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Pimecrolimus Пимекролимус…For treatment of mild to moderate atopic dermatitis.

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Pimecrolimus

137071-32-0 cas 

(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)- 3-{(E)-2-[(1R,3R,4S)-4-Chloro-3-methoxycyclohexyl]- 1-methylvinyl}-8-ethyl-5,6,8,11,12,13,14,15,16,17,

18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy- 14,16-dimethoxy-4,10,12, 18-tetramethyl-15,19-epoxy- 3H-pyrido[2,1-c][1,4]oxaazacyclotricosine-1, 7,20,21(4H,23H)-tetrone

The systematic name of pimecrolimus is (lR,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(lE)-2- {(1 R,3R,4S)-4-chloro-3-methoxycyclohexyl} – 1 -methylvinyl] – 17-ethyl- 1,14- dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-ll,28-dioxa-4-aza- tricyclo[22.3.1.049]octacos-18-ene-2,3,10,16-tetraone.

Pimecrolimus is the 32 epichloro derivative of ascomycin.

Elidel, NCGC00167506-01,  DSSTox_CID_26674, DSSTox_RID_81811, DSSTox_GSID_46674, 137071-32-0, Tox21_112504
Molecular Formula: C43H68ClNO11   Molecular Weight: 810.45312
4-11-2008
Pharmaceutical Composition
Canada 2200966 2006-12-19 expiry   2015-10-26
United States 6423722 1998-12-26              2018-12-26

PATENT AND EXPIRY DATE

5912238 Jun 15, 2016
5912238*PED Dec 15, 2016
6352998 Oct 26, 2015
6352998*PED Apr 26, 2016
6423722 Jun 26, 2018
6423722*PED Dec 26, 2018

Viktor Gyollai, Csaba Szabo, “Methods of preparing pimecrolimus.” U.S. Patent US20060142564, issued June 29, 2006.

US20060142564 Link out

NDA..021302, 13 DEC 2001… VALEANT BERMUDA..ELIDEL1% TOPICAL CREAM

Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is currently available as a topical cream, once marketed by Novartis, (however Galderma will be promoting the molecule in Canada in early 2007) under the trade name Elidel.

NMR…http://file.selleckchem.com/downloads/nmr/S500401-Pimecrolimus-NMR-Selleck.pdf

HPLC…….http://file.selleckchem.com/downloads/hplc/S500401-Pimecrolimus-HPLC-Selleck.pdf

http://file.selleckchem.com/downloads/hplc/S500401-Pimecrolimus-HPLC-Selleck.pdf

Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis (however, Galderma has been promoting the compound in Canada since early 2007) under the trade name Elidel.

Pimecrolimus ball-and-stick.png

Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to macrophilin-12(also referred to as FKBP-12) and inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.

Pimecrolimus is a chemical that is used to treat atopic dermatitis (eczema). Atopic dermatitis is a skin condition characterized by redness, itching, scaling and inflammation of the skin. The cause of atopic dermatitis is not known; however, scientists believe that it may be due to activation of the immune system by various environmental or emotional triggers. Scientists do not know exactly how pimecrolimus reduces the manifestations of atopic dermatitis, but pimecrolimus reduces the action of T-cells and mast cells which are part of the immune system and contribute to responses of the immune system. Pimecrolimus prevents the activation of T-cells by blocking the effects of chemicals (cytokines) released by the body that stimulate T-cells. Pimecrolimus also reduces the ability of mast cells to release chemicals that promote inflammation.

Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals.[1] Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells.[2] It has lower permeation through the skin than topical steroids or topical tacrolimus[3] although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.[4] It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis,[5] cutaneous lupus erythematosus,[6]oral lichen planus,[7] vitiligo,[8] and psoriasis.[9][10] Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.[11]

Ascomycin macrolactams belong to a new group of immunosuppressive, immunomodulatory and anti-inflammatory agents and include, e.g., ascomycin (FK520), tacrolimus (FK506) and pimecrolimus (ASM 981). The main biological effect of ascomycin macrolactams appears to be the inhibition of the synthesis of both Th1 and Th2-type cytokines in target cells.

As used herein, the term “ascomycin macrolactam” means ascomycin, a derivative of ascomycin, such as, e.g., tacrolimus and pimecrolimus, or a prodrug or metabolite of ascomycin or a derivative thereof.

Ascomycin, also called immunomycin, is a structurally complex macrolide produced by Streptomyces hygroscopicus. Ascomycin acts by binding to immunophilins, especially macrophilin-12. It appears that ascomycin inhibits the production of Th1 (interferon- and IL-2) and Th2 (IL-4 and IL-10) cytokines. Additionally, ascomycin preferentially inhibits the activation of mast cells, an important cellular component of the atopic response. Ascomycin produces a more selective immunomodulatory effect in that it inhibits the elicitation phase of allergic contact dermatitis but does not impair the primary immune response when administered systemically. The chemical structure of ascomycin is depicted below.

Figure US08536190-20130917-C00001

Tacrolimus (FK506) is a synthetic derivatives of ascomycin. As a calcineurin inhibitor, it works through the FK-binding protein and inhibits the dephosphorylation of nuclear factor of activated T cells (NFAT), thereby preventing the transport of the cytoplasmic component of NFAT to the cell nucleus. This leads to transcriptional inhibition of proinflammatory cytokine genes such as, e.g., interleukin 2, which are dependent on the nuclear factor of activated NFAT. The chemical structure of tacrolimus is depicted below.

Figure US08536190-20130917-C00002

Pimecrolimus, an ascomycin derivative, is a calcineurin inhibitor that binds with high affinity to the cytosolic receptor macrophilin-12, inhibiting the calcium-dependent phosphatase calcineurin, an enzyme required for the dephosphorylation of the cytosolic form of the nuclear factor of the activated T cell (NF-AT). It thus targets T cell activation and proliferation by blocking the release of both TH1 and TH2 cytokines such as IF-g, IL-2, -4, -5, and -10.3 It also prevents the production of TNF-a and the release of proinflammatory mediators such as histamine, hexosaminidase, and tryptase from activated mast cells.3 It does not have general antiproliferative activity on keratinocytes, endothelial cells, and fibroblasts, and in contrast to corticosteroids, it does not affect the differentiation, maturation, functions, and viability of human dendritic cells. The chemical structure of pimecrolimus is depicted below.

Figure US08536190-20130917-C00003

Pimecrolimus is an anti-inflammatory compound derived from the macrolactam natural product ascomycin, produced by certain strains of Streptomyces.

In January 2006, the United States Food and Drug Administration (FDA) announced that Elidel packaging would be required to carry a black box warning regarding the potential increased risk of lymph node or skin cancer, as for the similar drug tacrolimus. Whereas current practice by UKdermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.[12]

Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the American Academy of Dermatology Association Task Force finds that there is no causal proof that topical immunomodulators cause lymphoma or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism.[13] Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy.[14] However, there are still some strong debates and controversies regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.[15] Dermatologists’ and Allergists’ professional societies, the American Academy of Dermatology[1], and the American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states “None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship.”[2].

Click here for structure editor

Pimecrolimus binds with high affinity to macrophilin-12 (FKBP-12) and inhibits the calcium-dependent phosphatase, calcineurin. As a consequence, it inhibits T cell activation by blocking the transcription of early cytokines. In particular, pimecrolimus inhibits at nanomolar concentrations Interleukin-2 and interferon gamma (Th1-type) and Interleukin-4 and Interleukin-10 (Th2-type) cytokine synthesis in human T cells. Also, pimecrolimus prevents the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen/lgE.

ELIDEL® (pimecrolimus) Cream 1% contains the compound pimecrolimus, the immunosuppressant 33-epi-chloro-derivative of the macrolactam ascomycin.

Chemically, pimecrolimus is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2{(1R,3R,4S)-4-chloro-3-methoxycyclohexyl}-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25 dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.0 4,9]octacos-18-ene2,3,10,16-tetraone.

The compound has the empirical formula C43H68CINO11 and the molecular weight of 810.47. The structural formula is

Elidel® (pimecrolimus) Structural Formula Illustration

Pimecrolimus is a white to off-white fine crystalline powder. It is soluble in methanol and ethanol and insoluble in water.

Each gram of ELIDEL Cream 1% contains 10 mg of pimecrolimus in a whitish cream base of benzyl alcohol, cetyl alcohol, citric acid, mono- and di-glycerides, oleyl alcohol, propylene glycol, sodium cetostearyl sulphate, sodium hydroxide, stearyl alcohol, triglycerides, and water.

The second representative of the immunosuppressive macrolides for topical application – after tacrolimus (Protopic ®) – has 21 October in the trade. Pimecrolimus is approved for short-term and intermittent long-term treatment for patients aged two years who suffer from mild to moderate atopic dermatitis.

Pimecrolimus is a lipophilic derivative of macrolactam Ascomycin. The macrolides inhibit the production and release of pro-inflammatory cytokines by blocking the phosphatase calcineurin.The anti-inflammatory effect unfolds the drug in the skin. Since he is only minimally absorbed to not measurable, it hardly affects the local or systemic immune response. Therefore, the authorization neither restricts nor a maximum daily dose treatable area or duration of therapy.The cream can also be applied on the face, head and neck, and in skin folds, but not simultaneously with other anti-inflammatory topical agents such as glucocorticoids.

In studies in phases II and III patients aged three months and treated a maximum of one year.In two six-week trials involving 186 infants and young children as well as 403 children and adolescents, the verum symptoms and itching decreased significantly better than the cream base. Already in the first week of itching in 44 percent of children and 70 percent of the infants improved significantly. In adults, pimecrolimus was less effective than 0.1 percent betamethasone 17-valerate.

In the long-term treatment the verum significantly reduced the incidence of flares, revealed two studies with 713 and 251 patients. About a half and one year each about twice as many of the small patients were free of acute disease exacerbations than with the cream base (example: 61 versus 34 per cent of children, 70 versus 33 percent of infants older than six months). Moreover, the use of topical corticosteroids decreased significantly.

In a study of 192 adults with moderate to severe eczema half suffered six months no relapses more (24 percent with placebo). In the long-term therapy pimecrolimus was less effective than 0.1 percent triamcinolone acetonide cream and 1 percent hydrocortisone cream in adults.

The new topicum is-apart from burning and irritation at the application site – relatively well tolerated. It is neither kontaktsensibilisierend still phototoxic or sensitizing and does not cause skin atrophy. As in atopic Ekzen but usually a long-term therapy is necessary studies can reveal long-term adverse effects of the immunosuppressant on the skin only beyond one year.Also available from direct comparative studies between tacrolimus and pimecrolimus. They could help to delineate the importance of the two immunosuppressants.

Pimecrolimus (registry number 137071-32-0; Figure 1) is a macro lide having anti-inflammatory, antiproliferative and immunosuppressive properties. This substance is present as an active ingredient in the Elidel ® drug recently approved in Europe and in the USA for topical treatment of inflammatory conditions of the skin such as atopic dermatitis.

Figure imgf000002_0001

Figure 1: structural formula of pimecrolimus

19th Ed., vol. π, pg. 1627, spray-drying consists of bringing together a highly dispersed liquid and a sufficient volume of hot air to produce evaporation and drying of the liquid droplets. Spray-drying however is often limited to aqueous solutions unless special expensive safety measures are taken. Also, in spite of the short contact time, certain undesirable physical and chemical characteristics of the emerging solids are in particular cases unavoidable. The turbulence present in a spray-drier as a result of the moving air may alter the product in an undesirable manner. Modifications to the spray-drying technique are disclosed in WO 03/063821 and WO 03/063822. [00012] European Patent EP 427 680 Bl discloses a method of synthesizing amorphous pimecrolimus (Example 66a). The method yields amorphous pimecrolimus as a colorless foamy resin.

U.S. Patent No. US 6,423,722 discloses crystalline forms of pimecrolimus, such as form A, form B, etc. US 722 also contend that by performing example 66a from the European Patent EP 427 680 Bl, amorphous pimecrolimus is obtained.

The preparation of pimecrolimus was described for the first time in the patent application EP427680 on behalf of Sandoz. Used as raw material in such document is ascomycin (compound identified by registry number 11011-38-4), a natural product obtained through fermentation from Streptomyces strains (such as for example Streptomyces hygroscopicus var ascomyceticus, or Streptomyces hygroscopicus tsukubaensis N°9993). Pimecrolimus is obtained from the ascomycin through a sequence of four steps of synthesis (scheme 1)

Figure imgf000003_0001

Scheme 1 : synthesis process described in EP427680

From a structural point of view, pimecrolimus is the 33-epi-chloro derivative of ascomycin. As described in EP427680, the simultaneous presence – in the structure of ascomycin – of two secondary hydroxyl groups in position 24 and in position 33, requires the protection of the hydroxyl in position 24 before substituting the second hydroxyl in position 33 with an atom of chlorine.

In order to obtain the monoprotection of the hydroxyl in position 24 of ascomycin, such synthesis process provides for the preparation of 24,33-disilyl derivative and the subsequent selective removal of the silyl ester in position 33.

The high ratio between the silylating agent and the substrate and the non-complete selectivity of the subsequent step of deprotection requires carrying out two chromatographic purifications on the column of silica gel (Baumann K., Bacher M., Damont A., Hogenauer K., Steck A. Tetrahedron, (2003), 59, 1075-1087). The general yields of such synthesis process are not indicated in literature; an experiment by the applicant revealed that such yields amount to about 16% molar starting from ascomycin.

Other synthesis processes were recently proposed as alternatives to the synthesis of EP427680.

In particular, the International patent application WO2006040111 on behalf of Novartis provides for the direct substitution of the hydroxyl in position 33 of ascomycin with an atom of chlorine and a second alternative, described in the international patent application WO2006060614 on behalf of Teva, uses – as a synthetic intermediate – a sulfonate derivative in position 33 of ascomycin. Both the proposed synthetic alternatives are not entirely satisfactory in that in WO2006040111 the proposed halogenating agents (chlorophosphorane and N- chlorosuccinimide) are not capable, according to the same authors, of regioselectively substituting the hydroxyl function in position 33, while in WO2006060614 the quality characteristics of the obtained product are, even after chromatographic purification and/or crystallisation, low for a product to be used for pharmaceutical purposes (i.e. purity of 96% as described in the experimental part).

Generally, purified enzymatic systems may be used for the organic synthesis of polyfunctional molecules (Wang Y-F, Wong C-H. J Org Chem (1988) 53, 3127- 3129; Santaniello E., Ferraboschi P., Grisenti P., Manzocchi A. Chem. Rev. (1992), 92(5), 1071-140; Ferraboschi P., Casati S., De Grandi S., Grisenti P., Santaniello E. Biocatalysis (1994), 10(1-4), 279-88); WO2006024582). WO2007103348 and WO2005105811 describe the acylation of rapamycin in position 42 in the presence of lipase from Candida antartica.

…………………….

EP2432791A1

Figure imgf000009_0001

Scheme 2: synthesis of pimecrolimus for enzymatic transesterification of ascomycin.

Figure imgf000013_0001

Scheme 3. Synthesis of pimecrolimus for enzyme-catalyzed alcoholysis from 33,24- diacetate of ascomycin

Example 1

Preparation of the 33-acetyl derivative of ascomvcin (compound I of scheme II)

Lipase from Candida antarctica (CAL B, Novozym 435) [0.140 g (2 U/mg)

FLUKA] was added to a solution of ascomycin (100 mg; 0.126 mmol) in toluene (8 ml) and vinyl acetate (4.5 eq; 0.473 g). The reaction is kept under stirring at the temperature of 30° C for 80 hrs then the enzyme is taken away for filtration and the filtrate is concentrated at low pressure to obtain 105 mg of 33-acetyl ascomycin.

A sample of such intermediate was purified for analytical purposes by chromatography on silica gel (n-hexane/acetone = 8/2 v/v as eluents) and thus crystallised by acetone/water.

The following analysis were carried out on such sample: 1H-NMR (500MHz) δ:

2.10 (CH3CO), 3.92 and 4.70 (24CH and 33CH); IR (cm-1): 3484.245, 2935.287,

1735.331, 1649.741, 1450.039,

1372.278; DSC: endotherm at 134.25° C; [α]D=-74,0° (c=0.5 CHCl3).

Spectrum of MS (ESI +): m/z: 856.4 (M+23; 100.0%)

Elementary analysis calculated for C45H7iNO13: C 64.80%; H, 8.58%; N, 1.68%;

O, 24.94%

Elementary analysis found: C 64.78%; H, 8.54%; N, 1.59%; O, 24.89%

Preparation of the 24-tgrt-butyldimethylsilylether-33 -acetyl derivative of ascomvcin (intermediate 24-silyl-33-Oac; compound II of scheme 2)

2,6-lutidine (0.29Og; 2.7 mmolels) and tert-butyldimethylsilyl triflate (0.238g; 0.9 mmoles) are added to a solution of 33-acetyl derivative of ascomycin (150 mg;

0.18 mmoles) in dichloromethane (5ml). The reaction is left under stirring at ambient temperature for 30 minutes. After this period the reaction mixture is washed with a solution saturated with sodium bicarbonate (5 ml) and organic phase obtained is washed in sequence with HCl 0.1N (5 ml 3 times) and with a solution at 30% of NaCl (5ml). The organic phase is anhydrified on sodium sulphate, filtered and concentrated to residue under vacuum to obtain 128 mg of product.

Spectrum of MS (ESI +): m/z: 970.5 (M+23; 100.0%)

1H-NMR (500 MHz) δ: 0.05 and 0.06 ((CHs)2Si), 0.90 ((CH3)3C-Si), 2.10

(CH3CO), 4.70 (33CH)

IR (cm-‘): 3462.948, 2934.450, 1739.236, 1649.937

Elementary analysis calculated for C51H85NOi3Si: C 64.59%; H, 9.03%; N, 1.48%; O, 21.93%

Elementary analysis found: C 64.50%; H, 9.05%; N, 1.41%; O, 21.88%

DSC= endoderma a 236,43° C. [α]D=-81,4° (c=0.5 CHCl3).

Preparation of 24-tert-butyldimethylsilylether of ascomycin (intermediate 24- silyl-33-OH; compound III of scheme 2) n-octan-1-ol (0.035g; 0.265 mmoles) and CAL B (Novozym 435) [0.100 g (2

U/mg) FLUKA] are added to a solution of 24-tert-butyldimethylsilylether-33- acetyl derivative of ascomycin (50 mg; 0.053 mmoles) in tert-butylmethylether (4 ml). The reaction is kept under stirring at the temperature of 40° C for 120 hours.

After this period the reaction mixture is filtered and the filtrate is evaporated to residue under vacuum to obtain a reaction raw product which is purified by chromatography on silica gel: 44 mg of product (0.048 mmoles) are recovered through elution with petroleum ether/acetone 7/3.

The chemical/physical properties of the obtained product match those of a reference sample obtained according to patent EP427680.

Preparation of 24-tert-butyldimethylsilylether-33-epi-chloro ascomycin

(intermediate 24-silyl-33-chloro; compound IV of scheme 2)

A solution of 24-silyl FR520, i.e. 24-silyl ascomycin (165 g; 0.18 moles) in anhydrous toluene (1.4 litres) and pyridine (50 ml) is added to a suspension of dichlorotriphenylphosphorane (99.95g) in anhydrous toluene (1.1 litres), under stirring at ambient temperature (20-25 °C) in inert atmosphere.

After adding, the reaction mixture is heated at the temperature of 60° C for 1 hour.

After this period the temperature of the reaction mixture is taken to 25° C and thus the organic phase is washed in sequence with water (1 time with 1 L) and with an aqueous solution of NaCl at 10% (4 times with 1 L each time), then it is anhydrified on sodium sulphate, filtered and concentrated under vacuum to obtain about 250 g of a moist solid of toluene. Such residue product is retaken with n- hexane (500 ml) and then evaporated to dryness (in order to remove the toluene present). The residue product is diluted in n-hexane (500 ml) under stirring at ambient temperature for about 45 minutes and then the undissolved solid taken away for filtration on buckner (it is the sub-product of dichlorophosphorane).

The filtrate is concentrated at low pressure to obtain 148.6 g of a solid which is subsequently purified by chromatography on silica gel (elution with n- heptane/acetone = 9/1) to obtain 123 g (0.13 moles) of product.

The chemical/physical properties of the obtained product match those described in literature (EP427680).

Preparation of the pimecrolimus from 24-fert-butyldimethylsilylether-33-epi- chloro ascomycin

The intermediate 24-silyl-33 chloro (123g; 0.13 Moles; compound IV of scheme

2) is dissolved under stirring at ambient temperature in a dichloromethane/methanol mixture=l/l=v/v (1.1 litres) then p-toluenesulfonic acid monohydrate (10.11 g) is added.

The reaction is kept under stirring at the temperature of 20-25° C for 72 hours, thus a solution of water (600 ml) and sodium bicarbonate (4.46 g) is added to the reaction mixture. The reaction mixture is kept under stirring at ambient temperature for 10 minutes, the organic phase is then prepared and washed with an aqueous solution at 10% of sodium chloride (600 ml).

The organic phase is anhydrified on sodium sulphate, filtered and concentrated under vacuum to obtain 119 g of raw pimecrolimus. Such raw product is purified by chromatography on silica gel (n-hexane/acetone as eluents) and thus crystallised by ethyl acetate, cyclohexane/water to obtain 66 g (81.5 mmoles) of purified pimecrolimus.

The chemical/physical data obtained matches the data indicated in literature.

Example 2

Preparation of ascomvcin 24.33-diacetate (intermediate 24, 33-diacetate; compound V of scheme 3)

DMAP (4.5 eq; 0.136 g) and acetic anhydride (4.5 eq; 0.114 g) are added to a solution of ascomycin (200 mg; 0.25 mmoles) in pyridine (2.5 ml), under stirring at the temperature of 0° C.

The reaction is kept under stirring for 1.5 hours at the temperature of 0° C then it is diluted with water and it is extracted with ethyl acetate (3 times with 5 ml). The organic extracts are washed with HCl 0.5 N (5 times with 10 ml), anhydrified on

Na2SO4 concentrated under vacuum.

The residue product was purified by chromatography on silica gel (n- hexane/acetone 8/2 v/v as eluent) to obtain ascomycin 24,32-diacetate (210 mg;

0.24 mmoles).

We carried out the following analysis on such purified sample:

1H-NMR (500 MHz) δ: 2.02 and 2.06 (2 CH3CO), 5.20 and 4.70 (24CH and

33CH);

IR (Cm-1): 3462.749, 2935.824, 1734.403, 1650.739, 1449.091, 1371.079.

DSC: endothermic peak at 234.10° C ; [α]D=- 100.0° (C=0.5 CHCl3).

Spectrum of MS (ESI+): m/z: 898.4 (100.0%; m+23).

Elementary analysis calculated for C47H73NO14: C 64.44%; H 8.40%; N 1.60%; O

25.57%

Elementary analysis found: C 64.55%; H 8.44%; N 1.61%; O 25.40%

Preparation of the 24-acetyl ascomycin (intermediate 24-acetate-33-OH; compound VI of scheme 3)

Lipase from Candida antartica (CAL B Novozym 435) [1.1 g (2 U/mg) FLUKA] is added to a solution of ascomycin 33,24-diacetate (500 mg; 0.57 mmol) in

TBDME (25 ml) and n-octan-1-ol (4.5 eq; 0.371 g). The reaction is kept under stirring at 30° C for 100 hours, then the enzyme is taken away for filtration and the obtained filtrate is concentrated under low pressure to obtain 425 mg (0.51 mmoles) of product.

A sample was purified for analytical purposes by chromatography on silica gel (n- hexane/acetone = 7:3 v/v as eluents) and thus crystallised by acetone/water.

We carried out the following analysis on such purified sample: 1H-NMR

(500MHz) δ: 2.05 (CH3CO); IR (an 1): 3491.528, 2935.860, 1744.728, 1710.227,

1652.310, 1448.662, 1371.335. DSC: endothermic peak at 134.68° C; [α]D=-

102.7° (c=0.5 CHCl3)

Spectrum of MS (ESI +): m/z: 856.4 (M+23; 100.0%)

Elementary analysis calculated for C45H71NO13: C 64.80%; H, 8.58%; N, 1.68%;

0, 24.94%

Elementary analysis found: C 64.71%; H, 8.49%; N, 1.60%; O, 24.97%

Preparation of the 24-acetyl-33epi-chloro ascomycin (intermediate 24-Acetate-33- chloro; compound VII of scheme 3) Supported triphenylphosphine (0.335 g; 1.1 mmoles) is added to a solution of 24- acetyl ascomycin (400 mg; 0.48 mmoles) in carbon tetrachloride (5 ml). The reaction mixture is kept under reflux for 3 hours then it is cooled at ambient temperature. The obtained suspension is filtered and the filtrate is concentrated to residue under vacuum to obtain 0.45g of reaction raw product which is purified by chromatography on silica gel: 163mg (0.19 mmoles) of product are obtained by elution with petroleum ether/acetone = 90/10.

1H-NMR δ: 2.08 (CH3CO); 4.60 (33CH); IR (Cm“1)= 3464.941, 2934.360,

1738.993, 1650.366, 1450.424, 1371.557; DSC: endothermic peak at 231.67° C

[α]D=-75.2° (c=0.5 CHCl3)

Spectrum of MS (ESI +): m/z: 874.3 (M+23; 100.0%)

Elementary analysis calculated for C45H70ClNO12: C 63.40%; H, 8.28%; Cl,

4.16%; N, 1.64%; O, 22.52%

Elementary analysis found: C 63.31%; H, 8.30%; Cl, 4.05%; N, 1.58%; O,

22.42%.

Preparation of pimecrolimus from 24-acetyl-33-epi-chloro ascomycin

A solution of 24-acetyl-33-epi-chloro ascomycin (200 mg; 0.23 mmoles; compound VII) in methanol (2 ml) and HCl 3N (1 ml) is stirred at ambient temperature for 40 hours. After this period, the reaction is neutralised with an aqueous bicarbonate solution, the methanol evaporated under vacuum. The mixture is extracted with dichloromethane (3 times with 5 ml), anhydrified on sodium sulphate, filtered and concentrated to residue to obtain a residue product which is purified by chromatography on silica gel (n-hexane/acetone as eluents) and thus crystallised by ethyl acetate, cyclohexane/water to obtain 78 mg of purified pimecrolimus (0.096 mmoles).

The chemical/physical characteristics of the obtained product matches the data indicated in literature for pimecrolimus.

Example 4 (comparative*)

Verification of the method of synthesis of pimecrolimus described in EP427680 Imidazole (508 mg) and tert-Butyldimethylsilylchloride (1.125 g) are added in portions to a solution of 2g (2.53 mmoles) of ascomycin in anhydrous N,N- dimethylformamide (40 ml). The reaction mixture is kept under stirring at ambient temperature for 4.5 days. The reaction is thus processed diluting it with ethyl acetate (200 ml) and processing it using water (5 x 100 ml). The organic phase is separated, anhydrified on sodium sulphate, filtered and evaporated to residue under vacuum to obtain a foamy raw product which is subsequently purified by chromatography on silica gel (1:30 p/p): 2.1 g (2.05 mmoles; yields 81% molars) of ascomycin 24,33 disilyl intermediate are obtained by elution with n- hexane/ethyl acetate 3/1. The chemical/physical data of such intermediate matches that indicated in EP427680.

2.1 g (2.05 mmoles) of ascomycin 24,33 disilyl intermediate are dissolved in a solution under stirring at the temperature of 0°C composed of acetonitrile (42 ml) and aqueous HF 40% (23.1 ml). The reaction mixture is kept under stirring at the temperature of 0°C for 2 hours then it is diluted with dichloromethane (30 ml). Then the reaction is washed in sequence with a saturated aqueous solution using sodium bicarbonate (30 ml) and water (30 ml). The separated organic phase is anhydrified on sodium sulphate, filtered and evaporated to residue under vacuum to obtain a foamy residue which is subsequently purified by chromatography on silica gel (1:30 p/p): 839 mg (0.92 mmoles; yields 45% molars) of ascomycin 24 monosilyl intermediate are obtained by elution with dichloromethane/methanol 9/1. The chemical/physical data of such intermediate matches that obtained on the compound III scheme 2 and matches the data of literature indicated in EP427680. A mixture of 839 mg (0.92 mmoles; yields 45% molars) of ascomycin 24 monosilyl intermediate, triphenylphosphine (337 mg) in carbon tetrachloride (36.4 ml) is heated under stirring under reflux for 15 hours. After this period the reaction mixture is evaporated to residue under vacuum to obtain a solid product purified by chromatography on silica gel (1:30 p/p): 535 mg (0.57 mmoles; yields 63% molars) of ascomycin 24 monosilyl intermediate, 33-chloro derivative are obtained by elution with n-hexane/ethyl acetate 2/1. The chemical/physical data of such intermediate matches those we obtained on compound IV scheme 2 and matches the data of literature indicated in EP427680.

535 mg (0.57 mmoles) of ascomycin 24 monosilyl intermediate, 33-chloro derivative are dissolved under stirring at ambient temperature in acetonitrile (16.4 ml) and aqueous HF 40% (0.44 ml). The reaction mixture is kept under stirring at ambient temperature for 45′ and then it is diluted with ethyl acetate (100 ml). The organic phase is thus washed in sequence with an aqueous solution of sodium bicarbonate (70 ml) with water (2 x 70 ml) and thus it is anhydrified on sodium sulphate, filtered and evaporated under vacuum to obtain a solid which is subsequently purified by chromatography on silica gel (1 :30 p/p): 323 mg (0.399 mmoles; yields 70% molars) of pimecrolimus is obtained by elution with n- hexane/ethyl acetate 2/3. The chemical/physical characteristics of the obtained product matches the data indicated in literature regarding pimecrolimus; the overall yield of the process is 16%.

………………………..

POLYMORPHS…….WO2006060615A1

Example 7: Preparation of amorphous pimecrolimus by precipitation [00094] 19,5 g purified pimecrolimus (colorless resin) was dissolved in 217 ml acetone at 4O0C and concentrated. Residue: 38,76 g. The residue was diluted with 6 ml distilled water with stirring. Finally 1 ml acetone was added. This solution was added slowly to 2 L chilled distilled water that was stirred efficiently. After the addition had been completed, the suspension was stirred 20 min at O0C. Then the solid was filtered and dried at 450C in vacuum oven overnight. Product: 15,65 g yellowish solid. Amorphous (XRD, DSC).

Example 8: Preparation of amorphous pimecrolimus by grinding

[00095] Procedure of grinding: 200 mg of Pimecrolimus sample was ground gently in an agate mortar using a pestle for half a minute. ,

References

  1.  Allen BR, Lakhanpaul M, Morris A, Lateo S, Davies T, Scott G, Cardno M, Ebelin ME, Burtin P, Stephenson TJ (2003). “Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients”Arch Dis Child 88 (11): 969–973. doi:10.1136/adc.88.11.969.PMC 1719352PMID 14612358.
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  6.  Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stücker M, Bader A, Altmeyer P, Freitag M (2004). “Pimecrolimus 1% cream for cutaneous lupus erythematosus”. J Am Acad Dermatol 51(3): 407–410. doi:10.1016/j.jaad.2004.01.044PMID 15337984.
  7.  Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, Nassiri Kashani M, Firooz A (2007). “Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus”. J Am Acad Dermatol 57 (5): 806–813.doi:10.1016/j.jaad.2007.06.022PMID 17658663.
  8.  Boone B, Ongenae K, Van Geel N, Vernijns S, De Keyser S, Naeyaert JM (2007). “Topical pimecrolimus in the treatment of vitiligo”. Eur J Dermatol 17 (1): 55–61. doi:10.1111/j.1610-0387.2006.06124.xPMID 17081269.
  9. Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, Gambichler T (2006). “1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study”. Arch Dermatol 142 (9): 1138–1143. doi:10.1001/archderm.142.9.1138PMID 16983001.
  10.  Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M (2008). “Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study”. Dermatology 216 (2): 133–136.doi:10.1159/000111510PMID 18216475.
  11.  Scheinfeld N (2004). “The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review”. Dermatol. Online J. 10 (1): 3. PMID 15347485.
  12.  N H Cox and Catherine H Smith (December 2002). “Advice to dermatologists re topical tacrolimus” (DOC). Therapy Guidelines Committee. British Association of Dermatologists.
  13.  Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ, Frieden IJ; American Academy of Dermatology Association Task Force (2006). “The use of topical calcineurin inhibitors in dermatology: safety concerns Report of the American Academy of Dermatology Association Task Force”J Am Acad Dermatol 54 (5): 818–823. doi:10.1016/j.jaad.2006.01.054.PMID 16635663.
  14.  Spergel JM, Leung DY (2006). “Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence”. Curr Allergy Asthma Rep 6 (4): 270–274. doi:10.1007/s11882-006-0059-7PMID 16822378.
  15.  Stern RS (2006). “Topical calcineurin inhibitors labeling: putting the “box” in perspective”.Archives of Dermatology 142 (9): 1233–1235. doi:10.1001/archderm.142.9.1233.PMID 16983018.
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    Little known grapes from the South of France at attractive prices. Little known grapes from the South of France at attractive prices. It’s not totally clear why The Worst Witch at the Vaudeville Theatre needed to be a musical. It’s not totally clear why The Worst Witch at the Vaudeville Theatre needed to be a musical. ‘Five-a-day’ soup sold by Asda and Waitrose is pulled from shelves over listeria fears. ‘Five-a-day’ soup sold by Asda and Waitrose is pulled from shelves over listeria fears. Trumps Dorian Tweet Whips Up a Fight Over a Science Powerhouse. Trumps Dorian Tweet Whips Up a Fight Over a Science Powerhouse. Rugby World Cup news Even at ten-years-old Owen Farrell was the boy who could be king. Rugby World Cup news Even at ten-years-old Owen Farrell was the boy who could be king. Manchester City stunned by newly-promoted Norwich. Manchester City stunned by newly-promoted Norwich. Real-Time Surveillance Will Test the British Tolerance for Cameras. Real-Time Surveillance Will Test the British Tolerance for Cameras. Who has the longest playoff streak in the NFL http://vencercrisostomo.com/25/what-do-i-get-with-wwe-network Is GameStop having a midnight release for Borderlands 3 Seoul restaurant is ordered to take down pictures of North Korean past leaders and flag. Seoul restaurant is ordered to take down pictures of North Korean past leaders and flag. New York Uncovers $1 Billion in Sackler Family Wire Transfers. New York Uncovers $1 Billion in Sackler Family Wire Transfers. Global model for regulation? Try Canada. Global model for regulation? Try Canada. A Tokyo Itinerary, Over-the-Top Hats and More. A Tokyo Itinerary, Over-the-Top Hats and More. Jim Jefferies believes Craig Levein will be fighting for his job if Hearts lose against Hibernian. Jim Jefferies believes Craig Levein will be fighting for his job if Hearts lose against Hibernian. Beth Allen Finds Home and Success in Europe. Beth Allen Finds Home and Success in Europe. New York Uncovers $1 Billion in Sackler Family Wire Transfers. New York Uncovers $1 Billion in Sackler Family Wire Transfers. Jean Edward Smith, Biographer of the Underrated, Dies at 86. Jean Edward Smith, Biographer of the Underrated, Dies at 86.

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    Scores of tigers rescued from infamous Thai temple have died media. Scores of tigers rescued from infamous Thai temple have died media. How a Ceramist Transformed a Los Angeles Treehouse. How a Ceramist Transformed a Los Angeles Treehouse. What the Skateboarders Are Wearing at the LES Skate Park. What the Skateboarders Are Wearing at the LES Skate Park. U.S. Soldier Killed in Afghanistan Just Over a Week After Trump Scraps Peace Talks. U.S. Soldier Killed in Afghanistan Just Over a Week After Trump Scraps Peace Talks. Eddie Stobart make delayed warning about profits amid takeover interest. Eddie Stobart make delayed warning about profits amid takeover interest. U.S. sees break in new measles cases. U.S. sees break in new measles cases. Taking Out a Student Loan Is Better Than Dropping Out. Taking Out a Student Loan Is Better Than Dropping Out. How will a new wireless standard certification being rolled out today affect you? How will a new wireless standard certification being rolled out today affect you? Convicted RFK assassin Sirhan Sirhan stabbed in California prison reports. Convicted RFK assassin Sirhan Sirhan stabbed in California prison reports. MLB notebook Heart procedure for Nats Martinez. MLB notebook Heart procedure for Nats Martinez. ‘SNL’ fires new hire over racist comments. ‘SNL’ fires new hire over racist comments. Are Ravens dangerous http://vencercrisostomo.com/49/who-is-number-25-for-the-texans Who is worth more Beyonce or Rihanna Huma Abedin attends the New York premiere of Downton Abbey without husband Anthony Weiner. Huma Abedin attends the New York premiere of Downton Abbey without husband Anthony Weiner. Daily Report Facebooks Lucrative Long View. Daily Report Facebooks Lucrative Long View. California governor acts to stem ‘epidemic’ of youth vaping. California governor acts to stem ‘epidemic’ of youth vaping. Deliveroo Ad Implying Delivery Anywhere (Even Space) Is Banned in U.K. Deliveroo Ad Implying Delivery Anywhere (Even Space) Is Banned in U.K. Golden, Going Gone 18-Karat Gold Toilet Is Stolen. Golden, Going Gone 18-Karat Gold Toilet Is Stolen. Iranians Detained for Happy Video Are Released on Bail. Iranians Detained for Happy Video Are Released on Bail. New Hikes in Sonoma. New Hikes in Sonoma. White storks are released in Britain in the hope they will breed after more than 600 years. White storks are released in Britain in the hope they will breed after more than 600 years.

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    Heres When Your Favorite Shows Are Returning This Fall. Heres When Your Favorite Shows Are Returning This Fall. Amazon Echo link could be turning UK parents off the name Alexa. Amazon Echo link could be turning UK parents off the name Alexa. Getting started with NFC on the phone and in the home. Getting started with NFC on the phone and in the home. Trump floats possible defense treaty with Israel. Trump floats possible defense treaty with Israel. UPDATE 2-Saudi says to meet oil commitment to Asian refiners, some changes – sources. UPDATE 2-Saudi says to meet oil commitment to Asian refiners, some changes – sources. Long Before Netflix and Chill, He Was the Netflix C.E.O. Long Before Netflix and Chill, He Was the Netflix C.E.O. What ingredients should I avoid in acne prone skin http://cocorelaxcr.com/2077/how-does-makeup-improve-the-appearance-of-a-woman Can hair gel make you go bald Disgraced cardinal George Pell officially files appeal to the High Court to fight sex abuse charges. Disgraced cardinal George Pell officially files appeal to the High Court to fight sex abuse charges. An Anthony Bourdain Auction Will Include His Treasured Knife. An Anthony Bourdain Auction Will Include His Treasured Knife. Moroccan Journalist on Trial for an Abortion She Says She Never Had. Moroccan Journalist on Trial for an Abortion She Says She Never Had. What Does a Great Player Look Like Now? What Does a Great Player Look Like Now? Scientists are warning of cataclysmic collisions in space. Scientists are warning of cataclysmic collisions in space. Apple TV Plus Is Just $5. Will People Pay for It? Apple TV Plus Is Just $5. Will People Pay for It? If You Hate Floss, Its O.K. to Try These Alternatives. If You Hate Floss, Its O.K. to Try These Alternatives.

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    More than 20,000 mining jobs are set to spring up in Australia in the next five years. More than 20,000 mining jobs are set to spring up in Australia in the next five years. Rachel Cusk Said She Was Done With Autobiography. These Essays Suggest Otherwise. Rachel Cusk Said She Was Done With Autobiography. These Essays Suggest Otherwise. University student, 20, lost his right testicle ‘due to NHS blunders’. University student, 20, lost his right testicle ‘due to NHS blunders’. Israel’s Netanyahu fights for record fifth term. Israel’s Netanyahu fights for record fifth term. U.S. questions Iran’s credibility on Saudi attacks. U.S. questions Iran’s credibility on Saudi attacks. Ryan Moore to ride favourite Sir Dragonet inInvestec Derby at Epsom. Ryan Moore to ride favourite Sir Dragonet inInvestec Derby at Epsom. Met Police chief Cressida Dick is shown knives hidden inside LIPSTICK and combs. Met Police chief Cressida Dick is shown knives hidden inside LIPSTICK and combs. FIFA Claims Deep Pool of Bidders for 2023 Womens World Cup. FIFA Claims Deep Pool of Bidders for 2023 Womens World Cup. What We Found About Notre-Dames Lead, and What It May Mean for You. What We Found About Notre-Dames Lead, and What It May Mean for You. Дышат ли кожаные куртки https://momoda.ru/345/mozhno-li-nosit-mokasiny-iz-ugg-na-ulicze Как называется свитер без рук Supreme Court judges will decide whether Boris Johnson broke the law when he prorogued Parliament. Supreme Court judges will decide whether Boris Johnson broke the law when he prorogued Parliament. Cheese oatcake triangles. Cheese oatcake triangles. Countdown star Rachel Riley’s unborn baby stopped kicking for two days due to stress of online abuse. Countdown star Rachel Riley’s unborn baby stopped kicking for two days due to stress of online abuse. Heart-stopping pictures show daredevils somersaulting on precipices and dangling from cranes. Heart-stopping pictures show daredevils somersaulting on precipices and dangling from cranes.

    Thai ‘Tiger Temple’ blames government for deaths of rescued tigers. Thai ‘Tiger Temple’ blames government for deaths of rescued tigers. J.Lo reveals who will walk her down the aisle during wedding with A-Rod. J.Lo reveals who will walk her down the aisle during wedding with A-Rod. Editor’s Choice Pictures. Editor’s Choice Pictures. Play music on your phone through your bedside lamp! Play music on your phone through your bedside lamp! Katie Rodihan, Heath Hyatt. Katie Rodihan, Heath Hyatt. U.S. states launch Google antitrust probe. U.S. states launch Google antitrust probe. China’s economy is getting worse. That makes a trade deal more likely. China’s economy is getting worse. That makes a trade deal more likely. Working Families Party Endorses Elizabeth Warren. Heres Why It Matters. Working Families Party Endorses Elizabeth Warren. Heres Why It Matters. How the Blues Went From Last Place to the Stanley Cup Finals. How the Blues Went From Last Place to the Stanley Cup Finals. Rihanna defended by Slave Play playwright after she’s late and texting at Broadway play. Rihanna defended by Slave Play playwright after she’s late and texting at Broadway play.

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    Lesbian driver high on meth and cannabis when she died in crash had similar crash weeks earlier. Lesbian driver high on meth and cannabis when she died in crash had similar crash weeks earlier. A New Date Brings New Faces to the BMW PGA Championship. A New Date Brings New Faces to the BMW PGA Championship. Plane noise rises to record levels as number of flights soars. Plane noise rises to record levels as number of flights soars. The Week in Tech Silicon Valleys Alternate Reality. The Week in Tech Silicon Valleys Alternate Reality. Britain will be hotter than Madrid this weekend with temperatures as high as 78F. Britain will be hotter than Madrid this weekend with temperatures as high as 78F. For One Playwright, It Wouldnt Be Home Without a Little Melodrama. For One Playwright, It Wouldnt Be Home Without a Little Melodrama. RPT-WeWork obtains commitments for US$6bn IPO-linked debt. RPT-WeWork obtains commitments for US$6bn IPO-linked debt. Big Fashion Books of Fall. Big Fashion Books of Fall. Can Esther Duflo eradicate poverty? Can Esther Duflo eradicate poverty? Mamets American Buffalo Is Headed Back to Broadway. Mamets American Buffalo Is Headed Back to Broadway. Honduran migrant and her two-year-old son drown while attempting to swim from Mexico. Honduran migrant and her two-year-old son drown while attempting to swim from Mexico. Boris Johnson ‘has Brexit blueprint’ but he’s terrified it will leak to public. Boris Johnson ‘has Brexit blueprint’ but he’s terrified it will leak to public. How Much Watching Time Do You Have This Weekend? How Much Watching Time Do You Have This Weekend? How many seasons has Carson Wentz been in the NFL http://astronauttheatre.com/1177/how-is-the-president-elected-in-a-parliamentary-system What channel is the Bears Vikings game on State Supreme Court rules two designers can refuse to make wedding invitations for same-sex couple. State Supreme Court rules two designers can refuse to make wedding invitations for same-sex couple. Ghost crabs can produce an angry growl with teeth in their stomach which they evolved to digest food. Ghost crabs can produce an angry growl with teeth in their stomach which they evolved to digest food. Breakingviews TV Out of Africa. Breakingviews TV Out of Africa. How to Cook Every Day This Week. How to Cook Every Day This Week. Dolly Everett’s parents release video about bullying. Dolly Everett’s parents release video about bullying. A Book Fair in Buenos Aires. A Book Fair in Buenos Aires. Is That Your Money? Is That Your Money? The Inspector reviews Mannings Hotel in Truro, Cornwall. The Inspector reviews Mannings Hotel in Truro, Cornwall. Saudi oil attacks came from southwest Iran, U.S. official says, raising tensions. Saudi oil attacks came from southwest Iran, U.S. official says, raising tensions. Double meningitis amputee pleads for university students to get their jab ahead of freshers’ week. Double meningitis amputee pleads for university students to get their jab ahead of freshers’ week. Hustlers Review Ripping Off the Suits. Hustlers Review Ripping Off the Suits. Love Island host Sophie Monk stuns in a skintight dress outside Nine HQ in Perth. Love Island host Sophie Monk stuns in a skintight dress outside Nine HQ in Perth. Rising Car Prices Are Sending Even Strong-Credit Buyers to the Used Lot. Rising Car Prices Are Sending Even Strong-Credit Buyers to the Used Lot.

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    She the North Bianca Andreescu Joins the Raptors in Canadian Sports Lore. She the North Bianca Andreescu Joins the Raptors in Canadian Sports Lore. A Shadowy Industry Group Shapes Food Policy Around the World. A Shadowy Industry Group Shapes Food Policy Around the World. Love Island host Sophie Monk stuns in a skintight dress outside Nine HQ in Perth. Love Island host Sophie Monk stuns in a skintight dress outside Nine HQ in Perth. Human hearts evolved to be better at endurance tasks. Human hearts evolved to be better at endurance tasks. Google Says a Change in Its Algorithm Will Highlight Original Reporting. Google Says a Change in Its Algorithm Will Highlight Original Reporting. What is a good moisturizer for natural black hair Can you clean your face with coconut oil What is clear nail polish good for Kayaker, 22, who has her right leg amputated after an accident in the water six years ago. Kayaker, 22, who has her right leg amputated after an accident in the water six years ago. Football betting adverts from two gambling firms are banned by watchdog. Football betting adverts from two gambling firms are banned by watchdog. Pregnant bride dies from stroke minutes before reaching the altar in Brazil. Pregnant bride dies from stroke minutes before reaching the altar in Brazil. All cars to have tracker that wakes up drivers falling asleep at wheel. All cars to have tracker that wakes up drivers falling asleep at wheel. Francis Bacon Read Just as He Painted Deep, Dark and Bleak. Francis Bacon Read Just as He Painted Deep, Dark and Bleak. Office space provider We Work shelves floatover fears it would fail to attract enough backers. Office space provider We Work shelves floatover fears it would fail to attract enough backers. For Libyan Jews, This Spicy Fish Stew Is the Taste of Rosh Hashana. For Libyan Jews, This Spicy Fish Stew Is the Taste of Rosh Hashana. The Ups and Downs of Life Without Wheels of My Own. The Ups and Downs of Life Without Wheels of My Own. A New Direction. A New Direction. Facebook Suspends Netanyahu Campaign Bot for Hate Speech. Facebook Suspends Netanyahu Campaign Bot for Hate Speech. Trump Races for Trade Deals With Japan and India as China Fight Persists. Trump Races for Trade Deals With Japan and India as China Fight Persists. Dressing for the Great British Identity Crisis. Dressing for the Great British Identity Crisis.

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    Succession Season 2, Episode 6 Recap Damage, Control. Succession Season 2, Episode 6 Recap Damage, Control.

    For Some Cord Cutters, Streaming Super Bowl Was a Nonstarter. For Some Cord Cutters, Streaming Super Bowl Was a Nonstarter. Radiotherapy treatment for prostate cancer could be cut from two months to just FIVE DAYS. Radiotherapy treatment for prostate cancer could be cut from two months to just FIVE DAYS. Rob Lowe gets into character as New York City firefighter to film scenes for 911 Lone Star. Rob Lowe gets into character as New York City firefighter to film scenes for 911 Lone Star. Best cash Isas 2019 Where to get the best cash Isa rates and deals. Best cash Isas 2019 Where to get the best cash Isa rates and deals. Irish fintech FINEOS, ASXs biggest IPO this year, opens higher on debut. Irish fintech FINEOS, ASXs biggest IPO this year, opens higher on debut. Charges Against Another Parent Revealed in the College Admissions Scandal. Charges Against Another Parent Revealed in the College Admissions Scandal. Gone Missing A Little Boy, a Favorite Uncle, an Old Ladys Mind. Gone Missing A Little Boy, a Favorite Uncle, an Old Ladys Mind. Сколько по времени делают карту Сбербанка link Как узнать баланс карты Сбербанка по номеру 900 Another Day of Life Review A Memoir of War, in Full Color. Another Day of Life Review A Memoir of War, in Full Color. The Sixties just an era of Manson and mayhem? Try telling that to Lulu and Julie Andrews… The Sixties just an era of Manson and mayhem? Try telling that to Lulu and Julie Andrews… Notorious inmate who taunted police while on the run now sets up YouTube account from his jail cell. Notorious inmate who taunted police while on the run now sets up YouTube account from his jail cell. Test flight shows balloon space tourism no flight of fancy. Test flight shows balloon space tourism no flight of fancy. The 145-Pound Long Snapper and Other Tales of College Admissions Puffery. The 145-Pound Long Snapper and Other Tales of College Admissions Puffery. Fed Jumps Into Market to Push Down Rates, a First Since the Financial Crisis. Fed Jumps Into Market to Push Down Rates, a First Since the Financial Crisis. In Belgium, Congo’s president sees pomp and protests. In Belgium, Congo’s president sees pomp and protests. Woman, 46, is rushed to hospital after being shot on the streets of north London. Woman, 46, is rushed to hospital after being shot on the streets of north London. A Six Senses Resort to Open in Portugal. A Six Senses Resort to Open in Portugal. How Tokyo is readying for the global spotlight. How Tokyo is readying for the global spotlight.

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    Rory McIlroy Beats Brooks Koepka for PGA Tour Player of the Year. Rory McIlroy Beats Brooks Koepka for PGA Tour Player of the Year. France’s Macron to meet Qatari emir in wake of Saudi oil attack. France’s Macron to meet Qatari emir in wake of Saudi oil attack. Does Anyone Really Love Private Health Insurance? Does Anyone Really Love Private Health Insurance? Cokie Roberts Dies; Veteran Broadcast Journalist Was 75. Cokie Roberts Dies; Veteran Broadcast Journalist Was 75. MLB notebook Pirates’ Vazquez jailed on lurid charges. MLB notebook Pirates’ Vazquez jailed on lurid charges. Azerbaijan’s Silk Road city now a UNESCO site. Azerbaijan’s Silk Road city now a UNESCO site. H.D.R. Is Coming to a TV Near You. Heres Why You Should Care. H.D.R. Is Coming to a TV Near You. Heres Why You Should Care. Firefighters overturn their truck as they rush to tackle burning car at demonstration for students. Firefighters overturn their truck as they rush to tackle burning car at demonstration for students. Heart-stopping pictures show daredevils somersaulting on precipices and dangling from cranes. Heart-stopping pictures show daredevils somersaulting on precipices and dangling from cranes. What division is Nebraska read more What is Kansas University’s mascot Chelsea dealt blow after N’Golo Kante is ruled out of Sheffield United clash. Chelsea dealt blow after N’Golo Kante is ruled out of Sheffield United clash. On the Runway Moving. On the Runway Moving. Anna Begum. Anna Begum. Grieving Sean can still lift our spirits. Grieving Sean can still lift our spirits. 5,000 boozy students drink, party and collapse on streets. 5,000 boozy students drink, party and collapse on streets. Key Points About the U.A.W. Strike Against General Motors. Key Points About the U.A.W. Strike Against General Motors. Jeremy Corbyn sits on the fence AGAIN over Brexit. Jeremy Corbyn sits on the fence AGAIN over Brexit. SpaceX asks for permission to fly Starship prototype 12 MILES into the air once vehicle is completed. SpaceX asks for permission to fly Starship prototype 12 MILES into the air once vehicle is completed. Woman, 25, says her life could have been saved if she had a smear test. Woman, 25, says her life could have been saved if she had a smear test. The private world of Ben Stokes by the sports writer who knows him best. The private world of Ben Stokes by the sports writer who knows him best. North Korea could have up to 40 nuclear weapons by the end of the year. North Korea could have up to 40 nuclear weapons by the end of the year. Zayn Malik’s youngest sister Safaa has got married aged 17. Zayn Malik’s youngest sister Safaa has got married aged 17. FIFA and Premier League Document Saudi Link in BeIN Piracy Fight. FIFA and Premier League Document Saudi Link in BeIN Piracy Fight. Belmont Starters Put Through Final Preparations. Belmont Starters Put Through Final Preparations.

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    Julien Macdonald’s Southwark Cathedral show dubbed the ‘antithesis of Christian gospel’. Julien Macdonald’s Southwark Cathedral show dubbed the ‘antithesis of Christian gospel’. Texas Techs Perfect Storm Started on a West Texas Ranch. Texas Techs Perfect Storm Started on a West Texas Ranch. Students forced to wait three months for at least 9,675 worth of deposits. Students forced to wait three months for at least 9,675 worth of deposits. David Koch, Embraced as an Arts Patron, Even as Criticism Grew. David Koch, Embraced as an Arts Patron, Even as Criticism Grew. Father-of-two who fell unconscious on a flight to Brisbane is left stranded in a Sri Lankan hospital. Father-of-two who fell unconscious on a flight to Brisbane is left stranded in a Sri Lankan hospital. Serena Williams Lost, but Her Legacy Is Winning. Serena Williams Lost, but Her Legacy Is Winning. Nigeria Plans to Airlift Its Citizens Out of South Africa After Xenophobic Riots. Nigeria Plans to Airlift Its Citizens Out of South Africa After Xenophobic Riots. Vaping Bad Were 2 Wisconsin Brothers the Walter Whites of THC Oils? Vaping Bad Were 2 Wisconsin Brothers the Walter Whites of THC Oils?

    Trump to Revoke Californias Authority to Set Stricter Auto Emissions Rules. Trump to Revoke Californias Authority to Set Stricter Auto Emissions Rules. Portsmouth fan who kicked and punched Sunderland player is banned from grounds for three years. Portsmouth fan who kicked and punched Sunderland player is banned from grounds for three years. Tammy Abraham My mum ‘was in tears’ from racist abuse. Tammy Abraham My mum ‘was in tears’ from racist abuse. Apple quietly killed off 3D Touch with the new iPhones and replaced it with a haptic system. Apple quietly killed off 3D Touch with the new iPhones and replaced it with a haptic system. Climate Denialist to Depart White House National Security Council. Climate Denialist to Depart White House National Security Council.

    Dannii Minogue wanted to ‘SLAP’ Kyle Sandilands over THIS question during interview. Dannii Minogue wanted to ‘SLAP’ Kyle Sandilands over THIS question during interview. How much is Demaryius Thomas Worth continue What year did the Detroit Lions start playing on Thanksgiving Transfer news Ex-Tottenham forward Fernando Llorente ‘agrees two-year deal with Napoli’. Transfer news Ex-Tottenham forward Fernando Llorente ‘agrees two-year deal with Napoli’. Aaron Carter reacts after brother Nick gets restraining order on him accusing him of murder threats. Aaron Carter reacts after brother Nick gets restraining order on him accusing him of murder threats.

    Mourners arrive for Danny Frawley funeral in Melbourne. Mourners arrive for Danny Frawley funeral in Melbourne. Nina Agdal flaunts lithe frame in sexy bodysuit as she meets up with friends in LA. Nina Agdal flaunts lithe frame in sexy bodysuit as she meets up with friends in LA. Student finds gun inside bus driver’s purse. Student finds gun inside bus driver’s purse. Hurricane Sandy Storm WAS more powerful than Hurricane Katrina. Hurricane Sandy Storm WAS more powerful than Hurricane Katrina. Australia Bushfires Arrive Early, Destroying Historic Lodge in Omen of Future. Australia Bushfires Arrive Early, Destroying Historic Lodge in Omen of Future. Kanye Wests New Yeezy Shoes Draw Comparisons to Crocs and a Colander. Kanye Wests New Yeezy Shoes Draw Comparisons to Crocs and a Colander. Popular dogs breeds such as Labradors are needier than their more wolf-like counterparts. Popular dogs breeds such as Labradors are needier than their more wolf-like counterparts.

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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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

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