TETRABENAZINE

Tetrabenazine

 Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder and is marketed under the trade names Nitoman in Canada and Xenazine in New Zealand and some parts of Europe, and is also available in the USA as an orphan drug. On August 15, 2008 the U.S. Food and Drug Administration (FDA) approved the use of tetrabenazine to treat chorea associated with Huntington's disease (HD), the first in the US.^[15] The compound has been known since the 1950s.

Tetrabenazine (TBZ), which was introduced in 1956 as an antipsychotic drug,¹ is currently used as treatment for hyperkinetic movement disorders.^2,3 TBZ is considered a classical inhibitor of vesicular monamine transporter 2 (VMAT2).⁴ VMAT2 is the only transport that moves cytoplasmic dopamine into synaptic vesicles for storage and subsequent release in the central nervous system.⁵ It has been shown to deplete cerebral monoamines in rat brain by reversibly inhibiting VMAT2.^1,5 TBZ (Xenazine^®) is approved by the U.S. Food and Drug Administration (FDA) to treat chorea, the jerky, involuntary movement, that occurs in people with Huntington’s disorder.⁶ It is also used to alleviate tics in Tourette’s syndrome⁷ and movement disorders in tardive dyskinesia.⁸

Systematic (IUPAC) name
(SS,RR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one
Clinical data
Trade names	Xenazine
AHFS/Drugs.com	Consumer Drug Information
Pregnancy category	C
Legal status	℞-only (US)
Routes of administration	Oral (tablets, 25 mg)
Pharmacokinetic data
Bioavailability	Low, extensive first pass effect
Protein binding	82–85%
Metabolism	Hepatic (CYP2D6-mediated)
Excretion	Renal and fecal
Identifiers
CAS Registry Number	58-46-8
ATC code	N07XX06
PubChem	CID: 6018
IUPHAR/BPS	4834
DrugBank	DB04844
ChemSpider	5796
UNII	Z9O08YRN8O
Synonyms	Ro-1-9569
Chemical data
Formula	C19H27NO3
Molecular mass	317.427 g/mol

 



Paper 2
 

 http://www.hgxb.com.cn/EN/abstract/abstract12047.shtml

...............
 PAPER

J Labelled Comp Radiopharm. 2011 Jun 15; 54(7): 367–370.

doi:  10.1002/jlcr.1881

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126153/




 The TBZ (4) for these reactions was prepared by reacting 3,4-dihydro-6,7-dimethoxyisoquinoline (3) and the Mannich base (2) as shown in Scheme 1.¹⁴ The α,β-unsaturated TBZ (5), which was the original substrate, was obtained by further treatment with chloranil in refluxing benzene.

Tetrabenazine (4a)

To a solution of 3,4-dihydro-6,7-dimethoxyisoquinoline hydrochloride (3, 3.5 g, 15.4 mmol) in cold H₂O (20 mL) in an ice water bath, was added 3-(dimethylaminomethyl)-5-methyl-2-hexanone (2, 3.15 g, 18.3 mmol) as the free base with stirring. Precipitate formed within 3 h, and stirring was continued until the solid-gummy precipitate prevented stirring. The mixture was allowed to stand at RT (room temperature) for 3 days. The solid–gum mixture was filtered, and the yellow solid–gum mixture was dissolved in hot MeOH. The solution was chilled at −10°C for 18 h. The pale yellow solid was filtered to give 2.1 g (43%) of TBZ (4a).

TLC: R_f = 0.62; silica gel; 4% MeOH/96% CH₂Cl₂.

MS: (DCl-NH₃) m/z 318 (M+H).

UV: (EtOH) λ_max 282.0 nm (ε4431).

¹H NMR: (300 MHz, CDCl₃) δ 6.61 (s, 1H), 6.55 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.51 (br dd, 1H), 3.29 (dd, 1H), 3.13 (m, 2H), 2.90 (dd, 1H), 2.75 (m, 2H), 2.57 (m, 2H), 2.35 (t, 1H), 1.81 (ddd, 1H), 1.65 (m, 1H), 1.04 (ddd, 1H), 0.92 (d, 3H), 0.89 (d, 3H) ppm.

¹³C NMR: (75 MHz, CDCl₃) δ 210.00, 147.86, 147.54, 128.60, 126.11, 111.53, 107.94, 62.48, 61.52, 56.01, 55.92, 50.58, 47.62, 47.57, 36.09, 29.38, 25.44, 23.21, 22.11 ppm.

EA: Anal. Calc for C₁₉H₁₇NO₃: C, 71.89; H, 8.57; N, 4.41. Found C, 72.15; H, 8.69; N, 4.47.

HPLC: Brownlee 25 cm × 4.6 mm silica gel column; 30% isopropanol/70% hexane; 1 mL/min; ret. time 5.94 min; purity >99.5%.

.......
…………………….
Patent for preparing tetrabenazine
http://www.google.com/patents/WO2012081031A1?cl=en
Chemically tetrabenazine is cis rac -1, 3, 4, 6, 7, 1 lb-hexahydro-9, 10-dimethoxy-3-(2- methylpropyl)-2Hbenzo[a]quinolizin-2-one and it is represented by compound of structural formula I.

Formula 1
The proprietary name of tetrabenazine is Xenazine and is marketed by Biovail Americas. Xenazine is indicated for the treatment of chorea associated with Huntington’s disease. U.S. patent no. 2,830,993 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 1 -carbethoxymethyl-6, 7-dimethoxy-l , 2, 3, 4- tetrahydroisoquinoline compound of structural formula IV is being reacted with mono- isobutylmalonic acid dimethyl ester compound of structural formula V and paraformaldehyde in methanol solvent to get l-carbethoxymethyl-2 (2, 2-dicarbomethoxy-4-methyl-n-pentyl)-6, 7- dimethoxy-1, 2, 3, 4-tetrahydroisoquinoline compound of structural formula VI. The 1- carbethoxymethyl-2(2,2-dicarbomethoxy-4-methyl-n-pentyl)-6,7-dimethoxy-l ,2,3,4- tetrahydroisoquinoline compound of structural formula VI is subjected to Dieckmann cyclization , hydrolysis and decarboxylation to get tetrabenazine compound of structural formula I, which is recrystallized from di-isopropyl ether solvent.

Formula I
Scheme I
U. S. patent no. 4,678,792 discloses a process for the preparation of 6, 7-dimethoxy-3, 4- dihydroisoquinoline compound of structural formula VII wherein 2-(3, 4-dimethoxyphenyl)- ethylamine compound of structural formula II is being reacted with chloral hydrate at 120°C to get N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III. The N- formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III is further reacted with polyphosphoric acid to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII. The 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being used as an intermediate for the preparation of tetrabenazine compound of structural formula I.

Formula III
Formula II
Polyphosphoric acid

Formula VII
Scheme II
Bull. Korean Chem. Soc. 2002 Volume (23). No. l , page no. 149 discloses N-formylation of various amines and alcohols with formic acid in toluene.
U.S. patent publication no. 2010/0130480 discloses a process for the preparation of 6, 7- dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII by reacting 2-(3, 4- dimethoxyphenyl)-ethylamine compound of structural formula II with hexamethylenetetramine in presence of acetic acid or trifluoroacetic acid.

Hexamethylenetetramine
Formula II Formula VII
U.S. patent publication no. 2008/0167337 discloses a process for the preparation of tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is reacted with 3-dimethylaminomethyl-5-methyl-hexan-2-one methiodide compound of structural formula VIII to get crude tetrabenazine compound. The crude tetrabenazine compound was purified by employing flash column chromatography technique and

Formula VIII Formula I
The prior-art processes for preparing N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine compound of structural formula III produces below mentioned compound of structural formula XVII, XVIII, XIX, XX, XXI and XXII as a by-product of the reaction due to the demethylation and formylation of resulting hydroxy compounds.

Formula XX Formula XXI Formula XXII
The compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII are being carry- forwarded into the further steps of reactions of preparing tetrabenazine compound of structural formula I and therefore there is a need in the art to develop an improved process of preparing 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII, which obviates the prior-art problems. Accordingly there is provided a process of preparing tetrabenazine compound of structural formula I wherein 6, 7-dimethoxy-3, 4-dihydroisoquinoline compound of structural formula VII is being formed without the formation of above mentioned compounds of structural formula XVII, XVIII, XIX, XX, XXI and XXII.
EXAMPLE: PROCESS FOR THE PREPARATION OF SUBSTANTIAL PURE CRYSTALLINE FORM A OF TETRABENAZINE
Stage A: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoIine
Step 1 : Process for the preparation of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine
A solution of 2-(3, 4-dimethoxyphenyl)-ethylamine (500gm) in toluene (2000ml) was added formic acid (150gm) at 25°C, the resulting reaction mixture was diluted with toluene (500ml) and heated up to 45°C. The reaction mixture was maintained at 40-45°C for 5 hours and then the resulting reaction mixture was concentrated under reduced pressure at 50°C to get the title compound
Yield: 570gm
Purity: 99.98% (By HPLC)
Step 2: Process for the preparation of 6, 7-dimethoxy-3, 4-dihydroisoquinoline
A solution of N-formyl-2-(3, 4-dimethoxyphenyl)-ethylamine (250gm) obtained from step 1 in toluene (500ml) and polyphosphoric acid (50gm) was heated at 110°C for 5 hours. The resulting reaction mixture was cooled to 50°C, quenched with water (500ml) and pH of the resulting solution was adjusted to about 8.3 with aqueous solution of sodium hydroxide [sodium hydroxide (690gm) + water (690ml)]. The resulting reaction mass was extracted by ethyl acetate (2 1250ml), dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get 6, 7-dimethoxy-3, 4-dihydroisoquinoline (190gm).
Yield: 215gm
Purity: 99.67% (By HPLC)
Stage B: Process for the preparation of 3-((dimethylamino) methyi)-5-methylhexan-2-one methiodide
Step 1 : Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one Dimethylamine hydrochloride (180gm) and paraformaldehyde (lOOgm) were added to a solution of 5-methylhexan-2-one (900ml) in methanol (1600ml). The resulting reaction mass was heated at reflux for 12 hours, and then the pH was adjusted to about 8.75 with aqueous solution of sodium hydroxide [sodium hydroxide(90gm) + water (900ml)] at 25 °C. The resulting reaction solution was extracted by toluene (2x1234ml). The organic layer was dried over anhydrous sodium sulfate (50gm) and concentrated under reduced pressure to get title compound.
Yield: 900gm
Purity: 99.80% (By HPLC)
Step 2: Process for the preparation of 3-((dimethylamino) methyl)-5-methylhexan-2-one methiodide
Methyl iodide (323gm) was added dropwise to a solution of 3-((dimethylamino) methyl)-5- methylhexan-2-one (195gm) obtained from step 1 , in ethyl acetate (1650ml) at 25-30°C in 30 minutes. The resulting reaction mixture was stirred at 25 °C for 12 hours and then the resulting solids were filtered, washed with water (200ml) and suck-dried to get wet compound (400gm). The wet compound was slurried with water (1000ml) at 25°C for 1 hour and then it was again filtered, washed with water (200ml) and dried at 45-50°C to get title compound
Yield: 300gm
Purity: 99.86% (By HPLC)
Stage C: Preparation of substantial pure crystalline form A of Tetrabenazine
3-((Dimethylamino) methyl)-5-methylhexan-2-one methiodide (80gm) was added to the solution of 6, 7-dimethoxy-3, 4-dihydroisoquinoline (40gm) in isopropanol (288ml) at 25°C and the resulting reaction mass was heated at 40-45°C for 15 hours. The resulting insoluble material was filtered, washed with isopropanol (80ml) and filtrate was concentrated under reduced pressure up to the 150ml reaction volume. The reaction solution was diluted with methylene dichloride (1200ml) and water (1000ml) and pH was adjusted to 8.5 with sodium hydroxide solution [10%, 100ml]. The organic layer was separated, washed with water (3 x 1000ml) and concentrated under reduced pressure to obtain residue. The residue was dissolved in methanol (300ml) at 50°C, and resulting solution was treated with an activated carbon (20gm) at 50-60°C for 30minutes and then it was filtered and filtrate was further stirred at 20-25°C for 2 hours. The resulting solids were filtered, washed with methanol (150ml), dried at 50-55°C for 8 hours. The resulting solids were milled, sifted through 40 mesh sieve and micronized.
Yield: 65gm
Purity: 99.96% (By HPLC)

……………………

PATENT
 http://www.google.ga/patents/WO2008154243A1?cl=en

Ia Single "R,R" R R enantiomer of tetrabenazine
Ib Single "S, S" enantiomer of tetrabenazine

 + TETRABENAZINE

Example 10 Removal The Boc Protecting Group From First Intermediate 12 And Amino Cyclization Provide (+)-Tetrabenazine XVII

[0063] First intermediate 12 (1.0 eq) was dissolved in 10% Me₂S- dichloromethane to provide an 82 mM solution. The solution was cooled to 0 ⁰C and triisopropylsilane (1.1 eq.) followed by TFA (precooled to 0 ⁰C) was added to the reaction mixture to provide a final concentration of 41 mM. The reaction mixture was permitted to stir at 0 ⁰C for 1 h. Following the allotted time the reaction mixture was quenched at 0 ⁰C by the addition of saturated aqueous potassium carbonate solution and concentrated under reduced pressure to remove the majority of the dimethylsulfide. The mixture was extracted with five portions of dichloromethane, and the combined organic extracts were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure to provide the crude product as a yellow solid. The crude product was recrystallized from 3.5% dimethoxyethane in hexanes. The resulting colorless crystals were washed with hexanes to provide pure (+)- tetrabenazine (XVII) 46%: mp 126.0 ⁰C (3.5% DME-hexanes) (a crystal polymorph was observed at

116 ⁰C); [α]²⁶ _D +37.2 (c 0.41, CH₂Cl₂); ¹H NMR (CD₂Cl₂) δ 0.89 (apparent t, J = 7.2 Hz, 6H), 0.98 (ddd, J = 12, 6.0, 4.0 Hz, IH), 1.59-1.68 (m, IH), 1.74 (ddd, J = 12, 5.9, 5.7 Hz, IH), 2.32 (apparent t, J = 11.7 Hz, IH), 2.46 (apparent t, J = 12.3 Hz, IH), 2.55 (ddd, J = 12, 10.0, 3.8 Hz, IH), 2.65-2.73 (m, 2H), 2.83 (dd, J = 5.5, 2.8Hz, IH), 2.97-3.07 (m, IH), 3.07-3.14 (m, IH), 3.25 (dd, J =9.7, 6.3 Hz, IH), 3.47 (apparent d, J = 12Hz, IH), 3.75 (s, 3H), 3.77 (s, 3H), 6.55 (s, IH), 6.60 (s, IH) ¹³C NMR (CD₂Cl₂) δ 21.98, 23.02, 25.51, 29.46, 35.16, 47.47, 47.63, 50.47, 55.87, 56.01, 61.47, 62.46, 108.46, 111.72, 126.37, 128.96, 147.65, 147.98, 209.72;
-84HRMS-(ESI+) calcd for (C₁₉H₂₇NO₃ + H) ([M+H]⁺ 318.2069, found 318.2082.
...........................
 http://www.google.ga/patents/WO2012000308A1?cl=en

 
.................
 INDIAN PATENT

APPLICATION NUMBER	4923/CHE/2012
APPLICANT NAME	MYLAN LABORATORIES LTD

...............

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XENAZINE (tetrabenazine) is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43; the pKa is 6.51. Tetrabenazine is a hexahydro-dimethoxy-benzoquinolizine derivative and has the following chemical name: cis rac –1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)2H-benzo[a]quinolizin-2-one.
The empirical formula C₁₉H₂₇NO₃ is represented by the following structural formula:
Tetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.
Each XENAZINE (tetrabenazine) Tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient.
XENAZINE (tetrabenazine) Tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose, magnesium stearate, maize starch, and talc. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient.
XENAZINE (tetrabenazine) is supplied as a yellowish-buff scored tablet containing 25 mg of XENAZINE or as a white non-scored tablet containing 12.5 mg of XENAZINE.

Référence
1		CAROON ET AL. J.MED.CHEM. vol. 26, 1983, pages 1426 - 1433
2		KOEPPE, R. A. ET AL.: 'Assessment of extrastriatal vesicular monoamine transporter binding site density using stereoisomers of [11C]dihydrotetrabenazine' J CEREB BLOOD FLOW METAB vol. 19, 1999, pages 1376 - 1384
3		NEUROLOGY vol. 66, no. 3, 2006, pages 366 - 372
4		See also references of EP2176226A1

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