ROPINIROLE

 
4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride

ROPINIROLE

(sk&f 101468-a)

Ropinirole (INN; trade names Requip, Repreve, Ronirol, Adartrel) is a dopamine agonist of the non-ergoline class of medications. It is manufactured by GlaxoSmithKline (GSK), Cipla, Dr. Reddy's Laboratories and Sun Pharmaceutical. It is used in the treatment of Parkinson's disease and restless legs syndrome (RLS). Ropinirole is one of three medications approved by the FDA to treat RLS, the other two being pramipexole (Mirapex) and gabapentin enacarbil (Horizant). The discovery of the drug's utility in RLS has been used as an example of successful drug repurposing.^[2]
Ropinirole's patent expired in May 2008, and the drug is now available in generic form.^[3]

Synthesis

Ropinirole synthesis: G. Gallagher, Jr., U.S. Patent 4,452,808 (1984 to Smithkline Beckman Corporation); idem et al., ^[10]

The sequence for preparing this agent starts with the homologation of the carboxylic acid in (). The acid is thus reduced to the carbinol () by means of diborane. The hydroxyl is thus next converted to the mesylate in the usual way and that displaced with cyanide. Hydrolysis of the resulting nitrile gives the resulting arylacetic acid (). The acid chloride from that acid is then taken on to the amide () by rxn with dipropylamine. Reduction of the amide with diborane completes the synthesis of the sidechain, affording the amine (). Condensation of the transient anion, from removal of a benzylic proton, with ethyl oxalate gives the chain-extented glyoxylate ester (). Saponification of the ester with NaOH followed by decarboxylation of the resulting α-ketoacid gives (). The nitro group is hydrogenated to give the transient amine (). Intramolecular cyclization of the amine and acid function then occurs to give the indolone lactam, ropinirole.
 10..........Gallagher, G.; Lavanchy, P. G.; Wilson, J. W.; Hieble, J. P.; Demarinis, R. M. (1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: A prejunctional dopamine receptor agonist". Journal of Medicinal Chemistry 28 (10): 1533. doi:10.1021/jm00148a028

http://www.google.com/patents/EP1848691B1?cl=en

• Ropinirole is a dopamine agonist and having selective affinity for dopamine D2-like receptors and little or no affinity for non-dopaminergic brain receptors. Ropinirole is indicated as adjunct therapy to levodopa in patients with advanced Parkinson's disease. Also, recent clinical trials have focused on its use, as monotherapy in patients with early Parkinson's disease
• 
  
  Ropinirole was first reported in US patent no: 4,452,880 . It discloses the process for the preparation of Ropinirole hydrochloride as shown in following Scheme-1
  

  
• 
  
  The process as shown above comprises conversion of 2-methyl-3-nitro phenyl acetic acid (II) with thionyl chloride to 2-Methyl-3-nitro-phenylacetyl chloride (III), which upon reaction with Di-n-propyl amine (DPA) gives 2-Methyl-3-nitro phenyl-N,N-di-n-propyl acetamide (IV) in syrup form. This intermediate (IV) is further reduced with Borane/THF and subsequent treatment with HCl/NaOH to give 2-Methyl-3-nitro phenyl ethyl-N,N-di-n-propyl amine (V). Further, compound (V) is treated with Na metal, Ethanol and diethyl oxalate to obtain Ethyl 6-(2-di-n-propylaminoethyl)-2-nitrophenyl pyruvate (VI), which is further treated with hydrogen peroxide , NaOH and HCl and converted to 6-(2-Di-n-propylaminoethyl)-2-nitro phenyl acetic acid hydrochloride (VII). This intermediate is reduced with palladium/carbon to give Ropinirole hydrochloride (Ia).
• 
  
  Alternative process for the preparation of Ropinirole is described in J. Med. Chem. 1985, 28, 1533-1536 as shown in Scheme-2. The process comprises, the reduction 2-Methyl-3-nitrobenzoic acid (VIII) with diborane to carbinol of formula (IX). The carbinol compound (IX) is chlorinated with thionyl chloride in pyridine to give highly lachrymatory compound of formula (X), which is further converted to compound of formula (XII) by reaction with Potassium cyanide and followed by hydrolysis. 2-methyl-3-nitrophenyl acetic acid (XII) is converted to its acid chloride with thionyl chloride and treated with Di-n-propylamine to give 2-Methyl-3-nitrophenyl-N,N-di-n-propyl acetamide of formula (IV). The compound of formula (IV) is further reduced with borane in THF under reflux to give 2-Methyl-3-nitrophenylethyl-N,N-din-propyl amine (V). The amine of formula (V) is reacted with potassium metal in Ethanol and diethyl oxalate resulting in compound (VI) (where R= H), which is treated with hydrogen peroxide, NaOH and HCl to give the intermediate 2-Nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII). This intermediate is hydrogenated on palladium/carbon in ethanol to give desired compound Ropinirole hydrochloride of formula (Ia)
  

  
• 
  
  However, the above described process suffers with the following drawbacks:
  

  1. (i) 2-Methyl-3-nitro benzyl chloride of formula (X) is highly lachrymator and very difficult to handle at commercial production
  2. (ii) The reduction of 2-Methyl-3-nitro benzoic acid (VIII) is carried out with borane/THF, which is highly flammable and hazardous for handling in an industrial scale.
  3. (iii) It involves the use of potassium cyanide in the cynation reaction for the preparation of 2-Methyl-3-nitro benzyl cyanide. Potassium cyanide is highly toxic substance and requires special precaution for its use in production. It is highly desirable to avoid such toxic material.
  4. (iv) Also, this process gives lower yield
  5. (v) Additionally, isolation of intermediate compound of formula (V) as described in Scheme 1 requires the use of Kugelrohr apparatus. Use of such apparatus for commercial production is not feasible.
• 
  
  Overall, the process for the preparation of Ropinirole hydrochloride described in the prior art having disadvantage with respect to the use of toxic, lachrymator material and special apparatus in the process. Also, it gives lower yield. Hence, the process is not feasible for commercial production. So, there is a need for the process for the preparation of Ropinirole hydrochloride, which is easy to handle, suitable for commercial production and obviates the shortcomings of the known processes .

Reaction Scheme 3:

Example-14Preparation of Ropinirole hydrochloride
• 2-Nitro-6-[2-(N,N-Di-n-propyl amino)ethyl]phenyl acetic acid hydrochloride (100g) is dissolved methanol (2000ml) and then hydrogenated in presence of 10% Palladium on charcoal.. The reaction mixture is filtered to obtain clear solution. Methanol is distilled out under vacuum at 50°C. Isoprpanol (100ml) is added to the residue and it is cooled, filtered and washed with isopropanol to obtain light yellow crystalline Ropinirole hydrochloride. The product is dried at 60-70°C under vacuum. Yield 65-75g.

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..........................
Fortunak, J. M.; Giles, R. G.; Walsgrove, T. C. Eur. Pat. 0 300 614 A1, 1989; Chem. Abstr.1989, 110, 212605r







..........................
https://www.google.com/patents/US20050192338
4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one (Ropinirole). This compound is described in EP-A-0 113 964 as being useful in cardiovascular therapy, and in EP-A-0 299 602 as agent useful in the treatment of Parkinson's disease based on its selective interaction with dopamine D₂-receptors.
EP-A-0 113 964 describes a process for the preparation of substituted indolinone derivatives, which comprises reduction by catalytic hydrogenation of a 2-nitrophenyl acetic acid precursor followed by spontaneous cyclization of the intermediate so formed. An improvement of this process by carrying out the reduction by transfer hydrogenation in water is described in EP-A-0 266 033. In industrial scale production of Ropinirole this reaction sequence is difficult to implement as 2-methyl-3-nitrophenyl acetic acid is required as starting material, which, however, is not commercially available. It can be obtained from o-toluic acid in five steps using expensive reagents like sodium borohydride. Moreover, the expensive and flammable borane is required in the selective reduction of an amide intermediate.
EP-A-0 300 614 discloses an alternative process for the preparation of substituted indolinone derivatives, which comprises reductive cyclization of 2-(2′-bromoethyl) β-nitrostyrene. This reaction route contains a step using Pd/C and in the reaction sequence for obtaining 2-(2′-bromoethyl) β-nitrostyrene a potentially dangerous bromination step is required.
An improvement to the reaction sequence disclosed in EP-A-0 300 614 is described in WO 91/16306 by replacing the halogen leaving group by a sulfonate group.
A further alternative process for the preparation of substituted indolone derivatives is disclosed in WO 94/15918. According to this document the indolone derivative is obtained by reduction of the corresponding isatin precursor compounds.
A problem of the present invention is to provide an improved process for the preparation of Ropinirole. In particular, the process provided should simplify the synthesis, for example by employing a synthetic route which does not contain dangerous or low-yield chemical steps.
Furthermore, the process should use commercially available, cheap starting materials and reagents. A further aim is to avoid the use of Pd/C.
It has now unexpectedly been found that 4-substituted-2-indolinones can easily be obtained by cyclizing O-acyl hydroxamic acid derivatives.

Such conversion can be carried out by methods known to the person skilled in the art and being described for example in EP-A-0 300 614, WO 91/16306 and WO 94/15918. A possible synthesis route and examples of possible conversion routes are illustrated in the following scheme 1.

 EXAMPLE 7 Synthesis of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride (Ropinirole, 1a) from N-[(phenVlacetyl)oxy]-2-{2-[2-(dipropylamino)-ethyl]phenyl}acetamide hydrochloride (15 a, R=phenyl)
A mixture of 2.09 g (5.00 mmol) of N-[(phenylacetyl)oxy]-2-{2-[2-(dipropylamino)ethyl]phenyl}acetamide hydrochloride, 3.24 g of anhydrous ferric chloride (20.0 mmol) and 15 cm³ of dichloromethane is stirred for 2 hours at reflux. The reaction mixture is evaporated, the residue suspended in minimal amount of dichloromethane and transferred to a silica column. Column chromatography with the eluent of methylene chloride:methanol:conc. NH₃ solution=8:1:0.1 yields, after evaporation of the solvent, Ropinirole base as an oil. The evaporated residue is crystallized from isopropanol (5 cm³) and conc. HCl (0.5 cm³) to give 618 mg (41.7%) of 4-[2-dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride 

melting at 239°-242° C.
IR (potassium bromide): 3417, 1759, 1724, 1703, 1614, 1597, 1456, 1242, 968, 795, 775; 

¹H-NMR (500 MHz, deuterochloroform): 0.91 (t, 6H, J=7.4 Hz, 12-CH₃), 1.71 (sex, 4H, J=7.7 Hz, 11-CH₂), 2.98 (brt, 2H, 8-CH₂), 3.02 (m, 4H, 1-CH₂), 3.18 (brt, 2H, 9-CH₂), 3.54 (s, 2H, 3-CH₂), 6.72 (d, 1H, J=7.7 Hz, 7-ArH), 6.84 (d, 1H, J=7.7 Hz, 5-ArH), 7.13 (t, 1H, J=7.8 Hz, 6-ArH), 10.42 (s, 1H, 1-NH), 10.84 (br, 1-H, NH⁺); 

¹³C-NMR (500 MHz, deuterochloroform): 11.8 (q, C-12), 17.3 (t, C-11), 27.7 (t, C-8), 35.5 (t, C-3), 52.5 (t, C-9), 53.9 (t, C-10), 108.6 (d, C-7), 122.6 (d, C-5), 125.9 (s, C-3a), 128.7 (d, C-6), 134.0 (s, C-4), 144.7 (s, C-7a), 177.0 (s, C-2). 


EXAMPLE 8 Synthesis of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride (Ropinirole, 1a) from O-benzovl hydroxamic acid derivative formed in situ A mixture of 2.970 g (10.67 mmol) of 2-{2-[2-(dipropylamino)ethyl]phenyl}-N-hydroxyacetamide, 1.305 cm³ (11.24 mmol) of benzoyl chloride and 25 cm³ of dichloromethane is stirred at room temperature for 0.5 hour. Anhydrous ferric chloride (5.192 g, 32.01 mmol) is added and the mixture is stirred for 2 hours at reflux. The reaction mixture is evaporated, the residue suspended in minimal amount of dichloromethane and transferred to a silica column. Column chromatography with the eluent of methylene chloride:methanol:conc. NH₃ solution=8:1:0.1 yields after evaporation of the solvent Ropinirole base as an oil. This oil is crystallized from isopropanol (15 cm³) and conc. HCl (1 cm³) to give 800 mg (2.695 mmol, yield 25.3%) of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride melting at 239°-242° C.


EXAMPLE 9 Synthesis of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride (Ropinirole, 1a) from O-acetyl hydroxamic acid derivative
A mixture of 11.18 g (40.16 mmol) of 2-{2-[2-(dipropylamino)ethyl]phenyl}-N-hydroxyacetamide, 3.00 cm³ (42.17 mmol) of acetyl chloride and 100 cm³ of dichloromethane is stirred at room temperature for 0.5 hour. Anhydrous ferric chloride (19.54 g, 0.120 mol) is added and the mixture is stirred for 2 hours at 50° C. The reaction mixture is evaporated, the residue suspended in minimal amount of dichloromethane and transferred to a silica column. Column chromatography with the eluent of methylene chloride:methanol:conc. NH₃ solution=8:1:0.1 yields after evaporation of the solvent Ropinirole base as an oil. The evaporation residue is crystallized from isopropanol (50 cm³) and conc. HCl (4 cm³) to give 4.899 g (41.1%) of 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride having a melting point of 239°-242° C.


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

Org. Process Res. Dev., 2013, 17 (4), pp 714–717

DOI: 10.1021/op400024a

A new and efficient manufacturing technology is disclosed in the present work for the preparation of 4-(2-hydroxyethyl)-1,3-dihydro-2H-indol-2-one, which is a key intermediate for ropinirole hydrochloride. The whole process gives the target molecule in 71% overall yield with 99% purity. In the final step, a novel nitro reduction/ring-closing/debenzylation takes place in one pot. All the intermediates can be used directly for the next step without purification in this process.

1. 4.
   

   (a) Gallagher, G., Jr.; Lavanchy, P. G.; Wilson, J. M.; Hieble, J. P.; DeMarinis, R. M. J. Med. Chem. 1985, 28, 1533

   (b) DeMarinis, R. M.; Gallagher, G., Jr.; Hall, R. F.; Franz, R. G.; Webster, C.; Huffman, W. F.; Schwartz, M. S.; Kaiser, C.; Ross, S. T.; Wilson, J. W.; Hieble, P. J. Med. Chem. 1986, 29, 939
2. 5.
   

   (a) Giles, R.; Walsgrove, T. C. U.S. Patent 5,336,781 A, 1994;
   

   Chem. Abstr. 1994, 116,106086.
   

   (b) Dagger, R. E.; Fortunak, J. M.; Mastrocola, A. J. Heterocycl. Chem. 1995, 32,875

   (c) Hayler, J. D.; Howie, S. L. B.; Giles, R. G.; Negus, A.; Oxley, P. W.; Walsgrove, T. C.; Whiter, M. Org. Process Res. Dev. 1998, 2, 3

 https://www.google.com/patents/US7378439
Ropinirole is described in U.S. Pat. No. 4,452,808 as being useful in cardiovascular therapy and in U.S. Pat. No. 4,824,860 as an agent useful in treating Parkinson's disease. The processes for the preparation of Ropinirole HC 1 and its derivatives have previously been described. U.S. Pat. No. 4,452,808 describes the preparation of 4-aminoalkyl-2(3H)-indolones staring from either 4-aminoalkyl-7-hydroxy-2(3H)-indolones or 2-methyl-3-nitro-benzene acetic acid by two different processes. Particularly those processes involving reductive cyclization of nitrostyrene intermediates in presence of acetyl chloride and Iron (III) chloride described in EP 0300614 and WO 91/16306 are of particular relevance. Present invention discloses a novel route and novel intermediates for the preparation of Ropinirole. Present invention comprises of 6 steps leading to desired moiety.
U.S. patents namely U.S. Pat. No. 4,452,808, U.S. Pat. No. 5,336,781, U.S. Pat. No. 4,997,954, U.S. Pat. No. 4,314,944 molecule called Ropinirole. For the present purpose U.S. Pat. No. 4,452,808 and U.S. Pat. No. 4,314,944 are more relevant. Few patents deal with Ropinirole mainly from method of treatment point of view and therefore are not directly related to the present invention.
WO 91/16306 and EP 0300614 are relevant from the point of view of reductive cyclization and are dealt at appropriate place hereafter.
The processes for the preparation of Ropinirole HCl and its derivatives have previously been described. U.S. Pat. No. 4,452,808 describes the preparation of 4-aminoalkyl-2(3H)-indolones starting from either 4-aminoalkyl-7-hydroxy-2(3H)-indolones or 2-methyl-3-nitro-benzene acetic acid by two different processes. The 7-hydroxy intermediate (i) is first converted to its tetrazolo derivative (ii) which is then hydrogenated to get Ropinirole as shown in Scheme 1. Preparation of 7-hydroxy intermediate (i) is described in U.S. Pat. No. 4,314,944 by following a series of steps starting from p-methoxy phenethylamine. Second process described in U.S. Pat. No. 4,452,808 allows preparation of Ropinirole by following a series of steps starting from 2-methyl-3-nitro benzeneacetic acid.

Particularly those processes involving reductive cyclization of nitro styrene intermediates in presence of acetyl chloride and Iron (III) chloride described in EP 0300614 and WO 91/16306, are of relevance, as far as this invention is concerned.
Scheme 2 depicts the route disclosed in EP0300614. EP0300614 describes the preparation of Ropinirole by condensation of 4-[2-(bromoethyl)-1,3-dihydro-2H-indol-2-one (iii) with di-n-propyl amine (iv). The intermediate (iii) is prepared by following a series of steps starting from 2-(2-bromoethyl)benzaldehyde. Major drawback is a possible formation of an elimination product due to loss of HBr as shown in Scheme 2. Such reaction can impact the purity of desired product and can influence the yield aspects.

Elimination Product The process as described in WO 91/16306 is an improved process for the preparation of Ropinirole comprising of number of steps, total of eight starting from Isochroman, to get the final product Ropinirole. It discloses the route wherein condensation of di-n-propylamine with a novel intermediate of formula (v) is carried out. Intermediate (v) is prepared by series of steps starting from Isochroman. The process involves well over 7 steps and therefore is a longer one.

The Gabriel synthesis is well known in the art and consists of treatment of alkyl halide with Potassium pthalimide to form an intermediate N-alkyl phthalimide followed by deprotection to give primary alkyl amine.

In the present invention the Gabriel synthesis is employed to introduce the amino group at the 2 position of ethyl side chain. The process disclosed in the present invention describes preparation of Ropinirole from commercially available 2-(2′-Bromoethyl) benzaldehyde in six synthetic steps and is economical.
The novel process of the present invention can be depicted as shown in the scheme 3.

...........


 Example—6 Preparation of 4[2-(di-n-propylamino)ethyl]-1,3-dihydro-2-indol-2-one Hydrochloride I
A mixture of 4(2′-aminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride (5 gm, 0.0235 mol), propionaldehyde (5 ml, 0.0687 mol) and 1 gm of 10% Pd/C (50% wet with water) in methanol (200 ml) was hydrogenated at 5 Kg/cm² hydrogen pressure at room temperature for 24 hrs. The mixture was filtered through celite bed and the bed was washed with methanol (20 ml). The filtrate was concentrated to dryness, slurried in ethanol (40 ml) at 5-10° C. The cream coloured solid was collected at suction, washed with ethanol (20 ml) and dried, Yield: 2.86 gm (41%) as a off white solid. Purity 90%
Example—6A To a stirred clear solution of 4-[2-(di-n-propyl amino)ethyl]-1,3-dihydro-2-indol-2-one hydrochloride-I (2.86 gm, 0.084 mol), in water (25 ml) was added Sodium hydroxide solution (2.5 gm in 2.5 ml water) at 0 to 5° C. over a period of 30 min., raised the temperature to 25° C. to 35° C. extracted (2×25 ml) with MDC. To this MDC extract, Acetic anhydride (0.625 ml, 0.006 mol) was added dropwise at temperature 25° C. to 35° C. and maintain for 3 hrs at same temperature. The MDC layer was washed with 2×12.5 ml sodium bicarbonate solution followed by 12.5 ml water. MDC layer was evaporated on rotary evaporator under vacuum at 45° C. to 50° C. till complete removal of solvent. To the obtained residue, 12.5 ml of isopropyl alcohol was added and stirred for 10-15 min at 25° C. to 35° C. to a clear solution. The reaction mixture was further cooled to 5° C.-10° C. and to this chilled solution 9 ml of ethanolic hydrochloride was added dropwise to get precipitate of hydrochloride salt of the title compound and further dried. Yield: 2.12 gm (85%) as a bluish-offwhite solid, Purity 95% MS-m/z=261
NMR (200 MHz) DMSO; d 0.92 (t, 6H, CH3); d 1.69 (m, 4H, —CH₂); d 3.01-3.15 (m, 8HN (CH₂)3, Ar—CH₂); d 3.55 (s, 2H, COCH₂); d 6.7 (d, 1H, Ar—H); d 6.8 (s, 1H, Ar—H); d 7.14 (t, 1H, Ar—H); d 10.78 (s, 1H, NH).



 https://www.google.com/patents/WO2011072704A1?cl=en

Thus, the present invention provides highly pure Ropinirole API in improved overall yield.

Impurity A Impurity B Impurity C
The steps of the process for the preparation of Ropinirole and pharmaceutically acceptable salts thereof according to the present invention will be described in detail. Stase I: Preparation of 6-[2-(di-n-propylamino) ethyl] -2-nitrophenyl acetic acid hydrochloride

Formula II Formula III Formula IV
Stage I comprises Step I and II. According to Step I, N-[2-(2-methyl-3-nitrophenyl)ethyl]-N- propylpropan-1 -amine hydrochloride, i.e. Formula II, is converted into ethyl 6-[2-(di-«- propylamino)ethyl]-2-nitrophenyl pyruvate, i.e. Formula III. A solution of sodium ethoxide is prepared by carefully adding absolute ethanol into a suspension of sodium metal in anhydrous tetrahydrofuran under inert atmosphere. Subsequently, calculated amount of diethyl oxalate and N-[2-(2-methyl-3-nitrophenyl) ethyl] -N-propylpropan-1 -amine hydrochloride (i.e. Formula II) is added to the sodium ethoxide solution. The reaction mixture is maintained at temperature of 25 to 30°C for 70-72 hours to obtain ethyl 6-[2-(di-/?-propylamino)ethyl]-2-nitrophenyl pyruvate (i.e. Formula III).
Further, in Step II ethyl-6-[2-(di-«-propylamino) ethyl]-2-nitrophenyl pyruvate (i.e. Formula III) is converted into 6-[2-(di-«-propylamino) ethyl] -2-nitrophenyl acetic acid hydrochloride (i.e. Formula IV). Compound of Formula III is dissolved in a biphasic solvent mixture containing toluene, methanol and water. NaOH, H₂0₂ and Na₂S₂0₅ are added into the biphasic solution to achieve hydrolyzation, decarboxylation and decoloration with no isolation of the intermediates. The biphasic solution is then filtered and the layers are separated.
The obtained compound is converted into its hydrochloride additional salt form and further it is purified. The salt formation is obtained by adjusting the pH value of the aqueous layer obtained in step II to less than pH 2 using concentrated HC1 solution. The purification process includes passing the aqueous solution of crude compound of Formula IV through activated charcoal; treating the filtrate with sodium chloride aqueous solution at temperature of about 65-70°C then gradually cooling the solution mixture to temperature of about 25-30°C and filtering. Further purification using methanol and acetone provides compound of Formula IV in high purity.
Stage II: Preparation of crude Ropinirole hydrochloride
The preparation of crude Ropinirole hydrochloride from 6-[2-(di-w-propylamino) ethyl]-2- nitrophenyl acetic acid hydrochloride intermediate is achieved by subjecting 6-[2-(di-«- propylamino) ethyl] -2-nitrophenyl acetic acid hydrochloride (Formula IV) to hydrogenation using Pd/C as catalyst and methanol as solvent.
Stage III: Treatment to remove impurities
According to the present invention the following process has been developed for the removal of the structurally similar impurities generated during the preparation of Ropinirole. Said process comprises: (1) dissolving the crude hydrogenation product in a biphasic solvent mixture containing appropriate amount of toluene and water, adjusting the pH value of the aqueous layer to about pH 9 by adding appropriate amount of sodium hydroxide aqueous solution into the biphasic mass and separating the layers and collecting the organic layer. This step has been used to effectively remove impurity C from the crude Ropinirole;
(2) adding designed amount of water to the organic layer obtained from previous step (1) to form a biphasic mass. Bring the pH value of the aqueous layer to above pH 12, separating the layers and collecting the organic layer. This step has been used to selectively remove impurity A from the crude Ropinirole;
(3) the organic layer obtained from previous step (2) is once more mixed with designed amount of water to form a biphasic mass. Adjust the pH value of the aqueous layer to about pH 9 by adding appropriate amount of sodium hydroxide aqueous solution into the biphasic system, separating the layers and collecting the organic layer. This step is used to remove the remaining impurity C;
(4) treating the organic layer obtained from previous step (3) with suitable reducing agent and thereby converting the small quantities of impurity B into the desired compound Ropinirole free base; and
(5) optionally reacting the thus obtained Ropinirole free base with IPA HC1 solution to produce crude Ropinirole hydrochloride essentially free of the process-related structural similar impurities. Stage IV: Re-crystallization of Ropinirole hydrochloride
Crude Ropinirole hydrochloride is re-crystallized in a mixture of solvent comprised of methanol and acetone to obtain crystalline Ropinirole hydrochloride with chemical purity above 99.9%. The process of the present invention will be demonstrated in more details with reference to the following examples, which are provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner. Example 1 : Preparation of 6-[2-(di-n-propylamino) ethyl] -2-nitrophenyl acetic acid
hydrochloride
Under nitrogen atmosphere, 38 g of sodium metal (cut into pieces) is suspended in 350 ml of anhydrous tetrahydrofuran (THF) and 350 ml of absolute ethanol is carefully added over a period of 120-180 minutes, while maintaining the temperature below 15°C and it is stirred for additional 60-90 min. The solution is stirred at about 25-30°C until all the sodium metal has been dissolved. This will generally take 20-24 hrs. The solution is cooled down to temperature below 15°C and 225 ml of diethyl oxalate is charged, over a period of 40-70 min, while maintaining the temperature below 15°C. Subsequently, a solution of 100 g of N-[2-(2-methyl-3- nitrophenyl)ethyl]-N-propylpropan-l -amine hydrochloride in 50 ml anhydrous THF and 100 ml absolute ethanol (preheated till dissolved and cooled at 30-35 °C) is charged at temperature of about 25-30°C and the reaction mass is stirred for approximately 70-72 hrs at temperature of about 25-30°C. The solvents are removed by rapid distillation under reduced pressure and maintaining the temperature below 35°C.
1800 ml of dichloromethane is charged to the red oily residue, stirred till dissolution and the reaction mass is cooled to about below 5°C. Add 65 ml of aq. HC1 (37% w/w) while keeping the solution temperature below 15°C (pH=7.0 ± 0.2). Then 1300 ml of D.M. water is added to form a biphasic mass. The biphasic mass is warmed up to temperature 25-30°C and the biphasic mass is stirred for about 30-45 min. The biphasic mass is filtered through a Celite bed and the wet cake is washed with 300 ml dichloromethane. The organic layer is collected and the solvents are distilled off. Vacuum is applied towards the end of distillation to remove the residue solvent.
To the deep red oily residue, 620 ml of toluene, 45 ml of methanol and 500 ml of D.M. water is added at temperature about 25-30°C. The mixture is stirred to dissolution. 230 ml of aq. NaOH (20% w/v) is added under stirring till pH value is more than pH 12. Then the amount of water required to have total volume of water added from the 2 last steps equal to 780 ml is added. The reaction mass is stirred for 90-120 min and cooled down to temperature of about 0-5°C. Subsequently, 44 ml of aq. H₂0₂ (30% w/w) is charged over a period of 15 min and further the reaction mass is stirred for additional 5-10 min by maintaining the temperature below 15°C. A solution of 22 g Na₂S₂0₅ in 44 ml D.M. water is formed and added to the reaction mass for a period of 5-10 min while maintaining the temperature below 15°C, and stirring continuously for 45-60 min while keeping temperature below 15°C. 65 ml aq. NaOH (50% w/v) is added till pH value is more than pH 12, allowing the reaction mass to warm up to 25-30°C. The biphasic reaction mass is filtered through filter paper and separate the layers.
About 1 10 ml of aq. HC1 (37%, w/w) is added to the aqueous layer till pH value is less than 2, while maintaining the temperature at about 25-30°C. The reaction mass is heated to temperature of about 65-70°C and stirred until dissolution. 25 g of activated charcoal is charged under stirring. Continue heating the reaction mass with stirring at temperature of about 65-70°C for an additional period of 45-75 min. The hot suspension is filtered through a Celite bed and the solids are washed with 45 ml D.M. water. The filtrate is heated to temperature of 65-70°C and 125 g NaCl is added to the solution. The reaction mass is stirred for additional 15-30 min while maintaining the temperature at about 65-70°C.
The liquid is gradually cooled to about 25-30°C over a period of 3-4 hrs and it is let stand at such temperature for additional 45-60 min. The solid is filtered and the wet cake is dried in vacuum oven at 60°C till LOD <5%. The yield obtained is about 70-90 g. In a 250 ml 3-neck round-bottom flask, the mass obtained from the previous step is added to 160 ml of MeOH with stirring. The mixture is heated to 65-70°C till a homogenous mass is formed and stirring is continued for additional 10-15 min. The hot suspension is filtered through filter paper and slurry wash with 80 ml MeOH. MeOH is distilled off under atmospheric pressure. 160 ml Acetone is added to the residue and the mixture is heated at temperature of 45-50°C to form a homogenous mass and stirring is continued at the same temperature for additional 30-60 min. The suspension is cooled slowly to temperature of 25-30°C over a period of 90-180 min. Then it is further cooled to 0-5°C over a period of 30 min. Stirring is continued for additional 90 to 120 min at temperature of 0-5°C. This suspension is filtered and the solids are washed with 80 ml chilled Acetone. The wet cake is dried in vacuum oven at 60°C till LOD <1%. The yield obtained is about 65-80 g. Example 2: Preparation of crude 4-[2-(di-«-propylamino) ethyl]-l , 3-dihydro-lH-indol-2-one hydrochloride

100 g of 6-[2-(di-tt-propylamino) ethyl] -2-nitrophenyl acetic acid hydrochloride is dissolved in 1500 ml methanol and the solution is charged to a high pressure reactor. A suspension of 20 g of Pd/C 5 % (50% wet) in 50 ml methanol is added (wash the flask which contained the suspension with 50 ml methanol) and the reactor is sealed. Hydrogen gas is charged at temperature of about 25-35°C until the pressure reaches 2.8-4.4 kg/cm² and the mixture is stirred for about 2-4 hrs. The catalyst is filtered and washed with 200 ml methanol. The filtrate is evaporated to dryness (apply vacuum at the end of distillation).
The residue is charged to 1000 ml D.M. water and 2000 ml toluene. About -18 ml aq. NaOH (50% w/v) is added to adjust the pH value of the aqueous layer to pH 9.0-9.2. The mixture is stirred for 10-20 min and the layers are separated. The aqueous layer is extracted with 2000 ml toluene. The two organic layers are combined and 1000 ml of D.M. water is added. The pH value of the aqueous layer is brought to above pH 12 using about -4 ml of aq. NaOH (50% w/v). The mixture is stirred for 10-20 min and the layers are separated. 1000 ml D.M. water is added to the organic layer and the pH value of the aqueous layer is adjusted to pH 9.0-9.2 using about -1 ml aq. HCl (37% w/w). The mixture is stirred for 10-20 min and the layers are separated.
1000 ml D.M. water and lOOg of Na₂S₂0₄ (or Na₂S₂0₃ or Na₂S₂0₅) are added to the organic layer and the reaction mass is stirred for 60-90 min. The pH value of the aqueous layer is brought to above pH 10 using about -18 ml aq. NaOH (50% w/v). The reaction mass is stirred for 10-20 min and the layers are separated. The organic layer is concentrated by distillation under reduced pressure until the volume of the reaction mass is approximately 1 L. The mass is passed through a celite bed to filter off the inorganic particles followed by rinse the flask with 100 ml toluene. The filtrate is concentrated to dryness by distillation under reduced pressure.
The oily residue is dissolved in 300 ml toluene and 64 ml of IPA-HCl (15-25 % w/v) is added while stirring at temperature of 25-35°C. The mass is cooled gradually to 0-5°C over a period of time 90-150 min and the reaction mass is stirred continuously for additional 2-3 hours. The suspension is filtered through a Buchner funnel, slurry washed with 100 ml toluene, and the wet cake is suck dry for 45-60min. Then, the wet cake is dried in vacuum oven at temperature of 50- 55°C till LOD < 0.5%. The yield (Ropinirole hydrochloride crude) obtained is 60-75 g.
Example 3 : Purification of 4-[2-(Di-«-propylamino) ethyl]- 1, 3-dihydro-lH-indol-2-one
hydrochloride (Ropinirole hydrochloride)
100 g of crude 4-[2-(di-«-propylamino) ethyl]-l, 3-dihydro-lH-indol-2-one hydrochloride is added into 375 ml methanol. The mixture is degassed at temperature of 25-30°C and heated to 64-66°C with stirring until dissolution. Then, the mixture is cooled to temperature of 60-63°C and filtered under inert atmosphere. The filtrate is re-heated to 60-63°C and 200 ml acetone is added over a period of 5-15 min, maintaining the solution temperature at 55-60°C. The mass is cooled to 0-5°C over a period of 60-120 min and stirring is continued for 60-90 minutes. The suspension is filtered through Buchner funnel and slurry-washed with 200 ml Acetone. The wet cake is dried in vacuum oven at 50-55°C till LOD < 0.5%. The yield obtained is 80-90 g.
The present invention describes a large-scale manufacture process for the preparation of Ropinirole hydrochloride in high purity at relative low production cost compared to the available processes for producing similar products. Therefore, the Ropinirole hydrochloride according to the process of the present invention is obtained in excellent yield (above 40%) and in high purity (above 99.9%).

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http://www.google.com/patents/EP1568689A1?cl=en




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 http://pubs.acs.org/doi/abs/10.1021/op970037c

Org. Proc. Res. Dev., 1998, 2 (1), pp 3–9

DOI: 10.1021/op970037c

 Two plant syntheses of ropinirole {4-[2-(di-n-propylamino)ethyl]-1,3-dihydro-2H-indolin-2-one hydrochloride, SK&F-101468-A} using the ferric chloride mediated cyclisation of β-nitrostyrenes to form 3-chlorooxindoles as the key step are described. The first synthesis suffered the severe limitation of the final-step chemistry being nonselective in the reaction between di-n-propylamine and the bromide precursor to ropinirole as both substitution and elimination pathways were promoted and by-product formation at a level of 40% resulted. This problem was rectified in the latter synthesis by the more selective reaction between di-n-propylamine and the sulfonate ester precursor promoting ropinirole formation to a level of 88%. This second synthesis is now used as the commercial route, and problems (and their solutions) identified during the development of this route are now described. The identification of novel by-products which enabled the Sommelet oxidation step to be optimised is also reported. A unimolecular decomposition mechanism during hydrolysis of the hexaminium salt to form the key benzaldehyde intermediate is proposed and substantiated with experimental data.

Key green chemistry research areas—a perspective from pharmaceutical manufacturers

DJC Constable, PJ Dunn, JD Hayler, GR Humphrey… - Green …, 2007 - pubs.rsc.org

... The consequences of activation are illustrated by the synthesis of the dopamine agonist
ropinirole 1 (Scheme 1). 15 The toluenesulfonate (2, R = OTs) is displaced with dipropylamine
affording ropinirole in 85% yield. ... Scheme 1 The synthesis of ropinirole 1. ...

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http://pubs.rsc.org/en/content/articlelanding/2014/md/c4md00066h#!divAbstract


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http://www.google.com/patents/US20050159605

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Org. Process Res. Dev., 2013, 17 (3), pp 519–532

DOI: 10.1021/op300229k

Ropinirole·HCl is used for treatment of Parkinson’s disease.

Two patent applications disclose polymorphic forms of ropinirole·HCl. WO/2005/074387 claims form I and form II of ropinirole·HCl. WO/2005/080333 claims form I of ropinirole·HCl.(116, 117)The form II claimed in the 074387 patent application is identical to form I claimed in the 080333 patent application. Hence, form I claimed in the 074387 patent application becomes a novel crystalline form. Both form I and form II claimed in the 074387 patent application are characterized by techniques such as XRPD and DSC which are not enough to distinguish the two forms to be different. The comparison of XRPD 2θ values is given in Table 6.

Table 6. Comparison of XRPD values of ropinirole·HCl polymorphs form I and form II

2θ value
form I	form II	difference	form I	form II	difference
7.16			26.26
7.36	7.47	0.11	26.75	26.87	0.12
9.94	10.14	0.2	27.03	27.14	0.11
11.43	11.54	0.11	27.61	27.72	0.11
13.42	13.53	0.11	28.49
14.7	14.83	0.13		28.81
15.36	15.52	0.16		29.55
16.44	16.54	0.1	30.06	29.85	0.21
17.43	17.55	0.12		30.22	0.16
18.33	18.53	0.2	30.76	30.55	0.21
19.22	19.35	0.13		31.02
20.27	20.42	0.15	31.48
21.19	21.32	0.13	31.80	31.91	0.11
22.21	22.24	0.03	33.10	33.21	0.11
22.41		0.17	35.33	35.48	0.15
22.59	22.68	0.09	36.11	36.39	0.28
22.75		0.07		36.7
23.66	23.82	0.16	37.04	37.22	0.18
24.58	24.82	0.24	38.26	38.33	0.07
25.13	25.31	0.18	38.98	39.06	0.08
25.93	26.04	0.11

Most of the values disclosed for form I match those of form II (within ±0.2). However, intensities of the peaks in the two XRPD patterns were different. A sample of ropinirole·HCl was triturated in a mortar/pestle. XRPD of the sample was recorded before and after trituration. The XRPD pattern of the non-triturated sample is similar to that of form II and that of the triturated sample is similar to that of form I reported in WO/2005/074387. The overlay of XRPD patterns of both samples shows that the two forms are identical and that no extra peaks due to another form are present. The only change seen is the reduction in the intensity of the triturated sample along with changes in the intensities of individual peaks. Another change is seen when the sample is analyzed under the microscope; the non-triturated sample has a rectangular shape which, on grinding, changes to fine powder (Figure 9). In the non-triturated sample, the peak at 2θ = 7.4 has 100% intensity which decreases to 27% in the triturated sample, and a peak at 2θ = 23.7 has 8% intensity that increases to 100% in the triturated sample. It is well-known that such variation in intensity in the XRPD is associated with preferred orientation.(118) There are very few reports that show a variation in peak intensity of XRPD spectra to be a function of particle size.(119, 120) In ropinirole·HCl, both forms I and II are identical, and the variation in the peak intensity is due to the preferred orientation associated with changes in particle size or shape. In patent WO/2005/074387, the characterization data provided are not enough to prove the two forms to be different.

Figure 9. XRPD spectra and microscopic images of non-triturated and triturated ropinirole·HCl.

1. 116.
   

   Patel, H. V.; Dipchandani, J. G.; Jani, R. J.; Thennati, R. Novel crystalline forms of 4-[2-di-N-propylamino)ethyl]-2(3H)-indolone hydrochloride. WO/2005/074387, 2005
   
2. 117.
   

   Nadkarni, S. S.; Patel, H. M.; Parekh, N. R. Process for purification of ropinirole. WO/2005/080333, 2005.
   
3. 118.
   

   Ohannesian, L. Handbook of Pharmaceutical Analysis; Marcel Dekker: New York, 2002.
   
4. 119.
   

   Kang, F.PXRD Investigation of Changes in Dehydration Behavior of GSK241572 Hydrate after Micronization. http://www.icdd.com/ppxrd/09/presentations/2010-ppxrd-kang.pdf
   
5. 120.
   

   Froster, A.; Gordon, K.; Schmierer, D.; Soper, N.; Wu, V.; Rades, T.Characterisation of two polymorphic forms of Ranitidine-HCl. Internet J. Vib. Spectrosc.www.ijvs.com/volume2/edition2/section2.html.

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Journal of Heterocyclic Chemistry, , vol. 32, # 3 p. 875 - 882


URQUIMA S.A. Patent: WO2005/40115 A1, 2005 ; Location in patent: Page/Page column 6 ;


Gallagher, Gregory; Lavanchy, Patricia G.; Wilson, James W.; Hieble, J. Paul; DeMarinis, Robert M. Journal of Medicinal Chemistry, 1985 , vol. 28, # 10 p. 1533 - 1536

WO2006123356A1 *	Feb 15, 2006	Nov 23, 2006	Alembic Ltd	Process for the preparation of indolone derivative
EP0113964B1	Nov 30, 1983	Oct 22, 1986	Smithkline Beckman Corporation	4-aminoalkyl-2(3h)-indolones
EP0266033B1	Aug 25, 1987	Jun 22, 1994	SMITH KLINE & FRENCH LABORATORIES LIMITED	Process for the preparation of indolinone-2 derivatives
EP1242376B1	Nov 30, 2000	Jun 9, 2004	DSM Fine Chemicals Austria Nfg GmbH & CoKG	Method for producing oxindoles
EP1568689A1	Feb 19, 2004	Aug 31, 2005	CF Pharma Gyogyszergyarto Kft.	Process for the preparation of the 2-oxoindole derivative, Ropinirole
US4452808 *	Dec 7, 1982	Jun 5, 1984	Smithkline Beckman Corporation	4-Aminoalkyl-2(3H)-indolones
US7230118	Oct 13, 2004	Jun 12, 2007	Urquima S.A.	Process for the preparation of ropinirole
US7378439	Jul 9, 2004	May 27, 2008	Usv, Ltd.	Process for the preparation of 4-(2-dipropylaminoethyl)-1,3-dihydro-2H-indol-2-one hydrochloride
US20090043111	Aug 6, 2007	Feb 12, 2009	Meizheng Liu	Novel process for ropinirole preparation

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12 best beaches in Asia Pacific

Life's a beach. With so many to choose from, and so little time,Skyscanner has picked some of the prettiest beaches for action, relaxation and seclusion. Join us at these top beach destinations for a stunning tropical getaway!

1. Palawan, Philippines

Get away from it all at the Bacuit Archipelago in Palawan. A short distance away from El Nido in Palawan, its 45 enchanting islands are riddled with karst cliffs, limestone formations, and gorgeous lagoons. This is beachcomber paradise; charter a boat and go island-hopping!
Check flights to Palawan
Read more: 8 must-see places in Southeast Asia for great views: bucket list 2015

Spend your days island-hopping around the Bacuit Archipelago; you're sure to be enchanted!

2. Phi Phi Islands, Thailand

Featured in the movie "The Beach", the Phi Phi Islands are the jewel in Thailand's island crown. Even with all the hype, you'll be hard-pressed not to be impressed with the glittering turquoise waters and sheer cliffs. Take it easy and wind down… Phi Phi Don, the largest and only inhabited island, doesn't even have roads!

Read more: 8 must-do water sports in Asia: wet, wild, wonderful

Escape from the hustle and bustle of the city to the Phi Phi Islands

3. Goa, India

Where to begin with Goa's spectacularly scenic and amazingly diverse beaches? Depending on where you go, Goa has everything from adrenaline to adventure, solitude to sunbathing. Our picks are Mandrem Beach for honeymooners, Agonda Beach for relaxing, Baga Beach for parties, nightlife and fantastic seafood, and of course, the former hippie enclave of Anjuna Beach, for its famed trance music and colourful flea markets.

Read more: Best yoga retreats in Asia: wellness holidays at a glance

Laze about the spectacular white sand beaches in Goa

4. Soneva Gili, Maldives

As expensive as it is gorgeous, Soneva Gili (in the Maldives) is the ultimate in luxury retreats. Rustic-chic rules at this tiny coral atoll set in a sparkling lagoon, complete with spacious villas, fine dining and private butlers. For a simultaneously serene and sensual experience, indulge yourself at the Six Senses spa, which is located over open water and has glass panels below the massage tables!

Read more: 7 bizarre Asian massages you have to try once

Live in a paradise with the sea beneath your feet

5. White Beach, Boracay, Philippines

There's a good reason why Boracay, developed as it is, still makes it on this list. Boracay's White Beach is simply stunning, with extraordinarily pure powder sands that extend forever into shallow azure waters. From water sports and diving, to spas and shopping, there's something for everybody. Laze on lounge chairs while sipping cocktails, watch the sunset with dining on great food, and join in the raucous, rocking nightlife for a classic beach holiday. Fly to Caticlan then ride a boat to Boracay.

Read more: 5 things uniquely Philippines

Stay cool at Boracay's most popular beach and be sure to catch the stunning sunsets

6. Whitehaven, Whitsunday Islands, Australia

Often voted Australia's best beach, Queensland's iconic Whitehaven Beach is a seven kilometre stretch of crystal clear waters and pristine sands, backed by the verdant rainforests of the Whitsunday Islands. Explore the colourful cove of Hill Inlet, or hike up to the lookout at Tongue Point for a stunning, much-photographed view.

Read more: Top 5 things to do in Whitsundays, Australia

Relax at Queensland's most beautiful beach

7. Sipadan, Malaysia

Possibly one of the best dive sites in the world, Sipadan's lush and healthy coral reefs support thriving populations of sea turtles and reef sharks. Especially around Barracuda Point, divers can swim among huge schools of fish. However, conservation regulations mean that only 120 diving permits are allowed every day, so do book your dives early. Otherwise, there's first-rate snorkelling, and pleasant strolls along the sands to spot friendly monitor lizards. Get to Sipadan by domestic transfer to Tawau Airport.

Read more: Top 5 places to go diving in Southeast Asia

Apart from living above the waters, be sure to scuba dive when in Sipadan

8. Koh Rong, Cambodia

Idyllic and picturesque, this island off the coast of Sihanoukville is an unspoiled tropical paradise. With over 40 kilometres of white sand beaches and turquoise-green waters, Koh Rong offers the simple pleasures of relaxing with a cold beer and freshly-caught seafood. Most developments are very new, so get there before everyone else does! Get to Koh Rong by ferry after flying in to Phnom Penh.

Read more: Skyscanner's Chinese horoscope travel advice for 2015

Like many others, Koh Rong is a cliched beach paradise- go before it gets too crowded!

9. Haad Rin Beach, Koh Phangan, Thailand

Calling all party animals! For a once-in-a-lifetime experience, few places can beat the hedonism of Koh Phangan's infamous Full Moon parties. These are wild, all-night affairs of throbbing music, inexpensive drinks, and thousands of fellow party-goers all out to have a fantastic time. And if you need to recover from that hangover, there are quieter, just-as-pretty beaches, perfect for taking it easy the next day. Get to Koh Phangan by ferry after flying to Koh Samui or consider alternative airports: Chumphon or Surat Thani.

Read more: Best ladies' nights in Singapore

Island paradise in the day and party island at night- be sure to join in the partying at Koh Phangan!

10. Mui Ne Beach, Vietnam

Adrenaline, here we come! For those who love the heady contrast of excitement and relaxation, Mui Ne Beach is right up your alley. With strong winds, big waves, and clear skies, Mui Ne is ideal for wind-surfing, kite-surfing and all sorts of physical activities. Still not enough? Mui Ne has some dramatic and unusual scenery: giant sand dunes, like a piece of desert next to the sea, and perfect for dune-trekking. Get to Mui Ne Beach from Ho Chi Minh City.

Read more: 7 ideas for the 7 Singapore long weekends this 2015

Mui Ne Beach definitely has variety, from untouched beach beauty to exclusive resorts and swanky shops

11. Hot Water Beach, Coromandel Peninsula, New Zealand

Not far from Auckland is the truly unique Hot Water Beach. The presence of hot springs along the coast means that hot water bubbles up through the sands, allowing visitors to dig their own personal, steaming spa pool to relax in… at least until the tide comes in. Arrive about an hour before low tide, and don't forget to bring a spade!

Read more: Long travel weekends in 2015

Digging your own DIY spa pool is a must-do!

12. La Digue, Seychelles

All right, this beach isn't in Asia, but we at Skyscanner couldn't resist adding to the list. The exotic, faraway islands of the Seychelles are on many travellers' bucket lists, attracting famous honeymooners like Prince William and Duchess Kate. Their pick? The exclusive and exquisite island of La Digue, home to L'Anse Source D'Argent, one of the world's top beaches.

Read more: 5 awesome islands near Bali that aren't Bali

Frolic in this tropical paradise and island-hop to nearby islands from this convenient springboard

 

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