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Phase 3 FDA -Acorafloxacin (Avarofloxacin) Granted QIDP and Fast Track Designation

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Avarofloxacin .HCl/Acorafloxacin. HCl
cas no  1001162-01-1 
3-Quinolinecarboxylic acid, 7-[(3E)-3-(2-amino-1-fluoroethylidene)-1-piperidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-, hydrochloride (1:1)
2. 7-[(3E)-3-(2-amino-1-fluoroethylidene)piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid monohydrochloride
PHASE 2 FURIEX,FOR  acute bacterial skin and skin structure (ABSSSI)Infection, 
February 25, 2013
Avarofloxacin Granted QIDP and Fast Track Designation

JNJ-Q2, JNJ-32729463-AAA

CAS NO   878592-87-1 of base

7-[3-[2-Amino-1(E)-fluoroethylidene]piperidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

 

Figure imgf000063_0002

Furiex Pharmaceuticals Inc. announced that the FDA has granted Qualified Infectious Disease Product (QIDP) and Fast Track designation for avarofloxacin (JNJ-Q2). Avarofloxacin is a Phase 3-ready broad-spectrum fluoroquinolone antibiotic for the treatment of acute bacterial skin and skin-structure (ABSSSI) infections, community-acquired pneumonia and has proven to be effective in treating methicillin-resistant Staphylococcus aureus (MRSA) infections.

Avarofloxacin is an investigational novel fluoroquinolone antibiotic that has been shown to be effective in a Phase 2 study of ABSSSI infections. In this study, avarofloxacin demonstrated favorable efficacy for both early clinical response endpoints as well as all clinical cure endpoints for the intent to treat population.

Avarofloxacin has a low tendency for development of drug resistance and exhibits a broad range of antibacterial activities in vitro, including MRSA, fluoroquinolone-resistant Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug resistant strains), gram positive, gram negative, atypical respiratory pathogens (such as legionella and mycoplasma) and anaerobic bacteria, which are often associated with abscesses of the skin and other organs.

The availability of IV and oral formulations for avarofloxacin differentiates it from a number of other products for MRSA infections which are only available for intravenous administration.

For more information call (919) 456-7800or visit http://www.furiex.com/

About Methicillin-Resistant Staphylococcus aureus (MRSA)

MRSA is a strain of the bacteria Staphylococcus aureus (staph) which commonly causes skin and soft tissue infections and is resistant to many antibiotics. Although MRSA had previously been primarily a hospital-acquired pathogen, its incidence has been rising in the community, and it has become the most frequent cause of skin and soft tissue infections presenting to emergency departments in the United States. There are a limited number of antibiotics approved to treat MRSA, and their frequent usage has led to emergence of multi-drug resistant bacteria. Thus, we believe there is significant unmet medical need for new antibiotics such as avarofloxacin that provide flexible (hospital and outpatient) treatment options for MRSA.

WO-2006/101603 describes 7-amino alkylidenyl- heterocyclic quinolones as antimicrobial compounds and the synthesis of 7-[(3E)-3-(2-amino-l-fluoroethylidene)-l- piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid is disclosed as compound (303) in Table 1 on page 20. This compound is conveniently referred to as compound ‘A’ hereafter.

compound ‘A’

Figure imgf000002_0001

7-[(3E)-3-(2-amino-1 -fluoroethylidene)-1 -piperidinyl]-1 -cyclopropyl-6-fluoro- 1 ,4-dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid

The in vitro antibacterial properties of compound ‘A’ are described by Morrow B.J. et al. in Antimicrobial Agents and Chemotherapy, vol. 54, pp. 1995 – 1964 (2010).

WO-2008/005670 discloses one-pot methods for the production of substituted allylic alcohols as well as extractive methods for the separation of certain isomeric alcohol products which are useful for preparing quinolones such as the antimicrobial compound 7-[(3E)-3-(2-amino- 1 -fluoroethylidene)- 1 -piperidinyl]- 1 -cyclopropyl-6-fluoro- 1 ,4- dihydro-8-methoxy-4-oxo 3-quinolinecarboxylic acid (i.e. compound ‘Α’). An important intermediate in the overall synthesis route of said antimicrobial compound ‘A’ is 2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-lH-isoindole-l,3(2H)- dione and its hydrochloric acid salt thereof : compound (1 )

Figure imgf000003_0001

2-[(2E)-2-fluoro-2-(3-piperidinylidene)ethyl]-1 H-isoindole-1 ,3(2H)-dione compound (1 ) .HCI

Figure imgf000003_0002

Compound (1) introduces the desired E- stereochemistry into the overall synthesis route for the antimicrobial compound ‘Α’.

WO-2008/005670 discloses a synthesis route for compound (1) on page 38 as depicted below :

Figure imgf000003_0003

– highly enriched (E)

Figure imgf000004_0001

(Step 3a) O

The detailed reaction procedure for compound (1) is disclosed in WO-2008/005670 in Example 1 on pages 37 to 44 affording compound (1) in Method A with a E:Z ratio of 97:3 in an approximate overall yield of 18 % in Method A (step 1 for the first 3 heptane layers has a yield of 34 % with a ratio E:Z of 71 :29, step 2a has a yield of 53.4% with a ratio E:Z of 97:3, and step 3 has quantitave yield), or affording compound (1) in Method B with an approximate overall yield of 15% with a ratio E:Z of 94.4 : 5.6. WO-2008/005670 discloses a synthesis route for the hydrochloric acid addition salt of compound (1) on page 15 in Scheme 2 as depicted below :

Figure imgf000004_0002

into n-butanol,

Figure imgf000005_0001

1 ) 5/6 N HCl in IPA

2) heat to distill

3) add IPA

enriched E-isomer

Figure imgf000005_0002

compound (1 ) .HCl

The detailed reaction procedure to prepare the HCl salt of compound (1) is disclosed in WO-2008/005670 in Example 4 on pages 49 to 52 affording >95% of desired E-isomer with an overall yield of 18 – 22% starting from N-boc-3-piperidone.

The reaction procedures described in WO-2008/005670 for the preparation of compound (1) or its HCl salt are characterized by lack of selectivity of the Wadsworth- Emmons-Horner reaction which produces the undesired Z-isomer in large quantities. This undesired Z-isomer requires additional time consuming separation steps.

Hence there is a need for a more efficient and less waste-producing procedure for the preparation of compound (1) or its HCl salt. WO-2010/056633 discloses a synthesis scheme XIV on page 87 to prepare tert-butyl 4- (2-ethoxy-2-oxoethylidene)piperidinyl-l-carboxylate and a synthesis scheme XXVI on page 111 to prepare (l-benzyl-piperidin-4-ylidene)bromoacetic acid ethyl ester.

In a first embodiment the present invention relates to an improved process for preparing compounds of formula (III) having an improved ratio of the desired (E)-isomer over the undesired (Z)-isomer.

Figure imgf000006_0001

(I)

In a further embodiment the compound (E)-(III) is then converted in to compound (1) or its hydrochloric acid addition salt thereof.

…………………………..

WO 2008005670

http://www.google.com/patents/WO2008005670A2?cl=en

Scheme 1

Figure imgf000013_0001

3 eq NaBH4 OH

30 – 4O0C

Figure imgf000013_0002

2a 2b 2a

Figure imgf000013_0003

2b shows the preparation of alcohol 2

 

 

Scheme 2

Figure imgf000016_0001

1 ) HCI (5 eq )

Figure imgf000016_0002

aqueous layer to enriched E isomer pH 9-10 then extract into n-Butanol, discard aqueous layer

 

Preparation of

7-[3-(2-Amino-l-fluoroethylidene)piperidin-l-yl]-l-cyclopropyl- 6-fluoro-8-methoxy-4-oxo-l,4-dihydroquinoline-3-carboxylic acid (10) and its HCl salt (12)

Figure imgf000039_0001

7-[3-(2-Amino-1-fluoro-ethyhdene)-piperidin-1-yl]-1-cyclopropyl–fluoro-8-mΘthoxy-4-oxo-1 ,4-dιhydro-quιnolιne-3-carboxylιc acid (10)

Step 1: Preparation of 3-(l-fluoro-2-hydroxyethylidene)piperidine-l-carboxylic acid tert-butyl ester (2a)

Figure imgf000040_0001

A 22-L 4-neck round bottom flask, equipped with a thermocouple controller, overhead mechanical stirrer, condenser, nitrogen inlet adapter, and stopper, was charged with N-Boc-3-piperidone (663.36 g, 3.34 mol), 2-methoxyethanol (6.0 L) and 2-fluorotriethylphosphonoacetate (843.54 g, 3.49 mol). The mixture was stirred to obtain a homogeneous solution and then CS2CO3 was added in portions over 1.5 h. After the CS2CO3 addition was complete, NaBH4 was added in portions over 6 h; during most of this addition the reaction temperature was maintained between 35 0C to 40 0C. After the addition was complete, the reaction was allowed to stir overnight after which time HPLC analysis indicated that the reaction was complete. This run was combined with two additional runs of equal size and transferred to a stirred 100-L Hastalloy® reactor containing water (90 L). The aqueous mixture was extracted with heptane (4 x 20 L) followed by extraction with MTBE (methyl tert-butyl ether) (20 L). The first three heptane extracts provided 842 g of the allylic alcohol as 71:29 (E: Z) mixture (HPLC and NMR). The product mixture from the first three heptane extractions was carried on to the next step without any additional purification. The fourth heptane extract gave 114 g of product that was a 67:33 mixture of is: Z alcohols (NMR). MTBE extraction and concentration gave 1.1 Kg of product as a 33:67 mixture of E:Z alcohols (HPLC). The total overall yield for both isomers was 2.06 Kg (83%). 1H NMR of 2a (400 MHz, CDCl3): £ 1.45 (s, 9 H), 1.52 (m, 2 H), 2.40 (m, 2 H), 3.45 (m, 2 H), 3.90 (s, 2 H), 4.25 (d, 2 H). 1H NMR of 2b (400 MHz, CDCl3): δ 1.46 (s, 9 H), 1.65 (m, 2 H), 2.27 (m, 2 H), 3.45 (m, 2 H), 4.1 (s, 2 H), 4.25 (d, 2 H).

Step 2, Method A: Preparation of 3-is-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester (3-ϋ)

Figure imgf000041_0001

A 22-L 4-neck round bottom flask, equipped with a thermocouple controller, overhead mechanical stirrer, condenser, pressure-equalizing addition funnel, nitrogen inlet adapter, and stopper, was charged with E:Z alcohol mixture 2a and 2b (377.5 g, 1.296 mol corrected), 2-MeTHF (3.31 L), phthalimide (232.8 g, 1.581 mol), and Ph3P (411.3 g, 1.568 mol). The white suspension was stirred under N2 and cooled to -12 0C in an acetone/Dry-Ice bath, DIAD (309 mL, 1.49 mol) was added via the addition funnel over a 36-min period, while the reaction temperature was maintained at -15 0C to -10 0C. After the addition, the reaction was warmed to 20 0C in a water bath and stirred for 2 h. The reaction was cooled to 0 0C in an ice/water bath and quenched with cold 1.0 M HCl (950 mL). The aqueous phase was separated and EtOAc (1.70 L) was added to the organic phase. This phase was washed with cold 1.0 M HCl (0.95 L) (the aqueous phase was pH < 2) and then separated. The organic phase was next washed with cold 4 NNaOH (1.70 L), the alkaline aqueous phase (pH > 13) was separated and the EtOAc layer washed with brine (1.70 L). Concentration of the organic phase at 60 0C under house vacuum (-120 mm Hg) afforded 1,442.0 g of crude 3. This run was repeated on the same scale to provide an additional 1,431.0 g of crude material for a combined yield of 2,873 g (159%). HPLC analysis (area%) indicated crude 3 was a mixture of 3-E (29.4%), 3-Z (10.4 %), Ph3PO (51.0 %), and phthalimide (1.1 %). This was purified by recrystallization as described in step 2a.

Step 2a, Method A: Purification of 3-is-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester

Figure imgf000042_0001

A 22-L 4-neck round bottom flask equipped with a thermocouple controller, overhead mechanical stirrer, condenser, pressure-equalizing addition funnel, nitrogen inlet adapter and stopper was charged with the combined crude 3 (2,873 g) and MeOH (9.0 L). The solution was stirred under nitrogen and heated to 65 0C, while hot (60 0C) D.I. water (7.8 L) was added over a 15-min period. The solution was stirred at 65 0C for 5 min, and then the heating mantle was replaced with a water bath, and the mixture was gradually cooled to 0 0C over a 4-h period, and continued stirring for 1 h at 0 0C. The off-white solid was collected by filtration, and dried by air-suction at 60 0C for 20 h, this provided 1,172.6 g of a mixture of 3-E and 3-Z.

The partially purified product above was recrystallized a second time in the same manner using hot MeOH (7.2 L) and hot water (5.0 L) except that the water was added over a 10-min period to afford 515.6 g (53.4%) of 3-E as a 97:3 mixture of E:Z geometric isomers. This material was used in the next step without additional purification. . 1H NMR of 3-E (400 MHz, CDCl3): δ 1.48 (s, 9 H), 1.52-1.66 (m, 2 H), 2.28-2.38 (m, 2 H), 3.40-3.51 (m, 2 H), 4.18 (s, 2 H), 4.55 (d, J= 21.0 Hz, 2 H), 7.68- 7.77 (m, 2 H), 7.80-7.89 (m, 2 H). MS: 397 (M+Na)+, 771 (2M+Na)+.

3 -E-[2-( 1 ,3 -dioxo- 1 ,3-dihydroisoindol-2-yl)- 1 -fluoroethylidene]-piperidine- 1 – carboxylic acid tert-butyl ester was also prepared with Method B below: Step 2, Method B: Preparation of 3-£-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester (3-E)

Preparation of the methanesulfonate and chloride derivatives

Figure imgf000043_0001

2a

A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with 2a (297.0 g, 1.21 mol) and CH2Cl2 (3.9 L). The solution was cooled to 0 0C under N2 and EtsN (320 mL, 2.30 mol) was added via the addition funnel over a 10- min period. This was followed by methanesulfonyl chloride (115 mL, 1.49 mol) added over a 60-min period then the reaction was stirred for an additional 60-min at 0 0C. The mixture was poured into a mixture of deionized water (4.4 L) and saturated NaHCθ3 (0.78 L), the layers were separated, the aqueous layer was extracted with CH2Cl2 (2 x 2 L). All the CH2Cl2 layers were combined and washed with saturated NaHCθ3 (2 L). The CH2Cl2 was removed under vacuum at 40 0C to afford a mixture of the mesylate and chloride (342.3 g). This mixture was taken on to the next step without any purification.

Conversion of the methanesulfonate/chloride to phthalimide 3

Figure imgf000043_0002

A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with the mixture of the mesylate and chloride from above (342.2 g, 1.21 mol) and DMF (2.0 L) followed by potassium phthalimide (224.9 g, 1.21 mol). The mixture was stirred at 60 0C for 1-h then at 20 0C for 18 h. The mixture was poured into ice- water, allowed to stand for 30-min and filtered. The liquors from the filtration were allowed to stand at 0 0C over the weekend and filtered again. The combined solids were dissolved in acetone (4 L) and concentrated on the rotary evaporator, this process was repeated a second time to give the phthalimide derivative 3 as a mixture oiEIZ (79/31) isomers (263.2 g, 58.1 %).

Step 2a, Method B: Purification of 3-£-[2-(l,3-dioxo-l,3-dihydroisoindol-2-yl)-l- fluoroethylidene]-piperidine-l-carboxylic acid tert-butyl ester

Figure imgf000044_0001

A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with the crude phthalimide derivative 3 (263.1 g) and MeOH (2.74 L). The mixture was heated to 66 – 68 0C while water (2.1 L) was added over 20-min, the mixture was stirred at 68 0C for 5-min, then gradually cooled to 20 0C for 18-h. While the crystallization mixture was cooling it was seeded at 60 0C, 56 0C and 530C. This crystallization gave a white solid that was filtered and dried under vacuum at 50 0C to afford 3-E (118.8 g, 45.2%) as a mixture containing 94.4% E and 5.6% Z isomers (NMR analysis).

Step 3: Preparation of 2-[2-fluoro-2-(3-piperidinylidene)ethyl]-lH-isoindole-l,3)- dione (4)

Figure imgf000045_0001

A 12-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with 3-E (578.0 g, 1.544 mol) and CH2Cl2 (4.5 L). The solution was stirred at 200C under N2 and TFA (476 mL, 6.18 mol) was added via the addition funnel over a 10-min period. The mixture was gently heated to 38 0C and stirred for 3 h. The solvent was removed under vacuum to give the TFA salt of 4 (962.6 g). This material was dissolved in CH2Cl2 (4.0 L) and washed with 2.5 NNa2CO3 (4.6 L)-followed by saturated NaHCO3 (4.6 L). The organic phase was dried (MgSO4), filtered, and condensed in vacuo. The off-white solid was dried at 40 0C under vacuum (20 mm Hg) for 20 h to afford 464.3 g of the free base of 4 as slightly yellowish foamy substance. 1H NMR of 4 TFA salt (400 MHz, CDCl3): δ 1.87-1.98 (m, 2 H), 2.42-2.55 (m, 2 H), 3.38-3.50 (m, 2 H), 4.08-4.18 (br s, 2 H), 4.50 (d, J= 21.0 Hz, 2 H), 7.69-7.78 (m, 2 H), 7.79-7.87 (m, 2 H), 7.98-8.23 (br s, 1 H), 12.48 (s, 1 H). MS: 275 (MH)+, 549 (2M+H)+.

Step 4: Preparation of l-Cyclopropyl-ό^-difluoro-S-methoxy^-oxo-l^- dihydroquinoline-3-carboxylic acid difluoroborate ester (6)

Figure imgf000045_0002

A 22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure equalizing addition funnel, and a nitrogen inlet adapter was charged with quinoline-3-carboxylic acid 5 (450.0 g, 1.524 mol), THF (5.40 L) and K2CO3 (247.2 g, 1.753 mol). This suspension was first stirred at 20 0C under N2 for 5 min, and BF3 »Et20 (259 mL, 2.04 mol) was added dropwise via the addition funnel to the stirred mixture over a 5-min period. After the addition, the mixture was heated to reflux (66 0C) for 6 h. The reaction was cooled to 10 0C, diluted with Et2O (9.0 L) and stirred for 10 min. The solid was filtered and washed with Et2O (200 mL x 2) and then dried at 50 0C under house vacuum (-160 mm Hg) for 20 h to afford 771.O g of crude difluoroborate ester 6. After this, the crude material was suspended in MeCN (8.0 L) and stirred at 20 0C for 20 min; the solid was collected by filtration. The filter cake was re-suspended and stirred in MeCN four more times (2.0 L x 4), and all filtrates were combined and concentrated at 60 0C under hi-vac (~10 mmHg). The resulting off- white solid was dried at 50 0C under house vacuum (-160 mmHg) for 20 h to afford 508.66 g (97.2% isolated yield, HPLC = 99.2% by area) of pure difluoroborate ester 6. 1H NMR of 6 (400 MHz, CD3CN): «51.17-1.28 (m, 2 H), 1.29-1.40 (m, 2 H), 4.19 (s, 3 H), 4.40-4.52 (m, 1 H), 8.16 (dd, J= 6.9, 7.0 Hz, 1 H), 9.17 (s, 1 H). MS: 344 (MH)+, 667 (2M-F)+.

Step 5: Preparation of intermediate 8

Figure imgf000046_0001
Figure imgf000046_0002

A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel and a nitrogen inlet adapter was charged with difluoroborate ester 6 (320.0 g, 0.933 mol), DMF (1.10 L) and piperidine 4 (289.0 g, 1.053 mole). This suspension was stirred at 20 0C under N2 for 5 min, EtsN (299 mL, 2.15 mol) was added to the stirred mixture via the addition funnel over an additional 5-min period. After this addition, the mixture was heated to 60 0C and stirred for 3 h, to give crude intermediate 7. HPLC analysis (area%) indicated crude 7 is a mixture of 7 (40.5%), 8 (1.7 %), 6 (24.1%), and the rest of unknowns (33.7%). MS: 598 (MH)+. The coupled crude product 7 was carried on to the next step without isolation.

Removal of the Fluoroborate Ester The above stirred reaction mixture containing 7 was treated in the same flask with EtOH (6.80 L) and Et3N (299 mL, 2.147 mol) under N2 at 60 0C. The amber solution was heated to reflux at 72 0C for 2 h and cooled to 20 0C. The reaction mixture was poured into a rapidly stirred 22-L 4-neck round bottom flask containing a 1 : 1 (v/v) ice-water mixture (8.0 L) over a 10-min period; stirring was continued for -10 min. Cold 1 NHCl (4.0 L) was added to the solution over 20 min to adjust the pH from 9-10 to 3; stirring was continued for an additional 20 min at 0 0C. The yellow solid was isolated by filtration and dried in a filter funnel by air-suction using house vacuum (-160 mm Hg) at 20 0C for 20 h to afford 1,889.0 g of crude 8 as a damp solid (HPLC = 33.6%, area%).

Purification of Intermediate 8

To a 22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with crude 8 (1889.0 g), MeCN (3.6 L) and EtOH (3.2 L). The suspension was heated to reflux (76 0C), while D.I. H2O (500 mL) was added over 10 min. The solution was stirred at 76 0C for 5 min, and then gradually cooled to 10 0C over 1 h; stirred for an additional hour. The yellow solid was collected by filtration, dried in a vacuum oven under house vacuum (-160 mm Hg) at 60 0C for 20 h to afford 229. Ig (45%) of 8, which was used in next step without further purification. 1H ΝMR of 8 (400 MHz, DMSO-d6): £ 1.02-1.10 (m, 2 H), 1.11-1.19 (m, 2 H), 1.67-1.79 (m, 2 H), 2.34-2.45 (m, 2 H), 3.38-3.49 (m, 2 H), 3.78 (s, 3 H), 4.10 (s, 2 H), 4.15-4.26 (m, 1 H), 4.54 (d, J= 21.0 Hz, 1 H), 7.72 (d, J= 9.1 Hz, 1 H), 7.81 (s, 4 H), 8.71 (s, I H), 14.98 (s, 1 H). MS: 550 (MH)+.

Step 6: Preparation of 7-[3-(2-amino-l-fluoro-ethylidene)-piperidin-l-yl]-l- cyclopropyl-6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (10)

Figure imgf000048_0001

8 10 A

22-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel and a nitrogen inlet adapter was charged with 8 (253.6 g, 0.462 mol) and MeOH (5.10 L). This suspension was stirred at 20 0C under N2 and H2NNH2 (86.9 mL, 2.796 mol) was added over a 5-min period. The yellow suspension was heated to 65 0C and refluxed for 1 h. The reaction was cooled to 60 0C and MeCN (3.84 L) was added. The mixture was heated to reflux for 5 min, and then cooled to 20 0C in a water bath. The light-yellow solid was collected by filtration and the filter cake was washed with MeCN (150 mL x 2). The combined filtrate was concentrated at 60 0C affording 322.0 g of crude product 10. This product was recrystallized from a mixture of MeOH (1.0 L) and water (1.195 L) to give 176.6 g (91.2%) of pure product 10 as a light yellow solid.

BASE FORM

1H NMR of 10 (400 MHz, DMSO- d6): £ 1.0-1.09 (m, 2 H), 1.10-1.19 (m, 2 H), 1.66-1.78 (m, 2 H), 2.30-2.41 (m, 2 H), 3.17 (s, 2 H), 3.35 (s, 1 H), 3.36-3. 47 (m, 2 H), 3.74 (s, 3 H), 3.89 (s, 2 H), 4.13-4.22 (m, 1 H), 5.35-6.18 (br, 2 H), 7.74 (d, J= 8.9 Hz, 1 H), 8.69 (s, 1 H).

MS: 420 (MH)+.

 

Example 3

Preparation of7-[3-(2-Amino-l-fluoro-ethylidene)-piperidin-l-yl]-l-cyclopropyl-

6-fluoro-8-methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid hydrogen chloride salt (12)

Figure imgf000049_0001

7-[3-(2-amino-l-fluoro-ethylidene)-piperidin-l-yl]-l-cyclopropyl-6-fluoro-8- methoxy-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (10) was prepared as described in Step 6 of Example 1.

A 5-L 4-neck round bottom flask equipped with an overhead stirrer, thermocouple, condenser, pressure-equalizing addition funnel, and a nitrogen inlet adapter was charged with compound 10 (176.0 g, 0.4196 mol) and EtOH (2.40 L). The suspension was stirred under N2 and cooled to 10 0C with an ice/water bath. A solution of HCl in EtOH (1.25 M, 350 mL) was added via the addition funnel over a 20-min period. After the addition, the reaction was stirred at 10 0C for 5 min. The water bath was replaced with a heating mantle and the solution was heated to 76 0C and stirred for 5 min. The heating mantle was replaced with the water bath, the solution was cooled to 0 0C over 1 h and stirred at this temperature for an additional 1 h. The solid was collected by filtration, washed with ice-cold EtOH (100 mL x 2) and dried at 60 0C under vacuum (~4 mmHg) for 60 h. There was obtained 88.9 g (82%) of HCl salt 12 as an off-white to very light-yellow solid.

 

HCl SALT

1H NMR of HCl salt 12 (400 MHz, CD3CO2D): £ 1.10-1.19 (m, 2 H), 1.29-1.38 (m, 2 H), 1.81-1.93 (m, 2 H), 2.51-2.60 (m, 2 H), 3.48- 3.60 (m, 2 H), 3.86 (s, 3 H), 4.08 (s, 2 H), 4.18 (s, 1 H), 4.19-4.30 (m, 2 H), 7.92 (d, J= 8.6 Hz, 1 H), 8.98 (s, 1 H) 11.65 (s, 1 H).

MS: 420 (MH)+

 

………………………………………

http://www.google.com/patents/WO2013045599A1?cl=en

Experiment 6

Figure imgf000033_0001

(VI) compound (1 ) .HCI

Compound (1) .HCI salt from Compound (Via) :

9.8 ml (90.6 mmol) of 1-chloroethyl chloro formate are added slowly to a solution of 30 g (82.3 mmol) of compound (E)-(Va) in 165 ml of toluene kept at 0°C. The reaction mixture is stirred 1 hour at room temperature than 1 hour at 80°C and filtered. 24 ml of ethanol and 15.35 ml (90.6 mmol) of 6M HCI solution in isopropanol are added to the filtrate and the resulting mixture is refluxed for 4 hours then cooled to 0°C. The precipitate is filtered, washed with 16 ml of acetone and 16 ml of toluene and dried under vacuum to give 21.94 g of compound (1) . HCI salt. Yield: 86%>.

NMR and MS data are identical to those of the literature.

 

  1. Avarofloxacin nonproprietary drug name

    November 28, 2012. N12/130. STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN (ZZ-145). AVAROFLOXACIN.

  2. [PDF]

    Avarofloxacin hydrochloride nonproprietary drug name

    http://www.ama-assn.org/resources/doc/usan/avarofloxacin-hydrochloride.pdf

     

    WO2006101603A1 Feb 2, 2006 Sep 28, 2006 Janssen Pharmaceutica Nv 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones
    WO2008005670A2 Jun 14, 2007 Jan 10, 2008 Janssen Pharmaceutica Nv One-pot condensation reduction methods for preparing substituted allylic alcohols
    WO2010056633A2 Nov 10, 2009 May 20, 2010 Janssen Pharmaceutica Nv 7-amino alkylidenyl-heterocyclic quinolones and naphthyridones

     


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DR ANTHONY CRASTO

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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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