C-aryl glucoside sglt2 inhibitors and method for their production WO 2006034489 A2

D-​Glucitol, 1,​5-​anhydro-​1-​C-​[4-​chloro-​3-​[(4-​ethylphenyl)​methyl]​phenyl]​-​, (1S)​-

(2S,3R,4R,5S,6R)-2-(3-(4-ethylbenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol
cas  879545-38-7

http://www.google.com/patents/WO2006034489A2?cl=en

EXAMPLE 1

A. 5-Bromo-2-chloro-4'-ethylbenzophenone

[00119] To a 2L round bottom flask containing a magnetic stirred suspension of commercial 5-bromo-2-chlorobenzoic acid (41Og, 1.74 mol) in 700 mL OfCH₂Cl₂ ^'was added oxalyl chloride (235g, 1.85 mol) followed by 1.5 mL of DMF. To trap the resultant HCl, the flask was fitted with tubing so that the gas was discharged above the surface of a stirred aq KOH solution. When the vigorous evolution of gas ceased after two hours, the homogeneous reaction was stirred overnight prior to removal of the volatiles under vacuum using a rotary evaporator. 

The resultant oil solidified during subsequent evacuation. [00120] After dissolving the crude 5-bromo-2-chlorobenzoyl chloride in 530 ml of ethylbenzene, the yellow solution was cooled to -3⁰C prior to adding AlCl₃ (257g, 1.93 mol) in ~30g portions over 60 min to insure that the temperature did not exceed 1O⁰C. The copious amounts of HCl gas which began to evolve after 60% of the AlCl₃ had been added were trapped by passing the gas over a stirred cone. 

NaOH solution. If the reaction were more concentrated, a magnetic stirrer could not have maintained stirring upon completion of the addition of AlCl₃. After stirring for 1 hr as the bath warmed to ~15°C, the bath was removed. After 4 hr at 2O⁰C, the thick syrup was poured over ice (1.5 kg). Subsequently, once the stirred suspension had cooled, H₂O (IL ) was added prior to being extracted 4x with EtOAc. The combined organic extracts were washed 2x with IN HCl, 3x with IM KOH, and 2x with brine prior to drying over Na₂SO₄. The volatiles were removed using first a rotary evaporator and then by heating at ~60°C at 1 Torr. IH NMR analysis of the resultant dark oil revealed the residue to be a 1 : 14 mixture of ortho/para isomers. Dissolution in hexane and followed by filtration through a silica gel pad removed most of the color. Concentration of the eluent yielded 56Og (99%) of a 14:1 mixture of 5-bromo-2- chloro-4 ' -ethylbenzophenone / 5 -bromo-2-chloro-2 ' -ethylbenzophenone. [00121] HPLC retention time: 4.7 min, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄.

5-Bromo-2-chIoro-4'-ethyIbenzophenone

[00122] ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, 2H, JAB = 8.2 Hz), 7.54 (dd, IH, J = 2.2 Hz, J = 8.8 Hz), 7.32 (d, IH, J = 8.8 Hz), 7.295 (d, 2H, J_AB = 8.2 Hz), 2.72 (q, 2H, JK7.7 Hz), 1.27 (t, 3H, J=7.7 Hz).

[00123] ¹³C NMR (100 MHz, CDCl₃) δ 193.13. 151.33, 140.49, 133.8, 133.52, 131.6, 131.44, 130.34, 130.16, 128.28, 120.44, 29.04, 15.02. 5-Bromo-2-chloro-2'-ethylbenzophenone (distinctive signals) [00124] ¹K NMR (400 MHz, CDCl₃) δ 2.64 (q, 2H, J=7.7 Hz), 1.23 (t, 3H, J=7.7 Hz). [00125] ¹³C NMR (100 MHz, CDCl₃) δ 28.9, 15.5.

B. 5-Bromo-2-chloro-4'-ethyldiphenylmethane 

[00126] To a stirred solution OfEt₃SiH (400 g, 3.45 mol and 5-bromo-2-chloro-4'- ethylbenzophenone (534g, 1.65 mol) containing -7% of the isomeric ketone in 300 mL of TFA at 30⁰C was added CF₃SO₃H (1.5 g, 0.01 mol). Within minutes the temperature increased causing the solution to reflux violently. Caution this moderate exotherm requires cooling with an external ice bath. After 1 hr, HPLC revealed the reaction to be 90% complete. After addition of an additional Et₃SiH (2Og ) and heating overnight at 70⁰C, the reaction was > 95% complete by HPLC analysis. Upon cooling, the volatiles were removed by bulb to bulb distillation at reduced pressure. The resultant ~ IL of light gray oil was poured into IL OfH₂O. The mixture was extracted 3x with hexane; the combined organic layers were washed 3x with H₂O, 2x with aq Na₂CO₃ and 2x with brine before drying over Na₂SO₄. After concentration using a rotary evaporator, ~ 1 L of clear light amber oil remained. 

This material was further concentrated; the (Et₃Si)₂O (450 mL) was removed by distillation at 0.6 Torr. Once the temperature at the distillation head reached 75°C, the pot was allowed to cool. IH NMR analysis of the pot revealed it to contain an ~ 8: 1 mixture of diarylmethane to (Et₃Si)₂O. Crystallization of this mixture was achieved by pouring the product into vigorously stirred 10⁰C 85% EtOHTH₂O (1.2L), After stirring for several hours, the crystals were collected by filtration, washed with cold 1:1 EtOHZH₂O and dried under vacuum. The 5~bromo~2-chloro-4'-ethyldiphenyl- methane (500 g), obtained as a low melting solid containing ~1% (Et₃Si)₂O, was used without further purification.

[00127] HPLC retention time: 5.3 min, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄.

[00128] ¹H NMR (125 MHz, CDCl₃) δ 7.27-7.23 (m, 3H), 7.14 (d, 2H, J_AB = 7.7 Hz), 7.09 (d, 2H, JA_B = 7.7 Hz), 2.63 (q, 2H, J=7.7 Hz), 1.23 (t, 3H, J=7.7 Hz). [00129] ¹³C NMR (100 MHz, CDCl₃) δ 142.46. 141.08, 135.68, 133.64, 133.13, 130.85, 130.55, 128.83, 128.1, 120.0, 38.62, 28.43, 15.51.

C. 2,3,4,6-tetra-O-TrimethyIsilyl-D-gIucolactone [00130] To a stirred -5°C solution of gluconolactone (239g, 1.34 mol) and N- methylmorpholine (1180 mL, 10.73 mol) in 2.4L of THF under Ar was added trimethylsilyl chloride (1022 mL, 8.05 mol) via dropping funnel at a rate such that the temperature did not exceed 5⁰C. After 1 hr the stirred reaction was heated to 35⁰C for 5 hr whereupon it was allowed to cool to 20⁰C as the reaction stirred overnight. After dilution with 3.6L of toluene, the mixture was cooled to 0-5⁰C prior to cautiously adding 7L OfH₂O at a rate such that the temperature did not exceed 10°C. Note a severe exotherm results upon addition of the first portion OfH₂O. After mixing, the phases were allowed to separate and then split. The organic phase was washed with aq. NaH₂PO₄ (2L), H₂O (IL), and brine (IL). The organic layer was then concentrated under vacuum using a rotary evaporator; the resultant light yellow oil was twice taken up 250 mL of toluene and reconcentrated to yield 616g. 

D.

[00131] To a stirred -78° solution of Part B 5-bromo-2-chloro-4'- ethyldiphenylmethane (88g, 0.28 mol) in 450 niL of 1 :2 dry THF/toluene under Ar was slowly added 2.5 M n-BuLi (136 niL, 0.34 mol) in hexane at a rate that maintained the temperature below -55°. After stirring for 10 minutes following the addition, this solution was transferred by cannula to a stirred -78° solution of Part C 2,3,4,6-tetra-O-trimethylsilyl-D-glucolactone (153g, 0.33 mol) in toluene (350 mL )at a rate that maintained the reaction below -55°. The solution was stirred for 30 min at - 78° prior to quenching by addition of 400 mL of MeOH containing methanesulfonic acid (28 mL, 0.45 mol). 

The reaction was stirred overnight for 18 hr at 2O⁰C. The reaction was stirred overnight for 18 hr at 2O⁰C. HPLC analysis revealed a new peak which by LC/MS correspond to the mass of the expected O-methylglucoside. The reaction, once complete, was quenched by the addition OfNaHCO₃ (42 g, 0.5 mol) in 200 mL ofH₂O. If the pH was not weakly basic, more NaHCO₃ was added prior to dilution 2 fold with H₂O and 3 extractions with EtOAc. The combined EtOAc fractions were washed with brine and dried over Na₂SO₄. After concentration using a rotary evaporator, the oil (14O g, 90% pure by HPLC analysis) was not further purified but instead was carried forward as an impure diastereomeric mixture.

[00132] ¹H NMR (400 MHz, CDCl₃) δ 7.37 (m, IH), 7.23 (m, 2H), 7.02 (m, 4H), 5.14 (m, IH), 5.06 (m, IH), 4.07 (m, IH), 4.03 (d, IH, JA_B = 15.4 Hz), 3.97 (d, IH, JAB = 15.4 Hz), 3.80 - 3.70 (m, 4H), 3.60 (m, IH), 3.48 (m, IH), 3.31 (m, IH), 2.84 (s, 3H), 2.53 (q, 2H, J =7.5 Hz ), 1.14 (t, 3H, J =7.5 Hz). [00133] ¹³C NMR (100 MHz, CDCl₃) δ 144.4, 140.7, 138.94, 136.9, 132.51, 131.6, 130.96, 130.6, 130.2, 129.16, 103.36, 77.0, 74.86, 72.48, 64.27, 51.57, 41.33, 30.75, 17.9. [00134] HPLC retention time: 4.28 min, 90% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄. [00135] LC/MS: [M-OMe]⁺ 391, 393; [M+Naf 445, 447.

E.

[00136] A solution of Part D O-methylglucoside (206g, 0.49 mol) in THF (1 L) containing diisopropylethylamine (465 g, 3.6 mol) and DMAP (0.5g, 4.1 mmol) was cooled to O⁰C. Acetic anhydride (326g, 3.19 mol) was slowly added at such a rate that the temperature did not exceed 5°C. After the solution gradually warmed to 20⁰C, it was stirred for 10 hours whereupon tic analysis revealed complete conversion to the tetraacetate. The reaction was quenched by addition of EtOAc (1.5 L) and 10% aq. H₃PO₄ (1.5 L). After separation of the layers, the aq. phase was extracted 2x with EtOAc. The combined organic phases were washed Ix with brine prior to drying over Na₂SO₄ and concentration under vacuum. The resultant oil was dissolved twice in 300 mL of toluene and reconcentrated to yield a thick oil (30Og, 95% HPLC purity) that was used without further purification of the resulting impure diastereomeric mixture.

[00137] ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, IH, J = 8.3 Hz), 7.28 (dd, IH, J = 8.3 Hz, J = 2.2 Hz), 7.24 (d, IH, J = 2.2 Hz), 7.11 (d, 2H, JAB = 8.3 Hz), 7.04 (d, 2H, JAB = 8.3 Hz), 5.56 (t, IH, J = 9.7 Hz), 5.21 (t, IH, J = 10.1 Hz), 4.93 (t, IH, J = 10.1 Hz), 4.20 (dd, IH, J = 12 Hz, J = 2 Hz), 4.12 (d, IH, JA_B = 15.4 Hz), 4.02 (m, IH)₅ 4.018 (d, IH, JAB = 15.4 Hz), 3.10 (s, 3H), 2.606 (q, 2H, J = 7.7 Hz), 2.097 (s, 3H), 2.05 (s, 3H), 1.94 (s, 3H), 1.72sd (s, 3H), 1.21 (t, 3H, J=7.7 Hz) . [00138] ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 170.05, 169.47, 168.9, 142.2, 138.74, 136.4, 135.1, 134.7, 129.8, 129.4, 128.6, 128.0, 126.0, 100.02, 73.83, 71.33, 68.87, 68.77, 62.11, 49.43, 38.75, 28.4, 22.64, 20.68, 20.58, 20.16, 15.5. [00139] HPLC retention time: 4.81 min, 90% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOHTH₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOHTH₂O + 0.2 % H₃PO₄.

F.

[00140] A stirred solution of the above crude oil (301g, 0.51 mol) in CH₂Cl₂ (500 mL) containing one equivalent of H₂O (9g, 0.5 mol) and Et₃SiH (188g, 1.62 mol) was cooled to -2O⁰C prior to addition OfBF₃-Et₂O (145g, 1.02 mol). During the addition, the temperature was maintained < 0⁰C. The reaction was subsequently stirred 2hr at 10⁰C and 18 hr at 15 - 2O⁰C before being quenched by addition of CH₂Cl₂ (500 mL) and H₂O (500 mL). After separation of the layers, the aq phase was extracted once with CH₂Cl₂. The combined organic layers were washed Ix with aq NaHCO₃ and brine prior to drying over Na₂SO₄. After removal of the Na₂SO₄ by filtration, Ac₂O (6.4g, 65 mmol), diisopropylethylamine (9.5g, 74 mmol) and DMAP (lOOmg, 0.8 mmol) were added. The solution was stirred at 20⁰C for 18 hr to insure that any glucoside hydroxyls that hydrolyzed during the reduction and work-up were reacetylated. The oil, obtained after concentration under vacuum, crystallized upon addition of EtOH. After filtration the purity of this material by HPLC was 98%; recrystallization from EtOH yielded the tetraacetylated beta-C-glucoside as a white solid (18Og, 99.8% purity. The overall conversion for procedures D - F was 61%. [00141] HPLC retention time: 4.74 min, 100% pure, YMC S5 C-18 4.6x50mm column, 2.5 niL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOHTH₂O + 0.2 % H₃PO₄. [00142] ¹H NMR (500 MHz, CDCl₃) δ 7.35 (d, IH, J = 8.2 Hz), 7.19 (dd, IH, J = 8.2 Hz, J = 2.2 Hz), 7.11 (d, 2H, JA_B = 8.5 Hz), 7.086 (d, IH, J = 2.2 Hz), 7.06 (d, 2H, JA_B = 8.5 Hz), 5.28 (t, IH, J = 9.7 Hz), 5.20 (t, IH, J = 9.7 Hz), 5.04 (t, IH, J = 9.7 Hz), 4.31 (d, IH, J = 9.9 Hz), 4.26 (dd, IH, J = 12 Hz, J = 5 Hz), 4.135 (dd, IH, J = 12 Hz, J = 5 Hz), 4.095 (d, IH, J_AB = 7.7 Hz), 3.995 (d, IH, J_AB = 7.7 Hz), 3.79 (m, IH), 2.605 (q, 2H, J = 7.7 Hz), 2.069 (s, 3H), 2.04 (s, 3H), 1.98 (s, 3H), 1.67 (s, 3H), 1.21 (t, 3H, J=7.7 Hz) .

[00143] ¹³C NMR (125 MHz, CDCl₃) δ 170.64, 170.3, 169.4, 168.7, 142.2, 138.78, 136.4, 135.1, 134.6, 129.9, 129.8, 128.7, 128.0, 125.9, 79.45, 76.1, 74.1, 72.5, 68.45, 62.2, 38.6, 28.4, 20.7, 20.6, 20.59, 20.2, 15.55. [00144] LC-MS [M+NH/] at m/z 578.3

G.

[00145] To the white suspension formed by stirring the tetraacetylated beta-C- glucoside of Part F (25g, 44.6 mmol) for 5 min in 2:3 THF/MeOH (350 mL)under N₂ at 20⁰C was added LiOH-H₂O (2.Og, 50 mmol) in H₂O (70 mL). After 15 min, the reaction was an opaque solution; after 2.5 hr, by HPLC analysis the reaction was 98% complete. The conversion increased to 99% after stirring overnight whereupon the volatiles were removed using a rotary evaporator such that the volume was reduced to 150 mL. The residue, after addition of 10% aq KHSO₄ (100 mL) was further diluted with 100 mL OfH₂O prior to being extracted 3x with EtOAc. After drying over Na₂SO₄, the volatiles were removed using a rotary evaporator and the resultant oil in the minimum amount of EtOAc foamed under vacuum. The amount of EtOAc trapped in this material can be reduced by drying under vacuum. This glassy off white solid was scraped out and further dried at 0.15 Torr at 25°C for 24 hr to yield 17.3 g of desired C-arylglucoside containing 6.7 mol% of EtOAc.

HPLC retention time: 4.21 min, 98.8% pure, YMC S5 C-18 4.6x50mm column, 2.5 mL/min, detection at 22OnM; 4 min gradient 0-100% B hold 2 min at 100% B. Solvent A: 10% MeOH/H₂O + 0.2 % H₃PO₄. Solvent B: 90% MeOH/H₂O + 0.2 % H₃PO₄.

¹H NMR (500 MHz, CD₃OD) δ 7.34 (d, IH, J = 8.2 Hz), 7.33 (d, IH, J = 1.7 Hz), 7.27 (dd, IH, J = 8.2 Hz, J = 1.7 Hz), 7.08 (partially superimposed AB quartet, 4H), 4.1-4.0 (m, 3H), 3.86 (d, IH, J=I 1.6 Hz), 3.68 (dd, IH, J=5.3, 10.6 Hz), 3.46-3.26 (m, 4H) Hz), 2.57 (q, 2H, J=7 Hz), 1.19 (t, 3H, J=7 Hz) .

¹³C NMR (125 MHz, CD₃OD) δ 143.2, 140.0, 139.7, 138.1, 134.5, 131.98, 130.1, 129.8, 128.8, 128.2, 82.8, 82.14, 79.7, 76.4, 71.9, 63.1, 39.7, 29.4, 16.25.

MS [M+Na⁺] at m/z Theoretical 415.1288; Observed 415.1293 [00150] 

Anal for C_2IH₂₅ClO₅ ^• 0.07 EtOAc ^• 0.19 H₂O Calcd C 63.51, H 6.50, Cl 8.80; Found C 63.63, H 6.63, Cl 8.82

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
WO2003099836A1 *	May 15, 2003	Dec 4, 2003	Squibb Bristol Myers Co	C-aryl glucoside sglt2 inhibitors and method
WO2004063209A2 *	Dec 23, 2003	Jul 29, 2004	Squibb Bristol Myers Co	Methods of producing c-aryl glucoside sglt2 inhibitors

more...........

Chinese Chemical Letters

Volume 19, Issue 7, July 2008, Pages 814–816

Abstract

A convenient approach for the preparation of (2S,3R,4R,5S,6R)-2-(3-(4-ethylbenzyl)-4-chlorophenyl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol 1 is developed. The target compound via four steps is synthesized from 4-bromo-2-(bromomethyl)-1-chlorobenzene and the isomers of undesired ortho-products were avoided during the preparation

more................
improved preparation of C-aryl glucoside SGLT2 inhibitors
ARKIVOC (Gainesville, FL, United States) (2008), (15), 65-70. Publisher: (Arkat USA Inc., )

Improved preparation of C-aryl glucoside SGLT2 inhibitors

Yong-Hai Liu, Da-Li Li and Lu-De Lu

Skip other details (including permanent urls, DOI, citation information)

Volume 2008, Issue 15, pp. 65-70

DOI: http://dx.doi.org/10.3998/ark.5550190.0009.f08

 http://quod.lib.umich.edu/a/ark/5550190.0009.f08/1

  JALGAON, MAHARASHTRA, INDIA


.

 

 


 
 
 
 
 




.


 


 

 

.

MANUDEVI

Process for the preparation of fluvoxazmine maleate US 6433225 B1

Fluvoxamine

2-{[(E)-{5-Methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene}amino]oxy}ethanamine[1]
Clinical data
Trade names	Faverin, Fevarin, Floxyfral, Luvox
AHFS/Drugs.com	monograph
MedlinePlus	a682275
Pregnancy cat.	C
Legal status	AU: Prescription Only (S4) CA: ℞-only UK: POM US: ℞-only
Routes	Oral
Pharmacokinetic data
Bioavailability	53% (90% confidence interval: 44-62%)[2]
Protein binding	80%[2]
Metabolism	Hepatic (via cytochrome P450enzymes. Mostly via oxidative demethylation)[2]
Half-life	12-13 hours (single dose), 22 hours (repeated dosing)[2]
Excretion	Renal (98%; 94% as metabolites, 4% as unchanged drug)[2]
Identifiers
CAS number	54739-18-3
ATC code	N06AB08
PubChem	CID 5324346
DrugBank	DB00176
ChemSpider	4481878
UNII	O4L1XPO44W
KEGG	D07984
ChEBI	CHEBI:5138
ChEMBL	CHEMBL814
Chemical data
Formula	C15H21F3N2O2
Mol. mass	318.335

Process for the preparation of fluvoxazmine maleate
US 6433225 B1
http://www.google.co.in/patents/US6433225

U.S. Pat. No. 4,085,225 discloses the process for the preparation of fluvoxamine maleate, a compound of formula I, by alkylation reaction of 5-methoxy-4′-trifluoromethylvalerophenone oxime, a compound of formula II, with 2-chloroethylamine hydrochloride in dimethylformamide in the presence of a base viz. potassium hydroxide for two days at 25° C.

Subsequently the solvent is removed under vacuum then the residue is acidified and extracted with ether to remove the unreacted oxime. The fluvoxamine base is then obtained by extraction into ether after basification, and the ether extract is washed with NaHCO₃ solution. The fluvoxamine base is then treated with maleic acid in ethanol, and the residue obtained by concentration under vacuum is recrystallised from acetonitrile to obtain fluvoxamine maleate I. This process when attempted by us was found to be very time consuming. Moreover, the requirement of various solvents posed the problem of their recovery and re-usability.

In an alternate route described in the above mentioned patent, the oxime II is converted to I in a five step process viz., alkylation of II with ethylene oxide to give the hydroxyethyl compound III, which is converted to a mesylate derivative IV with methanesulfonyl chloride and triethylamine, and then aminated with ammonia to give fluvoxamine base.

The base is then converted to the maleate salt I, which is finally purified by recrystallization from acetonitrile.

Although in principle, the process described gives the desired product, viz. fluvoxamine maleate I, it was not found to be attractive as it involves a number of unit operations, use of several solvents, and handling of toxic and explosive ethylene oxide, a potential carcinogen. The number of operations used result in long occupancy of reactors and utilities, and high-energy consumption making it a commercially unviable process on a large scale. Also, for large-scale operations, the use of several different solvents in the process poses ecological and other usual problems such as storage, their recovery and re-usability. Furthermore, purification of the intermediate III requires cumbersome technique viz. chromatography over silica gel.

The lengthy work-up procedure in U.S. Pat. No. 4,085,225 requires complete removal of organic solvents at different stages; a simple and efficient process has been found wherein:

(a) the alkylation reaction could occur very rapidly in a water immiscible inert aprotic solvent in the presence of a facilitator;

(b) the unwanted reaction components i.e. the excess base, salts and the added facilitator could be easily removed in one step by washing the reaction mixture with water;

(c) the organic layer containing fluvoxamine base treated with maleic acid; and

(d) the fluvoxamine maleate obtained in a substantially pure form by recrystallization.

EXAMPLE 1To a stirred mixture of toluene (1.20 lit.), PEG-400 (0.4 lit) and powdered potassium hydroxide (86.0 g on 100% basis, 1.53 mol.) at ambient temperature is added 5-methoxy-4′-trifluoromethylvalerophenone oxime (100 g, 0.363 mol.), followed by 2-chloroethyl amine hydrochloride (50.56 g, 0.435 mol.). The mixture is stirred at 30-35° C. for 2 hours. Water (1.2 lit.) is then added, stirred for 30 mins. and the aqueous layer is separated out. The organic layer is washed with water (˜3×500 ml) until the washings are neutral. To the washed organic layer is added a solution of maleic acid (14.14 g, 0.363 mol.) in water (65 ml) and the mixture is stirred at 25-30° C. temperature for 2 hours, then cooled to 5-10° C. when the maleate salt crystallizes out. The crystallized fluvoxamine maleate is filtered, washed with toluene (200 ml) and sucked to dryness. The crude fluvoxamine maleate thus obtained is dissolved in water (300 ml) at 50-55° C. to get a clear solution, then gradually cooled to 5-8° C. and then further stirred at this temperature for 2 hours. The recrystallised fluvoxamine maleate is filtered, washed with chilled water (5° C., 100 ml) and sucked dry. The product is finally dried at 50-55° C. to constant weight. The fluvoxamine maleate obtained complies with the specifications of British Pharmacopoeia, 1999.
EXAMPLE 2This process when scaled up in pilot plant on 4.0 kg scale input of 5-methoxy-4′-trifluoromethylvalerophenone oxime gave 4.5 kg (71.2%) of fluvoxamine maleate, complying to the specifications of British Pharmacopoeia, 1999.

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
US4085225	19 Mar 1976	18 Apr 1978	U.S. Philips Corporation	Oxime ethers having anti-depressive activity

NON-PATENT CITATIONS

Reference
1	*	Database CAPLUS on STN, Acc. No. 1977:72203, "Substituted 4'-trifluoromethylvalerophenone O-(2-aminoethyl)oxime derivatives with antidepressive action.' NL 7503310 (abstract).*
2		Database CAPLUS on STN, Acc. No. 1977:72203, ‘Substituted 4'-trifluoromethylvalerophenone O-(2-aminoethyl)oxime derivatives with antidepressive action.’ NL 7503310 (abstract).*
3	*	Database CAPLUS on STN, Acc. No. 1982:562585, Welle et al., "Oxime ether compounds.' CH 629761 (abstract).*
4		Database CAPLUS on STN, Acc. No. 1982:562585, Welle et al., ‘Oxime ether compounds.’ CH 629761 (abstract).*
5	*	Database CAPLUS on STN, Acc. No. 1997:403525, Matarrese et al., "Synthesis of [O-methyl-11-C]fluvoxamine-a potential serotonin uptake site radioligand.' Appl. Radiat. Isot. (1997), 48(6), pp. 749-754 (abstract).
6		Database CAPLUS on STN, Acc. No. 1997:403525, Matarrese et al., ‘Synthesis of [O-methyl-11-C]fluvoxamine—a potential serotonin uptake site radioligand.’ Appl. Radiat. Isot. (1997), 48(6), pp. 749-754 (abstract).

* Cited by examiner

REFERENCED BY

Citing Patent	Filing date	Publication date	Applicant	Title
US20110092548 *	21 Jul 2006	21 Apr 2011	Takuro Minowada	Method for treating/preventing disease using cognitive ability of cerebrum and pharmaceutical
WO2014035107A1 *	27 Aug 2013	6 Mar 2014	Estechpharma Co., Ltd.	Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same

MORE.............

Fluvoxamine

Fluvoxamine is an antidepressant drug consisting of an oxime ether functions which can exist in an E and Z configuration. The pharmacological effect is associated with the E-isomer; thus, the European Pharmacopoeia limits the Z-isomer to less than 0.2 percent. The ¹H NMR spec-trum of a 1: 1 mixture (for spectrum and structural formula see Fig. 2) reveals the resonance signals of the hydrogen at C10 (δ = 4.2-4.5 ppm) and C2 (δ = 2.5-3.0 ppm) to be well ^separated and, therefore, appropriate for evaluation. In order to find out the optimal pulse repetition period the T1 relaxation time was measured first. A recovery of the z-magnetization of > 99.9% was achieved using seven times the longest T1 which results in a pulse repetition time of 8 sec. Using the optimized parameter (see below) and after checking the linearity, the limit of quantification of the Z-isomer could be determined to be 0.15 %, which meets the limit demanded by the European Pharmacopoeia. For details see ref. [6].

Figure 2: ¹H NMR spectrum of a mixture of the isomers of fluvoxamine, containing 47.6% E-fluvoxamine
and 53.2% Z-fluvoxamine, in MeOH-d₄

Parameters fluvoxamine:
 

Bruker Avance 400 MHz operating at 400.13 MHz equipped with BBO-head for ( 1H-channel, X-channel). The data processing was performed using BRUKER X-WIN NMR 3.0 software under Microsoft Windows. Pulse repetition period: 8 sec Number of scans: 128 Spectral width: 4595 Hz Transmitter offset: 2.76 ppm Digital resolution: 0.14 Hz/pt Solution: 15 mg fluvoxamine in 650µl MeOH-d4 Referencing: centre of the solvent peak: 3.31 ppm

WO 2012044577 A1.......Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases

 
  Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)

 



 Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)




 WO 2012044577 A1.......Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
 http://www.google.com/patents/WO2012044577A1?cl=en

In another embodiment, the compound of Formula I is Compound 1 :

Compound 1

or a pharmaceutically acceptable salt thereof. Compound I is known as N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide. WO 2005/030140 describes the synthesis of N-(4-{[6,7- bis(methyloxy)quinolin-4-yl]oxy }phenyl)-N'-(4-fluorophenyl)cyclopropane-l, l- dicarboxamide (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289). Example 48 is on paragraph [0353] in WO 2005/030140.

[0013] In another embodiment, the compound of Formula I is Compound 2:

Compound 2
  Foretinib (Exelixis, GlaxoSmithKline) (aka XL-880)

or a pharmaceutically acceptable salt thereof. Compound 2 is known as is N-[3-fluoro-4- ({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]quinolin-4-yl}oxy)phenyl]-N'-(4- fluorophenyl)cyc!opropane- 1,1 -dicarboxamide. WO 2005-030140 describes the synthesis of Compound (I) (Examples 25, 30, 36, 42, 43 and 44) and also discloses the therapeutic activity of this molecule to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 312). Compound 2 has been measured to have a c-Met IC50 value of about 0.6 nanomolar (nM). PC1YUS09/064341, which claims priority to U.S. provisional application 61/199,088, filed November 13, 2008, describes a scaled-up synthesis of Compound I.