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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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New Antibacterial oxazolidinones in pipeline by Wockhardt


WCK ?

(5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

(5S)-N- {3-[3,5-difluoro-4-(4-hydroxy-(4-methoxymethyl)-piperidin- lyl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

MF C19 H25 F2 N3 O5, MW 413.42

Acetamide, N-​[[(5S)​-​3-​[3,​5-​difluoro-​4-​[4-​hydroxy-​4-​(methoxymethyl)​-​1-​piperidinyl]​phenyl]​-​2-​oxo-​5-​oxazolidinyl]​methyl]​-

CAS 957796-51-9

Antibacterial oxazolidinones

Wockhardt Ltd,  Innovator

Wockhardt Research Center,

THIS MAY BE WCK 4086?????….WATCHOUT THIS POST FOR UPDATION

PATENTS

WO 2015173664, US8217058, WO 2012059823, IN 2011MU03726 

 

s1

Oxazolidinone represent a novel chemical class of synthetic antimicrobial agents. Linezolid represents the first member of this class to be used clinically. Oxazolidinones display activity against important Gram-positive human and veterinary pathogens including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin Resistant Enterococci (VRE) and β-lactam Resistant Streptococcus pneumoniae (PRSP). The oxazolidinones also show activity against Gram-negative aerobic bacteria, Gram-positive and Gram-negative anaerobes. (Diekema D J et al., Lancet 2001 ; 358: 1975-82).

Various oxazolidinones and their methods of preparation are disclosed in the literature. International Publication No. WO 1995/25106 discloses substituted piperidino phenyloxazolidinones and International Publication No. WO 1996/13502 discloses phenyloxazolidinones having a multisubstituted azetidinyl or pyrrolidinyl moiety. US Patent Publication No. 2004/0063954, International Publication Nos. WO 2004/007489 and WO 2004/007488 disclose piperidinyl phenyl oxazolidinones for antimicrobial use.

Pyrrolidinyl/piperidinyl phenyl oxazohdinone antibacterial agents are also described in Kim H Y et al., Bioorg. & Med. Chem. Lett., (2003), 13:2227-2230. International Publication No. WO 1996/35691 discloses spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinone derivatives. Diazepeno phenyloxazolidinone derivatives are disclosed in the International Publication No. WO 1999/24428. International Publication No. WO 2002/06278 discloses substituted aminopiperidino phenyloxazolidinone derivatives.

Various other methods of preparation of oxazolidinones are reported in US Patent No. 7087784, US Patent No. 6740754, US Patent No. 4948801 , US Patent No. 3654298, US Patent No. 5837870, Canadian Patent No. 681830, J. Med. Chem., 32, 1673 (1989), Tetrahedron, 45, 1323 (1989), J. Med. Chem., 33, 2569 (1990), Tetrahedron Letters, 37, 7937-40 (1996) and Organic Process Research and Development, 11 , 739-741(2007).

Indian Patent Application No. 2534/MUM/2007 discloses a process for the preparation of substituted piperidino phenyloxazolidinones. International Publication No. WO2012/059823 further discloses the process for the preparation of phosphoric acid mono-(L-{4-[(5)-5-(acetylaminomethyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}4-methoxymethyl piperidine-4-yl)ester.

US Patent No. 8217058 discloses (5S)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide as an antibacterial agent and its process for preparation.

PATENT

WO2015173664

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015173664&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

 

In some embodiments, there is provided a process for preparation of a compound of Formula (I) as shown in Scheme 1

(I I) (I N)

Scheme 1

 

 

Example 1

Preparation of (55)-iV-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)- phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (I)

To a stirred solution of lithium teri-butoxide (59.1 g, 0.74 mol) in tetrahydrofuran (500 ml) was added a solution of [3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-carbamic acid benzyl ester (II) (100 g, 0.25 mol) in 500 ml of tetrahydrofuran slowly at room temperature. The resulting mixture was stirred for 3 hours at room temperature (formation of lumps observed). The reaction mixture was cooled to temperature of 10°C to 15°C and acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) (95.2 g, 0.49 mol) was added in one lot, after 5 minutes methanol (2.36 g, 0.075 mol) was added in one portion. The resulting mixture was stirred further at temperature of 10°C to 15°C. After 5 hours the reaction mixture was allowed to warm to room temperature and stirring continued further for 16 hours. An aqueous solution of saturated ammonium chloride (100 ml) was added to the reaction mixture, the resulting mixture was stirred well and the solvent evaporated under reduced pressure (35°C, 150 mm Hg). The residual mixture was diluted with water (1 L stirred well and filtered under suction, the residual solid was washed with additional fresh water (100 ml). The residual mass was suspended in acetone (500 ml), stirred well and the mixture diluted with hexane (1 L), slowly. The mixture was stirred further for 1 hour and filtered under suction. The residual solid was washed with a 2:1 mixture of acetone and water (100 ml). The residual solid was dried at 45°C, for 3.5 hour at 4 mm Hg, to obtain the 78 g of (55)-N-{3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l -yl)-phenyl]-2-oxo-oxazolidin-5-ylmethylj -acetamide (I) as white solid, in 77% yield.

Analysis:

Mass: 414 (M+l ); for Molecular Weight: 413 and Molecular Formula:

Melting Point: 178-179°C;

1H NMR (400 MHz, DMSO): δ 8.18-8.21 (m, 1H), 7.19-7.25 (d, 2H), 4.07-4.71 (m, 1H), 4.32 (s, 1H), 4.02-4.07 (t, 1H), 3.64-3.68 (t, 1H), 3.14 (s, 2H), 2.81-2.83 (d, 2H), 1.81 (s, 3H), 1.63-1.69 (t, 2H), 1.42-1.45 (d, 2H);

Purity as determined by HPLC: 97.65%.

Example 2

Preparation of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III)

Step-I: Preparation of l-amino-3-chloro-propan-2-ol hydrochloride (VI)

Benzaldehyde (118.67 g, 1.03 mol) was dissolved in ethanol (297 ml) under stirring and the solution was cooled to 18-19°C. To this solution aqueous ammonia solution (25%) (101.58 ml) was added slowly, followed by slow addition of S-epichlorohydrin (100 g, 1 mol). The resulting mixture was warmed to 40°C and stirred for 7 hours. The mixture was allowed to cool to room temperature and stirred further. After 16 hours, the reaction mixture was concentrated to 50% volume under reduced pressure. Toluene (228 ml) was added to the reaction mixture followed by addition of aqueous hydrochloric acid (162 ml of concentrated hydrochloric acid diluted with 152 ml of water). The mixture thus obtained for 3 hours at 45°C, the resulting mixture was allowed to cool to room temperature and the toluene layer separated. The toluene layer was further extracted with water (56 ml). The combined aqueous layer was diluted with ethanol (56 ml) and the mixture evaporated under reduced pressure. This process was repeated again. To the final concentrate was added ethanol (180 ml), stirred for 10 minutes and the mixture cooled to -28°C to -30°C and maintained at this temperature for 2 hours. The separated solid was filtered under suction and the residue washed with cold (-30°C) ethanol (50 ml). The residue was dried at 45°C, under reduced pressure (4 mm Hg) for 3 hours, to obtain 96 g of l-amino-3-chloro-propan-2-ol hydrochloride (VI) as white solid in 61% yield.

Analysis:

Mass: 110 (M+l) as free base; for Molecular Weight: 145.5 and Molecular Formula:

1H NMR (400 MHz, D20): δ 4.02-4.08 (m, 1H), 3.51-3.61 (m, 2H), 3.12-3.16 (dd, 1H), 2.93 -2.99 (dd, 1H).

Step-II: Preparation of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III).

A stirred solution of dichloromethane (220.8 ml) containing the step-I salt (96 g, 0.66 mol) was cooled to 18-20°C. Acetic anhydride (154.78 g, 1.5175 mol) was added slowly (slight exothermic). Pyridine (67.76 g, 0.8577 mol) was added slowly (exothermic) while maintaining the temperature at 18-20°C. The resulting mixture was heated to 40°C for 5 hours. The reaction mixture was allowed to cool to room temperature and stirring continued for further 16 hours. The reaction mass was cooled to 3-6°C and diluted with 170 ml of fresh water. To this was added an aqueous solution of potassium carbonate (191.2 g of K2CO3 in 382 ml water). The reaction mixture was further diluted with additional dichloromethane (170 ml) and water (425 ml). The reaction mass was stirred well and the dichloromethane layer separated. The aqueous layer was further extracted with 2×170 ml dichloromethane. The combined dichloromethane layer was washed with aqueous sodium chloride solution (13.6 g of sodium chloride in 493 ml water). The solvent was evaporated till a volume of 170 ml and the residual layer was diluted with toluene (340 ml), stirred well and the solvent was evaporated completely at 40°C under reduced pressure (4 mm Hg). To the residue ethyl acetate (170 ml) and hexane (187 ml) were added and the mixture stirred for 30 minute. The separated solid was filtered under suction and the residue washed with 50 ml of a 1 :1 mixture of ethyl acetate and hexane. The solid obtained was dried under reduced pressure (4 mm Hg) at 45°C for 3.5 hours, to obtain 96 g of acetic acid l-(acetylamino-methyl)-2-chloro-ethyl ester (III) as a white solid, in 75% yield.

Analysis:

Mass: 194 (M+l); for Molecular Weight: 193 and Molecular Formula: C7Hi2ClN03; 1H NMR (400 MHz, CDC13): 5 5.69 (s, 1H), 5.0-5.1 (m, 1H), 3.4-3.7 (m, 4H), 2.1 (s, 3H), 1.9 (s, 3H).

PATENT

http://www.google.st/patents/WO2007132314A2?cl=en

 

Figure imgf000004_0001

Wockhardt Ltd,

Figure imgf000006_0001
Figure imgf000006_0002

(3) (4)

Scheme -1

Figure imgf000008_0001

(6) Formula π Scheme-2

Figure imgf000010_0001

Formula II Formula in

Figure imgf000010_0002

Formula I(a) Scheme-4

Example -11 : (5S)-N- {3-[3,5-difluoro-4-(4-hydroxy-(4-methoxymethyl)-piperidin- lyl)phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

The example- 10 (54.86 g, 0.144 mol) was suspended in methanol (1100 ml) under stirring at RT. Sodium metal (4 g, 0.174 mol) was added in small lots in 2 min to the above suspension under stirring. The reaction mixture was warmed to 40-420C and was stirred at this temperature for about 40 hrs. After completion of the reaction (TLC), the solvent was evaporated under reduced pressure to obtain a thick slurry. The thick slurry thus obtained was gradually added to water (1100 ml) under stirring. After the complete addition, the pH of the aqueous suspension was adjusted to 7 by adding sufficient quantity of glacial acetic acid. The separated solid was filtered and the residue was washed with water. The obtained solid was further purified by column chromatography over silica gel to obtain the product as a white solid, 32.7 g, 55 % yield.

M.P.: 173-1740C;

MS : M+l= 414(MH+, 100%); for M.F.: Ci9H25F2N3O5

1H-NMR (400 MHz, CDCl3): δ 7.0-7.1 (m, 2H5Ar-H), 6.0 (t, IH, NH), 4.70-4.80 (m, IH), 4.00 (t,lH), 3.70-3.75 (m, 2H), 3.5-3.7 (m, IH), 3.43 (s, 3H, OCH3), 3.37-3.42 (m, 2H), 3.30 (s, 2H, -OCH2), 3.0-3.05 (m, 2H), 2.22(bs,lH ,-OH),2.04 (s, 3H, COCH3), 1.70-1.75 (m, 4H).

 

Patent

INDIAN 3049/MUM/2010

Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxy methyl-piperidin-4-yl) ester

Figure imgf000022_0001

Specific intermediate compounds of the invention include:
6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]octane;
1-(2,6-Difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol;
[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester;
(5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-hydroxymethyl-oxazolidin-2-one;
(5R)-Methanesulfonic acid 3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester;
(5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one; and
(5S)- N-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide.

 

Examples

Preparation of Intermediate-1: 1-(2,6-Difluoro-4-nitrophenyl)-piperidin-4-one
Chloroform (9.3 L) was charged in a 20 L reaction assembly and 4-piperidone hydrochloride (1.17 Kg, 7.62 mol) was added under stirring followed by triethylamine (2.14 Kg, 2.95 L, 21.1 mol). After 30 minutes of stirring, 3,4,5-trifluoronitrobenzene (1.5 Kg, 8.47 mol) was added to the mixture in one lot and the contents were heated to 65-70ºC for 8 h. After completion of the reaction, chloroform was removed under vacuum to obtain a syrupy mass. At this stage, water (10 L) was added to the mass and the chloroform recovery was continued under vacuum below 65oC till the chloroform was removed completely. The slurry was cooled to RT and filtered. The solid product was washed with water (3 L) followed by hexanes (2 L). The product was dried in a vacuum oven below 70oC to obtain the product as a yellow solid, 1.88 Kg ; Yield 97%.
M.P.: 130-132oC; MS: 257(M+1); M.F.: C11H10F2N2O3.

 

Preparation of Intermediate 3: 1-(2,6-Difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol

Method A:
Preparation of Intermediate–2: (Stage-I): 6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]octane
A solution of trimethylsulfoxonium iodide (1.504kg, 6.836mol) in acetonitrile (7L) was cooled to 0 to 5oC. , under argon atmosphere. Potassium tert-butoxide (0.736kg, 6.552 mol) was added in small lots over 0.5h. The resulting solution was stirred for 2h at the same temperature. To this solution was added 1-(2,6-Difluoro-4-nitrophenyl)-piperidin-4-one ( 1.4kg, 5.46mol) in small lots over a period of 1h, while maintaining the temp. between 5-10oC. The resulting mixture was stirred for 1h. The solvent was evaporated to a minimum amount possible, under reduced pressure while maintaining the temperature below 10oC. The residue was poured in water( 18L) and the pH adjusted to neutral with dilute acetic acid. The resulting slurry was stirred well and the separated solid filtered under suction. The solid was washed with fresh water till the filtrate was free of acetic acid. The solid was dried at 80oC, for 6h, under reduced pressure to obtain the product as pale yellow solid, 1.264kgs, yield 85%.
M.P.: 96-97oC; MS: M+1: 271; M.F.: C12H12F2N2O3,.
Preparation of Intermediate-3: (Stage-II): 1-(2,6-Difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol
To a solution of sodium methoxide (236g, 4.35mol) in methanol (3L), at RT, was added 6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro [2.5]octane (964g, 3.57mol) in small portions and the reaction mixture was stirred for 26h at RT. Acetic acid (265g, 4.44mol) was added slowly to neutralize the pH of the solution. The resulting mixture was poured into chilled water(18L) and stirred for 1h. The separated solid was filtered under suction. The solid was washed with additional water till the filtrate was free of acetic acid. The solid was dried for 10hat RT under reduced pressure, to obtain the product as a pale yellow solid, 973g, yield, 90%
M.P.: 84-86oC; MS: 303 (M+1); M.F.: C13H16F2N2O4

Method B:
Dimethylsulfoxide (DMSO, 100 ml) and methanol (500 ml) were charged in a 1 L glass reaction assembly. Potassium hydroxide (59.2g, 0.898 mol) was charged in the assembly followed by trimethylsulfoxonium iodide (94.5 g, 0.43 mol) and the contents were stirred for 30 minutes and then cooled to 10oC-15oC. To the cooled contents was added 1-(2,6-difluoro-4-nitrophenyl)-piperidin-4-one (100 g, 0.39 mol) in small lots. After the addition, the temperature was allowed to raise to RT and the contents were further stirred for 24 h (ring opening of the epoxide intermediate viz. 6-(2,6-difluoro-4-nitrophenyl)-1-oxa-6-azaspiro[2.5]octane takes place).
[Physical data of the intermediate: M.P.: 96-970C, MS: 271(M+1); M.F.: C12H12F2N2O3, .
After completion of the reaction the contents were poured slowly in ice-water (600g crushed ice in 600 ml water). The precipitated solid product was filtered and was washed with water:methanol, 2:1 (100 ml X 2). The wet product was used in the next step.
M.P.: 84-86oC; MS: 303 (M+1);.M.F.: C13H16F2N2O4,:

Preparation of Intermediate -5: [3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester

Method A: Preparation of Intermediate 4: ( Stage-I)
Water (1.19 L) and methanol (595 ml) were charged in a 3 L glass reaction assembly, followed by 1-(2,6-difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol (85 g, 0.281 mol) and the contents were stirred. Sodium dithionite (288 g, 1.407 mol) was added in one lot and the reaction mixture was heated to 80oC for 8 h. After completion of the reaction (TLC), methanol was recovered under vacuum below 65oC. After the recovery, the aqueous residue was extracted with chloroform (400 ml X 3). The combined chloroform extract (containing the intermediate 1-(4-amino-2,6-difluoro-phenyl)-4-methoxymethyl-piperidin-4-ol) was dried over anhydrous Sodium sulfate and used in the next step (carbamate formation).

Preparation of Intermediate -5: (Stage-II):
The above chloroform extract was charged in a 3 L glass reaction assembly. Sodium bicarbonate (70 g, 0.843 mol) was added to the extract and the contents were cooled to 15oC-20oC. Benzylchloroformate solution (50% in toluene, 48 g, 96 ml, 0.281 mol) was added slowly to the above mixture under stirring. After completion of the addition, the reaction mixture was stirred at RT for 2 h. After completion of the reaction (TLC), the contents were filtered on a Buchner assembly and the solid cake was washed with chloroform (85 ml X 2). The combined filtrate was evaporated under vacuum below 50oC to obtain yellowish oily mass, which was poured slowly in hexanes (850 ml) under stirring to obtain a precipitate. The precipitated product was filtered and washed with hexanes (100 ml X 2). The product was dried in a vacuum oven below 65oC to obtain 60.2 g brownish product (Yield = 38% on the basis of step-I input).
M.P.: 138-140oC; MS: 407(M+1); M.F.: C21H24F2N2O4.:.

Method B: : Preparation of Intermediate 4: ( Stage-I): To a solution of 1-(2,6-difluoro-4-nitro-phenyl)-4-methoxymethyl-piperidin-4-ol (973g, 3.22 mol) in ethyl acetae (10L) was added 10% Pd-C, (250g, 50% wet) and the resulting miture was hydrogenated in a pressure at 30 PSI, 45-55oC, for 3h. The catakyst was filtered and the residue was washed with additional ethyl acetate( 200ml). The combined filtrates were used as such for the next reaction (carbamate formation)

Preparation of Intermediate -5: (Stage-II):
To the above filtrate was added sodium bicarbonate(406g, 4.83 mol) and the mixture warmed to 40-45oC. To this mixture was added a 50% solution of Benzyl chloroformate in toluene(1.373L, 4.025 mol), drop-wise, over a period of 1h. Stir the resulting mixture for 1h and filter the insoluble material. The residue was washed with 300ml of ethyl acetate. The filtrates were combined and the solvent evaporated under reduced pressure, below 55oC.. Cool the residue and dilute it with hexane(10L). The resulting slurry was stirred well and the separated solid was filtered under suction. The residue was washed with additional hexane ( 2L). The solid was dried for 10h at RT, to obtain the product as dark brown solid, 1200g, yield, 96%.
M.P.: 138-140oC; MS: 407( M+1); M.F.: C21H24F2N2O.

Preparation of Intermediate -6:

(5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-hydroxymethyl-oxazolidin-2-one

To a mixture of [3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-carbamic acid benzyl ester (100g, 0.237 mol) in dry tetrahydrofuran (THF) (2 L) at 40ºC was added drop-wise n-BuLi in hexane (1.6M, 45.5 g, 455 ml, 0.711 mol) under nitrogen atmosphere. The contents were stirred for 1 h at 40ºC and R-(-)-glycidyl butyrate (68.25 g, 0.474 mol) was added gradually. After the addition of R-(-)-glycidyl butyrate, the reaction mixture was stirred for 5-6 h at 40oC till completion of the reaction (TLC). After completion of the reaction, a solution of sodium methoxide (2 g) in methanol (66 ml) was added to the contents followed by water (8 ml) and the contents were stirred for an additional 0.5 h. Water (1 L) was added to the solution and the contents were extracted with ethyl acetate (1 L). The aqueous layer was further extracted with ethyl acetate (3 X 500 ml). The combined organic layer was evaporated under vacuum to obtain a thick residue. tert-Butyl methyl ether (1 L) was added to the residue and the contents were stirred for about 1 h to obtain a solid product, which was filtered and washed with tert-butyl methyl ether (2 X 100 ml). The product was dried under vacuum below 60ºC to obtain the product as a 46.5 g dark brown compound, 46.5g ,yield 51%.
M.P.: 117-119oC; MS: 373(M+1); M.F.: C17H22F2N2O5..

Preparation of Intermediate -7: (5R)-Methanesulfonic acid 3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester

To a mixture of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-hydroxymethyl-oxazolidin-2-one (45 g, 0.121 mol) in dichloromethane (0.3 L), was added triethylamine (24.5 g, 34 ml, 0.242 mol) while stirring. Methanesulfonyl chloride (18 g, 12.2 ml, 0.157 mol) was added to the above solution over a period of 1 h at 10oC -20oC and the reaction mixture was stirred for additional 2 h at RT. After completion of the reaction (TLC), the contents were evaporated under vacuum at 40oC to obtain an oily residue. Water (450 ml) was added to the residue and the traces of dichloromethane were removed under vacuum. The solid product thus obtained was filtered, washed with water (2 X 50 ml) and dried under vacuum at 70oC to obtain 50.6 g brownish compound. Yield = 93%; M.P.:106-108oC; MS: 451(M+1); M.F.: C18H24F2N2O7S.

Preparation of Intermediate 8a: (5R)-3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one

Method A:
To a solution of (R)-3-(3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one (2g, 5.3 mmol),in tetrahydrofuran (20 mL), under argon , was added diphenylphosphoryl azide (1.63mL, 5.9 mmol). The solution was cooled to 0oC in an ice-bath. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.76mL, 4.9mmol) was added drop-wise over 15min..The reaction was stirred at same temperature for 1 hr, and then warmed to room temperature and stirred under for 16 hr. The reaction mixture was diluted with ethyl acetate (20 mL), and water (20mL). After separation of water layer, the organic layer was washed with water and 0.5M citric acid monohydrate (10 mL). The organic layer was dried over sodium sulfate and the solvent evaporated under reduced pressure.The residue was triturated with ether to obtain the product as a buff colored solid, 1.32g (62%).
M.P.: 106-108oC; M.S.- 398(M+1); M.F.- C17H21F2N5O4,

Method B:
To a solution of (5R)-methanesulfonic acid 3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl ester (20 g, 0.044 mol, wet) in N,N-dimethylformamide (30 ml), was added sodium azide (8.6 g, 0.133 mol) in a single lot. The reaction mixture was gradually heated and the temperature was maintained at 70ºC for 8 h. After completion of the reaction (TLC), the contents were cooled to 20-25ºC and poured slowly into chilled water (300 ml). The solid product thus obtained was filtered and washed with water (2 x 50 ml). The wet product was air dried to obtain 16.5g dark brown compound (being an azide, it was NOT exposed to heat during drying) Yield ~ 93%.
M.P.: 106-108oC; MS : 398(M+1); M.F.: C17H21F2N5O4;:

Preparation of Intermediate 8b: (5S)-N-2-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-phthalimide

Method A:
A mixture of (5R)-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-methanesulfonate(10g, 0.022 mol), Potassium phthalimide (12.2g, 0.066 mol) and DMF (50ml) was heated, with stirring, at 90oC for 4h. The resulting mixture was cooled to RT and poured over ice-water mixture. The separated solid was filtered, washed with water and dried under suction to obtain the product as a white solid, 9.46g, in 85% yield.
M.P.: 154-156 oC; MS: 502 (M+1); M.F. C25H25F2N3O6.

Method B:
To tetrahydrofuran (30 ml) were added triphenylphosphine (2.11g, 8 mmol)) and diethyldiazocarboxylate (1.62g, 8 mmol)), and the solution stirred at room temperature. After 10 minute phthalimide (1.18g, 8 mmol)) was added and after a further stirring for 10 minute, (R)-3-(3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl) oxazolidin-2-one (2g, 5.3 mmol) was added and stirring continued further at room temperature. After 8 hrs ice-cold water (4 ml) was added to the reaction mixture and the resulting mixture was extracted by ethyl acetate (2 x 20ml). The ethyl acetate extract was dried (over sodium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as an off-white solid, 1.56g, yield 58%.
M.P.: 154-156 oC; MS : 502 (M+1); M.F. C25H25F2N3O6.

Preparation of Intermediate 10: (5S)- N-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide
via
Intermediate 9: 5-aminomethyl-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-oxazolidin-2-one

Method A:
To a solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one (10 g, 0.025 mol) in methanol (100 ml), were charged cobalt chloride (0.6 g, 0.0025 mol) followed by sodium borohydride (0.95 g, 0.025 mol) in small lots over a period of 30 minutes. The reaction mixture was stirred at RT for additional 2 h. After completion of the reaction , the contents were evaporated under vacuum below 40oC to obtain a sticky mass. The contents were suspended in a mixture of water (100 ml) and ethyl acetate (50 ml) and stirred for 15 minutes. The contents were filtered through a filter-aid bed and the bed was washed with ethyl acetate (2 X 25 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (4 X 50 ml). The combined organic layer was washed with 1% HCl solution (100 ml). The aqueous layer was separated and washed with dichloromethane (4 X 50 ml). The pH of the aqueous layer was adjusted to 8 by adding saturated sodium bicarbonate solution. The contents were extracted with ethyl acetate (6 X 50 ml) till no amine spot was seen in the final organic extract. The combined organic layer (containing the intermediate 5-aminomethyl-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-oxazolidin-2-one) was dried over anhydrous sodium sulfate.

Triethylamine (3.3 g, 4.5 ml, 0.0327 mol) was added to the above organic layer and acetyl chloride (2.17 g, 2 ml, 0.0277 mol) was added gradually over a period of 1 h at RT. The reaction mixture was stirred for 2 h and after completion of the reaction (TLC), the contents were washed with water (50 ml) and the layers separated. Activated carbon (1 g) was added to the organic layer and the contents were stirred for 15 minutes. The contents were filtered on a celite bed and the carbon-celite bed was washed with ethyl acetate (2 X 10 ml). The combined filtrate was evaporated under vacuum to obtain a slurry, which was filtered on a Buchner assembly and the product was washed with ethyl acetate (2 X 10 ml). The product was dried under vacuum at 70oC to obtain 5 g off-white solid. Yield = 48% (on the basis of azide). HPLC Purity ~ 98%.
M.P.: 178-179oC; MS : 414 (M+1); M.F.: C19H25F2N3O5.

Method B:
A solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)-phenyl]-5-azidomethyl-oxazolidin-2-one (50 g, 0.125 mol) in ethyl acetatel (1L ml), were charged with 5g of 10% of Pd-C catalyst(50% wet) and the resulting mixture was hydrogenated at 30psi for 3h at 50oC.. The resulting mixture was cooled and filtered under suction over celite bed. The residue was washed with additional ethyl acetate (200ml). The combined filtrates were concentrated to 500ml volume.

To the above ethyl acetate solution was added Triethyl amine (19.1g, 0.189 mol), and acetic anhydride (16.1g, 1.58mol) in a single lot in few minutes). The reaction mixture was stirred for 16h at R.T. .The resulting mixture was cooled to 0-5oC, stirred for 0.5h and filtered under suction. The residue was washed with cold ethyl acetate(100ml) and dried at 70oC under reduced pressure to obtain the product as a a off-white solid, 43.5g, in 84% yield over two steps.
HPLC Purity ~ 98%
M.P.: 178-179oC; MS : 414 (M+1); M.F.: C19H25F2N3O5.

Method C:
To a solution of (S)-N-2-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-phthalimide (2.77g, 0.0055mol) in ethanol (20ml) was added hydrazine hydrate ( 0.554g, 0.011mol) and the resulting solution stirred at RT for 6h. The solvent was evaporated under reduced pressure, the residue suspended in 3% sodium carbonate solution and extracted in dichloromethane (40ml). The dichloromethane layer was dried and to this solution was added triethylamine(1.11g, 0.011mol) and acetic anhydride (0.67g, 0.007mol) and the solution stirred for 6h at RT. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography to obtain the product as white solid, 1.94g, in 85% yield.
M.P.: 178-179oC; MS: 414 (M+1); M.F.: C19H25F2N3O5.

Method D:
A mixture of (5R)-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-1-yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-methanesulfonate (1gm, 4.4mmol) and sodium diformylamide (2gms, 22mmol) in DMF (5ml) was stirred at 95 ºC. for 15hrs. Then a mixture of conc. HCl (0.6ml) and water (0.6ml) and ethanol (8ml) were added. The solution was stirred at 75ºC for 5hrs. The mixture was concentrated under reduced pressure at 60-75 ºC. Water (1ml), ammonia solution (0.5ml) and acetic anhydride (1ml) was added to the residue and the mixture stirred at 70-75 ºC for 4-5 hrs. The solution was cooled to room temperature, diluted with water (5ml) and the separated solid filtered. The residue was washed with water (4ml.) and dried in a vacuum oven at 50ºC to obtain the product as an off-white solid, 0.37g, in 41% yield.
M.P.: 178-179oC; MS : 414 (M+1); M.F.: C19H25F2N3O5.

Method E:

To tetrahydrofuran (30 ml) were added triphenylphosphine (2.11g, 8 mmol)) and diethyldiazocarboxylate (1.62g, 8 mmol)), and the solution stirred at room temperature. After 10 min acetamide (0.475g, 8 mmol)) was added and after a further stirring for 10 min, (R)-3-(3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-1-yl)phenyl)-5-(hydroxymethyl) oxazolidin-2-one (2g, 5.3 mmol) was added and stirring continued further at room temperature. After 16 hrs ice-cold water (4ml) was added to the reaction mixture and the resulting mixture was extracted by ethyl acetate (2 x 20ml). The ethyl acetate extract was dried (over sodium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as an off-white solid, 0.50g, yield 22%.
M.P.: 178-179oC; MS: 414 (M+1); M.F.: C19H25F2N3O5.
Preparation of Intermediate -11: (S)-N-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-di-O-benzylphosphoryloxy-piperi din-1yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide

To a solution of (S)-N-{3-[3,5-difluoro-4-(4-methoxymethyl-4-hydroxypiperidine-1yl)-phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (0.2 mmol) and tetrazole (0.6 mmol) in dichloromethane (5 ml) was added dibenzyl N,N,diisopropylphosphoramidite (0.4 mmol) and the resulting mixture was stirred for 4h. The resulting solution was cooled to 0 oC and 0.6 ml of 0.5M m-chloroperbenzoic acid solution in dichloromethane was added. After 4h, the solvent was evaporated under residue pressure and the residue chromatographed on a column of silica gel to obtain the product as a off-white solid in 75% yield,
MS: 674 (M+1); M.F. C33H38F2N3O8P;

Example A: Phosphoric acid mono-(1-{4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester

To a suspension of (S)-N-{3-[3,5-difluoro-4-(4-methoxymethyl-4-di-O-benzylphosphoryl- oxypiperidine-1yl)phenyl]-2-oxo-oxazolidin-5-yl methyl}-acetamide (0.15 mmol) and 20 % palladium hydroxide (20 mg) in 20 ml of a mixture of dichloromethane /aqueous methanol was stirred at room temperature for 6h. The catalyst was filtered and the residue evaporated under reduced pressure. The residue obtained was triturated with acetone to obtain a white solid as product in 70% yield.
MP. >140 °C; MS : 494(M+1) M.F.: C19H26F2N3O8P.

 

PATENT

WO 2012059823

http://www.google.co.in/patents/WO2012059823A1?cl=en

Phosphoric acid mono-(l-{4-[(S)-5-(acetylamino- methyl)-2-oxo-oxazolidin-3-yl]-2,6-difluorophenyl}-4-methoxymethyl-piperidin-4-yl) ester of Formula (A),
Figure imgf000022_0001
the process comprising the steps of:
a) Converting intermediate of Formula (1) into intermediate of Formula (3)
Figure imgf000022_0002
b) Converting intermediate of Formula (3) into intermediate of Formula (5)
Figure imgf000022_0003

c) Converting intermediate of Formula (5) into intermediate of structure (6)

Figure imgf000022_0004
(5) <6> d) Converting intermediate of Formula (6) into intermediate of Formula (10)
Figure imgf000023_0001
e) Converting intermediate of Formula (10) into intermediate of Formula (11),
Figure imgf000023_0002

f) Converting intermediate of Formula (11) into compound of Formula (A) or Pharmaceutically acceptable salts thereof

Figure imgf000023_0003

 

 

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003

ormu a-

Scheme-1

Preparation of Intermediate 10: (5S)- N-{ 3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl- piperidin- 1 -yl)-phenyl] -2-oxo-oxazolidin-5-ylmethyl } -acetamide

via

Intermediate 9: 5-aminomethyl-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l- yl)-phenyl] -oxazolidin-2-one

Method A:

To a solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)- phenyl]-5-azidomethyl-oxazolidin-2-one (10 g, 0.025 mol) in methanol (100 ml), were charged cobalt chloride (0.6 g, 0.0025 mol) followed by sodium borohydride (0.95 g, 0.025 mol) in small lots over a period of 30 minutes. The reaction mixture was stirred at RT for additional 2 h. After completion of the reaction , the contents were evaporated under vacuum below 40°C to obtain a sticky mass. The contents were suspended in a mixture of water (100 ml) and ethyl acetate (50 ml) and stirred for 15 minutes. The contents were filtered through a filter-aid bed and the bed was washed with ethyl acetate (2 X 25 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate (4 X 50 ml). The combined organic layer was washed with 1% HC1 solution (100 ml). The aqueous layer was separated and washed with dichloromethane (4 X 50 ml). The pH of the aqueous layer was adjusted to 8 by adding saturated sodium bicarbonate solution. The contents were extracted with ethyl acetate (6 X 50 ml) till no amine spot was seen in the final organic extract. The combined organic layer (containing the intermediate 5-aminomethyl-3-[3,5-difluoro-4-(4- hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-oxazolidin-2-one) was dried over anhydrous sodium sulfate.

Triethylamine (3.3 g, 4.5 ml, 0.0327 mol) was added to the above organic layer and acetyl chloride (2.17 g, 2 ml, 0.0277 mol) was added gradually over a period of 1 h at RT. The reaction mixture was stirred for 2 h and after completion of the reaction (TLC), the contents were washed with water (50 ml) and the layers separated. Activated carbon (1 g) was added to the organic layer and the contents were stirred for 15 minutes. The contents were filtered on a celite bed and the carbon-celite bed was washed with ethyl acetate (2 X 10 ml). The combined filtrate was evaporated under vacuum to obtain a slurry, which was filtered on a Buchner assembly and the product was washed with ethyl acetate (2 X 10 ml). The product was dried under vacuum at 70°C to obtain 5 g off-white solid. Yield = 48% (on the basis of azide). HPLC Purity ~ 98%.

M.P.: 178-179°C; MS : 414 (M+l); M.F.: C19H25F2N3O5. Method B:

A solution of (5R)-3-[3,5-difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)-phenyl]-5- azidomethyl-oxazolidin-2-one (50 g, 0.125 mol) in ethyl acetatel (1L ml), were charged with 5g of 10% of Pd-C catalyst(50% wet) and the resulting mixture was hydrogenated at 30psi for 3h at 50°C. The resulting mixture was cooled and filtered under suction over celite bed. The residue was washed with additional ethyl acetate (200ml). The combined filtrates were concentrated to 500ml volume. To the above ethyl acetate solution was added Triethyl amine (19. lg, 0.189 mol), and acetic anhydride (16. lg, 1.58mol) in a single lot in few minutes). The reaction mixture was stirred for 16h at R.T. .The resulting mixture was cooled to 0-5°C, stirred for 0.5h and filtered under suction. The residue was washed with cold ethyl acetate( 100ml) and dried at 70°C under reduced pressure to obtain the product as a a off-white solid, 43.5g, in 84% yield over two steps.

HPLC Purity ~ 98%

M.P.: 178-179°C; MS : 414 (M+l); M.F.: C19H25F2N3O5. Method C:

To a solution of (S)-N-2-{3-[3,5-Difluoro-4-(4-methoxymethyl-4-hydroxypiperidine- lyl)phenyl]-2-oxo-oxazolidin-5-yl methyl }-phthalimide (2.77g, 0.0055mol) in ethanol (20ml) was added hydrazine hydrate ( 0.554g, 0.01 lmol) and the resulting solution stirred at RT for 6h. The solvent was evaporated under reduced pressure, the residue suspended in 3% sodium carbonate solution and extracted in dichloromethane (40ml). The dichloromethane layer was dried and to this solution was added triethylamine(l.l lg, 0.01 lmol) and acetic anhydride (0.67g, 0.007mol) and the solution stirred for 6h at RT. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography to obtain the product as white solid, 1.94g, in 85% yield.

M.P.: 178-179°C; MS: 414 (M+l); M.F.: C19H25F2N3O5. Method D:

A mixture of (5R)-{3-[3,5-Difluoro-4-(4-hydroxy-4-methoxymethyl-piperidin-l-yl)phenyl]- 2-oxo-oxazolidin-5-yl methyl }-methanesulfonate (lgm, 4.4mmol) and sodium diformylamide (2gms, 22mmol) in DMF (5ml) was stirred at 95 °C. for 15hrs. Then a mixture of cone. HC1 (0.6ml) and water (0.6ml) and ethanol (8ml) were added. The solution was stirred at 75°C for 5hrs. The mixture was concentrated under reduced pressure at 60-75 °C. Water (1ml), ammonia solution (0.5ml) and acetic anhydride (1ml) was added to the residue and the mixture stirred at 70-75 °C for 4-5 hrs. The solution was cooled to room temperature, diluted with water (5ml) and the separated solid filtered. The residue was washed with water (4ml.) and dried in a vacuum oven at 50°C to obtain the product as an off-white solid, 0.37g, in 41% yield.

M.P.: 178-179°C; MS : 414 (M+l); M.F.: C19H25F2N3O5. Method E:

To tetrahydrofuran (30 ml) were added triphenylphosphine (2.1 lg, 8 mmol)) and diethyldiazocarboxylate (1.62g, 8 mmol)), and the solution stirred at room temperature. After 10 min acetamide (0.475g, 8 mmol)) was added and after a further stirring for 10 min, (R)-3- (3,5-difluoro-4-(4-hydroxy-4-(methoxymethyl)piperidin-l-yl)phenyl)-5-(hydroxymethyl) oxazolidin-2-one (2g, 5.3 mmol) was added and stirring continued further at room temperature. After 16 hrs ice-cold water (4ml) was added to the reaction mixture and the resulting mixture was extracted by ethyl acetate (2 x 20ml). The ethyl acetate extract was dried (over sodium sulfate) and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to obtain the product as an off-white solid, 0.50g, yield 22%.

M.P.: 178-179°C; MS: 414 (M+l); M.F.: C19H25F2N3O5.

 

PATENT

http://www.google.co.in/patents/WO2008038092A2?cl=en

Wockhardt Research Center,

Figure imgf000010_0001

IV

Figure imgf000010_0002

V

‘ Scheme-1 ‘

/////////

SEE FULL ZOLID SERIES…………http://drugsynthesisint.blogspot.in/p/zolid.html

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WCK Series by Wockhardt for treating the bacterial infection


BASE : 1174020-25-7
  • C14 H16 N2 O4 . Na, 
  • 1,​6-​Diazabicyclo[3.2.1]​octane-​2-​carboxylic acid, 7-​oxo-​6-​(phenylmethoxy)​-​, sodium salt (1:1)​, (1R,​2S,​5R)​-
  • SODIUM (2S, 5R)-6-(BENZYLOXY)-7-OXO-1,6-DIAZABICYCLO[3.2.1]OCTANE-2-CARBOXYLATE

sodium (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate…..WO2014135929


Patent

WO 2015136473

http://www.google.com/patents/WO2015136473A1?cl=en

 

EXAMPLES

The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods, and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

Example 1

Synthesis of sodium (25, 5R)-6-(benzyloxy)-7-oxo-l,6-diazabicvclor3.2.11octane-2- carboxylate

Step 1; Preparation of -Γl-Γ(feΓt-butyldimethylsilyl -oxymethyll-5-Γdimethyl(oxido -λ-4-sulfanylidenel-4-oxo-pentyll-carbamic acid tert-butyl ester (III):

To a suspension of trimethylsulfoxonium iodide (180.36 gm, 0.819 mol) in tetrahydrofuran (900 ml), sodium hydride (32.89 g, 0.819 mol, 60% in mineral oil) was charged in one portion at 30°C temperature. The reaction mixture was stirred for 15 minutes and then dropwise addition of dimethylsulphoxide (1.125 ml) was done over a period of 3 hours at room temperature to provide a white suspension. The white suspension was added to a pre-cooled a solution of 2-(feri-butyldimethylsilyl-oxymethyl)-5-oxo-pyrrolidine-l-carboxylic acid tert-buty\ ester (II) (225 g, 0.683 mol, prepared as per J. Org Chem.; 2011, 76, 5574 and WO2009067600) in tetrahydrofuran (675 ml) and triethylamine (123.48 ml, 0.887 mol) mixture at -13°C by maintaining the reaction mixture temperature below -10°C. The resulting suspension was stirred for additional 1 hour at -10°C. The reaction mixture was carefully quenched by addition of saturated aqueous ammonium chloride (1.0 L) at -10°C to 10°C. The reaction was extracted by adding ethyl acetate (1.5 L). The layers were separated and aqueous layer was re-extracted with ethyl acetate (500 ml x 3). The combined organic layer was washed successively with saturated aqueous sodium bicarbonate (1.0 L), water (2.0 L) followed by saturated aqueous sodium chloride solution (1.0 L). Organic layer was dried over sodium sulfate and evaporated under vacuum to provide 265 g of 5-[l-[(ieri-butyldimethylsilyl)-oxymethyl]-5-[dimethyl(oxido)- -4-sulfanylidene]-4-oxo-pentyl]-carbamic acid tert-buty\ ester (III) as an yellow oily mass.

Analysis:

Mass: 422.3 (M+l); for Molecular weight: 421.68 and Molecular Formula:

1H NMR (CDC13): δ 4.77 (br d, 1H), 4.38 (br s, 1H), 3.58 (br s, 3H), 3.39 (s, 3H), 3.38 (s, 3H), 2.17-2.27 (m, 2H), 1.73-1.82 (m, 2H), 1.43 (s, 9H), 0.88 (s, 9H), 0.01 (s, 3H), 0.04 (s, 3H).

Step 2: Preparation of 5-r4-benzyloxyimino-l-(fert-butyldimethylsilyl-oxymethyl)-5-chloro-pentyll-carbamic acid tert- butyl ester (IV):

To a suspension of 5-[l-[(ieri-butyldimethylsilyl)-oxymethyl]-5-[dimethyl(oxido)- -4-sulfanylidene]-4-oxo-pentyl]-carbamic acid tert-butyl ester (III) (440.0 g, 1.045 mol) in tetrahydrofuran (6.6 L), O-benzhydroxylamine hydrochloride (200.0 g, 1.254 mol) was charged. The reaction mixture was heated to 50°C for 2.5 hours. The reaction mixture was filtered through pad of celite and filtrate was concentrated to provide a residue. The residue was dissolved in ethyl acetate (5.0 L) and washed successively with saturated aqueous sodium bicarbonate (1.5 L), water (1.5 L) and saturated aqueous sodium chloride (1.5 L). Organic layer was dried over sodium sulfate. Solvent was evaporated under vacuum to yield 463.0 g of 5-[4-benzyloxyimino-l-(tert-butyldimethylsilyl-oxymethyl)-5-chloro-pentyl]-carbamic acid tert-butyl ester (IV) as an oily mass.

Analysis:

Mass: 486.1 (M+l); for Molecular weight: 485.4 and Molecular Formula:

1H NMR (CDCI3): δ 7.26-1 6 (m, 5H), 5.10 (s, 2H), 4.66 (br d, 1H), 3.58-4.27 (m, 2H), 3.56-3.58 (m, 3H), 2.40-2.57 (m, 2H), 1.68-1.89 (m, 2H), 1.44 (s, 9H), 0.89 (s, 9H), 0.02 (s, 3H), 0.04 (s, 3H).

Step 3: Preparation of 5-5-benzyloxyimino-2-(fert-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (V):

To a solution of 5-[4-benzyloxyimino-l-(tert-butyldimethylsilyl-oxymethyl)-5-chloro-pentyl]-carbamic acid tert-butyl ester (IV) (463.0 g 0.954 mol) in tetrahydrofuran (6.9 L), was charged potassium feri-butoxide (139.2 g, 1.241 mol) in portions over a period of 30 minutes by maintaining temperature -10°C. The resulting suspension was stirred for additional 1.5 hours at -10°C to -5°C. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (2.0 L) at -5°C to 10°C. The organic layer was separated and aqueous layer was extracted with ethyl acetate (1.0 L x 2). The combined organic layer was washed with saturated aqueous sodium chloride solution (2.0 L). Organic layer was dried over sodium sulfate, and then evaporated under vacuum to yield 394.0 g of 5-5-benzyloxyimino-2-(ieri-butyldimethylsilyl-oxymethyl)-piperidine- 1 -carboxylic acid tert-butyl ester (V) as an yellow oily mass.

Analysis:

Mass: 449.4 (M+l) for Molecular weight: 448.68 and Molecular Formula: C24H4oN204Si;

1H NMR (CDC13): δ 7.25-1 3 (m, 5H), 5.04-5.14 (m, 2H), 4.35 (br s, 1H), 3.95 (br s, 1H), 3.63-3.74 (br d, 2H), 3.60-3.63 (m, 1H), 2.70-2.77 (m, 1H), 2.33-2.41 (m, 1H), 1.79-1.95 (m, 2H), 1.44 (s, 9H), 0.88 (s, 9H), 0.03 (s, 3H), 0.04 (s, 3H).

Step 4: Preparation of (25,5R5)-5-benzyloxyamino-2-(tert-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (VI):

To a solution of 5-5-benzyloxyimino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (V) (394.0 g, 0.879 mol) in dichloromethane (5.0 L) and glacial acetic acid (788 ml), was charged sodium cyanoborohydride (70.88 g, 1.14 mol) one portion. The resulting reaction mixture was stirred at temperature of about 25 °C to 30°C for 2 hours. The mixture was quenched with adding aqueous solution of sodium bicarbonate (1.3 kg) in water (5.0 L). The organic layer was separated and aqueous layer was extracted with dichloromethane (2.0 L). The combined organic layer washed successively with water (2.0 L), saturated aqueous

sodium chloride (2.0 L) and dried over sodium sulfate. Solvent was evaporated under vacuum to provide a residue. The residue was purified by silica gel column chromatography to yield 208 g of (25,5i?5)-5-benzyloxyamino-2-(ieri-butyldimethylsilyl-oxymethyl)-piperidine- 1 -carboxylic acid tert-buty\ ester (VI) as pale yellow liquid.

Analysis:

Mass: 451.4 (M+l); for Molecular weight: 450.70 and Molecular Formula: C24H42N204Si;

1H NMR (CDC13): δ 7..26-7.36 (m, 5H), 4.90-5.50 (br s, 1H), 4.70 (dd, 2H), 4.09-4.25 (m, 2H), 3.56-3.72 (m, 2H), 2.55-3.14 (m, 2H), 1.21-1.94 (m, 4H), 1.45 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H).

Step 5: Preparation of (25,5R5)-5-benzyloxyamino-2-(tert-butyldimethylsilyl-oxymethyl)-piperidine (VII):

To a solution of 5-5-benzyloxyamino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine-l-carboxylic acid tert-butyl ester (VI) (208 g, 0.462 mol) in dichloromethane (3.0 L), boron trifluoride diethyletherate complex (114.15 ml, 0.924 mol) was charged in one portion. The resulting reaction mixture was stirred at temperature of about 25°C to 35°C temperature for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (2.0 L). The organic layer was separated and aqueous layer was extracted with dichloromethane (1.5 L x 2). The combined organic layer was washed with saturated aqueous sodium chloride (1.0 L) and dried over sodium sulfate. Solvent was evaporated under vacuum to yield 159 g of (25,5i?5)-5-benzyloxyamino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine (VII) as a yellowish syrup.

Analysis:

Mass: 351.3 (M+l); for Molecular weight: 350.58 and Molecular Formula: C19H34N202Si.

Step-6: Preparation of (25,5R)-6-benzyloxy-2-(fert-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicyclo-r3.2.11octane (VIII):

Part 1; Preparation of (2S,5RS)-6-benzyloxy-2-(fert-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicvclo-r3.2.11octane:

To a solution of (25,5i?5)-5-benzyloxyamino-2-(feri-butyldimethylsilyl-oxymethyl)-piperidine (VII) (159.0 g, 0.454 mol) in a mixture of acetonitrile (2.38 L) and diisopropylethylamine (316.5 ml, 1.81 mol) was added triphosgene (59.27 gm, 0.199 mol) dissolved in acetonitrile (760 ml) at -15°C over 30 minutes under stirring. The resulting reaction mixture was stirred for additional 1 hour at -10°C. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (2.0 L) at -5°C to 10°C. Acetonitrile was evaporated from the reaction mixture under vacuum and to the left over aqueous phase, dichloromethane (2.5 L) was added. The organic layer was separated and aqueous layer extracted with dichloromethane (1.5 L x 2). The combined organic layer was washed successively with water (2.0 L), saturated aqueous sodium chloride (2.0 L) and dried over sodium sulfate. Solvent was evaporated under vacuum and the residue was passed through a silica gel bed to yield 83.0 g of diastereomeric mixture (25, 5i?5)-6-benzyloxy-2-(feri-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicyclo-[3.2.1]octane in 50:50 ratio as a yellow liquid.

Part-2: Separation of diastereomers to prepare (25,5R)-6-benzyloxy-2-(fert-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicvclo-r3.2.11octane:

A mixture of diastereomers (2S,5Z?S)-6-benzyloxy-2-(teri-butyl-dimethylsilyl-oxymethyl)-7-oxo-l,6-diaza-bicyclo-[3.2.1]octane in 50:50 ratio (47.0 gm, 0.125 mol), was dissolved in n-hexane (141 ml) and stirred at temperature of about 10°C to 15°C for 1 hour. Precipitated solid was filtered and washed with n-hexane (47 ml) to provide 12.0 g of diastereomerically pure (25,5i?)-6-benzyloxy-2-(tert-butyl-dimethylsilyl-oxymethyl)-7-oxo- 1,6-diaza-bicyclo-[3.2.1] octane (VIII) as a white crystalline material.

Analysis:

Mass: 377.3 (M+l); for Molecular weight: 376.58 and Molecular Formula:

1H NMR (CDCI3): δ Ί -Ί.ΑΑ (m, 5H), 4.95 (dd, 2H), 3.76-3.85 (ddd, 2H), 3.37-3.40 (m, 1H), 3.28-3.31 (m, 2H), 2.89 (brd, 1H), 1.90-2.02 (m, 2H), 1.62- 1.74 (m, 2H), 1.56 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).

Diastereomeric purity as determined by HPLC: 99.85%

Step-7: Preparation of (25,5R)-6-benzyloxy-2-hvdroxymethyl)-7-oxo-l,6-diaza-bicvclo-r3.2.11octane (IX):

To a solution of (25,5i?)-6-benzyloxy-2-(ieri-butyl-dimethylsilyl-oxymethyl)-7-oxo- l,6-diaza-bicyclo-[3.2.1]octane (VIII) ( 12.0 g, 31.9 rnmol) in tetrahydrofuran (180 ml) was charged tetra 7? -butyl ammonium fluoride (38.0 ml, 38 mmol, 1 M in tetrahydrofuran) at room temperature. The reaction mixture was stirred for 2 hours. It was quenched with saturated aqueous ammonium chloride ( 100 ml). The organic layer was separated and aqueous layer extracted with dichloromethane (150 ml x 3). The combined organic layer was washed with saturated aqueous sodium chloride (150 ml), dried over sodium sulfate and evaporated under vacuum to yield 24.0 g of (25,5i?)-6-benzyloxy-2-hydroxymethyl)-7-oxo-l ,6-diaza-bicyclo-[3.2.1]octane (IX) as a yellow liquid. The compound of Formula (IX) was purified by silica gel (60-120 mesh) column chromatography using a mixture of ethyl acetate and hexane as an eluent.

Analysis:

Mass: 263.1 (M+l); for Molecular weight: 262.31 and Molecular Formula: C14H18N203

1H NMR (CDCb): δ 7.34-7.42 (m, 5H), 4.95 (dd, 2H), 3.67-3.73 (m, 1H), 3.53-3.60 (m, 2H), 3.32-3.34 (m, 1H), 2.88-3.01 (m, 2H), 2.09 (brs, 1H), 1.57-2.03 (m, 2H), 1.53- 1.57 (m, 1H), 1.37- 1.40 (m, 1H).

Step 8: Preparation of sodium salt of (25, 5R)-6-benzyloxy-7-oxo-l,6-diaza-bicvclor3.2.11-octane-2-carboxylic acid (I):

Step I:

Compound of Formula (IX) obtained in step 8 above was used without any further purification. To the clear solution of (25,5i?)-6-benzyloxy-2-hydroxymethyl)-7-oxo-l,6-diaza-bicyclo-[3.2.1]octane (IX) (24.0 g, 31.8 mmol) (quantities added based upon theoretical basis i.e 8.3 g ) in dichloromethane (160 ml), was added Dess-Martin reagent (24.1 g, 57.24 mmol) in portions over 15 minutes. The resulting suspension was stirred for 2 hours at 25°C. The reaction was quenched by adding a solution, prepared from saturated aqueous sodium hydrogen carbonate solution (160 ml) and 72.0 g of sodium thiosulfate. Diethyl ether (160 ml) was added to the reaction mixture and it was stirred for 5-10 minutes and filtered through celite. Biphasic layer from filtrate was separated. Organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (160 ml) followed by saturated aqueous sodium chloride solution (160 ml). Organic layer was dried over sodium sulfate and evaporated to dryness at 30°C to obtain 20.0 g of intermediate aldehyde, which was used immediately for the next reaction.

Step II:

To the crude intermediate aldehyde (20.0 g, 31.6 mmol) (quantities added based upon theoretical yield i.e. 8.2 g) obtained as above, was charged i-butyl alcohol (160 ml) and cyclohexene (10.8 ml, 110.6 mmol). The reaction mixture was cooled to temperature of about 10°C to 15°C. To this mixture was added clear solution prepared from sodium hypophosphate (14.8 g, 94.8 mmol) and sodium chlorite (5.7 g, 63.2 mmol) in water (82.0 ml) over a period of 30 minutes by maintaining temperature between 10°C to 15°C. The reaction mixture was further stirred for 1 hour and was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was subjected to evaporation under vacuum at 40°C to remove i-butyl alcohol. Resulting mixture was extracted with dichloromethane (3 x 150 ml). Layers were separated. Combined organic layer was washed with aqueous brine solution, dried over sodium sulfate and evaporated to dryness under vacuum to obtain 16.0 g of crude residue. To this residue was added acetone (83 ml) to provide a clear solution and to it was added dropwise a solution of sodium 2-ethyl hexanoate (4.5 g) in acetone (24 ml). The reaction mixture was stirred for 15 hours at 25°C to 30°C to provide a suspension. To the suspension was added diethyl ether (215 ml) and stirred for 30 minutes. Resulting solid was filtered over suction, and wet cake was washed with cold acetone (83 ml) followed by diethyl ether (83 ml). The solid was dried under vacuum at 40°C to provide 3.6 g of off-white colored, non-hygroscopic sodium salt of (25, 5i?)-6-benzyloxy-7-oxo-l,6-diaza-bicyclo[3.2.1]-octane-2-carboxylic acid (I).

Analysis:

Mass: 275.2 as M-1 (for free acid) for Molecular Weight: 298 and Molecular Formula:

NMR (DMSO-d6): δ 7.43-7.32 (m, 5H), 4.88 (q, 2H), 3.48 (s, IH), 3.21 (d, IH), 2.73 (d, IH), 2.04-2.09 (m, IH), 1.77-1.74 (m, IH), 1.65-1.72 (m, IH), 1.55-1.59 (m, IH);

Purity as determined by HPLC: 97.47%;

[a]D25: -42.34° (c 0.5, water).

Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.

 

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