WO2020213014A1 - An improved process for the preparation of valbenazine and its salts - Google Patents
An improved process for the preparation of valbenazine and its salts Download PDFInfo
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- WO2020213014A1 WO2020213014A1 PCT/IN2020/050368 IN2020050368W WO2020213014A1 WO 2020213014 A1 WO2020213014 A1 WO 2020213014A1 IN 2020050368 W IN2020050368 W IN 2020050368W WO 2020213014 A1 WO2020213014 A1 WO 2020213014A1
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- 0 CC(C)C[C@@](CN(CCc1c2)[C@](C3)c1cc(OC)c2OC)[C@@]3OC([C@](C(C)CC**)N)=O Chemical compound CC(C)C[C@@](CN(CCc1c2)[C@](C3)c1cc(OC)c2OC)[C@@]3OC([C@](C(C)CC**)N)=O 0.000 description 3
- GEJDGVNQKABXKG-CFKGEZKQSA-N CC(C)C[C@H](CN(CCc1c2)[C@H](C3)c1cc(OC)c2OC)[C@@H]3OC([C@H](C(C)C)N)=O Chemical compound CC(C)C[C@H](CN(CCc1c2)[C@H](C3)c1cc(OC)c2OC)[C@@H]3OC([C@H](C(C)C)N)=O GEJDGVNQKABXKG-CFKGEZKQSA-N 0.000 description 1
- TXYMVANDPQOMEU-DNRBGDKYSA-N CC(C)C[C@H](CN(CCc1c2)[C@H](C3)c1cc(OC)c2OC)[C@@H]3OC([C@H](C(C)C)NC(OC(C)(C)C)=O)=O Chemical compound CC(C)C[C@H](CN(CCc1c2)[C@H](C3)c1cc(OC)c2OC)[C@@H]3OC([C@H](C(C)C)NC(OC(C)(C)C)=O)=O TXYMVANDPQOMEU-DNRBGDKYSA-N 0.000 description 1
- SZXBQTSZISFIAO-ZETCQYMHSA-N CC(C)[C@@H](C(O)=O)NC(OC(C)(C)C)=O Chemical compound CC(C)[C@@H](C(O)=O)NC(OC(C)(C)C)=O SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N Cc(cc1)ccc1S(O)(=O)=O Chemical compound Cc(cc1)ccc1S(O)(=O)=O JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention relates to an improved process for the preparation of Valbenazine tosylate. Further the present invention relates to crystalline acid addition salts of Valbenazine and their preparation thereof.
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF VALBENAZINE
AND ITS SALTS
CROSS-REFERENCE TO RELATED APPLICATIONS:
This application claims the benefit of the filing date of Indian provisional Application No IN201941015724 filed on April 19, 2019, the contents of which are incorporated herein in their entirety by reference.
FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Valbenazine tosylate. Further the present invention relates to crystalline acid addition salts of Valbenazine and their preparation thereof.
BACKGROUND OF THE INVENTION:
Valbenazine is chemically known as [(2R,3R,l lbR)-9,10-dimethoxy-3-(2- methylpropyl)-2,3,4,6,7,l lb-hexahydro-lH-benzo[a]quinolizin-2-yl] (2S)-2-amino-3- methylbutanoate;
FDA approved Valbenazine Tosylate under the brand name INGREZZA for the treatment of tardive dyskinesia in adults. Tardive dyskinesia is a neurological disorder characterized by involuntary movements in patients with chronic kidney disease (CKD). Valbenazine tosylate is represented by formula I.
Formula I
Valbenazine and its pharmaceutically acceptable salts was first disclosed in US 8039627 patent.
US patent 10065952 B2 disclosed crystalline Form I, Form II, Form IV, Form V and Form VI of Valbenazine ditosylate and its amorphous form.
US patent 10160757B2 disclosed method for preparing Valbenazine ditosylate; comprising: (a) reacting (S)-(2R,3R,l lbR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,l lb- hexahydro- lH-pyrido[2, l-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride with a base, and (b) reacting the product of (a) with p-toluenesufonic acid.
WO2018067945 disclosed Valbenazine ditosylate crystalline forms T10, T12, and Me-THF solvate, THF-solvate, isobutanol- solvate, and (+)-Tetrabenazine-(-)-DPTTA salt, and also disclosed salts of Valbenazine namely fumarate, stearate, palmitate, sulfate, mesylate. Valbenazine stearate as Form SI, Valbenazine palmitate as Form PI; Valbenazine sulfate as form HS1, Valbenazine mesylate designated as Form MS.
The inventors of the present invention have developed an improved process for the preparation of Valbenazine Tosylate which is more feasible for practice with better yields. Further the inventors prepared crystalline salts of Valbenazine which can be used for purification.
OBJECT AND SUMMARY OF THE INVENTION:
The main aspect of the present invention is to provides an improved process for the preparation of Valbenazine ditosylate comprising the steps of:
a) reacting the Hydroxy CSA compound with Boc-L- Valine in the presence of coupling agent, catalyst, organic solvent to obtain solid material of Boc-L- Valinate.
b) deprotecting Boc-L-Valinate with p-Toulene sulfonic acid in the presence of an organic solvent to obtain Valbenazine ditosylate.
Boc-L-Valinate Valbenazine tosylate
In another aspect, the present invention provides an improved process for the preparation of Valbenazine ditosylate comprising the steps of:
a) reacting the Hydroxy CSA compound with Boc-L- Valine in the presence of coupling agent, catalyst, organic solvent to obtain Boc-L-Valinate.
b) deprotecting Boc-L-Valinate with p-Toluene sulfonic acid in-situ without isolation of Boc-L-Valinate to obtain Valbenazine Tosylate.
Yet in another aspect, the present invention provides a process for the preparation of Valbenazine ditosylate comprising the steps of:
a) deprotecting Boc-L-Valinate using a base to obtain Valbenazine,
b) reacting Valbenazine with p-toluenesulfonic acid in the presence of solvent to obtain Valbenazine ditosylate.
Yet in another aspect, the present invention provides Boc-L-Valinate.
Yet in another aspect, the present invention provides crystalline Boc-L-Valinate.
Yet in another aspect, the crystalline Boc-L-Valinate is characterized by powder X- ray diffraction pattern shown in Figure 1 having peaks at 6.67, 9.60, 10.18, 11.71, 13.92, 14.47, 14.83, 15.50, 16.54, 17.67, 18.21, 19.41, 19.71, 20.26, 20.93, 21.22, 21.87, 22.70, 23.27, 23.63, 24.95, 25.34, 25.77, 26.97, 29.09, 30.02, 30.76.
Yet in another aspect, the present invention provides crystalline acid addition salts of Valbenazine selected from Oxalate, Glutamate, Salicylate, Cinnamate, tartrate, Citrate, (L) Maleate, Malate, (S) Mandelate.
Yet in another embodiment, the present invention provides crystalline Valbenazine Oxalate characterized by powder X-ray diffraction pattern shown in Figure 2 having characteristic peaks at 4.17, 5.66, 7.50, 8.76, 9.02, 11.45, 12.20, 12.84,14.03, 14.46, 15.25, 15.75, 16.47, 17.39, 18.26, 19.08, 19.49, 19.99, 20.44, 21.43, 21.77, 22.38, 23.31,
23.66, 24.50, 25.28, 25.94, 26.35, 27.14,27.91, 28.88, 29.52, 31.35, 32.72 ± 0.2° degrees 2Q.
Yet in another aspect, the present invention provides crystalline Valbenazine
Glutamate characterized by powder X-ray diffraction pattern shown in Figure 3 having characteristic peaks at 7.20, 10.10, 13.58, 14.55, 17.80, 18.92, 19.88, 20.41, 21.30,21.92, 23.00, 23.67, 24.09, 25.48, 26.01, 26.34, 26.76, 27.51, 27.87, 28.69, 29.49, 29.86, 30.88, 31.31, 31.99, 32.61, 32.91, 33.57 ± 0.2° degrees 2Q.
Yet in another aspect, the present invention provides crystalline Valbenazine
Salicylate characterized by powder X-ray diffraction pattern shown in Figure 4 having characteristic peaks at 7.06, 14.32,17.82,18.94,19.26, 20.11,21.81,23.18,25.71, 28.52, 29.24, 32.19, 33.07, 34.82, 36.91,44.68 ± 0.2° degrees 2Q.
Yet in another aspect, the present invention provides crystalline Valbenazine
Cinnamate characterized by powder X-ray diffraction pattern shown in Figure 5 having characteristic peaks at 7.26, 14.60, 18.16, 19.08, 19.57, 20.39, 22.04, 23.34, 25.95, 27.80, 28.61,29.55,32.43,33.33, 33.62, 34.80, 35.12, 37.18, 37.63, 39.20, 39.81, 40.89, 45.03 ± 0.2° degrees 2Q.
Yet in another aspect, the present invention provides crystalline Valbenazine tartrate.
Yet in another aspect, the present invention provides crystalline Valbenazine Citrate.
Yet in another aspect, the present invention provides crystalline Valbenazine (L)- Maleate.
Yet in another aspect, the present invention provides crystalline Valbenazine (S)- Malate.
Yet in another aspect, the present invention provides crystalline Valbenazine (S)- Mandelate.
Yet in another aspect, the present invention provides a process for the preparation of crystalline acid addition salts of Valbenazine comprising the steps of:
a) dissolving Valbenazine in a solvent
b) heating the reaction mass,
c) adding acid, and
d) isolating Valbenazine salt.
Brief description of the figures:
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline Boc-L- Valinate.
Figure 2 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline Valbenazine Oxalate
Figure 3 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline Valbenazine Glutamate,
Figure 4 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline Valbenazine Salicylate
Figure 5 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline Valbenazine Cinnamate
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of Valbenazine ditosylate.
In one embodiment, the present invention relates to process for the preparation of Valbenazine Tosylate comprising the steps of:
a) reacting the Hydroxy CSA compound with Boc-L-Valine in the presence of a coupling agent, catalyst, organic solvent to obtain Boc-L-Valinate.
In another embodiment, the present invention relates to an improved process for the preparation of Valbenazine Tosylate comprising the steps of:
a) reacting the Hydroxy CSA compound with Boc-L- Valine in the presence of a coupling agent, catalyst and organic solvent to obtain Boc-L- Valinate.
b) deprotecting Boc-L- Valinate with p-Toluene sulfonic acid without isolation of Boc-L- Valinate in presence of a solvent to obtain Valbenazine Tosylate.
Yet in another embodiment, the present invention relates to process for the preparation of Valbenazine ditosylate comprising the steps of:
a) deprotecting Boc-L-Valinate in the presence of a base to obtain Valbenazine,
According to the present invention, hydroxy CSA compound may be reacted with Boc-L- Valine in presence of a coupling agent selected from the group consisting of l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), N,N'- Dicyclohexylcarbodiimide (DCC), Diisopropyl carbodiimide(DIC), carbonyl di imidizole(CDI), N,N-Di-tert-butyl carbodiimide, preferably l-(3-
dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDC.HC1) and a dimethyl amino pyridine catalyst using organic solvent selected from the group consisting of dichloromethane, 1,1 dichloroethane, chloroform, 1,2 dichloroethane, N,N-dimethyl formamide, Dimethyl sulfoxide, tetrahydrofuran, 2-methyl tetrahydrofuran, Toluene preferably dichloromethane to obtain Boc-L-Valinate compound. The Boc-L-Valinate compound may be treated with a base selected from tri-potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, dipotassium phosphate preferably tri-potassium phosphate in presence of a solvent selected from protic or aprotic solvents like methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide etc., to obtain Valbenazine base which may be treated with p- toluene sulfonic acid monohydrate in presence of a solvent selected from protic or aprotic solvents like Acetonitrile, Propionitrile, Butyronitrile, Acetone, Methyl ethyl ketone, Methyl isobutyl ketone, Ethyl acetate, Isopropyl acetate, Methanol, Ethanol, Isopropyl alcohol, Dimethyl formamide, Dimethyl acetamide, Dimethylsulfoxide, etc (protic or aprotic solvent) to obtain Valbenzine ditosylate.
Yet in another embodiment, the present invention relates to Boc-L-Valinate.
Yet in another embodiment, the present invention relates to crystalline Boc-L- Valinate.
Yet in another embodiment, the present invention relates to crystalline Boc-L- Valinate characterized by powder X-ray diffraction pattern shown in Figure 1 having characteristic peaks at 6.67, 9.60, 10.18, 11.71, 13.92, 14.47, 14.83, 15.50, 16.54, 17.67, 18.21, 19.41, 19.71, 20.26, 20.93, 21.22, 21.87, 22.70, 23.27, 23.63, 24.95, 25.34, 25.77, 26.97, 29.09, 30.02, 30.76 ± 0.2° degrees 2Q.
Yet in another embodiment, the present invention relates to crystalline acid addition salts of Valbenazine selected from Oxalate, Glutamate, Salicylate, Cinnamate, tartarate, Citrate, (L) Maleate, Malate, (S) Mandelate.
Yet in another embodiment, the present invention relates to crystalline Valbenazine Oxalate characterized by powder X-ray diffraction pattern shown in Figure 2 having
characteristic peaks at 4.17, 5.66, 7.50, 8.76, 9.02, 11.45, 12.20, 12.84, 14.03, 14.46, 15.25, 15.75, 16.47, 17.39, 18.26, 19.08, 19.49, 19.99, 20.44, 21.43, 21.77, 22.38, 23.31, 23.66, 24.50, 25.28, 25.94, 26.35, 27.14, 27.91, 28.88, 29.52, 31.35, 32.72 ± 0.2° degrees 2Q.
Yet in another embodiment, the present invention relates to crystalline Valbenazine Glutamate characterized by powder X-ray diffraction pattern shown in Figure 3 having characteristic peaks at 7.20, 10.10, 13.58, 14.55, 17.80, 18.92, 19.88, 20.41, 21.30, 21.92, 23.00, 23.67, 24.09, 25.48, 26.01, 26.34, 26.76, 27.51, 27.87,28.69, 29.49, 29.86, 30.88, 31.31, 31.99, 32.61, 32.91, 33.57 ± 0.2° degrees 2Q.
Yet in another embodiment, the present invention relates to crystalline Valbenazine Salicylate characterized by powder X-ray diffraction pattern shown in Figure 4 having characteristic peaks at 7.06, 14.32, 17.82, 18.94, 19.26, 20.11, 21.81, 23.18, 25.71, 28.52, 29.24, 32.19, 33.07, 34.82, 36.91, 44.68 ± 0.2° degrees 2Q.
Yet in another embodiment, the present invention relates to crystalline Valbenazine Cinnamate characterized by powder X-ray diffraction pattern shown in Figure 5 having characteristic peaks at 7.26, 14.60, 18.16, 19.08, 19.57, 20.39, 22.04, 23.34, 25.95, 27.80, 28.61, 29.55, 32.43, 33.33, 33.62, 34.80, 35.12, 37.18, 37.63, 39.20, 39.81, 40.89, 45.03 ± 0.2° degrees 2Q.
Yet in another embodiment, the present invention relates to crystalline Valbenazine tartrate.
Yet in another embodiment, the present invention relates to crystalline Valbenazine Citrate.
Yet in another embodiment, the present invention relates to crystalline Valbenazine (L)-Maleate.
Yet in another embodiment, the present invention relates to crystalline Valbenazine (S)- Malate.
Yet in another embodiment, the present invention relates to crystalline Valbenazine (S)- Mandelate.
Yet in another embodiment, the present invention relates to a process for the preparation of crystalline acid addition salts of Valbenazine comprising the steps of: a) dissolving Valbenazine in a solvent,
b) heating the reaction mass,
c) adding acid, and
d) isolating Valbenazine salt.
According to the present invention, Valbenazine may be dissolved in a solvent selected from the group consisting of Acetonitrile, N-Methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, Methyl isobutyl ketone preferably Acetonitrile and heated to 50°C followed by addition of an acid selected from Oxalic acid / L-Glutamic acid / Salicylic acid / Cinnamic acid / tartaric acid / Citric acid / Malic acid / (L) Maleic acid / (S) Mandelic acid and maintained for about 2-3 hrs at 45-50°C and filtered to obtain the crystalline acid addition salt of Valbenazine. If a residue is formed, it may be taken in Heptane and maintained for about 15 hours to get corresponding solid Valbenazine salt.
PXRD Analysis
The said cocrystal of the present invention is characterized by their X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of said cocrystal of the invention was measured on BROKER D-8 Discover powder diffractometer equipped with goniometer of Q/2Q configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 0.4 seconds step time.
The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention in anyway.
Example 1: Process for the isolation of solid Boc-L-Valinate compound
Hydroxy camphor sulfonic acid [CSA] compound (lOOg) was taken in dichloromethane (500ml) and Sodium hydroxide solution (8g in 200 ml of water) was
added to it. Reaction mass was stirred for 30 min and the layers were separated. The organic layer was dried on molecular sieves and concentrated to get 58g of Hydroxy compound. Hydroxy compound (40g) was taken in dichloromethane (200ml) and to it, Boc-L-Valine (32.7g), 4- Dimethylaminopyridine [DMAP] (4.6g) was added at 25- 30°C and the solution was cooled to 0-5°C. To the cooled solution, N-Ethyl- N’ -(3- dimethyl aminopropyl) carbodiimide, Hydrochloride [EDC.HC1] (48g) was charged and maintained at 0-5°C for 4 hrs. Water (120 ml) was charged to it and stirred for 30 min. Layers were separated. The organic layer was washed with 5% Citric acid solution (160ml) followed by water washing (120ml). Organic layer was concentrated to residue. Heptane (130ml) was charged to the residue and stirred for 3 hours to get solid material of Boc-L-Valinate compound.
Example 2: Process for the preparation of Valbenazine Tosylate
Boc-L-Valinate (5g) was taken in Acetonitrile (25ml) and heated to 50-55°C. To this p-toluene sulfonic acid monohydrate (4.6g dissolved in 15 ml acetonitrile) was added at 50-55°C and maintained at the same temperature for 6 hrs. The reaction mixture was cooled to 25 °C and filtered and washed with acetonitrile and dried under vacuum at 45-50°C to get 5.6g of Valbenazine Tosylate compound.
Example 3: Process for the preparation of Valbenazine Tosylate from Boc-L- Valinate Intermediate
Hydroxy camphor sulfonic acid [CSA] intermediate (120g) was taken in dichloromethane (600ml) and Sodium hydroxide solution (lOg in 240 ml of water) was added and stirred for 30 minutes and layers were separated. The organic layer was washed with water (240ml) and concentrated to solid and stripped out with dichloromethane (2x 120ml) to get 70g of solid material. 34g of solid compound was dissolved in dichloromethane (170ml) and to it Boc-L-Valine (27.8g), DMAP (3.9g) was added at 25-30°C and the solution was cooled to 0-5°C. To the cooled solution EDC.HC1 (36.6g) was charged and maintained at 0-5°C for 3 hrs. Water (100 ml) was charged to the reaction mass and layers were separated. The Organic layer was washed with 5% Citric acid solution (100ml) followed by water washing (100ml) and the organic layer was concentrated to get residue of Boc-L-Valinate (25g). Boc-L- Valinate residue (25g) was taken in Acetonitrile (125 ml) and heated to 50-55°C. To the hot solution, p-Toluene sulfonic acid monohydrate solution (19.7g dissolved in
75ml acetonitrile at 40-45°C) was added at 50-55°C and maintained at the same temperature for 4-5 hrs. The reaction mixture was cooled to 25°C and stirred for 15 hrs. Reaction mass was filtered and washed with acetonitrile (55ml) and material was dried under vacuum at 50°C to get 27.8g of Valbenazine Tosylate.
Example 4: Preparation of Valbenazine Oxalate
Valbenazine free base (4g) was dissolved in Acetonitrile (40ml) and heated to 50°C. Oxalic acid (0.86g) was charged to it and stirred for 3 hrs at 45-50°C and cooled to 25 °C and maintained for 15 hrs. the material was filtered and washed with acetonitrile (16ml) and dried to get 3.2g.
Example 5: Preparation of Valbenazine Glutamate
Valbenazine free base (3g) was dissolved in Acetonitrile (9ml) and heated to 50°C. L-Glutamic acid solution (2.1g in 12ml Acetonitrile) was charged to it and stirred for 3 hrs at 45-50°C and cooled to 27°C and maintained for 15 hrs. the material was filtered and washed with acetonitrile (6ml) and dried to get 3.2g.
Example 6: Preparation of Valbenazine (S) Mandelate
Valbenazine free base (3g) was dissolved in Acetonitrile (9ml) and heated to 50°C. (S)-Mandelic acid solution (2.18g in 6ml Acetonitrile) was charged to it and stirred for 3 hrs at 45-50°C and distilled out to get residue and charged Heptane (30ml) to get solid material and stirred for 15 hrs. to get 4.8g of Valbenazine Mandelate.
Example 7: Preparation of Valbenazine Salicylate
Valbenazine free base (4g) was dissolved in Acetonitrile (40ml) and heated to 50°C. Salicylic acid (2.6g) was charged to it and stirred for 3 hrs at 45-50°C and distilled out to get residue and charged Heptane (30ml) to get solid material and stirred for 15 hrs. to get 5.6g of Valbenazine Salicylate.
Example 8: Preparation of Valbenazine Cinnamate
Valbenazine free base (4g) was dissolved in Acetonitrile (20ml) and heated to 50°C. Cinnamic acid (2.8g) was charged to it and stirred for 2 hrs at 45-50°C and distilled out to get residue and charged Heptane (40ml) to get solid material and stirred for 15 hrs. to get 5.5g of Valbenazine Cinnamate.
Example 9: Example 9: Preparation of Valbenazine (L) Malate
Valbenazine free base (3g) was dissolved in Acetonitrile (9ml) and heated to 50°C. L-Malic acid solution (0.96g in 6ml Acetonitrile) was charged to it and stirred for 3 hrs at 45-50°C and distilled out to get residue and charged Heptane (30ml) to get solid material and stirred for 15 hrs. to get 3.5g of Valbenazine Maleate.
Example 10: Preparation of Valbenazine Maleate
Valbenazine free base (3g) was dissolved in Acetonitrile (9ml) and heated to 50°C. Maleic acid solution (0.83g in 6ml Acetonitrile) was charged to it and stirred for 3 hrs at 45-50°C and distilled out to get residue and charged Heptane (30ml) to get solid material and stirred for 15 hrs. to get 3.5g of Valbenazine Mandelate.
Example 11: Deprotection of Boc-L-Valinate using Potassium phosphate and isolation of Valbenazine Tosylate
Boc-L-Valinate residue (5g) was taken in Methanol (25 ml) and K3P04 (1.2g) was added to it along with water (3.5ml) and heated to 68-70°C. Reaction was refluxed for 12 hrs. reaction mass was concentrated, dichloromethane (50ml) and water (25ml) was added and stirred for 30 min. layers were separated. Organic layer was washed with water (25ml) and concentrated to residue. Residue was dissolved in acetonitrile (25ml) and p-Toluene sulfonic acid solution (3.67g in 15ml dissolved at 40-50°C) was added to it and stirred for 3hrs. Reaction mass was cooled to 27 °C and stirred for 12 hrs. Slurry was filtered and washed with acetonitrile (10ml) and material was dried under vacuum at 50°C to get 5.2g of Valbenazine Tosylate.
Example 12: Preparation of Hydroxy Compound from Tetrabenazine.
Tetrabenazine (250g) and Lithium chloride (33.4g) is charged into the flask along with Methylene dichloride (500 ml) and cooled to 0+3 °C. Methanol (750 ml) is added to reaction mass at 0±3°C followed by acetic acid (20.8 g). Reaction mass is further cooled to -8±2°C. Sodium borohydride aqueous solution (1.25g of Sodium hydroxide, 24g of sodium borohydride in 125 ml water) is added to the reaction mass at -5±5°C. Reaction mass is stirred for 3 hours at -5±5°C. Reaction mass temperature is raised to 25°C and ammonium chloride aqueous solution (lOOg in 500ml of water) is added to it at 25±5°C followed by sodium hydroxide solution (37.5g in 500ml of water) and Methylene dichloride (1500 ml) and stirred for 30 minutes. Layer separated and
Organic layer is washed with water (750 ml). Organic layer is distilled out completely under vacuum. Ethyl acetate (1250ml) is charged to the reaction mass and distilled out atmospherically till the reaction volume reaches to around 3 volumes inside the flask. Again, Ethyl acetate (500 ml) is charged to the reaction mass and distilled out atmospherically till the reaction volume reaches to around 3 volumes inside the flask. Reaction mass is cooled to 20+3 °C and stirred for 2 hours at the 20+3 °C. Reaction slurry is then filtered off and washed with ethyl acetate (375 ml). On drying under vacuum at 50-55°C, 221 g material is obtained with 99.5% purity and the diastereomer is less than 0.5%.
Example 13: Preparation of Hydroxy CSA Compound from Hydroxy Compound.
Hydroxy Compound (200g) and (IS) (+)- 10-Camphor sulfonic acid (146g) are charged into the flask and dissolved in ethanol (1800 ml) and water (200 ml). Reaction mass is heated to 70+3°C and stirred for 30 minutes. Reaction mass is gradually cooled to 50+3 °C and further cooled to 20+3 °C, and maintained for 3 hours at 20+3°C. It is then filtered off and washed with ethanol (300 ml). On drying under vacuum at 60-65°C, 132 g material is obtained with 99.9% purity and Isomer impurity is less than 0.2%.
Example 14: Preparation of Valbenazine Tosylate from Hydroxy CSA Compound.
Hydroxy CSA compound (l lOg) is charged into the flask and dissolved in Methylene dichloride (660 ml). Sodium hydroxide aqueous solution (8.8g sodium hydroxide in 330ml water) is added to reaction mass at 27+3°C. Reaction mass is stirred for 30 mins and layers are separated. Organic layer is washed with water (330ml). Organic layer is distilled out completely under vacuum at below 50°C. Methylene dichloride (550 ml) is added to residue and cool to room temperature. Boc-L-Valine (52 g) is added to the reaction mass and cooled to -3+3°C. 4-Dimethylamino pyridine (4.8g) and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide HC1 (57.4g) is charged to the reaction mass at -3+3°C and stirred for 2 hours. Water (330 ml) is added to the reaction mass and reaction mixture is stirred at room temperature for 30 minutes. Organic layer is separated and washed with aqueous citric acid solution (22g of Citric acid dissolved in 440 ml of water) followed by water (330ml). Organic layer is
concentrated under vacuum at below 50°C. Acetonitrile (110 ml) is charged to residue and distilled out completely under vacuum. Acetonitrile (550 ml) is charged to residue followed by p-toluene sulfonic acid (85.4 g). Reaction mass is heated to 53±3°C and maintained for 8 hours. Reaction mass is cooled to 27±3°C and maintained for 3 hours followed by filtration and drying at 60°C for 6 hours to obtain 122.5 g of Valbenazine Tosylate with the purity of 99.82% and individual impurity below 0.04%.
Example 15: Purification of Valbenazine Tosylate.
Valbenazine Tosylate (110 g) is charged to the flask along with Acetonitrile (330 ml) and water (22ml). Reaction mass is heated to 73+3 °C and filtered through micron filter with Acetonitrile (220ml) washing. Filtrate is concentrated under vacuum at below 60°C till the residual volume reaches to around 2 volumes. Acetonitrile (220 ml) is added to the reaction mass and again distilled out under vacuum till the residual volume reaches to around 2 volumes. Acetonitrile (220 ml) is added to the reaction mass and again distilled out under vacuum till the residual volume reaches to around 2 volumes. Acetonitrile (550 ml) is charged to the reaction mass and heated to 73±3°C for 30 minutes and gradually cooled to 27±3°C. Slurry is stirred for 2 hours and filtered off, followed by washing with acetonitrile (220 ml). Filtered material is dried under vacuum at 70±3°C for 12 hours to obtain 105g of Valbenazine Tosylate with 99.93% purity and individual impurity less than 0.03%.
Claims
1. A process for the preparation of Valbenazine Tosylate, comprising the steps of: a) reacting Hydroxy CSA compound with Boc-L-Valine in the presence of a coupling agent, catalyst and organic solvent to obtain Boc-L-Valinate.
2. A process for the preparation of Valbenazine ditosylate comprising the steps of: a) reacting the Hydroxy CSA compound with Boc-L-Valine in presence of a coupling agent, catalyst and organic solvent to obtain Boc-L-Valinate.
3. The process as claimed in claims 1 & 2, wherein the coupling agent is selected from the group consisting of l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), N,N'-Dicyclohexylcarbodiimide, Diisopropyl carbodiimide(DIC), carbonyl di imidizole(CDI), N,N-Di-tert-butyl carbodiimide and the catalyst is dimethyl amino pyridine.
4. The process as claimed in claims 1 & 2, wherein the organic solvent in step (a) is selected from dichloromethane, 1,1-dichloroethane, chloroform, 1,2 dichloroethane, N,N-dimethyl formamide, Dimethyl sulfoxide, tetrahydrofuran or mixtures thereof and the solvent in step (b) is selected from Acetonitrile, Propionitrile, Butyronitrile, Acetone, Methyl ethyl ketone, Methyl isobutyl ketone, Ethyl acetate, Isopropyl acetate, Methanol, Ethanol, Isopropyl alcohol, Dimethyl formamide, Dimethyl acetamide, Dimethylsulfoxide.
5. A process for the preparation of Valbenazine ditosylate comprising the steps of: a) deprotecting Boc-L-Valinate in the presence of a base to obtain Valbenazine,
6. The process as claimed in claim 5, wherein step the base is selected from the group consisting of tri-potassium phosphate, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, sodium bicarbonate, dipotassium phosphate and the solvent is selected from the group consisting of protic or aprotic solvents like methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide.
7. Crystalline Boc-L-Valinate characterized by PXRD spectrum having peaks at 6.67, 9.60, 10.18, 11.71, 13.92, 14.47, 14.83, 15.50, 16.54,17.67, 18.21, 19.41, 19.71, 20.26, 20.93, 21.22, 21.87, 22.70, 23.27, 23.63, 24.95, 25.34, 25.77, 26.97, 29.09, 30.02, 30.76 + 0.2° 2Q.
8. Valbenazine acid addition salt selected from:
a) Valbenazine Oxalate;
b) Valbenazine Glutamate;
c) Valbenazine Salicylate;
d) Valbenazine Cinnamate;
e) Valbenazine tartrate;
f) Valbenazine Citrate;
g) Valbenazine Maleate;
h) Valbenazine Mandelate;
9. A process for the preparation of acid addition salts of Valbenazine comprising the steps of:
a) dissolving Valbenazine in a solvent,
b) heating the reaction mass,
c) adding acid, and
d) isolating Valbenazine salt.
10. The process as claimed in claim 9, wherein solvent is selected from the group consisting of Acetonitrile, N-Methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, Methyl isobutyl ketone and acid selected from Oxalic acid / L-Glutamic acid / Salicylic acid / Cinnamic acid / tartaric acid / Citric acid / Malic acid / (L) Maleic acid / (S) Mandelic acid .
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8039627B2 (en) | 2006-11-08 | 2011-10-18 | Neurocrine Biosciences, Inc. | Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-A]isoquinolin-2-ol compounds and methods relating thereto |
| WO2018067945A1 (en) | 2016-10-06 | 2018-04-12 | Assia Chemical Industries Ltd. | Solid state forms of valbenazine |
| US10065952B2 (en) | 2015-10-30 | 2018-09-04 | Neurocrine Biosciences, Inc. | Valbenazine salts and polymorphs thereof |
| US10160757B2 (en) | 2015-12-23 | 2018-12-25 | Neuroscrine Biosciences, Inc. | Synthetic methods for preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) |
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- 2020-04-20 WO PCT/IN2020/050368 patent/WO2020213014A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8039627B2 (en) | 2006-11-08 | 2011-10-18 | Neurocrine Biosciences, Inc. | Substituted 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-A]isoquinolin-2-ol compounds and methods relating thereto |
| US10065952B2 (en) | 2015-10-30 | 2018-09-04 | Neurocrine Biosciences, Inc. | Valbenazine salts and polymorphs thereof |
| US10160757B2 (en) | 2015-12-23 | 2018-12-25 | Neuroscrine Biosciences, Inc. | Synthetic methods for preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) |
| WO2018067945A1 (en) | 2016-10-06 | 2018-04-12 | Assia Chemical Industries Ltd. | Solid state forms of valbenazine |
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