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VARDENAFIL

October 18, 2015 12:48 pm / 1 Comment on VARDENAFIL

VARDENAFIL

Vardenafil hydrochloride (CAS NO.224785-91-5)

Formula	C₂₃H₃₂N₆O₄S
Mol. mass	488.604 g/mol

4-[2-Ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-9-methyl-7-propyl-3,5,6,8-tetrazabicyclo[4.3.0]nona-3,7,9-trien-2-one

Vivanza, Vardenafil (INN), Levitra (TN), STK642629, , LEVITRA

Vardenafil (INN) is a PDE5 inhibitor used for treating erectile dysfunction that is sold under the trade names Levitra (Bayer AG, GSK, and SP) andStaxyn.

Vardenafil was co-marketed by Bayer Pharmaceuticals, GlaxoSmithKline, and Schering-Plough under the trade name Levitra. As of 2005, the co-promotion rights of GSK on Levitra have been returned to Bayer in many markets outside the U.S. In Italy, Bayer sells vardenafil as Levitra and GSK sells it as Vivanza. Thus, because of European Union trade rules, parallel imports might result in Vivanza sold next to Levitra in the EU.

Vardenafil (Levitra) is an oral therapy for the treatment of erectile dysfunction. It is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpus cavernosum is the cGMPspecific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

An orally disintegrating form, marketed as Staxyn, has been gaining approvals in countries such as the United States^[1] and Canada.^[2]

Vardenafil’s indications and contra-indications are the same as with other PDE5 inhibitors; it is closely related in function to sildenafil citrate (Viagra) and tadalafil (Cialis). The difference between the vardenafil molecule and sildenafil citrate is a nitrogen atom’s position and the change of sildenafil’spiperazine ring methyl group to an ethyl group. Tadalafil is structurally different from both sildenafil and vardenafil. Vardenafil’s relatively short effective time is comparable to but somewhat longer than sildenafil’s.

Beyond its indications for erectile dysfunction, vardenafil may be effective in the treatment of premature ejaculation, where it may significantly increase the time from vaginal penetration to ejaculation.^[3]

The common, adverse drug reactions (side-effects) are the same as with other PDE5 inhibitors. The frequent vardenafil-specific side-effect is nausea; the infrequent side-effects are abdominal pain, back pain, photosensitivity, abnormal vision, eye pain, facial edema, hypotension, palpitation,tachycardia, arthralgia, myalgia, rash, itch, and priapism.

One possibly serious, but rare, side-effect with vardenafil is heart attack. Also, in rare cases, vardenafil use may cause priapism, a very painful emergency condition that can cause impotence if left untreated.^[4]

On 18 October 2007, the U.S. Food and Drug Administration (FDA) announced that a warning about possible deafness (sudden hearing loss) would be added to the drug labels of Vardenafil, and other PDE5 inhibitors.^[5]

Vardenafil, as with all PDE5 inhibitors, should not be used by men taking nitrate medications, because combining them with vardenafil might provoke potentially life-threatening hypotension (low blood pressure).

Further, Vardenafil causing lengthening of the QT interval. Therefore it should not be taken by men taking other medications that affect the QT interval (such as amiodarone).

Levitra 20mg Oral Tablet

It is available in 2.5 mg, 5 mg, 10 mg, and 20 mg doses in round orange tablets. The normal starting dose is 10 mg (roughly equivalent to 50 mg of sildenafil). Vardenafil should be taken 1 to 2 hours prior to sexual activity, with a maximum dose frequency of once per day. In some territories, such as the UK, only certain doses may be available.

Vardenafil is also available under the name Staxyn as a tablet which dissolves on the tongue rather than being swallowed in the form of a pill.

STAXYN is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5.

Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula:

STAXYN (vardenafil hydrochloride) Structural Formula Illustration

Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.

LEVITRA

TRIHYDRATE, HCL SALT

US2002137930A

vardenafil hydrochloride is piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, mono -hydrochloride and can be structurally represented by Formula I.

The monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guaosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). It is commercially available in products sold under the brand name LEVITRA formulated as 2.5 mg, 5 mg, 10 mg, 20 mg film-coated tablets.

U.S. Pat. No. 6,362,178 B1 discloses vardenafil, its related compounds and processes for their preparation. The patent describes a process in which vardenafil is obtained by recrystallization in ether in Example 19. Vardenafil produced as per Example 19 is hereinafter referred as “crystalline Form I” of vardenafil. The patent also describes processes for the preparation of its monohydrochloride and dihydrochloride salts, which are formed in a combination of ether and dichloromethane. The patent also describes a process for the preparation of vardenafil monohydrochloride trihydrate.

U.S. Patent Application Publication No. 2005/0203298 also describes a process for the preparation of vardenafil, and its monohydrochloride trihydrate.

Chemical synthesis of vardenafil has mostly been directed to the preparation of the trihydrate of monohydrochloride of vardenafil.

In WO 99/24433, sulphonamide-substituted imidazotriazinones are described as potent inhibitors of either one or more of the cyclic guanosine 3′,5′-monophosphate-metabolizing phosphodiesterases (cGMP PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these cGMP PDEs are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.

According to WO 99/24433, the sulphonamide-substituted imidazotriazinones described therein are prepared from corresponding 2-ethoxyphenyl-substituted imidazotriazinones by reaction with chlorosulphonic acid and subsequent reaction with an appropriate amine, as is illustrated by the following scheme (R¹to R⁶here have the meanings indicated in WO 99/24433):

In this process, highly reactive chlorosulphonic acid has to be used as a reagent. Moreover, the imidazotriazinonesulphonyl chlorides formed as intermediates are sensitive to hydrolysis, which, in particular in the conversion of this preparation process to the industrial scale, can lead to not inconsiderable yield variations.

It was therefore the object of the present invention to make available a process for the preparation of sulphonamide-substituted imidazotriazinones in which the disadvantages of the above process known from the prior art are avoided.

This object is achieved according to the present invention by a process as in claim 1. In particular, in the process according to the invention as in claim 1 the use of chlorosulphonic acid is avoided by introduction of the sulphonic acid via a reaction with sulphuric acid and subsequent reaction with thionyl chloride. Moreover, the reaction with thionyl chloride and the subsequent reaction with an amine is carried out in a one-pot process, so that the imidazotriazinonesulphonyl chloride intermediate, which is sensitive to hydrolysis, does not need to be isolated. By means of this, yield variations on account of partial hydrolysis of this intermediate can be excluded. As a result of these advantages, the process according to the invention is much simpler to carry out on the industrial scale than the process described in WO 99/24433.

………………….

SYNTHESIS

US6362178

2-butyrylamino-propionic acid

EXAMPLE 1A 2-Butyrylaminopropionic acid

22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred for 1 hour at room temperature and for 1 hour at 40° C. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred for 2 hours at −10° C. and for one hour at room temperature.

With ice-cooling, 125 ml of water are added dropwise and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is titrated with acetone and the mother liquor is filtered off with suction. The solvent is removed and the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution and the resulting solution is evaporated to dryness. The residue is taken up in conc. HCl and once more evaporated to dryness. The residue is stirred with acetone, precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.

200 MHz ¹H-NMR (DMSO-d6): 0.84, t, 3H; 1.22, d, 3H; 1.50, hex, 2H; 2.07, t, 2H; 4.20, quin., 1H; 8.09, d, 1H.

EXAMPLE 3A 2-Ethoxybenzonitrile

25 g (210 mmol) of 2-hydroxybenzonitrile are refluxed with 87 g of potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide in 500 ml of acetone overnight. The solid is filtered off, the solvent is removed under reduced pressure and the residue is distilled under reduced pressure. This gives 30.0 g (97%) of a colourless liquid.

200 MHz ¹H-NMR (DMSO-d6): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H; 7.51, dt, 2H.

2-ethoxybenzamidine hydrochloride

EXAMPLE 4A 2-Ethoxybenzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml of toluene, and the suspension is cooled to 0° C. 200 ml of a 2M solution of trimethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until the evolution of gas has ceased. After addition of 29.44 g (200 mmol) of 2-ethoxybenzonitrile, the reaction mixture is stirred at 80° C. (bath) overnight.

With ice-cooling, the cooled reaction mixture is added to a suspension of 100 g of silica gel and 950 ml of chloroform, and the mixture is stirred at room temperature for 30 minutes. The mixture is filtered off with suction, and the filter residue is washed with the same amount of methanol. The mother liquor is concentrated, the resulting residue is stirred with a mixture of dichloromethane and methanol (9:1), the solid is filtered off with suction and the mother liquor is concentrated. This gives 30.4 g (76%) of a colourless solid.

200 MHz ¹H-NMR (DMSO-d6): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H; 7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

EXAMPLE 10A 2-(2-Ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

7.16 g (45 mmol) of 2-butyrylamino-propionic acid and 10.67 g of pyridine are dissolved in 45 ml of THF and, after addition of a spatula tip of DMAP, heated to reflux. 12.29 g (90 mmol) of ethyl oxalyl chloride are slowly added dropwise, and the reaction mixture is refluxed for 3 hours. The mixture is poured into ice-water and extracted three times with ethyl acetate and the organic phase is dried over sodium sulphate and concentrated using a rotary evaporator. The residue is taken up in 15 ml of ethanol and refluxed with 2.15 g of sodium bicarbonate for 2.5 hours. The cooled solution is filtered.

With ice-cooling, 2.25 g (45 mmol) of hydrazine hydrate are added dropwise to a solution of 9.03 g (45 mmol) of 2-ethoxybenzamidine hydrochloride in 45 ml of ethanol, and the resulting suspension is stirred at room temperature for another 10 minutes. The ethanolic solution described above is added to this reaction mixture, and the mixture is stirred at a bath temperature of 70° C. for 4 hours. After filtration, the mixture is concentrated, the residue is partitioned between dichloromethane and water, the organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure.

This residue is dissolved in 60 ml of 1,2-dichloroethane and, after addition of 7.5 ml of phosphorus oxychloride, refluxed for 2 hours. The mixture is diluted with dichloromethane and neutralized by addition of sodium bicarbonate solution and solid sodium bicarbonate. The organic phase is dried and the solvent is removed under reduced pressure. Chromatography using ethyl acetate and crystallization afford 4.00 g (28%) of a colourless solid, R_f=0.42 (dichloromethane/methanol=95:5)

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H; 1.56, t, 3H; 1.89, hex, 2H; 2.67, s, 3H; 3.00, t, 2H; 4.26, quart., 2H; 7.05, m, 2H; 7.50, dt, 1H; 8.17, dd, 1H; 10.00, s, 1H.

EXAMPLE 15A 4-Ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride

At 0° C., 2.00 g (6.4 mmol) of 2-(2-ethoxy-phenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are slowly added to 3.83 ml of chlorosulphonic acid. At room temperature, the reaction mixture is stirred ovemight, and then poured into ice-water and extracted with dichloromethane. This gives 2.40 g (91%) of a colourless foam.

200 MHz ¹H-NMR (CDCl₃): 1.03, t, 3H; 1.61, t, 2H; 1.92, hex, 2H; 2.67, s, 3H; 3.10, t, 2H; 4.42, quart., 2H; 7.27, t, 1H; 8.20, dd, 1H; 8.67, d, 1H; 10.18, s, 1H.

Example 19 2-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

470 mg (1.14 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 20 ml of dichloromethane and cooled to 0° C. 390 mg (3.42 mmol) of N-ethylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed twice with water and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 370 mg (66%) of a colourless solid.

400 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H; 1.59, t, 3H; 1.88, hex, 2H; 2.42, quart., 2H; 2.56, m, 4H; 2.63, s, 3H; 3.00, t, 2H; 3.10, m, 4H; 4.33, quart., 2H, 7.17, d, 1H; 7.88, dd, 1H; 8.44, d, 1H; 9.75, s, 1H.

…………………….

US7977478

EXAMPLE 7 Preparation of the Trihydrate of Vardenafil Monohydrochloride

14 g of vardenafil hydrochloride was taken into a round bottom flask followed by the addition of 70 ml water and the pH of the reaction mass was adjusted using sodium hydroxide to 11 at 30° C. 280 ml of dichloromethane was added to the above reaction mass and the layers were separated. The organic layer was dried over sodium sulfate and the organic layer was transferred into a round bottom flask and subjected to heating for distillation at 40° C. for 1.5 hours. The solid material was transferred into a round bottom flask and 36 ml of a mixture of acetone and water in 12:1 ratio was added with stirring, then 2.2 ml of 36% aqueous hydrochloric acid was added with stirring. The reaction mass was heated to a temperature of about 45° C. and the undissolved particles were removed by filtration. The filtrate was taken into a round bottom flask and cooled to 5° C., maintained for 45 minutes at 3 to 5° C. followed by the filtration of the solid which was then subjected to suction drying and finally dried at 40° C. to yield 9.0 g of the trihydrate of vardenafil monohydrochloride.

……………………..

US20050203298

STARTING COMPOUNDS

Example I Preparation of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo-[5,1-f][2,4]triazin-4-oneIa) Preparation of 2-butyrylaminopropionic acid

A solution of 100 kg of D,L-alanine in aqueous sodium hydroxide solution is reacted in the cold with 119 kg of butyryl chloride. After addition of butyl acetate, the mixture is acidified with hydrochloric acid, the organic phase is separated off and the aqueous phase is re-extracted. The organic phase is dried by azeotropic distillation. The crystallizate is isolated, washed with butyl acetate and dried.

Yield: 132.6 kg (68%)

¹H-NMR: δ=0.8 (t, 3H), 1.25 (d, 3H), 1.5 (m, 2H), 2.1 (t, 2H), 4.2 (q, 1H), 8.1 (d, NH), 12.0-12.7 (s, COOH)

MS: 336 (2M+NH₄, 40), 319 (2M+H, 15), 177 (M+NH₄, 100), 160 (M+H, 20)

Ib) Preparation of 2-ethoxybenzonitrile

260 kg of thionyl chloride are added at 85-95° C. to a suspension of 250 kg of 2-ethoxybenzamide in toluene under metering control. The reaction mixture is stirred in the presence of heat. Thionyl chloride and toluene are then distilled off in vacuo. The product is employed in the subsequent stage as a crude product.

Yield: 228.5 kg (crude product)

¹H-NMR: δ=1.45 (t, 3H), 4.15 (q, 2H), 7.0 (m, 2H, phenyl), 7.5 (m, 2H, phenyl)

MS: 312 (2M+N₄, 35), 165 (M+NH₄, 100), 147 (5)

Ic) Preparation of 2-ethoxy-N-hydroxybenzamidine

111 kg of 2-ethoxybenzonitrile (crude product) from Example Ib are heated under reflux with 164 1 of triethylamine and 73 kg of hydroxylamine hydrochloride in isopropanol. The reaction mixture is treated with water and cooled. The crystallizate is isolated, washed and employed in the subsequent stage as a moist product.

Yield: 92.6 kg (moist product)

¹H-NMR: δ=1.35 (t, 3H), 4.1 (q, 2H), 5.6 (s, 2H), 6.9-7.4 (4H, phenyl), 9.4 (s, 1H, OH)

MS: 361 (2M+H, 30), 198 (M+N, 30), 181 (M+H, 100)

Id) Preparation of 2-ethoxybenzamidine hydrochloride

135 kg of 2-ethoxy-N-hydroxybenzamidine (moist product) from Example Ic are hydrogenated at 50-60° C. in acetic acid using palladium on carbon as a catalyst. For the work-up, the hydrogenation reaction is freed from the catalyst, treated with hydrochloric acid and concentrated. Residual acetic acid and water are removed by azeotropic distillation with toluene. The crystallizate is isolated and dried in vacuo.

Yield: 136.4 kg

H-NMR: 1.35 (t, 3H), 4.15 (q, 2H), 7.1-7.7 (m, 4H, phenyl), 9.1-9.4 (2×s, 3H), 10.5-10.7 (s, 1H)

MS: 329 (2M+H, 10), 165 (M+H, 100)

Ie) Preparation of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one

231 kg of 2-butyrylaminopropionic acid from Example Ia are treated in tetrahydrofuran with 341 kg of pyridine, catalytic amounts of 4-N,N-dimethylaminopyridine and 392 kg of ethyl chloroxalate and stirred with heating under reflux. The reaction mixture is taken up in ethyl acetate, washed with water and the ethyl acetate phase is concentrated. The distillation residue is taken up in methanol and reacted with the following solution.

192 kg of 2-ethoxybenzamidine hydrochloride from Example Id are treated in methanol with 47.5 kg of hydrazine hydrate and the mixture is stirred at room temperature. The solution is combined with the solution of 2-butyrylamino-1-ethoxycarbonylpropenyl ethyl oxalate prepared above. The reaction mixture thus obtained is stirred with heating under reflux. Methanol is removed by distillation and replaced by acetic acid.

Option A:

138.6 kg of phosphorus oxychloride are added and stirred in the presence of heat.

Acetic acid is distilled off in vacuo. The residue is treated with water and dichloromethane or optionally methyl isobutyl ketone and rendered neutral using sodium hydroxide solution. The organic phase is concentrated, and the residue is dissolved in acetone and crystallized with cooling. The crystallizate is isolated, washed and dried.

Option B:

At least 190 kg of acetyl chloride are added and stirred in the presence of heat. Acetic acid is distilled off in vacuo. The distillation residue is treated with acetone and water, and the product is crystallized by rendering neutral with sodium hydroxide solution. The product is isolated, washed and dried.

Yield: 90-160 kg

¹H-NMR: δ=1.0 (t, 3H), 1.6 (t, 3H), 1.9 (m, 2H), 2.8 (s, 3H), 3.3 (t, 2H), 4.3 (q, 2H), 7.0-8.2 (Ar, 4H), 10.3 (CONH, 1H)

MS: 313 (M+H, 100), 149 (25), 151 (40), 121 (15)

HPLC: Kromasil C-18 phase, neutral phosphate buffer, acetonitrile, 233 nm, linear gradient of 30% acetonitrile ->80% acetonitrile (30 min.): 99 area % (R_t19.1)

PREPARATION EXAMPLES Example 1a 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-fl-][1,2,4]triazin-2-yl)benzenesulphonic acid

194 kg of 2-(2-ethoxyphenyl)-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one from Example Ie are reacted with 504 kg of concentrated sulphuric acid. The reaction mixture is added to water, cooled, and the crystallizate is isolated and dried in vacuo.

Yield: 195.2 kg

¹H-NMR: δ=0.95 (t, 3H), 1.3 (t, 3H), 1.8 (m, 2H), 2.6 (s, 3H), 3.05 (t, 2H), 4.1 (q, 2H), 7.15 (Ar, 1H), 7.75 (m, 2H), 12.3 (SO₂OH)

MS: 393 (M+H, 100), 365 (25), 151 (40)

HPLC: X-Terra C-18 phase, aqueous phosphoric acid, acetonitrile, 242 nm, linear gradient of 10% acetonitrile ->90% acetonitrile (20 min.):

98 area % (R, 9.2)

Example 1b) 2-[2-ethoxy-5-(4-ethlylpiperazin-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

22.5 kg of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]-triazin-2-yl)benzenesulphonic acid from Example 1a are reacted with 74 kg of thionyl chloride and catalytic amounts of dimethylformamide until the evolution of gas has ended. Xylene is repeatedly added to the reaction mixture and thionyl chloride is distilled off. 15.1 kg of N-ethylpiperazine are added to the suspension and it is stirred. After the addition of water, it is adjusted to pH 1 using hydrochloric acid, and the phases are separated. The aqueous phase is treated with acetone and rendered neutral by addition of sodium hydroxide solution. The mixture is cooled, and the crystallizate is isolated, washed and dried in vacuo.

Yield: 26.1 kg

¹H-NMR: δ=1.0 (2×t, 6H), 1.6 (t, 3H), 1.9 (m, 2H), 2.45 (q, 2H), 2.55 (m, 4H), 2.65 (s, 3H), 3.0 (t, 2H), 3.1 (m, 4H), 4.35 (q, 2H), 7.15 (Ar, 1H), 7.9 (Ar, 1H), 8.4 (Ar, 1H), 9.8 (CONH)

MS: 489 (M+H, 100), 345 (10), 313, (10), 285 (10), 113 (20)

HPLC: X-Terra C-18 phase, neutral phosphate buffer, acetonitrile, 242 nm, linear gradient of 20% acetonitrile ->75% acetonitrile (20 min.): 98 area % (R_t16.3)

1 c) 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-fl][1,2,4]triazin-4-one hydrochloride trihydrate

22.5 kg of 2-[2-ethoxy-5-(4-ethylpiperazin-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one from Example 1b are dissolved in 5.1 kg of concentrated hydrochloric acid and acetone/water (12:1 v/v) in the presence of heat. The clear solution is filtered hot and crystallized by cooling and seeding. The crystallizate is isolated, washed and dried in vacuo at about 30° C. and about 300 mbar.

Yield: 25.4 kg

M.p. (DSC): 192° C.

HPLC: X-Terra C-18 phase, neutral phosphate buffer, acetonitrile, 242 nm, linear gradient of 20% acetonitrile ->75% acetonitrile (20 min.): 99 area % (R_t16.3)

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US20050203298 *	May 5, 2005	Sep 15, 2005	Bayer Healthcare Aktiengesellschaft	Process for the preparation of sulphonamide-substituted imidazotriazinones
US20060111354 *	Jul 3, 2003	May 25, 2006	Peter Serno	Medicaments containing vardenafil hydrochloride trihydrate
WO2004006894A1 *	Jul 3, 2003	Jan 22, 2004	Bayer Healthcare Ag	Medicaments containing vardenafil hydrochloride trihydrate

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US2009196900	8-7-2009	Use of Phosphodiesterase Inhibitor as a Component of Implantable Medical Devices
US2009163504	6-26-2009	Method for healing a wound using a phosphodiesterase type five inhibitor
US2009074796	3-20-2009	Pde5 inhibitor compositions and methods for immunotherapy
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US2008268046	10-31-2008	Formulations with Controlled Release of Active Ingredient
US2008194529	8-15-2008	HIGHLY SELECTIVE and LONG-ACTING PDE5 MODULATORS

US2008187588	8-8-2008	Formulations With Controlled Release Of Active Ingredient
US2008085897	4-11-2008	Use of 2-alkoxyphenyl-substituted imidazotriazinones
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US2007299088	12-28-2007	Novel Uses of 2-Phenyl-Substituted Imidazotriazinone Derivatives
US7276504	10-3-2007	Use of 2-alkoxyphenyl-substituted imidazotriazinones
US2006264624	11-24-2006	Methods for synthesizing imidazotriazinones
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US6930108	8-17-2005	Use of 2-alkoxyphenol-substituted imidazotriazinones
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US2005014756	1-21-2005	Process for the preparation of sulphonamide-substituted imidazotriazinones
US6777551	8-18-2004	Process for the preparation of sulphonamide-substituted imidazotriazinones
US2004152700	8-6-2004	Novel use of 2-phenyl-substituted imidazotriazinones
US2003144296	7-32-2003	Daily treatment for erectile dysfunction using a PDE5 inhibitor
US6566360	5-21-2003	2-phenyl substituted imidatriazinones as phosphodiesterase inhibitors
US6362178	3-27-2002	2-phenyl substituted imidazotriazinones as phosphodiesterase inhibitors
US2001053780	12-21-2001	Daily treatment for erectile dysfunction using a PDE5 inhibitor
WO9924433	5-21-1999	2-PHENYL SUBSTITUTED IMIDAZOTRIAZINONES AS PHOSPHODIESTERASE INHIBITORS

////////////

Etelcalcetide, AMG 416, KAI-4169, velcalcetide

October 16, 2015 7:45 am / 4 Comments on Etelcalcetide, AMG 416, KAI-4169, velcalcetide

H-L-Cys-OH

S— S

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂

AMG 416 IS (Ac-D-Cys(L-Cys-OH)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂)

Etelcalcetide (AMG 416, KAI-4169, velcalcetide)

The main chain has 7 amino acids, all in the D-configuration. The side-chain cysteine residue is in the L-configuration. The molecular formula of AMG 416 (free base) is C38H73N21O10S2, and has a calculated average molecular mass of 1048.3 Da.

D-Argininamide, N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-, disulfide with L-cysteine, hydrochloride (1:?)

N-Acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide disulfide with L-cysteine hydrochloride

http://www.amgenpipeline.com/pipeline/

WO 2011/014707. , the compound may be represented as follows:

H-L-Cys-OH

S— S

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂

The main chain has 7 amino acids, all in the D-configuration and the side-chain cysteine residue is in the L-configuration. The amino terminal is acetylated and the carboxyl-terminal is amidated. This compound (“AMG-416”) has utility for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients. A liquid formulation comprising AMG-416 may be administered to a subject intravenously. The hydrochloride salt of AMG-416 may be represented as follows:

H-L-Cys-OH

S— S

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · x(HCl)

Therapeutic peptides pose a number of challenges with respect to their formulation. Peptides in general, and particularly those that contain a disulfide bond, typically have only moderate or poor stability in aqueous solution. Peptides are prone to amide bond hydrolysis at both high and low pH.

Disulfide bonds can be unstable even under quite mild conditions (close to neutral pH). In addition, disulfide containing peptides that are not cyclic are particularly prone to dimer formation. Accordingly, therapeutic peptides are often provided in lyophilized form, as a dry powder or cake, for later reconstitution.

A lyophilized formulation of a therapeutic peptide has the advantage of providing stability for long periods of time, but is less convenient to use as it requires the addition of one or more diluents and there is the potential risk for errors due to the use of an improper type or amount of diluent, as well as risk of contamination. In addition, the lyophilization process is time consuming and costly.

H-L-Cys-OH

S— S

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂

Generic Name:Etelcalcetide
Synonym:KAI-4169
CAS Number:1262780-97-1
N-acetyl-D-cysteinyl-S-(L-cysteine disulfide)-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide
Mechanism of Action:Activates calcium sensing receptor on parathyroid glands reducing PTH synthesis and secretion
Indication: secondary hyperparathyroidism associated with chronic kidney disease
Development Stage: Phase III
Developer:KAI Pharmaceuticals/Amgen Inc.

H-L-Cys-OH

S— S

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · x(HCl)

HYDROCHLORIDE

Generic Name:Etelcalcetide Hydrochloride
AMG 416, KAI-4169, previously also known as velcalcetide hydrochloride
CAS :1334237-71-6
Chemical Name:N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-argininamide disulfide with L-cysteine hydrochloride
Mechanism of Action:Activates calcium sensing receptor on parathyroid glands reducing PTH synthesis and secretion
Indication: secondary hyperparathyroidism associated with chronic kidney disease
Development Stage: Phase III
Developer:KAI Pharmaceuticals/Amgen Inc.

Method for preparing etelcalcetide and its salts, particularly hydrochloride. See WO2014210489, for a prior filing claiming stable liquid formulation of etelcalcetide. Amgen, following its acquisition of KAI Pharmaceuticals, and Japanese licensee Ono Pharmaceuticals are developing etelcalcetide, a long-acting iv isozyme-selective peptide-based protein kinase C epsilon inhibitor and agonist of the calcium-sensing receptor, for treating secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease receiving dialysis.

In August 2015, an NDA was submitted seeking approval of the drug for SHPT in patients with chronic kidney disease (CKD) on hemodialysis (HD) in the US.

In September 2015, Amgen filed an MAA under the centralized procedure in the EU for the approval of etelcalcetide for treating SHPT in patients with CKD on HD therapy.

KAI is also investigating a transdermal patch formulation of the drug for treating primary HPT.

AMG 416

Secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis

AMG 416 is a peptide agonist of the human cell surface calcium-sensing receptor (CaSR). It is being investigated as a treatment for secondary hyperparathyroidism in patients with chronic kidney disease receiving dialysis.

Etelcalcetide is a novel calcimimetic agent that suppresses the secretion of parathyroid hormone and is in clinical development for the treatment of SHPT in patients with CKD on hemodialysis. Etelcalcetide is administered intravenously three times per week at the end of each dialysis session. It acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in parathyroid hormone (PTH). Sustained elevations in PTH are known to be associated with significant clinical consequences for patients with CKD.

The submission includes data from three Phase 3 studies, all of which met the primary endpoints, including two pooled placebo-controlled trials in more than 1,000 patients and a head-to-head study evaluating etelcalcetide compared with cinacalcet.

About Secondary HyperparathyroidismSHPT is a common and serious condition that is often progressive among patients with CKD, and it affects many of the approximately two million people throughout the world who are receiving dialysis, including 450,000 people in the U.S. The disorder develops early in the course of CKD and usually manifests as increased levels of PTH as a result of increased production from the parathyroid glands (four small glands in the neck). Patients with end stage renal disease who require maintenance dialysis often have substantial elevations of PTH that are commonly associated with abnormal calcium and phosphorus levels and an increased risk of significant clinical consequences.

About Etelcalcetide (AMG 416)Etelcalcetide is a novel calcimimetic agent in clinical development for the treatment of SHPT in CKD patients on hemodialysis that is administered intravenously at the end of the dialysis session. Etelcalcetide binds to and activates the calcium-sensing receptor on the parathyroid gland, thereby decreasing PTH levels.

About Sensipar^® (cinacalcet)Sensipar^® (cinacalcet) is the first oral calcimimetic agent approved by the FDA for the treatment of SHPT in adult patients with CKD on dialysis. Sensipar is not indicated for use in adult patients with CKD who are not on dialysis because of an increased risk of hypocalcemia. The therapy is also approved in the U.S. for treatment of hypercalcemia in adult patients with parathyroid carcinoma and hypercalcemia in adult patients with primary HPT for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. Sensipar binds to the calcium-sensing receptor, resulting in a drop in PTH levels by inhibiting PTH synthesis and secretion. In addition, the reductions in PTH lower serum calcium and phosphorus levels.

Milestones

25 Aug 2015 Preregistration for Secondary hyperparathyroidism in USA (IV)
29 May 2015 Pooled analysis efficacy and adverse events data from two phase III trials in secondary hyperparathyroidism released by Amgen
21 Apr 2015 Amgen plans to submit Biological License Application to USFDA and Marketing Authorisation Application to EMA for Secondary hyperparathyroidism

PATENT

WO2011014707

http://www.google.com/patents/WO2011014707A2?cl=en

PATENT

WO 2015154031

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015154031&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

The hydrochloride salt of AMG 416 has the chemical structure:

H-L-Cys-OH

s— s

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · x(HCl)

(SEQ ID NO:l)

AMG 416 and a method for its preparation are described in International Pat. Publication No. WO 2011/014707, which is incorporated herein by reference for any purpose. As described in International Pat. Publication No. WO 2011/014707, AMG 416 may be assembled by solid-phase synthesis from the corresponding Fmoc-protected D-amino acids. After cleavage from the resin, the material may be treated with Boc-L-Cys(NPyS)-OH to form the disulfide bond. The Boc group may then be removed with trifluoroacetate (TFA) and the resulting product purified by reverse-phase high pressure liquid chromatography (HPLC) and isolated as the TFA salt form by lyophilization. The TFA salt can be converted to a pharmaceutically acceptable salt by carrying out a subsequent salt exchange procedure. Such procedures are well known in the art and include, e.g., an ion exchange technique, optionally followed by purification of the resultant product (for example by reverse phase liquid chromatography or reverse osmosis).

There is a need for an efficient method of producing AMG 416, or a pharmaceutically acceptable salt thereof (e.g., AMG 416 HC1), and particularly one appropriate for commercial scale manufacturing.

In a first aspect, provided is a method for preparing AMG 416, the method comprising: providing a resin-bound peptide having a structure selected from the group consisting of Fmoc-D-Cys(Trt)-D-Ala-D- Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:2) and Ac-D-Cys(Trt)-D-Ala-D- Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:3); cleaving the peptide from the solid support; and activating the side chain of the D-Cys residue of the cleaved peptide.

In a second aspect, provided is a method for preparing AMG 416, the method comprising: providing a peptide having a structure of Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ (SEQ ID NO:4); and contacting the peptide with L-Cys to produce a conjugated product.

In yet a third aspect provided is a method for preparing AMG 416, the method comprising: providing a resin-bound peptide having a structure selected from the group consisting of Fmoc-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:2) and Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-[Resin] (SEQ ID NO:3); cleaving the peptide from the solid support, i.e., to provide an unsupported peptide, and activating the side chain of the D-Cys residue of the unsupported peptide to generate an AMG 416 SPy intermediate (where SPy is 2-pyridinesulfenyl or S-Pyr), dissolving the AMG 416 SPy intermediate in an aqueous 0.1% TFA (trifluoroacetic acid solution), and purifying the AMG 416 SPy derivative by HPLC.

The term “AMG 416”, also known as etelcalcetide, formerly known as velcalcetide or KAI-4169, refers to a compound having the chemical name: N-acetyl-D-cysteinyl-D-alanyl-D-arginyl-D-arginyl-D-arginyl-D-alanyl-D-arginamide disulfide with L-cysteine, which has the following structural formula:

H-L-Cys-OH

s— s

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂

Reference to AMG 416, or to any compound or AMG 416 fragment, intermediate, or precursor as described herein, is intended to encompass neutral, uncharged forms thereof, as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

The terms “AMG 416 hydrochloride” and “AMG 416 HC1” are interchangeable and refer to a hydrochloride salt form of AMG 416 having the following structural formula:

H-L-Cys-OH

s— s

Ac-D-Cys-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂ · xHCl

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the chemical structure of AMG 416 (Ac-D-Cys(L-Cys-OH)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂) (SEQ ID NO: l).

FIG. 2 shows the chemical structure of Rink Amide AM resin and Ac-D-Cys(Trt)- D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-Resin (SEQ ID NO:3).

FIG. 3 shows a reaction scheme in which the SPy intermediate product (Ac-D-Cys(SPy)-D-Ala-D-Arg-D-Arg-D-Arg-D-Ala-D-Arg-NH₂) (SEQ ID NO:4) is formed from the peptidyl-resin (Ac-D-Cys(Trt)-D-Ala-D-Arg(Pbf)-D-Arg(Pbf)-D-Arg(Pbf)-D-Ala-D-Arg(Pbf)-NH-Resin) (SEQ ID NO:3).

FIG. 4 shows a reaction scheme in which a TFA salt of AMG 416 is formed from the SPy intermediate (AA^1_7(SPy)).

FIG. 5 shows a reaction scheme in which the HC1 salt of AMG 416 is formed from the TFA salt of AMG 416.

FIG. 6 shows a reaction scheme in which Boc-D-Arg(Pbf)-OH is formed from Boc-D-Arg-OH.

FIG. 7 shows a reaction scheme in which D-Arg(Pbf)-OH is formed from Boc-D-Arg(Pbf)-OH.

EXAMPLE 5

Purification of the SPy Intermediate and Production of AMG 416 HC1

An alternative method for preparation of AMG 416 HC1 salt is described here. As described in Example 2 above, the SPy intermediate product was dried at 20°C under full vacuum after cleavage from the resin, precipitation and filtration. The precipitate was then dissolved in a 0.1% TFA aqueous solution and loaded onto a C-18 column for HPLC purification. The column was run at <60 bar and the solution temperature was 15-25 °C throughout. The eluents were 0.1% TFA in acetonitrile and 0.1% TFA in water. The fractions were stored at 5°C, they were sampled and then fractions were pooled. The combined pools from two runs were diluted and a concentration/purification run was performed using the same HPLC column to decrease the total volume and remove additional impurities. The fractions were stored at 5°C.

The fractions containing the AMG 416 SPy intermediate were subjected to azeotropic distillation to change the solvent from the 0.1% TFA to a 15% water in IPA solution, charging with IPA as needed. To the resultant AMG 416 SPy intermediate in IPA solution was then added L-Cysteine 1.15 eq and the reaction was allowed to proceed at room temperature for conjugation to occur and to form the AMG 416 TFA salt as described above in Example 4. The AMG 416 TFA solution was added to a solution of 12M aqueous HC1, 0.27 L/kg and IPA 49.4 L/kg over 3 hours via subsurface addition, resulting in direct precipitation of the AMG 416 4.5 HC1 salt. The batch was aged for 3 hours and sampled for analysis.

The material was filtered and slurry washed with 96 wt% IPA, 10 L/kg. The cake was then re-slurried for 4 hours in 10 L/kg of 96% wt% IPA. The material was filtered and further slurry washed with 96% IPA, 10 L/kg and then IPA 10 L/kg. The material was dried under full vacuum at 25°C. The dry cake was dissolved in water 8 L/kg and the batch was concentrated via distillation to remove residual IPA and achieve the desired concentration. The solution temperature was kept below 25 °C throughout the distillation.

PATENT

WO2014210489

SEE

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=2A32CFD9CE075079399E9DD298899C9D.wapp2nC?docId=WO2014210489&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

EXAMPLE 1

Solubility of AMG 416 in Succinate Buffered Saline

In this study, the solubility of AMG 416 in succinate buffered-saline was investigated. AMG 416 HC1 (103 mg powder, 80 mg peptide) was dissolved in 200 iL of sodium succinate buffered saline (25 mM succinate, 0.9% saline, pH 4.5). After briefly vortexing, a clear solution was obtained with a nominal concentration of 400 mg/mL. Because expansion of the solution volume was not determined, the solubility of AMG 416 can be conservatively stated as at least 200 mg/mL. Although the maximal solubility was not determined in this experiment, AMG 416 is soluble in pH 4.5 succinate buffered saline to concentrations of at least 200 mg/mL.

REFERENCES

KAI-4169, a novel calcium sensing receptor agonist, decreases serum iPTH, FGF-23 and improves serum bone markers in a phase 2 study in hemodialysis subjects with chronic kidney disease-mineral and bone disorder
49th Congr Eur Renal Assoc – Eur Dialysis Transpl Assoc (May 24-27, Paris) 2012, Abst SAO054

KAI-4169, a novel peptide agonist of the calcium sensing receptor, attenuates PTH and soft tissue calcification and restores parathyroid gland VDR levels in uremic rats
49th Congr Eur Renal Assoc – Eur Dialysis Transpl Assoc (May 24-27, Paris) 2012, Abst SAO014

Long term safety and efficacy of velcalcetide (AMG 416), a calcium-sensing receptor (CaSR) agonist, for the treatment of secondary hyperparathyroidism (SHPT) in hemodialysis (HD) patients
Kidney Week (November 5-10, Atlanta, GA) 2013, Abst SA-PO575

Preclinical PK and PD relationship for KAI-4169, a novel calcimimetic
93rd Annu Meet Endo Soc (June 4-7, Boston) 2011, Abst P1-198

KAI-4169, a novel calcimimetic for the treatment of secondary hyperparathyroidism
93rd Annu Meet Endo Soc (June 4-7, Boston) 2011, Abst P2-98

Characterization of KAI-4169, a novel peptide for the treatment of chronic kidney disease – Mineral and bone disorder, in a phase I study in healthy males
44th Annu Meet Am Soc Nephrol (ASN) (November 8-13, Philadelphia) 2011, Abst FR-PO1238

WO2011014707A2	Jul 29, 2010	Feb 3, 2011	Kai Pharmaceuticals, Inc.	Therapeutic agents for reducing parathyroid hormone levels

//////////////Etelcalcetide, AMG 416, KAI-4169, velcalcetide, peptide drugs

Monoclonal Antibody Therapy: What is in the name or clear description?

October 15, 2015 4:23 am / Leave a comment

Leaders in Pharmaceutical Business Intelligence Group, LLC, Doing Business As LPBI Group, Newton, MA

Monoclonal Antibody Therapy: What is in the name or clear description?

Curator: Demet Sag, PhD, CRA, GCP

What is in the name?

Nomenclature is important part of the scientific community so we can stay on the same page in all kinds of communications for clarity. Therefore, a defined nomenclature scheme for assigning generic, or nonproprietary, names to monoclonal antibody drugs is used by the World Health Organization’s International Nonproprietary Names (INN) and the United States Adopted Names (USAN). In general, word stems are used to identify classes of drugs, in most cases placed at the end of the word.

Knowing what Antibody relies on understanding of immune response system so that one can modify the cells, choose correct biomarkers from the primary pathways (like Notch, WNT etc), know signaling from outside to inside (like GPCRs, MAPKs, nuclear transcription receptors), personalized gene make up (genomics) and key gene regulation mechanisms. Thus…

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Daprodustat, ダプロデュスタット

October 13, 2015 7:28 am / Leave a comment

ChemSpider 2D Image | daprodustat | C19H27N3O6

Daprodustat, GSK1278863

ダプロデュスタット

CAS 960539-70-2

GSK1278863; GSK 1278863; GSK-1278863; Daprodustat

C19H27N3O6
Exact Mass: 393.18999

(1,3-dicyclohexyl-2,4,6-trioxohexahydropyrimidine-5-carbonyl)glycine

N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine

2-(1,3-dicyclohexyl-2,4,6-triohexahydropyrimidine-5-carboxamide acetic acid
Mechanism of Action: HIF-prolyl hydroxylase inhibitor
Indication: anemia, diabetic wounds, and reduction of ischemic complications
Development Stage: Phase II
Developer:GlaxoSmithKline

UNII:JVR38ZM64B

ダプロデュスタット
Daprodustat

C₁₉H₂₇N₃O₆ : 393.43
[960539-70-2]

Daprodustat , also known as GSK1278863, is a novel HIF-prolyl hydroxylase inhibitor. Hypoxia inducible factor (HIF) stabilization by HIF-prolyl hydroxylase (PHD) inhibitors may improve ischemic conditions such as peripheral artery disease (PAD). Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease

Originator GlaxoSmithKline
Class Antianaemics; Pyrimidines; Small molecules
Mechanism of ActionErythropoiesis stimulants; Prolyl hydroxylase inhibitors

Phase II Anaemia; Perioperative ischaemia
Phase I Diabetic foot ulcer; Tendon injuries
DiscontinuedPeripheral arterial disorders

Most Recent Events

27 Jul 2015No recent reports of development identified – Phase-II for Anaemia in India and New Zealand (PO)
27 Jul 2015Daprodustat is still in phase II trials for Anaemia in the USA, Australia, Canada, Czech Republic, Denmark, France, Germany, Hungary, Japan, Poland, Russia, Spain, South Korea, and United Kingdom
01 Jun 2015GlaxoSmithKline completes a phase I trial in Tendon injuries (In volunteers) in USA (PO) (NCT02231190)

WHO ATC code:

B03 (Antianemic Preparations)C (Cardiovascular System)

C01 (Cardiac Therapy)

D03 (Preparations for Treatment of Wounds and Ulcers)

M09A-X (Other drugs for disorders of the musculo-skeletal system)

EPhMRA code:

B3 (Anti-Anaemic Preparations)C1 (Cardiac Therapy)

C6A (Other Cardiovascular Products)

D3A (Wound Healing Agents)

M5X (All Other Musculoskeletal Products)

Daprodustat (INN) (GSK1278863) is a drug which acts as a HIF prolyl-hydroxylase inhibitor and thereby increases endogenous production of erythropoietin, which stimulates production of hemoglobin and red blood cells. It is in Phase III clinical trials for the treatment of anemia secondary to chronic kidney disease.^[1]^[2] Due to its potential applications in athletic doping, it has also been incorporated into screens for performance-enhancing drugs.^[3]

SYN 1

SYN 2

^PATENT

WO 2007150011

https://www.google.com.ar/patents/WO2007150011A2

Illustrated Methods of preparation

Scheme 1

a) 1. NaH, THF, rt 2. R¹NCO, 60 ⁰C; b) 1. NaH, THF or dioxane, rt 2. R⁴NCX, heat; c) H₂NCH₂CO₂H, DBU, EtOH, 160⁰C, microwave.

Scheme 2

a) R¹NH₂, CH₂Cl₂ or R¹NH₂-HCl, base, CH₂Cl₂; b) CH₂(C(O)Cl)₂, CH₂Cl₂, reflux or CH₂(CO₂Et)₂, NaOEt, MeO(CH₂)₂OH, reflux or 1. EtO₂CCH₂COCl, CHCl₃, 70 ⁰C 2.

DBU, CHCl₃, 70 ⁰C; c) 1. YCNCH₂CO₂Et,, EtPr’₂N, CHCl₃ or CH₂Cl₂ 2. aq NaOH, EtOH, rt. Scheme 3 (for R¹ = R⁴)

a) CDI,

DMF, 70 ⁰C or , EtOAc, rt

Scheme 4

a) OCNCH₂CO₂Et, EtPr’₂N, CHCl₃ or CH₂Cl₂; b) 1. R¹HaI, Na/K₂CO₃, DMF or DMA, 100 ⁰C or R¹HaI, pol-BEMP, DMF, 120 ⁰C, microwave 2. aq NaOH, MeOH or EtOH, rt.

Scheme 5

a) 1. CH₂(CO₂H)₂, THF, O ⁰C – rt 2. EtOH, reflux; b) 1. OCNCH₂CO₂Et, EtPr’₂N, CH₂Cl₂ 2. aq NaOH, EtOH, rt.

Scheme 6

a) 1. Phthalimide, DIAD, PPh₃, THF 2. (NH₂)₂, EtOH, reflux.

Scheme 7

a) Ac₂O, AcOH, 130 ⁰C.

Example 18

N-T(1 ,3-Dicvclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahvdro-5-pyrimidinyl)carbonyl1grycine Method 1

18.1a) h3-Dicvclohexyl-2A6(lH,3H,5H)-pyrimidinetrione. Dicyclohexylurea (3.0 g, 13.39 mmoles) was stirred in chloroform (80 mL) and treated with a solution of malonyl dichloride (1.3 mL, 13.39 mmoles) in chloroform (20 mL), added dropwise under argon. The mixture was heated at 50⁰C for 4 hours, wasahed with 1 molar hydrochloric acid and evaporated onto silica gel. Flash chromatography (10-30% ethyl acetate in hexane) to give the title compound (2.13 g, 55%). 1Η NMR (400 MHz, OMSO-d₆) δ ppm 4.46 (tt, J=12.13, 3.54 Hz, 2 H), 3.69 (s, 2 H), 2.15 (qd, J=12.46, 3.28 Hz, 4 H), 1.77 (d, J=13.14 Hz, 4 H), 1.59 (t, J=12.76 Hz, 6 H), 1.26 (q, J=12.97 Hz, 4 H), 1.04 – 1.16 (m, 2 H)

18.1b) N-r(1.3-Dicvclohexyl-6-hvdroxy-2.4-dioxo-1.2.3.4-tetrahvdro-5- pyrimidinvDcarbonyll glycine. Ethyl isocyanatoacetate (802 uL, 7.15 mmoles) was added to a mixture of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (2.1 g, 7.15 mmoles) and diisopropylethylamine (2.47 mL, 14.3 mmoles) in dichloromethane (100 mL) and stirred overnight. The reaction mixture was washed with 1 molar hydrochloric acid (x2) and evaporated. The residue was dissolved in ethanol (10 mL) and treated with 1.0 molar sodium hydroxide (5 mL). The mixture was stirred for 72 hours, acidified and extracted into ethyl acetate. Some ester remained, therefore the solution was evaporated and ther residue was dissolved in 1 molar soldium hydroxide solution with warming and strred for 2 hours. The mixture was acidified with IM HCl and extracted with ethyl acetate (x2). The combined extracts were washed with 1 molar hydrochloric acid , dried and evaporated to a solid which was slurried in a mixture of diethyl ether and hexane, collected, washed with the same solvent mixture and dried to give the title compound (1.86 g, 66%). IH NMR (400 MHz, DMSO-^₆) δ ppm 13.07 (br. s., 1 H), 10.19 (t, J=5.31 Hz, 1 H), 4.63 (t, J=10.99 Hz, 2 H), 4.12 (d, J=5.56 Hz, 2 H), 2.27 (q, J=I 1.71 Hz, 4 H), 1.79 (d, J=12.88 Hz, 4 H), 1.50 – 1.69 (m, 6 H), 1.28 (q, J=12.97 Hz, 4 H), 1.12 (q, J=12.72 Hz, 2 H)

Method 2

18.2a) 1.3-Dicvclohexyl-2.4.6πH.3H.5H)-pyrimidinetrione. A solution of N₅N- dicyclohexylcarbodiimide (254 g; 1.23 mol.) in anhydrous TΗF (700 mL) was added dropwise to a cold (0 ⁰C) solution of malonic acid (64.1 g; 0.616 mol.) in anhydrous TΗF (300 mL) over a period of- 30 minutes. The mixture was stirred and allowed to warm to room temperature over 2 h. (After 1 h, the mixture became very thick with precipitate so further anhydrous TΗF (500 mL) was added to facilitate agitation.). The mixture was filtered and the filtrate evaporated to afford a yellow solid which was immediately slurried in ethanol (1 L) and heated to reflux temperature. The mixture was then allowed to cool to room temperature then filtered and the solid washed with cold ethanol (250 mL) to afford the title compound (129.4 g; 72%) as a colorless solid. 1Η NMR (400 MHz, DMSO-(Z₆) δ ppm 1.03 – 1.18 (m, 2 H) 1.18 – 1.34 (m, 4 H) 1.59 (t, J=13.14 Hz, 6 H) 1.76 (d, J=12.88 Hz, 4 H) 2.04 – 2.24 (m, 4 H) 3.69 (s, 2 H) 4.35 – 4.54 (m, 2 H).

18.2b) Ethyl N-[(l .3-dicvclohexyl-6-hvdroxy-2.4-dioxo- 1.2.3.4-tetrahydro-5- pyrimidinyPcarbonyll glycinate. A solution of l,3-dicyclohexyl-2,4,6(lH,3H,5H)-pyrimidinetrione (120.0 g; 0.41 mol.) and diisopropylethylamine (105.8 g; 0.82 mol.) in dichloromethane (1 L) was stirred and treated dropwise with a solution of ethyl isocyanatoacetate (53.0 g; 0.41 mol.) in dichloromethane (500 mL) and the mixture was then stirred at room temperature overnight. The mixture was then treated dropwise with 6M aq. hydrochloric acid (500 mL) and the separated organic layer was dried and evaporated. The resulting solid was slurried in hexanes (500 mL) and heated to reflux temperature. The mixture was then allowed to cool and filtered to afford ethyl N- [(1 ,3-dicyclohexyl-6-hydroxy-2,4-dioxo- 1 ,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.1 g; 92%) as a cream powder. IH NMR (400 MHz, CHLOROFORM-,/) δ ppm 1.24 (s, 2 H) 1.37 (s, 7 H) 1.52 – 1.76 (m, 6 H) 1.78 – 1.94 (m, 4 H) 2.25 – 2.48 (m, 4 H) 4.17 (d, J=5.81 Hz, 2 H) 4.28 (q, J=7.24 Hz, 2 H) 4.74 (s, 2 H) 10.37 (t, J=4.67 Hz, 1 H). 18.2c)

N-rπ^-Dicyclohexyl-ό-hydroxy^^-dioxo-l^J^-tetralivdro-S- pyrimidinyDcarbonyll glycine. A stirred suspension of ethyl Ν-[(l,3-dicyclohexyl-6-hydroxy-2,4- dioxo-l,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (159.0 g; 0.377 mol.) in ethanol (1.5 L) was treated dropwise with 6M aq. Sodium hydroxide (250 mL) and stirred at room temperature for 3 h. The solution was then acidified by the dropwise addition of 6M aq. hydrochloric acid (300 mL), diluted with water (IL) and then filtered. The crude solid was slurried in water (2 L) then stirred vigorously and heated at 35 ⁰C for 1 h and filtered and dried. The solid material (~ 138 g) was then crystallized from glacial acetic acid (1.5 L) (with hot filtration to remove a small amount of insoluble material). The solid, which crystallized upon cooling, was collected and washed with cold glacial acetic acid (3 x 100 mL) to afford N-[(l,3-dicyclohexyl-6-hydroxy-2,4-dioxo-l,2,3,4- tetrahydro-5-pyrimidinyl)carbonyl]glycine (116.2 g; 78%) as a colorless solid.

IH NMR (400 MHz, DMSO-(Z₆) δ ppm 1.11 (d, J=12.88 Hz, 2 H) 1.27 (q, J=12.80 Hz, 4 H) 1.62 (s, 6 H) 1.70 – 1.90 (m, J=12.88 Hz, 4 H) 2.11 – 2.44 (m, 4 H) 4.11 (d, J=5.81 Hz, 2 H) 4.45 – 4.77 (m, 2 H) 10.19 (t, J=5.81 Hz, 1 H) 13.08 (s, 1 H).

References

Jump up^ Schmid H, Jelkmann W. Investigational therapies for renal disease-induced anemia. Expert Opin Investig Drugs. 2016 Aug;25(8):901-16. . doi:10.1080/13543784.2016.1182981. PMID 27122198. Missing or empty |title= (help)
Jump up^ Ariazi JL, Duffy KJ, Adams DF, Fitch DM, Luo L, Pappalardi M, Biju M, DiFilippo EH, Shaw T, Wiggall K, Erickson-Miller C. Discovery and Preclinical Characterization of GSK1278863 (Daprodustat), a Small Molecule Hypoxia Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia. J Pharmacol Exp Ther. 2017 Dec;363(3):336-347. . doi:10.1124/jpet.117.242503. PMID 28928122. Missing or empty |title= (help)
Jump up^ Thevis M, Milosovich S, Licea-Perez H, Knecht D, Cavalier T, Schänzer W. Mass spectrometric characterization of a prolyl hydroxylase inhibitor GSK1278863, its bishydroxylated metabolite, and its implementation into routine doping controls. Drug Test Anal. 2016 Aug;8(8):858-63. . doi:10.1002/dta.1870. PMID 26361079. Missing or empty |title= (help)

Daprodustat
Clinical data

Synonyms	GSK1278863
ATC code	None
Identifiers
IUPAC name [show]
CAS Number	960539-70-2
PubChem CID	91617630
Chemical and physical data
Formula	C₁₉H₂₇N₃O₆
Molar mass	393.44 g/mol
3D model (JSmol)	Interactive image

//////////////Daprodustat, GSK1278863, ダプロデュスタット , HIF-prolyl hydroxylase inhibitor, anemia, diabetic wounds, reduction of ischemic complications, Phase II, GlaxoSmithKline

C1CCC(CC1)N2C(=O)C(C(=O)N(C2=O)C3CCCCC3)C(=O)NCC(=O)O

Sparsentan, PS433540, RE-021

October 12, 2015 4:02 am / Leave a comment

Sparsentan (PS433540, RE-021)

C₃₂H₄₀N₄O₅S
Average mass592.749

FDA APPROVED 2023/2/17, Filspari

4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2′-(ethoxymethyl)-[1,1′-biphenyl]-2-sulfonamide

4′-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methvn-N-(3,4- dimethyl-5-isoxazolyl)-2′-ethoxymethyl [ 1 , l’-biphenyll -2-sulfonamide

Sparsentan
PS433540; RE-021, formerly known as DARA
CAS :254740-64-2
4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(4,5- dimethylisoxazol-3-yl)-2-(ethoxymethyl)biphenyl-2-sulfonamide
Mechanism of Action:acting as both an Endothelin Receptor Antagonist (ERA) and Angiotensin Receptor Blocker (ARB).
Indication: Focal Segmental Glomerulosclerosis (FSGS).Focal Segmental Glomerulosclerosis (FSGS) is a rare and severe nephropathy which affects approximately 50,000 patients in the United States. Most cases of FSGS are pediatric.
Development Stage: Phase II
Developer:Retrophin, Inc

OriginatorBristol-Myers Squibb
DeveloperRetrophin
ClassAntihypertensives; Isoxazoles; Small molecules; Spiro compounds; Sulfonamides
Mechanism of ActionAngiotensin type 1 receptor antagonists; Endothelin A receptor antagonists
Orphan Drug Status Yes – Focal segmental glomerulosclerosis
- 09 Jan 2015 Sparsentan receives Orphan Drug status for Focal segmental glomerulosclerosis in USA
- 31 Dec 2013 Phase-II/III clinical trials in Focal segmental glomerulosclerosis in USA (PO)
- 07 May 2012I nvestigation in Focal segmental glomerulosclerosis in USA (PO)

Sparsentan is an investigational therapeutic agent which acts as both a selective endothelin receptor antagonist and an angiotensin receptor blocker. Retrophin is conducting the Phase 2 DUET trial of Sparsentan for the treatment of FSGS, a rare and severe nephropathy that is a leading cause of end-stage renal disease. There are currently no therapies approved for the treatment of FSGS in the United States. Ligand licensed worldwide rights of Sparsentan (RE-021) to Retrophin in 2012 .The Food and Drug Administration (FDA) has granted orphan drug designation for Retrophins sparsentan for the treatment of focal segmental glomerulosclerosis (FSGS) in January 2015.

In 2006, the drug candidate was licensed to Pharmacopeia by Bristol-Myers Squibb for worldwide development and commercialization. In 2012, a license was obtained by Retrophin from Ligand. In 2015, Orphan Drug Designation was assigned by the FDA for the treatment of focal segmental glomerulosclerosis.

Sparsentan, also known as RE-021, BMS346567, PS433540 and DARA-a, is a Dual angiotensin II and endothelin A receptor antagonist. Retrophin intends to develop RE-021 for orphan indications of severe kidney diseases including Focal Segmental Glomerulosclerosis (FSGS) as well as conduct proof-of-concept studies in resistant hypertension and diabetic nephropathy. RE-021, with its unique dual blockade of angiotensin and endothelin receptors, is expected to provide meaningful clinical benefits in mitigating proteinuria in indications where there are no approved therapies

Sparsentan, sold under the brand name Filspari, is a medication used for the treatment of primary immunoglobulin A nephropathy.^[1] Sparsentan is an endothelin and angiotensin II receptor antagonist.^[1]^[4] It is taken by mouth.^[1]

The most common side effects include swelling of the extremities, low blood pressure, dizziness, high blood potassium, anemia, injury to the kidney, and increased liver enzymes in the blood.^[5]

It was approved for medical use in the United States in February 2023.^[5]^[6]^[7] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.^[8]

PATENT

WO 2000001389

https://www.google.co.in/patents/WO2000001389A1?cl=en

Figure imgf000030_0001

Figure imgf000033_0001

Example 41

4′- [(2-Butyl-4-oxo- 1.3-diazaspiro [4.4! non- l-en-3-yl)methyll -N-(3.4- dimethyl-5-isoxazolyl)-2′-hydroxymethyl[l, l’-biphenyl! -2-sulfonamide

A. 4′-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methyll-N-(3.4- dimethyl-5-isoxazolyl)-N-[(2-trimethylsilylethoxy)methyl]-2′- hydroxym ethyl [1, l’-biphenyl] -2-sulfonamide P14 (243 mg, 0.41 mmol) was used to alkylate 2-butyl-4-oxo-l,3- diazaspiro[4.4]non-l-ene hydrochloride according to General Method 4. 41A (100 mg, 35% yield) was isolated as a slightly yellow oil after silica gel chromatography using 1:1 hexanes/ethyl acetate as eluant. B. 4′- [(2-Butyl-4-oxo- 1 ,3-diazaspiro [4.41 non- l-en-3-yl)methvn -N-0.4- dimethyl-5-isoxazolyl)-2′-hydroxymethyl[l,l’-biphenyn-2- sulfonamide

Deprotection of 41A (100 mg, 0.14 mmol) according to General Method 8 (ethanol) gave the title compound as white solid in 46% yield following silica gel chromatography (96:4 methanol/chloroform eluant):

MS m/e 565 (ESI+ mode); HPLC retention time 3.21 min (Method A);

HPLC purity >98%.

Example 42

4′-[(2-Butyl-4-oxo-1.3-diazaspiro[4.41non-l-en-3-yl)methvn-N-(3,4- dimethyl-5-isoxazolyl)-2′-ethoxymethyl [ 1 , l’-biphenyll -2-sulfonamide

A. 4′- [(2-Butyl-4-oxo- 1 ,3-diazaspiro [4.41 non- l-en-3-yl)methyll -N-(3 ,4- dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyll-2′- hvdroxym ethyl [1 , l’-biphenyl] -2-sulfonamide

Triethylsilane (6 ml) and TFA (6 ml) were added to a solution of 5F (960 mg, 1.5 mmol) in 15 ml dichloromethane at RT. The mixture was stirred at RT for 2 h and was then concentrated. The residue was taken up in ethyl acetate and was washed successively with aqueous sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel using 100:2 dichloromethane/methanol to afford 42A (740 mg, 77%) as a colorless gum. Rf=0.13, silica gel, 100:5 dichloromethane/methanol. B. 4′- [(2-Butyl-4-oxo- 1.3-diazaspiro [4.41 non- l-en-3-yl)methyll -N-(3.4- dimethyl-5-isoxazolyl)-N-r(2-methoxyethoxy)methyll-2′- ethoxymethyl[l.l’-biphenyll-2-sulfonamide A mixture of 42A (100 mg, 0.15 mmol), iodoethane (960 mg, 6.1 mmol) and silver (I) oxide (180 mg, 0.77 mmol) in 0.7 ml DMF was heated at 40 ° C for 16 h.. Additional iodoethane (190 mg, 1.2 mmol) and silver (I) oxide (71 mg, 0.31 mmol) were added and the reaction mixture was heated at 40 ° C for an additional 4 h. The mixture was diluted with 1:4 hexanes/ethylacetate and was then washed with water and brine. The organic layer was dried over sodium sulfate and was then concentrated. The residue was chromatographed on silica gel using 200:3 dichloromethane/methanol as eluant to afford 42B (51mg, 49%) as a colorless gum. Rf=0.35, silica gel, 100:5 dichloromethane/methanol.

C. 4^,-[(2-Butyl-4-oxo-1.3-diazaspirof4.41non-l-en-3-yl)methyll-N-(3.4- dimethyl-5-isoxazolyl )-2′-ethoxym ethyl [ 1. l’-biphenyll -2-sulfonamide

42B (51 mg) was deprotected according to General Method 7 to afford the title compound in 80% yield following preparative reverse-phase HPLC purification: white solid; m.p. 74-80 ° C (amorphous); IH NMR (CDCL, )δ0.87(tr, J=7Hz, 3H), 0.99(tr, J=7Hz, 3H), 1.32(m, 2H), 1.59(m, 2H), 1.75-2.02(m, 11H), 2.16(s, 3H), 2.35(m, 2H), 3.38 (m, 2H), 4.23(m, 2H), 4.73(s, 2H), 7.11-7.85 (m, 7H); MS m/e 593 (ESI+ mode); HPLC retention time 18.22 min. (Method E); HPLC purity >97%.

PATENT

WO 2001044239

http://www.google.co.in/patents/WO2001044239A2?cl=en

……………………

Dual angiotensin II and endothelin A receptor antagonists: Synthesis of 2′-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics
J Med Chem 2005, 48(1): 171

J. Med. Chem., 2002, 45 (18), pp 3829–3835

DOI: 10.1021/jm020138n

http://pubs.acs.org/doi/abs/10.1021/jm020138n

BMS 248360 A DIFFERENT COMPD

The ET_A receptor antagonist (2) (N-(3,4-dimethyl-5-isoxazolyl)-4‘-(2-oxazolyl)-[1,1‘-biphenyl]-2-sulfonamide, BMS-193884) shares the same biphenyl core as a large number of AT₁ receptor antagonists, including irbesartan (3). Thus, it was hypothesized that merging the structural elements of 2 with those of the biphenyl AT₁ antagonists (e.g., irbesartan) would yield a compound with dual activity for both receptors. This strategy led to the design, synthesis, and discovery of (15) (4‘-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-2‘-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-[1,1‘-biphenyl]-2-sulfonamide, BMS-248360) as a potent and orally active dual antagonist of both AT₁ and ET_Areceptors. Compound 15 represents a new approach to treating hypertension.

Scheme 2 ^{a DIFFERENT COMPD}

^a (a) DIBAL, toluene; (b) NaBH₄, MeOH; (c) (Ph)₃P, CBr₄, THF (51% from 9); (d) compound 7, NaH, DMF; (e) 1 N HCl; (f) compound 4, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (g) 6 N aqueous HCl/EtOH (60% from 10); (h) 13, sodium triacetoxy borohydride, AcOH, (i) diisopropylcarbodiimide, CH₂Cl₂ (31% from 12).

PATENT

WO 2010135350

http://www.google.com/patents/WO2010135350A2?cl=en

Compound 1 :

Scheme IV

Scheme V

Formula IV 1

Scheme VII

Formula Vl

A solution of 2-(2,4-dimethylphenyl)benzenesulfonic acid (Compound 12) (0.5 g, 1.9 mmol) in 50 mL of anhydrous acetonitrile was prepared and transferred to a round-bottom flask. After flushing with nitrogen gas, N-bromosuccinimide (0.75 g, 4.2 mmol) was added followed by 50 mg (0.2 mmol) of benzoyl peroxide. The solution was heated at reflux for 3 hours. The solvent was removed in-vacuo and the resulting syrup purified by silica gel chromatography (1 :1 hexanes/EtOAc) to yield Compound 13 as a white solid. ¹H NMR (500 MHz, CD3CN) 8.12 (d, J = 7.5 Hz, IH), 7.92 (t, J = 7.5 Hz, IH), 7.78 (d, J= 7.5 Hz, IH), 7.74-7.71 (m, 2H), 7.68-7.65 (m, 2H), 5.12 (s, 2H), 4.70 (s, 2H). Example 4 2-(4-Bromomethyl-2-ethoxymethylphenyl)benzenesulfonic acid (Compound 14)

A solution of 20 mg (0.058 mmol) of (l-bromomethylbenzo[3,4- d])benzo[l,2-f]-2-oxa-l,l-dioxo-l-thiocycloheptane (Compound 13) in ethanol was stirred at elevated temperature until the starting material was consumed to give crude product (compound 14) that was used directly in the next step without isolation or purification.

Example 5

2-(4-((2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl>2- ethoxymethylphenyl)benzenesulfonic acid (Compound 15)

To the above ethanol solution of crude 2-(4-bromomethyl-2- ethoxymethylphenyl)benzenesulfonic acid (Compound 14) described in Example 4 was added approximately 25 mL of anhydrous DMF. The ethanol was removed from the system under reduced pressure. Approximately 15 mg (0.065 mmol) of 2-butyl-l,3- diazaspiro[4.4]non-l-en-4-one (compound 7 in Scheme IV) was added followed by 300 μL of a IM solution of lithium bis-trimethylsilylamide in THF. The solution was allowed to stir at room temperature for 3 hours. The solvents were removed under reduced pressure and the remaining residue purified by preparative RP-HPLC employing a Cl 8 column and gradient elution (H₂O:MeCN) affording the title compound as a white solid; [M+H]+ calcd for C₂₇H₃₄N₂O₅S 499.21, found, 499.31 ; ¹H NMR (500 MHz, CD3CN) 8.04 (t, J= 5.5 Hz, IH), 7.44-7.10 (m, 2H), 7.28 (s, IH), 7.22 (d, J= 8.0 Hz, 2H), 7.08- 7.04 (m, 2H), 4.74 (br s, 2H), 4.32 (d, J= 13.0 Hz IH), 4.13 (d, J= 13.0 Hz IH), 3.40- 3.31 (m, 2H), 2.66 (t, J= 8 Hz, 2H), 2.18-2.13 (m, 5H), 1.96-1.90 (m, 2H obscured by solvent), 1.48 (m, 2H), 1.27 (s, J= 7 Hz, 2H), 1.16 (t, J= 7 Hz, 3H), 0.78 (t, J= 7.5 Hz, 3H).

Example 6

2-(4-((2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl>2- ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16)

To a solution of DMF (155 μL, 2 mmol, 2 equiv.) in dichloromethane (5 mL) at 0 ⁰C was added dropwise oxalyl chloride (175 μL, 2 mmol, 2 equiv.) followed by a dichloromethane (5 mL) solution of 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l- en-3-yl)methyl)-2-ethoxymethylphenyl)benzenesulfonic acid (Compound 15) (0.50 g, 1.0 mmol). The resulting mixture was stirred at 0 ⁰C for ~2 hours, diluted with additional dichloromethane (25 mL), washed with saturated sodium bicarbonate solution (10 mL), water (10 mL), and brine (10 mL), dried over sodium sulfate, and then concentrated to give crude sulfonyl chloride (compound 16) that was used without purification.

Example 7

N-(3,4-Dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en- 3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1)

[0062] To a solution of 5-amino-3,4-dimethylisoxazole (60 mg, 0.54 mmol) in THF at -60 °C was added dropwise potassium tert-butoxide (1 mL of 1 M solution) followed by a solution of crude 2-(4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3- yl)methyl)-2-ethoxymethylphenyl)benzenesulfonyl chloride (Compound 16) (0.28 g, 0.54 mmol) in THF (4 mL). The resulting mixture was stirred at about -60 °C for 1 hour, allowed to warm to room temperature overnight, and then quenched with IN HCl solution to about pH 4. Standard workup of extraction with ethyl acetate, washing with water, drying, and concentration provided the final compounds as a white solid. ¹H NMR (400 MHz, CDCl₃) 8.03 (dd, J = 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J = 7.5, 2H), 1.37 (sextet, J = 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H).

Example 8 l-Bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17)

To a solution of ethyl 4-bromo-3-ethoxymethylbenzoate (9.4 g, 33 mmol) in toluene (56 mL) at about -10 ⁰C was added 51 g of a 20% diisobutylaluminum hydride solution in toluene (ca. 70 mmol). The reaction was stirred at the same temperature for about 30 minutes until the reduction was completed, and then quenched with icy 5% NaOH solution to keep the temperature below about 10 °C. Organic phase of the resulting mixture was separated and the aqueous phase was extracted with toluene. The combined organic phase was concentrated in vacuo to a final volume of ~60 mL toluene solution of l-bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17) that was used in next step without purification.

Example 9 l-Bromo-2-ethoxymethyl-4-methanesulfonyloxymethylbenzene (Compound 18)

To a solution of 1 -bromo-2-ethoxymethyl-4-hydroxymethylbenzene (Compound 17) (8.4 g, 33 mmol) in toluene (60 mL) prepared in Example 8 at about -10 °C was added methanesulfonyl chloride (7.9 g, 68 mmol). The reaction was stirred at the same temperature for about 30 minutes until the reduction was completed, and then quenched with icy water to keep the temperature at about 0 °C. The organic layer was separated and washed again with icy water to provide a crude product solution of 1 – bromo-2-ethoxymethyl-4-methanesulfonyloxymethylbenzene (Compound 18) that was used without purification.

Example 10

1 -Bromo-4-((2-butyl-4-oxo- 1 ,3 -diazaspiro [4.4]non- 1 -en-3 -yl)methy l)-2- ethoxymethylbenzene bisoxalic acid salt (Compound 19)

To the crude solution of 1 -bromo-2-ethoxymethyl-4- methanesulfonyloxymethylbenzene (Compound 18) (1 1 g, 33 mmol) in toluene (80 mL) prepared in Example 9 was added a 75% solution of methyltributylammonium chloride in water (0.47 mL). The resulting mixture was added to a solution of 2-butyl-4-oxo-l,3- diazaspiro[4.4]non-l-ene (compound 7 in Scheme VI) (7.5 g, 32 mmol) in dichloromethane (33 mL) pretreated with a 10 M NaOH solution (23 mL). The reaction mixture was stirred at room temperature for 2 hours until compound 18 was not longer detectable by HPLC analysis and then was quenched with water (40 mL). After stirring about 10 minutes, the organic layer was separated and aqueous layer was extracted with toluene. The combined organic phase was washed with water and concentrated to a small volume. Filtration through a silica gel pad using ethyl acetate as solvent followed by concentration yielded 1 -bromo-4-((2-buty 1-4-oxo- 1 ,3 -diazaspiro [4.4]non- 1 -en-3 – yl)methyl)-2-ethoxymethylbenzene as a crude oil product.

The crude oil was dissolved in ethyl acetate (22 mL) and warmed to around 50 °C. Anhydrous oxalic acid (4.6 g) was added to the warm solution at once and the resulting mixture was stirred until a solution was obtained. The mixture was cooled gradually and the bisoxalic acid salt (compound 19) was crystallized. Filtration and drying provided pure product (compound 19) in 50-60% yield from ethyl 4-bromo-3- ethoxymethylbenzoate in 3 steps. ¹H NMR (400 MHz, CDCl₃) 12.32 (bs, 4H), 7.58 (d, J = 7.8, IH), 7.36 (s, IH), 7.12 (d, J= 7.8, IH), 4.90 (s, 2H), 4.56 (s, 2H), 3.68 (q, J= 7.5, 2H), 2.87-2.77 (m, 2H), 2.40-1.95 (m, 8H), 1.62-1.53 (m, 2H), 1.38-1.28 (m, 4H), and 1.82 (t, J= 7.5, 3H).

Example 11

N-(3,4-Dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en- 3yl)methyl-2-ethoxymethylphenyl)phenylsulfonamide (Compound 1)

To a suspension of l-bromo-4-((2-butyl-4-oxo-l,3-diazaspiro[4.4]non- l-en-3-yl)methyl)-2-ethoxymethylbenzene bisoxalic acid salt (Compound 19) (5.0 g, 8.3 mmol) in toluene (20 niL) under nitrogen was added water (30 mL) and pH was adjusted to 8-9 by addition of a 2 M NaOH solution at room temperature. The organic phase was separated and mixed with 2-(N-(3,4-dimethyl-5-isoxazolyl)-N- methoxymethylamino)sulfonylphenylboronic acid pinacol ester (Scheme VII, Formula IX, where R⁸is methoxymethyl and M = boronic acid pinacol ester) (3.6 g, 8.5 mmol), bis(dibenzylideneacetone)palladium(0) (Pd(dba)₂) (0.12 g), and a standard phosphine ligand. After a 2 M sodium carbonate solution was added, the reaction mixture was warmed to 70 ⁰C and stirred until the reaction was complete by HPLC analysis. The reaction was cooled to room temperature and quenched with water, and then separated in phases. The organic phase was treated with activated carbon, filtered through a pad of silica gel, and was concentrated to afford a crude mixture.

The crude reaction mixture was dissolved in ethanol (40 mL) after palladium catalyst was removed and was treated with 6 M HCl solution (ca. 40 mL). The mixture was warmed to 75-80 °C and stirred for about 2 hours until the reaction was completed by HPLC analysis. After the mixture was cooled to room temperature, the pH of the mixture was adjusted to 8 by addition of 10 M NaOH solution. The mixture was stirred for 2 more hours and the pH was adjusted to 6 by adding 2 M HCl and the crystal seeds. Filtration of the crystalline solid followed by drying provided N-(3,4-dimethyl-5- isoxazolyl)-2-(4-(2-butyl-4-oxo-l,3-diazospiro[4.4]non-l-en-3yl)methyl-2- ethoxymethylphenyl)phenylsulfonamide (Compound 1) as a white solid.¹H NMR (400 MHz, CDCIa) 8.03 (dd, J= 8.0 and 1.2, IH), 7.60 (td, J = 7.5 and 1.5, IH), 7.50 (td, J = 7.7 and 1.5, IH), 7.36 (s, IH), 7.28 (d, J= 2.1, 1 H), 7.25 (dd, J = 7.5 and 1.2, IH), 7.09 (dd, J= 7.9 and 1.6, IH), 6.61 (bs, IH), 4.77 (AB quartet, J= 15.5 and 8.1, 2H), 4.18 (AB quartet, J= 12.0 and 35, 2H), 3.45-3.32 (m, 2H), 2.39 (t, J= 7.5, 2H), 2.26 (s, 3H), 2.02- 1.84 (m, 8H), 1.82 (s, 3H), 1.63 (quint, J= 7.5, 2H), 1.37 (sextet, J= 7.3, 2H), 1.07 (t, J = 7.0, 3H), and 0.90 (t J= 7.3, 3H).

US20040002493 *	Aug 20, 2001	Jan 1, 2004	Kousuke Tani	Benzoic acid derivatives and pharmaceutical agents comprising the same as active ingredient
US20070054806 *	Sep 6, 2006	Mar 8, 2007	Bayer Cropscience Gmbh	Novel sulfonamide-comprising solid formulations
US20070054807 *	Sep 8, 2006	Mar 8, 2007	Bayer Cropscience Gmbh	Storage-stable formulations of sulfonamides

Sparsentan
Clinical data

Trade names	Filspari
Other names	RE-021, PS433540
AHFS/Drugs.com	Monograph
MedlinePlus	a623018
License data	US DailyMed: Sparsentan
Pregnancy category	Contraindicated
Routes of administration	By mouth
ATC code	C09XX01 (WHO)
Legal status
Legal status	US: ℞-only^[1] EU: Rx-only^[2]^[3]
Identifiers
CAS Number	254740-64-2
PubChem CID	10257882
DrugBank	DB12548
UNII	9242RO5URM
KEGG	D11776
ChEBI	CHEBI:229526
ECHA InfoCard	100.275.317
Chemical and physical data
3D model (JSmol)	Interactive image
show SMILES
show InChI

References

^ Jump up to:^a ^b ^c ^d ^e ^f “Filspari- sparsentan tablet, film coated”. DailyMed. 17 February 2023. Retrieved 6 March 2023.
^ Jump up to:^a ^b ^c ^d “Filspari EPAR”. European Medicines Agency (EMA). 22 February 2024. Retrieved 24 February 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
^ Jump up to:^a ^b “Filspari Product information”. Union Register of medicinal products. 23 April 2024. Retrieved 7 September 2024.
^ Chiu AW, Bredenkamp N (September 2023). “Sparsentan: A First-in-Class Dual Endothelin and Angiotensin II Receptor Antagonist”. The Annals of Pharmacotherapy. 58 (6): 645–656. doi:10.1177/10600280231198925. PMID 37706310. S2CID 261743204.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q “Drug Trials Snapshots: Filspari”. U.S. Food and Drug Administration (FDA). 17 February 2023. Retrieved 7 September 2024. This article incorporates text from this source, which is in the public domain.
^ “Travere Therapeutics Announces FDA Accelerated Approval of Filspari (sparsentan), the First and Only Non-immunosuppressive Therapy for the Reduction of Proteinuria in IgA Nephropathy” (Press release). Travere Therapeutics. 17 February 2023. Retrieved 17 February 2023 – via GlobeNewswire.
^ Syed YY (April 2023). “Sparsentan: First Approval”. Drugs. 83 (6): 563–568. doi:10.1007/s40265-023-01864-x. PMC 10232600. PMID 37022667.
^ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
^ “PHARMACOPEIA LAUNCHES STUDY OF DARA COMPOUND | FDAnews”. http://www.fdanews.com.
^ “Ligand Licenses DARA Program to Retrophin”. investor.ligand.com. 21 February 2012.
^ https://www.fiercebiotech.com/biotech/retrophin-sheds-shkreli-connection-new-name-travere-therapeutics. {{cite news}}: Missing or empty |title= (help)
^ “Ongoing Non-malignant Hematological, Neurological, and Other Disorder Indications Accelerated Approvals”. U.S. Food and Drug Administration (FDA). 21 August 2024. Retrieved 7 September 2024.
^ “Travere Therapeutics Announces Full FDA Approval of Filspari (sparsentan), the Only Non-Immunosuppressive Treatment that Significantly Slows Kidney Function Decline in IgA Nephropathy” (Press release). Travere Therapeutics. 5 September 2024. Retrieved 7 September 2024 – via GlobeNewswire.
^ “Despite trial scare, Travere’s Filspari gains full FDA nod in kidney disease showdown with Novartis”. fiercepharma.com.

External links

Clinical trial number NCT03762850 for “A Study of the Effect and Safety of Sparsentan in the Treatment of Patients With IgA Nephropathy (PROTECT)” at ClinicalTrials.gov

SYN

https://doi.org/10.1021/acs.jmedchem.4c02079
J. Med. Chem. 2025, 68, 2147−2182

Sparsentan (Filspari). Sparsentan (27), marketed by Travere Therapeutics, is an oral, dual endothelin angiotensin receptor antagonist that received accelerated USFDA approval in February 2023 for reducing proteinuria in adults with primary immunoglobulin A (IgA) nephropathy who are at risk of rapid
disease progression.205206,207 Also known as Berger’s disease, IgAnephropathy is an immune-complex mediated disease characterized by deposits of IgA in the kidneys, resulting in inflammation and damage which can eventually lead to kidney failure. Typical treatment of IgA nephropathy has focused
on supportive care to slow kidney decline, for example, lowering blood pressure, reducing proteinuria, and minimizing lifestyle risk factors; immunosuppressive therapy has also been utilized, though it is controversial and carries risks.208 Sparsentan is the first nonimmunosuppressive treatment for IgA nephropathy and has received first-in-class and orphan drug designations. Accelerated approval was based on reduction of proteinuria (which is a risk factor for disease progression) during interim
analysis in phase III clinical trials. 209 endothelin type A (ETASparsentan blocks ) and angiotensin II type 1 receptors(AT1), interrupting the signaling pathway that contributes to disease progression. 210
The structure of the drug combines 211,212 elements that target both of these receptor types.
213 Thesynthesis of sparsentan (27), as shown in Scheme 50 and Scheme 51, was disclosed by Retrophin Pharmaceuticals (now Travere Therapeutics). Its telescoped sequences and isolation of intermediates as salts suggest that this route may be suitable for large-scale manufacturing.
The synthesis of the spirocyclic imidazolinone intermediate 27.7 is shown in Scheme 50.
Displacement of the benzylic bromide in 27.1 with sodium ethoxide produced ether 27.2. Reduction of the ester with sodium borohydride and zinc chloride yielded alcohol 27.3 which was then converted to mesylate 27.4. Reaction with spirocyclic imidazolinone 27.5 under phase transfer conditions
yielded 27.6 whichwasisolatedasthebisoxalatesalt (27.7).The sequence from 27.1 to 27.7 is telescoped, and no yields were given in the patent.
The construction of the biphenyl framework is shown in Scheme 51. Treatment of aryl bromide 27.8 with n-BuLi and triisopropyl borate followed by reaction with pinacol yielded boronic ester 27.9. Intermediates 27.7 and 27.9 were coupled via a Suzuki reaction to form the biphenyl which was isolated as
the camphorsulfonate salt (27.10). The synthesis was finished with deprotection of the methoxymethyl group under acidic conditions followed by recrystallization from isopropanol and heptane to yield sparsentan (27).

(206) Donadio, J. V.; Grande, J. P. IgA nephropathy. N. Engl. J. Med.2002, 347, 738−748.
(207) Fabiano, R. C. G.; Pinheiro, S. V. B.; Simões e Silva, A. C.Immunoglobulin A nephropathy: a pathophysiology view. Inflammation Res. 2016, 65, 757−770.
(208) Floege, J.; Rauen, T.; Tang, S. C. W. Current treatment of IgAnephropathy. Springer Semin. Immunopathol. 2021, 43, 717−728.
(209) Rovin, B.H.; Barratt, J.; Heerspink, H. J. L.; Alpers, C. E.; Bieler,S.; Chae, D.-W.; Diva, U. A.; Floege, J.; Gesualdo, L.; Inrig, J. K.; et al.Efficacy and safety of sparsentan versus irbesartan in patients with IgA
nephropathy (PROTECT): 2-year results from a randomised, active controlled, phase 3 trial. Lancet 2023, 402, 2077−2090.
(210) Komers, R.; Plotkin, H. Dual inhibition of renin-angiotensin aldosterone system and endothelin-1 in treatment of chronic kidney disease. Am. J. Physiol.: Regul., Integr. Comp. Physiol. 2016, 310, R877−
R884.
(211) Murugesan, N.; Tellew, J. E.; Gu, Z.; Kunst, B. L.; Fadnis, L.;Cornelius, L. A.; Baska, R. A. F.; Yang, Y.; Beyer, S. M.; Monshizadegan, H.; et al. Discovery of N-isoxazolyl biphenylsulfonamides as potent dual
angiotensin II and endothelin A receptor antagonists. J. Med. Chem.2002, 45, 3829−3835.
(212) Murugesan, N.; Gu, Z.; Fadnis, L.; Tellew, J. E.; Baska, R. A. F.; Yang, Y.; Beyer, S. M.; Monshizadegan, H.; Dickinson, K. E.; Valentine,M.T.; et al. Dual angiotensin II and endothelin A receptor antagonists:
synthesis of 2′-substituted N-3-isoxazolyl biphenylsulfonamides withimproved potencyandpharmacokinetics. J. Med. Chem. 2005, 48, 171−179.
(213) Komers, R.; Shih, A. Biphenyl sulfonamide compounds for the treatment of kidney diseases or disorders. WO 2018071784, 2018.

//////////////Sparsentan, PS433540, RE-021, Bristol-Myers Squibb, ORPHAN DRUG, Retrophin, FDA 2023, APPROVALS 2023

O=S(C1=CC=CC=C1C2=CC=C(CN3C(CCCC)=NC4(CCCC4)C3=O)C=C2COCC)(NC5=NOC(C)=C5C)=O,

Synthesis of a fluorinated Ezetimibe analogue

October 9, 2015 7:32 am / Leave a comment

Synthesis of a fluorinated Ezetimibe analogue using radical allylation of [small alpha]-bromo-[small alpha]-fluoro-[small beta]-lactam

New J. Chem., 2015, Advance Article
DOI: 10.1039/C5NJ01969A, Paper

Atsushi Tarui, Ayumi Tanaka, Masakazu Ueo, Kazuyuki Sato, Masaaki Omote, Akira Ando

Atsushi Tarui,^a Ayumi Tanaka,^a Masakazu Ueo,^a Kazuyuki Sato,^a Masaaki Omote^a and Akira Ando*^a

*Corresponding authors

^aFaculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Japan
E-mail: aando@pharm.setsunan.ac.jp

A facile and efficient synthesis of a fluorinated Ezetimibe analogue was achieved by radical allylation, Wacker oxidation, and nucleophilic arylation of [small alpha]-bromo-[small alpha]-fluoro-[small beta]-lactam

The synthesis of an α-fluoro-β-lactam-containing Ezetimibe analogue was accomplished starting from α-bromo-α-fluoro-β-lactam which was readily prepared from ethyl dibromofluoroacetate. A facile and efficient method for the introduction of the C3 alkyl side chain was realized via radical allylation. The diastereoselective allylation of α-bromo-α-fluoro-β-lactam was successfully applied to construct the relative configuration of the β-lactam nucleus between C3 and C4. Further modification of the allyl side chain gave the 3′-(4-fluorophenyl)-3′-hydroxypropyl group through Wacker oxidation and nucleophilic arylation.

http://pubs.rsc.org/en/Content/ArticleLanding/2015/NJ/C5NJ01969A?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FNJ+%28RSC+-+New+J.+Chem.+latest+articles%29#!divAbstract

Acceptability of Draft Labeling to Support ANDA Approval Guidance for Industry

October 9, 2015 3:28 am / Leave a comment

Acceptability of Draft Labeling to Support ANDA Approval Guidance for Industry

INTRODUCTION This guidance provides recommendations and information related to the submission of proposed labeling with abbreviated new drug applications (ANDAs) under section 505(j)(2)(A)(v) of the Federal Food, Drug, and Cosmetic Act (the Act) and FDA’s implementing regulations (21 CFR 314.94(a)(8)). This guidance is intended to assist applicants submitting ANDAs under section 505(j) of the Act to the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and Research (CDER). It explains FDA’s interpretation of the regulatory provision related to the submission of copies of applicants’ proposed labeling in ANDAs and clarifies that OGD will accept draft labeling and does not require the submission of final printed labeling (FPL) in order to approve an ANDA. FDA is implementing this guidance without prior public comment because the Agency has determined that prior public participation is not feasible or appropriate (see 21 CFR 10.115(g)(2) and (g)(3)). FDA made this determination because this guidance presents a less burdensome policy that is consistent with the public health. In general, FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

DISCUSSION OGD is issuing this guidance to provide regulated industry and other interested persons with our current thinking on the requirement that ANDA applicants submit copies of proposed labeling in their applications. Specifically, OGD is clarifying whether submission of FPL as opposed to draft labeling is required in order for OGD to approve an ANDA…………http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm465628.pdf

Acceptability of Draft Labeling to Support Abbreviated New Drug Application Approval; Guidance for Industry

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EZETIMIBE POSTER

October 8, 2015 3:51 am / Leave a comment

The synthesis of ezetimibe with high stereochemical purity

Krzysztof Bańkowski , Katarzyna Sidoryk , Katarzyna Filip , Joanna Zagrodzka

Pharmaceutical Research Institute (IF), Rydygiera 8, Warszawa 01-793, Poland

Ezetimibe, (3R,4S)-1-(4-fluorophenyl)-3-((3S)-3-(4-fluorophenyl)- 3-hydroxypropyl)-4-(4-hydroxyphenyl)-2-azetidinone, is an anti-hyperlipidemic drug which is used to lower cholesterol level. It acts by decreasing cholesterol absorption in the intestine.

The three chiral centers in the ezetimibe molecule give rise to eight stereoisomers and the synthesis of stereochemical pure ezetimibe is a significant challenge. The synthesis of ezetymibe is described in many patents and patent applications, however the problem of stereochemical purity of the final product and its intermediates is almost completely omitted.

The synthesis of ezetimibe was realized by a procedure shown below, according to Schering Co. patents No US 6,207,822, EP 1137634:

We have investigated the sterochemical course of all steps of this process and found that for the preparation of optical pure ezetimibe the providing of pure (S,R,S,S) – EZ-6 is cru-cial. This diastereomer (product of anti-condensation of EZ-4 + EZ-5) is usually contaminated with (S,R,R,S) – EZ-6 isomer (syn-condensation), and also with (R,R,S,S) – EZ-6 isomer derived from small amount of (R,S)-alcohol EZ-4 which is usually occurring in required (S,S)-alcohol. The presence of (R,R,S,S) – EZ-6 diastereomer leads to (R,R,S) -“iso-ezetimibe” which is very difficult to remove from ezetimibe.
The synthesis of ezetimibe was optimized, all chemical and sterochemical impurities were isolated and/or synthesized and characterized by NMR, MS and HPLC techniques. The method for the purification of desired key intermediate (S,R,S,S)-6 was elaborated. These al-lowed us to develop the large scale efficient synthesis of pharmaceutical pure Ezetimibe (HPLC > 99,5 %, (R,R,S)-isomer < 0,1 %, single unknown impurity < 0,1 %, total impurities < 0,6 % ).

Ezetimibe has the chemical name 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone (hereinafter referred to by its adopted name “ezetimibe”) and is structurally represented by Formula I.

Ezetimibe is in a class of lipid lowering compounds that selectively inhibit the intestinal absorption of cholesterol and related phytosterols. It is commercially available in products sold using the trademark ZETIA as a tablet for oral administration containing 10 mg of ezetimibe, and in combination products with simvastatin using the trademark VYTORIN.

U.S. Pat. No. 6,096,883 discloses generically and specifically ezetimibe and its related compounds along with their pharmaceutical compositions

The preparation of ezetimibe ezetimibe first disclosed in U.S. Patent US 5767115.

Hydrogen Debenzylation get ezetimibe, the method disclosed in this patent require the use of several key intermediates purified by column chromatography, increasing the difficulty and cost of industrial production.

US patent US5767115 to improve the synthesis process have also been reported. For example: W02006137080 US5767115 on the basis of synthesis of intermediate compound 3 were improved optimization, using pivaloyl chloride and the formation of a mixed anhydride intermediate compound 2, and then with the chiral auxiliary (S) -4- phenyl-2- oxazolidinone reaction intermediate compound 3; US Patent US6133001 discloses a microbial catalytic asymmetric reduction of carbonyl to give chiral hydroxy, instead US5767115 Synthesis of (R) -CBS catalyst;

W02008089984 reported the use of a rhodium catalyst [(S, S) -N- (piperidyl-N-sulfonyl) -I, 2-diphenyl ethylenediamine] (η 6-mesitylene) Ruthenium right of intermediate compound 9Said reduction.

W02008032338 reports by reacting the intermediate compound 8 with a salt of an aliphatic amine which was purified manner, although effectively improve the purity, but adds steps, and the yield was significantly reduced.

In addition to the synthetic route based on open Pu Xi US5767115, US Patent US6207822, US Patent US5856473, US patent US5886171, W02005066120, W02005113496, W02006050634, W02007017705 also disclose the ezetimibe different preparation methods.

Patent W02007072088 discloses another synthetic route for preparing ezetimibe ezetimibe, which is a small step synthesis reaction, the specific synthetic route is as follows:

Another US: 5739321; US: 1 5886171 reported the route: the (4S) – hydroxytetrahydrofuran _2_ one and N- (4- fluorophenyl) -4-benzyloxy-benzylidene methylamine as starting Preparation of raw ezetimibe, the reaction scheme is as follows:

…………

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014012372&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Since the first report since the synthesis method, there are already several ezetimibe ezetimibe synthetic route reports, such as document US 5856473, US 5739321, EP 1137634, EP 720599, WO 1995/08532 EP 0720599, provides ezetimibe ezetimibe synthetic route.

Example 9 Preparation of Compound 8 embodiment.

Hydrogenation bottle was added 7a (2.14 g, 4.3 mmol), methanol (30 mL), was added Pd / C (50 mg :), transferred into the autoclave, and replaced with hydrogen three times, filled with hydrogen 5 atm, room temperature and stirred for 6 hours, venting of hydrogen, filtered through Celite, with a small amount of methanol (10 mL), dried and concentrated, the residue was mixed solvent of methyl t-butyl ether, and recrystallized from n-hexane to give compound 8, 78% yield

8, 1H-NMR (300 MHz, DMSO ₆ ) [delta] = 9.50 (s, 1H), 7.41-7.07 (m, 10H), 6.79 (d, J = 8.6 Hz, 2H), 5.27-5.25 (m, 1H) , 4.78-4.71 (m, 1H), 4.47-4.44 (m, 1H), 3.07-3.08 (m, 1H), 1.85-1.75 (m, 4H) ppm. 10 Compound la (P = Bn benzyl)

Example 3 (Preparation -2a of.

The reaction is as follows: Under an argon atmosphere, [Pd (C ₃ H ₅ ) Cl] ₂ (54.8 mg, 0.15 mmol) and (&& 5 Lc (193 mg, 0.25 mmol) were added to a Schlenk tube, was added anhydrous CH ₂ C1 ₂ C50 mL), stirred at room temperature for 10 minutes, the substrate was added successively lb (4.12 g, 10 mmol), K ₂ C0 ₃(1.0 M solution, 30 mL, 30 mmol) and p-fluoroaniline (3.33 g, 30 mmol ). After stirring at room temperature for three hours, liquid separation, the aqueous phase was extracted with dichloromethane (3 x 50 mL), The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated

(I?) – 2a, 85% yield, 93% ee.

Example 4 Compound Example (Preparation -2b of.

The reaction is as follows: Under an argon atmosphere, [Pd (C ₃ H ₅ ) Cl] ₂ (54.8 mg, 0.15 mmol) and (&& 5) -La (165 mg, 0.25 mmol) were added to a Schlenk tube, was added anhydrous CH ₂ C1 ₂ C50 mL), stirred at room temperature for 10 minutes, the substrate was added successively lb (3.78 g, 10 mmol), K ₂ C0 ₃(1.0 M solution, 30 mL, 30 mmol) and p-fluoroaniline (3.33 g, 30 mmol). After stirring at room temperature for three hours, liquid separation, the aqueous phase was extracted with dichloromethane (3 x 50 mL), The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, purified by column chromatography to give asymmetric amination the product of (i?) – 2b. The reaction formula is as follows:

(R) -2b, colorless liquid, yield 86%, [a] _D^2Q = -89.1 (c 1.00, CHC1 ₃ ), EE 95% [determined by high-performance liquid chromatography, chiral AD-H column, n hexane / isopropanol = 95: 5, 1.0 mL / min, 254 nm; t _R (minor) = 4.15 min; t _R . (Major) = 4.60 min] 1H NMR (300 MHz, CDCl ₃ ) [delta] = 7.20 (d, J = 8.4 Hz, 2H), 6.89-6.78 (m, 4H), 6.51-6.47 (m, 2H), 6.34 (s, 1H), 5.88 (s, 1H), 5.26 (s, 1H), 4.19-4.08 (m, 2H), 4.00 (s, br, 1H), 1.20 (t, J = 7.2 Hz, 3H), 0.97 (s, 9H), 0.18 (s, 6H) ppm; ¹³ C NMR (100 MHz, CDCl ₃ ) [delta] = 166.1, 155.8 (d, J _(F , _C) = 234.3 Hz), 155.1 (s), 143.0 (d, J _(F , _C) = 1.9 Hz), 140.4 (s), 133.1 (s), 128.5 (s), 125.2 (s), 120.0 (s), 115.4 (d, J _(F , C) = 22.3 Hz), 114.1 (d, J _(F , _C) = 7.4 Hz), 60.6 , 58.9, 25.5, 18.0, 13.9, -4.5 ppm; ¹⁹ F-NMR (376 MHz, CDCl ₃ ) [delta] -127.5 ppm.

Preparation Example 5 Compound 4a embodiment.

(I?) – 2a (3.44 g, 8.48 mmol) and nucleophiles 3a (2.82 g, 12.7 mmol) was added in an eggplant-shaped flask, tetrahydrofuran (100 mL), DBU (4.25 g, 16.96 mmol was stirred at room temperature for 12 hours, thin layer chromatography until starting material disappeared by TLC the reaction mixture was concentrated and purified by column chromatography, to obtain compound 4a, 82% yield (Note: Allyl allyl).

ESI-MS m / z: 628.4 [M + H ⁺ ]; HRMS (ESI) m / z:. calcd for C ₃₇ H ₃₆ N0 ₆ F ₂⁺¹ : 628.2505, Found:

⁺ ]. After the reaction system may also not treated directly in the next step. The reaction formula is as follows:

: Example 6 Preparation of Compound 5a.

To the reaction system of Example 5 is continued morpholine (4.43 g, 50.88 mmol) and Pd (PPh ₃ ) ₄ , and stirring was continued at room temperature for 6 hours, concentrated purified by chromatography (98 mg, 0.0848 mmol) after column .

The total yield from the compound 2a to 5a rate of 71%. Compound 5a is composed of a pair of non-enantiomer at a ratio of 2 or 3: 1. No need to separate the non-enantiomer, can be used directly in the next step.

ESI-MS m / z: 544.2 [M + H +]; HRMS (ESI) m / z:. Calcd for C33H31NO4 F ₂ Na ⁺¹ : 566.2113, Found: 566.2113 [M + Na ⁺ ].

Preparation Example 7 Compound 6a embodiment.

Compound 5a (3.5 g, 6.4 mmol) and anhydrous tetrahydrofuran (50 mL) was added an eggplant-shaped flask, and cooled to -20 ° C under slowly added dropwise amino lithium hexamethyldisilazide (LiHMDS) (1.0 M THF, 14 ml, 14 mmol). The reaction system was stirred at this temperature continued for 40 minutes, 5 mL of water was added to quench the reaction, and extracted with dichloromethane (3 x 100 mL), the organic phase was dried over anhydrous sodium sulfate

6a, 77% yield. [A] _D^2Q = +1.9 (c 1.00, MeOH), 95% EE [by the high performance liquid chromatography, chiral OD-H column n is isopropanol = 70:30, 1.0 mL / min, 254 nm; t _R (Major) = 19.60 min; t _R . (minor) = 25.83 min] 1H NMR (400 MHz, CDCl ₃ ) [delta] = 7.98-7.94 (m, 2H), 7.41-7.30 ( m, 5H), 7.25-7.23 (m, 4H), 7.09 (t, J = 8.8 Hz, 2H), 6.96-6.88 (m, 4H), 5.02 (s, 1H), 4.67 (d, J = 2.4 Hz , 1H), 3.31-3.23 (m, 1H), 3.17-3.08 (m, 2H), 2.42-2.20 (m, 2H) ppm; ¹³ C NMR (100 MHz, CDCl ₃ ) [delta] = 197.2, 167.1, 165.6 ( d, J _(F , _C) = 253.9 Hz), 158.9, 158.8 (d, J _(F , _C) = 242.2 Hz), 136.5, 133.7 (d, J _(F , _C) = 2.7 Hz), 132.9 (d , J _(F , _C) = 2.8 Hz), 130.5 (d, J _(F , C) = 9.4 Hz), 129.3, 128.5, 127.9, 127.3, 127.1, 118.2 (d, J _(F , _C) = 7.9 Hz ), 115.7 (d, J _(F , _C) = 8.4 Hz), 115.5 (d, J _(F , c) = 8.3 Hz), 115.3, 69.9, 60.9, 59.6, 35.4, 23.0 ppm; ¹⁹ F NMR (376 MHz, CDCl ₃ ) [delta] -104.8, -117.9 ppm.

Compound 6a is the same as reported in the literature specific rotation direction, the same NMR data reported in the literature. References:

(A) Wu, G; Wong, Y;. Chen, X .; Ding, ZJ Org Chem 1999, 64, 3714. (b) Sasikala, CHVA;. Padi, PR; Sunkara, V; Ramayya, P .; Dubey , PK; Uppala, VBR;… Praveen, C. Org Process Res Dev 2009, 13, 907. (c) Sova, M .; Mravljak, J .; Kovac, A .; Pecar, S .; Casar, Z .; Gobec, S .; Synthesis, 2010, 20, 3433.

Preparation Example 8 Compound 7a embodiment.

In dichloromethane (40 mL) and tetrahydrofuran (5 mL) were added to an eggplant-shaped flask, and cooled to 0 ° C, was added borane dimethyl sulfide complex (0.46 mL, 7.23 mmol) and – (+) – 2-methyl–CBS- oxazaborolidine (133 mg, 0.482 mmol). Compound 6 (; 2.4 _§ , 4.82 11 ^ 101) was dissolved in dichloromethane (2011 ^) in the join. Stirred at the same temperature for 5 hours. After completion of the reaction with methanol (10 mL) quenched the reaction was concentrated, added to 1 mol per liter of dilute hydrochloric acid, methylene-wan (X) was extracted, the organic phase was washed with saturated sodium chloride wash paint, concentrated, ethyl acetate – n-hexane to give the compound 7a, 90% yield,> 99%. Reaction

6a 7a

7a, 1H-NMR (300MHz, CDCI3) δ = 7.47-7.21 (m, 11H), 7.07-6.92 (m, 6H), 5.05 (s, 2H), 4.75-4.72 (m, 1H), 4.58 (m, 1H), 3.17-3.09 (m, 1H), 2.04-1.85 (m, 4H) ppm.

¹H NMR spectrum of C₂₄H₂₁F₂NO₃ in CDCL3 at 400 MHz.

Patent

http://www.google.com/patents/CN103086938A?cl=en

Another report line 2: (5S) – acetyl-5- (4-fluorophenyl) valeric acid as reaction intermediates for the preparation of ezetimibe, the synthesis process is as follows:

Figure CN103086938AD00071

Figure CN103086938AD00081

Figure CN103086938AD00101

Figure CN103086938AD00111

Seventh Embodiment

The 7 (20g, 0.04mol) was dissolved in methanol (25OmL) was added ammonium formate (25g, 0.4mol), 10% palladium / carbon (Ig) and formic acid (2mL, 0.04mol), stirred at room temperature 20min, filtered palladium / carbon, the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate, washed with saturated brine, and dried. The organic phase was concentrated to approximately 40mL, was slowly added thereto at room temperature, methyl tert-butyl ether, stirring lh, floc filtered and the filtrate was concentrated to dryness. The residue was dissolved in ethyl acetate, petroleum ether was added, stirred at room temperature 2h, filtered, and dried to give a white solid Ezetimibe 6.4g, yield 38.9%, [a] 2 ° D = _23.7. IH-NMR (DMS0-d6) δ: 9.51 (s, 1Η), 7.32-7.08 (m, 10Η), 6.75 (d, J = 8.4, 2Η), 5.27 (d, J = 4.5, 1Η), 4.80 ( d, J = 2.1, 1Η), 4.49 (m, 1Η), 3.08 (m, 1Η), 1.68-1.82 (m, 4Η).

PATENT

http://www.google.com/patents/CN102675177A?cl=en

Figure CN102675177AD00071

ezetimibe ezetimibe synthesis and purification methods:

A Method: IOOml reactor was added to 60ml of ethanol, was added glacial acetic acid and 6g 2. 4g compound 10, followed by stirring for 20 minutes, O. 6g 20% Pd (OH) 2 / C, purged with nitrogen, purged with hydrogen , under hydrogen atmosphere, 10 ° C at atmospheric pressure for 18 hours the reaction inches, TLC analysis showed complete conversion of compound 10, suction filtered, the mother liquor was concentrated to dryness under reduced pressure to a pale yellow solid, the resulting solid was dissolved with 40ml ko alcohol, filtered, the mother liquor 56ml of purified water was slowly added dropwise, after the large amount of solid precipitated, suction filtered, the filter cake rinsed with an aqueous solution of an ice drained, and dried in vacuo to give a white solid product, the resulting product was dissolved in 32ml ko alcohol, purified water was slowly added dropwise 160ml a large number of solid precipitation, filtration, alcohol use ko – after pumping out water rinse, 60 ° C and dried under vacuum to obtain the product 4. Og, yield: 81 · 4%.

B method: to IOOml reaction flask 60ml of methanol, acetic acid 2. 4g and 6g compound 10,

Stirred for 20 minutes, added I. 2g 20% Pd (OH) 2 / C, purged with nitrogen, purged with hydrogen under a hydrogen atmosphere, the reaction for 18 hours at ambient temperature and pressure inch, TLC analysis showed complete conversion of compound 10, suction filtered, the mother liquor concentrated to dryness under reduced pressure to a pale yellow solid, the resulting solid was dissolved with 40ml isopropanol, filtered, and the mother liquor was slowly added dropwise 56ml of purified water, a large number of solid precipitation, filtration, filter cake washed with isopropanol – water rinse after pumping dried, and dried in vacuo to give a white solid product, the resulting product was dissolved in 32ml isopropanol was slowly added dropwise 160ml of purified water, large amount of solid precipitated, suction filtered, washed with isopropanol – water rinse after draining, 60 ° C under vacuum drying products 3. 7g, yield: 75.3%.

C Method: To a IOOml 60ml of methanol was added to the reaction vessel, was added glacial acetic acid and 6g 2. 4g compound 10, followed by stirring for 20 minutes, O. 8g 20% Pd (OH) 2 / C, purged with nitrogen, purged with hydrogen , under hydrogen atmosphere, 30 ° C at atmospheric pressure for 18 hours the reaction inches, TLC analysis showed complete conversion of compound 10, suction filtered, the mother liquor was concentrated to dryness under reduced pressure to a pale yellow solid, the resulting solid was dissolved with 40ml ko alcohol, filtered, the mother liquor 56ml of purified water was slowly added dropwise, after the large amount of solid precipitated, suction filtered, the filter cake washed with methanol – water rinsing after drained, and dried in vacuo to give a white solid product, the resulting product was dissolved in 32ml of methanol, 160ml of purified water was slowly added dropwise a large number of solid precipitation, filtration, washed with methanol – after pumping out water rinse, 60 ° C under vacuum drying products 3. 5g, Yield: 71.3%.

PATENT

http://www.google.co.in/patents/CN102531985A?cl=en

Scheme 1

PATENT

http://www.google.com/patents/US20070049748

Processes for preparation of ezetimibe and its intermediates have also been described in U.S. Pat. Nos. 6,207,822, 5,856,473, 5,739,321, and 5,886,171, International Application Publication No. WO 2006/050634, and in Journal of Medicinal Chemistry 1998, 41, 973-980, Journal of Organic Chemistry 1999, 64, 3714-3718, and Tetrahedron Letters, 44(4), 801-804.

EXAMPLE 1 DETERMINATION OF IMPURITIES IN EZETIMIBE

Determining the level of impurities in ezetimibe using HPLC. The HPLC analysis conditions are as described in Table 1.

TABLE 1


HPLC method for detecting the level of the impurities.


Column:	Zorbax SB-C18 150 × 4.6 mm, 3.5 μm
Flow:	1.0 ml/minute
Column oven	Ambient
temperature:
Wave length:	230 nm
Injection volume:	10 μl
Run time:	65 minutes
Elution:	Gradient
Diluent:	Acetonitrile
Gradient Program:	Time	% B	% A
	(in minutes)	concentration.	concentration.
	0.01	35	65
	10.0	35	65
	35.0	80	20
	55.0	80	20
	60.0	35	65
	65.0	35	65

Mobile phase A = Buffer:Acetonitrile is 80:20 (v/v)
Mobile phase B = Buffer:Acetonitrile is 20:80 (v/v)
Buffer: 2.76 g of sodium dihydrogen phosphate monohydrate was
dissolved in 1000 ml of water and the pH was adjusted to 5.0 with
dilute NaOH solution.

IMPURITY NAME	RRT

Benzyl ezetimibe impurity	2.6
Benzyl ezetimibe diol impurity	2.2
Lactam cleaved alcohol impurity	1.8
Ezetimibe diol impurity	0.66
Lactam cleaved acid impurity	1.5

PATENT

http://www.google.com/patents/CN104230978A?cl=en

Figure CN104230978AD00051

Example 4. Synthesis of ezetimibe

[0042] To a 500ml bottle of single oral Compound I (PG1 = PG2 = trimethylsilyl) (10g, 13.3mmol), BSA (lOml), TBAF (0. 2g, 0. 66mmol) and methyl tert-butyl ether 100ml. Stirred for 15 minutes at room temperature, the disappearance of the test compound 8, the reaction was terminated. The pre-mixed solution of isopropanol and 2N sulfuric acid was added to the above solution and stirred at room temperature for 1 hour. Crystallized from aqueous isopropanol final product, the product was filtered and washed with aqueous isopropanol, washed with water until the eluate pH is less than 5. Drying at 60 ° to give the final product 5g, yield: 91%, optical yield was 100%. ΐ NMR (400MHz, d6-D MS0): δ 1. 68 (m, 2H), 1 · 82 (m, 2H), 3. 07 (m, 1H), 4. 47 (d, 1H), 4. 79 (d, 1H), 5. 25 (d, 1H), 6. 75 (d, 2H), 7. 10 (m, 4H), 7. 21 (m, 4H), 7. 29 (m, 2H ), 9. 43 (s, 1H).

Patent

http://www.google.com/patents/CN102531985B?cl=en

CN2006 / 10150638 discloses another improved synthetic process, the intermediate acid chloride (IV) first converted to the Weinreb amide, and then reacted with a Grignard reagent to give the key intermediate I.

………………….

……………

http://pubs.rsc.org/en/content/articlelanding/2014/ra/c3ra43861a#!divAbstract

The synthesis of four-membered azacycles is of importance because of the chemical and biological relevance of these compounds. Recent progress in copper-catalyzed reactions has been applicable to a variety of research fields, such as heterocyclic synthesis. The aim of the current review is to summarize the synthesis of strained four-membered ring taking advantage of copper catalyzed and mediated processes.

Graphical abstract: Novel achievements with an old metal: copper-promoted synthesis of four-membered azacycles

……………

http://www.google.com.tr/patents/WO2006137080A1?cl=en

Taken toluene (250 ml) into cleaned R.B.Flask under nitrogen atmosphere and cooled to 0-5°C. Borane DMS complex and (R)-tetrahydro-l-phenyl-3,3-diphenyl-l H,3H-pyrrol (l,2-c)(l,3,2) oxaza borolidine (R-phenyl CBS) is charged into the reaction mass at 0°C. 25 gm of Keto compound of formula-X is dissolved in toluene(50 ml) and added to the reaction mass at 0-5°C. Maintained the reaction mass for 3 hrs and quenched with methanol and followed by 1 N hydrochloric acid solution. Organic layer separated and washed with 5% hydrogen peroxide solution and 5% sodium sulfate solution and followed by with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 75°C. Product is isolated in diisopropyl ether and dried the product at 60-70°C for 6 hrs. (Yield: 15 gm). Example-2: Preparation of compound of hydroxy compound of formula-XL

Taken toluene (250 nil) into cleaned R.B.Flask under nitrogen atmosphere and cooled to 0-5°C. DIP Chloride (Mole ratio 1:1.5) into the reaction mass at O⁰C. 25 gm of keto compound of formula-X is dissolved in toluene(50 ml) and added to the reaction mass at 0-5⁰C. Maintained the reaction mass for 3 hrs and quenched with ammonia solution. Organic layer separated and washed with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 75⁰C. Residue is taken for next stage directly without any purification.

Step-h: Preparation of compound of formula-I (Ezetimibe).

Taken compound of formula-XII (10 gm) and isopropanol (100 ml) into a hydrogenation flask, added 5 % Pd/C ( 4gm) at 25°C and maintained at 45-50⁰C for 3 hrs under hydrogen pressure, filtered through hyflow and washed the Pd/C with isopropanol(20 ml). Distilled the solvent completely under vacuum at below 7O⁰C, product is recrystallised in dichloromethane (Yield: 6 gm).

Purification of Ezetimibe (formula-1).

Ezetimibe (10 gm) is dissolved in 30 ml of methanol and filtered through hyflow and saturated with DM.Water(30 ml) and stirred for 1 hr at 20-25⁰C. Product filtered and dried for 6-8 hrs at 80-85⁰C (Yield:9 gm):

……………….

http://www.google.com.tr/patents/WO2005049592A1?cl=en

scheme A.

The compound of the formula 2

is an useful intermediate for the preparation of ezetimibe. The intermediates represented by the formula 2 can be prepared economically in good yields as represented by the scheme B.

wherein X is O or S; Y is O, S or N(lower alkyl); and R is alkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl or lower alkoxy carbonyl, wherein substituents on phenyl and naphthyl are selected from the group consisting of lower alkyl and phenyl. The starting compounds of formula 3 are known or can be obtained from known methods. The reduction may be carried out in a neutral organic solvent or a combination of the neutral organic solvents. Neutral organic solvent means the solvent that is unreactive in the reduction reaction. The preferable organic solvents are chloroalkanes such as methylene dichloride, chloroform, carbon tetrachloride and ethylene dichloride; carbocyclic aromatics such as toluene and benzene; ethers such as methyl tert-butyl ether, diethylether and isopropyl ether; heterocyclic compound such as tetrahydrofuran; dimethylformamide; dimethylsulfoxide; alkanes such as pentane and hexane; and acetonitrile. More preferable solvents are toluene, diethyl ether, isopropyl ether, hexane, methylene dichloride and ethylene dichloride. The preferable reaction temperature is below the boiling temperature of the solvent used, more preferably between about -40°C and the boiling temperature of the solvent, still more preferably between about -20°C and 40°C and most preferably between about -10°C and 10°C. Quantity of (-)-DIP chloride used is preferably at least about 0.3 mole, more preferably about 0.5 to 10 mole, most preferably about 0.8 to 5 mole per mole of the keto compound of formula 3. Yield of the hydroxy compound of formula 2 is usually above 80%, typically between 90 % to 100%. The compounds of formula 2 wherein X is O; Y is O; and R is alkyl, unsubstituted or substituted phenyl are the preferred. Preferable conditions for obtaining a hydroxy compound of formula 2 from the corresponding keto compound of formula is that the keto compound of the formula 3 is mixed with a neutral solvent, reduced with (-)-DIP chloride at a temperature between -40°C and the boiling temperature of the solvent, more preferably between about -20°C and 40°C and most preferably between about -10°C and 10°C. The reaction mass may be subjected to usual work up. The reaction mass may be used directly in the next step to produce finally ezetimibe, or the hydroxy compound may be isolated and used in the next step. The invention will now be further described by the following examples, which are illustrative rather than limiting. Example 1 3-[5-(4-fluorophenyl)-1 ,5-dioxopentyl]-4-phenyl-2-oxazolidinone (100 gm) is dissolved in toluene (750 ml), the mixture of (-)-β- chlorodiisopinocampheylborane ((-)-DIP chloride) in heptane (545 ml, 1.5M) and toluene (750 ml) is added at 0°C to 5°C for 1 hour. The reaction mixture is stirred for 15 hours at 25°C to 30°C and 340 ml of 10% sodium chloride is then added at the same temperature. The layers are separated and the organic layer is washed with 5% sodium bicarbonate (300 ml), 1 N sulfuric acid (300 ml), and 10% sodium chloride (300 ml). Then the organic layer is dried on sodium sulfate to give 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyI-2- oxazolidinone in 96% yield. Example 2 The organic layer of 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4- phenyl-2-oxazolidinone from example 1 is mixed with 4-fluoro-N-(4- hydroxyphenyl)methylene-benzenamine (121 gm) and cooled to -10°C. Then diisopropylethylamine (260 ml) is added to the reaction mixture for 45 minutes at -10°C to -15°C, trimethylsilylchloride (135 ml) is added and stirred for 1 hour at -20°C to -25°C. The reaction mixture is cooled to -30°C, TiCI₄ (35 ml) is slowly added to the reaction mixture at -30°C to -35°C and stirred for 3 hours at the same temperature. 5% Aq. tartaric acid solution (1700 ml) is added to the reaction mixture at 0°C, stirred for 1 hour and allowed the temperature to rise to 25°C. Then 20% Aq. NaHSO₃ (350 ml) solution and stirred for 2 hours at 25°C to 30°C. The organic layer is separated and washed with 1000 ml water, concentrated to 250 ml volume and added 100 ml bistrimethylsilylacetamide. Then the reaction mixture is heated to reflux for 30 minutes. The organic layer is concentrated to remove methylene dichloride, crystallized from the mixture of ethyl acetate (250 ml) and n-heptane (250 ml), and filtered and dried to give 135 gm of compound 4 (prot = trimethylsilyl).

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US7906502	21 Haz 2006	15 Mar 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US8383810	12 Ara 2011	26 Şub 2013	Merck Sharp & Dohme Corp.	Process for the synthesis of azetidinones

WO2005049592A1 *	24 Kas 2003	2 Haz 2005	Hetero Drugs Ltd	A novel process for ezetimibe intermediate
US5856473 *	31 Eki 1996	5 Oca 1999	Schering Corporation	Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-( phenyl or 4-fluorophenyl!)-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone

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Ciraparantag, Aripazine

October 6, 2015 3:41 am / Leave a comment

Ciraparantag
PER977， Aripazine
CAS Number:1438492-26-2
Chemical Name:N1,N1-[piperazine-1,4-diylbis(propane-1,3-diyl)]bis-L-argininamide

(2S,2’S)-N,N’-(Piperazine-1,4-diyldipropane-3,1-diyl)bis(2-amino-5-carbamimidamidopentanamide)

2S,2’S)-N,N’-(piperazine-1,4-diylbis(propane-3,1-diyl))bis(2-amino-5-guanidinopentanamide)

C22H48N12O2
Mw: 512.40232
Mechanism of Action: an intravenously administered anticoagulant Reversal Agent

Blood coagulation factor modulators; Factor Xa inhibitors
Indication: Anticoagulant Reversal
Development Stage: Phase II
Developer:Perosphere, Inc..Perosphere Inc.

Highest Development Phases

Phase IIHaemorrhage

Most Recent Events

02 Apr 2015Ciraparantag receives Fast Track designation for Haemorrhage [IV] (In volunteers) in USA
05 Nov 2014Efficacy and adverse events data from a phase I/II trial in Haemorrhage released by Perosphere
06 Oct 2014Aripazine is available for licensing as of 06 Oct 2014. http://www.perosphere.com/

Aripazine（PER977, ciraparantag）

Ciraparantag, also known as PER977, is a A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins. PER977 is water-soluble, cationic molecule that is designed to bind specifically to unfractionated heparin and low-molecular-weight heparin through noncovalent hydrogen bonding and charge–charge interactions.

PER-977 is an intravenous heparin neutralizer in phase II clinical trials at Perosphere to reverse edoxaban’s induced anticoagulation.

In April 2015, fast track designation was assigned in the U.S. as an investigational anticoagulant reversal agent.

WO 2013082210

http://www.google.com/patents/WO2013082210A1?cl=en

In one scheme, the compound of Formula V (DAP)

is synthesized by reacting excess equivalents (e.g., at least about two equivalents) of compound 1

with one equivalent of compound 2

in the presence of a peptide coupling reagent, to obtain a compound 3

wherein PI is a protecting group and P2 is a protecting group or is a hydrogen.

the coupling involved reacting compound 1, wherein PI was Boc and P2 was a hydrogen (depicted as Boc-Arg-OH HCl below), with compound 2 as depicted below:

The resultant crude product was more than 95% pure by thin layer

chromatography (TLC).

Subsequently, the deprotection step was carried out as depicted below:

The deprotected product was purified by preparative HPLC using 1% acetic acid buffer. Product purity of >98% was observed. Residual TFA was removed by low quantity of DOWEX resin. The molecular weight of DAP (the compound of Formula V) is 512.4, and the compound synthesized according to the above scheme exhibited the following primary peak by mass spectroscopy: [M+H]⁺=513.4.

References

1: Dzik WH. Reversal of oral factor Xa inhibitors by prothrombin complex concentrates: a re-appraisal. J Thromb Haemost. 2015 Jun;13 Suppl 1:S187-94. doi: 10.1111/jth.12949. PubMed PMID: 26149022.

2: Crowther M, Crowther MA. Antidotes for Novel Oral Anticoagulants: Current Status and Future Potential. Arterioscler Thromb Vasc Biol. 2015 Aug;35(8):1736-45. doi: 10.1161/ATVBAHA.114.303402. Epub 2015 Jun 18. PubMed PMID: 26088576.

3: Sullivan DW Jr, Gad SC, Laulicht B, Bakhru S, Steiner S. Nonclinical Safety Assessment of PER977: A Small Molecule Reversal Agent for New Oral Anticoagulants and Heparins. Int J Toxicol. 2015 Jun 15. pii: 1091581815590667. [Epub ahead of print] PubMed PMID: 26079256.

4: Mo Y, Yam FK. Recent advances in the development of specific antidotes for target-specific oral anticoagulants. Pharmacotherapy. 2015 Feb;35(2):198-207. doi: 10.1002/phar.1532. Epub 2015 Feb 3. PubMed PMID: 25644580.

5: Yates SW. Interrupting anticoagulation in patients with nonvalvular atrial fibrillation. P T. 2014 Dec;39(12):858-80. PubMed PMID: 25516695; PubMed Central PMCID: PMC4264672.

6: Vanden Daelen S, Peetermans M, Vanassche T, Verhamme P, Vandermeulen E. Monitoring and reversal strategies for new oral anticoagulants. Expert Rev Cardiovasc Ther. 2015 Jan;13(1):95-103. doi: 10.1586/14779072.2015.987126. Epub 2014 Nov 28. PubMed PMID: 25431993.

7: Costin J, Ansell J, Laulicht B, Bakhru S, Steiner S. Reversal agents in development for the new oral anticoagulants. Postgrad Med. 2014 Nov;126(7):19-24. doi: 10.3810/pgm.2014.11.2829. Review. PubMed PMID: 25387210.

8: Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, Dishy V, Noveck RJ, Costin JC. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med. 2014 Nov 27;371(22):2141-2. doi: 10.1056/NEJMc1411800. Epub 2014 Nov 5. PubMed PMID: 25371966.

9: Hankey GJ. Intracranial hemorrhage and novel anticoagulants for atrial fibrillation: what have we learned? Curr Cardiol Rep. 2014 May;16(5):480. doi: 10.1007/s11886-014-0480-9. Review. PubMed PMID: 24643903.

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BEXAGLIFLOZIN

October 5, 2015 3:57 am / Leave a comment

Bexagliflozin
THR1442; THR-1442, EGT 0001442; EGT1442
CAS :1118567-05-7
(2S,3R,4R,5S,6R)-2-[4-chloro-3-({4-[2- (cyclopropyloxy) ethoxy] phenyl} methyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol

D-Glucitol, 1,5-anhydro-1-C-(4-chloro-3-((4-(2-(cyclopropyloxy)ethoxy)phenyl)methyl)phenyl)-, (1S)-

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

1-[4-Chloro-3-[4-[2-(cyclopropyloxy)ethoxy]benzyl]phenyl]-1-deoxy-beta-D-glucopyranose
1,5-Anhydro-1(S)-[4-chloro-3-[4-[2-(cyclopropyloxy)ethoxy]benzyl]phenyl]-D-glucitol

(1S)-1,5-anhydro-1-C-[4-chloro-3-({4-[2- (cyclopropyloxy)ethoxy]phenyl}methyl)phenyl]-D-glucitol

Chemical Formula: C24H29ClO7
Exact Mass: 464.16018

Mechanism of Action:SGLT2 inhibitor, Sodium-glucose transporter 2 inhibitors
Indication:Type 2 diabetes

FDA APPROVED

1/20/2023

Brenzavvy

To improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise
Drug Trials Snapshot
Phase II
Developer:Theracos, Inc.

Conditions	Phases	Recruitment	Interventions	Sponsor/Collaborators
Diabetes Mellitus Type 2	Phase 2	Completed	Drug: EGT0001442\|Drug: Placebo capsules to match EGT0001442	Theracos
Diabetes Mellitus	Phase 2	Completed	Drug: EGT0001442\|Drug: Placebo	Theracos
Type 2 Diabetes Mellitus	Phase 3	Not yet recruiting	Drug: Bexagliflozin\|Drug: Placebo	Theracos
Diabetes Mellitus, Type 2	Phase 2\|Phase 3	Recruiting	Drug: Bexagliflozin tablets	Theracos

DIPROLINE COMPLEX

Bexagliflozin diproline
RN: 1118567-48-8, C24-H29-Cl-O7.2C5-H9-N-O2

Molecular Weight, 695.2013

L-Proline, compd. with (1S)-1,5-anhydro-1-C-(4-chloro-3-((4-(2-(cyclopropyloxy)ethoxy)phenyl)methyl)phenyl)-D-glucitol (2:1)

Bexagliflozin [(2S,3R,4R,5S,6R)-2-[4-chloro-3-({4-[2-(cyclopropyloxy) ethoxy] phenyl} methyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol] is an orally administered drug for the treatment of Type 2 Diabetes Mellitus (T2DM) and is classified as a Sodium Glucose co-Transporter 2 (SGLT2) Inhibitor. It is in Phase 2b study to evaluate the effect of bexagliflozin tablets in subjects with type 2 diabetes mellitus.

2D chemical structure of 1118567-05-7

Bexagliflozin, also known as EGT1442, is a potent and selective SGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and prolongs the survival of stroke-prone rats. The IC(50) values for EGT1442 against human SGLT1 and SGLT2 are 5.6μM and 2nM, respectively. In normal rats and dogs a saturable urinary glucose excretion was produced with an ED(50) of 0.38 and 0.09mg/kg, respectively. EGT1442 showed favorable properties both in vitro and in vivo and could be beneficial to the management of type 2 diabetic patients.

One promising target for therapeutic intervention in diabetes and related disorders is the glucose transport system of the kidneys. Cellular glucose transport is conducted by either facilitative (“passive”) glucose transporters (GLUTs) or sodium-dependent (“active”) glucose cotransporters (SGLTs). SGLTl is found predominantly in the intestinal brush border, while SGLT2 is localized in the renal proximal tubule and is reportedly responsible for the majority of glucose reuptake by the kidneys.

Recent studies suggest that inhibition of renal SGLT may be a useful approach to treating hyperglycemia by increasing the amount of glucose excreted in the urine (Arakawa K, et al., Br J Pharmacol 132:578-86, 2001; Oku A, et al., Diabetes 48:1794-1800, 1999).

The potential of this therapeutic approach is further supported by recent findings that mutations in the SGL T2 gene occur in cases of familial renal glucosuria, an apparently benign syndrome characterized by urinary glucose excretion in the presence of normal serum glucose levels and the absence of general renal dysfunction or other disease (Santer R, et al., J Am Soc Nephrol 14:2873-82, 2003). Therefore, compounds which inhibit SGLT, particularly SGL T2, are promising candidates for use as antidiabetic drugs.

Compounds previously described as useful for inhibiting SGLT include C-glycoside derivatives (such as those described in US6414126, US20040138439, US20050209166, US20050233988, WO2005085237, US7094763, US20060009400, US20060019948, US20060035841, US20060122126, US20060234953, WO2006108842, US20070049537 and WO2007136116), O-glycoside derivatives (such as those described in US6683056, US20050187168, US20060166899, US20060234954, US20060247179 and US20070185197), spiroketal-glycoside derivatives (described in WO2006080421), cyclohexane derivatives (such as those described in WO2006011469), and thio- glucopyranoside derivatives (such as those described in US20050209309 and WO2006073197).

PATENT

WO 2009026537……………PRODUCT PATENT

http://www.google.co.in/patents/WO2009026537A1?cl=en

Example 19

[0289] The synthesis of compound BQ within the invention is given below.

[0290] Preparation of 2-cyclopropoxyethanol (Intermediate BO)

To a suspension of Mg powder (0.87 g, 36.1 mmol) and iodine (catalytic) in THF (4 mL) was added slowly BrCH₂CH₂Br (4.6 g, 24.5 mmol) in THF (8 mL). The exothermic reaction was cooled in an ice-bath. After complete addition OfBrCH₂CH₂Br, a solution of 2- (2-bromoethyl)-l,3-dioxolane (1 g, 5.6 mmol) was added dropwise. The reaction mixture was then kept at reflux for 24 h, quenched by addition of aqueous NH₄Cl, and extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give crude intermediate BO (400 mg) as yellow oil. [0292] Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate (Intermediate BP)

^{Ts0^}°V

To a solution of 2-cyclopropoxyethanol (400 mg, 3.92 mmol) in DCM (10 niL) were added TsCl (821 mg, 4.31 mmol) and Et₃N (0.6 mL, 4.31 mmol). The reaction was stirred at room temperature overnight. Then, IN HCl was added, and the reaction was extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated to give a yellow oil. The oil was purified by preparative TLC to obtain intermediate BP (50 mg) as a yellow oil.

Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2- cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound BQ)

To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate Dl) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added 2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg, 0.08 mmol) and Cs₂CO₃ (52 mg, 0.16 mmol). The mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EA, washed with brine, dried with anhydrous Na₂SO₄ and concentrated to an oil. The oil was purified by preparative HPLC to obtain compound BQ (11 mg) as a colorless oil. ¹H NMR (CD₃OD): δ 7.30 (m, 3H), 7.11 (d, J= 8.8 Hz, 2H), 6.82 (d, J= 8.8 Hz, 2H), 4.13 (m, 5H), 3.85 (m, 3H), 3.81 (m, IH), 3.40 (m, 4H), 3.30 (m, IH), 0.52 (m, 4H); MS ESI (m/z) 465 (M+H)⁺, calc. 464.

Example 33

The synthesis of complex DM within the invention is outlined in FIG. 30, with the details given below.

Preparation of 2-cyclopropoxyethanol (Intermediate BO)

To a suspension of Mg powder (86.7 g, 3.6 mol) and I₂(catalytic) in anhydrous THF (0.7 L) was added slowly 1,2-dibromoethane (460 g, 2.4 mol) in anhydrous THF (2 L) at a rate that maintained the reaction temperature between 40-55° C. A solution of 2-(2-bromoethyl)-1,3-dioxolane (100 g, 0.56 mol) in anhydrous THF (750 mL) was added dropwise, and the reaction mixture was kept at 40-55° C. for 16 h. The reaction was quenched by addition of an aqueous solution of ammonium chloride. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, and concentrated to give intermediate BO (27 g) as yellow oil, which was used in the next step without further purification.

Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate (Intermediate BP)

To a stirred solution of sodium hydroxide (32 g, 0.8 mol) in water (180 mL) and THF (180 mL) was added crude 2-cyclopropoxyethanol from the previous step (27 g, 0.26 mol) at −5 to 0° C. A solution of p-toluenesulfonyl chloride (52 g, 0.27 mol) in THF (360 mL) was added dropwise, and the reaction mixture was kept at −5 to 0° C. for 16 h. The reaction mixture was then incubated at room temperature for 30 min, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×1.0 L). The combined organic layers were washed with brine, dried over Na₂SO₄and concentrated to get the crude intermediate BP as a yellow oil (53.3 g), which was used for the preparation of intermediate DK below without further purification.

Preparation of 4-(5-bromo-2-chlorobenzyl)phenol (Intermediate H)

To a stirred solution of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (intermediate B) (747 g, 2.31 mol) in dichloromethane was added slowly boron tribromide (1.15 kg, 4.62 mol) at −78° C. The reaction mixture was allowed to warm to room temperature. When the reaction was complete as measured by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, then with water, and then with brine, and dried over Na₂SO₄. The residue was concentrated and then recrystallized in petroleum ether to obtain intermediate H as a white solid (460 g, yield 68%). ¹H NMR (CDCl₃, 400 MHz): δ 7.23˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H).

Preparation of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene (Intermediate DK)

A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) and Cs₂CO₃(135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crude intermediate BP from the second preceeding step above) (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, then with brine, and dried over Na₂SO₄. The residue was concentrated and then purified by flash column chromatography on silica gel (eluent PE:EA=10:1) to give intermediate DK as a liquid (51 g, yield 64%). ¹H NMR (CDCl₃, 400 MHz): δ 7.22˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H), 0.49-0.52 (m, 2H).

Preparation of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Intermediate DL)

To a stirred solution of 4-bromo-1-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene (213 g) in anhydrous THF/toluene (1:2 v/v, 1.7 L) under argon was added n-BuLi (2.5 M in hexane, 245.9 mL) dropwise at −60±5° C. The mixture was stirred for 30 min, and then transferred to a stirred solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (310.5 g) in toluene (1.6 L) at −60±5° C. The reaction mixture was continuously stirred at −60±5° C. for 1 before quenching with an aqueous solution of saturated ammonium chloride (1.5 L). The mixture was allowed to warm to room temperature and stirred for 1 h. The organic layer was separated and the water layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (1 L), dried over Na₂SO₄, and concentrated. The residue was dissolved in methanol (450 mL), and methanesulfonic acid (9.2 mL) was added at 0° C. The solution was allowed to warm to room temperature and stirred for 2.0 h. The reaction was quenched with an aqueous solution of sodium bicarbonate (50 g) in water (500 mL) and then additional water (900 mL) was added. The mixture was extracted with ethyl acetate (3×1.0 L). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The crude product was used in the next step without further purification.

Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex (Complex DM)

To a stirred solution of crude (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol from the previous step in CH₂Cl₂/CH₃CN (1:1, 1.3 L) at −5° C. was added triethylsilane (28.2 mL, 563 mmol), followed by BF₃.Et₂O (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm gradually to room temperature. The reaction was quenched by addition of an aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na₂SO₄and concentrated to give the crude product (230 g, purity 82.3%). To the crude product was added L-proline (113.7 g) in EtOH/H₂O (15:1 v/v, 2.09 L), and the mixture was stirred at 80° C. for 1 h until it became a clear solution. Hexane (3.0 L) was added dropwise over 50 min, while the temperature was maintained at about 60° C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/H₂O (15:1 v/v, 2×300 mL), hexane (2×900 mL), and dried at 45° C. under vacuum for 10 h to give pure complex DM as a white solid (209 g; HPLC purity 99.2% (UV)). ¹H NMR (CD₃OD, 400 MHz): δ 7.25˜7.34 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.84 (d, J=8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53 (m, 2H).

Crystalline complex DM was analyzed by X-ray powder diffraction using CuK_α1radiation. The diffraction pattern is shown inFIG. 31 and summarized in Table 1 (only peaks up to 30° in 2θ are listed). The melting point of complex DM was determined by differential scanning calorimetry (DSC) as 151±1° C. (evaluated as onset-temperature; heating from 50° C. to 200° C. at 10° C./min). The DSC spectrum is shown in FIG. 32.

Preparation of (3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Intermediate D)

To a stirred solution of (3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Intermediate C) (2 g, 5.9 mmol) in dichloromethane was added BBr₃(14.6 mL, 1 M) dropwise at −78° C. After the addition was complete, the mixture was allowed to warm to 0° C. and held at this temperature for 2 h. When LC-MS showed that no starting material remained, the mixture was cooled to −78° C. again, and quenched with water. When the temperature was stable, saturated NaHCO₃solution was added. The mixture was evaporated under reduced pressure, and the residue was extracted with EtOAc. The organic layer was washed with NaHCO₃and brine, dried over Na₂SO₄, evaporated and purified to obtain intermediate D (0.7 g).

In addition, for use in the synthesis of certain compounds of the invention, the 2S isomer (intermediate D1) and the 2R isomer (intermediate D2) of intermediate D were separated by preparative LC-MS. Intermediate D1: ¹H NMR (CD₃OD): δ 7.30 (m, 3H), 6.97 (d, 2H, J=6.8 Hz), 6.68 (d, 2H, J=6.8 Hz), 4.56 (s, 1H), 4.16 (s, 1H), 3.91˜4.02 (m, 5H), 3.79 (m, 1H), 3.64 (m, 1H). Intermediate D2: ¹H NMR (CD₃OD): δ 7.29˜7.33 (m, 3H), 7.00 (d, 2H, J=6.8 Hz), 6.70 (d, 2H, J=6.8 Hz), 4.58 (d, 1H, J=4.0 Hz), 3.96˜4.02 (m, 4H), 3.93˜3.95 (m, 1H), 3.81˜3.85 (m, 1H), 3.64˜3.69 (m, 1H).

PATENT

http://www.google.com/patents/US20130267694

Example 14 Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol crystals

This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by crystallization of ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(442-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol bis(L-proline) complex in methanol/water solvent mixture.

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (1.3 kg) was added to a propylene drum (25 L) and methanol (3.6 kg) and water (1.3 kg) and the mixture was stirred until the solids dissolved. The solution was filtered through filter membrane (Millipore, 0.45 μm) into a clean glass reactor (50 L). The mixture was refluxed for 30 min and water (7.2 kg) was added over 1.0 h while maintaining the temperature between 50 and 65° C. The mixture was slowly cooled to ˜42° C. over 2 h. A suspension of seed crystal (26 g) in cold (−5° C.) mixture of methanol/water (78 mL, 2.8/6.5 (w/w)) and the slow cooling was continued to −5° C. over 12 h. The suspension was stirred for another 5 h and was filtered. The solid was slurried with cold water and filtered (0 to 5° C., 3×2.6 kg). The filter cake was dried under reduced pressure for 24 h until the loss on drying was no more than 0.5% to give a white solid (825 g, 92% yield, 99.3% pure by \HPLC-0001).

Example 15 Preparation of 4-(2-Chloro-5-Iodobenzyl)Phenol

This example describes preparation of 4-(2-chloro-5-iodobenzyl)phenol using gaseous hydrobromic acid.

Preparation of (2-chloro-5-iodophenyl)methan-1-ol

A 250 mL of 4-necked flask equipped with thermometer and mechanical stirring was charged with NaBH₄(4.16 g, 0.11 mol) and THF (60 mL) under argon. After cooling to 0˜5° C. with stirring, a solution of iodine in THF (12.7 g I₂in 25 mL THF) was added slowly dropwise over 30 min and the reaction temperature was maintained below 10° C. After the addition was completed, a solution of 2-chloro-5-iodobenzoic acid (15.0 g, 50 mmol) in THF (20 mL) was added dropwise over 30 min and kept the reaction temperature below 10° C. After stirring for another 3 h at 20˜25° C., the reaction mixture was heated to reflux for additional 16 h and monitored by TLC (PE/EA=1:1, R_f=0.2). The mixture was cooled to 20˜25° C. and poured into ice water (100 mL), extracted with ethyl acetate (2×100 mL), washed with water (2×100 mL), brine (100 mL), concentrated and the residue was purified by flash chromatography (PE:EA=20:1 as eluant, 200 mL) to give an off-white solid. Yield: 10.0 g (70%) MS ESI (m/z): 269 [M+1]⁺.

Preparation of 4-(2-Chloro-5-Iodobenzyl)Phenol

A 100 mL of 4-necked flask equipped with thermometer and mechanical stirrer was charged with (2-chloro-5-iodophenyl)methanol (268.5 mg, 1 mmol), anhydrous ZnCl₂(136.3 mg, 1 mmol), dichloromethane (5.0 mL) and n-hexane (29 mL) under argon. After stirring for 10 min at 20 to 25° C., HBr (gas) was bubbled into the mixture for 10 min and a solution of phenol (197.6 mg, 2.1 mmol) in dry dichloromethane (3.0 mL) was added dropwise over 30 min. After bubbling HBr for additional 2 h, the mixture was refluxed for 3 days. The conversion was about 65%. The mixture was quenched with ice water (50 mL), extracted with ethyl acetate (2×30 mL), washed with water (2×30 mL), brine (30 mL), concentrated and the residue was purified by flash chromatography (PE:EA=25:1 as eluant, 200 mL) to give an off-white solid. Yield: 180 mg (52%). ¹H NMR (CDCl₃, 400 MHz): δ 7.44 (d, J=8.4 Hz, 2H), 7.03˜7.09 (m, 3H), 6.77 (d, J=8.4 Hz, 2H), 4.76 (s, 1H), 3.95 (s, 2H), 3.82 (s, 2H). MS ESI (m/z): 345 [M+1]⁺. ¹³C NMR (CDCl₃, 100 MHz): δ 154.1, 141.4, 139.5, 136.6, 134.2, 131.2, 130.9, 130.1, 115.5, 91.67, 38.07.

Example 16 Preparation of 2-(4-(2-Cyclopropoxyethoxy)Benzyl)-1-Chloro-4-Iodobenzene

This example describes the preparation of 2-(4-(2-cyclopropoxyethoxy)benzyl)-1-chloro-4-iodobenzene via coupling of the 4-(2-chloro-5-iodobenzyl)phenol with 2-cyclopropoxyethyl 4-methylbenzenesulfonate.

Under nitrogen a 500 L glass-lined reactor was charged with acetone (123 kg) with stirring (120 RPM), 4-(2-chloro-5-iodobenzyl)phenol (19.37 kg, 0.056 kmol), 2-cyclopropoxyethyl 4-methylbenzenesulfonate (15.85 kg, 0.062 kmol), cesium carbonate (18.31 kg, 0.0562 kmol) powder, potassium carbonate (23.3 kg, 0.169 kmol) powder and TBAI (4.15 kg, 0.011 kmol). After stirring for 4045 h at 40° C., TLC (PE:EA=4:1, Rf=0.3) showed that starting material was consumed. The mixture was cooled to 20˜25° C.

The reaction mixture was filtered over diatomite (28 kg) and the filter cake was washed with acetone (2×31 kg). The combined filtrates were transferred to a 500 L glass-lined reactor and concentrated. The residue was dissolved in ethyl acetate (175 kg, washed with water (2×97 kg) and concentrated until the volume was about 100 L and was transferred to a 200 L glass-lined reactor and continued to concentrate to get about 22.5 kg of crude material.

The crude material was dissolved in methanol/n-hexane (10:1, 110 kg) under refluxing for 30 min with stirring (100 RPM) until it was a clear solution. The mixture was cooled to 5 to 10° C. and some crystal seeds (20 g) were added. The suspension was stirred for another 5 h at 5 to 10° C. The mixture was filtered at 0 to 5° C. and the filter cake was washed with pre-cooled methanol/n-hexane (10:1, 5° C., 2×11 kg). The filter cake was dried under at 15 to 20° C. for 15 h to give off-white to white solid. Yield: 18.1 kg, 75%. Melting Point: 31° C. (DSC onset). ¹H NMR (CDCl₃, 400 MHz): δ 7.45˜7.50 (m, 2H), 7.09˜7.12 (m, 3H), 6.88 (d, J=8.8 Hz, 2H), 4.11 (t, J=5.2 Hz, 2H), 3.99 (s, 2H), 3.88 (t, J=5.2 Hz, 2H), 3.40˜3.44 (m, 1H), 0.63˜0.67 (m, 2H), 0.49˜0.54 (m, 1H). MS ESI (m/z): 429 [M+1]⁺. ¹³C NMR (CDCl₃, 100 MHz): δ 157.5, 141.5, 139.5, 136.6, 134.2, 131.2, 130.8, 129.9, 114.9, 91.66, 69.00, 67.13, 53.72, 38.08, 5.63.

Example 9 Preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex

This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(L-proline) complex by co-crystallization of ((2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol with L-proline in ethanol/water/n-heptane solvent mixture.

The crude (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (2.5 kg) was added to a glass reactor containing ethanol (95%, 16 kg) and L-proline (1.24 kg) and the mixture was refluxed for 1 h. While keeping the temperature above 60° C., n-heptane (8.5 kg) was added over 40 min. The mixture was slowly cooled to 25 to 20° C. and stirred at this temperature for 10 h. The mixture was filtered and the solids were washed with cold (−5° C.) ethanol (95%, 2×2.5 L) and n-heptane (2×5 L) and the solids were dried under reduced pressure at 55 to 65° C. for 20 h to give a white solid (3.03 kg, 81% yield, 99.4% pure by HPLC-0001).

Example 7 Preparation of ((2S,3R,4R,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6-(Hydroxymethyl)Tetrahydro-2H-Pyran-3,4,5-triol

This example describes preparation of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol by removal of the anomeric OH or OMe.

(2S,3R,4S,5S,6R)-2-(4-Chloro-3-(4-(2-Cyclopropoxyethoxy)Benzyl)Phenyl)-6-(Hydroxymethyl)-2-Methoxytetrahydro-2H-Pyran-3,4,5-Triol Solution

A 30 L glass reactor equipped with a thermometer was charged with crude (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (1.15 kg), DCM (2.3 kg) and acetonitrile (1.4 kg), and the mixture was magnetically stirred until all the solids dissolved under nitrogen sparging. The solution was cooled to ˜−15° C.

Triethylsilane Solution:

BF₃.Et₂O (1.2 kg) was added to a cold (−20 to −15° C.) solution of triethysilane (1.08 kg) dichloromethane (2.3 kg) and acetonitrile (1.4 kg) with nitrogen sparging.

The cold (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy)benzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol solution was added to the cold triethylsilane solution at such a rate to maintain the temperature between −20 and −15° C. (˜2 to 3 h).

The reaction mixture was stirred for another 2 to 3 h and then quenched by addition of an aqueous solution of sodium bicarbonate (7.4% w/w, 7.8 kg) and the reaction mixture was stirred for about 15 min. The solvents were removed under reduced pressure (2 h, temperature below 40° C.). The residue was partitioned between ethyl acetate (6.9 kg) and water (3.9 kg). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×3.5 kg). The combined organic layers were washed with brine (2×3.8 kg) and the solvents were removed under reduced pressure. Anhydrous ethanol (2.3 kg) was added and concentrated to give the crude product of the title compound (1 kg, 90% yield, 90% HPLC-0001) as yellow solid.

PATENT

WO 2011153953

https://www.google.com/patents/WO2011153953A1?cl=en

Example 1. Preparation of (2S.iR. R.5S.6R)-2-(4-chloro-3-(4-(2-cvclopropoxyethoxy) benzyl)phenyl)-6-(hvdroxymethyl)tetrahvdro-2H-pyran-3,4,5-triol, bis(X-proline) complex

Example 1A

Preparation of 2-cyclopropoxyethanol (1)

To a suspension of Mg powder (86.7 g, 3.6 mol) and iodine (cat) in anhydrous THF (0.7 L) was added slowly 1,2-dibromoethane (460 g, 2.4 mol) in anhydrous THF (2 L) slowly at a rate as to keep the internal temperature between 40-55 °C. After the addition, a solution of 2-(2-bromoethyl)-l,3-dioxolane (lOOg, 0.56 mol) in anhydrous THF (750 mL) was added dropwise. The reaction mixture was kept at 40-55 °C for 16h and was quenched by addition of aqueous solution of ammonium chloride. The mixture was extracted with methylene chloride. The organic layer was dried over sodium sulfate, and concentrated to give the title product (27 g) as yellow oil, which was directly used without further purification.

Example IB

Preparation of 2-cyclopropoxyethyl 4-methylbenzenesulfonate (2)

To a stirred solution of sodium hydroxide (32 g, 0.8 mol) in water (180 mL) and THF (180 mL) was added Example 1A (27 g, 0.26 mol) at -5 to 0 °C. Afterwards, a solution of ji?-toluenesulfonyl chloride (52 g, 0.27 mol) in THF (360 mL) was added dropwise. The reaction mixture was kept at -5 to 0 °C for 16 h. The reaction mixture was then kept at room temperature for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×1.0 L). The combined organic layers were washed with brine, dried over Na₂S0₄ and concentrated to get the crude product as yellow oil (53.3 g). It was used directly without further purification.

Example 1C

Preparation of 4-(5-bromo-2-chlorobenzyl)phenol (3)

To a stirred solution of 4-bromo-l-chloro-2-(4-ethoxybenzyl)benzene (747 g, 2.31 mol) in dichloromethane was added boron tribromide (1.15 kg, 4.62 mol) slowly at -78 °C. The reaction mixture was allowed to rise to room temperature. When the reaction was complete as measure by TLC, the reaction was quenched with water. The mixture was extracted with dichloromethane. The organic layer was washed with aqueous solution of saturated sodium bicarbonate, water, brine, dried over Na₂S0₄, and concentrated. The residue was recrystallized in petroleum ether to give the title compound as a white solid (460 g, yield 68%). 1H NMR (CDC1₃, 400MHz): δ 7.23-7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 5.01 (s, 1H), 4.00 (s, 2H).

Example ID

Preparation of 4-bro -l-chloro-2-(4-(2-cyclopropoxyethoxy)benzyl)benzene (4)

A mixture of Example 1C (56.7 g, 210 mmol) and Cs₂C0₃ (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 0.5 h. Example IB (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight. It was diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na₂S0₄, and concentrated. The residue was purified by flash column

chromatography on silica gel eluting with petroleum ether:ethyl acetate (10:1) to give the title compound as liquid (51 g, yield 64%). 1H NMR (CDC1₃, 400MHz): δ 7.22-7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H), 0.49-0.52(m, 2H).

Example IE

Preparation of (25,5R, S,55,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6-(hydroxymethyl)-2-metlioxytetraliydro-2H-pyran-3,4,5-triol (5)

To a stirred solution of Example ID (213 g) in anhydrous THF/toluene (1 :2 (v/v), 1.7 L) under argon was added n-BuLi (2.5 M hexane, 245.9 mL) drop wise at -60 ± 5 °C. The mixture was stirred for 30 min. before transferred to a stirred solution of 2,3,4,6-tetra-O- trimethylsilyl-P-Z -glucolactone (310.5 g) in toluene (1.6 L) at -60 ± 5 °C. The reaction mixture was continuously stirred at -60 ± 5 °C for 1 h before quenching with aqueous solution of saturated ammonium chloride (1.5 L). Then mixture was allowed to warm to room temperature and stirred for 1 h. The organic layer was separated and the water layer was extracted with ethyl acetate (3×500 niL). The combined organic layers were washed with brine (1 L), dried over Na₂S0₄, and concentrated. The residue was dissolved in methanol (450 mL) and methanesulfonic acid (9.2 mL) was added at 0 °C. The solution was allowed to warm to room temperature and stirred for 20 h. It was quenched with aqueous solution of sodium bicarbonate (50 g) in water (500 mL) and additional water (900 mL) was added. The mixture was extracted with ethyl acetate (3×1.0 L). The combined organic layers were washed with brine, dried over Na₂S0₄, concentrated and used directly in the next step without further purification.

Example IF

Preparation of (25,5R, R,55,6R)-2-(4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, bis(Z-proline) complex (7)

To stirred solution of Example IE in CH₂C1₂/CH₃CN (650 mL:650 mL) at -5 °C was added triethylsilane (28.2 mL, 563 mmol), and followed by BF₃-Et₂0 (52.3 mL, 418.9 mmol). The reaction was stirred for 16 h while the temperature was allowed to warm to room temperature gradually. The reaction was quenched with aqueous solution of saturated sodium bicarbonate to pH 8.0. The organic volatiles were removed under vacuum. The residue was partitioned between ethyl acetate (2.25 L) and water (2.25 L). The organic layer was separated, washed with brine, dried over Na₂S0₄ and concentrated to give the crude product 6 (230 g, purity 82.3%). This product and L-proline (113.7 g) in EtOH/H₂0 (15:1 v/v, 2.09 L) was stirred at 80 °C for 1 h when it became a clear solution. Hexane (3.0 L) was added dropwise into the above hot solution over 50 min, with the temperature being kept at about 60 °C. The reaction mixture was stirred overnight at room temperature. The solid was filtered and washed with EtOH/ H₂0 (15:1 (v/v), 2×300 mL), hexane (2×900 mL), and dried at 45 °C under vacuum for 10 h to give the pure title compound 7 as a white solid (209 g).

Purity (HPLC) 99.2% (UV). 1H NMR (CD₃OD, 400 MHz): δ 7.25—7.34 (m, 3H), 7.11 (d, J = 8.8 Hz, 2H), 6.84 (d, J= 8.8 Hz, 2H), 4.03-4.11 (m, 5H), 3.96-4.00 (m, 2H), 3.83-3.90 (m, 3H), 3.68-3.72 (m, 1H), 3.36-3.46 (m, 6H), 3.21-3.30 (m, 3H), 2.26-2.34 (m, 2H), 2.08-2.17 (m, 2H), 1.94-2.02 (m, 4H), 0.56-0.57 (m, 2H), 0.52-0.53(m, 2H).

Example 2. Direct Preparation of Crystalline Compound 8 from Complex 7

This example illustrates the preparation of a crystalline form of (2S, 3R, 4R, 5S, 6R)-2- (4-chloro-3-(4-(2-cyclopropoxyethoxy) benzyl)phenyl)-6- (hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol.

To a 5.0 L 4-necked flask equipped with a mechanical stirrer was added the starting co-crystal (150.0 g) and methanol (300 mL). The mixture was stirred at room temperature with mechanical stirring (anchor agitator, 2-blades 9 cm) until a cloudy solution/suspension formed, to which distilled water (1500 mL) was added dropwise at a rate of -12.5 mL/min. As the mixture warmed from the exotherm of adding water to methanol, the mixture became clear after adding about 1/5 to 1/3 of the water. After the addition was completed the reaction was stirred continuously at 80 rpm for another 5 h. The reaction mixture was filtered over medium-speed filter paper and the filter cake was washed with distilled water (450 mL and then 300 mL) and dried under vacuum using an oil pump (~6 mm Hg) at 45 °C for 48 hours to give the target product as a white crystalline solid (94.2 g, 93.9% yield, purity (HPLC): 99.3%).

Example 5. Indirect Preparation of Crystalline Compound 8 from Complex 7

[0113] To a 200 L glass lined reactor equipped with a double-tier paddle agitator and a glass condenser was added sequentially complex 7 (7.33 kg), ethyl acetate (67.5 kg) and pure water (74.0 kg). The mixture was heated to reflux and stirred at reflux for 30 min. The reaction mixture was cooled to approximately 50 °C and the organic layer was separated and the aqueous layer was extracted with ethyl acetate (34.0 kg). The combined organic layers were washed with pure water (3×74.0 kg) (IPC test showed that the IPC criteria for L-proline residue was met after three water washes). The mixture was concentrated at 40 °C under vacuum (-15 mmHg) for 3 h until the liquid level dropped below the lower-tier agitator paddle. The mixture (18 kg) was discharged and transferred to a 20L rotary evaporator. The mixture was concentrated under vacuum (40 °C, ~5 mmHg) to a minimum volume. The remaining trace amount of ethyl acetate was removed azeotropically at 40 °C under vacuum with methanol (10 kg). The residue was dried under vacuum of an oil pump (~6 mmHg) at 40 °C for 10 h to give 8 as a white amorphous solid (4.67 kg, purity (HPLC): 99.2%) which was used in the next step without further purification.

The recrystallization was accomplished by the following steps. To a 100 L glass line reactor equipped with a double-tier paddle agitator and a glass condenser was added the above amorphous 8 (4.67 kg) and methanol (18.0 kg). The mixture was refluxed at 70 °C for 30 min until a clear solution formed, to which pure water (45.0 kg) was added over 2 hours. After the addition was completed (the reaction temperature was 41 °C), the reaction mixture was cooled to room temperature and stirred at room temperature for 15 hours. The reaction mixture was filtered and the wet cake was washed with pure water (2×15 kg) and dried under vacuum at 55-60 °C for 12 hours to give the target product as an off-white crystalline solid (3.93 kg, yield: 84% in two steps; purity (HPLC): 99.7%).

Example 6. Direct Preparation of Crystalline Compound 8 from Amorphous 8

A 5 L 4-neck flask was charged with 8 (amorphous), 116 g, and methanol (580 mL). The reaction mixture was heated to 60 C with mechanical stirring and the solution became clear. Water (2320 mL) was added dropwise to the reaction solution at 40 mL/min at 50 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered and the filter cake was washed with water (2×200 mL), dried under vacuum at 55 °C for 12 hours, to afford white crystalline 8. Yield is 112.8 g (97.2%).

References:
1. Clinical Trial, A Dose Range Finding Study to Evaluate the Effect of Bexagliflozin Tablets in Subjects With Type 2 Diabetes Mellitus. NCT02390050 (retrieved on 26-03-2015).

WO2008144346A2 *

May 15, 2008

Nov 27, 2008

Squibb Bristol Myers Co

Crystal structures of sglt2 inhibitors and processes for their preparation

WO2009026537A1 *

Aug 22, 2008

Feb 26, 2009

Theracos Inc

Benzylbenzene derivatives and methods of use

CN1407990A *

Oct 2, 2000

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布里斯托尔-迈尔斯斯奎布公司

C-aryl glucoside sgltz inhibitors

WO2008144346A2 *	May 15, 2008	Nov 27, 2008	Squibb Bristol Myers Co	Crystal structures of sglt2 inhibitors and processes for their preparation
WO2009026537A1 *	Aug 22, 2008	Feb 26, 2009	Theracos Inc	Benzylbenzene derivatives and methods of use
CN1407990A *	Oct 2, 2000	Apr 2, 2003	布里斯托尔-迈尔斯斯奎布公司	C-aryl glucoside sgltz inhibitors

WO2010022313A2 *	Aug 21, 2009	Feb 25, 2010	Theracos, Inc.	Processes for the preparation of sglt2 inhibitors

////////BEXAGLIFLOZIN, APPROVALS 2023, FDA 2023

c1cc(ccc1Cc2cc(ccc2Cl)[C@H]3[C@@H]([C@H]([C@@H]([C@H](O3)CO)O)O)O)OCCOC4CC4

SYN

https://doi.org/10.1021/acs.jmedchem.4c02079J.Med.Chem.2025,68,2147−2182

Bexagliflozin (Brenzavvy). Bexagliflozin (3) was discoveredanddevelopedbyTheracosBioforthetreatmentof
type2diabetesmellitus.28Bexagliflozinisasodium-dependent glucose cotransporter 2 (SGLT2) inhibitor. Inhibition of SGLT2 reduces blood sugar without stimulating insulin release.29 Bexagliflozin shows >2000-fold selectivity forSGLT2 over SGLT1 and demonstrated improvement inglycemiccontrolwithaoncedaily,20mgdose.28Since 2011, there have been 11 therapeutics targeting
SGLT2.30Thesedrugsexhibit commonstructural features(abiarylmethaneandglycoside)andlikelyfacesimilarsynthetic challenges.31 The medicinal chemistry efforts to identifybexagliflozinweredisclosedintheprimaryliterature.32Apatent fromTheracos, Inc. in2013describedasyntheticapproachto bexagliflozinonmultikilogramscale.33Slightvariations inthe
reactionconditions,yieldandisolationstrategyofintermediates wereincludedinthepatent.Theimplementationoftelescoping intheprocessislikelyduetopoorcrystallinityofintermediates,
whichmaybeacommonchallengetootherSGLT2inhibitors.31
Anotherpatent disclosedbyPiramal Enterprises suggesteda
similarbondformationstrategybut includedanacetylationof bexagliflozinprior tothefinal isolation inorder toprovidea crystallinesolid.34
Bexagliflozinwas assembled by cryogenicmetal halogen exchangeof aryl iodide3.1with turboGrignard(i-PrMgCl·LiCl)andsubsequentadditiontoprotectedgluconolactone3.2
whichwaspreparedbytreatmentofD-(+)-glucono-1,4-lactonewithTMSClandNMMinTHFin94%yield(Scheme4).WhentheGrignardadditionwascomplete,thereactionwasquenchedand a solution of the product inEtOAcwas treatedwith
activated carbon, filtered, concentrated, and diluted with methanol.ThissolutionwastreatedwithconcentratedHCl to remove thesilyl protectinggroupsandprovidecrudemethyl ketal3.3inyields rangingfrom79to95%.Themethyl ketal
functionalitywasreducedusingtriethylsilaneandBF3·Et2Oin DCMandMeCNatcryogenictemperaturestoprovidecrude bexagliflozin (3) as a solid after concentrating the reaction mixture. Alternatively, a larger-scale demonstration of this processinthepatenttelescopedasolutionofcrudebexagliflozin toformabis-L-prolinecomplexinethanol,water,andheptane,
whichwasisolatedasacrystallinesolidin81%yield.Thiswas convertedto the free formin82%yieldbycrystallization in methanolandwater.Arecrystallizationofbexagliflozin(3)was
reported in 92% yield. Details on stereoselectivity of this
approachwerenotdisclosed.
Amilligram-togram-scaleconstructionofthearyliodide3.1 wasalsodisclosedintheTheracospatent from2013(Scheme 5).33First,carboxylicacid3.5wasreducedtoprimaryalcohol
3.6using sodiumborohydride and iodine. Next, the diaryl methanecorewas assembledbyFriedel−Crafts alkylationof phenol with3.6 after activationwithHBr andZnCl2. This reactionwasdemonstratedonmilligramscaleandachieved65% conversion, with 52% isolated yield after chromatographic purification.Analternativeapproachtoabromovariantofaryl iodide3.7waspresentedina2009patentfromTheracos,where Friedel−Craftsacylationprovidedtheanalogousbenzophenone intermediatewhichwas thensubsequentlyreduced.35Finally,alkylationofthephenolwasconductedusingthetosylatedether
3.8toprovidearyl iodide3.1in75%yieldonkilogramscale.A syntheticapproachtothetosylatedetherwasprovidedinthe earlyTheracospatent,35wherecyclopropylether formationin 3.10wasgeneratedviaGrignardformationandrearrangement of 2-(2-bromoethyl)-1,3-dioxolane 3.9 (Scheme 6). The primary alcohol 3.10was protectedas the tosylate3.8and employedinthealkylationstepwithoutpurification.Noyields wereprovided.

(28) Hoy, S. M. Bexagliflozin: first approval. Drugs 2023, 83, 447−
453.
(29) Hsia, D. S.; Grove, O.; Cefalu, W. T. An update on sodium
glucose co-transporter-2 inhibitors for the treatment of diabetes
mellitus. Curr. Opin. Endocrinol. Diabetes Obes. 2017, 24, 73−79.
(30) Guo, Y.-Y.; Zhang, J.-Y.; Sun, J.-F.; Gao, H. A comprehensive
review of small-molecule drugs for the treatment of type 2 diabetes
mellitus: Synthetic approaches and clinical applications. Eur. J. Med.
Chem. 2024, 267, No. 116185.
(31) Aguillón, A. R.; Mascarello, A.; Segretti, N. D.; de Azevedo, H. F.
Z.; Guimaraes, C. R. W.; Miranda, L. S. M.; de Souza, R. O. M. A.
Synthetic strategies toward SGLT2 inhibitors. Org. Process Res. Dev.
2018, 22, 467−488.
(32) Xu, B.; Feng, Y.; Cheng, H.; Song, Y.; Lv, B.; Wu, Y.; Wang, C.;
Li, S.; Xu, M.; Du, J.; et al. C-aryl glucosides substituted at the 4′
position as potent and selective renal sodium-dependent glucose co
transporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes.
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(33) Xu, B.; Lv, B.; Xu, G.; Seed, B.; Roberge, J. Y. Process for the
preparation of benzyl-benzene C-glycosides via coupling reaction as
potential SGLT2 inhibitors. US 20130267694, 2013.
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D. Aprocess for the preparation of SGLT2 inhibitor and intermediates
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B.; Seed, B.; Hadd, M. J.; et al. Preparation of benzylbenzene glycoside
derivatives as antidiabetic agents. WO 2009026537, 2009.

European Journal of Medicinal Chemistry

Volume 265, 5 February 2024, 116124

https://doi.org/10.1016/j.ejmech.2024.116124

Bexagliflozin (Brenzavvy)
On January 20, 2023, the FDA granted approval to Bexagliflozin, a medication developed by Theracos Inc, for the treatment of type 2 diabetes mellitus (T2DM) [104–106]. The SGLT2 inhibitor Bexagliflozin
can increase energy expenditure, reduce fluid retention, and increase urinary glucose excretion by inhibiting SGLT2 in renal tubular epithelial cells [106]. SGLT2 inhibitors have significant advantages compared to other drugs: (1) they can lower both pre-meal and post-meal blood sugar levels (not all drugs can lower both); (2) they have a lower risk of hypoglycemia as they do not stimulate insulin secretion; (3) they have adiuretic effect due to their primary action on the renal tubules, which
lowers systolic blood pressure; (4) research has shown that SGLT2 in hibitors have therapeutic effects on diabetic kidney disease [107,108].
The process of synthesizing Bexagliflozin started by conducting theFriedel-Crafts acylation of ethoxybenzene (BEXA-002) with 5-bromo-2-chlorobenzoic acid (BEXA-001) (Scheme 29) [109]. This reaction produced ketone BEXA-003. Subsequently, the carbonyl reduction of BEXA-003 was carried out using trifluoromethanesulfonic acid (TfOH),triethylsilane, and TFA. This step yielded BEXA-004. Next, n-butyllithium (n-BuLi) and pyrone BEXA-005 were combined with BEXA-004 at78◦C. This reaction produced an intermediate, which was thenreacted with triethylsilane and BF◦3⋅Et2O at 0C. The final product obtained from this reaction was BEXA-006, which contained a sugar ring.
BEXA-006 underwent dealkylation upon treatment with boron tribromide, resulting in the formation of BEXA-007, which was a phenol.
Subsequently, BEXA-007 was alkylated using 2-cyclopropoxyethyl4-methylbenzenesulfonate (BEXA-008) to yield Bexagliflozin.

[104] S.M. Hoy, Bexagliflozin: first approval, Drugs 83 (2023) 447–453.
[105] W. Zhang, A. Welihinda, J. Mechanic, H. Ding, L. Zhu, Y. Lu, Z. Deng, Z. Sheng,
B. Lv, Y. Chen, J.Y. Roberge, B. Seed, Y.X. Wang, EGT1442, a potent and selectiveSGLT2 inhibitor, attenuates blood glucose and HbA(1c) levels in db/db mice and
prolongs the survival of stroke-prone rats, Pharmacol. Res. 63 (2011) 284–293.
[106] O. Azzam, R. Carnagarin, L.M. Lugo-Gavidia, J. Nolde, V.B. Matthews, M.
P. Schlaich, Bexagliflozin for type 2 diabetes: an overview of the data, Expet Opin.
Pharmacother. 22 (2021) 2095–2103.
[107] B.F. Palmer, D.J. Clegg, Kidney-protective effects of SGLT2 inhibitors, Clin. J. Am.
Soc. Nephrol. 18 (2023) 279–289.
[108] M. Singh, A. Kumar, Risks associated with SGLT2 inhibitors: an overview, Curr.
Drug Saf. 13 (2018) 84–91.
[109] Y. Song, Y. Chen, H. Cheng, S. Li, Y. Wu, Y. Feng, B. Lv, B. Xu, B. Seed, M.J. Hadd,
J. Du, C. Wang, J.Y. Roberge, Preparation of Benzylbenzene Glycoside Derivatives
as Antidiabetic Agents, 2009. WO2009026537A1.

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