CN119977958A - Hydroxytetrabenazine intermediate and preparation method thereof - Google Patents
Hydroxytetrabenazine intermediate and preparation method thereof Download PDFInfo
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Abstract
本发明公开了羟基丁苯那嗪中间体及其制备方法，本发明提供了制备羟基丁苯那嗪路线中的新中间体化合物如式V和如式IV所示化合物，本发明制备方法整体路线短、生产周期短，每一步反应均能实现收率高、反应时间短、后处理操作简单等效果，利于工业化扩大生产规模。
The invention discloses a hydroxytetrabenazine intermediate and a preparation method thereof. The invention provides a new intermediate compound in the route of preparing hydroxytetrabenazine, such as a compound shown in formula V and a compound shown in formula IV. The preparation method of the invention has a short overall route and a short production cycle, and each step of the reaction can achieve the effects of high yield, short reaction time, simple post-processing operation, etc., which is conducive to industrial expansion of production scale.
Description
Technical Field
The invention relates to a preparation method of tetrabenazine, and particularly provides two types of tetrabenazine intermediates and a preparation method thereof.
Background
The hydroxy tetrabenazine (dihydrotetrabenazine, HTBZ or DHTBZ shown in the structural formula) is a carbonyl reduction product and a metabolite of tetrabenazine (tetrabenazine, TBZ) which belong to benzoisoquinoline derivatives, and is used as a clinical vesicle monoamine transporter-2 (VMAT-2) inhibitor, and the pharmacological effect is exerted by combining and inhibiting VMAT-2 so as to reduce the level of monoamine transmitters in brain.
In the central nervous system, VMAT-2 is responsible for storing and subsequently releasing monoamines such as dopamine, serotonin, norepinephrine, epinephrine, histamine, etc. from the cytoplasm into vesicles. The appearance of functional disorders in VMAT-2 will lead to a number of neurological and psychiatric disorders including Parkinson's Disease (PD), huntington's Disease (HD), schizophrenia, psychostimulant addiction and depression. For drug development, VMAT-2 is considered as an effective target for the treatment of the above-mentioned diseases. Tetrabenazine (tetrabenazine, TBZ) racemate was first found to be useful in modulating 5-hydroxytryptamine levels in 1957, and was later found to be a clinical VMAT-2 inhibitor, approved in europe for the treatment of Huntington's Disease (HD) in 1971, approved by the FDA in the united states for the treatment of excitatory dyskinesias caused by dopamine hyperactivity, such as huntington's disease and Tourette syndrome, and the like, as the first drug approved in the united states for the treatment of HD.
The tetrabenazine (alpha-HTBZ) is a metabolite of tetrabenazine and can act on the central nervous system VMAT-2 with high selectivity. Studies have shown that TBZ (racemate) is actually a prodrug and that it is alpha-HTBZ that is truly active in humans. Since TBZ is metabolized in vivo to produce multiple stereoisomers, only one of the enantiomers shows excellent therapeutic effects. On this basis, pentoxamine (valbenazine) has evolved into a new prodrug and is a new marketed drug that has been approved by the FDA in the united states for the treatment of Tardive Dyskinesia (TD) and HD.
At present, a plurality of research teams have completed the synthesis of tetrabenazine, the racemate and the asymmetry of the tetrabenazine. In 1958, hoffmann et al first reported a method for synthesizing TBZ and issued a related patent (US 2830993.1958-04-15) starting with 6, 7-dimethoxy-3, 4-dihydroisoquinoline and 3-isobutyl-3-buten-2-one, and carrying out Mannich reaction to form a ring. In 1965, whittaker et al used the precursor trimethyl quaternary ammonium salt of enone with 6, 7-dimethoxy-3, 4-dihydroisoquinoline to synthesize TBZ (GB 999095.1965-07-21). On this basis, grant et al have further improved the reaction in 2010 (WO 2010044981.2010-04-22) by reacting a quaternary ammonium iodide salt, which is 5-methyl-2-hexanone as a raw material, with 6, 7-dimethoxy-3, 4-dihydroisoquinoline to obtain the target product. In 2012 Chen et al improved the protocol (mol. Cryst. Liq. Cryst.2012,557, 39). Son et al report a method of intramolecular aza-Prins cyclization to butanazine in 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 synthesized the target product TBZ (org.biomol. Chem.2019,17,8827) in 6 steps by Diels-Alder reaction using propynyl alcohol and 6, 7-dimethoxy-3, 4-dihydroisoquinoline as raw materials, and the hydroxy tetrabenazine could be finally obtained from the synthesized tetrabenazine by sodium borohydride reduction.
Asymmetric synthesis of tetrabenazine has also been reported. Kilbourn et al, 1997, used the method of enzymatic hydrolysis kinetics resolution (Chirality 1997,9,59) to give enantiomerically pure (+) - α -HTBZ. In 2009, rehder et al converted racemic α -HTBZ mixtures to their isolatable (+) - α -HTBZ- (L) -tartrate salts with p-methylbenzoyl- (L) -tartaric acid (synth com 2009,39,3574). In 2009, rishel et al utilized organometallic palladium catalysis to achieve the first chemical asymmetric synthesis (j.org.chem.2009, 74,4001). A second asymmetric synthesis of (+) -TBZ was reported by Suh et al in 2010 (j.org.chem.2017, 82,1464). In 2012, johannes et al introduced chiral prosthetic groups for asymmetric synthesis (org. Lett.2012,14,3752). In the same year, reddy et al applied chiral sulfonamide to asymmetric synthesis of (-) - α -HTBZ (Tetrahedron Lett.2012,53,6916), 11 conversion steps total.
Most of the reported synthesis routes focus on the synthesis of Tetrabenazine (TBZ) and reduce carbonyl groups by NaBH 4, so that a plurality of isomers are generated, and complicated operation is brought to subsequent separation; in addition, the asymmetric control method of hydroxyl chirality has the problems of long synthetic route, limited chiral center construction, poor stereoselectivity of partial chemical reaction, multiple column chromatography separation and purification, expensive transition metal catalyst, toxic reagent which is harmful to the environment, and the like. Therefore, the design of a high-stereoselectivity synthesis method for preparing the hydroxy tetrabenazine improves the synthesis efficiency of chiral medicaments, and is still urgent and necessary.
Disclosure of Invention
The invention aims to overcome the defects of long preparation path, low yield, difficult separation of stereoisomers and the like of the hydroxy tetrabenazine in the prior art, provides a new path for preparing a compound VI by using a new intermediate, adopts a new compound V and a compound IV as intermediates, adopts a compound III as a raw material, and can prepare the compound VI only by 3 steps, the whole path directly avoids the generation of stereoisomers, and has the advantages of high yield, short reaction time, easy crystallization of the intermediates, contribution to separation, purification, large-scale production, convenient experimental operation and contribution to industrial production.
The invention solves the technical problems through the following technical proposal.
The invention provides a preparation method of a compound shown in a formula VI, which comprises the following steps:
in an organic solvent, in the presence of a metalized alkaline reagent and an activating reagent, carrying out alkylation reaction on a compound shown in a formula V and iodized isobutane to prepare a compound shown in a formula VI;
the metallized alkaline reagent is LDA.
In the alkylation reaction, the molar ratio of the metalized alkaline reagent to the compound shown as the formula V is (3.5-5.5) 1, preferably (3.6-4) 1, for example, 3.6:1 or 4:1.
In the alkylation reaction, the molar ratio of the activating reagent to the compound shown in the 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.
In the alkylation reaction, the molar ratio of the iodinated isobutane to the compound shown in the formula V is (2.5-4.5): 1, preferably (2.5-4.0): 1, such as 2.5:1, 3:1 or 4:1.
The alkylation reaction further comprises the steps of:
(a) A mixture of a compound of formula V and the organic solvent, a solution of the metallized alkaline reagent and the activating reagent;
(b) Mixing the mixture obtained in the step (a) with the iodo-isobutane to carry out alkylation reaction to obtain a compound shown in a formula VI;
Wherein the solution of the metallized alkaline reagent is a mixed solution of the metallized alkaline reagent and the organic solvent.
In the step (a), the mixture of the compound shown as the formula V and the organic solvent, the solution of the metalized alkaline reagent and the activating reagent are mixed at the temperature of-100 ℃ to-30 ℃, preferably-80 ℃ to-45 ℃, for example-78 ℃.
In the step (a), the temperature of the mixture of the compound shown as the formula V and the organic solvent, the solution of the metalized alkaline agent and the activating agent after mixing is-78 ℃ to-30 ℃, preferably-30 ℃ to-40 ℃, for example-35 ℃ or-40 ℃.
In the step (b), the temperature of the mixture obtained in the step (a) and the iodinated isobutane when mixed is-100 ℃ to-30 ℃, preferably-80 ℃ to-45 ℃, for example-78 ℃.
In the step (b), the temperature of the mixture obtained in the step (a) and the iodinated isobutane after being mixed is-78 ℃ to-30 ℃, preferably-30 ℃ to-40 ℃, for example-30 ℃.
The raw materials of the alkylation reaction consist of the organic solvent, the metalized alkaline reagent, the activating reagent, the compound shown as the formula V and the iodo isobutane.
In the alkylation reaction, the activating reagent is HMPA, DPU or DMA, preferably HMPA or DPU, such as HMPA.
In the alkylation reaction, the organic solvent is preferably an analytically pure organic solvent.
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.
In the step (a), the molar volume ratio of the compound shown in the formula V to the organic solvent is 0.1-0.5 mol/L, preferably 0.2-0.4 mol/L, for example 0.36mol/L.
In the 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 2.5mol/L, preferably 1.0 to 2.0mol/L, for example 1.0mol/L or 2.0mol/L.
After the alkylation reaction is completed, the method further comprises post-treatment, wherein the post-treatment can be conventional post-treatment of the alkylation reaction in the field, and comprises the steps of quenching and extraction.
In the post-treatment, the reagent used for quenching is an ammonium chloride aqueous solution, and the ammonium chloride aqueous solution is a saturated ammonium chloride aqueous solution.
In the post-treatment, the reagent used for the extraction is an organic solvent, and the organic solvent is preferably diethyl ether.
In a certain preferred embodiment, the preparation method of the compound shown in the formula VI further comprises a preparation method of the compound shown in the formula V, and the preparation method of the compound shown in the formula V comprises the following steps:
In acetic acid, reacting a compound shown in a formula IV with zinc or iron to prepare a compound shown in a formula V;
In the reaction, zinc is preferably zinc powder.
In the reaction, the molar ratio of the zinc to the compound represented by the formula IV is (3-15): 1, preferably (3-10): 1, more preferably (4-6): 1, for example, 4:1, 5:1 or 6:1.
In the reaction, the volume molar ratio of the acetic acid to the compound shown in the formula IV is 3.0-6.0L/mol, preferably 4.0-5.0L/mol, for example 4.7 or 4.8L/mol.
In the reaction, the reaction temperature of the reaction is 30 to 100 ℃, preferably 75 to 90 ℃, for example 75 ℃ or 90 ℃.
The reaction further comprises post-treatment after finishing, wherein the post-treatment comprises the steps of filtering, regulating pH, extracting and recrystallizing.
In the post-treatment, the reagent used for regulating the pH is sodium hydroxide solution, and the concentration of the sodium hydroxide solution is 3mol/L.
In the post-treatment, the reagent used for the extraction is an organic solvent, and the organic solvent is preferably ethyl acetate.
In the post-treatment, the reagents adopted for the recrystallization are ethyl acetate and petroleum ether.
In a certain preferred embodiment, the preparation method of the compound shown in the formula V further includes the preparation method of the compound shown in the formula IV, and the preparation method of the compound shown in the formula IV includes the following steps:
In an organic solvent, carrying out 1, 3-dipole addition reaction on a compound shown in a formula III and methyl 3-butenoate to prepare a compound shown in a formula IV;
In the 1, 3-dipolar addition reaction, the reaction temperature of the 1, 3-dipolar addition reaction is 80 to 110 ℃, preferably 80 to 100 ℃, for example 80 ℃ or 100 ℃.
In the 1, 3-dipole addition reaction, the molar ratio of the methyl 3-butenoate to the compound shown in the formula III is (1.5-3.5): 1, preferably (1.5-3): 1, for example, 1.5:1, 2.5:1 or 3:1.
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, for example toluene.
In the 1, 3-dipole addition reaction, the molar volume ratio of the compound shown in the formula III to the organic solvent is the conventional dosage of the 1, 3-dipole addition reaction in the field, preferably 0.05-0.5 mol/L, more preferably 0.1-0.3 mol/L, for example 0.15mol/L.
The 1, 3-dipolar addition reaction further comprises a post-treatment after the completion of the 1, 3-dipolar addition reaction, wherein the post-treatment is recrystallized.
In the post-treatment, the reagents adopted for the recrystallization are ethyl acetate and petroleum ether.
The invention also provides a compound shown as a formula IV,
The invention also provides a crystal form of the compound shown in the formula IV, the unit cell parameters of the crystal form are as followsα=90°,β=90°,γ=90°,
The invention also provides a compound shown as a formula V,
The invention also provides a preparation method of the compound shown in the formula V, which comprises the following steps:
In acetic acid, reacting a compound shown in a formula IV with zinc or iron to prepare a compound shown in a formula V;
In the preparation method of the compound shown in the formula V, each reaction condition is as described in any one of the invention.
The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps:
In an organic solvent, carrying out 1, 3-dipole addition reaction on a compound shown in a formula III and methyl 3-butenoate to prepare a compound shown in a formula IV;
In the preparation method of the compound shown in the formula IV, each reaction condition is as described in any one of the invention.
The present invention prepares a compound of formula VI by the following route,
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
(±) Means that the compound is a mixture of equal amounts of the dextroisomer and the levorotatory isomer, for example,Representation ofAndEqual amounts of mixtures of (3).
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
(1) Preparing a compound VI from a compound III serving as a raw material, providing two new compounds serving as intermediates, and obtaining a target product VI in only 3 steps through ingenious design of structures of the two intermediates, wherein the three-dimensional configuration of two optical centers in the compound VI can be basically determined through a 1, 3-dipolar addition reaction of the compound shown in the formula III, and the formation and separation of stereoisomers are directly avoided.
(2) The total yield and the yield of the single-step reaction are both higher, the yield of 3 steps in the whole route can reach 62%, the yield of each step in the single-step reaction is about 70%, wherein the yield of the alkylation reaction reaches about 70%, and the yields of the other 2 steps can reach more than 90%.
(3) The reaction time is greatly shortened, the reaction time of each step is basically less than or equal to 8 hours, the production period is shorter, and the industrialized production scale expansion is facilitated.
(4) The intermediate compound shown in the formula IV and the intermediate compound shown in the formula V have stable structures, the product is easy to crystallize, the post-treatment operation is simple, and the industrial production is facilitated.
Drawings
FIG. 1 is a single crystal diffraction pattern of a compound of formula IV;
FIG. 2 is a two-dimensional nuclear magnetic H-H COSY spectrum of a compound shown in formula V;
FIG. 3 is a two-dimensional nuclear magnetic NOESY spectrum of a compound shown in formula V.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
This example provides a total synthesis of the vesicular monoamine transporter-2 inhibitor, tetrabenazine.
(1) Preparation of Compounds of formula IV
The compound of formula III (5.0 g,24.1 mmol) was weighed out, toluene (50 mL) was added as a solvent, followed by methyl 3-butenoate (7.3 g,72.4 mmol). The reaction was transferred to a 100 ℃ oil bath and heated to reflux for 4 hours. TLC monitored the complete conversion of starting material, stopped heating, cooled the reaction to room temperature, and then concentrated under reduced pressure to remove toluene. Recrystallization from petroleum ether and ethyl acetate gave 6.8g of yellow crystals with 92% yield.
The structure of the compound shown in the formula IV is identified by taking yellow crystals obtained by recrystallization, and carrying out an X-ray single crystal diffraction experiment, wherein the X-ray single crystal diffraction is shown in figure 1, and specific data are shown in the following table 1. From the characterization result of the X-ray single crystal diffraction, the compound shown as the formula IV can be determinedIs exo-type raceme compound, the configuration of 3 position and 5 position is (3R, 5R) or (3S, 5S) respectively, namelyAnd (3) a mixture.
Single crystal unit cell data for the compounds of formula IV are as follows:
α=90°,β=90°,γ=90°。
Mp:96.9-98.9°C.
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).13C 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.
(2) Preparation of Compounds of formula V
The compound of formula IV (6.5 g,21.2 mmol) and zinc powder (5.5 g,84.6 mmol) were weighed, acetic acid (100 mL) was added to give a suspension, and the suspension was heated to 75℃for 5 hours under reflux. TLC monitors the completion of the reaction of the starting materials, stops heating, cools the reaction system to room temperature, filters, washes with water, then adjusts pH=8 with 3M NaOH solution, then extracts three times with ethyl acetate (3X 150 mL), washes the organic phase once with saturated saline, dries with anhydrous sodium sulfate, decompresses and concentrates, then recrystallizes with ethyl acetate and petroleum ether (solvent ratio (1-3): 2-4)) to obtain 5.6g of off-white solid, i.e. the compound shown in formula V, with a yield of 95%.
The structure of the compound shown in formula V is identified by subjecting the off-white solid obtained by recrystallization to H-H COSY and NOESY tests by two-dimensional nuclear magnetism, and the obtained two-dimensional spectra are shown in FIG. 2 and FIG. 3, and the compound shown in formula V can be determined based on the analysis of the H-H COSY and NOESY spectraIs exo-type raceme compound, the configuration of 3 position and 5 position is (3R, 5R) or (3S, 5S) respectively, namelyAnd (3) a mixture.
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).
13C 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.
(3) Preparation of Compounds of formula VI
The compound of formula V (2.0 g,7.2 mmol) was weighed, anhydrous THF (20 mL) was added, nitrogen was purged three times, and the mixture was moved to-78℃and stirred in a cold bath for 5 minutes. LDA (2M in THF,26mmol,13mL) and HMPA (1.3 mL,7.2 mmol) were then added and stirred at-78℃for 1 hour, followed by a temperature increase to-35℃and stirring for 1 hour. Then the reaction was cooled to-78 ℃, iodinated isobutane (3.3 g,18.0 mmol) was added, stirred for 2 hours, then warmed to-30 ℃ and stirred for 4 hours, and TLC monitored the reaction to completion. The reaction was quenched by adding saturated aqueous ammonium chloride at this temperature, followed by extraction with diethyl ether (3X 30 mL) three times, combining the organic phases, washing with saturated brine three times, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to give 1.6g of a yellow oily liquid in 67% yield.
Is thatIs a mixture of (a) and (b).
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).
13C 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.
(4) Preparation of hydroxy tetrabenazine racemate
The compound of formula VI (1.5 g,4.5 mmol) was weighed, dissolved in anhydrous THF (15 mL), purged with argon three times, added with LiAlH 4 (1M in THF,22.5mmol,22.5mL) solution, and after a large amount of bubbles had been formed, the reaction was heated to 70℃for 3.5 hours and then refluxed, and TLC monitored the completion of the reaction of the starting materials. Cooling to room temperature, quenching reaction by adding water (1 mL) and 10%wt NaOH (1 mL) water (3 mL) in sequence, extracting with ethyl acetate (3X 10 mL) three times, combining organic phases, drying with anhydrous sodium sulfate, decompressing and concentrating, purifying by column chromatography to obtain white solid (1.4 g) with 97% yield.
Is thatIs a mixture of (a) and (b).
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).
13C 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.
The total yield of the tetrabenazine racemate prepared in this example was 56.8%.
Example 2
(1) Preparation of Compounds of formula IV
The compound of formula III (5.0 g,24.1 mmol) was weighed out, toluene (50 mL) was added as a solvent, and methyl 3-butenoate (6.0 g,60.3 mmol) was then added. The reaction was transferred to an 80 ℃ oil bath and heated to reflux for 8 hours. TLC monitored the complete conversion of starting material, stopped heating, cooled the reaction to room temperature, and then concentrated under reduced pressure to remove toluene. Recrystallization from petroleum ether and ethyl acetate gave 6.1g of yellow crystals with 82% yield.
Comparing with the compound shown in the formula IV in the example 1, the obtained yellow crystal is exo-type raceme compound, and the configuration of the 3 position and the 5 position is (3R, 5R) or (3S, 5S) respectively, namelyAnd (3) a mixture.
(2) Preparation of Compounds of formula V
The compound of formula IV (3.2 g,10.4 mmol) and zinc powder (3.4 g,52.1 mmol) were weighed out and acetic acid (50 mL) was added to give a suspension, which was then stirred at 30℃for 24 hours. TLC monitored complete reaction of the starting material, stopped heating, cooled to room temperature, filtered, washed with water, then ph=8 adjusted with 3m noh solution, then extracted three times with ethyl acetate (3×100 mL), the organic phase washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then recrystallized with ethyl acetate petroleum ether to give 1.6g of off-white solid in 55% yield.
Comparing with the compound shown as the formula V in the example 1 to determine the compound shown as the formula VIs exo-type raceme compound, the configuration of 3 position and 5 position is (3R, 5R) or (3S, 5S) respectively, namelyAnd (3) a mixture.
(3) Preparation of Compounds of formula VI
The compound of formula V (2.0 g,7.2 mmol) was weighed, anhydrous THF (20 mL) was added, nitrogen was purged three times, and the mixture was moved to-78℃and stirred in a cold bath for 5 minutes. LDA (2M in THF,28.8mmol,28.8mL) and HMPA (1.5 mL,8.6 mmol) were then added and stirred at-78℃for 1 hour, followed by a temperature increase to-40℃and stirring for 1 hour. Then, iodoisobutane (5.3 g,28.8 mmol) was added and stirring was continued for 6 hours, and TLC monitored the reaction to completion. The reaction was quenched by adding saturated aqueous ammonium chloride at this temperature, followed by extraction with diethyl ether (3X 30 mL) three times, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 1.7g of a yellow oily liquid in 71% yield.
(4) Preparation of hydroxy tetrabenazine racemate
The compound of formula VI (1.5 g,4.5 mmol) was weighed, dissolved in anhydrous THF (15 mL), purged with argon three times, added with LiAlH 4 (1M in THF,13.5mmol,13.5mL) solution, and after a large amount of bubbles had been formed, the reaction was heated to 70℃for 2 hours under reflux, and TLC monitored the completion of the reaction of the starting materials. Cooling to room temperature, quenching reaction by adding water (1 mL) and 10%wt NaOH (1 mL) water (3 mL) in sequence, extracting with ethyl acetate (3X 10 mL) three times, combining organic phases, drying with anhydrous sodium sulfate, decompressing and concentrating, purifying by column chromatography to obtain white solid 1.2g, yield 83%.
The total yield of the tetrabenazine racemate prepared in this example was 26.6%.
Example 3
The present example provides a total synthesis of the vesicular monoamine transporter 2 inhibitor, tetrabenazine.
(1) Preparation of Compounds of formula IV
The compound of formula III (5.0 g,24.1 mmol) was weighed out, toluene (50 mL) was added as a solvent, followed by methyl 3-butenoate (3.6 g,36.2 mmol). The reaction was transferred to a 100 ℃ oil bath and heated to reflux for 3 hours. TLC monitored the complete conversion of starting material, stopped heating, cooled the reaction to room temperature, and then concentrated under reduced pressure to remove toluene. Recrystallization from petroleum ether and ethyl acetate gave 6.3g of yellow crystals with 85% yield.
Comparing with the compound shown in the formula IV in the example 1, the obtained yellow crystal is exo-type raceme compound, and the configuration of the 3 position and the 5 position is (3R, 5R) or (3S, 5S) respectively, namelyAnd (3) a mixture.
(2) Preparation of Compounds of formula V
The compound of formula IV (6.5 g,21.2 mmol) and zinc powder (8.3 g,126.9 mmol) were weighed, acetic acid (100 mL) was added to give a suspension, and the suspension was brought to 90℃and heated under reflux for 2 hours. TLC monitored complete reaction of the starting materials, stopped heating, cooled to room temperature, filtered, washed with water, then ph=8 adjusted with 3M NaOH solution, then extracted three times with ethyl acetate (3×150 mL), the organic phase washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then recrystallized with ethyl acetate petroleum ether to give 5.5g of a yellowish white solid with 94% yield.
Comparing with the compound shown as the formula V in the example 1 to determine the compound shown as the formula VIs exo-type raceme compound, the configuration of 3 position and 5 position is (3R, 5R) or (3S, 5S) respectively, namelyAnd (3) a mixture.
(3) Preparation of Compounds of formula VI
The compound of formula V (2.0 g,7.2 mmol) was weighed, anhydrous THF (20 mL) was added, nitrogen was purged three times, and the mixture was moved to-78℃and stirred in a cold bath for 5 minutes. LiHMDS (2M in THF,18.0mmol,9mL) and HMPA (0.65 mL,3.6 mmol) were then added and stirred for 1 hour at-78℃and iodoisobutane (4.0 g,21.6 mmol) was added and stirred for 4 hours, then warmed to-30℃and stirred for 4 hours, and TLC monitored the reaction to completion. The reaction was quenched by adding saturated aqueous ammonium chloride at this temperature, followed by extraction with diethyl ether (3X 30 mL) three times, combining the organic phases, washing with saturated brine three times, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography to give 1.0g of a yellow oily liquid in 42% yield.
(4) Preparation of hydroxy tetrabenazine racemate
The compound of formula VI (1.5 g,4.5 mmol) was weighed, dissolved in anhydrous THF (15 mL), purged with argon three times, added with LiAlH 4 (1M in THF,20.3mmol,20.3mL) solution, and heated to 70℃for 3 hours under reflux after a large amount of bubbles had been formed, and TLC monitored the completion of the reaction of the starting materials. Cooling to room temperature, quenching reaction by adding water (1 mL), 10%wt NaOH (1 mL) aqueous solution and water (3 mL) in turn, extracting with ethyl acetate (3X 10 mL) three times, combining organic phases, drying with anhydrous sodium sulfate, decompressing and concentrating, and purifying by column chromatography to obtain white solid 1.31g with the yield of 91%.
The total yield of the tetrabenazine racemate prepared in this example was 30.5%.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (10)
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