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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,

Altiratinib

October 9, 2015 8:45 am / 1 Comment on Altiratinib

Altiratinib
DCC-2701; DP-5164
CAS :1345847-93-9
N-[4-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Mechanism of Action:MET/TIE2/VEGFR2/TRK (A,B,C) kinase inhibitor
Indication:invasive solid tumors. The FDA has granted altiratinib Orphan Drug Designation for glioblastoma multiforme (GBM)
Development Stage:Phase I
Developer:Deciphera Pharmaceuticals, Llc

Altiratinib, also known as DCC-270, DP-5164, is an oral, selective and highly potent inhibitor of MET, TIE2, VEGFR2 and TRK kinases with potential anticancer activity. DCC-2701 effectively reduces tumor burden in vivo and blocks c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro. Importantly, DCC-2701’s anti-proliferative activity was dependent on c-MET activation induced by stromal human fibroblasts and to a lesser extent exogenous HGF. DCC-2701 may be superior to HGF antagonists that are in clinical trials and that pTyr(1349) levels might be a good indicator of c-MET activation and likely response to targeted therapy as a result of signals from the microenvironment. Inhibition of MET kinase blocks a key mechanism in tumor cells that causes cancer invasiveness and metastasis. (Oncogene. 2015 Jan 8;34(2):144-53.)

DCC-2701 is an angiogenesis inhibitor acting on Tie2 receptor, HGF receptor and VEGFR-2. The product is being evaluated in phase I clinical studies at Deciphera for the oral treatment of solid tumors.

Altiratinib(DCC-2701) is a novel c-MET/TIE-2/VEGFR inhibitor; effectively reduce tumor burden in vivo and block c-MET pTyr(1349)-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro.

SYNTHESIS

CLICK ON IMAGE TO ENLARGE

OR SEE

http://apisynthesisint.blogspot.in/2015/10/altiratinib-dcc-2701-dp-5164.html

PATENT

https://www.google.co.in/patents/WO2011137342A1?cl=en

Scheme 1

BEAWARE THIS IS NOT THE COMPD

Scheme 11

INTERMEDIATES

Scheme 9

[00108] A non-limiting example of Scheme 9 is illustrated below for the synthesis of 36, a specific example of 26 wherein X is F, Y is CI, and Zl , Z2, and Z3 are CH (Scheme 10). Addition of l ,2,4-trifluoro-5-nitrobenzene (33) to a solution of 2-chloropyridin-4-ol (34) and sodium hydride in DMF at 0 °C yields the nitro intermediate 35. The nitro moiety of 35 is subsequently reduced at RT in the presence of zinc dust and ammonium chloride in solution of me hanol and THF to yield amine 36.

Scheme 10

[00109] A non-limiting example of Scheme 7 is illustrated in Scheme 11, beginning with intermediate 36, prepared in Scheme 10. Thus, 36 readily reacts with acid chloride 13 (see Scheme 3) in the presence of triethylamine to yield chloro-pyridine 37. Chloro-pyridine 37 is then converted to 38, a specific example of 1 wherein Rl is F, X is F, Zl , Z2, and Z3 are CH and R3 is -C(0)CH₃, upon treatment with acetamide (an example of R3-NH2 27 where R3 is acetyl) and cesium carbonate in the presence of a catalytic amount of palladium acetate and xantphos.

NOTE 38 IS NOT THE FINAL PRODUCT

REFERENCES

Kwon Y, Smith BD, Zhou Y, Kaufman MD, Godwin AK. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene. 2015 Jan 8;34(2):144-53. doi: 10.1038/onc.2013.539. Epub 2013 Dec 23. PubMed PMID: 24362531; PubMed Central PMCID: PMC4067476.

////Altiratinib, DCC-2701, DP-5164, Phase I, Deciphera Pharmaceuticals

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 NMR

October 8, 2015 7:26 am / Leave a comment

Ezetimibe

Marcin Śnieżek, Sebastian Stecko, Irma Panfil, Bartłomiej Furman, and Marek Chmielewski *

Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

J. Org. Chem., 2013, 78 (14), pp 7048–7057

DOI: 10.1021/jo400807c..http://pubs.acs.org/doi/full/10.1021/jo400807c

Ezetimibe (1)

ezetimibe 1 (1.08 g, 80%) as a white solid.

Mp 164–166 °C [lit.(11) 155–157 °C];

99% ee;

[α]²⁰_D −28.1 (c 0.15, MeOH) [lit.(11) −32.6 (c 0.34, MeOH)];

¹H NMR (600 MHz, DMSO-d₆) δ 9.49 (1H, s), 7.28–7.24 (2H, m), 7.19–7.16 (4H, m), 7.11–7.07 (4H, m), 6.75–6.71 (2H, m), 5.25 (1H, d, J 4.3 Hz), 4.77 (1H, d, J 2.2 Hz), 4.49–4.59 (1H, m), 3.07–3.04 (1H, m) 1.84–1.66 (4H, m);

¹³C NMR (150 MHz, CDCl₃) δ 167.8, 162.3, and 160.7 (d, J_C–F 240.3 Hz), 159.3, 157.9, 157.7, 142.5, 134.4, 128.7, 128.3, 128.0, 127.9, 118.7, and 118.6 (d, J_C–F 8.1 Hz), 116.3, 116.2, 115.2, and 115.0 (d, J_C–F 20.7 Hz), 71.5, 60.0, 59.9, 36.8, 24.9;

HRMS (EI, TOF) m/z calcd for C₂₄H₂₁F₂NO₃ [M] 409.1489 found 409.1478. Anal. Calcd for C₂₄H₂₁F₂NO₃: C 70.41, H 5.17, F 9.28, N 3.42. Found: C 70.46, H 5.23, F 9.24, N 3.34.

(3S,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3′-hydroxypropyl)azetidin-2-one (20)

Method 1

To a cooled (0 °C) solution of lactone 19 (2.0 g, 4 mmol) in 160 mL of dry diethyl ether was added 12 mL of 1 M solution of t-BuMgCl in diethyl ether. After 2 h, 30 mL of aq NH₄Cl was added. The aqueous layer was extracted with ether (160 mL), the organic layer was washed with satd NaHCO₃ (50 mL) and dried (MgSO₄), and the solvent was removed under reduced pressure. Crude product 20 (1.64 g, 82%) obtained as a yellowish solid was used in the next step without further purification. An analytic sample was obtained by chromatography on silica gel (hexanes/ethyl acetate 7:3). Mp 130–133 °C [lit.(11) 132–134 °C]; [α]²⁰_D −42.2 (c 1.2, CHCl₃); ¹H NMR (600 MHz, CDCl₃) δ 7.42–7.20 (11H, m), 7.02–6.90 (6H, m), 5,04 (2H, s), 4.72–4.68 (1H, m), 4.55 (1H, d J 2.2 Hz), 3.07 (1H, dt J 7.1, 2.2 Hz), 2.05–1.93 (3H, m) 1.89–1.82 (2H, m); ¹³C NMR (150 MHz, CDCl₃) δ 167.6, 163.0, and 161.4 (d, J_C–F 244.2 Hz), 159.8 and 158.1 (d, J_C–F 241.8 Hz), 159.0, 140.0, 139.9, 136.6, 133.9, and 133.8 (d, J_C–F 2.9 Hz), 129.6, 128.6, 128.1, 127.5, 127.4 and 127.4, (d, J_C–F 8.0 Hz), 127.2, 118.4, 118.3, 115.8, 115.8, and 115.7 (d, J_C–F 22.0 Hz), 115.5, 115.4, and 115.3 (d, J_C–F 21.3 Hz), 73.3, 70.1, 61.1, 60.3, 36.5, 25.0; HRMS (ESI, TOF) m/z calcd for C₃₁H₂₇F₂NO₃Na [M + Na]⁺ 522.1851, found 522.1862; IR (KBr) v 3441, 1743, 1609, 1510 cm^–1. Anal. Calcd for C₃₁H₂₇F₂NO₃: C 74.53, H 5.45, N 2.80, F 7.61. Found: C 74.40, H 5.53, N 2.74, F 7.56.

Org. Process Res. Dev., 2009, 13 (5), pp 907–910

DOI: 10.1021/op900039z

http://pubs.acs.org/doi/abs/10.1021/op900039z

Preparation of 1-(4-Fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone 1 (Ezetimibe)

of compound 1. ¹H NMR (300 MHz, DMSO-d₆, δ) 1.72−1.84 (m, 4H), 3.08 (m, 1H), 4.45 (m, 1H), 4.8 (d, 1H, J = 2.0 Hz), 5.25 (d, 1H, J = 4.8), 6.75 (d, 2H, J = 8.4 Hz), 7.05−7.4 (m, 10H, Ar), 9.48 (s, 1H); IR: 3270.0, 2918, 1862, 1718.4, 1510 cm⁻¹. MS: m/z 409.2 (M⁺). Anal. Calcd for C₁₅H₁₇NO₅: C, 70.41; H, 5.17; N, 3.42. Found: C, 70.38; H, 5.27; N, 3.34.

Preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 10

compound 9 as a white solid. ¹H NMR (200 MHz, DMSO-d₆, δ) 1.6−1.9 (m, 4H), 2.0−2.2 (bs, 1H), 3.0−3.2 (m, 1H), 4.4−4.6 (m, 1H), 4.74 (m, 1H), 5.05 (s, 2H), 6.95−7.9 (m, 17H, Ar); IR: 3492, 2922, 2852, 1719 cm⁻¹; MS: m/z 499.3 (M⁺).

….

doi:10.1016/j.jpha.2015.04.002

Scheme 1.

Synthesis of ezetimibe and desfluoro ezetimibe impurity.

http://www.sciencedirect.com/science/article/pii/S2095177915000386

Fig. 4.

Fig. 2.

Structures of ezetimibe, desfluoro impurity and intermediates.

Comparison of ¹H, ¹³C and ¹⁹F NMRs of ezetimibe and desfluoro ezetimibe impurity.

Table 2.¹H and ¹³C NMR assignments for Eze-1 and desfluoro Eze-1.

Position^a	¹H–δ ppm		¹³C–δ ppm (DEPT)
Position^a	Eze-1^b	Desfluoro Eze-1^b	Eze-1^b	Desfluoro Eze-1^b
1	10.15 (br, OH)	10.13 (br, OH)	–	–
2	–	–	161.3 (C)	161.3 (C)
3	6.87 (d, J=8.5 Hz, 2H)	6.87 (dd, J=8.4, 1.8 Hz, 2H)	116.3 (2CH)	116.3 (2CH)
4	7.74 (d, J=8.5 Hz, 2H)	7.75 (dd, J=8.4, 1.8 Hz, 2H)	131.4 (2CH)	131.4 (2CH)
5	–	–	128.1 (C)	128.2 (C)
6	8.43 (s, 1H)	8.43 (s, 1H)	160.8 (CH)	160.8 (CH)
7	–	–	149.0 (d, ⁴J=2.6 Hz, C)	152.7 (C)
8	7.15–7.26 (m, 4H)	7.36 (dd, J=8.1, 7.5 Hz, 2H)	123.3 (d, ³J=8.4 Hz, 2CH)	121.6 (2CH)
9	7.15–7.26 (m, 4H)	7.17 (d, J=7.8 Hz, 2H)	116.5 (d, ²J=22 Hz, 2CH)	129.8 (2CH)
10	–	7.18 (t, J=6.3 Hz, 1H)	160.8 (d, ¹J=242 Hz, C)	126.0 (CH)

Assignments: s: singlet; d: doublet; t: triplet; m: multiplet; br: broad singlet. Mean values used for coupled signals.

aNumbering of all compounds shown in Fig. 2 and copies of NMR spectra are presented in Appendix A.

bSolvent is DMSO-d6.

R-Enantiomer in Ezetimibe

R-Enantiomer in Ezetimibe

ABOVE 1H NMR OF R ENANTIOMER

Isolation and Characterization of R-Enantiomer in Ezetimibe

http://www.scirp.org/journal/PaperDownload.aspx?paperID=36901

by K Chimalakonda – ‎2013 – ‎Related articles

HPLC1H and 13C NMR. The purity of isolated R-Isomer is about 98%. Keywords: Isolation; Characterization; (R)-Isomer; Ezetimibe; Supercritical Fluid …

http://file.scirp.org/Html/10-2200417_36901.htm

1H NMR VALUES FOR R ENANTIOMER

13C NMR OF R ENANTIOMER

13C NMR VALUES OF R ENANTIOMER

IR OF R ENANTIOMER

Ezetimibe for reference

163222-33-1

Ezetimibe
Systematic (IUPAC) name

(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
Clinical data
Trade names	Zetia
AHFS/Drugs.com	monograph
MedlinePlus	a603015
Pregnancy category	AU: C US: C
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: POM US: ℞-only
Routes	Oral
Pharmacokinetic data
Bioavailability	35–65%
Protein binding	>90%
Metabolism	Intestinal wall, hepatic
Half-life	19–30 hours
Excretion	Renal 11%, faecal 78%
Identifiers
CAS number	163222-33-1
ATC code	C10AX09
PubChem	CID 150311
DrugBank	DB00973
ChemSpider	132493
UNII	EOR26LQQ24
KEGG	D01966
ChEBI	CHEBI:49040
ChEMBL	CHEMBL1138
Chemical data
Formula	C₂₄H₂₁F₂N O₃
Molecular mass	409.4 g·mol⁻¹
SMILES [show]
InChI [show]
Physical data
Melting point	164 to 166 °C (327 to 331 °F)
(what is this?) (verify)

1H NMR OF R ENANTIOMER PREDICTED

Ezetimibe NMR spectra analysis, Chemical CAS NO. 163222-33-1 NMR spectral analysis, Ezetimibe H-NMR spectrum

13C NMR OF R ENANTIOMER PREDICTED

Ezetimibe NMR spectra analysis, Chemical CAS NO. 163222-33-1 NMR spectral analysis, Ezetimibe C-NMR spectrum

cosy

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 patent also describes a process for the preparation of ezetimibe.

The process described in the patent involves the use of methyl-4-(chloroformyl) butyrate and also involves isolation of the compound (3R,4S)-1-(4-fluorophenyl)-3-[3-(chloroformyl)-3-oxo-propyl]-4-(4-benzyloxyphenyl)-2-azetidinone as an intermediate. Chlorinated compounds are unstable and difficult to handle in large scale productions. The process described in the patent also involves the purification of intermediates using column chromatography, thus making the process difficult to be scaled up.

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.

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

EXAMPLE 10 PREPARATION OF 1-(4-FLUOROPHENYL)-3(R)-[3-(4-FLUOROPHENYL)-3(S)-HYDROXYPROPYL]-4(S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (FORMULA I)

50 g of (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(s)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone and 475 ml of methanol were taken into a round bottom flask. A mixture of 15 g of 5% palladium on carbon and 25 ml of water was added to it. The reaction mass was flushed with hydrogen gas and a hydrogen pressure of 3 to 5 kg/cm2 was applied. The reaction mass was stirred for 3 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the pressure was released and the reaction mass was filtered through perlite. The filter bed was washed with 100 ml of methanol. The filtrate was distilled completely at 70° C., and 400 ml of isopropanol was added to it. The reaction mass was heated to 45° C. and maintained for 10 minutes. The reaction mass was then allowed to cool to 28° C. 400 ml of water was added to the reaction mass and stirred for 1 hour, 20 minutes. The separated compound was filtered and washed with 100 ml of water. The wet cake was taken into another round bottom flask and 500 ml of chlorobenzene and 40 ml of methanol were added to it. The reaction mass was heated to 65° C. and maintained for 15 minutes. 25 ml of water was added to the reaction mass and stirred for 2 hours. The separated compound was filtered and washed with 100 ml of chlorobenzene. The wet cake was taken into another round bottom flask and 375 ml of chlorobenzene, and 30 ml of methanol were added to it. The reaction mass was heated to 62° C. and maintained for 10 minutes. The reaction mass was then cooled to 28° C. and 20 ml of water was added to it. The reaction mass was stirred for 20 minutes and then filtered and washed with 100 ml of chlorobenzene. The wet cake was taken into another round bottom flask and 400 ml of isopropanol was added to it. The reaction mass was heated to 46° C. and maintained for 15 minutes. 800 ml of water was added to the reaction mass at 45 to 46° C. and stirred for one hour. The separated solid was filtered and washed with water. The process of recrystallization in a combination of isopropanol and water was repeated and the obtained compound was dried at 70° C. for 5 hours to get 19.8 g of the title compound. (Yield 49.2%)

Purity by HPLC: 99.68%.

EXAMPLE 11 PURIFICATION OF 1-(4-FLUOROPHENYL)-3(R)-[3-(4-FLUOROPHENYL)-3(S)-HYDROXYPROPYL]-4(S)-(4-HYDROXYPHENYL)-2-AZETIDINONE (FORMULA I)

15.0 g of ezetimibe obtained above and 120 ml of isopropanol were taken into a round bottom flask and the reaction mass was heated to 48° C. The reaction mass was filtered through a perlite bed in the hot condition to make the solution particle free. The filtrate was taken into another round bottom flask and heated to 47° C. 240 ml of water was added at 47° C. After completion of the addition, the reaction mass was maintained at 47° C. for 1 hour. The separated solid was filtered and washed with 30 ml of water. The wet compound was dried at 70° C. for 8 hours to get 13.4 g of the title compound. (Yield 89%)

Purity by HPLC: 99.92.

benzyl ezetimibe impurity: less than 0.0003 area-%,

benzyl ezetimibe diol impurity: 0.004 area-%,

lactam cleaved alcohol impurity: 0.003 area-%,

lactam cleaved acid impurity: 0.01 area-%,

ezetimibe diol impurity: less than 0.0007 area-%.

Residual solvent content by gas chromatography:

Isopropyl alcohol: 1454 ppm

All other solvents: Less than 100 ppm.

WO1997045406A1 *	May 28, 1997	Dec 4, 1997	Schering Corp	3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
WO2004099132A2	May 5, 2004	Nov 18, 2004	Ram Chander Aryan	Process for the preparation of trans-isomers of diphenylazetidinone derivatives
WO2008032338A2 *	Sep 10, 2007	Mar 20, 2008	Reddy Maramreddy Sahadeva	Improved process for the preparation of ezetimibe and its intermediates
EP0720599A1	Sep 14, 1994	Jul 10, 1996	Schering Corporation	Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US20070049748	Aug 25, 2006	Mar 1, 2007	Uppala Venkata Bhaskara R	Preparation of ezetim

Citing Patent	Filing date	Publication date	Applicant	Title
US7470678	Jul 1, 2003	Dec 30, 2008	Astrazeneca Ab	Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684	Apr 25, 2007	Nov 30, 2010	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265	Jun 19, 2006	Jan 4, 2011	Astrazeneca Ab	N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[(2R or S)-2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-lysine, used as anticholesterol agents
US7871998	Dec 21, 2004	Jan 18, 2011	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048	Jun 21, 2006	Feb 22, 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502	Jun 21, 2006	Mar 15, 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US8013150 *	Feb 17, 2006	Sep 6, 2011	Msn Laboratories Ltd.	Process for the preparation of ezetimibe
US8383810	Dec 12, 2011	Feb 26, 2013	Merck Sharp & Dohme Corp.	Process for the synthesis of azetidinones
US20110130378 *	May 26, 2009	Jun 2, 2011	Lek Pharmaceuticals D.D.	Ezetimibe process and composition
US20110183956 *	Jul 29, 2009	Jul 28, 2011	Janez Mravljak	Process for the synthesis of ezetimibe and intermediates useful therefor
EP2128133A1	May 26, 2008	Dec 2, 2009	Lek Pharmaceuticals D.D.	Ezetimibe process and composition
WO2008096372A2 *	Feb 6, 2008	Aug 14, 2008	Pranav Gupta	Process for preparing highly pure ezetimibe using novel intermediates
WO2009150038A1	May 26, 2009	Dec 17, 2009	Lek Pharmaceuticals D.D.	Process for the preparation of ezetimibe and composition containing it
WO2009157019A2 *	Jun 23, 2009	Dec 30, 2009	Ind-Swift Laboratories Limited	Process for preparing ezetimibe using novel allyl intermediates

WO2005021497A2 *	Aug 27, 2004	Mar 10, 2005	Eduardo J Martinez	Tethered dimers and trimers of 1,4-diphenylazetidn-2-ones
WO2006127893A2 *	May 25, 2006	Nov 30, 2006	Microbia Inc	Processes for production of 4-(biphenylyl)azetidin-2-one phosphonic acids
WO2008096372A2 *	Feb 6, 2008	Aug 14, 2008	Pranav Gupta	Process for preparing highly pure ezetimibe using novel intermediates
US20070049748 *	Aug 25, 2006	Mar 1, 2007	Uppala Venkata Bhaskara R	Preparation of ezetimibe

/////

FDA Inspections at API Manufacturers – current Warning Letter Trends

October 8, 2015 7:00 am / Leave a comment

The Warning Letters the FDA sent to active ingredient manufacturers last fiscal year, show similar patterns. Find out more about the frequent deficiencies found in the area of responsibility of quality assurance and in the handling of electronic data in production facilities for active pharmaceutical ingredients.

http://www.gmp-compliance.org/enews_05046_FDA-Inspections-at-API-Manufacturers—current-Warning-Letter-Trends_9300,S-WKS_n.html

Taking a look at the Warning Letters the FDA issued after inspections of activesubstance manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking that only non-American companies are among the addressees. Almost half of them are Indian companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL); Thailand (1 WL); Czech Republic (1 WL).

The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or missing data integrity. Each of the 8 warning letters contains the following comment in the same wording:

“Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.”

The lack of access control on electronic (raw) data is an issue the FDA investigators have been observing for a long time, especially during inspections in pharmaceutical companies. In this as well as in the last fiscal year there were significant deficiencies in several companies – medicinal product as well as API manufacturers – as the comments in the appropriate Warning Letters show. For more information also see the GMP news Another FDA Warning Letter with Focus on “Data Integrity” and FDA Warning Letter on Data Integrity.

Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also affects other areas. In the Warning Letters, the following examples can be found for this:

“Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.”
“Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.”
Data were manipulated by laboratory staff (change of the file name), to fake results from identity tests in batches which in reality were not performed. Quality assurance was not able to uncover this manipulation.
Despite an unknown peak in the examination for residual solvents the relevant batches were released. Upon receipt of a complaint regarding this peak an examination was conducted with the result that the contamination originated in the production process itself. Preventive control measures to avoid this contamination were not established.
“Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected.”
As a result of a complaint (bad smell), a cause study was initiated which was completed prior to implementation of the preventive measures again. The CAPA measures subsequently carried out were obviously not associated with the reason for the complaint.
“Failure to have appropriate controls for issuance of batch records”.
The use of document templates for batch records is out of control. These can be printed out from the production staff’s personal computers. Although there is an SOP for the control of batch records there are no appropriate training records.
“Failure to have appropriate documentation and record controls.”
Data for tracing raw materials are not available. Log entries are without date/visa and partly corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this was not trained.
“Failure to record activities at the time they are performed and destruction of original records.”
Original records of critical process data on uncontrolled memos were transferred subsequently in new report templates (after batch approvals) and then destroyed.

This selection of examples shows the lack of fundamental GMP principles which leads to a blatant misconduct of staff and ultimately to quality defects in the final product. The main responsibility usually has the quality unit, which task it actually would be to ensure a thorough training in production and quality control and to monitor compliance with the appropriate regulations. These examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there are very similar findings in Warning Letters issued to medicinal product manufacturers. An analysis of these Warning Letters issued in the fiscal year 2015 will be part of one the coming newsletters.

/////Warning Letters, FDA, active ingredient manufacturers

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 % ).

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

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).

……………

WO2005066120A2 *	23 Ara 2004	21 Tem 2005	Prosenjit Bose	Process for asymmetric synthesis of hydroxy-alkyl substituted azetidinone derivatives
WO2006137080A1 *	17 Şub 2006	28 Ara 2006	Kumar Muppa Kishore	Improved process for the preparation of ezetimibe
WO2008151324A1 *	9 Haz 2008	11 Ara 2008	Teva Pharma	Reduction processes for the preparation of ezetimibe
US7470678	1 Tem 2003	30 Ara 2008	Astrazeneca Ab	Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684	25 Nis 2007	30 Kas 2010	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265	19 Haz 2006	4 Oca 2011	Astrazeneca Ab	2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US7871998	21 Ara 2004	18 Oca 2011	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048	21 Haz 2006	22 Şub 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502	21 Haz 2006	15 Mar 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US8013150	17 Şub 2006	6 Eyl 2011	Msn Laboratories Ltd.	Process for the preparation of ezetimibe

Cited Patent	Filing date	Publication date	Applicant	Title
US4044147 *	May 26, 1976	Aug 23, 1977	Pfizer Inc.	N-(acyl)-p-amino-N’-(monosubstituted)-benzamide anti-ulcer agents
US5248611 *	Jan 3, 1992	Sep 28, 1993	Scripps Clinic And Research Foundation	Stereoisomer separation method using antibody combing site-containing molecules
US5739321 *	May 31, 1996	Apr 14, 1998	Schering Corporation	3-hydroxy γ-lactone based enantionselective synthesis of azetidinones
US5846991 *	Dec 29, 1997	Dec 8, 1998	Nissan Chemical Industries, Ltd.	Pyrazole derivatives
US5856473 *	Oct 31, 1996	Jan 5, 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
US5859035 *	Mar 27, 1997	Jan 12, 1999	Merck & Co., Inc.	Arylheteroaryl inhibitors of farnesyl-protein transferase
US5886171 *	May 28, 1997	Mar 23, 1999	Schering Corporation	3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
US6194599 *	Apr 8, 1997	Feb 27, 2001	Catalytica, Inc.	Process for preparing biaryl compounds
US6207822 *	Dec 5, 1999	Mar 27, 2001	Schering Corporation	Process for the synthesis of azetidinones
US20030013699 *	May 22, 2002	Jan 16, 2003	Davis Harry R.	Methods for treating alzheimer’s disease and/or regulating levels of amyloid beta peptides in a subject
US20050124808 *	Sep 23, 2004	Jun 9, 2005	Dsm I.P. Assets B.V.	Process for preparing unsymmetrical biaryls and alkylated aromatic compounds from arylnitriles
US20060247273 *	Sep 24, 2004	Nov 2, 2006	Takayuki Kawaguchi	Carbamoyl-type benzofuran derivatives
US20090048441 *	Feb 17, 2006	Feb 19, 2009	Manne Satyanarayana Reddy	Process for the Preparation of Ezetimibe
USRE37721 *	Jun 15, 2000	May 28, 2002	Schering Corporation	Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents

Citing Patent	Filing date	Publication date	Applicant	Title
US7470678	Jul 1, 2003	Dec 30, 2008	Astrazeneca Ab	Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684	Apr 25, 2007	Nov 30, 2010	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265	Jun 19, 2006	Jan 4, 2011	Astrazeneca Ab	2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US7871998	Dec 21, 2004	Jan 18, 2011	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048	Jun 21, 2006	Feb 22, 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7906502	Jun 21, 2006	Mar 15, 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US8013150 *	Feb 17, 2006	Sep 6, 2011	Msn Laboratories Ltd.	Process for the preparation of ezetimibe
US8383810	Dec 12, 2011	Feb 26, 2013	Merck Sharp & Dohme Corp.	Process for the synthesis of azetidinones
US20050239766 *	Jul 1, 2003	Oct 27, 2005	Astrazeneca Ab	Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US20060160785 *	Dec 5, 2005	Jul 20, 2006	Judith Aronhime	Ezetimibe polymorphs
US20060234996 *	Apr 13, 2006	Oct 19, 2006	Itai Adin	Novel crystalline form of ezetimibe and processes for the preparation thereof
US20110130378 *	May 26, 2009	Jun 2, 2011	Lek Pharmaceuticals D.D.	Ezetimibe process and composition
US20110183956 *	Jul 29, 2009	Jul 28, 2011	Janez Mravljak	Process for the synthesis of ezetimibe and intermediates useful therefor
CN102219803A *	Apr 20, 2011	Oct 19, 2011	浙江大学	Preparation method of ezetimibe intermediate
EP2128133A1	May 26, 2008	Dec 2, 2009	Lek Pharmaceuticals D.D.	Ezetimibe process and composition
WO2008096372A2 *	Feb 6, 2008	Aug 14, 2008	Pranav Gupta	Process for preparing highly pure ezetimibe using novel intermediates
WO2009150038A1	May 26, 2009	Dec 17, 2009	Lek Pharmaceuticals D.D.	Process for the preparation of ezetimibe and composition containing it
WO2009157019A2 *	Jun 23, 2009	Dec 30, 2009	Ind-Swift Laboratories Limited	Process for preparing ezetimibe using novel allyl intermediates

CN1131416A *	Sep 14, 1994	Sep 18, 1996	先灵公司	Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
CN1330721A *	Oct 1, 1999	Jan 9, 2002	先灵公司	Resolution of trans-2-(alkoxycarbonylethyl)-laitams useful in synthesis of 1-(4-fluorophenyl)-3(R)-[3(s)-hydroxy-3-(flurophenyl)-propyl)]-4(s)-(4-hydroxyphenyl)-2-azetidinone

CN1931838A *	20 Oct 2006	21 Mar 2007	屠勇军	Azacyclo butanone derivative and its synthesis process
WO2007108007A1 *	12 Sep 2006	27 Sep 2007	Prabhavalkar Tirtha Suresh	A process for the preparation of ezetimibe via a novel intermediate
WO2008096372A2 *	6 Feb 2008	14 Aug 2008	Pranav Gupta	Process for preparing highly pure ezetimibe using novel intermediates
WO2009157019A2 *	23 Jun 2009	30 Dec 2009	Ind-Swift Laboratories Limited	Process for preparing ezetimibe using novel allyl intermediates

WO2008032338A2 *	10 Eyl 2007	20 Mar 2008	Reddy Manne Satyanarayana	Improved process for the preparation of ezetimibe and its intermediates
WO2008089984A2 *	24 Oca 2008	31 Tem 2008	Krka	Process for the preparation of ezetimibe and derivatives thereof
WO2008096372A2 *	6 Şub 2008	14 Ağu 2008	Pranav Gupta	Process for preparing highly pure ezetimibe using novel intermediates
WO2008106900A1 *	3 Mar 2008	12 Eyl 2008	Zentiva As	Method of manufacturing (3r, 4s) -1- (4-fluorophenyl) -3- [ (3s) -3- (4 -fluorophenyl) -3-hydroxypropyl) ] -4- (4-hyd roxyphenyl) -2-azetidinone
WO2008151324A1 *	9 Haz 2008	11 Ara 2008	Teva Pharma	Reduction processes for the preparation of ezetimibe
WO2009067960A2 *	5 Kas 2008	4 Haz 2009	Zentiva As	A method of manufacturing (3r,4s)-l-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3- hydroxypropyl)]-4-(4-hydroxyphenyl)-2-azetidinone and its intermediates
WO2011158052A1	17 Haz 2011	22 Ara 2011	Nanoform Cardiovascular Therapeutics Ltd.	Nanostructured ezetimibe compositions, process for the preparation thereof and pharmaceutical compositions containing them
WO2012155932A1	17 May 2011	22 Kas 2012	Pharmathen S.A.	Improved process for the preparation of ezetimibe
CN102531986A *	23 Şub 2012	4 Tem 2012	苏州朗科生物技术有限公司	Preparation method for ezetimibe
CN103044305A *	24 Oca 2013	17 Nis 2013	上海现代制药股份有限公司	Preparation method of ezetimibe intermediate
EP1922304A2 †	8 Eyl 2006	21 May 2008	Teva Pharmaceutical Industries Ltd	Processes for the preparation of (3r,4s)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((s)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
EP1953140A1 *	24 Oca 2007	6 Ağu 2008	Krka	Process for the preparation of ezetimibe and derivatives thereof
US7842684	25 Nis 2007	30 Kas 2010	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7863265	19 Haz 2006	4 Oca 2011	Astrazeneca Ab	2-azetidinone derivatives and their use as cholesterol absorption inhibitors for the treatment of hyperlipidaemia
US7871998	21 Ara 2004	18 Oca 2011	Astrazeneca Ab	Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048	21 Haz 2006	22 Şub 2011	Astrazeneca Ab	2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
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

////

FDA approves new injectable drug to treat schizophrenia, Aristada (aripiprazole lauroxil)

October 7, 2015 4:01 am / Leave a comment

SYNTHESIS

https://newdrugapprovals.org/2014/08/28/aripiprazole-lauroxil-alkermes-submits-new-drug-application/

For Immediate Release

October 6, 2015

Release

On October 5, the U.S. Food and Drug Administration approved Aristada (aripiprazole lauroxil) extended release injection to treat adults with schizophrenia. Aristada is administered by a health care professional every four to six weeks using an injection in the arm or buttocks.

Schizophrenia is a chronic, severe and disabling brain disorder affecting about one percent of Americans. Typically, symptoms are first seen in adults younger than 30 years of age and include hearing voices, believing other people are reading their minds or controlling their thoughts, and being suspicious or withdrawn.

“Long-acting medications to treat schizophrenia can improve the lives of patients,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Having a variety of treatment options and dosage forms available for patients with mental illness is important so that a treatment plan can be tailored to meet the patient’s needs.”

The efficacy of Aristada was demonstrated in part by a 12-week clinical trial in 622 participants. In participants with acute schizophrenia who had been stabilized with oral aripiprazole, Aristada was found to maintain the treatment effect compared to a placebo.

Aristada and other atypical antipsychotic drugs used to treat schizophrenia have a Boxed Warning alerting health care professionals about an increased risk of death associated with the off-label use of these drugs to treat behavioral problems in older people with dementia-related psychosis. No drug in this class is approved to treat patients with dementia-related psychosis. Aristada must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

The most common side effect reported by participants receiving Aristada in clinical trials was feeling the urge to move constantly (akathisia).

Aristada is manufactured by Alkermes, Inc. of Waltham, Massachusetts.

SYN

https://newdrugapprovals.org/2014/08/28/aripiprazole-lauroxil-alkermes-submits-new-drug-application/

Process Development for Low Cost Manufacturing

October 7, 2015 3:50 am / Leave a comment

Process Development for Low Cost Manufacturing on 23-24 nov 2015 , Hyderabad, INDIA

23.11.2015 – 24.11.2015

Dr John Knight, Scientific Update

Dr Will Watson, Scientific Update

Hotel Green Park – Hyderabad, India
: View Brochure; or click; https://scientificupdate.co.uk/index.php/training/scheduled-training-courses/details/213-Low-Cost-Manufacturing.html?utm_source=Scientific+Update+News&utm_campaign=d31c03d4e3-India_Courses_Hyderabad7_22_2015&utm_medium=email&utm_term=0_08c5e1fb69-d31c03d4e3-78584097

Chemical process research and development is recognised as a key function during the commercialisation of a new product particularly in the generic and contract manufacturing arms of the chemical, agrochemical and pharmaceutical industries.

The synthesis and individual processes must be economic, safe and must generate product that meets the necessary quality requirements.

This 2-day course presented by highly experienced process chemists will concentrate on the development and optimisation of efficient processes to target molecules with an emphasis on raw material cost, solvent choice, yield improvement, process efficiency and work up, and waste minimisation.

Process robustness testing and reaction optimisation via stastical methods will also be covered.

A discussion of patent issues and areas where engineering and technology can help reduce operating costs.

The use of engineering and technology solutions to reduce costs will be discussed and throughout the course the emphasis will be on minimising costs and maximising returns.

- Young Chemists who have just started work in industry as development chemists
- Organic Chemists/Medicinal Chemists in Research and Development who would like to gain an appreciation of development and scale up and who are perhaps contemplating moving into chemical development.
- Development and Production Chemists in industry who would like to improve their efficiency and gain an insight into alternative approaches to chemical development.
- Chemical Engineers who wish to understand a chemist’s approach to chemical development of batch processes. (Engineers would, however, need a good grounding in organic chemistry)
- Students who are about to enter the industry and can obtain company sponsorship.
- Experienced Chemists looking to refresh and/or augment their knowledge of chemical development
- Analytical Chemists who wish to gain a broader appreciation of process chemistry
- Managers who might benefit from a comprehensive and up to date overview of chemical development
- Introduction
  Route selection, raw material choice
  • Choosing the best route
  • Using the cheapest raw materials and reagents, back integration of raw material supply
  • Reducing the number of steps vs. reagent choice / yield and cost
  
  Solvent selection
  • Solvent cost, recyclability
  • Solvent reactivity and solvent swapping
  • Solvent choice for reaction and work up
  
  Reaction optimisation
  • Reaction understanding
  • Improving conversion, selectivity
  • Telescoping
  
  Process optimisation
  • Reaction quench
  • Work up
  • Product isolation (crystallisation, filtration and drying)
  
  Statistical methods of optimisation
  • Design of experiments
  • Factorial and fractional factorial design
  • Response surface analysis
  • Robustness testing
  
  Regulatory and Quality issues
  • Impurity control and tracking
  • Process validation and QbD
  • Vessel cleaning
  
  Patent issues
  • Patents basics
  • Patent definition
  • Where patents are in force
  • How to work around patents
  
  Use of technology and engineering
  • Flow chemistry
  • SMB chromatography
  • Separation technologies
  
  At the end of the course participants will have gained:
  
  • A logical investigative approach to chemical development and optimisation
  • An insight into the factors involved in development and scaleup
  • A preliminary knowledge of statistical methods of optimisation
  • Improved ability to decide which parts of the chemical process to examine in detail.
  • Ideas for efficient resource allocation
  • Improved troubleshooting and problem solving ability
  • A basic outline of the patent system
  • An appreciation of how to assess the main cost contributors in a process
- https://scientificupdate.co.uk/images/eventlist/brochures/7649_su_23-24_nov_2015_doe_hyderabad(v2f)_1433342973.pdf

///////////

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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Sparsentan (PS433540, RE-021)

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NOTE 38 IS NOT THE FINAL PRODUCT

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The synthesis of ezetimibe with high stereochemical purity

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For Immediate Release

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Process Development for Low Cost Manufacturing on 23-24 nov 2015 , Hyderabad, INDIA

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