WO 2016024289, NILOTINIB, New Patent by SUN PHARMA

NILOTINIB

WO 2016024289, NILOTINIB, New Patent by SUN

SUN PHARMACEUTICAL INDUSTRIES LTD [IN/IN]; 17/B, Mahal Industrial Estate, Off Mahakali Caves Road, Andheri (east), Mumbai 400093 (IN)

THENNATI, Rajamannar; (IN).
KILARU, Srinivasu; (IN).
VALANCE SURENDRAKUMAR, Macwan; (IN).
SHRIPRAKASH DHAR, Dwivedi; (IN)

The present invention provides novel salts of nilotinib and polymorphs thereof. The acid addition salts of nilotinib with benzenesulfonic acid, butanedisulfonic acid, 1-5- naphthalenedisulfonic acid, naphthalene-1-sulfonic acid and 1-hydroxynaphthoic acid; hydrates and anhydrates thereof.

Nilotinib, 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] -benzamide, having the following formula

is marketed under the name Tasigna® in US and Europe. Tasigna contains nilotinib monohydrate monohydrochloride salt and is available as capsules for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Tasigna is also indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib.

Nilotinib is considered a low solubility/low permeability (class IV) compound in the Biopharmaceutics Classification System (BCS). Therefore, dissolution of nilotinib can potentially be rate limiting step for in-vivo absorption. It is soluble in acidic media; being practically insoluble in buffer solutions of pH 4.5 and higher.

WIPO publication 2014059518A1 discloses crystalline forms of nilotinib hydrochloride and methods of the preparation of various crystalline solvates of nilotinib hydrochloride including benzyl alcohol, acetic acid and propylene glycol.

WIPO publication 2011033307A1 discloses nilotinib dihydrochloride and its hydrates and method for their preparation.

WIPO publication 2011163222A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts of nilotinib disclosed are hydrochloride, fumarate, 2-chloromandelate, succinate, adipate, L-tartrate, glutarate, p-toluenesulfonate, camphorsulfonate, glutamate, palmitate, quinate, citrate, maleate, acetate, L-malate, L-aspartate, formate, hydrobromide, oxalate and malonate.

WIPO publication number 2011086541A1 discloses a nilotinib monohydrochloride monohydrate salt and methods for preparing.

WIPO publication number 2010054056A2 describes several crystalline forms of nilotinib hydrochloride.

WIPO publication number 2007/015871A1 discloses the preparation of nilotinib salts and crystalline forms thereof. The salts are mixtures of nilotinib and one acid wherein the acids are selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, sulfonic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sul- fonic acid, citric acid, fumaric acid, gentisic acid, malonic acid, maleic acid, and tartaric acid.

WIPO publication number 2007015870A2 discloses several nilotinib salts including amorphous and crystalline forms of nilotinib free base, nilotinib HC1 and nilotinib sulfate along with their hydrate and solvates.

EXAMPLES:

Example 1: Preparation of nilotinib benzenesulfonate crystalline Form I

Nilotinib base (1 g) was suspended in water (20 ml). A solution of benzenesulfonic acid (0.4 g) in water (3ml) was added and the content was heated at 60 °C for 2-3 h. The mixture was cooled to 25-30 °C, filtered, washed with water (3 x 5 ml) and dried under vacuum for 2 h at 50-55 °C.

1H NMR (500 MHz, DMSO-d6) δ 2.40 (s,3H), 2.42 (s,3H), 7.35-7.37 (m,3H), 7.51-7.66 (m,5H),7.83 (d,lH), 7.96 (s,lH),8.08 (s,lH),8.30 (s,lH) 8.39 (s,lH),8.54 (d,lH), 8.61 (d,lH), 8.64 (s,lH), 8.75 (d,lH), 9.25 (s,lH), 9.34 (d,lH), 9.61 (s,lH), 10.84 (s,lH).

The salt provides an XRPD pattern substantially same as set forth in FIG. 1.

Example 2: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (100 g) was dissolved in 20 % water in THF solution (2000 ml) at 60-65 °C and insoluble matter was filtered. The filtrate was concentrated under vacuum below 60 °C. Filtered water (1000 ml) was added to the reaction mixture and it was heated at 50-55 °C, followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution (28.6 ml) at same temperature. The content was stirred at 50-55 °C for 2-3h. Reaction mixture as cooled to 25-30 °C and product was filtered, washed with water (200 ml x 2) and dried in air oven at 50-55 °C (yield: 115 g).

Sun Pharma managing director Dilip Shanghvi.

Purity (by HPLC):99.76%

1H NMR (400 MHz,DMSO-d6) δ 1.63-1.66(m,2H), 2.40(d,3H),2.42(s,3H),2.43-2.47(m,2H), 7.51-7.62(m,3H),7.85(dd,lH),7.96(s,lH),8.08(s,lH),8.34(s,lH),8.38(d,lH),8.52-8.55(m,lH), 8.60-8.62 (m,2H), 8.75(d,lH), 9.25(S,1H),9.34(S,1H),9.59(S,1H),10.86(S,1H)

Water content: 7.95 %.

The salt has a XRPD pattern substantially same as set forth in FIG. 2.

Example 3: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form II

Nilotinib base (300 g) was suspended in methanol (3000 ml) and aqueous hydrochloric acid was added to get pH less than 2. Reaction contents were heated at reflux and was filtered and washed with methanol (100 ml). 5% (w/w) NaOH (1200 ml) solution was added at 40-45 °C within 15 min, reaction mixture was stirred for 2h. Product was filtered, washed with water

(300 ml x 3) and dried for lh. Wet material was suspended in water (3000 ml), heated at 50- 55 °C followed by addition of 1,4-butanedisulfonic acid -60% aqueous solution. The reaction mixture was stirred at 50-55°C for 2hrs. Product was filtered at room temperature, washed with water (500 ml x 2) and dried in air oven at 50-55 °C (yield: 293 g).

Purity (by HPLC): 99.88 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.75-1.78(m,2H), 2.36(d,3H),2.38(s,3H),2.69- 2.72(m,2H),7.45(d,lH),7.68(d,lH),7.83(s,lH),7.88(dd,lH),7.97(s,lH),8.16-8.19(m,lH), 8.35

(s,2H), 8.63(d,lH),8.68(d,lH),9.04(d,lH),9.21(d,lH),9.53(br s,lH),9.69(d,lH)10.80 (s,lH)

Water content: 6.44 %

Example 4: Preparation of nilotinib butanedisulfonate (2: 1) crystalline Form III

Nilotinib butanedisulfonate (210g) was dissolved in acetic acid water mixture (50:50) (2520 ml) at 75-80 °C and was filtered to remove insoluble matter and washed with acetic acid water mixture (50:50) (210 ml). Water (3150ml) was added to the filtrate and stirred first at room temperature and then at 0-5 °C. Product was filtered and washed with water. Material was dried in air oven at 70-75 °C. Dried material was leached with methanol (3438 ml) at reflux temperature, filtered and dried in air oven 70-75°C (yield: 152.6 g)

Purity (by HPLC): 99.89 %

1H NMR (400 MHz,DMSO-d6+TFA-dl) δ 1.73-1.77(m,2H), 2.40(s,6H),2.67-2.70(m,2H), 7.50 (d,lH), 7.70(d,lH), 7.88-7.92(m,2H), 8.07(s,lH),8.23 (dd,lH), 8.34(s,2H), 8.67 (d,lH), 8.72 (d,lH), 9.09(d,lH), 9.23 (s,lH), 9.54(d,lH), 9.74(d,lH), 10.86(s,lH).

Water content: 0.61 %

The salt provides an XRPD pattern substantially same as set forth in FIG. 3.

Example 5: Preparation of crystalline form of nilotinib butanedisulfonate (2: 1)

Crystalline Nilotinib butanedisulfonate (1 g) of Example 2 was suspended in methanol (20 ml) and was stirred at reflux for 60 min. The mixture was cooled to room temperature. Solid was filtered, washed with methanol (2 ml x 3) and dried in air oven at 70-75°C (yield: 0.8 g)

Example 6: Preparation of nilotinib butanedisulfonate (1: 1) crystalline Form IV

Nilotinib base (20 g) was suspended in methanol (800 ml) and 1,4-butanedisulfonic acid -60

% aqueous solution (6 ml) was added at 50-55 °C, and was filtered to remove insoluble matter. Filtrate was stirred at room temperature for 2-3 h. Product formed was filtered, washed with methanol (20 ml x 2) and dried the product in air oven at 70-75 °C (yield: 18.4 g).

Purity (by HPLC):99.86 %

1H NMR (400 MHz,DMSO-d6) δ 1.64-1.68(m,4H), 2.47-2.5 l(m,4H), 2.41(s,3H), 2.42(d,3H), 7.52(d,lH), 7.83-7.89(m,2H), 7.99(s,lH), 8.15(s,lH), 8.36 (d,lH), 8.39(s,lH), 8.65-8.66(m,2H), 8.79(d,lH), 8.89(br s,lH), 9.36(s,lH), 9.41(br s,lH), 9.74(d,lH), 10.91(s,lH).

The salt has XRPD pattern substantially same as set forth in FIG. 4.

Example 7: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (2: 1) crystalline Form V

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.4 g; 0.6 eq.) in water (5ml) was added and the content was heated at 50-55 °C for lh. The mixture was cooled to 25-30 °C, filtered and washed with water (10 ml). The product was dried in air oven at 50-55°C (yield: 1.2 g).

1H NMR (400 MHz,DMSO-d6) δ 2.39 (s,3H), 2.42 (s,3H), 7.45-7.61 (m,4H),7.84 (d,lH), 7.97(s,2H),8.08 (m,lH),8.31 (s,lH) 8.38 (s,lH),8.55 (d,lH), 8.63 (s,2H), 8.75 (s,lH), 8.92 (d,lH), 9.26 (s, 1H), 9.34 (s,lH),9.62 (s,lH), 10.85 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 5.

Example 8: Preparation of nilotinib 1,5-napthalenedisulfonic acid salt (1: 1) crystalline Form VI

Nilotinib base (1 g) was suspended in water (20 ml). A solution of 1,5-napthalenedisulfonic acid (0.8 g; 1.2eq) in water (5 ml) was added and the content was heated at 50-55 °C for 1 h. The mixture was cooled to 25-30 °C, filtered, washed with water (10 ml) and dried in air oven at 50-55 °C (yield: 1.4g).

1H NMR(400 MHz,DMSO-d6) δ 2.40 (s,3H),2.41 (s,3H), 7.43-7.52 (m,3H),7.61 (d,lH), 7.85-7.99(m,5H),8.11 (s,lH),8.34 (s,2H), 8.64-8.67 (m,2H), 8.89-8.92 (m,4H),9.40(d,2H), 9.72 (s,lH), 10.87 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 6.

Example 9: Preparation of nilotinib napthalene-1- sulfonic acid salt crystalline Form VII Nilotinib base (1 g) was suspended in water (10 ml) and heated to 50-55 °C. A solution of napthelene-1 -sulfonic acid and methanol (10 ml) was added to it and heated at 70-75 °C for 30 min. The mixture was cooled to 25-30 °C and stirred for 10 min. The product was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1-2 h at 50-55 °C.

1H NMR (400 MHz,DMSO-d6) δ 2.41 (s,3H),2.42 (s,3H), 7.46-7.58 (m,5H), 7.70-8.00 (m,7H)8.11(s,lH)8.31(s,lH),8.37(s,lH),8.63-8.66 (m,3H), 8.81-8.89 (m,2H), 9.31 (s,lH), 9.37 (d,lH), 9.71 (d,lH), 10.86 (s,lH)

The salt has a XRPD pattern substantially same as set forth in FIG. 7.

Example 10: Preparation of nilotinib l-hydroxy-2-napthoic acid salt crystalline Form VIII Nilotinib base (1 g) was suspended in water (20 ml) and heated to 50-55 °C. l-Hydroxy-2-napthoic acid was added to it and the content was heated at 50-55 °C for 1 h. Methanol (5 ml) was added to the mixture and stirred for 30 min. The content was filtered, washed with water (2 x 2 ml) and dried under vacuum for 1 h at 50-55 °C.

1H NMR (400 MHz, DMSO-d6) δ 2.25 (s,3H), 2.41 (s,3H), 7.40-7.92 (m,l lH), 8.23-8.73 (m,8H), 9.24 (s,lH), 9.34(s,lH), 10.70 (s,lH).

The salt has a XRPD pattern substantially same as set forth in FIG. 8.

NILOTINIB

SYSTEMATIC (IUPAC) NAME
4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl]-3- [(4-pyridin-3-ylpyrimidin-2-yl) amino]benzamide
CLINICAL DATA
TRADE NAMES	Tasigna
AHFS/DRUGS.COM	monograph
MEDLINEPLUS	a608002
LICENCE DATA	EMA:Link, US FDA:link
PREGNANCY CATEGORY	AU: D US: D (Evidence of risk)
LEGAL STATUS	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
ROUTES OF ADMINISTRATION	Oral
PHARMACOKINETIC DATA
BIOAVAILABILITY	30%[1]
PROTEIN BINDING	98%[1]
METABOLISM	Hepatic (mostly CYP3A4-mediated)[1]
BIOLOGICAL HALF-LIFE	15-17 hours[1]
EXCRETION	Faeces (93%)[1]
IDENTIFIERS
CAS NUMBER	641571-10-0(base)
ATC CODE	L01XE08
PUBCHEM	CID 644241
IUPHAR/BPS	5697
DRUGBANK	DB04868
CHEMSPIDER	559260
UNII	F41401512X
KEGG	D08953
CHEBI	CHEBI:52172
CHEMBL	CHEMBL255863
PDB LIGAND ID	NIL (PDBe, RCSB PDB)
CHEMICAL DATA
FORMULA	C28H22F3N7O
MOLAR MASS	529.5245 g/mol

//////////////WO 2016024289, WO-2016024289, NILOTINIB, New Patent,  SUN

Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)C(=O)Nc4cc(cc(c4)n5cc(nc5)C)C(F)(F)F

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WO 2016024284, New Patent, MIRABEGRON, Wanbury Ltd

WO 2016024284, New Patent, MIRABEGRON, Wanbury Ltd

WANBURY LTD. [IN/IN]; BSEL tech park, B wing, 10th floor, sector 30A opp. Vashi Railway Station, Vashi Navi Mumbai 400703 Maharashtra (IN)

DR. NITIN SHARADCHANDRA PRADHAN; (IN).
DR. NILESH SUDHIR PATIL; (IN).
DR. RAJESH RAMCHANDRA WALAVALKAR; (IN).
MR. NILESH SUBHASH KULKARNI; (IN).
MR. SANTOSH NAMDEV RAWOOL; (IN).
MR. PURUSHOTTAM EKANATH AWATE; (IN)

LEFT , DR K CHANDRAN, DIRECTOR WANBURY

MR ASOK SHINKAR

The present invention relates to a novel process for preparation of Mirabegron of Formula (I) using intermediates of Formula (II), (IIIa), (Illb) and (IV).

The present invention relates to a process for preparation of Mirabegron of Formula

(I).

 

Formula (I)

The present invention further relates to the preparation of Mirabegron of Formula (I) by using compounds of Formula (II), (Ilia), (Illb) and (IV)

 

Formula (II)

 

Formula (IlIa) Formula (Illb)

Formula (IV)

Furthermore, the present invention relates to process for preparation of compound of Formula (II), (Ilia), (Illb) and (IV).

Background of the invention:

Mirabegron is chemically known as 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleactamide and is marketed under trade name Myrbetiq.

Mirabegron is a drug used for treatment of overactive bladder. It was first disclosed in US 6,346,532, wherein (R)-Styrene oxide is reacted with 4-nitrophenyl ethyl amine hydrochloride to obtain (R)-l- phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol, the later is then protected with BOC anhydride and subjected to reduction in the presence of Pd/C to yield N-[2-(4-Aminophenyl)ethyl]-N-[(2R)-2-hydroxy-2-phenylethyljcarbamic acid tert-butyl ester. Thus formed compound was then coupled with (2-amino-l,3-thiazol-4yl) acetic acid to obtain BOC protected Mirabegron which is de-protected to give Mirabegron hydrochloride.

The synthetic route proposed in US 6,346,532 is presented in Scheme-I.

Scheme-I

The major draw-backs of the presented synthetic scheme are as follows:

1. Less atomic efficiency

2. Low yield and extensive impurities formations

3. Use of expensive and sensitive protecting agents

4. Column chromatographic techniques for purifications of intermediates.

One more synthetic route for the preparation of Mirabegron have been proposed US 6,346,532, however it is not exemplified.

US 7,342,117 disclose a process for preparation of Mirabegron. The process involves the step of condensation of 4-nitrophenyl ethylamine and (R)- mandelic acid in presence of tri ethylamine, hydroxybentriazole and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide in N,N-dimethylformamide to obtain compound of Formula (A). The second step involves conversion of compound of Formula (A) to compound of Formula (B) in presence of l,3-dimethyl-2-imidazolidone and borontetrahydro fluoride in tetrahydrofuran. In third step, compound of Formula (B) is subjected to reduction using 10% palladium-carbon in methanol to afford (R)-2-[[2'-(4-aminophenyl)-ethyl amino] -1-phenylethanol (Formula IV), which was further condensed with 2-aminothiazol-4-yl acetic acid in presence of l-(3-dimethylaminopropyl)-3 -ethyl carbodiimide and hydrochloric acid in water to obtain Mirabegron of Formula (I). The schematic representation is as Scheme-II

 

Another patent application CN103193730, discloses a novel process for preparation of Mirabegron wherein the amino group of 2-aminothiazole-5-acetic acid is protected with a protecting group and is condensed with 4-amino phenyl ethanol to obtain an intermediate (A); which on further oxidation yields intermediate (B). The intermediate B is subjected to reductive amination with (R)-2-amino-l -phenyl ethanol and deprotection, simultaneously to yield Mirabegron. The schematic representation is as Scheme-Ill.

 

Formula (I)

Scheme-Ill

Other references wherein process for preparation of Mirabegron are disclosed CN103387500 and CN103232352.

Most of the prior art reported for preparation of Mirabegron uses expensive and sensitive protecting agents thereby making process less feasible on industrial scale. Furthermore, the yield and purity of Mirabegron obtained by the processes known in art is not satisfactory. It is well known fact that pharmaceutical products like Mirabegron should have high purity due to the therapeutic advantages and also due to the stringent requirements of regulatory agencies. The purity requirements can be fulfilled either by avoiding the formation of by-products during the process or by purifying the end product of the process. The inventors of present invention have skillfully developed the process to provide Mirabegron with unachieved level of purity. Furthermore, the process of present invention is simple, industrially viable, and economic and avoids unfavorable reaction conditions.

According to present invention, the process for preparation of compound of Formula (IV), is depicted in Scheme IV

The present invention further relates to a process for preparation of Mirabegron of Formula (I)

The schematic reaction scheme of Mirabegron according to present invention is depicted in Scheme-V.

 Wherein R is -OH or -CI

The detail of the invention provided in the following examples is given by the way of illustration only and should not be construed to limit the scope of the present invention.

EXAMPLES

Example 1: Preparation of [2-(formylamino)-l,3-thiazol-4-yl]acetyl chloride; Formula (V); wherein R is -CI

20g of [2-(formylamino)-l,3-thiazol-4-yl]acetic acid was added to 250 ml of methylene dichloride and the mixture was cooled to -10°C followed by lot wise addition of 25g of phosphorous pentachloride. The mixture stirred while maintaining temperature of -10°C for 2-3 hours. After confirming completion of reaction, the product was filtered out, washed with methylene dichloride and dried to obtain 24g (Yield: 92%) of compound of Formula (V); wherein R is -CI

Example 2: Preparation of 4-nitrophenyl-[2-(formylamino)-l,3-thiazol-4-yl]acetate; Formula (IlIa)

2g of p-nitrophenol was added to 40ml of methylene chloride and 4.963g of potassium carbonate, the mixture was cooled to 10-15°C followed by lot wise addition of 3.95g of compound of Formula (V) of example 1. After confirming completion of reaction, 5.87g (Yield: 99%) of compound of Formula (Ilia) was isolated. The obtained compound has been identified by;

HNMR(D₂0 Exchange)

8.614 (S,lH),7.359(d,2H),8.119(d,2H),6.561(S,lH),3.765(S,2H).

Example 3: Preparation of (2-amino-l,3-thiazol-4-yl)acetyl chloride; Formula (VI); wherein R is -CI

5g of (2-amino-l,3-thiazol-4-yl)acetic acid was added to 50 ml of methylene dichloride with few drops of dimethylformamide and 6g of oxalyl chloride at temperature ranging from 0-5°C. the mixture was maintained at 0-5°C for 4-5 hours and after completion of reaction, solid mass was filtered out, washed with methylene dichloride and dried to afford 5g (Yield: 89%) of compound of Formula (VI); wherein R is -CI

Example 4: Preparation of 4-nitrophenyl-(2-amino-l,3-thiazol-4-yl)acetate; Formula (Illb)

2g of p-nitrophenol was added to 40ml of methylene chloride and 4.96g of potassium carbonate, and the mixture was cooled to 10-15 °C followed by lot wise addition of 3.95g of compound of Formula (VI) prepared in example 3. After confirming completion of reaction, 6.18g (Yield: 99%) of 4-nitrophenyl-(2-amino-l,3-thiazol-4-yl)acetate of Formula (Illb) was isolated.

The obtained compound has been identified by

HNMR ( D₂O Exchange)

7.359(d,2H),8.1 19(d,2H),6.425(S,lH).3.775(S,2H).

Example 5: In-situ preparation of (lR)-2-[[2-(4-aminophenyl)ethyl]amino]-l-phenylethanol or its hydrochloride salt, of Formula (IV)

Step I - Preparation of (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide of Formula (IX)

(R)-2-hydroxy-2-phenylacetic acid (75g), triethylamine (50g), hydroxybenzotriazole (HOBt) (33.3g) and l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC.HC1) (50g) were added to a mixture of 2-(4-nitrophenyl)ethylamine hydrochloride (100g) in Ν,Ν-dimethylformamide (375ml) at 25-30°C. The mixture was stirred for 30 minutes followed by addition of another lot of HOBt (33.3g) and EDC.HC1 (50g) in reaction mixture. The reaction mixture was maintained at 25-30°C for 15 hours under stirring. After completion of reaction, water (1850ml) was added to the reaction mixture and stirred. Subsequently, ethyl acetate (1500ml) was added to the reaction mixture at 25-30°C and stirred. The organic phase was separated from aqueous phase, and was washed sequentially with 1M HC1 solution, 20%aqueous potassium carbonate solution and water. The organic solvent was distilled out under reduced pressure to obtain residue comprising of (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl] -2 -phenyl ethanamide of Formula (IX)

Step II - Preparation of (2R)-2-hydroxy-N-[2-(4-aminophenyl)ethyl]-2-phenylethanamide of Formula (X)

The residue from step I, methanol (740ml) and Raney Nickel (14.8g) were charged into an autoclave vessel, 10 kg/cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and the mixture was maintained under stiring 6 hours. Reaction mixture filtered through hyflo bed. Distilled off the solvent completely from the filtrate under reduced pressure to obtain residue comprising (2R)-2-hydroxy-N-[2-(4-aminophenyl)ethyl]-2-phenylethanamide of Formula (X)

Step III - Preparation of (lR)-2-[[2-(4-aminophenyl)ethyl]amino]-l-phenylethanol dihydrochloride salt, of Formula (IV)

The residue of step II was added in tetrahydrofuran (665ml) and the mixture was cooled to -5 to 0°C. To this cooled mixture was then successively added sodium borohydride (56.26g) and BF3-diethyl ether (466g), and the mixture was stirred for 15 minutes. The temperature of reaction mixture was gradually increased to 50-55°C and was maintained under stirring for 5 hours. After completion of reaction, the reaction mixture was cooled to 0-5°C and 50% sodium hydroxide solution was added till pH is basic. The temperature of reaction mixture is then raised to 25-30°C followed by addition of ethyl acetate (500ml). The organic layer was separated and subjected to distillation to afford a residue. To the residue was added isopropyl alcohol (665ml) and mixture was refluxed for 30 minutes. The mixture was then allowed to cool to 40-45°C, isopropyl alcohol hydrochloride (200ml) was added till pH acidic and mixture was stirred for 2 hours to afford precipitate. The precipitate was filtered out and washed with isopropyl alcohol. The wet cake thus obtained was added to 20% aqueous sodium hydroxide solution (till pH basic) followed by addition of dichloromethane (500ml). The organic layer was separated from aqueous layer and was subjected to distillation under reduced pressure to obtain residue. The residue was taken in toluene (500ml), heated to 55-60°C for 30 minutes and cooled to 10-15°C. The precipitate obtained was filtered, washed with toluene and to the wet cake afforded was added isopropyl alcohol (665ml). The mixture was refluxed for 30 minutes and then cooled to 50-55°C. At 50-55°C slowly isopropyl alcohol hydrochloride (200ml) till pH acidic was added and mixture was stirred for 2 hours to obtain precipitate. The precipitate was filtered out, washed with isopropyl alcohol and dried to get (lR)-2-[[2-(4-aminophenyl)ethyl]amino]-l-phenylethanol dihydrochloride salt, of Formula (IV)

Yield-70%

HPLC Purity: 98%

Example 6: Alternate method for preparation of (2R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylethanamide of Formula (IX)

Step I - A mixture of (R)-2-hydroxy-2-phenylacetic acid (lOg), dichloromethane (50ml) and triethylamine (24ml) was cooled to 0-5°C and slowly para-toluene sulfonyl chloride (12.53g) was added to it. The temperature of reaction mixture was raised to 25-30°C and maintained for 12 hours. After completion of reaction, water (100ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. The organic phase was separated and distills out completely under reduced pressure to obtain [(R)-2-hydroxy -2-phenyl acetic tosyl ester].

Yield-56%

Step II - 2-(4-nitrophenyl)ethylamine hydrochloride (6g) was added to dichloromethane (50ml) and stirred for 30 minutes at 25-30°C. The mixture was

then cooled to 0-5 °C and triethylamine (13ml) was added. To say cooled mixture was then slowly added a mixture of (R)-2-hydroxy -2-phenyl acetic tosyl ester (lOg) and dichloromethane (50ml). The temperature of reaction mixture was then raised to reflux temperature and maintained for 5 hours. After completion of reaction, water (50ml) was added to the reaction mixture and the mixture was stirred for 15 minutes. The organic phase was separated and distill out completely under reduced pressure to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide

Yield-70%, Purity-96%

Example 7: Preparation of compound of Formula (II) from compound of Formula (V); wherein R is -OH

1.58g of [2-(formylamino)-l,3-thiazol-4-yl]acetic acid of Formula (V) was added solution of (1R )-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) in water (2g of Formula (IV) in 50ml water) followed by addition of 0.66g concentrated hydrochloric acid and 3.27g of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride. The mixture was stirred at 25-30°C for 0.5 hours. After completion of reaction, pH was adjusted to 8-9 using aqueous saturated solution of sodium carbonate. The solid precipitated out was filtered, washed with water and dried to obtain 2.1g of compound of Formula (II). (Yield: 72%) The obtained compound has been identified by HNMR

2.502(m,4H),2.599(m,2H),3.685(S,2H),4.9(S, NH protons),7.01(m, 10H, aromatic), 8.54(S,1H), 10.0(S, -OH proton),

HNMR(D20 Exchange) 2.502(m,4H),2.60(m,2H),4.57(m,lH),7.0(m, 10H, aromatic), 8.43(S,1H)

Example 8: Preparation of compound of Formula (II) from compound of Formula (V); wherein R is -CI

lOg of ( 1R)-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5), was added to 150ml of acetonitrile with 16.17g of potassium carbonate and the mixture was cooled to 10-15°C. 18.8g of Formula (V) of example 1 was added to above mixture at 10-15°C in lot wise. After completion of reaction, the reaction mixture was concentrated under vacuum and 90ml of water was added for isolation. The product was then filtered out, washed with water and dried to obtain 72g (Yield: 70%) of compound of Formula (II).

Example 9: Preparation of compound of Formula (II) from compound of Formula (IlIa)

5.87g of compound of Formula (IlIa) was added to 40 ml of methylene dichloride with 2.36 g of potassium carbonate and 3.67g of ( 1))-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol (Formula-IV ; prepared by methods known in prior art/ as given in example 5) . The mixture was stirred at 25-30°C for 1 hour. After completion of reaction, the reaction mixture was concentrated followed by addition of 60 ml of water to isolate lg of compound of Formula (II).

Example 10: Insitu preparation of compound of Formula (II) without isolation of compound of Formula (IlIa)

2g of p-nitrophenol was added to 40 ml of methylene chloride with 4.963g of potassium carbonate, and the mixture was cooled to 10-15°C followed by lot wise addition of 3.95g of [2-(formylamino)-l,3-thiazol-4-yl]acetyl chloride of Formula (V) of example 1. After confirming complete formation of compound of Formula (Ilia), 2.36g of potassium carbonate and 3.67g of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1 -phenyl ethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5) was added insitu, and the mixture was stirred at 25-30°C for 1 hour. After completion of reaction, the reaction mixture was concentrated followed by addition of 60 ml of water to isolate lg of compound of Formula (II).

Example 11: Preparation of Mirabegron from compound of Formula (II)

To 2g of compound of Formula (II) was added 30ml of 10% sodium hydroxide and the mixture was stirred at 55-60°C for 3 hours. After completion of reaction, the mixture was cooled to 25-30°C and the solid obtained was filtered, washed with water and dried to yield 1.3g of Mirabegron. (Yield: 70%)

Example 12: Preparation of Mirabegron from compound of Formula (Illb)

6.18g of 4-nitrophenyl-(2-amino-l,3-thiazol-4-yl)acetate was added to 40ml of methylene dichloride with 2.36g of potassium carbonate and 3.65g of (1R)-2-{ [2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5), and the mixture was stirred at 25-30°C for 1 hour. After completion of reaction, solid was filtered out, washed with methylene dichlrode and dried to yield lg of Mirabegron of Formula (I).

Example 13: Insitu preparation of Mirabegron without isolation of compound of Formula (Illb)

To 40ml of methylene chloride was added 2g of p-nitrophenol and 4.96g of potassium carbonate, and the mixture was cooled to 10-15°C followed by lot wise addition of 3.95g of compound of Formula (VI) prepared in example 3. After confirming complete formation of compound of Formula (Illb), 2.36g of potassium carbonate and 3.65g of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) (prepared by methods known in prior art/ as given in example 5) was added insitu, and the mixture was stirred at 25-30°C for 1 hour. After completion of reaction, After completion of reaction, solid was filtered out, washed with methylene dichlrode and dried to yield lg of Mirabegron of Formula (I).

Example 14: Preparation of Mirabegron from compound of Formula (VI); wherein R is -CI

To 20ml of acetone was added 2g of (l/?)-2-{[2-(4-aminophenyl)ethyl]amino}-l-phenylethanol of Formula (IV) and 2.15g of potassium carbonate, and the mixture was cooled to 10-15°C followed by addition of (2-amino-l,3-thiazol-4-yl)acetyl chloride of Formula (VI). After completion of reaction, acetone was concentrated under vacuum and 90ml of water was added for for isolation. The product was then filtered out, washed with water and dried to obtain 2g (Yield: 70%) of Mirabegron.

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WO 2016020324, BASF AG, Vismodegib , New patent

WO 2016020324, BASF AG, vismodegib , new patent


 

WO2016020324,  MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS
BASF SE [DE/DE]; 67056 Ludwigshafen (DE)
VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)


The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.
Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),
Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

formula 1
Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).
The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.
The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.
Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.
Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.
The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).
The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.
A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.
Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.
Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy
.
Example 1 :
314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.
TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).
H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).


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