example 3.6:1 or 4:1.

[0016] In the alkylation reaction, the molar ratio of the activation reagent to the compound represented by formula V is (0.5-2.0):1, preferably (0.5-1.2):1, for example 0.5:1, 1:1 or 1.2:1.

[0017] In the alkylation reaction, the molar ratio of the isobutyl iodide to the compound represented by formula V is (2.5-4.5):1, preferably (2.5-4.0):1, for example 2.5:1, 3:1 or 4:1.

[0018] The alkylation reaction further comprises the following steps:

[0019] (a) mixing a mixture of the compound represented by formula V and the organic solvent, a solution of the metallized alkaline agent and the activating agent;

[0020] (b) mixing the mixture obtained in step (a) with the isobutyl iodide to undergo the alkylation reaction to obtain a compound as shown in Formula VI;

[0021] Wherein, the solution of the metallized alkaline reagent is a mixed solution of the metallized alkaline reagent and the organic solvent.

[0022] In the step (a), the temperature of the mixture of the compound represented by formula V and the organic solvent, the solution of the metallized alkaline reagent and the activation reagent when mixed is -100°C to -30°C, preferably -80°C to -45°C, for example -78°C.

[0023] In the step (a), the temperature of the mixture of the compound represented by formula V and the organic solvent, the solution of the metallized alkaline reagent and the activating reagent after mixing is -78°C to -30°C, preferably -30°C to -40°C, for example -35°C or -40°C.

[0024] In the step (b), the temperature at which the mixture obtained in the step (a) is mixed with the isobutyl iodide is -100°C to -30°C, preferably -80°C to -45°C, for example -78°C.

[0025] In the step (b), the temperature of the mixture obtained in the step (a) after mixing with the isobutyl iodide is -78°C to -30°C, preferably -30°C to -40°C, for example -30°C.

[0026] The raw materials for the alkylation reaction are composed of the organic solvent, the metallized alkaline reagent, the activation reagent, the compound shown in formula V and the iodinated isobutane.

[0027] In the alkylation reaction, the activating agent is HMPA, DPU or DMA, preferably HMPA or DPU, such as HMPA.

[0028] In the alkylation reaction, the organic solvent is preferably an analytically pure organic solvent.

[0029] In the alkylation reaction, the organic solvent may be a conventional organic solvent for alkylation reactions in the art, preferably THF, DME or DMF, such as THF.

[0030] In step (a), the molar volume ratio of the compound represented by formula V to the organic solvent is 0.1 to 0.5 mol / L, preferably 0.2 to 0.4 mol / L, for example 0.36 mol / L.

[0031] In step (a), the molar volume ratio of the metallized alkaline reagent to the organic solvent in the solution of the metallized alkaline reagent is 0.8 to 2.5 mol / L, preferably 1.0 to 2.0 mol / L, for example 1.0 mol / L or 2.0 mol / L.

[0032] After the alkylation reaction is completed, post-treatment is further included. The post-treatment can be a conventional post-treatment of alkylation reactions in the art, which includes the following steps: quenching and extraction.

[0033] In the post-treatment, the quenching reagent is an aqueous solution of ammonium chloride, and the aqueous solution of ammonium chloride is a saturated aqueous solution of ammonium chloride.

[0034] In the post-treatment, the reagent used for the extraction is an organic solvent, and the organic solvent is preferably diethyl ether.

[0035] In a preferred embodiment, the method for preparing the compound as shown in Formula VI further includes the method for preparing the compound as shown in Formula V, and the method for preparing the compound as shown in Formula V includes the following steps:

[0036] In acetic acid, the compound represented by formula IV is reacted with zinc or iron to obtain a compound represented by formula V;

[0037]

[0038] In the reaction, the zinc is preferably zinc powder.

[0039] In the reaction, the molar ratio of zinc to the compound represented by formula IV is (3-15):1, preferably (3-10):1, more preferably (4-6):1, for example 4:1, 5:1 or 6:1.

[0040] In the reaction, the volume molar ratio of the acetic acid to the compound represented by formula IV is 3.0 to 6.0 L / mol, preferably 4.0 to 5.0 L / mol, for example 4.7 or 4.8 L / mol.

[0041] In the reaction, the reaction temperature is 30-100°C, preferably 75-90°C, such as 75°C or 90°C.

[0042] After the reaction is completed, post-treatment is also included, and the post-treatment includes the following steps: filtration, pH adjustment, extraction and recrystallization.

[0043] In the post-treatment, the reagent used to adjust the pH is a sodium hydroxide solution, and the concentration of the sodium hydroxide solution is 3 mol / L.

[0044] In the post-treatment, the reagent used for the extraction is an organic solvent, and the organic solvent is preferably ethyl acetate.

[0045] In the post-treatment, the reagents used for the recrystallization are ethyl acetate and petroleum ether.

[0046] In a preferred embodiment, the method for preparing the compound as shown in formula V further includes the method for preparing the compound as shown in formula IV, and the method for preparing the compound as shown in formula IV includes the following steps:

[0047] In an organic solvent, a compound represented by formula III and 3-butenoic acid methyl ester undergo a 1,3-dipolar addition reaction to obtain a compound represented by formula IV;

[0048]

[0049] In the 1,3-dipolar addition reaction, the reaction temperature of the 1,3-dipolar addition reaction is 80 to 110°C, preferably 80 to 100°C, for example 80°C or 100°C.

[0050] In the 1,3-dipolar addition reaction, the molar ratio of the methyl 3-butenoate to the compound represented by formula III is (1.5-3.5):1, preferably (1.5-3):1, for example 1.5:1, 2.5:1 or 3:1.

[0051] In the 1,3-dipolar addition reaction, the organic solvent is a conventional organic solvent for 1,3-dipolar addition reaction in the art, preferably DMF, xylene, toluene, ethyl acetate or DME, more preferably DMF or toluene, such as toluene.

[0052] In the 1,3-dipolar addition reaction, the molar volume ratio of the compound represented by formula III to the organic solvent is the conventional amount used in 1,3-dipolar addition reaction in the art, preferably 0.05 to 0.5 mol / L, more preferably 0.1 to 0.3 mol / L, for example 0.15 mol / L.

[0053] After the 1,3-dipole addition reaction is completed, a post-treatment is further included, and the post-treatment is recrystallization.

[0054] In the post-treatment, the reagents used for the recrystallization are ethyl acetate and petroleum ether.

[0055] The present invention also provides a compound as shown in formula IV,

[0056] The present invention also provides a crystalline form of a compound as shown in Formula IV, whose unit cell parameters are α=90°, β=90°, γ=90°,

[0057]

[0058] The present invention also provides a compound as shown in formula V,

[0059] The present invention also provides a method for preparing the compound as shown in formula V, which comprises the following steps:

[0060] In acetic acid, the compound represented by formula IV is reacted with zinc or iron to obtain a compound represented by formula V;

[0061]

[0062] In the method for preparing the compound represented by formula V, each reaction condition is as described in any one of the present invention.

[0063] The present invention also provides a method for preparing the compound as shown in formula IV, which comprises the following steps:

[0064] In an organic solvent, a compound represented by formula III and 3-butenoic acid methyl ester undergo a 1,3-dipolar addition reaction to obtain a compound represented by formula IV;

[0065]

[0066] In the method for preparing the compound of formula IV, each reaction condition is as described in any one of the present invention.

[0067] The present invention prepares the compound shown in Formula VI by the following route:

[0068]

[0069] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0070] (±) indicates that the compound is a mixture of equal amounts of right- and left-handed isomers, for example, express and An equal mixture of .

[0071] The reagents and raw materials used in the present invention are commercially available.

[0072] The positive and progressive effects of the present invention are:

[0073] (1) Compound VI is prepared from Compound III as a raw material, and two new compounds are provided as intermediates. Through the ingenious design of the structures of the two intermediates, the target product Compound VI can be obtained in only three steps; wherein, the stereo configuration of the two optically active centers in Compound VI can be basically determined through the 1,3-dipole addition reaction of the compound shown in Formula III, thereby directly avoiding the formation and separation of stereoisomers.

[0074] (2) The total yield and the yield of the single-step reaction are both high. The yield of the three steps of the entire route can reach 62%, and the yield of each step in the single-step reaction is about 70%. Among them, the yield of the alkylation reaction is about 70%, and the yields of the other two steps can reach more than 90%.

[0075] (3) The reaction time is greatly shortened. The reaction time of each step is basically less than or equal to 8 hours, and the production cycle is short, which is conducive to industrial expansion of production scale.

[0076] (4) The intermediates such as the compound of formula IV and the intermediates such as the compound of formula V have stable structures, the products are easy to crystallize, and the post-treatment operation is simple, which is conducive to industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] Figure 1 is a single crystal diffraction pattern of the compound represented by formula IV;

[0078] Figure 2 is a two-dimensional nuclear magnetic HH COSY spectrum of the compound represented by formula V;

[0079] Figure 3 It is the two-dimensional nuclear magnetic NOESY spectrum of the compound shown in formula V. DETAILED DESCRIPTION

[0080] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0081] Example 1

[0082] This embodiment provides a method for the total synthesis of hydroxytetrabenazine, a vesicular monoamine transporter-2 inhibitor.

[0083] (1) Preparation of the compound shown in Formula IV

[0084]

[0085] Weigh the compound shown in formula III (5.0 g, 24.1 mmol), add solvent toluene (50 mL), and then add methyl 3-butenoate (7.3 g, 72.4 mmol). Move the reaction system to a 100°C oil bath and heat under reflux for 4 hours. TLC monitoring shows that the raw material is basically converted, stop heating, cool the reaction system to room temperature, and then concentrate under reduced pressure to remove toluene. Recrystallize with petroleum ether and ethyl acetate to obtain 6.8 g of yellow crystals with a yield of 92%.

[0086] Structural identification of the compound shown in Formula IV: The yellow crystals obtained by recrystallization were subjected to X-ray single crystal diffraction experiments. Figure 1 The specific data are shown in Table 1. According to the characterization results of X-ray single crystal diffraction, it can be determined that the compound shown in Formula IV It is an exo racemic compound, and the configurations at positions 3 and 5 are (3R, 5R) or (3S, 5S), respectively. mixture.

[0087] The single crystal unit cell data of the compound shown in Formula IV are as follows:

[0088] α=90°, β=90°, γ=90°.

[0089] Mp:96.9-98.9℃.

[0090] 1H NMR (400MHz, CDCl3) δppm: 6.58 (s, 1H), 6.54 (s, 1H), 4.71 (dt, J = 13.3, 6.8Hz, 1H), 4.51 (t, J = 8.2Hz, 1H), 3.84 (s, 6H), 3.70 (s, 3H), 3.24-3 .17(m,1H),3.10(td,J=10.3,4.0Hz,1H),2.97-2.87(m,1H),2.76(dd,J=15.5,6.3Hz,2H),2.59(dd,J=15.6,7.0Hz,1H),2.53-2.40(m,2H). 13 C NMR (100MHz, CDCl3) δppm: 171.4, 147.9, 127.4, 125.4, 110.9, 109.9, 73.7, 62.1, 56.1, 56.0, 51.9, 48.4, 42.0, 40.0, 27.7.

[0091] (2) Preparation of the compound shown in Formula V

[0092]

[0093] Weigh the compound shown in formula IV (6.5 g, 21.2 mmol) and zinc powder (5.5 g, 84.6 mmol), then add acetic acid (100 mL) to obtain a suspension, and move to 75 ° C and heat under reflux for 5 hours. TLC monitors that the raw material reaction is complete, stop heating, cool the reaction system to room temperature, filter, wash with water, and then adjust the pH to 8 with 3M NaOH solution, and then extract with ethyl acetate (3×150 mL) three times, wash the organic phase with saturated brine once, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. Then recrystallize with ethyl acetate and petroleum ether (solvent ratio: (1-3): (2-4)) to obtain 5.6 g of yellow-white solid, that is, the compound shown in formula V, with a yield of 95%.

[0094] Structural identification of the compound shown in Formula V: The yellow-white solid obtained by recrystallization was subjected to HH COSY and NOESY tests by two-dimensional nuclear magnetic resonance. The obtained two-dimensional spectrum is as follows Figure 2 and Figure 3 As shown, according to the HH COSY and NOESY spectrum analysis, it can be determined that the compound shown in formula V It is an exo racemic compound, and the configurations at positions 3 and 5 are (3R, 5R) or (3S, 5S), respectively. mixture.

[0095] 1H NMR(500MHz,CDCl3)δppm 6.66(s,1H),6.61(s,1H),4.78(d,J=14.9Hz,1H),4.62(dd,J=11.6,4.4Hz,1H),4.22(d,J=11.1Hz,1H),3 .86(s,6H),2.94–2.83(m,3H),2.79(d,J=19.9Hz,1H),2.65(s,1H),2.37(s,1H),1.71(q,J=11.6Hz,1H).

[0096] 13 C NMR (126MHz, CDCl3) δppm:167.85,167.81,148.04,147.93,128.16,127.18 ,111.58,108.07,64.20,64.17,56.19,56.04,54.11,41.90,40.07,39.80.

[0097] (3) Preparation of the compound shown in Formula VI

[0098]

[0099] Weigh the compound shown in formula V (2.0 g, 7.2 mmol), add anhydrous THF (20 mL), replace nitrogen three times, move to -78 ° C cold bath and stir for 5 minutes. Then add LDA (2M in THF, 26 mmol, 13 mL) and HMPA (1.3 mL, 7.2 mmol), stir at -78 ° C for 1 hour, then warm to -35 ° C and stir for 1 hour. Then cool the reaction system to -78 ° C, add isobutyl iodide (3.3 g, 18.0 mmol), stir for 2 hours, then warm to -30 ° C and stir for 4 hours, and monitor the reaction by TLC until the reaction is completed. At this temperature, add saturated ammonium chloride aqueous solution to quench the reaction, then extract with ether (3×30 mL) three times, combine the organic phases, wash three times with saturated brine, then dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.6 g of yellow oily liquid with a yield of 67%.

[0100] for mixture.

[0101] 1H NMR (500MHz, CDCl3) δppm: 6.65 (s, 1H), 6.61 (s, 1H), 4.81-4.77 (m, 1H), 4.64-4.60 (m, 1H), 3 .96-3.90(m,1H),3.86(d,J=1.3Hz,6H),2.86(d,J=14.9Hz,1H),2.83-2.76(m,1H),2.75-2. 71(m,1H),2.62(d,J=15.1Hz,1H),2.32-2.26(m,1H),2.03(d,J=12.9Hz,1H),1.92-1.83(m, 2H),1.80-1.72(m,1H),1.59(d,J=10.5Hz,2H),0.98(d,J=6.5Hz,3H),0.92(d,J=6.6Hz,3H).

[0102] 13 C NMR (126MHz, CDCl3) δppm: 171.2, 148.0, 147.9, 128.4, 127.4, 111.6, 108. 1,69.3,56.18,56.0,53.5,48.9,40.1,40.0,39.0,28.5,26.8,23.3,22.5.

[0103] (4) Preparation of Hydroxytetrabenazine Racemate

[0104]

[0105] Weigh the compound shown in formula VI (1.5 g, 4.5 mmol), add anhydrous THF (15 mL) to dissolve, replace argon three times, add LiAlH4 (1M in THF, 22.5 mmol, 22.5 mL) solution, a large number of bubbles are generated, and then move to 70 ° C and heat under reflux for 3.5 hours. After TLC monitoring, the reaction of the raw material is complete. Cool to room temperature, add water (1 mL) and 10% wt NaOH (1 mL) aqueous solution (3 mL) to quench the reaction, and then extract with ethyl acetate (3×10 mL) three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.4 g of white solid, with a yield of 97%.

[0106] for mixture.

[0107] 1H NMR (400MHz, CDCl3) δ6.67(s,1H),6.58(s,1H),3.84(s,6H),3.39(td,J=10.4,4.5Hz,1H),3.14–2.97(m,4H),2.66–2.55(m,2H),2.45(td,J=11.4 ,4.1Hz,1H),1.97(t,J=11.4Hz,1H),1.77–1.77(m,3H),1.61–1.55(m,1H ),1.49(q,J=11.6Hz,1H),1.09–1.02(m,1H),0.93(dd,J=9.0,6.5Hz,6H).

[0108] 13 C NMR (101MHz, CDCl3) δ147.6,147.3,129.4,126.5,111.6,108.0,74.7,61.0,60.2,56.1,56.0,52.0,41.7,40.7,39.8,29.3,25.5,24.3,21.9.

[0109] The total yield of the hydroxytetrabenazine racemate prepared in this example is 56.8%.

[0110] Example 2

[0111] (1) Preparation of the compound shown in Formula IV

[0112]

[0113] Weigh the compound shown in formula III (5.0 g, 24.1 mmol), add solvent toluene (50 mL), and then add methyl 3-butenoate (6.0 g, 60.3 mmol). Move the reaction system to an 80°C oil bath and heat under reflux for 8 hours. TLC monitoring shows that the raw material is basically converted, stop heating, cool the reaction system to room temperature, and then concentrate under reduced pressure to remove toluene. Recrystallize with petroleum ether and ethyl acetate to obtain 6.1 g of yellow crystals with a yield of 82%.

[0114] Compared with the compound shown in Formula IV in Example 1, the obtained yellow crystal is an exo-type racemic compound, and the configurations of the 3-position and 5-position are (3R, 5R) or (3S, 5S), that is, mixture.

[0115] (2) Preparation of the compound shown in Formula V

[0116]

[0117] Weigh the compound shown in formula IV (3.2 g, 10.4 mmol) and zinc powder (3.4 g, 52.1 mmol), then add acetic acid (50 mL) to obtain a suspension, and move to 30°C and stir for 24 hours. TLC monitoring shows that the raw material has not reacted completely, stop heating, cool the reaction system to room temperature, filter, wash with water, adjust pH to 8 with 3M NaOH solution, extract three times with ethyl acetate (3×100 mL), wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then recrystallize with ethyl acetate petroleum ether to obtain 1.6 g of yellow-white solid, with a yield of 55%.

[0118] Compare with the compound shown in Formula V in Example 1 to determine the compound shown in Formula V It is an exo racemic compound, and the configurations at positions 3 and 5 are (3R, 5R) or (3S, 5S), respectively. mixture.

[0119] (3) Preparation of the compound shown in Formula VI

[0120]

[0121] Weigh the compound shown in formula V (2.0 g, 7.2 mmol), add anhydrous THF (20 mL), replace nitrogen three times, move to -78 ° C cold bath and stir for 5 minutes. Then add LDA (2M in THF, 28.8 mmol, 28.8 mL) and HMPA (1.5 mL, 8.6 mmol), stir at -78 ° C for 1 hour, then warm to -40 ° C and stir for 1 hour. Then add isobutyl iodide (5.3 g, 28.8 mmol), continue stirring for 6 hours, and monitor the reaction by TLC until the reaction is completed. At this temperature, add saturated ammonium chloride aqueous solution to quench the reaction, then extract with ether (3×30 mL) three times, combine the organic phases, wash with saturated brine three times, then dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.7 g of yellow oily liquid with a yield of 71%.

[0122] (4) Preparation of Hydroxytetrabenazine Racemate

[0123]

[0124] Weigh the compound shown in formula VI (1.5 g, 4.5 mmol), add anhydrous THF (15 mL) to dissolve, replace argon three times, add LiAlH4 (1M in THF, 13.5 mmol, 13.5 mL) solution, a large number of bubbles are generated, and then move to 70 ° C and heat under reflux for 2 hours. After TLC monitoring, the reaction of the raw material is complete. Cool to room temperature, add water (1 mL) and 10% wt NaOH (1 mL) aqueous solution (3 mL) in sequence to quench the reaction, and then extract with ethyl acetate (3×10 mL) three times, combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.2 g of white solid, with a yield of 83%.

[0125] The total yield of the hydroxytetrabenazine racemate prepared in this example is 26.6%.

[0126] Example 3

[0127] This embodiment provides a method for the total synthesis of hydroxytetrabenazine, a vesicular monoamine transporter 2 inhibitor.

[0128] (1) Preparation of the compound shown in Formula IV

[0129]

[0130] Weigh the compound shown in formula III (5.0 g, 24.1 mmol), add solvent toluene (50 mL), and then add 3-butenoic acid methyl ester (3.6 g, 36.2 mmol). Move the reaction system to a 100°C oil bath and heat under reflux for 3 hours. TLC monitoring shows that the raw material is basically converted, stop heating, cool the reaction system to room temperature, and then concentrate under reduced pressure to remove toluene. Recrystallize with petroleum ether and ethyl acetate to obtain 6.3 g of yellow crystals with a yield of 85%.

[0131] Compared with the compound shown in Formula IV in Example 1, the obtained yellow crystal is an exo-type racemic compound, and the configurations of the 3-position and 5-position are (3R, 5R) or (3S, 5S), that is, mixture.

[0132] (2) Preparation of the compound shown in Formula V

[0133]

[0134] Weigh the compound shown in formula IV (6.5 g, 21.2 mmol) and zinc powder (8.3 g, 126.9 mmol), then add acetic acid (100 mL) to obtain a suspension, and move to 90°C and heat under reflux for 2 hours. TLC monitors that the raw material reaction is complete, stop heating, cool the reaction system to room temperature, filter, wash with water, and then adjust pH to 8 with 3M NaOH solution, then extract three times with ethyl acetate (3×150 mL), wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then recrystallize with ethyl acetate petroleum ether to obtain 5.5 g of yellow-white solid, with a yield of 94%.

[0135] Compare with the compound shown in Formula V in Example 1 to determine the compound shown in Formula V It is an exo racemic compound, and the configurations at positions 3 and 5 are (3R, 5R) or (3S, 5S), respectively. mixture.

[0136] (3) Preparation of the compound shown in Formula VI

[0137]

[0138] Weigh the compound shown in formula V (2.0 g, 7.2 mmol), add anhydrous THF (20 mL), replace nitrogen three times, move to -78 ° C cold bath and stir for 5 minutes. Then add LiHMDS (2M in THF, 18.0 mmol, 9 mL) and HMPA (0.65 mL, 3.6 mmol), stir at -78 ° C for 1 hour, add isobutyl iodide (4.0 g, 21.6 mmol), stir for 4 hours, then warm to -30 ° C and stir for 4 hours, and monitor the reaction by TLC until the reaction is completed. At this temperature, add saturated ammonium chloride aqueous solution to quench the reaction, then extract with ether (3×30 mL) three times, combine the organic phases, wash three times with saturated brine, then dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 1.0 g of yellow oily liquid with a yield of 42%.

[0139] (4) Preparation of Hydroxytetrabenazine Racemate

[0140]

[0141] Weigh the compound shown in formula VI (1.5 g, 4.5 mmol), add anhydrous THF (15 mL) to dissolve, replace argon three times, add LiAlH4 (1M in THF, 20.3 mmol, 20.3 mL) solution, a large number of bubbles are generated, and then move to 70 ° C and heat under reflux for 3 hours. After TLC monitoring, the reaction of the raw material is complete. Cool to room temperature, add water (1 mL) and 10% wt NaOH (1 mL) aqueous solution, and water (3 mL) to quench the reaction, and then extract with ethyl acetate (3×10 mL) three times, combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Purify by column chromatography to obtain 1.31 g of white solid with a yield of 91%.

[0142] The total yield of the hydroxytetrabenazine racemate prepared in this example is 30.5%.

[0143] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a compound as shown in formula VI, characterized in that: It includes the following steps: In an organic solvent, in the presence of a metallized alkaline reagent and an activating reagent, an alkylation reaction is carried out between the compound represented by formula V and isobutyl iodide to obtain a compound represented by formula VI; The metallized alkaline agent is LDA.

2. The method for preparing the compound of formula VI as claimed in claim 1, characterized in that: The alkylation reaction satisfies one or more of the following conditions: (1) The molar ratio of the activation reagent to the compound represented by formula V is (0.5-2.0):1; (2) The molar ratio of the metallized alkaline reagent to the compound represented by formula V is (3.5-5.5):1; (3) The molar ratio of the isobutyl iodide to the compound represented by formula V is (2.5-4.5):1; (4) The organic solvent is THF, DME or DMF; (5) The activation reagent is HMPA, DPU or DMA; (6) The alkylation reaction further comprises the following steps: (a) mixing a mixture of the compound represented by formula V and the organic solvent, a solution of the metallized alkaline agent and the activating agent; (b) mixing the mixture obtained in step (a) with the isobutyl iodide to undergo the alkylation reaction to obtain a compound as shown in Formula VI; Wherein, the solution of the metallized alkaline reagent is a mixed solution of the metallized alkaline reagent and the organic solvent; (7) After the alkylation reaction is completed, a post-treatment is further included, and the post-treatment includes the following steps: quenching and extraction. The reagent used for the quenching is a saturated ammonium chloride aqueous solution, and the reagent used for the extraction is diethyl ether.

3. The method for preparing the compound of formula VI as claimed in claim 2, characterized in that: The alkylation reaction satisfies one or more of the following conditions: (1) The molar ratio of the metallized alkaline agent to the compound represented by formula V is (3.6-4):1; (2) The molar ratio of the activation reagent to the compound of Formula V is 0.5:1, 1:1 or 1.2:1; (3) The molar ratio of the isobutyl iodide to the compound of formula V is 2.5:1, 3:1 or 4:1; (4) The raw materials for the alkylation reaction are composed of the organic solvent, the metallized alkaline reagent, the activation reagent, the compound represented by formula V and the iodinated isobutylene; (5) The activation reagent is HMPA or DPU; (6) The organic solvent is THF; (7) In the step (a), the temperature of the mixture of the compound represented by formula V and the organic solvent, the solution of the metallized alkaline reagent and the activation reagent when mixed is -100°C to -30°C; (8) In step (a), the temperature of the mixture of the compound represented by formula V and the organic solvent, the solution of the metallized alkaline reagent and the activation reagent after mixing is -78°C to -30°C; (9) In the step (b), the temperature at which the mixture obtained in the step (a) is mixed with the isobutyl iodide is -100°C to -30°C; (10) In the step (b), the temperature of the mixture obtained in the step (a) after mixing with the isobutyl iodide is -78°C to -30°C; (11) In step (a), the molar volume ratio of the compound represented by formula V to the organic solvent is 0.1 to 0.5 mol / L; (12) In step (a), the molar volume ratio of the metallized alkaline reagent to the organic solvent in the solution of the metallized alkaline reagent is 0.8 to 2.5 mol / L.

4. The method for preparing the compound of formula VI as claimed in claim 3, characterized in that: The alkylation reaction satisfies one or more of the following conditions: (1) In step (a), the temperature of the mixture of the compound represented by formula V and the organic solvent, the solution of the metallized alkaline reagent and the activation reagent when mixed is -80°C to -45°C; (2) In step (a), the temperature of the mixture of the compound represented by formula V and the organic solvent, the solution of the metallized alkaline reagent and the activation reagent after mixing is -30°C to -40°C; (3) In the step (b), the temperature at which the mixture obtained in the step (a) is mixed with the isobutyl iodide is -80°C to -45°C; (4) In the step (b), the temperature of the mixture obtained in the step (a) after mixing with the isobutyl iodide is -30°C to -40°C; (5) In step (a), the molar volume ratio of the compound represented by formula V to the organic solvent is 0.2 to 0.4 mol / L; (6) In step (a), the molar volume ratio of the metallized alkaline reagent to the organic solvent in the solution of the metallized alkaline reagent is 1.0 to 2.0 mol / L.

5. The method for preparing the compound of formula VI as claimed in claim 1, characterized in that: The method for preparing the compound shown in Formula VI further comprises the following steps: In acetic acid, the compound represented by formula IV is reacted with zinc or iron to obtain a compound represented by formula V; 6. The method for preparing the compound of formula VI as claimed in claim 5, characterized in that: The method for preparing the compound of formula V satisfies one or more of the following conditions: (1) The zinc is zinc powder; (2) The molar ratio of zinc to the compound of formula IV is (3-15):1, for example, 4:1, 5:1, 6:1 or 10:1; (3) The volume molar ratio of the acetic acid to the compound represented by formula IV is 3.0 to 6.0 L / mol, preferably 4.0 to 5.0 L / mol; (4) The reaction temperature of the reaction is 30 to 100° C., preferably 75 to 90° C.; (5) After the reaction is completed, post-treatment is also included, and the post-treatment includes the following steps: filtration, pH adjustment, extraction and recrystallization; the reagent used for adjusting the pH is sodium hydroxide solution, the reagent used for extraction is ethyl acetate, and the reagents used for recrystallization are ethyl acetate and petroleum ether.

7. The method for preparing the compound of formula VI as claimed in claim 5, characterized in that: The method for preparing the compound shown in Formula IV further comprises the following steps: In an organic solvent, a compound represented by formula III and 3-butenoic acid methyl ester undergo a 1,3-dipolar addition reaction to obtain a compound represented by formula IV; 8. The method for preparing the compound of formula VI as claimed in claim 7, characterized in that: The 1,3-dipolar addition reaction satisfies one or more of the following conditions: (1) The reaction temperature of the 1,3-dipolar addition reaction is 80 to 110° C., preferably 80 to 100° C.; (2) The molar ratio of the methyl 3-butenoate to the compound represented by formula III is (1.5-3.5):1, for example, 1.5:1, 2.5:1 or 3:1; (3) The organic solvent is DMF, xylene, toluene, ethyl acetate or DME, preferably DMF or toluene; (4) The molar volume ratio of the compound represented by formula III to the organic solvent is 0.05 to 0.5 mol / L, preferably 0.1 to 0.3 mol / L; (5) After the 1,3-dipolar addition reaction is completed, post-treatment is also included, and the post-treatment includes recrystallization; the reagents used for the recrystallization are ethyl acetate and petroleum ether.

9. A compound of formula IV or a compound of formula V, 10. A method for preparing a compound as represented by formula V or a compound as represented by formula IV, characterized in that: The method for preparing the compound of formula V comprises the following steps: reacting the compound of formula IV with zinc or iron in acetic acid to obtain the compound of formula V; The preparation method of the compound shown in formula IV comprises the following steps: in an organic solvent, subjecting the compound shown in formula III and 3-butenoic acid methyl ester to a 1,3-dipolar addition reaction to obtain the compound shown in formula IV; Preferably, in the method for preparing the compound represented by formula V, each reaction condition is as described in claim 5 or 6; In the method for preparing the compound shown in formula IV, the reaction conditions are as described in claim 7 or 8.

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