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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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Chief Advisor Industry Advisory Board Amity University Noida, India. 26th Aug 2022


DR ANTHONY MELVIN CRASTO is Chief Advisor Industry Advisory Board Amity Univ. Noida, INDIA

Journey begins with online meet. 26th aug 2022
Service to education is service to humanity
Brochure for First Industry Advisory Board meeting at Amity Institute of Pharmacy is attached. Date 26th Aug 2022
it as hybrid-Online/offline.

Thnx
Dr Sandeep Arora
#amity
@amity #education #pharmacy
Amity University
Amity University, Greater Noida Campus

DIFLUPREDNATE


Difluprednate.svg
ChemSpider 2D Image | Difluprednate | C27H34F2O7

(1R,3aS,3bS,5S,9aS,9bR,10S,11aS)-1-[2-(acetyloxy)acetyl]-5,9b-difluoro-10-hydroxy-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl butanoate

(6a,11b)-21-(Acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione

(6α,11β)-21-(acetyloxy)-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butanoate

(6α,11β)-21-Acetoxy-6,9-difluor-11-hydroxy-3,20-dioxopregna-1,4-dien-17-ylbutyrat[German][ACD/IUPAC Name]

(6α,11β)-21-Acetoxy-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butyrate[ACD/IUPAC Name]

23674-86-4[RN]

245-815-4[EINECS]

2652

6a,9a-Difluoroprednisolone-21-acetate-17-butyrate

DIFLUPREDNATE

CAS# 23674-86-4

  • Molecular FormulaC27H34F2O7
  • Average mass508.552 Da
  • W 6309
  • W-6309
  • DFBA
  • Difluoroprednisolone butyrate acetate

S8A06QG2QE

TU3831500

дифлупреднат[Russian][INN]

ديفلوبريدنات[Arabic][INN]

二氟泼尼酯[Chinese][INN]

(1R,3aS,3bS,5S,9aS,9bR,10S,11aS)-1-[2-(acetyloxy)acetyl]-5,9b-difluoro-10-hydroxy-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl butanoate

(6a,11b)-21-(Acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione

(6α,11β)-21-(acetyloxy)-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butanoate

(6α,11β)-21-Acetoxy-6,9-difluoro-11-hydroxy-3,20-dioxopregna-1,4-dien-17-yl butyrate

23674-86-4[RN]245-815-4[EINECS]2652, 6a,9a-Difluoroprednisolone-21-acetate-17-butyrate

Difluprednate is a topical corticosteroid used for the symptomatic treatment of inflammation and pain associated with ocular surgery.

Difluprednate is a corticosteroid, It is chemically a butyrate ester of 6(alpha),9(alpha)-difluoro prednisolone acetate. Accordingly, difluprednate is sometimes abbreviated DFBA, for difluoroprednisolone butyrate acetate.

Difluprednate is a topical corticosteroid indicated for the treatment of infammation and pain associated with ocular surgery. It is a butyrate ester of 6(α), 9(α)-difluoro prednisolone acetate. Difluprednate is abbreviated DFBA, or difluoroprednisolone butyrate acetate. It is indicated for treatment of endogenous anterior uveiti.

Approval

On June 24, 2008, the US Food and Drug Administration (FDA) approved difluprednate for the treatment of post-operative ocular inflammation and pain.[1] It is marketed by Alcon under the tradename Durezol.

Depositor-Supplied Patent Identifiers

Publication NumberTitlePriority DateGrant Date
US-2020325543-A1Diagnostic method2017-11-20 
WO-2012088044-A2Compositions and methods for improving ocular surface health, corneal clarity, optical function and maintaining visual acuity2010-12-20 
US-7790905-B2Pharmaceutical propylene glycol solvate compositions2002-02-152010-09-07
US-7927613-B2Pharmaceutical co-crystal compositions2002-02-152011-04-19

PATENT

WO/2022/118271DIFLUPREDNATE FOR REDUCING THE ADVERSE EFFECTS OF OCULAR INFLAMMATION

SYN 1

Synthetic Reference

Process for preparation of Difluprednate from sterol fermentation product; Ding, Kai; Xu, Feifei; Assignee Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Peop. Rep. China; East China University of Science and Technology; 2014; Patent Information; Aug 06, 2014; CN; 103965277; A

SYN 2

Synthetic Reference

Preparation method of Difluprednate; Tian, Yuan; Zhou, Shengan; Guo, Bin; Xu, Zhiguo; Assignee Guangzhou Renheng Pharmaceutical Technology Co., Ltd., Peop. Rep. China 2017; Patent Information; May 10, 2017; CN; 106632561; A

SYN3

Synthetic Reference

Shailesh, Singh; Bharat, Suthar; Jain, Ashish; Gaikwad, Vinod; Kulkarni, Kuldip. Process for preparing difluprednate. Assignee Ajanta Pharma Ltd., India. IN 2013MU02535. (2015).

SYN4

Synthetic Reference

Sun, Hongbin; Chen, Bo. Method for preparation of Difluprednate. Assignee China Pharmaceutical University, Peop. Rep. China. CN 103509075. (2014).

PATENT

https://patents.google.com/patent/CN103509075A/en

CN103509075A - 一种制备二氟泼尼酯的方法 - Google Patents

Embodiment 1:4, pregnant steroid-17 α of 9 (11)-diene, 21-dihydroxyl-3,20-diketone-21-acetic ester (formula III compound)

10g hydrocortisone-21 acetic ester (formula II compound) is joined in 250mL eggplant type bottle, add 50mL N, dinethylformamide and 8.8mL pyridine, slowly heat up and make material dissolution complete, slowly cooling afterwards, slowly be added dropwise to 4.4mL methylsulfonyl chloride, add rear solution to be yellow completely.Be warming up to 85 ℃ of stirrings, the reaction solution thick one-tenth that can slowly become sticky is faint yellow, adds slightly some DMFs and makes reaction solution dilution, can normally stir, and keeps this thermotonus one hour, and reaction solution slowly becomes grey black during this period.TLC follows the tracks of (sherwood oil: ethyl acetate=1: 1) show that reaction finishes.Stop heating, treat that the backward reaction solution of slow cooling adds 200mL methyl alcohol, stir 1min, reaction flask is placed in to crystallization under ice-water bath.Suction filtration after 1h, makes water and methanol wash filter cake, crude product productive rate 100%.With methyl alcohol-methylene dichloride mixed solvent system recrystallization, obtain sterling, M.P.231-235 ℃, productive rate 90%. 1H-NMR(300MHz,CDCl 3):δ(ppm)5.75(1H,s,4-H),5.55(1H,s,11-H),5.07(1H,d,J=5Hz,21-H),4.84(1H,d,J=5Hz,21-H),2.15(3H,s,H-21-OAc),1.31(3H,s,19-CH 3),0.65(3H,s,18-CH 3),0.66-2.90(m,17H,backbone).

Embodiment 2:4,9 (11)-diene-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters (formula IV compound)

By 9.4g4, pregnant steroid-17 α of 9 (11)-diene, 21-dihydroxyl-3,20-diketone-21-acetic ester (formula III compound) and 10g4-Dimethylamino pyridine add in 1000mL eggplant-shape bottle, add again 50mL diethylene glycol dimethyl ether and 260mL methylene dichloride, heated and stirred makes dissolution of solid, slowly adds 32mL butyryl oxide slightly after cooling, is warming up to 80 ℃ of return stirrings.After 23h, TLC follows the tracks of, and raw material primitive reaction is complete, stops heating and stirs.Vacuum concentration is removed methylene dichloride.After being down to room temperature, add frozen water in reaction flask, white solid standing to be separated out.Suction filtration, saturated sodium bicarbonate aqueous solution washing leaching cake, dries under infrared lamp, obtain 4,9 (11)-diene-17 α, 21-dihydroxyl-3,20-ketone-21-acetic ester 17 iophenoxic acid esters (formula IV compound) sterling 10.65g, M.P220-224 ℃, productive rate 95.9%. 1H-NMR(500MHz,CDCl 3):δ(ppm)5.75(1H,s,4-H),5.54(1H,m,11-H),4.87(1H,d,J=4.8Hz,O=C-CH 2-O,21-H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.75(2H,m,2-H),0.70(3H,s,18-CH 3),0.95(3H,t,J=4.4Hz),1.34(3H,s,18-CH 3),1.66(2H,m,-CH 2CH 3),2.17(3H,s,O=C-CH 3),2.32(2H,t,J=4.3Hz,O=C-CH 2),? 13C-NMR(75MHz,CDCl 3):δ(ppm)199.1,198.9,173.4,170.4,169.1,144.1,124.1,118.5,94.5,66.9,48.2,46.3,40.9,37.5,36.4,34.2,33.8,32.7,32.2,32.1,30.6,26.2,24.5,20.5,18.3,13.7,13.6;ESI-MS?m/z:457.2[M+H +],479.2[M+Na +];HRMS?for?C 27366+Na +?calcd?479.2410,found479.2402.

Embodiment 3:3,5,9 (11) pregnant steroid-3 of triolefin, 17 α, 21 trihydroxy–3,20-diketone-3,21-diacetate esters 17 iophenoxic acid esters (formula V)

10g4, pregnant steroid-17 α of 9 (11)-diene, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters add in 250mL eggplant type bottle, then add 80mL methylvinyl acetate, slowly drip while stirring the 1mL vitriol oil.Be warming up to 80 ℃ of stirring reactions, solution is thin out yellow clarification slowly.(sherwood oil: ethyl acetate=3: 1), raw material reaction is complete produces new point to TLC after 30min.Stop heating, wait to be cooled to 50 ℃, add 1mL triethylamine, be stirred to and be down to room temperature.Add water in reaction solution, ethyl acetate aqueous layer extracted three times, saturated common salt water washing organic phase twice, anhydrous sodium sulfate drying.After 30min, steam organic solvent and obtain brown color oily matter.Column chromatography is purified and is obtained 3,5,9 (11) pregnant steroid-3 of triolefin, 17 α, 21 trihydroxy–3,20-diketone-3,21-diacetate esters 17 iophenoxic acid esters, productive rate 90%. 1H-NMR(300MHz,CDCl 3):δ(ppm)5.74(1H,s,4-H),5.53(1H,s,11-H),5.45(1H,s,6-H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.17(3H,s,-COCH 3),1.17(3H,s,19-CH 3),0.96(3H,t,J=7.5Hz),0.70(3H,s,18-CH 3).

Embodiment 4:4, fluoro-17 α of 9 (11)-diene-6-, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters

10g3,5,9 (11) pregnant steroid-3 of triolefin, 17 α, 21 trihydroxy–3,20-diketone-3,21-diacetate esters 17 iophenoxic acid esters are dissolved in 60mL acetonitrile, and under nitrogen protection ,-4 ℃ are stirred half an hour.Slowly drip the acetonitrile suspension 40mL of Selecfluor in reaction flask, under nitrogen protection, react 2 hours, TLC (sherwood oil: ethyl acetate=3: 1) monitoring reaction, raw material reaction is complete.Stopped reaction, adds water in reaction flask, ethyl acetate extraction three times, saturated common salt water washing twice, anhydrous sodium sulfate drying.Vacuum concentration is removed organic solvent, obtain faint yellow solid 4,9 (11)-diene-6 α-fluoro-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VII) and 9 (11)-diene-6 β-fluoro-17 α, 21-dihydroxyl-3, the mixture of 20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VI), productive rate 85%. 1H-NMR(500MHz,CDC1 3):δ(ppm)5.90(1H,d,J=4.5Hz,4-H),5.59(1H,s,11-H),5.07(1H,m,6-H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.17(3H,s,-COCH 3),1.46(3H,s,18-CH 3),0.96(3H,t,J=7.5Hz),0.73(3H,s,19-CH 3).

Embodiment 5:4,9 (11)-diene-6 α-fluoro-17 α, 21-dihydroxyl-3,20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VII)

14g4, 9 (11)-diene-6 α-fluoro-17 α, 21-dihydroxyl-3, 20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VII) and 9 (11)-diene-6 β-fluoro-17 α, 21-dihydroxyl-3, the mixture of 20-diketone-21-acetic ester 17 iophenoxic acid esters (formula VI) adds in dry three-necked bottle, add while stirring 400mL acetum, under room temperature, slowly pass into anhydrous hydrogen chloride gas (98% vitriol oil is added dropwise in 37% concentrated hydrochloric acid solution and makes) until saturated, be stirred to raw material and be dissolved into yellow solution completely, continue to stir 2h, TLC monitoring reacts completely, stop stirring, in reaction solution, add the aqueous solution, after separating out solid, suction filtration, saturated sodium bicarbonate aqueous solution washing, dry, be weighed as 13g, productive rate is 93%. 1H?NMR(300MHz,CDCl 3):δ(ppm)6.10(s,1H),5.61(s,1H),5.41-5.16(m,1H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.82(dd,J=28.3,15.7Hz,3H),2.50(s,2H),2.32(t,J=7.4Hz,2H),2.17(s,3H),1.96(s,5H),1.66(d,J=7.4Hz,2H),1.46(s,2H),1.33(s,3H),0.96(s,3H),0.71(s,3H).

Embodiment 6:6 α-fluoro-9 α-bromo-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (formula VIII)

13g 6 α-fluoro-4; 9; (11)-diene-pregnant steroid-3,20-22 ketone-17-butyric ester-20-acetic ester is dissolved in and fills 300mL1, in the eggplant type bottle of 4 dioxane; add while stirring 40mL 0.46mol/L high chloro acid solution; under room temperature, stir after several minutes, add 14g N-succinimide in reaction system, under nitrogen protection, stir; raw material dissolves gradually, and it is faint yellow that reaction solution is.(the sherwood oil: ethyl acetate=12: 5) monitoring, raw material primitive reaction is complete, adds 10%Na of TLC after 2h 2sO 3unnecessary N-succinimide is fallen in aqueous solution cancellation, and checks (it is blue that test paper no longer becomes) with starch-kalium iodide test paper.Add water in reaction flask, ethyl acetate extraction three times, twice of saturated common salt water washing organic phase, anhydrous sodium sulfate drying organic phase, after 30min, be spin-dried for organic phase, obtain faint yellow oily matter, column chromatography purification (sherwood oil: ethyl acetate=12: 1) obtain white solid 6 α-fluoro-9 α-bromo-11 beta-hydroxies-4-alkene-pregnant steroid-3, the about 14g of 20-diketone-17-butyric ester-20-acetic ester, productive rate is 89%. 1H-NMR(300MHz,CDCl 3):δ(ppm)5.93(1H,d,J=4.5,4-H),5.06(1H,m,6-H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.17(3H,s,-COCH 3),1.84(3H,s,18-CH 3),0.96(3H,t,J=7.5Hz),1.02(3H,s,19-CH 3),4.72(1H,s,11-H);ESI-MS?m/z:593.3,595.3[M+Na +].

Embodiment 7:6 α-fluoro-9 β, 11 beta epoxides-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (formula IX)

14g 6 α-fluoro-9 α-bromo-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester drops in 500mL eggplant type bottle, adds 200mL acetone, stirs raw material is fully dissolved, and adds afterwards 3g Potassium ethanoate, is warming up to 60 ℃ of return stirring 13h.TLC (sherwood oil: ethyl acetate=2: 1) monitoring finds that new product occurs.Stop heating, in reaction solution, add water, ethyl acetate extraction, anhydrous sodium sulfate drying organic phase, after standing 30min, steams except organic solvent, obtains yellow oil, productive rate 96%.Column chromatography is purified, and obtains white solid powder, and nuclear-magnetism confirmation structure is 6 α-fluoro-9 β, 11 beta epoxides-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester. 1H-NMR(300MHz,CDC1 3):δ(ppm)6.11(1H,d,J=4.5Hz,4-H),5.31(1H,m,6-H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.17(3H,s,-COCH 3),0.94(3H,s,18-CH 3),0.97(3H,t,J=7.5Hz),1.55(3H,s,19-CH 3),3.52(1H,s,11-H);ESI-MS?m/z:491.2[M+H +],513.2[M+Na +].

Embodiment 8:6 α, 9 α-fluoro-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (formula X)

100mg 6 α-fluoro-9 β, 11 beta epoxides-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester drops in the Plastic Bottle of tetrafluoroethylene, adds 2mL methylene dichloride to dissolve, and stirs at-20 ℃.1mL Olah reagent with under 1mL methylene dichloride low temperature, mix after, be slowly added dropwise in reaction system, maintain low temperature and stir 2 hours, TLC monitoring reaction finishes.Reaction flask shifts out low-temp reaction groove, is slowly added dropwise to the 1mol/L NaOH aqueous solution by excessive HF cancellation, is adjusted to pH7~8.Add chloroform in reaction system, extraction, organic layer is used respectively aqueous hydrochloric acid and the saturated common salt water washing of 3mol/L, anhydrous sodium sulfate drying, after standing 30min, steams except organic solvent, column chromatography is further purified and is obtained white solid powder 6 α, 9 α-fluoro-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester, productive rate 90%. 1H-NMR(300MHz,CDCl 3):δ(ppm)?6.11(1H,d,J=4.5Hz,4-H),5.27(1H,m,6-H),4.64-4.91(2H,ABq,J=16.6Hz,21-H),2.17(3H,s,-COCH 3),4.40(1H,d,J=4.5Hz,11-H),1.02(3H,s,18-CH 3),0.96(3H,t,J=7.5Hz),1.52(3H,s,19-CH 3);ESI-MS?m/z:533.3[M+Na +]

Embodiment 9:6 α, 9 α-fluoro-11 beta-hydroxies-Isosorbide-5-Nitrae-diene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester (difluprednate) (formula I)

40mg 6 α, 9 α-fluoro-11 beta-hydroxies-4-alkene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester is dissolved in 3mL dioxane, adds 28mgDDQ, and 100 ℃ of return stirrings heat up.TLC monitoring reaction (sherwood oil: ethyl acetate=12: 8) after 13h, generate the larger product of polarity, steam except organic solvent dioxane, obtain brown color oily matter, add a small amount of methylene dichloride lysate, suction filtration, elimination solid residue, filtrate is washed with sodium bicarbonate aqueous solution after adding a small amount of methylene dichloride again, steams except organic phase rear pillar Chromatographic purification, obtain white solid powder 6 α, 9 α-fluoro-11 beta-hydroxies-Isosorbide-5-Nitrae-diene-pregnant steroid-3,20-diketone-17-butyric ester-20-acetic ester, be title molecule difluprednate, productive rate 70%. 1h-NMR (300MHz, CDCl 3): δ (ppm) 7.20 (1H, d, J=4.5Hz, 1-H), 6.43 (1H, s, 4-H), 6.38 (1H, d, J=6Hz, 2-H), 5.36 (1H, m, 6-H), 4.64-4.91 (2H, ABq, J=16.6Hz, 21-H), 4.43 (1H, d, J=4.5Hz, 11-H), 2.27 (2H, m ,-CH 2-CH 3), 2.17 (3H, s, O=C-CH 3), 1.55 (3H, s, 19-CH 3), 1.02 (3H, s, 18-CH 3), 0.93 (3H, t, J=4.5Hz, 0=C-CH 2cH 2cH 3); ESI-MS m/z:509.3[M+H +]; HRMS for C 273572+ H +calcd 509.2351, found 509.2356.M.P.188-190 ℃ (literature value M.P.190-194 ℃); [α] d22=+30.1 ° of (literature values [α] d22=+31.7 °).

Claims (6)

Hide Dependent 

1. a method of preparing difluprednate, as following reaction formula:

Specifically comprise the following steps:

(1) by hydrocortisone-21-acetic ester (formula II compound):

Carry out dehydration reaction, generate formula III compound:

(2) formula III compound is carried out to butyric acid esterification, obtains formula IV compound:

(3) formula IV compound is carried out to the reaction of enolization esterifying reagent, obtains formula V compound:

(4) formula V compound is reacted with fluoro reagent and obtains formula VI and formula VII compound:

(5) by formula VI compound, through configuration reversal, reaction obtains formula VII compound;

(6) formula VII compound is reacted with N-bromo-succinimide and water, obtains formula VIII compound:

(7) formula VIII compound epoxidation under alkaline condition is obtained to formula IX compound:

(8) formula IX compound is reacted with fluorination reagent and obtains formula X compound:

(9) dehydrogenation of formula X compound oxidation is obtained to formula I compound (difluprednate).

2. method as claimed in claim 1, is characterized in that, in step (2), formula III compound is obtained to formula IV compound through fourth esterification, and the fourth esterifying reagent adopting is butyryl oxide or butyryl chloride; The alkaline catalysts adopting is pyridine, triethylamine or DMAP; The solvent adopting is methylene dichloride, diethylene glycol dimethyl ether, 1, the mixture of the optional solvents in 2-ethylene dichloride, dioxane, trichloromethane, DMF, methyl-sulphoxide, N,N-dimethylacetamide or above-mentioned solvent.

3. method as claimed in claim 1, is characterized in that, in step (3), formula IV compound is obtained to formula V compound through enolization esterification, and the enolization esterifying reagent adopting is diacetyl oxide, Acetyl Chloride 98Min., methylvinyl acetate or vinyl-acetic ester; The catalyzer adopting is the vitriol oil or tosic acid; The solvent adopting is the mixture of the optional solvents in methylene dichloride, chloroform, toluene, methylvinyl acetate, vinyl-acetic ester or above-mentioned solvent.

4. method as claimed in claim 1, is characterized in that, in step (4), formula V compound is obtained to formula VI compound and formula VII compound through fluoridizing, and the fluoro reagent adopting is Selectfluor or Accufluor; The solvent adopting is the mixture of the optional solvents in methylene dichloride, chloroform, toluene, acetonitrile or above-mentioned solvent.

5. method as claimed in claim 1, it is characterized in that, in step (8), formula IX compound is obtained to formula X compound through fluoridizing open loop, the fluorination reagent adopting is aqueous hydrogen fluoride solution, hydrogen fluoride pyridine solution (Olah reagent) or hydrogen fluoride triethylamine solution; The solvent adopting is methylene dichloride, chloroform, 1, the mixture of the optional solvents in 2-ethylene dichloride, tetrahydrofuran (THF), toluene or above-mentioned solvent; Range of reaction temperature is-50~50 ℃.

6. a key intermediate compound for synthetic difluprednate, shown in IV compound:

CN103509075A - 一种制备二氟泼尼酯的方法 - Google Patents

Patent 

Publication numberPriority datePublication dateAssigneeTitle

US3780177A *1967-06-161973-12-18Warner Lambert Co17-butyrate,21-ester derivatives of 6alpha,9alpha-difluoroprednisolone,compositions and use

US4525303A *1982-06-211985-06-25Dainippon Ink And Chemicals Inc.Process for preparation of steroids

CN101397321A *2007-09-292009-04-01天津药业研究院有限公司Preparation of hydrocortisone and derivatives thereof

CN102076344A *2008-05-282011-05-25瓦利杜斯生物医药有限公司Non-hormonal steroid modulators of nf-kb for treatment of disease

CN102134266A *2010-12-302011-07-27北京市科益丰生物技术发展有限公司Preparation method of melengestrol acetate

Publication numberPriority datePublication dateAssigneeTitle

CN102964412A *2012-11-272013-03-13山东省医药工业研究所Novel crystal form and preparation method of difluprednate

CN103965277A *2014-05-192014-08-06中国科学院上海有机化学研究所Method for synthesizing difluprednate from sterol fermentation product

CN106632561A *2016-12-162017-05-10广州仁恒医药科技股份有限公司Method for preparing difluprednate

CN106749464A *2016-12-292017-05-31奥锐特药业有限公司Steroidal epoxide carries out open loop, the method for fluorination reaction and its device

CN107915766A *2016-10-112018-04-17江苏福锌雨医药科技有限公司A kind of preparation method of fludrocortison acetate

CN108503679A *2018-04-032018-09-07广州仁恒医药科技股份有限公司A kind of purification process of Difluprednate intermediate

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Clinical trials

Difluprednate ophthalmic emulsion 0.05% is also being studied in other ocular inflammatory diseases, including a phase 3 study evaluating difluprednate for the treatment of anterior uveitis[2][3]

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References

  1. ^ “Sirion Therapeutics Announces FDA Approval of Durezol for Treatment of Postoperative Ocular Inflammation and Pain” (Press release). Sirion Therapeutics, Inc. 2008-06-24. Retrieved 2008-06-30.
  2. ^ Clinical trial number NCT00501579 for “Study of Difluprednate in the Treatment of Uveitis” at ClinicalTrials.gov
  3. ^ Sheppard JD, Toyos MM, Kempen JH, Kaur P, Foster CS (May 2014). “Difluprednate 0.05% versus prednisolone acetate 1% for endogenous anterior uveitis: a phase III, multicenter, randomized study”Investigative Ophthalmology & Visual Science55 (5): 2993–3002. doi:10.1167/iovs.13-12660PMC 4581692PMID 24677110.
Clinical data
AHFS/Drugs.comMonograph
MedlinePlusa609025
License dataUS FDADifluprednate
Routes of
administration
eye drops
ATC codeD07AC19 (WHO)
Legal status
Legal statusUS: ℞-only
Identifiers
showIUPAC name
CAS Number23674-86-4 
PubChem CID32037
DrugBankDB06781 
ChemSpider391990 
UNIIS8A06QG2QE
KEGGD01266 
ChEBICHEBI:31485
ChEMBLChEMBL1201749 
CompTox Dashboard (EPA)DTXSID0046773 
ECHA InfoCard100.041.636 
Chemical and physical data
FormulaC27H34F2O7
Molar mass508.559 g·mol−1
3D model (JSmol)Interactive image
showSMILES
showInChI
  (what is this?)  (verify)

///////////////DIFLUPREDNATE, W 6309, W-6309, DFBA, Difluoroprednisolone butyrate acetate, S8A06QG2QE, TU3831500, дифлупреднат , ديفلوبريدنات , 二氟泼尼酯 , OCCULAR, PAIN

CCCC(=O)OC1(CCC2C1(CC(C3(C2CC(C4=CC(=O)C=CC43C)F)F)O)C)C(=O)COC(=O)C

Anthony crasto is now Consultant Glenmark Lifesciences at Glenmark Life Sciences!


I’m happy to share that I’m starting a new position as Consultant Glenmark Lifesciences at Glenmark Life Sciences!
17th Jan 2022, A new innings

I retired 16th Jan 2022 at 58 yrs from Glenmark . completed 16 yrs 2 months

30 plus years in the field of Process research

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MY NEW DRUG APPROVALS BLOG HAS CLOCKED 35 LAKH VIEWS IN 7 CONTINENTS, 226 COUNTRIES


MY NEW DRUG APPROVALS BLOG HAS CLOCKED 35 LAKH VIEWS IN 7 CONTINENTS, 226 COUNTRIES

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Service to education is service to humanity, Taking free education to the world, Every difficulty an opportunity,In the dark but yet in light,proud of my disabilty, Taking industry experience to students, See the ability not the disabilty, The only disability in life is a bad attitude !!!, Dreamt a billion when hit by million, Mentor to the world

🌎All my awards, https://lnkd.in/fGxx9VF

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Sept 2021, This blog New Drug Approvals approaching 34 lakh views


NEW DRUG APPROVALS FAST APPROACING 34 LAKH VIEWS in 225 countries 7 continents. 5 lakh viewers in USA alone

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Anthony Crasto conferred ABPnews award for “Outstanding contribution to Education Sector”


DSC00403 Conferred prestigious award at event ABP News Presents Healthcare Leadership Awards 26th November, 2018 at Taj Lands End, Mumbai India
Dedicated to Shobha Crasto​ Aishal crasto Lionel crasto
Service to education is service to humanity
Society recognises efforts done towards it

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/////////////award,  event ABP News, Healthcare, Leadership,  26th, November, 2018, Taj Lands End, Mumbai,  India, education, anthony crasto

Anthony Melvin Crasto gets International award for Outstanding contribution to Pharma society by CMO ASIA 31st July 2018 Le Méridien Sentosa Singapore


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Conferred CMO Asia award 2018 🇸🇬 singapore

Shobha and Aishal crasto collect my International award for Excellence in Pharma by CMO ASIA 31st July 2018 | at an award function in Le Méridien Singapore, Sentosa

Thanking one and all for support

They went thru the paralysis trauma for years and now getting recognition for the efforts
God when he shuts one door he opens many more
My family proudly hold the honor outstanding contribution to pharma society at CMO Asia 🇸🇬 singapore

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//////////////Anthony Crasto, International award,   outstanding contribution to Pharma society, CMO ASIA,  31st July 2018 ,  Le Méridien,  Sentosa,  Singapore, 

National award to Anthony Melvin Crasto for contribution to Pharma society from Times Network for Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai, India


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DR ANTHONY MEVIN CRASTO Conferred prestigious individual national award at function for contribution to Pharma society from Times Network, National Awards for Marketing Excellence ( For Excellence in HEALTHCARE) | 5th July, 2018 | Taj Lands End, Mumbai India

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TIMES NOW 2 TIMES NOW 3

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////////////National award,  contribution to Pharma society, Times Network, Excellence in HEALTHCARE,  5th July, 2018, Taj Lands End, Mumbai,  India, ANTHONY CRASTO

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ANTHONY M CRASTO GETS PHARMA EXCELLENCE AWARD AT THE GOLDEN GLOBE TIGER AWARDS 2018


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Pic…. Shobha crasto, Lionel and Aishal collecting my award named The Golden Globe Tigers Awards 2018, for Excellence in Pharma, at kuala lumpur, Malaysia, 23 april 2018 at Pullman city centre hotel, Kuala lumpur, Malaysia. Dr Anthony could not travel as he is wheelchair bound and 90 percent paralysed

Image may contain: Anthony Melvin Crasto, sitting and outdoor

DR ANTHONY M CRASTO

The Golden Globe Tigers Award 2018 is the highest recognition amongst individual and organizations who have achieved the highest levels of standards and benchmark in numerous areas such as CSR, Pharma, Social Media & Digital Marketing, Education Leadership Award and so on. The award ceremony took place in Pullman Kuala Lumpur City Centre Hotel & Residences on the 23rd of April, where a number of respectable attendees were present not only from Malaysia but from many different parts of the world such as Iceland, Saudi Arabia, India, China, South Africa and such!

The Golden Globe Tigers Award not only aims to increase awareness on CSR practices but also continuously innovate practices towards sustainable development. It is organized by the founder of the World CSR Day, World Sustainability Congress and World Women Leadership Congress.

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Dr. Anthony  Melvin Crasto, graduated from Mumbai  University, Completed his Ph.D from ICT, 1991, Mumbai, India, in the field of Organic Chemistry, Currently he is working with GLENMARK PHARMACEUTICALS LTD,  Research Centre as a Principal Scientist, in Process Research at Mahape, Navi Mumbai, India, for the last 10 years,  His total  Industry experience is  30 +yrs with major Multinationals companies.

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 various multinationals in his career like BASF, Novartis, Sanofi, Pfizer etc., He has worked in Drug Discovery, Natural products, Bulk Drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP,  Scaleups, Pharma Plant, API plant etc, he is now helping millions, His friends call him worlddrugtracker.

His New Drug Approvals,  All about drugs,  EurekamomentsOrganic spectroscopy international, etc in Organic/ Medchem  are some most read blogs. He has hands on experience in initiation and developing Novel routes for Drug molecules and implementing them on commercial scale over a 30  year tenure till date Feb’  2018,  Around 30 plus commercial products in his career. He has good knowledge of IPM, GMP, QbD, Regulatory aspects, Technology transfer,  Manufacturing,  Formulations, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc. He has several  International  patents published worldwide.

He suffered a one in a million disease in the form of 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 several million hits on Google,  60 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 is a prolific presenter and is invited to major conferences in Mumbai, where he can travel easily. He speaks at universities on topics of  Drug discovery, Patents, Qbd, GMP, Tech transfer, polymorphism, Literature search tools, Computer programs and Topics of  interest to Pharma Students.

His extraordinary skill on the Computers give him the edge to write/present his thoughts. He demonstrates them to students and professionals alike.

Notably he has 20 lakh plus views on New Drug Approvals Blog in 216 countries, This blog has 3.5 lakh viewers in USA alone.

AWARDS

“100 Most Impactful Health care Leaders Global listing”, conferred at Taj lands end, Mumbai, India on 14 Feb 2014 by World Health Wellness congress and awards

“Best Worlddrugtracker “ Award for lifetime acheivement in Pharma… 7 th July 2017 , The venue…Taj land ends, Bandra, Mumbai India

“Lifetime achievement award” WORLD HEALTH CONGRESS 2017 in Hyderabad, 22 aug 2017 at JNTUH KUKATPALLY. HYDERABAD, TELANGANA, INDIA,

” Lifetime Achievement Award”, at the The Middle East Healthcare Leadership Awards – 12th October, 2017 -The Address, Dubai Mall, Dubai…UAE……….Mohammed Bin Rashid Boulevard, Downtown Dubai – Dubai – United Arab Emirates

International award for Outstanding contribution in Pharma  at World Health and wellness Congress award, 14th Feb, 2018, at Taj Lands ends, Bandra, Mumbai, India

Conferred very prestigious IDMA award for contribution to society in Pharma at INDIAN DRUGS ANNUAL DAY 2018 VMCC IITBombay Powai, Mumbai India 22 Feb 2018,I was Guest of honor at and was felicitated by president,Indian Drug manufacturers association (IDMA)

The Golden Globe Tigers Awards 2018, for Excellence in Pharma, at kuala lumpur, Malaysia, 23 april 2018 at Pullman hotel.

Biography

READ MY BIOGRAPHY……….http://scijourno.com/2017/01/09/dr-anthony-crasto/  Written by Mr. Amrit B. Karmarkar
Director, InClinition

 

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ALL ABOUT DRUGS, LIVE, BY DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER, HELPING MILLIONS, 9 MILLION HITS ON GOOGLE, PUSHING BOUNDARIES,2.5 LAKH PLUS CONNECTIONS WORLDWIDE, 18 LAKH PLUS VIEWS ON THIS BLOG IN 216 COUNTRIES, THE VIEWS EXPRESSED ARE MY PERSONAL AND IN NO-WAY SUGGEST THE VIEWS OF THE PROFESSIONAL BODY OR THE COMPANY THAT I REPRESENT, USE CTRL AND+ KEY TO ENLARGE BLOG VIEW……………………A 90 % PARALYSED MAN IN ACTION FOR YOU, I AM SUFFERING FROM TRANSVERSE MYLITIS AND BOUND TO A WHEEL CHAIR, WITH DEATH ON THE HORIZON, I HAVE LOT TO ACHEIVE

 

 

 

 

 

 

 

 

 

 

 

 

 

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