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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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WO 2018067805, NEW PATENT, SOTAGLIFLOZIN, TEVA


Image result

WO-2018067805

(WO2018067805) SOLID STATE FORMS OF SOTAGLIFLOZIN

TEVA PHARMACEUTICAL INDUSTRIES LTD.

GIAFFREDA, Stefano Luca; (IT).
MODENA, Enrico; (IT).
IANNI, Cristina; (IT).
MUTHUSAMY, Anantha Rajmohan; (IN).
KANNIAH, Sundara Lakshmi; (IN)

Stefano Luca Giaffreda at PolyCrystallineStefano Luca Giaffreda

Enrico Modena at PolyCrystallineEnrico Modena

Sundara Lakshmi KanniahSundara Lakshmi Kanniah
Novel crystalline forms of sotagliflozin (designated as Forms A and E) and their hydrate and monohydrate, processes for their preparation and compositions comprising them are claimed. Also claims are their use for treating diabetes. Sotagliflozin is known to be an inhibitor of sodium glucose transporter-1 and -2, useful for treating insulin dependent diabetes and non-insulin dependent diabetes

Sotagliflozin has the chemical name (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H- pyran-3,4,5-triol. Sotagliflozin has the following chemical structure:

[0003] Sotagliflozin is an orally available L-xyloside based molecule that apparently inhibits both sodium-glucose transporter type 1 (SGLT1) and type 2 (SGLT2). SGLT1 is primarily responsible for glucose and galactose absorption in the gastrointestinal tract, and SGLT2 is responsible for most of the glucose reabsorption performed by the kidney.

[0004] Sotagliflozin is known from WO 2008/109591. Amorphous forms and crystalline forms (i.e. Form 1 and Form 2) of Sotagliflozin are disclosed in WO2010/009197.

[0005] Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single compound, like Sotagliflozin, may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis – “TGA”, or differential scanning calorimetry – “DSC”), powder X-ray diffraction (PXRD) pattern, infrared absorption fingerprint, Raman absorption fingerprint, and solid state (13C-) NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

[0006] Different salts and solid state forms (including solvated forms) of an active pharmaceutical ingredient may possess different properties. Such variations in the properties of different salts and solid state forms and solvates may provide a basis for improving

formulation, for example, by facilitating better processing or handling characteristics, improving the dissolution profile, or improving stability (polymorph as well as chemical stability) and shelf-life. These variations in the properties of different salts and solid state forms may also provide improvements to the final dosage form, for instance, if they serve to improve bioavailability. Different salts and solid state forms and solvates of an active pharmaceutical ingredient may also give rise to a variety of polymorphs or crystalline forms, which may in turn provide additional opportunities to use variations in the properties and characteristics of a solid active pharmaceutical ingredient for providing an improved product.

[0007] Discovering new salts, solid state forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other salts or polymorphic forms. New salts, polymorphic forms and solvates of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product (dissolution profile, bioavailability, etc.). It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity or polymorphic stability which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms (including solvated forms) of Sotagliflozin.

EXAMPLES

Sotagliflozin Form-2 may be prepared according to WO2010/009197. Sotaglifiozin Form-2 may also be prepared according to Example 16 below.

Working examples:

Example- 1 : Preparation of Sotagliflozin (Amorphous Form)

[0080] 2 g of Sotagliflozin (Form-2) was taken in 250ml round bottom flask and applied vacuum (approx. 50 mbar) with continuous rotation of the flask. The flask was externally heated by hot air flow maintained at few centimetres from the rotating flask wall for few minutes until the compound melts at around 130°C and the melt was quenched to room temperature (25°C) with water bath. The amorphous solid (1.8 g) was scratched from the walls of the flask.

Example-2: Preparation of Sotagliflozin Form A

[0081] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of water, was left at variable temperature as follows: heating from 10°C to 50°C at the rate of 20°C/hr, held at 50°C for 3 hrs; cooling from 50°C to 10°C at the rate of 20°C/hr, held at 10°C for 3hrs; again heating from 10°C to 50°C at the rate of 10°C/hr, held at 50°C for 3hrs; again cooling from 50°C to 10°C at the rate of 10°C/hr, held at 10°Cfor 3hrs; further heating from 10°C to 50°C at the rate of 5°C/hr, held at 50°C for 3hrs; further cooling from 50°C to 10°C at the rate of 5°C/hr, held at 10°C for 3hrs; followed by raising the temperature from 10°C to 25°C at the rate of 10°C/hr, held at 25°C for 24hrs. The suspension was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form A has been confirmed by PXRD as presented in figure 1.

Example-3 : Preparation of Sotagliflozin Form B

[0082] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Toluene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD as presented in figure 2.

Example-4: Preparation of Sotagliflozin Form B

[0083] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Heptane at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-5 : Preparation of Sotagliflozin Form B

[0084] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Mesitylene at room temperature (20-25°C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-6: Preparation of Sotagliflozin Form B

[0085] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of p-Xylene at room temperature (20-25 °C). The suspension was stirred for 15days which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form B has been confirmed by PXRD.

Example-7: Preparation of Sotagliflozin Form C

[0086] 100 mg of Sotagliflozin (Amorphous form, prepared according to example 1) was suspended in 2 ml of Water at 50°C. The suspension was stirred for 72hrs which was filtered under vacuum and was dried at room temperature by vacuum suction. Sotagliflozin Form C has been confirmed by PXRD as presented in figure 3.

Example-8: Preparation of Sotagliflozin Form D

[0087] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of ethanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20 ml vial and left open to allow evaporation of the solvent (25°C/1 atm). Solid was observed after 3 days; it was collected and analyzed by PXRD. Sotagliflozin Form D has been confirmed by PXRD as presented in figure 4.

Example-9: Preparation of Sotagliflozin Form E

[0088] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of isopropyl acetate. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. The crystals were observed after 9 days; it was collected and analyzed by PXRD. Sotagliflozin Form E has been confirmed by PXRD as presented in figure 5.

Example-9: Preparation of Sotagliflozin Form F

[0089] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 2-propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened to allow evaporation of the solvent (4-7°C/l atm). The crystals were observed after 13 days; it was collected and analyzed by PXRD. Sotagliflozin Form F has been confirmed by PXRD as presented in figure 6.

Example- 10: Preparation of Sotagliflozin Form G

[0090] 30 mg of Sotagliflozin (Form-2) was dissolved in 3ml of 1 -propanol. The solution was stirred at 25°C for lhr (for dissolution) and then filtered. The solution was kept in a 20ml vial and left opened in the refrigerator (4-7°C/l atm) to allow evaporation of the solvent. Solid was observed after 24 days; it was collected and analyzed by PXRD.

Sotagliflozin Form G has been confirmed by PXRD as presented in figure 7.

Example- 11 : Preparation of Sotagliflozin Form H

[0091] 15 mg of Sotagliflozin (Form- A) was kept in DVS (dynamic vapor sorption) instrument. The kinetic sorption measurement was performed at 25 °C in two full cycle of sorption and desorption as follows, from 40%RH to 90%RH, 90%RH to 0%RH then again from 0% to 90%RH, 90%RH to 0%RH. After completion of experiment, the powder was collected and analyzed by PXRD. Sotagliflozin Form H has been confirmed by PXRD as presented in figure 8.

Example- 12: Preparation of Sotagliflozin Form I

[0092] Procedure to prepare saturated solution: 1500 mg of Sotagliflozin were dissolved in 1ml of 2-Methoxyethanol and the solution was stirred overnight at 25°C; the solution was then filtered. Taken ΙΟΟμί from above saturated stock solution, 500μί of Diisopropylether was added drop by drop, no solid was observed left the solution overnight under stirring, added again 500μί of Diisopropylether into the entire solution. The solid was precipitated, stirred for 30min and filtered under vacuum. Sotagliflozin Form I has been confirmed by PXRD as presented in figure 9.

Example-13: Preparation of Sotagliflozin Form K

[0093] 10-20mg of Sotagliflozin (Form D) was kept for drying in a natural air convection oven (MPM instruments modelM40-VN) at 60°C for lh. Sotagliflozin Form K has been confirmed by PXRD as presented in figure 10.

Example-14: Preparation of Sotagliflozin Form E:

[0094] Sotagliflozin (2g) and ethyl acetate (6ml) were heated to reflux temperature (71-74°C). Heptane (6ml) was added at reflux, reaction mass was stirred for additional 15 minutes and then cooled to room temperature. Solid was precipitated out during cooling at about 57°C. A mixture of ethyl acetate and heptane (1 : 1 v/v, 24 ml) was added and the reaction mixture was heated to reflux temperature (71-74°C) to obtain a clear solution which was maintained for 15 minutes. Reaction mass was cooled to room temperature (25-30°C) and stirred for 3 hours. The slurry was filtered, washed with a mixture of ethyl acetate and heptane (l : lv/v, 8ml) and dried under vacuum at 50°C for 2Hrs. The obtained solid (1.8g) was analyzed by PXRD-Form E.

Example-15: Preparation of Sotagliflozin Form D:

[0095] 2g of sotagliflozin Form F was kept in glass petri-dish and exposed to 80%RH for 60hrs at room temperature. Solid was collected (2g) and analyzed for PXRD-Form D.

Example-16: Preparation of Sotagliflozin Form 2:

[0096] 50 gm of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(Methylthio) tetrahydro-2H-pyran-3,4,5-triyl triacetate (SOT-1) and 500ml of methanol were charged in round bottom flask, the slurry was cooled to 20°C then added sodium methoxide solution prepared in methanol (2.45gm of sodium methoxide in 50ml of methanol) at 20°C

over the period of 10 min and stirred the mass for 2hr at 20°C.The reaction completion was ensured by HPLC. Once the reaction is completed added 2.5gm Norit carbon to the reaction mass at 23°C and stirred for 30min. Filtered the reaction mass through Hyflo bed and washed with 20ml of methanol. Taken the filtrate into the flask and concentrated under vacuum at 45°C up to 3 volumes with respect to SOT-1 then cooled to 21°C over the period of 60 min, added 560ml of Water at 21°C over the period of 30min and stirred for 30min at 21 °C, the reaction mass left overnight (without stirring) and stirred for lhr. The obtained slurry was filtered under vacuum and washed with 55ml*3times of water then kept for suction at 20-30°C for 30min. The material was dried at 50-60°C for 9hrs under vacuum to obtain 35gm of Sotagliflozin. 5.7gm of Sotagliflozin (5.7gr, Sotagliflozin) and 28.5ml of Methyl ethyl ketone (28.5ml) were charged in round bottom flask, the slurry was stirred at 22-25°C for 5-10min gradually raised the temperature to 78°C then added 114 ml of n-Heptane (114ml) at 78°C over the period of 55min. Once the addition of n-heptane was completed, seeds of Form-2 (20 mg) were added, the slurry was gradually cooled down to 25-27°C over the period of 60 min. The obtained slurry was stirred for 2-3hrs at 25-27°C and the mass was kept overnight (without stirring) at 25-27°C then stirred for 3hr at 23 °C. The mass was filtered under vacuum and washed with 10ml of n-Heptane then kept for suction for 30min at 25-30°C. The material was dried at 50°C for 2hrs under vacuum to obtain Form-2 of Sotagliflozin.

Preparation of Form 2- Seeds

[0097] Sotagliflozin (2gr, amorphous) was dissolved in methyl ethyl ketone (10ml) The slurry was heated to 80°C, then n-Heptane (40ml) was added over 60mins. The hazy solution was cooled to 20-30° over 60mins and stirred for 3hr. The slurry was kept overnight at 20-30°C (without stirring). The obtained slurry was filtered under vacuum and washed with n-Heptane (10ml) . The material was dried at 50 °C for 4hrs under vacuum to obtain the 1.9gm of Sotagliflozin Form -2 as confirmed by PXRD.

///////////WO 2018067805, NEW PATENT,  SOTAGLIFLOZIN, TEVA

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Sotagliflozin, LX 4211 in phase 2 For type 1, 2 diabetes


ChemSpider 2D Image | LX4211 | C21H25ClO5S

LX 4211, Sotagliflozin, LP-802034 , lex 1287 

UNII-6B4ZBS263Y

Methyl (5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-thio-beta-L-xylopyranoside

β-L-Xylopyranoside, methyl 5-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-thio-, (5S)-

 (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol,

(5S)-Methyl 5-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-1-thio-beta-L-xylopyranoside

1018899-04-1

C21H25ClO5S, 424.94, LP-802034  

LX-4211 is a dual SGLT2/1 inhibitor; Antidiabetic agents.

LX-4211 is a SGLT-2 inhibitor being evaluated in phase II clinical studies at Lexicon Pharmaceuticals for the oral treatment of type 2 diabetes.

Summary

  • Co-administration of LX4211 led to a nearly one-third reduction in mealtime insulin for Type 1 diabetics.
  • Although there was no reduction in basal insulin use, the LX4211 group saw better glucose control, lower HbA1c, and weight loss.
  • Partnering LX4211 is still management’s top priority but independent development in Type 1 diabetes is at least an option.

Lexicon Pharmaceuticals (LXRX) continues to generate data on its SGLT-1/2 inhibitor LX4211 that suggest this is an effective and promising medication for treating not only Type 2 diabetes (the common target for non-insulin medications for diabetes), but also Type 1 as well. Lexicon’s most recent update, a small short-term Phase II study in Type 1 diabetics is certainly a positive update, but it’s not what investors really want to see. Lexicon still needs to find a development partner for LX4211 and the ongoing delays don’t help sentiment or the long-term prospects for the drug.

A Potentially Meaningful Addition To Type 1 Care

On Monday morning, Lexicon released top-line data from a small (33-patient) Phase II study of LX4211 in Type 1 diabetics on insulin. The results support the notion that SGLT inhibition can play a valuable role in improving glucose control for Type 1 diabetics.

This small study enrolled generally well-controlled patients (HbA1c levels ranging from 7 to 9, with an average of 7.9) and the addition of LX4211 led to 32% reduction in bolus (mealtime) insulin versus a 6% reduction in the placebo group. Even with the lower bolus insulin, patients in the LX4211 group showed a 0.55% reduction in HbA1c versus a 0.06% reduction in the placebo group. Patients taking LX4211 demonstrated better glucose control (more time spent in the target range of 70-180 mg/dL) and saw a 1.7kg weight loss versus a 0.5kg weight gain in the placebo group

……………………..

 Scheme 1 :

Figure imgf000018_0001
Figure imgf000018_0002
 Scheme 2:
Figure imgf000019_0001
Scheme 3:
Figure imgf000019_0002

3(a) 3(b)

Figure imgf000019_0003
 Scheme 4:
Figure imgf000020_0001

4(a) 4(b)

Figure imgf000020_0002

Scheme 3:

Figure US20090030198A1-20090129-C00011

…………………

http://www.google.com/patents/EP2332947A1?cl=en

EXAMPLES

    • Aspects of this invention can be understood from the following examples.

6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone

    • To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24°C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)δ1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 – 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) δ26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73.
    • To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20°C. The mixture was cooled to 0-5°C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20°C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), δ 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
    • To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20°C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20°C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

6.2. Alternative synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahvdrofuro[2.3-d][1,3]dioxol-5-yl)(morpholino)methanone

    • A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO4 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO4 (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0L, approximate 6% household grade) was mixed with the K2HPO4 solution. Approximately 20% of the NaClO2 solution (1.6 L) and bleach/K2HPO4 solution (400 mL),∼1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO2 solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPO4 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25°C. Additional charges of TEMPO (14.3g, 0.5 mol%) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to < 10°C and quenched with Na2SO3 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3PO4 until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15°C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L x 3). The combined organic layer was concentrated under vacuo (∼100-120 torr) at < 35°C (28-32°C vapor, 45-50°C bath) to low volume (- 6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached < 1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5°C and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) δ5.96 (d, J = 3.6 Hz, 1H), 4.5 8 (d, J = 3.6 Hz, 1H), 4.53 (d, J =3.2Hz,1H), 4.30 (d, J= 3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) 8 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25. 1.
    • The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (-80 L) to remove excess morpholine. When final volume reached -12 L, heptane (14 L) was added slowly at 60-70°C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97% pure, 98% yield). m.p.: 136°C (DSC). 1H NMR (CDCl3), δ 6.02 (d, J = 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). 13C NMR (methanol-d4) δ 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.

1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene:

Figure US20090030198A1-20090129-C00019

6.3. Synthesis of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene

    • A 2L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with 2-chloro-5-iodobenzoic acid (199.41 g, 0.706 mol), dichloromethane (1.2L, KF = 0.003 wt% water) and the suspension was set stirring at ambient temperature. Then N,N-dimethylformamide (0.6 mL, 1.1 mol %) was added followed by oxalyl chloride (63 mL, 0.722 mol, 1.02 equiv) which was added over 11 min. The reaction was allowed to stir at ambient overnight and became a solution. After 18.75hours, additional oxalyl chloride (6 mL, 0.069 mol, 0.10 equiv) was added to consume unreacted starting material. After 2 hours, the reaction mixture was concentrated in vacuo to afford crude 2-chloro-5-iodobenzoyl chloride as a pale yellow foam which will be carried forward to the next step.
    • A jacketed 2L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF = 0.003 wt% water) and the suspension was set stirring under nitrogen and was cooled to about 6°C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9°C. The resulting orange solution was diluted with dichloromethane (75mL) and was cooled to -7°C. Then a solution of 2-chloro-5-iodobenzoyl chloride (≤ 0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3°C. The reaction mixture was warmed slightly and held at +5°C for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450mL pre-cooled (∼5°C) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10min with internal temperature remaining below 28°C. The quenched biphasic mixture was stirred at 20°C for 45min and the lower organic phase was washed with 1N aq. HCl (200mL), twice with saturated aq sodium bicarbonate (200mL per wash), and with saturated aq sodium chloride (200mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93g, 99.0 area% by HPLC at 220nm, 1.0 area% regioisomer at 200nm, 98.5 % “as-is” yield).
    • A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300mL, KF = 0.004 wt% water) and the suspension was set stirring under nitrogen and was cooled to about 5°C.Then triethylsilane (28mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24mL, 194.46mmo1,2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150mL) followed by saturated aq sodium bicarbonate (150mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq sodium bicarbonate (100 mL), and with saturated aq sodium chloride (50mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45°C was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45°C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220nm, 97.4 % “as-is” yield).

6.4. Synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2,3-d][1,3]dioxol-5-yl)methanone

    • To a solution of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (500mag, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5°C, and the mixture was stirred for 1.5 h at 0-5°C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5°C and the mixture was kept stirring for 1h, warmed to 20°C and stirred at 20°C for 2 hours. The reaction was quenched with saturated aq NH4CI, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76%) as a white solid. 1H NMR (CDCl3) δ 7. 88 (dd, J= 8.4, 2.0 Hz, 1H), 7.82 (d, J= 2.0 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.12 (d, J= 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.07 (d, J = 3.2 Hz, 1H), 5.21 (d, J = 3.2 Hz, 1H), 4.58 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 3.2 Hz, 1H), 4.16 (d, J = 7.2 Hz, 2H), 4.03 (q, J = 7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H), 1.37 (s, 3H).

6.5. Alternative synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone

    • To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4X to the morpholinoamide) at room temperature and cooled to -5°C. To the above solution was added dropwise a solution of i-PrMgCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at -5°C over 3 hours. This Grignard solution was used in the ketone formation below.
    • [0055]
      To a 50 L reactor equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity = 97 wt%, 2.01 kg, 7.34 mol) and THF (11 L, 5.5X) at room temperature and stirred for 45 minutes at room temperature and for 15 minutes at 30°C. The homogeneous solution was then cooled to – 25°C. To this solution was added a solution of t-BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at -25°C over 3 hours. Then the above Grignard solution was added to this solution at -20 over 41 minutes. The resulting solution was further stirred at -20°C before quench. The reaction mixture was added to 10 wt% aqueous NH4Cl (10 L, 5X) at 0°C with vigorous stirring, and stirred for 30 minutes at 0°C. To this mixture was added slowly 6 N HCl (4 L, 2X) at 0°C to obtain a clear solution and stirred for 30 minutes at 10°C. After phase split, the organic layer was washed with 25 wt% aq NaCl (5 L, 2.5X). Then the organic layer was concentrated to a 3X solution under the conditions (200 mbar, bath temp 50°C). EtOAc (24 L, 12X) was added, and evaporated to a 3X solution under the conditions (150 mbar, bath temp 50°C). After removed solids by a polish filtration, EtOAc (4 L, 2X) was added and concentrated to dryness (150 mbar, bath temp 50°C). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet. After EtOAc was added, the suspension was heated at 70°C to obtain a 2.5X homogeneous solution. To the resulting homogeneous solution was added slowly heptane (5 L, 2.5X) at the same temperature. A homogeneous solution was seeded and heptane (15 L, 7.5X) was added slowly to a little cloudy solution at 70°C. After stirred for 0.5 h at 70°C, the suspension was slowly cooled to 60°C and stirred for 1 h at 60°C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4X), dried under vacuum at 45°C to give the desired ketone as fluffy solids (2.57 kg, 100 wt% by HPLC, purity-adjusted yield: 81%).

(2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate:

Figure US20090030198A1-20090129-C00010

6.6. Synthesis of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

    • To a solution of the ketone (4-chloro-3-(4-ethoxybenzyl)phenyl)-((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (114.7 g, 0.265 mol) in MeOH (2 L, 17X) was added CeCl3.7H2O (118.5g, 1.2 equiv) and the mixture was stirred at 20°C until all solids were dissolved. The mixture was then cooled to -78°C and NaBH4 (12.03g, 1.2 equiv) was added in portions so that the temperature of the reaction did not exceed -70°C. The mixture was stirred at – 78°C for 1 hour, slowly warmed to 0°C and quenched with saturated aq NH4Cl (550 mL, 5X). The mixture was concentrated under vacuum to remove MeOH and then extracted with EtOAc (1.1L, 10X x2) and washed with brine (550 mL, 5X). The combined organics were concentrated under vacuum to afford the desired alcohol as a colorless oil (crude, 115g). To this colorless oil was added AcOH (650 mL) and H2O (450 mL) and the mixture was heated to 100°C and stirred for 15 hours. The mixture was then cooled to room temperature (20°C) and concentrated under vacuum to give a yellow oil (crude, ∼118 g). To this crude oil was added pyridine (500 mL) and the mixture was cooled to 0°C. Then, Ac2O (195 mL, -8.0 equiv) was added and the mixture was warmed to 20°C and stirred at 20°C for 2h. The reaction was quenched with H2O (500 mL) and diluted with EtOAc (1000 mL). The organic layer was separated and concentrated under vacuum to remove EtOAc and pyridine. The residue was diluted with EtOAc (1000 mL) and washed with aq NaHSO4 (1N, 500 mL, x2) and brine (300 mL). The organic layer was concentrated to afford the desired tetraacetate intermediate as a yellow foam (-133g).
    • To a solution of tetraacetate (133 g, 0.237 mol assuming pure) and thiourea (36.1, 2.0 equiv) in dioxane (530 mL, 4X) was added trimethylsilyl trifluoromethanesulfonate (TMSOTf) (64.5 mL, 1.5 equiv) and the reaction mixture was heated to 80°C for 3.5 hours. The mixture was cooled to 20°C and Mel (37 mL, 2.5 equiv) and N,N-diisopropylethylamine (DiPEA) (207 mL, 5.0 equiv) was added and the mixture was stirred at 20°C for 3h. The mixture was then diluted with methyl tertiary-butyl ether (MTBE) (1.3 L, 10X) and washed with H2O (650 mL, 5X x2). The organic layer was separated and concentrated under vacuum to give a yellow solid. To this yellow solid was added MeOH (650 mL, 5X) and the mixture was reslurried at 60°C for 2h and then cooled to 0°C and stirred at 0°C for 1 hour. The mixture was filtered and the cake was washed with MeOH (0°C, 70 mL, x3). The cake was dried under vacuum at 45°C overnight to afford the desired triacetate (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (88 g, 60% over 4 steps) as a pale yellow solid. 1H NMR (CDCl3) δ 7.37 (d, J= 8.0 Hz, 1H), 7.20 (dd, J= 8.0, 2.0 Hz, 1H), 7.07 (m, 2H), 6.85 (m, 2H), 5.32 (t, J = 9.6 Hz, 1H), 5.20 (t, J = 9.6 Hz, 1H), 5.05 (t, J= 9.6 Hz, 1H), 4.51 (d, J=9.6Hz, 1H), 4.38 (d, J= 9.6Hz, 1h), 4.04 (m, 2H), 2.17 (s, 3H), 2.11 (s, 3H), 2.02 (s, 3H), 1.73 (s, 3H), 1.42 (t, J= 7.2 Hz, 3H).

6.7. Alternative synthesis of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

    • To a 50 L reactor under nitrogen atmosphere, 40 L MeOH was charged, followed with the ketone (2.50 kg, 5.78 mol) and CeCl3.7H2O (2.16 kg, 1.0 equiv). Methanol (7.5 L) was added as rinse (totally 47.5 L, 19X). A freshly prepared solution of NaBH4 (87.5 g, 0.4 equiv) in aqueous 1 N NaOH (250 mL) was added slowly (35 min) at 15-25°C. The mixture was then stirred for 15 min. HPLC analysis of the reaction mixture showed approximately 90:10 diastereomeric ratio. The reaction was quenched with 10 wt% aq NH4Cl (2.5 L, 1X) and the mixture was concentrated under vacuum to 5X, diluted with water (10 L, 4X) and MTBE (12.5L, 5X). The mixture was cooled to 10°C and 6 N aq HCl was added until the pH of the mixture reached 2.0. Stirring was continued for 10 minutes and the layers were separated. The organic layer was washed with H2O (5L, 2X). The combined aqueous layer was extracted with MTBE (12.5 L, 5X). The combined organic layers were washed with brine (2.5 L, 1X) and concentrated under vacuum to 3X. MeCN (15 L, 6X) was added. The mixture was concentrated again to 10 L (4X) and any solid residue was removed by a polish filtration. The cake was washed with minimal amount of MeCN.
    • The organic filtrate was transferred to 50 L reactor, and a pre-prepared 20 mol% aqueous H2SO4 solution (61.8 mL 98% concentrated H2SO4 and 5 L H2O) was added. The mixture was heated to 80°C for 2 hours and then cooled to 20°C. The reaction was quenched with a solution of saturated aqueous K2CO3 (5 L, 2X) and diluted with MTBE (15 L, 6X). The organic layer was separated, washed with brine (5 L, 2X) and concentrated under vacuum to 5 L (2X). MeCN (12.5 L, 5X) was added and the mixture was concentrated to 7.5 L (3X).
    • The above MeCN solution of (3S,4R,SR,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2,3,4,5-tetraol was cooled to 10°C, added with dimethylaminopyridine (17.53 g, 2.5 mol%), followed by slow addition of acetic anhydride (3.23 L, 6.0 equiv) and triethylamine (5 L, 2X, 6.0 equiv) so that the temperature of the mixture was kept below 20°C. The reaction was then warmed to 20°C and stirred for 1 hour and diluted with MTBE (15 L, 6X). The mixture was slowly quenched with water (7.5 L, 3X). The organic layer was separated and washed with saturated aqueous KHCO3 (5L, 2X), 1 N NaHSO4 (5 L, 2X), and brine (5 L, 2X) in sequence.
    • The organic layer was then concentrated under vacuum to 5 L (2X). MeCN (12.5 L, 5X) was added and the solution was concentrated to 7.5 L (3X) (KF = 0.08%). Dioxane (12.5 L, 5X) was added and the solution was concentrated to 7.50 L (3X) (KF = 0.02%). Any residual solid was removed by a polish filtration and the cake was washed with minimal amount of dioxane (500 mL).
    • To the above filtrate was added thiourea (880 g, 2.0 equiv) and TMSOTf (1.57 L, 1.5 equiv). The reaction mixture was heated to 80°C for 3 hours (>97% conversion). The mixture was cooled to 20°C and methyl iodide (541 mL, 1.5 equiv) and diethylisopropylamine (3.02 L, 3.0 equiv) were added and the mixture was stirred at 20°C for 18 hours. An extra methyl iodide charge (90 mL, 0.25 equiv) was added and the mixture was stirred at 20°C for 1 hours. The mixture was then diluted with MTBE (25 L, 10X) and washed with water (12.5 L, 5X x2). The organic layer was separated and concentrated under vacuum to -5 L (2X). MeOH (12.5 L, 5X) was added and the mixture was concentrated to 5X to afford a slurry. The mixture was then heated at 60°C for 1 hour and cooled to 0°C and stirred at 0°C for 1 hour. The mixture was filtered and the cake was washed with MeOH (0°C, 2.5 L, 1X x2, 1.0 L, 0.4X). The cake was dried under vacuum at 45°C overnight to afford the desired triacetate (1.49 kg, 47% over 4 steps) as a pale yellow/off-white solid.

6.8. Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

  • To a slurry of (2S,3S,4R,SS,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (90.0 g, 0.164mo1) in MeOH (900 mL, 10X) was added NaOMe in MeOH (25 wt%, 18 mL, 0.2X) at 20°C and the mixture was stirred at 20°C for 2 hours until all solids disappeared. The mixture was then concentrated to 300 mL, added to H2O (1L) and stirred for 1 hour. The solid was filtered and washed with H2O (100 mL, x3) and the cake was dried under vacuum at 45°C overnight to afford the desired methyl thiolate (67.0g, 95%). 1H NMR (CDCl3) δ 7.38 (d, J = 8.4 Hz, 1H), 7.22 (m, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.35 (d, J = 9.6 Hz, 1H), 4.15 (d, J = 9.6 Hz, 1H), 4.10-3.95 (m, 3H), 3.64 (t, J = 8.8 Hz, 1H), 3.50 (m, 2H), 3.42 (br s, 1H), 2.95 (br s, 1H), 2.57 (br s, 1H), 2.17 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).

…………

http://www.google.com/patents/WO2010009197A1?cl=en

(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H- pyran-3,4,5-triol:

Figure imgf000003_0001

LEX-1287 The compound is an inhibitor of the sodium glucose co-transporter 2, and may be useful in the treatment of diabetes and a variety of other diseases and conditions. See U.S. patent application no. 11/862,690, filed September 28, 2007.

6.8. Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4- ethoxybenzyl)phenyl)-6-fmethylthio)tetrahydro-2H-pyran-3,4,5-triol To a slurry of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-

(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (90.0 g, 0.164mol) in MeOH (900 mL, 10X) was added NaOMe in MeOH (25 wt%, 18 mL, 0.2X) at 200C and the mixture was stirred at 200C for 2 hours until all solids disappeared. The mixture was then

18

LEX-1287 concentrated to 300 mL, added to H2O (IL) and stirred for 1 hour. The solid was filtered and washed with H2O (100 mL, x3) and the cake was dried under vacuum at 45°C overnight to afford the desired methyl thiolate (67.Og, 95%). IH NMR (CDC13) δ 7.38 (d, J = 8.4 Hz, IH), 7.22 (m, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 4.35 (d, J = 9.6 Hz, IH), 4.15 (d, J = 9.6 Hz, IH), 4.10-3.95 (m, 3H), 3.64 (t, J = 8.8 Hz, IH), 3.50 (m, 2H), 3.42 (br s, IH), 2.95 (br s, IH), 2.57 (br s, IH), 2.17 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).

2D chemical structure of 1018899-04-1

6.9. Preparation of Crystalline Anhydrous (2S,3R,4R,5S,6R)-2-(4-chloro-

3-f4-ethoxybenzyl)phenyl)-6-fmethylthio)tetrahydro-2H-pyran- 3,4,5-triol Form 1

Under slightly positive nitrogen pressure, to a 50 L reactor was charged MeOH (12 L) and the triacetate (1.70 Kg, 3.09 mol). Methanol (5L) was added as a rinse. The slurry was then added NaOMe in MeOH (25 wt%, 340 mL, 0.2X) in 15 minutes at 200C and the mixture was stirred at 200C for 2 hours until all solids disappeared. To the mixture was added slowly water (25.5 L, 15X) in 45 minutes with 5 g seeding (DSC123°C). Solids crashed out and the mixture was stirred at 200C for 1 hour, cooled to 00C and stirred for 30 minutes. The solid was filtered and washed with water (1.7 L, IX, x2) and the cake was dried under vacuum at 45°C overnight to afford the title compound (m.p. ~ 123 0C by DSC peak; 1.28 Kg, 97.7% yield).

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http://www.google.com/patents/US20090030198

Figure US20090030198A1-20090129-C00017

 EXAMPLES

Aspects of this invention can be understood from the following examples, which do not limit its scope.

6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone

Figure US20090030198A1-20090129-C00023

To a 12 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(−)-xylose (504.40 g, 3.360 mol), acetone (5 L, reagent grade) and anhydrous MgSOpowder (811.23 g, 6.740 mol/2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO(50 mL, 0.938 mol/0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24° C. over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH =8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5 S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPOuntil pH=7. The solvent was then evaporated and ethyl acetate (1.25 L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt % water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23 g, 86% yield, 96.7 area % pure by GC). 1H NMR (400 MHz, DMSO-d6) δ 1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93-4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 3C NMR (101 MHz, DMSO-d6) δ 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15×) and H2O (125 mL, 5×) was added NaHCO(33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol %) and TEMPO (0.40 g, 2 mol %) at 20° C. The mixture was cooled to 0-5° C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20° C. for 24h. Methanol (20 mL) was added and the mixture was stirred at 20° C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2×). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12× ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5×) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79%).1H NMR (methanol-d4), δ 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0 g, 24.5 mmol) in THF (100 ML, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20° C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20° C. for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4: 1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).

6.2. Alternative synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone

A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO(0.32 kg, 1.84 mol) and KH2PO(1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO(3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO(2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0 L, approximate 6% household grade) was mixed with the K2HPOsolution. Approximately 20% of the NaClO2solution (1.6 L) and bleach/K2HPOsolution (400 mL, 1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClOsolution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPOsolution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25° C. Additional charges of TEMPO (14.3 g, 0.5 mol %) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to <10° C. and quenched with Na2SO(1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3POuntil pH reached 2.0-2.1 (2.5-2.7 L) at 5-15° C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L ×3). The combined organic layer was concentrated under vacuo (˜100-120 torr) at <35° C. (28-32° C. vapor, 45-50° C. bath) to low volume (˜6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached <1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5° C. and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) δ 5.96 (d, J=3.6 Hz, 1H), 4.58 (d, J=3.6 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) δ 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25.1. The morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (7.85 kg, 26.9 mol), morpholine (2.40 L, 27.5 mol) and boric acid (340 g, 5.49 mol, 0.2 eq) were added to toluene (31 L). The resulting slurry was degassed and heated at reflux with a Dean-Stark trap under nitrogen for 12 h and then cooled to room temperature. The mixture was filtered to remove insolubles and the filter cake washed with toluene (5 L). The filtrate was concentrated to about 14 L and flushed with toluene (˜80 L) to remove excess morpholine. When final volume reached 12 L, heptane (14 L) was added slowly at 60-70° C. The resulting slurry was cooled gradually to room temperature and aged for 3 h. It was then filtered and washed with heptane (12 L) and dry under nitrogen gave a slightly pink solid (6.26 kg, 97% pure, 98% yield). m.p.: 136° C. (DSC). 1H NMR (CDCl3), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H). 13C NMR (methanol-d4) δ 26.84, 27.61, 44.24, 47.45, 68.16, 77.14, 81.14, 86.80, 106.87, 113.68, 169.05.

6.3. Synthesis of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene

Figure US20090030198A1-20090129-C00024

A 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with 2-chloro-5-iodobenzoic acid (199.41 g, 0.706 mol), dichloromethane (1.2L, KF=0.003 wt % water) and the suspension was set stirring at ambient temperature. Then N,N-dimethylformamide (0.6 mL, 1.1 mol %) was added followed by oxalyl chloride (63 mL, 0.722 mol, 1.02 equiv) which was added over 11 min. The reaction was allowed to stir at ambient overnight and became a solution. After 18.75hours, additional oxalyl chloride (6 mL, 0.069 mol, 0.10 equiv) was added to consume unreacted starting material. After 2 hours, the reaction mixture was concentrated in vacuo to afford crude 2-chloro-5-iodobenzoyl chloride as a pale yellow foam which will be carried forward to the next step. A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to −7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (<0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area % by HPLC at 220 nm, 1.0 area % regioisomer at 200 nm, 98.5 % “as-is” yield). A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4 % “as-is” yield).

6.4. Synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2,3-d][1,3]dioxol-5-yl)methanone

Figure US20090030198A1-20090129-C00025

To a solution of 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene (500 mg, 1.34 mmol) in THF (5.0 mL) was added i-PrMgCl (2.0M in THF, 1.0 mL, 2.00 mmol) at 0-5° C., and the mixture was stirred for 1.5 h at 0-5° C. A solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (146.5 mg, 0.536 mmol) in THF (1.0 mL) was added dropwise at 0-5° C. and the mixture was kept stirring for 1 h, warmed to 20° C. and stirred at 20° C. for 2 hours. The reaction was quenched with saturated aq NH4Cl, extracted with MTBE, washed with brine. The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (178 mg, 76%) as a white solid. 1H NMR (CDCl3) δ 7.88 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=2.0 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 6.07 (d, J=3.2 Hz, 1H), 5.21 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 4.56 (d, J=3.2 Hz, 1H), 4.16 (d, J=7.2 Hz, 2H), 4.03 (q, J=7.2 Hz, 2H), 1.54 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.37 (s, 3H).

6.5. Alternative synthesis of (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d]1,3]dioxol-5-yl)methanone

To a 20 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet was charged with the iodide (3.00 kg, 8.05 mol) and THF (8 L, 4× to the morpholinoamide) at room temperature and cooled to −5° C. To the above solution was added dropwise a solution of i-PrMgCl in THF (Aldrich 2 M, 4.39 L, 8.82 mol) at −5° C. over 3 hours. This Grignard solution was used in the ketone formation below. To a 50 L reactor equipped with a mechanical stirrer, a temperature controller, and a nitrogen inlet was charged the morpholinoamide (HPLC purity=97 wt %, 2.01 kg, 7.34 mol) and THF (11 L, 5.5×) at room temperature and stirred for 45 minutes at room temperature and for 15 minutes at 30° C. The homogeneous solution was then cooled to −25° C. To this solution was added a solution of t-BuMgCl in THF (Aldrich 1 M, 7.32 L, 7.91 mol) at −25° C. over 3 hours. Then the above Grignard solution was added to this solution at −20 over 41 minutes. The resulting solution was further stirred at −20° C. before quench. The reaction mixture was added to 10 wt % aqueous NH4Cl (10 L, 5×) at 0° C. with vigorous stirring, and stirred for 30 minutes at 0° C. To this mixture was added slowly 6 N HCl (4 L, 2×) at 0° C. to obtain a clear solution and stirred for 30 minutes at 10° C. After phase split, the organic layer was washed with 25 wt % aq NaCl (5 L, 2.5×). Then the organic layer was concentrated to a 3× solution under the conditions (200 mbar, bath temp 50° C.). EtOAc (24 L, 12×) was added, and evaporated to a 3× solution under the conditions (150 mbar, bath temp 50° C.). After removed solids by a polish filtration, EtOAc (4 L, 2×) was added and concentrated to dryness (150 mbar, bath temp 50° C.). The wet cake was then transferred to a 50 L reactor equipped with a mechanical stirrer, a temperature controller and a nitrogen inlet. After EtOAc was added, the suspension was heated at 70° C. to obtain a 2.5× homogeneous solution. To the resulting homogeneous solution was added slowly heptane (5 L, 2.5×) at the same temperature. A homogeneous solution was seeded and heptane (15 L, 7.5×) was added slowly to a little cloudy solution at 70° C. After stirred for 0.5 h at 70° C., the suspension was slowly cooled to 60° C. and stirred for 1 h at 60° C. The suspension was then slowly cool to room temperature and stirred for 14 h at the same temperature. The crystals were collected and washed with heptane (8 L, 4×), dried under vacuum at 45° C. to give the desired ketone as fluffy solids (2.57 kg, 100 wt % by HPLC, purity-adjusted yield: 81%).

6.6. Synthesis of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

Figure US20090030198A1-20090129-C00026

To a solution of the ketone (4-chloro-3-(4-ethoxybenzyl)phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (114.7 g, 0.265 mol) in MeOH (2 L, 17×) was added CeCl3.7H2O (118.5 g, 1.2 equiv) and the mixture was stirred at 20° C. until all solids were dissolved. The mixture was then cooled to −78° C. and NaBH(12.03 g, 1.2 equiv) was added in portions so that the temperature of the reaction did not exceed −70° C. The mixture was stirred at −78° C. for 1 hour, slowly warmed to 0° C. and quenched with saturated aq NH4Cl (550 mL, 5×). The mixture was concentrated under vacuum to remove MeOH and then extracted with EtOAc (1.1 L, 10× ×2) and washed with brine (550 mL, 5×). The combined organics were concentrated under vacuum to afford the desired alcohol as a colorless oil (crude, 115 g). To this colorless oil was added AcOH (650 mL) and H2O (450 mL) and the mixture was heated to 100° C. and stirred for 15 hours. The mixture was then cooled to room temperature (20° C.) and concentrated under vacuum to give a yellow oil (crude, 118 g). To this crude oil was added pyridine (500 mL) and the mixture was cooled to 0° C. Then, Ac2O (195 mL, ˜8.0 equiv) was added and the mixture was warmed to 20° C. and stirred at 20° C. for 2 h. The reaction was quenched with H2O (500 mL) and diluted with EtOAc (1000 mL). The organic layer was separated and concentrated under vacuum to remove EtOAc and pyridine. The residue was diluted with EtOAc (1000 mL) and washed with aq NaHSO(1N, 500 mL, ×2) and brine (300 mL). The organic layer was concentrated to afford the desired tetraacetate intermediate as a yellow foam (˜133 g). To a solution of tetraacetate (133 g, 0.237 mol assuming pure) and thiourea (36.1, 2.0 equiv) in dioxane (530 mL, 4×) was added trimethylsilyl trifluoromethanesulfonate (TMSOTf) (64.5 mL, 1.5 equiv) and the reaction mixture was heated to 80° C. for 3.5 hours. The mixture was cooled to 20° C. and MeI (37 mL, 2.5 equiv) and N,N-diisopropylethylamine (DiPEA) (207 mL, 5.0 equiv) was added and the mixture was stirred at 20° C. for 3 h. The mixture was then diluted with methyl tertiary-butyl ether (MTBE) (1. 3 L, 10×) and washed with H2O (650 mL, 5× ×2). The organic layer was separated and concentrated under vacuum to give a yellow solid. To this yellow solid was added MeOH (650 mL, 5×) and the mixture was reslurried at 60° C. for 2 h and then cooled to 0C and stirred at 0° C. for 1 hour. The mixture was filtered and the cake was washed with MeOH (0° C., 70 mL, ×3). The cake was dried under vacuum at 45° C. overnight to afford the desired triacetate (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (88 g, 60% over 4 steps) as a pale yellow solid. 1H NMR (CDCl3) 6 7.37 (d, J=8.0 Hz, 1H), 7.20 (dd, J=8.0, 2.0 Hz, 1H), 7.07 (m, 2H), 6.85 (m, 2H), 5.32 (t, J=9.6 Hz, 1H), 5.20 (t, J=9.6 Hz, 1H), 5.05 (t, J =9.6 Hz, 1H), 4.51 (d, J =9.6 Hz, 1H), 4.38 (d, J=9.6 Hz, 1h), 4.04 (m, 2H), 2.17 (s, 3H), 2. 11 (s, 3H), 2.02 (s, 3H), 1.73 (s, 3H), 1.42 (t, J=7.2 Hz, 3H).

6.7. Alternative synthesis of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

To a 50 L reactor under nitrogen atmosphere, 40 L MeOH was charged, followed with the ketone (2.50 kg, 5.78 mol) and CeCl3.7H2O (2.16 kg, 1.0 equiv). Methanol (7.5 L) was added as rinse (totally 47.5 L, 19×). A freshly prepared solution of NaBH(87.5 g, 0.4 equiv) in aqueous 1 N NaOH (250 mL) was added slowly (35 min) at 15-25° C. The mixture was then stirred for 15 min. HPLC analysis of the reaction mixture showed approximately 90:10 diastereomeric ratio. The reaction was quenched with 10 wt % aq NH4Cl (2.5 L, 1×) and the mixture was concentrated under vacuum to 5×, diluted with water (10 L, 4×) and MTBE (12.5 L, 5×). The mixture was cooled to 10° C. and 6 N aq HCl was added until the pH of the mixture reached 2.0. Stirring was continued for 10 minutes and the layers were separated. The organic layer was washed with H2O (5L, 2×). The combined aqueous layer was extracted with MTBE (12.5 L, 5×). The combined organic layers were washed with brine (2.5 L, 1×) and concentrated under vacuum to 3×. MeCN (15 L, 6×) was added. The mixture was concentrated again to 10 L (4×) and any solid residue was removed by a polish filtration. The cake was washed with minimal amount of MeCN. The organic filtrate was transferred to 50 L reactor, and a pre-prepared 20 mol % aqueous H2SOsolution (61.8 mL 98% concentrated H2SOand 5 L H2O) was added. The mixture was heated to 80° C. for 2 hours and then cooled to 20° C. The reaction was quenched with a solution of saturated aqueous K2CO(5 L, 2×) and diluted with MTBE (15 L, 6×). The organic layer was separated, washed with brine (5 L, 2×) and concentrated under vacuum to 5 L (2×). MeCN (12.5 L, 5×) was added and the mixture was concentrated to 7.5 L (3×). The above MeCN solution of (3S,4R,5R,6S)-6-(4-chloro-3-(4-ethoxybenzyl)phenyl)tetrahydro-2H-pyran-2,3,4,5-tetraol was cooled to 10° C., added with dimethylaminopyridine (17.53 g, 2.5 mol %), followed by slow addition of acetic anhydride (3.23 L, 6.0 equiv) and triethylamine (5 L, 2×, 6.0 equiv) so that the temperature of the mixture was kept below 20° C. The reaction was then warmed to 20° C. and stirred for 1 hour and diluted with MTBE (15 L, 6×). The mixture was slowly quenched with water (7.5 L, 3×). The organic layer was separated and washed with saturated aqueous KHCO(5L, 2×), 1 N NaHSO(5 L, 2×), and brine (5 L, 2×) in sequence. The organic layer was then concentrated under vacuum to 5 L (2×). MeCN (12.5 L, 5×) was added and the solution was concentrated to 7.5 L (3×) (KF=0.08%). Dioxane (12.5 L, 5×) was added and the solution was concentrated to 7.50 L (3×) (KF=0.02%). Any residual solid was removed by a polish filtration and the cake was washed with minimal amount of dioxane (500 mL). To the above filtrate was added thiourea (880 g, 2.0 equiv) and TMSOTf (1.57 L, 1.5 equiv). The reaction mixture was heated to 80° C. for 3 hours (>97% conversion). The mixture was cooled to 20° C. and methyl iodide (541 mL, 1.5 equiv) and diethylisopropylamine (3.02 L, 3.0 equiv) were added and the mixture was stirred at 20° C. for 18 hours. An extra methyl iodide charge (90 mL, 0.25 equiv) was added and the mixture was stirred at 20° C. for 1 hours. The mixture was then diluted with MTBE (25 L, 10×) and washed with water (12.5 L, 5× ×2). The organic layer was separated and concentrated under vacuum to ˜5 L (2×). MeOH (12.5 L, 5×) was added and the mixture was concentrated to 5× to afford a slurry. The mixture was then heated at 60° C. for 1 hour and cooled to 0° C. and stirred at 0° C. for 1 hour. The mixture was filtered and the cake was washed with MeOH (0° C., 2.5 L, 1× ×2, 1.0 L, 0.4×). The cake was dried under vacuum at 45° C. overnight to afford the desired triacetate (1.49 kg, 47% over 4 steps) as a pale yellow/off-white solid.

6.8. Synthesis of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol

Figure US20090030198A1-20090129-C00027

To a slurry of (2S,3S,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (90.0 g, 0. 164 mol) in MeOH (900 mL, 10×) was added NaOMe in MeOH (25 wt %, 18 mL, 0.2×) at 20° C. and the mixture was stirred at 20° C. for 2 hours until all solids disappeared. The mixture was then concentrated to 300 mL, added to H2O (1 L) and stirred for 1 hour. The solid was filtered and washed with H2O (100 mL, ×3) and the cake was dried under vacuum at 45° C. overnight to afford the desired methyl thiolate (67.0 g, 95%). 1H NMR (CDCl3) 6 7.38 (d, J=8.4 Hz, 1H), 7.22 (m, 2H), 7.11 (d, J=8.8 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 4.35 (d, J=9.6 Hz, 1H), 4.15 (d, J=9.6 Hz, 1H), 4.10-3.95 (m, 3H), 3.64 (t, J=8.8 Hz, 1H), 3.50 (m, 2H), 2.73 (br s, 3H), 2.17 (s, 3H), 1.40 (t, J=7.2 Hz, 3H).

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SGLT inhibitors: a novel target for diabetes.

Kanwal A, Banerjee SK.

Pharm Pat Anal. 2013 Jan;2(1):77-91. doi: 10.4155/ppa.12.78.

clinical trials………..http://clinicaltrials.gov/search/intervention=LX-4211+OR+LX4211

On the importance of synthetic organic chemistry in drug discovery: reflections on the discovery of antidiabetic agent ertugliflozinVincent Mascitti, Benjamin A. Thuma, Aaron C. Smith, Ralph P. Robinson, Thomas Brandt, Amit S. Kalgutkar, Tristan S. Maurer, Brian Samas, Raman SharmaMed. Chem. Commun., 2013, 4, 101

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