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Title:
A NOVEL PROCESS FOR PREPARATION OF ALOGLIPTIN BENZOATE
Document Type and Number:
WIPO Patent Application WO/2015/092807
Kind Code:
A1
Abstract:
The present invention provides a novel process for preparing Alogliptin free base and its benzoate salt which comprises insitu condensation process to produce protected Alogliptin by reacting 6-chloro-3-methylpyrimidine-2, 4(1H, 3H)-dione with 2-(halo methyl) benzonitirle in presence of a base, aprotic solvent followed by insitu reaction with protected (3R)-piperidin-3-amine at elevated temperature. The protected Alogliptinis deprotected to obtain Alogliptin free base and further converted to Alogliptin benzoate.

Inventors:
HARMAN FINOCHEM LIMITED (IN)
KADAM VIJAY TRIMBAK (IN)
BUDDHALA RAJASEKHAR RAO (IN)
SINGAMPALLLI SRI HAH (IN)
MINHAS HARPREET SINGH (IN)
MINHAS GURPREET SINGH (IN)
Application Number:
IN2014/000566
Publication Date:
June 25, 2015
Filing Date:
September 01, 2014
Export Citation:
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Assignee:
HARMAN FINOCHEM LIMITED (IN)
International Classes:
C07C275/24; C07D239/545; C07D403/04
Foreign References:
US20090275750A12009-11-05
Attorney, Agent or Firm:
P. ARUNA SREE (Gopakumar Nair Associates3rd Floor, 'shivmangal', Near Big Bazaar,Akurli Road, Kandivali ,, Maharashtra, IN)
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Claims:
We claim,

1. A novel process for preparing Alogliptin free base (formula-I) and Alogliptin benzoate (formula- II)

Formula-I FormuIa-II

Which comprises,

(a) Condensing 6-Chloro-3-methylpyrimidine-2,4(lH,3H)-dione with 2-(halo methyl) benzonitirle in presence of a base, aprotic solvent to obtain 2-[(6-chloro-2,4- dioxo-3,4-dihydropyrimidin-l(2H)-yl) methyl] benzonitrile which further reacts with protected (3R)- piperidin-3 -amine insitu at elevated temperature to obtain protected Alogliptin;

(b) deprotecting the protected Alogliptinin methylenedichloride in presence of a deprotecting agent at a temperature from -5 to 25°C to obtain Alogliptin free base.

(c) reacting Alogliptin free base with benzoic acid in presence of suitable solvent at a temperature of 40-80°C to isolate Alogliptinbenzoate.

2. The process according to claim 1, wherein the reaction of step (a) is optionally conducted in presence of a catalyst.

3. The process according to claim 2, wherein the catalyst is selected from the group consisting of potassium iodide, sodium iodide, sodium bromide, potassium bromide preferably potassium iodide.

4. The process according to claim 1, wherein the 2-(halo methyl) benzonitirle in step (a) is selected from the group consisting of 2-(bromo methyl) benzonitrile, 2- (chloro methyl) benzonitrile or 2-(iodo methyl) benzonitrile.

5. The process according to claim 4, wherein the 2-(chloro methyl) benzonitrileis used in presence of catalyst and 2-(bromo methyl) benzonitrileused in absence of catalyst.

6. The process according to claim 1, wherein the base is selected from inorganic base or organic base.

7. The process according to claim 6, wherein the inorganic base is selected from carbonate salts of alkali and alkaline earth metals and the organic base is trisubstituted amines.

8. The process according to claim 1, wherein the aprotic solvent in step (a) is selected from the group consisting of N,N-dimethylacetamide,N,N- dimethylformamide, dimethylsulfoxide preferably N,N-dimethylacetamide.

9. The process according to claim 1 , wherein the elevated temperature in step (a) is in the range of 50-100°C.

10. The process according to claim 1 , wherein amine protecting group in step (a) is selected from the group consisting of Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9- Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxyberizyl (DMPM), p- methoxyphenyl (PMP), Tosyl (Ts), Mesyl (Ms), Other Sulfonamides (Nosyl&Nps).

11. The process according to claim 1 , wherein the suitable solvent in step (c) is selected from the group consisting of DNS, DNS with 0.5-50% ethyl acetate, toluene, acetone or mixture thereof.

12. The process according to any of the preceding claims, wherein purity of protected Alogliptin, Alogliptin free base and Alogliptin benzoate is 96-98%, 99-100% and 99.5-100% respectively.

13. The process according to any of the preceding claims, wherein Alogliptin benzoate is obtained with S-isomer in the range of not more than 0.1%.

Description:
"A NOVEL PROCESS FOR PREPARATION OF ALOGLIPTIN BENZOATE" FIELD OF INVENTION:

The instant invention relates to a novel process for preparation of Alogliptin free base and its benzoate salt.

BACKGROUND OF INVENTION:

2-({6-[(3R)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxo-3,4-di hydropyrirnidin-l -(2H)- yl}methyl) benzonitirle known as Alogliptin (Formu a-I), is a selective serine protease dipeptidyl-peptidase IV (DPP TV) inhibitor.

Formula-I

DPP IV plays a key role in maintaining glucose homeostasis by controlling the incretin activity of glucagon-like peptide 1 (GLP-I) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide). Inhibition of DPP IV is therefore recognized as a novel therapeutic approach for the treatment of type 2 diabetes. DPP-IV inhibitors that have advantageous potency, stability, selectivity, toxicity and/or pharmacodynamics properties and which thus may be used effectively in pharmaceutical compositions to treat disease states by the inhibition of DPP-IV.

Alogliptin and its pharmaceutical acceptable salts and processes for their preparation are disclosed in US7, 807,689, US 7,781,584 and EP 1586571.

US 8,329,900and WO 2007035629 disclose a process for preparing Alogliptinas shown

Scheme-I

According to the Scheme-I, 6-chlorouracil (1) in mixture of DMF-DMSO reacts with a- bromo-o-toluenitirle in the presence of NaH and LiBr to produce benzylated-6- chlorouracil (2). Benzylated-6-chlorouracil further reacts with iodomethane in presence of NaH in DMF/THF to give methylated compound (3) which reacts with 3(R)- aminopiperidinedihydrochloridein presence of NaHC0 3 in methanol to give Alogliptin (4)·

According to the state of the art, WO 2010109468 describes a process form preparing pyrimidindione compounds, especially Alogliptin and its derivatives according to Scheme-II

(VIII) (VII) (VII - A)

(")

Scheme-II

According to WO'468 urea derivatives react with malonic acid derivative to form intermediates (VII & VII-A) which are converted to formula II by reacting with halogenating agent in presence of solvent. Formula II reacts with an amine (III) to displace the halogen group and form Alogliptin free base which further react with an acid to give Alogliptin acid salt.

WO 2013046229 discloses a novel process for preparing amorphous Alogliptin benzoate and its novel salts- fumarate, malate, sulfate, tosylate, oxalate, nitrate, tartarate salt. The drawback of the prior art processes involves in use of hazardous materials such as lithium hydride. Further, the methods described in the above processes are complex and expensive as the same involves the use of various expensive solvents and reagents.

Therefore, there is a need in the art to develop safe, cost-effective and industrially applicable process for the preparation of Alogliptin and its benzoate salt with high yield and high purity, which remains the objective of the invention, for which protection is sought.

Another object of the present invention is to enhance the reaction rate by using suitable catalyst.

SUMMARY OF THE INVENTION:

In accordance with the above object, the instant invention discloses a novel process for preparing Alogliptin free base (Formula-I) and its benzoate salt (Formula-II) that can be conducted on industrial scale in a cost-effective and safe manner.

According to one aspect, the present invention involves insitu condensation process for preparation of protected Alogliptin by reacting 6-chloro-3-methylpyrimidine-2,4(lH,3H)- dione of formula-IV with 2-(halo methyl) benzonitirle of formula-Ill to obtain 2-[(6- chloro-2,4-dioxo-3,4-dihydropyrimidin-l -(2H)-yl)methyl]benzonitrile of formula-V, which further reacts with protected (3R)-piperidin-3-amine of formula-VI at elevated temperature to obtain protected Alogliptin of formula-VII.

In another aspect, the present invention discloses the deprotection process to obtain Alogliptin free base from protected Alogliptin in presence of solvent and deprotecting agent at a temperature of -5 to 25°C.

In yet another aspect, the present invention provides a process for producing benzoate salt of Alogliptin free base with benzoic acid in presence of suitable solvent at a temperature of 40-80°C DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to a novel process for preparing Alogliptin free base (Formula- 1) and its benzoate salt (Formula-II).

Formula-I Formula-II

In an embodiment, the insitu condensation process for preparation of protected Alogliptin comprises

(a) reacting 6-Chloro-3-methylpyrimidine-2,4(lH,3H)-dione of formula-IV with 2- (halo methyl) benzonitirle of formula-IIIat elevated temperatureto obtain 2-[(6- chloro-2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)methyl]benzonitrileof formula-V and -

(b) Reacting 2-[(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)methyl]benzonitrileof formula- Vwith protected (3R)- piperidin-3 -amine of formula- VI at elevated temperature to obtain protected Alogliptin of formula- VII.

In the said process 2-(halo methyl) benzonitrile is selected from 2-(bromo methyl) benzonitrile,2-(chloro methyl) benzonitrile or 2-(iodo methyl) benzonitrile.

The condensation process is carried out in presence of inorganic or organic base, aprotic solvents and in presence or absence of suitable catalyst. The elevated temperature mentioned in said process is 50-100°C. The inorganic base is selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and sodium methoxide. The organic base is selected from trisubstituted amines such as triethyl amine, diisopropyl ethyl amine, N-methyl morpholineand N-methyl pyrrolidine.

The solvents used in the said process are selected from N,N-Dimethylacetamide,N,N- dimethylformamide, dimethylsulfoxide, dichloromethane, methanol, isopropyl alcohol, methyl tertiary butyl ether, ethyl acetate, heptane, diisopropyl ether or mixture of two or three solvents. Suitable catalyst is selected from potassium iodide, sodium iodide, sodium bromide, potassium bromide.

The protecting group for (3R)-piperidin-3-amine is selected from Carbobenzyloxy (Cbz), p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC), 9- Fluorenylmethyloxycarbonyl (FMOC), Acetyl (Ac), Benzoyl (Bz), Benzyl (Bn), Carbamate, p-Methoxybenzyl (PMB), 3,4-Dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), Tosyl (Ts),Mesyl (Ms) and other Sulfonamides (Nosyl&Nps).

The protected Alogliptin thus obtained has HPLC purity of 96-98%.

In another embodiment, the invention provides a process for preparation of Alogliptin free base (formula-I) from protected Alogliptin (formula-VII). The deprotection process is carried out in presence of solvent and deprotecting agent at a temperature of -5 to 25°C. The deprotection process is carried out by hydrogenolysis, using deprotection agents such as concentrated strong acids like HC1, HBr, H2SO4, CH3COOH, CF3COOH or mixture thereof or strong acids in solution form; bases such as Piperidine, aqueous or gaseous ammonia or methylamine; aliphatic amides, ammonium cerium(IV) nitrate, strong reducing agents like sodium in liquid ammonia or sodium naphthalenide; samarium iodide, tributyltin hydride or Pd/C, Palladium hydroxide.

However, in a preferred embodiment, the deprotection process for BOC deprotection involves methylenedichloride as solvent and alcoholic hydrochloric acid or trifluoroacetic acidas deprotecting agents. The Alogliptin free base thus obtained is 99-100% pure.

Another embodiment discloses a process for producing benzoate salt of Alogliptin free base by reacting Alogliptin free base with benzoic acid in presence of suitable solvent at 40-80°C. The suitable solvent is selected from denatured alcohol, (herein after "DNS") DNS with 0.5-50% ethyl acetate, toluene, acetone or mixture of them. The obtained Alogliptin benzoate is 99.5-100% pure. The chiral purity of Alogliptin benzoate is 99.9- 100% and S-isomer is less than 0.1% The process of the present invention to obtain Alogliptin free base and its benzoate salt is given in the reaction scheme-II

* mula-III

Formula-VII

Formula-V

Deprotection Methanloic.HCl

Formula-II Formula-I

Where R = BOC

Scheme-Ill

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Examplel: Protected Alogliptin

To the 125cc dimethylacetamide charged 0.28mole potassium carbonate after stirring it for 10-30 min at ambient temperature added 0.18mole of formula-IV with 0.186mole of formula-Ill (Where X= CI), 0.007mole potassium iodide at room temperature and stirred the reaction mass for 45-150 min at elevated temperature of 50-100°C. The insitu reaction was carried forwarded by adding 0.17mole of formula- VI and 0.23mole of potassium carbonate at elevated temperature and further stirred for 75-175min. After completion of reaction, 500cc water was slowly added at around 20-60°C and further stirred for 10-30 min. The wet solid wasdried at 40-90°C to obtain 95% of protected Alogliptin.

HPLC Purity: 96-98%

Example 2: Protected Alogliptin

To the 500cc dimethylacetamide charged 1.24mole potassium carbonate after stirring it for 10-30 min at ambient temperature added 0.62mole of formula-IV with 0.68mole of formula-Ill (Where X= Br) and stirred reaction mass for 45-150 min at elevated temperature of 50-100°C. The insitu reaction was carry forward by adding 0.625mole of formula- VI and 1.13moleof potassium carbonate at elevated temperature and further stirred for 75-175min. After completion of reaction, 2000cc water was slowly added at 20-60°C and further stirred for 10-30 min. The wet solid was dried at 40-90°C to obtain 94% of protected Alogliptin.

HPLC Purity: 96-98%

Example 3:Alogliptin free base

To the 1250cc methylene dichloride charged0.57mole of formula- VII (where R=BOC) and stirred for 10-30 min at a temperature of -5 to 25°C. 400cc 20-25% alcoholic hydrochloric acid was added for 30-90 min slowly and the reaction mass was stirred for 45-100 min at ambient temperature. After completion of reaction, the solvent was distilled out under vacuum. Charged lOOOcc water, washed aqueous layer with 2530cc methylenedichloride, collected organic layer and extracted with 960cc Water. Collected total aqueous layer and washed with 2530cc methylenedichloride and basify the aqueous layer with 10% NaOH solution, extracted with 2530cc methylenedichloride, collected organic layer and distilled under reduced pressure at 30-50°C and further recrystallized the product in methyl tertiary butyl ether, and finally filtered the product and the wet product was dried at 30-60°C to afford 74% of title compound.

HPLC PURITY: 99-100%

Example 4: Alogliptin benzoate

To the 800cc DNS added 0.295moleof formula-I at ambient temperature. The reaction mass was heated at 45-80°C and further slowly charged solution of 0.35 mole benzoic acid in 200cc DNS solution within 30-60min at 45-80°C. The reactions mass was stirred for another 30-60min and gradually cooled to room temperature and after stirring for 60- 90min at room temperature, isolated the product and washed with 400cc DNS. The wet product was dried at 30-60°C to afford 90% of the title compound.

HPLC PURITY: 99.5-100%

CHIRAL PURITY BY HPLC: 99 9-100 % ( S-isomer is less than 0.1%)