The present invention relates to an industrially feasible and cost effective process for the preparation of Betrixaban maleate having Formula IX.

HOOC. J[
HOOC
Formula IX Betrixaban Maleate
BACKGROUND OF THE INVENTION
Betrixaban is chemically known as N-(5-chloropyridin-2-yl)-2-([4-(N,N-dimethyl carbamimidoyl) benzoyl] amino)-5-methoxybenzamide) and has the structure shown in Formula VIII.

Formula VIII
BEVYXXA® contains Betrixaban in the form of its maleate salt, Betrixaban maleate. Betrixaban maleate has the structure shown in Formula IX below.

IJL,
HOOC HOOC
Formula IX Betrixaban Maleatc
BEVYXXA® is indicated for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness, who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE. It is available in 40 mg and 80 mg strengths as capsule dosage forms.
A class of benzamide based compound as specific factor Xa inhibitor including Betrixaban and pharmaceutically acceptable salts thereof are disclosed in the U.S. Patent No. 6,376,515 and U.S. Patent No. 8,518,977 respectively. According to one method of U.S. Patent No 6,376,515, 5-methoxy-2-nitro-benzoyl chloride or 5-methoxy-2-nitro-benzoic acid reacts with 5-chloro-pyridin-2-amine to obtain 2-nitro-N-(5-chloro-pyridin-2-yl)-5-methoxy benzamide followed by reduction of nitro group using tin chloride to obtain 2-amino-N-(5-chloro-pyridin-2-yl)-5-methoxy benzamide. The resulting benzamide compound then coupled with 4-cyanobenzoyl chloride to obtain N-(5-ChIoropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide which first reacts with HCl in methanol and then with dimethylamine followed by purification of the resulting product with column chromatography to obtain Betrixaban. One drawback of the process is the use of tin chloride during the reduction step leads to the formation of undesirable metal sludge, which poses serious pollution problem. Another drawback of the process is

the use of 4-cyano benzoyl chloride, which itself is unstable and is prepared by reaction of 4-cyano benzoic acid with oxalyl chloride which is a corrosive/hazardous reagent. Further, the use of column chromatography at commercial scale not only increases the solvent consumption, but also makes the process expensive and time consuming.
U.S. Patent No. 7,598,276 discloses Betrixaban maleate as crystalline form and process for its preparation. Similarly, U.S. Patent No. 8,946,269 discloses Betrixaban maleate crystalline form-II, form-Ill, and processes for the preparation thereof.
U.S. Patent No 7,598,276 also discloses process for the synthesis of Betrixaban by reacting N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide under basic condition using dimethylamino lithium (generated by reacting n-hexyl lithium with dimethylamine in THF) to obtain Betrixaban in 76% yield along with 1% of deschloro impurity. The said patent also discloses process for the synthesis of 2-amino-N-(5-chloro-pyridin-2-yl)-5-methoxy benzamide, which is the precursor of N-(5-chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide by hydrogenating 2-nitro-N-(5-chloro-pyridin-2-y])-5-methoxy benzamide using 5% Pt/C at temp 28°C at pressure of 30 psi for 16.5 hrs. This hydrogenation step results in the formation of desired product along with des-chloro impurity of Formula "M" of about 0.083%. The main drawback of the process is use of harsh reaction condition and longer reaction time (16 hrs) during the hydrogenation step which not only create operational unsuitability, rather the intermediate compound and Betrixaban product obtained according to the said process needs multiple purification which involves handling of large volume of solvent at commercial scale result in the effluent generation, low yield and high production cost. Further, in the said patent, in Example 1, gram scale process reports about 45% yield and Kg scale process reports about 85% yield respectively.

o fH3CW
(in i,
UN
0,N
TO
"^Sn
Formula

(b) reducing the compound of Formula III to the compound of Formula IV;
,!Nxx,
Formula IV
(c) coupling of the compound of Formula IV with 4-cyanobenzoic acid of Formula V to obtain compound of Formula VI;

OCH,

CN

NC

HN

COOH
Formula V

XL
Formula VI

(d) amidation of compound of Formula VI either with Turbo Grignard or Grignard reagent to obtain Betrixaban Hydrochloride of the Formula VII;
10 of 26


0C113
CI

Formula VII
(e) converting Betrixaban Hydrochloride of the Formula VII to Betrixaban free base of the Formula VIII and


HN
'OCH.
NH

Formula VIII
(f) converting Betrixaban free base of the Formula VIII to Betrixaban maleate of Formula IX.

Nil
OCH3

HN
a
UN

H00s L
HOOC

CI

Formula IX Betrixaban Maleate
11 of 26

In step (a), coupling of 5-methoxy-2-nitrobenzoic acid of Formula I with 5-chloropyridin-2-amine of Formula II is carried out in presence of coupling reagent, such as an amide-coupling reagent. Common amide coupling reagents include, but are not limited to, phosphorous oxychloride (POCh), 2-propanephosphonic acid anhydride (T3P), 1, 1'-carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-l,2,5-triazine (CDMT), carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3'-dimethylaminopropyl) carbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), preferably phosphorous oxychloride. The carbodiimides may be used alone or in conjunction with other reagents such as dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt). This coupling reaction is carried out in presence of solvents selected from the group comprising of nitrile, amide, ether, ester, chlorinated solvent, ketone solvent, hydrocarbon and the like such as acetonitrile (ACN), propionitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMAc), tetrahydrofuran (THF), N-Methyl-2-pyrrolidone (NMP), toluene, dichloromethane (DCM), acetone, ethyl acetate (EtOAc) or mixtures thereof preferably in acetonitrile. This coupling reaction may be carried out in presence of a base selected from the group comprising of pyridine, triethylamine (TEA), diisopropylethylamine (DIEA), dimethylaminopyridine (DMAP), N-methylmorpholine (NMM) or mixtures thereof preferably in pyridine. This coupling reaction is carried out at temperature of between -10°C to room temperature preferably at room temperature.
In step (b), reduction of the compound of Formula III to compound of Formula IV is carried out in presence of hydrogen gas along with metal catalyst. The metal catalysts is selected from Raney Ni, palladium, platinum, or sulfided platinum, rhodium, ruthenium, or compounds or compositions thereof, for example, palladium deposited carbon, barium sulfate or calcium carbonate and the like. This reaction is carried out in presence of alkanolamine selected from the group comprising of ethanolamine, diethanolamine, triethanolamine and the like. This reaction is preferably carried out using Raney Ni as metal catalyst along with ethanolamine in presence of hydrogen gas.
12 of 26

This reduction reaction is carried out at temperature 20°C to 40°C, and preferably at 30°C to 40°C, and more preferably at 35°C to 40°C using 0.1 to 1 Kg/cm"2 hydrogen pressure under inert atmosphere. This reduction reaction is carried out in solvent selected from the group comprising of ester such as ethyl acetate, isopropyl acetate and the like; chlorinated solvents such as methylene chloride, chloroform and the like; alcohols such as methanol, ethanol, propanol and the like; acid solvent such as formic acid, acetic acid and the like; water or mixtures thereof preferably ethyl acetate.
The inventors of the present invention have unexpectedly found that when the reduction of compound of Formula III to compound of Formula IV is carried out using Raney-Ni along with ethanolamine in suitable solvent at controlled hydrogen pressure, compound of Formula IV is obtained in high purity (purity more than 99%) with the controlled formation of impurities, disclosed in the prior arts.
In step (c), coupling of the compound of Formula IV with 4-cyanobenzoic acid of Formula V is carried out in presence of coupling reagent, such as an amide-coupling reagent. Common amide coupling reagents also include, but are not limited to, 1,1'-carbonyldiimidazole (CDI), phosphorous oxychloride (POCh), 2-propanephosphonic acid anhydride (T3P), 2-chloro-4,6-dimethoxy-l,2,5-triazine (CDMT), carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), and l-ethyl-3-(3'-dimethylaminopropyl) carbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) preferably 1,1'- carbonyldiimidazole. The carbodiimides may be used alone or in conjunction with other reagents such as dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt). This coupling reaction is carried out in solvents selected from the group comprising of dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), toluene, cyclohexane, acetonitrile (ACN), tetrahydrofuran (THF), dichloromethane (DCM), acetone, ethyl acetate (EtOAc) or mixtures thereof and preferably in dimethylacetamide. This coupling reaction is carried out at temperature of 40°C to 60°C and preferably at 50°C to 55°C Thus, in step (c) the inventor has avoided the use of unstable 4-cyano benzoyl chloride (prepared by
13 of 26

reaction of 4-cyano benzoic acid with oxalyl chloride) as disclosed in prior arts US 6,376,515 and US 8,518,977, which makes the work step simpler by reducing the additional purification of the desired compound at commercial scale. Apart from this, the inventor utilizes polar aprotic solvent, which not only makes the process safe and simple, rather increases the yield of the desired product (compound of Formula VI) which in turn makes the process cost effective and eco-friendly.
In step (d), amidation of compound of Formula VI is carried using dimethylamine either with Turbo Grignard such as iPrMgCl-LiCl solution or Grignard reagent, preferably with turbo Grignard reagent. During usage of Grignard reagent, LiCl is added to this reaction. Reaction of dimethylamine either with Turbo Grignard or Grignard reagent results in formation of ClMgN(CH3)2 (dimethylamine magnesium chloride), BrMgN(CH3)2 (dimethylamine magnesium bromide), IMgN(CH3)2 (dimethylamine magnesium iodide), ClZnN(CH3)2 (dimethylamine zinc chloride), BrZnN(CH3)2 (dimethylamine zinc bromide), IZnMgN(CH3)2 (dimethylamine zinc iodide), and the like depending upon the type of Turbo Grignard or Grignard reagent used. This reaction is carried out in solvent selected from the group comprising of ethers such as tetrahydrofuran, methyl tetrahydrofuran, ethyl ether, anisole, methyl tert-butyl ether, dimethyl ether, dioxane and the like, hydrocarbon solvents such as toluene, xylene, hexane, heptane, cyclohexane and the like and mixture thereof, preferably in tetrahydrofuran. This reaction is carried out at temperature of-10°C to -30°C, preferably at -10°C to -20°C under inert atmosphere.
Thus according to the present invention, reaction of compound of Formula VI with dimethylamine and Turbo Grignard such as iPrMgCl-LiCl solution or Grignard reagent, not only control the impurity formation mainly desmethyl impurity, rather makes the workup simpler and efficient compared to process as reported in the prior art US 8,524,907.
After the completion of the reaction, it further includes conventional method of separating the product, using acid such as hydrochloric acid or nitric acid for quenching the reaction, and then through the conventional operation such as concentrating, filtering and washing, to obtain Detrixaban hydrochloride.
14 of 26

In step (e), Betrixaban Hydrochloride of the Formula VII is converted to Betrixaban free base of the Formula VIII in presence of base selected from the group comprising of alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates. Preferably, the base is selected from potassium carbonate, sodium carbonate and the like. This reaction is carried out in solvent selected from the group comprising of halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; alcohols such as, methanol, ethanol, propanol, butanol and the like and mixtures thereof and preferably in dichloromethane and methanol mixture.
In step (f), Betrixaban free base of the Formula VIII is converted to Betrixaban maleate of Formula IX in presence of maleic acid. This reaction is carried out in presence of solvent selected from the group comprising of C1-4 alkanol, ketone, ether, water and mixture thereof. Preferably CM alkanol used in this step is selected from the group comprising of methanol, ethanol, propanol, butanol and the like. Ketone is selected from the group comprising of acetone and the like. Ether is selected from the group comprising of methyl-ferZ-butyl ether (MTBE) and the like. This reaction is carried out at temperature of-10°C to 40°C, preferably at 20°C to 25°C.
According to the present invention, Betrixaban maleate prepared according to the present invention is substantially pure and is free of impurities mainly deschloro impurity of Formula M and desmethyl impurity of Formula L.
The term "substantially pure" refers to Betrixaban free base or maleate salt that is at least about 99.3% pure, or 99.5% pure, or 99.7% pure, or 99.9% pure. Purity can be measured by any appropriate method, such as for example, HPLC etc.
15 of 26

Examples:
Synthesis of compound of Formula III (step a)
5-Methoxy-2-nitrobenzoic acid (150 g, 0.76 mol) and 2-amino-5-chloropyridine (97.82 g, 0.760 mol) were taken in acetonitrile (575 mL). Then pyridine (180.6 g, 3.0 eq., 2.28 mol) was also added at room temperature. The reaction mixture was cooled to 10-15°C. Phosphorous oxychloride (140 g, 1.20 eq., 0.91 mol) was added to this reaction mixture at 10-25°C and the addition funnel was rinsed with acetonitrile (25 mL). After complete addition, the reaction mixture was stirred at 20-25°C for 1-2 h and then cooled to 10-15°C and water (600 mL) was added slowly at 10-25°C. The reaction mixture was then warmed to 25-30°C and stirred for 2-3h. The precipitated solid was filtered, washed with water and suck dried at room temperature. The wet solid was triturated with water, solid was filtered, washed with water and sucked to dryness. The wet solid was taken to the next step without any further purification. Purity of the wet solid (HPLC): 99.8%
Synthesis of compound of Formula IV (step b)
The wet solid from the previous step was stirred with ethyl acetate (3750 mL) and ethanolamine (38.73 g) at 25-30°C in an autoclave till a clear solution obtained. A slurry of Raney Ni (29.25 g) in water (750 mL) was added to it under nitrogen atmosphere. The reaction mixture was heated to 35-40°C and hydrogenated under 0.5-1 kg/cm2 hydrogen pressure till completion of the reaction. After completion, the reaction mixture was filtered through hyflo bed and washed twice with a 1:1 mixture of ethyl acetate and water (300 mL each). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was evaporated under vacuum and the traces of ethyl acetate was removed by chasing with methanol. The residual mass was refluxed with methanol (600 mL) for 1 h, cooled to room temperature and further cooled to 0-5°C. After stirring for 2-3 h at 0-5 °C, the precipitated solid was filtered, washed with methanol, sucked to dryness and finally dried under vacuum at 45-50°C for 8-12h to furnish the desired product as yellow colored solid. Yield: 165g,
16 of 26

Yield (%): 78% (combined % yield of steps a and b) HPLC purity: 99.92%
Synthesis of compound of Formula VI (step c)
To a stirred solution of 4-cyanobenzoic acid (103.85 g, 0.70 mol) in dimethylacetamide (490 mL), CDI (114.45g, 0.70 mol) was added at room temperature. After stirring the reaction mixture at room temperature, 2-amino-iV-(5-chloropyridin-2-yl)-5-methoxybenzamide (140 g, 0.50 mol) was added and flushed with dimethylacetamide (70 mL) at ambient temperature. Then the reaction mixture was heated to 50-55°C and stirring continued till completion of the reaction. Methanol (2240 mL) was added to the reaction mixture and was refluxed for 1-2 h. It was cooled to room temperature and stirred for 2-3 h. The solid was filtered, washed with methanol, suck dried and finally dried under vacuum at 60-65°C for 16 h to furnish iV-(5-Chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide as yellowish solid. Yield: 192g, Yield (%): 93.6%. UPLC purity 99.84%.
Synthesis of compound of Formula VII (step d)
To a cold stirred mixture of /vr-(5-Chloropyridin-2-yl)-2-(4-cyanobenzamido)-5-methoxybenzamide (100 g) in 2M dimethylamine solution in tetrahydrofuran (922 mL) was added a solution of 1.3M iPrMgCl-LiCl in THF (1040 mL) at 0-10°C with stirring under nitrogen atmosphere for 2 h and stirred at 0 to 10°C for 1-2 h. After completion, the reaction mixture was added to a 2N aqueous HCl solution (1300 mL) at 0-30°C and pH was adjusted to 1.5-2.5 by 20% aqueous HCl solution. Then reaction mixture was stirred for 1 h at room temperature and separated the layers. Hyflo (20g) was added to the aqueous layer and the organic solvents were distilled off from aqueous later and the residual slurry was diluted with water (400 mL). The reaction mixture was stirred at room temperature for 1-2 h, and the solid was filtered, washed with water and suck dried. The resulting solid was dissolved in the organic layer and was filtered. Solvents evaporated under vacuum from the mother liquor and the traces residual solvent was displaced with
17 of 26

acetone by distillation. The residual mixture was refluxed with acetone (1000 mL) for 2-3 h, gradually cooled to room temperature and stirred for 8 h. The solid was filtered, washed with acetone and sucked to dryness to give Betrixaban Hydrochloride. HPLC purity: 99.9%
Synthesis of compound of Formula VIII (step e)
The suck dried material from above step (d) (Betrixaban Hydrochloride) was stirred in a mixture of methanol (150 mL), DCM (1350 mL) and 20% aqueous K2CO3 (1000 mL) at room temperature for 30 min and separated the layers. The aqueous layer was extracted with DCM at room temperature and the combined organic layers was washed with a mixture of methanol :water (1:5) (600 mL) and finally evaporated to give desired product.
Synthesis of compound of Formula IX (step f)
The residue from above step (e) was reacted with maleic acid (47.65 g) in 25% aqueous ethanol (1600 mL) for 1 h at room temperature to get a clear solution. The reaction mixture was treated with activated charcoal (5g), filtered through hyflo followed by 0.45 ^i filter and washed with aqueous ethanol (200 mL). The filtrate was concentrated under vacuum up to -250 mL residual mass. Water (200 mL) was then added and the mixture was again concentrated. The reaction mass was cooled to 25-30°C and diluted with water (800 mL). After stirring for 2 h at room temperature, the solid was filtered, washed with water and suck dried. The solid finally dried under vacuum at 40-45°C for 12-16 h to furnish the desired Betrixaban maleate as off white crystalline solid. Yield: HOg,
Yield (%): 79% (combined % yield of steps d, e and f) UPLC purity 100%.
While this complete patent application contains the description of the principal inventive concepts. The complete patent application pursuant here to, willfully and particularly describe the preferred embodiments of the present invention.

We claim:

A process for the preparation of Betrixaban maleate of Formula IX comprising the steps of:
(a) coupling of 5-methoxy-2-nitrobenzoic acid of Formula I with 5-chloropyridin-2-amine of Formula II to give compound of Formula III;


OClh
tx

Formula I Formula II

[I
ay.

Formula
(b) reducing the compound of Formula III to the compound of Formula IV;
H,N
Formula IV
(c) coupling of the compound of Formula IV with 4-cyanobenzoic acid of Formula V to obtain compound of Formula VI;

"
NC

CM
■11 Formula V

n
Formula VI

(d) amidation of compound of Formula VI either with Turbo Grignard or Grignard reagent to obtain Betrixaban Hydrochloride of the Formula VII;


OCH,

Formula VII
(e) converting Betrixaban Hydrochloride of the Formula VII to Betrixaban free base of the Formula VIII and

N
.0
UN
OCII,

MM

UN

CI

Formula VIII

(f) converting Betrixaban free base of the Formula VIII to Betrixaban maleate of Formula IX.


OCH
HOOC HOOC

I IN

N^

(31

Formula IX Betrixaban Maleate
2. The process as claimed in claim 1, wherein step (a) is carried out in presence of coupling reagent and a base wherein the coupling reagent is selected from phosphorous oxychloride (POCh), 2-propanephosphonic acid anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), 2-chloro-4,6-dimethoxy-l,2,5-triazine (CDMT), carbodiimides such as N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3'-dimethylaminopropyI) carbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and a base is selected from pyridine, triethylamine (TEA), diisopropylethylamine (DIEA), dimethylaminopyridine (DMAP), N-methylmorpholine (NMM) or mixtures thereof.
3. The process as claimed in claim 1, wherein step (a) is carried out in solvent selected from the group comprising of nitrile such as acetonitrile, propionitrile, amide solvent such as dimethylformamide, dimethylsulfoxide (DMSO), dimethylacetamide (DMAc), ethers such as tetrahydrofuran, chlorinates solvent such as dichloromethane, ketone solvent such as acetone, ester such as ethyl acetate or mixtures thereof.
4. The process as claimed in claim 1, wherein step (b) is carried out in presence of catalyst and alkanolamine wherein the catalyst is selected from the group comprising of Raney Ni, palladium, platinum, sulfided platinum, rhodium, iron, ruthenium and

alkanolamine is selected from the group comprising of ethanolamine, diethanolamine and triefhanolamine.
5. The process as claimed in claim 1, wherein step (c) is carried out in presence of coupling reagent selected from the group comprising of 1,1'- carbonyldiimidazole (CDI), phosphorous oxychloride (POCb), 2-propanephosphonic acid anhydride (T3P), 2-chloro-4,6-dimethoxy-l,2,5-triazine (CDMT), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3'-dimethylaminopropyl) carbodiimide, and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC).
6. The process as claimed in claim 1, wherein step (c) is carried out in solvent selected from the group comprising of dimethylacetamide, dimethylformamide, dimethyl sulfoxide (DMSO), toluene, cyclohexane acetonitrile, tetrahydrofuran, dichloromethane, acetone, ethyl acetate or mixtures thereof
7. The process as claimed in claim 1, wherein step (d) of amidine formation from the compound of Formula VI is carried out in presence of dimethylamine either with Turbo Grignard such as iPrMgCl-LiCl solution or Grignard reagent in solvent selected from the group comprising of tetrahydrofuran, methyl tetrahydrofuran, diethyl ether, anisole, methyl tert-butyl ether, dimethyl ether, dioxane, toluene, xylene, hexane, heptane, cyclohexane or mixture thereof.
8. The process as claimed in claim 1, wherein step (e) is carried out in solvent selected from the group comprising of halogenated hydrocarbon such as dichloromethane, dichloroethane, alcohols such as methanol ethanol, propanol, butanol or mixtures thereof.
9. The process as claimed in claim 1, wherein step (f) is carried out in solvent selected from the group comprising of Ci-4 alkanol, ketones, ethers, water or mixture thereof
10. A process for the preparation of Betrixaban maleate of Formula IX comprising the
steps of:

(a) coupling of 5-methoxy-2-nitrobenzoic acid of Formula I with 5-chloropyridin-2-amine of Formula II to give compound of Formula III;

O2N

T
VOCtf;
nil
a
Formula I Formula II

OCH,
Formula III

(b) reducing the compound of Formula III to the compound of Formula IV by
hydrogenation with metal catalyst and alkanolamine;
Formula IV
(c) coupling of the compound of Formula IV with 4-cyanobenzoic acid of Formula V
with 1,1'- carbonyldiimidazole to obtain compound of Formula VI;

U
COOH
Formula V Formula VI
(d) amidation of compound of Formula VI with Turbo Grignard to obtain Betrixaban Hydrochloride of the Formula VII;

Nil
HC1
O
N'^ci Formula VII

Formula VIII
(e) converting Betrixaban Hydrochloride of the Formula VII to Betrixaban free base of the Formula VIII and


(f) converting Betrixaban free base of the Formula VIII to Betrixaban maleate of Formula IX.

NH I


^X0

HOOC^ IJ
HOOC^
Formula IX