Specification
FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTIOAN: "A NOVEL PROCESS FOR THE PREPARATION OF ILOPERIDONE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF".
2. APPLICANT
(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: "H" WING, 4TH FLOOR, TEX CENTRE, OFF SAKI
VIHAR ROAD, CHANDIVALI, ANDHERI (EAST),
MUMBAI-400072, INDIA.
PREAMBLE TO THE DESCREPTION
The following specification particularly describes the invention and the manner in which it is to be performed.
TITLE: A novel process for the preparation of Iloperidone and pharmaceutically acceptable salts thereof.
TECHNICAL FIELD OF THE INVENTION: The present invention relates to a novel process for the preparation of 1- [4-[3-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)- l-piperidmyl]propoxy]-3-methoxyphenyI]- ethanone of formula I (Iloperidone).The process comprises contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II as base itself rather than use of its hydrochloride salt as reported in the prior art (Drugs of Future 2000, 25(1): 29, EP 0402644) and l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone of formula III. This invention also relates to a process for the preparation an unknown impurity of the formula IV herein referred as carbonated impurity formed during contact of compound of formula II and compound of formula III in presence of a base, method of its isolation and characterization thereof, as well as its use as a reference standard and reference marker in analytical department while evaluating the purity profile of iloperidone.
BACKGROUND OF THE INVENTION:
Iloperidone is an atypical antipsychotic. It is being investigated mainly for the treatment of schizophrenia. Hoechst Marion Roussel Inc. is the originator of this molecule; Vanda is currently developing this molecule for the treatment of schizophrenia. Uoperidone is 5-HT2 antagonist, which targets a selective set of dopamine, norepinephrine and serotonin receptor subtypes. The affinity for this particular set of receptors indicates that iloperidone has the potential to be a broad spectrum . antipsychotic, with efficacy against positive, negative, depressive and cognitive symptoms of schizophrenia, and a low propensity to induce side effects. Iloperidone's IUPAC name is l-[4-[3-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]propoxy]-3-methoxyphenyl]ethanone,It is a nonpharmacopeal product till date.
It is well known in the art that, for human administration, safety considerations require the establishment by national and international regulatory authorities of very low limits for identified but toxicologically uncharacterized impurities before an active pharmaceutical ingredient product (API) is commercialized. Typically these limits are less than about 0.15% by weight of each impurity. Therefore in the manufacturing
of active pharmaceutical ingredients knowledge of the purities of API is necessary.
The product mixture of a reaction is rarely a pure single compound complying to pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will in most cases be present. At certain stages during processing of an API, such as Iloperidone, it must be analyzed for purity typically to determine the presence of any intermediates or by-products as impurities. The API need not to be absolutely pure, as absolute purity is theoretically ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible and thus safe for human use.
Generally by-products and intermediates collectively hereinafter defined as impurities are identified spectroscopically and/or by other physical methods and then associated with a peak position, such as that in a chromatograph. The relative position in the chromatogram is known as the "retention time." The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "relative retention time (RRT)" to identify impurities. The RRT of an impurity is its retention time divided by retention time of "reference marker". The reference marker can be the API itself, or it may be a compound other than API that is added to, or already present in the mixture, in an amount sufficiently large to be detectable and sufficiently low so as not to saturate the column and to use that compound as the reference marker for the determination of RRT.
Those skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard". A reference standard is similar to a "reference
marker", which is used for qualitative analysis only, but used to quantify the amount of compound of reference standard in an unknown mixture as well. A reference standard is an "external standard", when a solution of a known concentration of reference standard and an unknown mixture are analyzed using the same technique.
In practice for analytical purpose some impurities generally present in the API are used as markers and there is a prime requirement to develop good safe, economical and workable process for the synthesis of such impurities used as markers. For this reason good chemical company generally has a separate fully dedicated facility for the synthesis of impurities.
Like any synthetic compound, iloperidone or pharmaceutically acceptable salt thereof can contain impurities that can come from many sources. They can be degradation products of iloperidone, unreacted intermediate(s) used in the preparation of iloperidone or by-products of reactions.
The present invention relates to an improved process for the preparation of iloperidone over the prior art by minimizing or eliminating the formation of unknown impurity and isolation and characterization of the said unknown of formula IV formed during the preparation of iloperidone of formula I, comprising contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone of formula III in presence of a base especially alkali metal carbonate. The said impurity of formula IV is a potential reference marker in analytical methods for the analysis the quality of iloperidone.
Iloperidone compound of formula (I) was first disclosed in EP0402644 by Hoechst-Roussel Pharmaceutical Inc. Method for preparation of
Iloperidone was first disclosed in EP0402644 (hereinafter referred as '644) , according to which, it was prepared by the condensation of the compound of formula (II) 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride and compound of formula (III) l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, in the presence of potassium carbonate as a base added in a single lot in dimethylformamide (DMF) followed by treating reaction mixture with water, extracting with organic solvent that is immiscible in water, washing, drying and concentrating the organic solvent to give the moist solid iloperidone, which was further recrystallized from the ethyl alcohol to produce iloperidone as a beige (i.e. light brown) solid with only 58% yield. EP0402644 discloses the use of suitable bases e.g. alkali metal carbonates for the condensation reaction. The process of EP 0402644 is depicted in scheme I,
Drugs of Future 2000, 25(1): 29 discloses the same process as disclosed in '644 for the preparation of iloperidone comprising the condensation of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride (II) with 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III) in presence of K2CO3 in hot DMF, there is no description of yield and iloperidone is obtained as a beige solid.
Journal of Medicinal Chemistry, 1995, Vol. 38, No. 7,1119-1131 discloses general synthesis of pharmaceutical active piperidine-1-yl-benzisoxazole derivative including iloperidone (HP 873), comprising the
condensation of l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (III) with 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole or its hydrochloride II in presence of K2CO3 using various combinations as given below:
Method D: DMF, K2CO3 70-90 °C Method E: CH3CN, K2CO3, KI, reflux. Method F: DMF, CH3CN, K2CO3, 90-100 °C
All three solvent systems for the condensation i.e. for Methods D, E & F suggest the use of organic solvent and mixture thereof for the preparation of target compounds. The said reference doesn't disclose the specific preparation of iloperidone; furthermore as disclosed therein the process to obtain desired analogue compounds required column chromatography and/ or recrystallization from different solvent to purify the compound, which ultimately resulted into the low yield of 17%-46% approximately.
1980/MUM/2007, discloses the drawbacks associated with DMF as a solvent. It mainly features the drawbacks associated with DMF as solvent. It highlights the low solubility of most preferred alkali metal carbonates used as a base for the condensation in inert solvents such as DMF, acetonitrile or butanol as disclosed in prior art. Because of the low solubility of inorganic base in organic solvent like DMF, base may not neutralize the acid by-product simultaneously with the result neutralization may be sluggish. It is observed that due to the slow neutralization of acid by- product from the reaction mixture, more time is required to complete the condensation and because of that there may be chances of decomposition of the target product, which ultimately reduces the yield and purity thereof. Furthermore, at industrial scale solvent extraction, washing, drying, chromatography and concentrating to isolate the product is cumbersome, and time-consuming and also lead to poor recovery of organic solvent used for the reaction.
1980/MUM/2007 discloses the preparation of iloperidone comprising the condensation of the HC1 salt of compound of formula (II) 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole and compound of formula (III) l-[4-(3-chloropropoxy)-3-methoxyphenyl]-ethanone, in the presence of potassium carbonate as a preferable base in water as solvent. However, the drawback associated with 1980/MUM/2007 is the use of 6-fluoro-3-(4-piperidinyl)~l,2-benzisoxazole hydrochloride, thereby consuming extra mole of base to neutralize the hydrochloride to generate the corresponding base which then undergoes the condensation with compound of formula III. Moreover the preparation of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole hydrochloride requires an additional unit operation. Due to excessive consumption of base; mother liquor is alkaline that requires additional acid quantity to neutralize to meet with effluent criteria.
The common factor in the prior art mentioned hereinabove for the preparation of iloperidone is use of potassium carbonate and a aprotic solvent DMF, which till the time of present application is preferred combination more particularly the use of potassium carbonate as a base and its addition to reaction mixture in a single lot is preferred for sensitive reaction requiring well balanced base strength.
The reaction for the preparation of iloperidone comprising contacting the compound of formula II with compound of formula III is a SN2 type reaction for which bases like sodium methoxide, sodium hydroxide, sodium tert butylate are too strong since they do not function as only proper acid scavengers but also gets involved chemically inducing side reactions. For chemical reactions of substances bearing sensitive functional groups, the use of very strong base as acid scavengers is not advised. To design a reaction that is both efficient and tolerant to functional group the choice of a well balanced base to act as acid
scavengers, which is neither too strong nor too weak is essential, therefore, generally carbonates are preferred.
However the inventors of the present invention practiced the processes as disclosed in'644 and Drugs of Future 2000, 25(1): 29 wherein potassium carbonate is used as a base and observed formation of about 15 % unknown impurity. Therefore it was thought to study the use of various carbonates which revealed that use of lithium carbonate and sodium carbonate used in combination with DMF as solvent minimizes the formation of the impurity of formula IV. But potassium carbonate and cesium carbonate used in combination with DMF results into the formation of the impurity of formula IV upto the extent of 15% and 29% respectively. Formation of less impurity with lithium carbonate and sodium carbonate while high level of impurity formation with potassium carbonate and cesium carbonate is attributed to the basicity of the alkali metal carbonates, use of an appropriate solvent that will ensure the availability of free ions of the salt used and solubility of the carbonates.
It is known that when we move in a group of alkali metals from top to bottom the cationic radii of respective ions increases along with polarisability. This causes the basicity of alkali metals carbonates viz.Li2CO33 (3.81 g) is added lot wise after every 2 h. First lot was of 1.90 g while the next four of 0.48 g each and maintain the temperature at 80°C for more 6 h. The temperature of the reaction mass was then cooled to 30-35°C. The reaction mass was then filtered and washed with H20 (5x50 mL) to obtain the crude product of iloperidone (17.3 g). The carbonated impurity is found to be nil.
ExampIe-9
To a well stirred suspension of compound of formula II (10.0 g) and compound of formula III (11.0 g) in H20 (100 mL) was added NaOH (1.81 g) in one lot and stirred for 10 min. Temperature was then raised to 80°C and maintained for 5 h. The reaction mass was cooled to room temperature and then filtered, washed with H20 (5x50 mL) to obtain the crude product of iloperidone (16.8 g).
Example-10
To a well stirred suspension of compound of formula II (10.0 g) and compound of formula III (11.0 g) in H20 (100 mL) was added at 30-35°C and temperature was then increased to 80°C. To this NaOH(1.81 g) is added lot wise after every 2 h. First lot was of 0.89 g while the next four of 0.23 g each and maintains the temperature at 80°C for more 6 h. The temperature of the reaction mass was then cooled to 30-35°C. The reaction mass was then filtered and washed with R20 (5x50 mL) to obtain the crude product of iloperidone (18.3 g) 97.7% purity.
Example-11
To a well stirred suspension of compound of formula III (11.0 g) in H2O (40 mL) was added compound of formula II (10.0 g) and stirred for 30 min at 30-35°C. The temperature was raised to 60°C and to the reaction mass was added NaOH solution (1.82 g in 40 mL H20) drop wise during lh. The reaction mass is further maintained at 60°C for 5 h. To this MeOH (140 mL) was added and stirred for another 45 min. The temperature of the reaction mass was cooled to 25-30°C and then filtered, washed with H2O (5x50 mL) to obtain the crude product of Comp-III. (17.0 g yield with 99.0 % purity). The crude product was dissolved in DMF by heating at 70°C to obtain a clear solution. To this clear solution charcoal was added and filtered through hyflow. Cooled it to room temperature and then water (10 vol.) was added drop wise. Stirred it for 15 min. and filtered to yield pure product with 99.9% purity.
Example-12: (Preparation of carbonated impurity of formula IV)
To a well stirred solution of compound of formula II (10.0 g) and compound of formula-Ill (11.0 g) in DMF (80 mL) was added K2C03 (12.71 g) in one lot and stirred for 10 min. Temperature was then raised to 90°C and maintained it for 16 h. DMF was recovered under reduced pressure. Oily concentrated mass was diluted with water (250 mL) to
yield semisolid suspension which was then extracted with ethyl acetate (5x 50 mL).The combined organic layer was dried over sodium sulfate and solvent was removed under vacuum. The obtained crude product. contained carbonated impurity of formula IV (13% by HPLC). It was isolated by column chromatography, eluted by 10 to 20 % ethyl acetate in hexane to yield semisolid material, carbonated impurity of formula IV is identified and named as 3-(4-acetyl-2-methoxyphenoxy)propyl 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine-l-carboxylate. Characterization of the impurity is supported by the following analytical tools:
'H NMR (Varian, 400MHz), (CDC13): 5 1.880(m,2H), 1.996(m,2HJ, 2.206(m,2H), 2.518(s, 3H), 2.999(t, 2H), 3.216(m,lH), 3.860(s,3H), 4.262(m,6H), 6.860(d,lH), 7.026(t,lH), 7.219(t,lH), 7.488(m,2H) and 7.589(m,lH)ppm.
13C NMR (Varian, 400MHz) (CDC13): 26.116, 28.857, 30.042, 34.138, 43.640, 55.929, 55.968, 62.186, 65.369, 65.694, 97.486(d), 110.537, 111355(d), 112.501(d), 122.131(d), 123.090(d), 130.589, 149.280, 152.579, 155.158, 160.308, 162.871, 163.846(d), 165.364 andl96.880 ppm.
IR (Shimadzu, KBr): 470.6, 569.0, 642.3, 804.3, 956.7, 1031.9, 1099.5, 1122.6, 1220.9, 1263.4, 1350.2, 1415.8, 1512.2, 1591.3, 1612.5, 1680.1, 1695.5, 2852.8, 2924.2, 2960.8 and 3076.6 cm-1.
LCMS (Thermo.) M/Z= 471.02 (M+l).
Example-13
To a well stirred solution hydrochloride of compound of formula II (10.0 g) and compound of formula III (9.45 g) in DMF (80 rnL) was added K2C03 (10.8g) in one lot and stirred for 10 min. Reaction mixture was heated at 90°C for 16 h. and then cooled to 50°C. DMF was recovered under reduced pressure. Oily concentrated mass was diluted with water (250 rnL) to yield semisolid suspension which was then extracted with ethyl acetate (5X 50 mL).The combined organic layer was dried and solvent was removed under vacuum to yield iloperidone of formula I (16.0 g) as crude product. The carbonated impurity is found to be 10.01%.
CLAIMS:
We claim:
1. Substantially pure Iloperidone of formula I or a pharmaceutically acceptable salt thereof comprising 1- [4-[3-[4-(6-fluoro- 1,2-benzisoxazol-3-yl)- 1 -piperidinyl]propoxy]-3-methoxyphenyl]- ethanone and impurity of formula IV in an amount upto 1.5%.
2. 3-(4-acetyl-2-methoxyphenoxy)propyl 4-(6-fluoro-l, 2-benzoisoxazol-3-yl)piperidine-l-carboxylate of formula IV or acid addition salt thereof.
3. A process for the preparation of iloperidone of formula I or a pharmaceutically acceptable salt thereof comprising:
a) contacting 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole of formula II with l-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone of formula III in a solvent.
b) optionally slow addition of base in multiple lots to the reaction mixture of process step a,
4. Process of claim 3 wherein base is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides organic bases or mixture thereof,
5. process of claim 3 wherein solvent is selected from the group
comprising DMF, alcohol, ketones, nitriles, acetamides, water,
pyrrolidinones, aromatic hydrocarbons or mixture thereof.
6. Process of 4 wherein alkali metal carbonate is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, preferably potassium carbonate or mixture thereof.
7. Process of 4 wherein alkali metal bicarbonate is selected from group of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate or mixture thereof.
8. Process of 4 wherein alkali metal hydroxide is selected from group comprising lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide preferably sodium hydroxide or mixture thereof.
9. Process of 4 wherein organic base is selected from primary, secondary and tertiary amines.