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Albaconazole
Albaconazole
7-chloro-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]quinazolin-4-one
Albaconazole (UR-9825) is a triazole antifungal. It has potential broad-spectrum activity.
Albaconazole is a broad-spectrum antifungal agent being evaluated in phase II clinical trials by Stiefel for the oral treatment of fungal infections, including toenail fungus, distal onychomycosis and subungual onychomycosis. Early clinical trials for the treatment of tinea pedis have been completed. In September 2005, Uriach, originator of albaconazole, granted Stiefel exclusive rights to develop and market albaconazole on a worldwide basis. In November 2006, Uriach’s R&D pipeline was transferred to Palau Pharma, a newly-created spin-out company. Under the terms of the agreement with Stiefel, Palau retains rights as comarketing partner in some European countries. In August 2013, Palau Pharma granted worldwide rights to Actavis. A triazole, albaconazole, has shown potent activity against a broad range of organisms, including pathogens resistant to other antifungals, such as fluconazole or itraconazole. It will be developed as an oral and topical formulation, and is expected to be available to the medical community for a variety of dermatological indications and fungal infections, including vulvovaginal candidiasis.
 |
|
| Systematic (IUPAC) name | |
|---|---|
| 7-Chloro-3-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]quinazolin-4-one | |
| Clinical data | |
| Identifiers | |
| CAS number | 187949-02-6  |
| ATC code | None |
| PubChem | CID 208952 |
| ChemSpider | 181045 |
| UNII | YDW24Y8IAB |
| KEGG | D09702 |
| ChEMBL | CHEMBL298817 |
| Chemical data | |
| Formula | C20H16ClF2N5O2 |
| Mol. mass | 431.823146 g/mol |
|
11-26-2003
|
Method for preparing pyrimidone derivatives with antifungal activity
|
The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.
The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.
EP 0783501; ES 2107376; ES 2120885; JP 1998508317; US 5807854; WO 9705130
…………………………………………..
The condensation of (R)-lactic acid (I) with morpholine (II) gives the corresponding morpholide (III), which is protected at the hydroxyl position with dihydropyran (IV) to yield the tetrahydropyranyl ether (V). The Grignard reaction of (V) with 2,4-difluorophenylmagnesium bromide (VI) affords the chiral 1-propanone (VII), which by a Corey’s diastereoselective epoxidation with trimethylsulfoxonium iodide is converted into the oxirane (VIII). The opening of the oxirane ring of (VIII) by means of 1,2,4-triazole (IX) and NaH provides the tertiary alcohol (X), which is treated with pyridine p-toluenesulfonate to give the deprotected diol (XI) as a (2R,3R) and (2R,3S) 4:1 diastereomeric mixture, from which the desired (2R,3R)-isomer (XII) was isolated by crystallization. The reaction of (XII) with Ms-Cl and TEA, followed by cyclization with NaOMe, yields the oxirane (XIII), which is finally condensed with 7-chloroquinazolin-4(3H)-one (XIV) by means of K2CO3 in hot NMP.
ES 2159488; WO 0166519
…………………………………………….
Alternatively, intermediate (XIII) can be obtained as follows: Heating of ethyl (S)-lactate (XIV) with morpholine affords amide (XVI), which then reacts with 3,4-dihydro-2H-pyran (A) in the presence of p-TsOH to give protected derivative (XVII). Grignard reaction between (XVII), bromo derivative (XVIII) and Mg turnings in THF yields protected ketone (XIX), which is treated with pyridinium p-toluenesulfonate (PPTS) (THP group removal) and reprotected by means of Tf2O and DIEA to give triflate derivative (XX). Conversion of (XX) into intermediate (XIII) is achieved by reaction with triazolone (VII) and NaH in THF.
Chem Pharm Bull 1993,41(6),1035-42
……………………………………
Alternatively, derivative (XXIX) can be obtained in an analogous way as its enantiomer (XIX). Diastereoselective epoxidation of (XXIX) with trimethylsulfoxonium iodide and NaH in DMSO provides oxirane (XXX) (3). THP group removal by means of PPTS in EtOH, followed by reaction with 3,5-dinitrobenzoyl chloride (XXXI) and NaHCO3 in CH2Cl2, yields a diastereomeric mixture from which dinitrobenzoate derivative (2R,3R)-(XXXII) is obtained by recrystallization (1). Hydrolysis of (2R,3R)-(XXXII) in MeOH by treatment with aqueous NaOH gives compound (2R,3R)-(XXXIII), which is converted into ester (2R,3S)-(XXXIV) by Mitsunobu reaction with benzoic acid, Ph3P and DEAD in THF. Subsequent debenzoylation of (2R,3S)-(XXXIV) with NaOMe in MeOH affords oxiranyl ethanol derivative (2R,3R)-(XXXV), which is first converted into its triflate derivative by means of Tf2O and DIEA in CH2Cl2, and then into triazolone derivative (2S,3R)-(XXXVI) by reaction with intermediate (VII) and NaH in CH2Cl2/DMF. Finally, oxirane derivative (2S,3R)-(XXXVI) reacts with triazole (XXVI) and NaH in DMF to furnish the desired product.
…………………………………………………..
ER-30346 is synthesized by thiazole ring formation of (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)thiobutanamide (I) and 4-bromoacetylbenzonitrile (II) by means of reflux in methanol. The thioamide (I) is obtained with excellent yield from a chiral nitrile (III) by heating with diethyl dithiophosphate in aqueous medium.
…………………………………………….
The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-a: The key step of this route is ring opening reaction of the trisubstituted oxirane (VII) by cyanide anion leading to the nitrile (III). The chiral oxirane (VII) is synthesized from (R)-lactic acid derivatives as already reported. The reaction of (VII) with diethylaluminum cyanide in toluene or lithium cyanide in tetrahydrofuran gives the nitrile (III) with high yield without any epimerization reaction.
…………………………………………..
The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-b: The starting material of this route is methyl (S)-3-hydroxy-2-methylpropionate (VIII), which contains one additional carbon between the hydroxyl group and the 2-position carbon of (R)-lactate, the starting material of route-a. The hydroxyl group of (VIII) is protected by triphenylmethyl group. Then, 2,4-difluorophenyl moiety is introduced to give the ketone (X). Direct conversion of the ketone (X) to the oxirane (XIV) by dimethylsulfoxonium methylide, the same condition for compound (IV) in route-a, does not proceed. The oxirane (XIV) having desired stereochemistry is obtained via oxidation reaction. The ketone (X) is converted to the exomethylene (XI) by Wittig reaction. The stereoselective oxidation of (XI) is achieved by means of osmium tetroxide in the presence of 4-methylmorpholine N-oxide to give the diol (XII) in 58% yield after separation of its epimer by column chromatography. After methanesulfonylation of the primary alcohol of (XII), a triazole moiety is introduced and the triphenylmethyl group is deprotected. Then, the primary hydroxyl group of (XVI) is oxidized under Swern oxidation condition to give the aldehyde (XVII), which is converted to the chiral nitrile intermediate (III) by means of heating with hydroxylamine-O-sulfonic acid.
………………………………..
A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure−activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures described in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found to be dependent on hydrophobicity, which, in turn, modulated the compound’s half-life. The 7-Cl derivative, (1R,2R)-7-chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic profile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (1R,2S) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was superior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration was limited to the first day. This was attributed to its short half-life in that species (t1/2 = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compound was found to be 6 and 9 h, respectively. Finally, 20 showed excellent protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administered to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.
The condensation of the chiral oxazolidinone (I) with 2,4-difluorophenacyl bromide (II) by means of NaHMDS in THF/Et2 O gives the chiral oxirane (III), which is treated with LiOH and H2O2 to eliminate the chiral auxiliary, yielding the carboxylic acid (IV). The cleavage of the oxirane ring of (IV) with 1,2,4-triazole (V) and NaH in hot DMF affords the chiral hydroxyacid (VI), which is submitted to Curtius rearrangement by means of DPPA in hot pyridine to provide the chiral oxazolidinone (VII). The cleavage of the oxazolidinone ring of (VII) by means of refluxing aq. HCl gives the chiral aminoalcohol (VIII), which is condensed with 2-amino-4-chlorobenzoic acid (IX) by means of DCC and HOBt to yield the corresponding amide (X). Finally, this compound is cyclized to the target quinazolinone by reaction with triethyl orthoformate in hot dioxane/NMP.
J Med Chem 1998,41(11),1869
http://pubs.acs.org/doi/abs/10.1021/jm9707277
(1R,2R)-7-Chloro-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]quinazolin-4(3H)-one (20, UR-9825). Precipitated from EtOH/H2O (66% yield from amine 11): white amorphous solid;
mp 93−110 °C (wide range);
IR (KBr) ν 1675, 1601, 1554, 1498 cm-1;
1H NMR (300 MHz, CDCl3) 8.58 (s, 1H, N
CH-N), 8.26 (d, J = 8.6, 1H, arom), 8.11 (d, J = 5.7, trace rotamer), 7.76 (s, 2H, triazol),
7.74 (d, J = 5.3, 1H, arom), 7.5 (m, 2H, arom), 7.10 (s, trace rotamer), 6.9−6.7 (m, 2H, arom),
5.91 (dq, Jd = 2, Jq = 7, 1H, MeCH), 5.54 (d, J = 2, 1H, OH),
5.15 (d, J = 14.2 1H, CH(H)), 4.9−4.7 (m, trace rotamer), 4.30 (d, trace rotamer), 3.99 (d, J = 14.2, 1H, CH(H)),
1.46 (d, J = 6.9, trace rotamer), 1.29 (d, J = 7, 3H, CHMe);
GC−MS 224 (Tr-CH2COHAr, C10H8F2N3O), 208 (group N-ethylheterocycle, C10H9ClN2O);
[α]D −8.0° (c 1, CHCl3).
Chiral HPLC (column, CicloBond SN 1; eluent, MeOH: Et3NHOAc in H2O at pH7 1:1; retention times: (S,S) (74) tR 12.6 min; (R,R) (20) tR 13.7 min). Area ratio: 0.01:99.99.
Anal. (C20H16ClF2N5O2) C, H, N.
KEY
Albaconazole,UNII-YDW24Y8IAB, UR-9825, UR 9825, W-0027
Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia
Duvelisib
Infinity and AbbVie partner to develop and commercialise duvelisib for cancer
INK 1197; IPI 145; 8-Chloro-2-phenyl-3-[(1S)-1-(9H-purin-6-ylamino)ethyl]-1(2H)-isoquinolinone
1(2H)-Isoquinolinone, 8-chloro-2-phenyl-3-((1S)-1-(9H-purin-6-ylamino)ethyl)-
8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one
(S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
UNII-610V23S0JI; IPI-145; INK-1197;
Originator…….. Millennium Pharmaceuticals
| Molecular Formula | C22H17ClN6O | |
| Molecular Weight | 416.86 | |
| CAS Registry Number | 1201438-56-3 |
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma, to treat patients with cancer.
Infinity Pharmaceuticals has partnered with AbbVie to develop and commercialise its duvelisib (IPI-145), an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K gamma, to treat patients with cancer.
Duvelisib has shown clinical activity against different blood cancers, such as indolent non-Hodgkin’s lymphoma (iNHL) and chronic lymphocytic leukemia (CLL).
AbbVie executive vice-president and chief scientific officer Michael Severino said: “We believe that duvelisib is a very promising investigational treatment based on clinical data showing activity in a broad range of blood cancers.”
Duvelisib (IPI-145, INK-1197), an inhibitor of PI3K-delta and –gamma, originated at Takeda subsidiary Intellikine. It is now being developed by Infinity Pharmaceuticals, which began a phase III trial in November, following US and EU grant of orphan drug status for both CLL and small lymphocytic leukemia
INK-1197 is a dual phosphatidylinositol 3-Kinase delta (PI3Kdelta) and gamma (PI3Kgamma) inhibitor in phase III clinical development at Infinity Pharmaceuticals for the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma. The company is also carring phase II trials for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma) are currently under way.
IPI-145 is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma. The PI3K-delta and PI3K-gamma isoforms are preferentially expressed in leukocytes (white blood cells), where they have distinct and non-overlapping roles in key cellular functions, including cell proliferation, cell differentiation, cell migration and immunity. Targeting PI3K-delta and PI3K-gamma may provide multiple opportunities to develop differentiated therapies for the treatment of blood cancers and inflammatory diseases.
Licensee Infinity Pharmaceuticals is developing INK-1197. In 2014, Infinity licensed Abbvie for joint commercialization in the U.S. and exclusive commercialization elsewhere. Originator Millennium Pharmaceuticals had also been developing the compound; however, no recent development has been reported for this research. In 2013, orphan drug designations were assigned by the FDA and the EMA for the treatment of chronic lymphocytic leukemia, for the treatment of small lymphocytic lymphoma and for the treatment of follicular lymphoma.
currently enrolling patients DYNAMO™, a Phase 2 study designed to evaluate the activity and safety of IPI-145 in approximately 120 people with refractory indolent non-Hodgkin lymphoma (iNHL) and DUO™, a Phase 3 clinical study of IPI-145 in approximately 300 people with relapsed/refractory chronic lymphocytic leukemia (CLL). These studies are supported by Phase 1 data reported at the 2013 American Society of Hematology (ASH) Annual Meeting which showed that IPI-145 was well tolerated and clinically active in a broad range of malignancies, including iNHL and CLL. These studies are part of DUETTS™, a worldwide investigation of IPI-145 in blood cancers.
WO 2011008302
http://www.google.com/patents/WO2011008302A1?cl=en
Reaction Scheme 1
Reaction Scheme 2:
201 202 203
204 205
Reaction Scheme 3:
Reaction Scheme 4A:
Reaction Scheme 4B:
2
Example 14b: Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)
(compound 4904)
Scheme 27b. The synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (9)
(compound 4904) is described.
[00493] The compound of Formula 4904 (compound 292 in Table 4) was synthesized using the synthetic transformations as described in Examples 12 and 14a, but 2-chloro-6-methyl benzoic acid (compound 4903) was used instead of 2, 6 ,dimethyl benzoic acid (compound 4403). By a similar method, compound 328 in Table 4 was synthesized using the synthetic transformations as described starting from the 2-chloro-6-methyl m-fluorobenzoic acid.
…………………………………….
http://www.google.com/patents/WO2012097000A1?cl=en OR http://www.google.com/patents/US8809349?cl=en
Formula (I):
(I),
or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In one embodiment, the method comprises any one, two, three, four, five, six, seven, or eight, or more of the following steps:
“Formula (I)” includes (S)-3-(l -(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one in its imide tautomer shown below as (1-1) and in its lactim tautomer shown below as (1-2):
(1-1)………………………………………………………………………………… (1-2)
[0055] FIG. 27 shows an FT-IR spectra of Polymorph Form C.
[0056] FIG. 28 shows a ‘H-NMR spectra of Polymorph Form C.
[0057] FIG. 29 shows a 13C-NMR spectra of Polymorph Form C.
Example 1
Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
Example 1A
1 2
[00563] Compound 1 (6.00 kg) was treated with 1-hydroxybenzotriazole monohydrate (HOBt»H20), triethylamine, Ν,Ο-dimethylhydroxylamine hydrochloride, and EDCI in dimethylacetamide (DMA) at
10 °C. The reaction was monitored by proton NMR and deemed complete after 2.6 hours, affording Compound 2 as a white solid in 95% yield. The R-enantiomer was not detected by proton NMR using (R)-(- ) -alpha-ace tylmandelic acid as a chiral-shift reagent.
[00564] Compound 3 (4.60 kg) was treated with p-toluenesulfonic acid monohydrate and 3,4-dihydro-2H- pyran (DHP) in ethyl acetate at 75 °C for 2.6 hours. The reaction was monitored by HPLC. Upon completion of the reaction, Compound 4 was obtained as a yellow solid in 80% yield with >99% (AUC) purity by HPLC analysis.
[00565] Compound 5 (3.30 kg) was treated with thionyl chloride and a catalytic amount of DMF in methylene chloride at 25 °C for five hours. The reaction was monitored by HPLC which indicated a 97.5% (AUC) conversion to compound 6. Compound 6 was treated in situ with aniline in methylene chloride at 25 °C for 15 hours. The reaction was monitored by HPLC and afforded Compound 7 as a brown solid in 81% yield with >99% (AUC) purity by HPLC analysis. [00566] Compound 2 was treated with 2.0 M isopropyl Grignard in THF at -20 °C. The resulting solution was added to Compound 7 (3.30 kg) pre -treated with 2.3 M n-hexyl lithium in tetrahydrofuran at -15 °C. The reaction was monitored by HPLC until a 99% (AUC) conversion to Compound 8 was observed.
Compound 8 was treated in situ with concentrated HC1 in isopropyl alcohol at 70 °C for eight hours. The reaction was monitored by HPLC and afforded Compound 9 as a brown solid in 85% yield with 98% (AUC) purity and 84% (AUC) ee by HPLC analysis.
Example ID
[00567] Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at 55 °C for 1-2 hours. The batch was filtered and treated with ammonium hydroxide in deionized (DI) water to afford enantiomerically enriched Compound 9 as a tan solid in 71% yield with >99% (AUC) purity and 91% (AUC) ee by HPLC analysis.
Example 2
Synthesis of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
Example 2A
[00568] To Compound 7 (20.1 g) was charged 100 mL of anhydrous THF. The resulting solution was cooled to about -10 °C and 80 mL of n-hexyl lithium (2.3 M in hexanes, 2.26 equiv.) was slowly added (e.g. , over about 20 min). The resulting solution was stirred at about -10 °C for about 20 min.
[00569] To Compound 2 (26.5 g; 1.39 equiv.) was charged 120 mL of anhydrous THF. The resulting mixture was cooled to about -10 °C and 60 mL of isopropyl magnesium chloride (2.0 M in THF, 1.47 equiv.) was slowly added (e.g. , over about 15-20 min). The resulting mixture was then stirred at about -10 °C for about 20 min. The mixture prepared from Compound 2 was added to the solution prepared from Compound 7 while maintaining the internal temperature between about -10 and about 0 °C. After the addition was complete (about 5 min), the cold bath was removed, and the resulting mixture was stirred at ambient temperature for about 1 h, then cooled. [00570] A solution of 100 mL of anisole and 33 mL of isobutyric acid (4.37 equiv.) was prepared. The anisole solution was cooled to an internal temperature of about -3 °C. The above reaction mixture was added to the anisole solution such that the internal temperature of the anisole solution was maintained at below about 5 °C. The ice bath was then removed (after about 15 min, the internal temperature was about 7 °C). To the mixture, 100 mL of 10 wt aqueous NaCl solution was rapidly added (the internal temperature increased from about 7 °C to about 15 °C). After stirring for about 30 min, the two phases were separated. The organic phase was washed with another 100 mL of 10 wt aqueous NaCl. The organic phase was transferred to a flask using 25 mL of anisole to facilitate the transfer. The anisole solution was then concentrated to 109 g. Then, 100 mL of anisole was added.
[00571] To the approximately 200 mL of anisole solution was added 50 mL of TFA (8 equiv.) while maintaining the internal temperature below about 45-50 °C. The resulting solution warmed to about 45-50 °C and stirred for about 15 hrs, then cooled to 20-25 °C. To this solution was added 300 mL of MTBE dropwise and then the resulting mixture was held at 20-25 °C for 1 h. The mixture was filtered, and the wet cake washed with approximately 50 mL of MTBE. The wet cake was conditioned on the filter for about 1 h under nitrogen. The wet cake was periodically mixed and re-smoothed during conditioning. The wet cake was then washed with 200 mL of MTBE. The wet cake was further conditioned for about 2 h (the wet cake was mixed and resmoothed after about 1.5 h). The wet cake was dried in a vacuum oven at about 40 °C for about 18 h to afford Compound 9»TFA salt in about 97.3% purity (AUC), which had about 99.1 % S- enantiomer (e.g. , chiral purity of about 99.1 %).
[00572] Compound 9»TFA salt (3 g) was suspended in 30 mL of EtOAc at about 20 °C. To the EtOAc suspension was added 4.5 mL (2.2 eq.) of a 14% aqueous ammonium hydroxide solution and the internal temperature decreased to about 17 °C. Water (5 mL) was added to the biphasic mixture. The biphasic mixture was stirred for 30 min. The mixing was stopped and the phases were allowed to separate. The aqueous phase was removed. To the organic phase (combined with 5 mL of EtOAc) was added 10 mL of 10% aqueous NaCl. The biphasic mixture was stirred for about 30 min. The aqueous phase was removed. The organic layer was concentrated to 9 g. To this EtOAc mixture was added 20 mL of i-PrOAc. The resulting mixture was concentrated to 14.8 g. With stirring, 10 mL of n-heptane was added dropwise. The suspension was stirred for about 30 min, then an additional 10 mL of n-heptane was added. The resulting suspension was stirred for 1 h. The suspension was filtered and the wet cake was washed with additional heptane. The wet cake was conditioned for 20 min under nitrogen, then dried in a vacuum oven at about 40 °C to afford Compound 9 free base in about 99.3% purity (AUC), which had about 99.2% S-enantiomer (e.g., chiral purity of about 99.2%).
Example 2B [00573] A mixture of Compound 7 (100 g, 0.407 mol, 1 wt) and THF (500 mL, 5 vol) was prepared and cooled to about 3 °C. n-Hexyllithium (2.3 M in hexanes, 400 mL, 0.920 mol, 2.26 equiv) was charged over about 110 minutes while maintaining the temperature below about 6 °C. The resulting solution was stirred at 0 ± 5 °C for about 30 minutes. Concurrently, a mixture of Compound 2 (126 g, 0.541 mol, 1.33 equiv) and THF (575 mL, 5.8 vol) was prepared. The resulting slurry was charged with isopropylmagnesium chloride (2.0 M in THF, 290 mL, 0.574 mol, 1.41 equiv) over about 85 minutes while maintaining the temperature below about 5 °C. The resulting mixture was stirred for about 35 minutes at 0 ± 5 °C. The Compound 2 magnesium salt mixture was transferred to the Compound 7 lithium salt mixture over about 1 hour while maintaining a temperature of 0 ± 5 °C. The solution was stirred for about 6 minutes upon completion of the transfer.
[00574] The solution was added to an about -5 °C stirring solution of isobutyric acid (165 mL, 1.78 mol, 4.37 equiv) in anisole (500 mL, 5 vol) over about 20 minutes during which time the temperature did not exceed about 6 °C. The resulting solution was stirred for about 40 minutes while being warmed to about 14 °C. Then, a 10% sodium chloride solution (500 mL, 5 vol) was rapidly added to the reaction. The temperature rose to about 21 °C. After agitating the mixture for about 6 minutes, the stirring was ceased and the lower aqueous layer was removed (about 700 mL). A second portion of 10% sodium chloride solution (500 mL, 5 vol) was added and the mixture was stirred for 5 minutes. Then, the stirring was ceased and the lower aqueous layer was removed. The volume of the organic layer was reduced by vacuum distillation to about 750 mL (7.5 vol).
[00575] Trifluoroacetic acid (250 mL, 3.26 mol, 8.0 equiv) was added and the resulting mixture was agitated at about 45 °C for about 15 hours. The mixture was cooled to about 35 °C and MTBE (1.5 L, 15 vol) was added over about 70 minutes. Upon completion of the addition, the mixture was agitated for about 45 minutes at about 25-30 °C. The solids were collected by vacuum filtration and conditioned under N2 for about 20 hours to afford Compound 9*TFA salt in about 97.5% purity (AUC), which had a chiral purity of about 99.3%.
[00576] Compound 9»TFA salt (100 g) was suspended EtOAc (1 L,10 vol) and 14% aqueous ammonia (250 mL, 2.5 vol). The mixture was agitated for about 30 minutes, then the lower aqueous layer was removed. A second portion of 14% aqueous ammonia (250 mL, 2.5 vol) was added to the organic layer. The mixture was stirred for 30 minutes, then the lower aqueous layer was removed. Isopropyl acetate (300 mL, 3 vol) was added, and the mixture was distilled under vacuum to 500 mL (5 vol) while periodically adding in additional isopropyl acetate (1 L, 10 vol).
[00577] Then, after vacuum-distilling to a volume of 600 mL (6 vol), heptanes (1.5 L, 15 vol) were added over about 110 minutes while maintaining a temperature between about 20 °C and about 30 °C. The resulting slurry was stirred for about 1 hour, then the solid was collected by vacuum filtration. The cake was washed with heptanes (330 mL, 3.3 vol) and conditioned for about 1 hour. The solid was dried in an about 45 °C vacuum oven for about 20 hours to afford Compound 9 free base in about 99.23% purity (AUC), which has a chiral purity of about 99.4%.
Example 3
Chiral Resolution of (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9)
[00578] In some instances, (S)-3-(l-aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) obtained by synthesis contained a minor amount of the corresponding (R)-isomer. Chiral resolution procedures were utilized to improve the enantiomeric purity of certain samples of (S)-3-(l-aminoethyl)-8- chloro-2-phenylisoquinolin- 1 (2H)-one.
[00579] In one experiment, Compound 9 (3.40 kg) was treated with D-tartaric acid in methanol at about 55 °C for about 1 to about 2 hours. The mixture was filtered and treated with ammonium hydroxide in deionized (DI) water to afford Compound 9 in greater than about 99% (AUC) purity, which had a chiral purity of about 91% (AUC).
[00580] In another procedure, MeOH (10 vol.) and Compound 9 (1 equiv.) were stirred at 55 ± 5 °C. D- Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for about 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. The cake was returned to the reactor and water (16 vol.) was charged. The mixture was stirred at 25 ± 5 °C. NH4OH was then charged over about 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the cake was washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9 free base with a chiral purity of about 99.0%.
Example 4
Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
[00581] A mixture of Compound 7 (1 equiv.) and anhydrous THF (5 vol.) was prepared. Separately, a mixture of Compound 2 (1.3 equiv.) and anhydrous THF (5 vol.) was prepared. Both mixtures were stirred for about 15 min at about 20 to about 25 °C and then cooled to -25 ± 15 °C. n-Hexyl lithium (2.05 equiv.) was added to the Compound 7 mixture, maintaining the temperature at > 5 °C. i-PrMgCl (1.33 equiv.) was added to the Compound 2 mixture, maintaining the temperature at > 5 °C. The Compound 2 mixture was transferred to the Compound 7 mixture under anhydrous conditions at 0 ± 5 °C. The resulting mixture was warmed to 20 ± 2 °C and held for about 1 h. Then, the reaction was cooled to -5 ± 5 °C, and 6 N HC1 (3.5 equiv.) was added to quench the reaction, maintaining temperature at below about 25 °C. The aqueous layer was drained, and the organic layer was distilled under reduced pressure until the volume was 2-3 volumes. IPA (3 vol.) was added and vacuum distillation was continued until the volume was 2-3 volumes. IPA (8 vol.) was added and the mixture temperature was adjusted to about 60 °C to about 75 °C. Cone. HC1 (1.5 vol.) was added and the mixture was subsequently held for 4 hours. The mixture was distilled under reduced pressure until the volume was 2.5-3.5 volumes. The mixture temperature was adjusted to 30 ± 10 °C. DI water (3 vol.) and DCM (7 vol.) were respectively added to the mixture. Then, NH4OH was added to the mixture, adjusting the pH to about 7.5 to about 9. The temperature was adjusted to about 20 to about 25 °C. The layers were separated and the aqueous layer was washed with DCM (0.3 vol.). The combined DCM layers were distilled until the volume was 2 volumes. i-PrOAc (3 vol.) was added and vacuum distillation was continued until the volume was 3 volumes. The temperature was adjusted to about 15 to about 30 °C. Heptane (12 vol.) was charged to the organic layer, and the mixture was held for 30 min. The mixture was filtered and filter cake was washed with heptane (3 vol.). The cake was vacuum dried at about 45 °C afford Compound 9.
[00582] Then, MeOH (10 vol.) and Compound 9 (1 equiv.) were combined and stirred while the temperature was adjusted to 55 ± 5 °C. D-Tartaric acid (0.95 equiv.) was charged. The mixture was held at 55 ± 5 °C for about 30 min and then cooled to about 20 to about 25 °C over about 3 h. The mixture was held for 30 min and then filtered. The filter cake was washed with MeOH (2.5 vol.) and then conditioned. Water (16 vol.) was added to the cake and the mixture was stirred at 25 ± 5 °C. NH4OH was charged over 1 h adjusting the pH to about 8 to about 9. The mixture was then filtered and the resulting cake washed with water (4 vol.) and then heptanes (4 vol.). The cake was conditioned and then vacuum dried at 45-50 °C to afford Compound 9.
[00583] To a mixture of i-PrOH (4 vol.) and Compound 9 (1 equiv.) was added Compound 4 (1.8 equiv.), Et3N (2.5 equiv.) and i-PrOH (4 vol.). The mixture was agitated and the temperature was adjusted to 82 ± 5 °C. The mixture was held for 24 h. Then the mixture was cooled to about 20 to about 25 °C over about 2 h. The mixture was filtered and the cake was washed with i-PrOH (2 vol.), DI water (25 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford Compound 10.
To a mixture of EtOH (2.5 vol.) and Compound 10 (1 equiv.) was added EtOH (2.5 vol.) and DI water (2 vol.). The mixture was agitated at about 20 to about 25 °C. Cone. HC1 (3.5 equiv.) was added and the temperature was adjusted to 35 ± 5 °C. The mixture was held for about 1.5 h. The mixture was cooled to 25 ± 5 °C and then polish filtered to a particulate free vessel. NH4OH was added, adjusting the pH to about 8 to about 9. Crystal seeds of Form C of a compound of Formula (I) (0.3 wt ) were added to the mixture which was held for 30 minutes. DI water (13 vol.) was added over about 2 h. The mixture was held for 1 h and then filtered. The resulting cake was washed with DI water (4 vol.) and n-heptane (2 vol.) respectively. The cake was conditioned for about 24 h and then DCM (5 vol.) was added. This mixture was agitated for about 12 h at about 20 to about 25 °C. The mixture was filtered and the cake washed with DCM (1 vol.). The cake was conditioned for about 6 h. The cake was then vacuum-dried at 50 ± 5 °C. To the cake was added DI water (10 vol.), and i-PrOH (0.8 vol.) and the mixture was agitated at 25 ± 5 °C for about 6 h. An XRPD sample confirmed the compound of Formula (I) was Form C. The mixture was filtered and the cake was washed with DI water (5 vol.) followed by n-heptane (3 vol.). The cake was conditioned and then vacuum dried at 50 ± 5 °C to afford a compound of Formula (I) as polymorph Form C. Example 5
Synthesis of (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
Example 5A
[00584] Compound 9 (2.39 kg) was treated with Compound 4 and triethylamine in isopropyl alcohol at 80 °C for 24 hours. The reaction was monitored by HPLC until completion, affording 8-chloro-2-phenyl-3- ((lS)-l-(9-(tetrahydro-2H^yran-2-yl)-9H^urin-6-ylamino)ethyl)isoquinolin-l(2H)-one (compound 10) as a tan solid in 94% yield with 98% (AUC) purity by HPLC analysis.
[00585] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (compound 10) (3.63 kg) was treated with HC1 in ethanol at 30 °C for 2.3 hours. The reaction was monitored by HPLC until completion, and afforded a compound of Formula (I) as a tan solid in 92% yield with >99% (AUC) purity and 90.9% (AUC) ee by HPLC analysis.
Example 5B
[00586] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (0.72 mmol), 6-chloro- 9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (344 mg, 1.44 mmol) and DIPEA
(279 mg, 2.16 mmol) were dissolved in «-BuOH (20 mL), and the resulting mixture was stirred at reflux for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the product, 8-chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H- pyran-2-yl)-9H-purin-6-ylamino)ethyl)isoquinolin-l(2H)-one (Compound 10), as a white solid (60% yield). [00587] 8-Chloro-2-phenyl-3-((lS)-l-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)- isoquinolin-l(2H)-one (Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHC03 aqueous solution and the pH was adjusted to about 7-8. The mixture was extracted with CH2C12 (50 mL x 3), dried over anhydrous Na2S04, and filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexanes (1 : 1). The solid was collected by filtration and dried in vacuo to afford the product (S)-3-(l-(9H-purin-6-ylamino) ethyl)-8-chloro-2-phenylisoquinolin- l(2H)-one (Formula (I)) (90% yield) as a white solid as polymorph Form A.
Example 5C
[00588] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) and 6-chloro-9- (tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) are combined in the presence of triethylamine and isopropyl alcohol. The reaction solution is heated at 82 °C for 24 hours to afford Compound 10. The intermediate compound 10 is treated with concentrated HCl and ethanol under aqueous conditions at 35 °C to remove the tetrahydropyranyl group to yield (S)-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2- phenylisoquinolin-l(2H)-one. Isolation/purification under aqueous conditions affords polymorph Form C.
Example 6
Synthesis of (S)-3-(l-(9H^urin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
[00589] 3-(l-Aminoethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (Compound 9) (150 g; 90% ee) and 6- chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Compound 4) (216 g, 1.8 equiv) were charged to a round bottom flask followed by addition of IPA (1.2 L; 8 vol) and triethylamine (175 mL; 2.5 equiv). The resultant slurry was stirred at reflux for one day. Heptane (1.5 L; 10 vol) was added dropwise over two hours. The batch was then cooled to 0-5 °C, held for one hour and filtered. The cake was washed with heptane (450 mL; 3 vol) and returned to the reactor. IPA (300 mL; 2 vol) and water (2.25 L; 15 vol) were added and the resultant slurry stirred at 20-25 °C for three and half hours then filtered. The cake was washed with water (1.5 L; 10 vol) and heptane (450 mL; 3 vol) and then vacuum dried at 48 °C for two and half days to give 227 g (90.1 %) of the intermediate (Compound 10) as an off-white solid with >99% (AUC) purity and >94 ee (chiral HPLC). The ee was determined by converting a sample of the cake to the final product and analyzing it with chiral HPLC.
[00590] The intermediate (Compound 10) (200 g) was slurried in an ethanol (900 mL; 4.5 vol) / water (300 mL; 1.5 vol) mixture at 22 °C followed by addition of cone. HC1 (300 mL; 1.5 vol) and holding for one and half hours at 25-35 °C. Addition of HC1 resulted in complete dissolution of all solids producing a dark brown solution. Ammonium hydroxide (260 mL) was added adjusting the pH to 8-9. Product seeds of polymorph Form C (0.5 g) (Form A seeds can also be used) were then added and the batch which was held for ten minutes followed by addition of water (3 L; 15 vol) over two hours resulting in crystallization of the product. The batch was held for 3.5 hours at 20-25 °C and then filtered. The cake was washed with water (1 L; 5 vol) followed by heptane (800 mL; 4 vol) and vacuum dried at 52 °C for 23 hours to give 155.5 g (93.5%) of product with 99.6% (AUC) purity and 93.8% ee (chiral HPLC).
Example 7
-3-(l-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one
[00591] A mixtue of isopropanol (20.20 kg, 8 vol.), Compound 9 (3.17 kg, 9.04 mol, 1 eq.), Compound 4 (4.61 kg, 16.27 mol, 1.8 eq.) and triethylamine (2.62 kg, 20.02 mol, 2.4 eq.) was prepared and heated to an internal temperature of 82 ± 5 °C. The mixture was stirred at that temperature for an additional about 24 h. The temperature was adjusted to 20 ± 5 °C slowly over a period of about 2 h and the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a Sharkskin paper. The filter cake was rinsed sequentially with IPA (5.15 kg, 3 vol.), purified water (80.80 kg, 25 vol.) and n-heptane (4.30 kg, 2 vol.). The cake was further dried for about 4 days in vacuo at 50 ± 5 °C to afford Compound 10.
[00592] To a mixture of ethanol (17.7 kg, 5 vol.) and Compound 10 (4.45 kg, 8.88 mol. 1.0 eq.) was added purified water (8.94 kg, 2 vol.). To this mixture was slowly added concentrated HC1 (3.10 kg, 3.5 eq.) while maintaining the temperature below about 35 °C. The mixture was stirred at 30 ± 5 °C for about 1.5 h and HPLC analysis indicated the presence the compound of Formula (I) in 99.8% (AUC) purity with respect to compound 10.
[00593] Then, the compound of Formula (I) mixture was cooled to 25 ± 5 °C. The pH of the mixture was adjusted to about 8 using pre filtered ammonium hydroxide (1.90 kg). After stirring for about 15 min, Form C crystal seeds (13.88 g) were added. After stirring for about 15 min, purified water (58.0 kg, 13 vol.) was charged over a period of about 2 h. After stirring the mixture for 15 h at 25 ± 5 °C, the solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper. The filter cake was rinsed with purified water (18.55 kg, 4 vol.) followed by pre -filtered n-heptane (6.10 kg, 2 vol.). After conditioning the filter cake for about 24 h, HPLC analysis of the filter cake indicated the presence the compound of Formula (I) in about 99.2% (AUC) purity.
[00594] To the filter cake was added dichloromethane (29.9 kg, 5 vol.) and the slurry was stirred at 25 ± 5 °C for about 24 h. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with DCM (6.10 kg, 1 vol.). After conditioning the filter cake for about 22 h, the filter cake was dried for about 2 days in vacuo at 50 ± 5 °C to afford the compound of Formula (I) in 99.6% (AUC) purity. The compound of Formula (I) was consistent with a Form A reference by XRPD.
[00595] To this solid was added purified water (44.6 kg, 10 vol.) and pre filtered 2-propanol (3.0 kg, 0.8 vol.). After stirring for about 6 h, a sample of the solids in the slurry was analyzed by XRPD and was consistent with a Form C reference. The solids were isolated via vacuum filtration through a 24″ polypropylene table top filter equipped with a PTFE cloth over Sharkskin paper, and the filter cake was rinsed with purified water (22.35 kg, 5 vol.) followed by pre filtered n-heptane (9.15 kg, 3 vol.). After conditioning the filter cake for about 18 h, the filter cake was dried in vacuo for about 5 days at 50 ± 5 °C.
[00596] This process afforded a compound of Formula (I) in about 99.6% (AUC) purity, and a chiral purity of greater than about 99% (AUC). An XRPD of the solid was consistent with a Form C reference standard. :H NMR (DMSO-<i6) and IR of the product conformed with reference standard.
…………………………..
http://www.google.com/patents/US20140120083
In some embodiments, the compound has the following structure:
which is also referred to herein as Compound 292.
In some embodiments, a polymorph of a compound disclosed herein is used. Exemplary polymorphs are disclosed in U.S. Patent Publication No. 2012-0184568 (“the ‘568 publication”), which is hereby incorporated by reference in its entirety.
In one embodiment, the compound is Form A of Compound 292, as described in the ‘568 publication. In another embodiment, the compound is Form B of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form C of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form D of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form E of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form F of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form G of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form H of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form I of Compound 292, as described in the ‘568 publication. In yet another embodiment, the compound is Form J of Compound 292, as described in the ‘568 publication.
In specific embodiments, provided herein is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application. In specific embodiments, provided herein is a pharmaceutically acceptable form of Compound 292, which is a crystalline monohydrate of the free base of Compound 292, as described, for example, in the ‘568 application.
Any of the compounds (PI3K modulators) disclosed herein can be in the form of pharmaceutically acceptable salts, hydrates, solvates, chelates, non-covalent complexes, isomers, prodrugs, isotopically labeled derivatives, or mixtures thereof.
Chemical entities described herein can be synthesized according to exemplary methods disclosed in U.S. Patent Publication No. US 2009/0312319, International Patent Publication No. WO 2011/008302A1, and U.S. Patent Publication No. 2012-0184568, each of which is hereby incorporated by reference in its entirety, and/or according to methods known in the art.
……………………………………………
KEY Duvelisib, IPI-145, INK-1197, AbbVie, INFINITY, chronic lymphocytic leukemia, phase 3, orphan drug
| WO2013088404A1 | Dec 14, 2012 | Jun 20, 2013 | Novartis Ag | Use of inhibitors of the activity or function of PI3K |
| WO2014004470A1 * | Jun 25, 2013 | Jan 3, 2014 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors |
| WO2014072937A1 | Nov 7, 2013 | May 15, 2014 | Rhizen Pharmaceuticals Sa | Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor |
| US7449477 * | Nov 22, 2004 | Nov 11, 2008 | Eli Lilly And Company | 7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (protein kinase B) |
| US20090312319 * | Jul 15, 2009 | Dec 17, 2009 | Intellikine | Certain chemical entities, compositions and methods |
| US20100168153 * | Nov 16, 2007 | Jul 1, 2010 | Novartis Ag | Salts and crystall forms of 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile |
| WO2013012915A1 | Jul 18, 2012 | Jan 24, 2013 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013012918A1 | Jul 18, 2012 | Jan 24, 2013 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013032591A1 | Jul 18, 2012 | Mar 7, 2013 | Infinity Pharmaceuticals Inc. | Heterocyclic compounds and uses thereof |
| WO2013049332A1 | Sep 27, 2012 | Apr 4, 2013 | Infinity Pharmaceuticals, Inc. | Inhibitors of monoacylglycerol lipase and methods of their use |
| WO2013088404A1 | Dec 14, 2012 | Jun 20, 2013 | Novartis Ag | Use of inhibitors of the activity or function of PI3K |
| WO2013154878A1 | Apr 3, 2013 | Oct 17, 2013 | Infinity Pharmaceuticals, Inc. | Heterocyclic compounds and uses thereof |
| WO2014004470A1 * | Jun 25, 2013 | Jan 3, 2014 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using pi3 kinase inhibitors |
| WO2014071105A1 | Nov 1, 2013 | May 8, 2014 | Infinity Pharmaceuticals, Inc. | Treatment of rheumatoid arthritis and asthma using p13 kinase inhibitors |
| WO2014071109A1 | Nov 1, 2013 | May 8, 2014 | Infinity Pharmaceuticals, Inc. | Treatment of cancers using pi3 kinase isoform modulators |
| WO2014072937A1 | Nov 7, 2013 | May 15, 2014 | Rhizen Pharmaceuticals Sa | Pharmaceutical compositions containing a pde4 inhibitor and a pi3 delta or dual pi3 delta-gamma kinase inhibitor |
| WO2001081346A2 | Apr 24, 2001 | Nov 1, 2001 | Icos Corp | Inhibitors of human phosphatidyl-inositol 3-kinase delta |
| US6800620 | Jan 6, 2003 | Oct 5, 2004 | Icos | Contacting leukocytes, osteoclasts with an enzyme inhibitors, a 9h-purin-3h-quinazolin-4-one derivatives, treating bone-resorption disorder, antiproliferative agents treating leukemia cells |
| US20060276470 * | Aug 18, 2003 | Dec 7, 2006 | Jackson Shaun P | (+-)-7-Methyl-2-morpholin-4-yl-9-(1-phenylaminoethyl)-pyrido[1,2-a]pyrimidin-4-one, for example; selective inhibitors of phosphoinositide (PI) 3-kinase beta for use in anti-thrombotic therapy |
| US20080032960 * | Apr 4, 2007 | Feb 7, 2008 | Regents Of The University Of California | PI3 kinase antagonists |
Tecadenoson…………Atrial Fibrillation
CVT-510 (tecadenoson) has chemical structure (8 :
EXAMPLE 1
The compounds of this invention may be prepared by conventional methods of organic chemistry. The reaction sequence outlined below, is a general method, useful for the preparation of compounds of this invention.
According to this method, oxacycloalkyl carboxylic acid is heated in a mixture of dioxane, diphenylphosphoryazide and triethylamine for 1 hour. To this mixture is added benzyl alcohol and the reaction is further heated over night to give intermediate compound 1. Compound 1 is dissolved in methanol. Next, concentrated HC1, Pd/C is added and the mixture is placed under hydrogen at 1 atm. The mixture is stirred overnight at room temperature and filtered. The residue is recrystallized to give intermediate compound 2. 6-chloropurine riboside is combined and the mixture is compound 2 dissolved in methanol and treated with triethylamine. The reaction is heated to 80° C for 30 hours. Isolation and purification leads to Compound 3.
EXAMPLE 2
Compounds of this invention prepared according to the method of Example 1 were tested in two functional models specific for adenosine A, receptor agonist function. The first was the A , receptor mediated inhibition of isoproterenol stimulated cAMP accumulation in DDT cells. The EC50 of each derivative is shown in Table I. Also shown in Table I is the ability of each derivative to stimulate cAMP production in PC 12 cells, a function of agonist stimulation of adenosine A2 receptors. The ratio of the relative potency of each compound in stimulating either an A, receptor or an A2 receptor effect is termed the selectivity of each compound for the A, receptor. As can be seen in Table I, each derivative is relatively selective as an A, receptor agonist. The use of measuring cAMP metabolism as an assay for adenosine A , receptor function has been previously described (Scammells, P., Baker, S., Belardinelli, L., and Olsson, R. , 1994, Substituted 1 ,3-dipropylxanthines as irreversible antagonists of A, adenosine receptors. J. Med. Chem 37: 2794-2712, 1994).
Table I
Compound R EC50 (nM) ECS, (nM) A,/A2 A-/A, DDT cells PC 12 cells
I 4-arninopyran 12 970 0.012 80.0
II (±)-3-aminotetrahydrofuran 13 1400 0.0093 107.6
III (R)-3-aminotetrahydrofuran 1.08 448 0.0024 414
IV ( 1 )-caprolactam 161 181 0.889 1.12
V (S)-3-aminotetrahydrofuran 3.40 7680 0.00044 2258
Compounds were also tested in a whole organ model of A, receptor activation with respect to atrial and AV nodal function. In this model, guinea pig hearts are isolated and perfused with saline containing compound while atrial rate and AV nodal conduction time are assessed by electrographic measurement of atrial cycle length and AV intervals, as detailed in Belardinelli, L, Lu, J. Dennis, D. Martens, J, and Shryock J. (1994); The cardiac effects of a novel A,-adenosine receptor agonist in guinea pig isolated heart. J. Pharm. Exp. Therap. 271:1371-1382 (1994). As shown in Figure 1, each derivative was effective in slowing the atrial rate and prolonging the AV nodal conduction time of spontaneously beating hearts in a concentration-dependent manner, demonstrating efficacy as adenosine A, receptor agonists in the intact heart.
EXAMPLE 3
Preparation ofN-benzyloxycarbonyl-4-aminopyran.
A mixture of 4-pyranylcarboxylic acid (2.28 gm, 20 mmol), diphenylphosphorylazide (4.31 ml, 20 mmol), triethylamine (2.78 ml, 20 mmol) in dioxane (40 ml) was heated in a 100° C oil bath under dry nitrogen for 1 hour. Benzyl alcohol (2.7 ml, 26 mmol) was added, and heating was continued at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice with EtOAc. The extracts were washed with water, sodium bicarbonate, brine and then dried over MgSO4, and concentrated to an oil which solidified upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 1.85 g of a white solid (40%).
Preparation of 4-aminopyran.
N-benzyloxycarbonyl-4-aminopyran (1.85 gm, 7.87 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C ( 10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of eelite and concentrated. The residue was co-evaporated twice with MeOH/EtOAc and recrystallized from MeOH/EtOAc to afford 980 mg (91 %) of white needles (mp 228-230° C).
Preparation of 6-(4-aminopyran)-purine riboside. A mixture of 6-chloropurine riboside (0.318 gm, 1. 1 mmol), 4-aminopyran-HCl
(0.220 mg,
1.6 mmol) and triethylamine (0.385 ml, 2.5 mmol) in methanol (10 ml) was heated to 80° C for 30 hours. The mixture was cooled, concentrated and the residue chromatographed (90: 10: 1, CH2 Cl2/MeOH/PrNH2). The appropriate fractions were collected and recliromatographed using a chromatotron
(2 mm plate, 90: 10: 1, CH2 Cl2/MeOH/PrNH2) to give an off white foam (0.37 gm, 95%).
EXAMPLE 4
Preparation of N-benzyloxycarbonyl-3-aminotetrahydrofuran. A mixture of 3-tetrahydrofuroic acid (3.5 gm, 30 mmol), diphenylphosphorylazide (6.82 ml, 32 mmol), triethylamine (5 ml, 36 mmol) in dioxane (35 ml) was stirred at RT for 20 min then heated in a 100° C oil bath under dry nitrogen for 2 hours. Benzyl alcohol (4.7 ml, 45 mmol) was added, and continued heating at 100° C for 22 hours. The mixture was cooled, filtered from a white precipitate and concentrated. The residue was dissolved in 2N HC1 and extracted twice using EtOAc. The extracts were washed with water, sodium bicarbonate, brine dried over MgSO4, and then concentrated to an oil which solidifies upon standing. The oil was chromatographed (30% to 60% EtO Ac/Hex) to give 3.4 g of an oil (51
%).
Preparation of 3-aminotetrahydrofuran.
N-benzyloxycarbonyl-3-aminotetrahydrofuran (3.4 gm, 15 mmol) was dissolved in MeOH (50 ml) along with cone. HC1 and Pd-C (10%, 300 mg). The vessel was charged with hydrogen at 1 atm and the mixture was allowed to stir for 18 hours at room temperature. The mixture was filtered through a pad of celite and concentrated. The residue was co-evaporated two times with MeOH/EtOAc and recrystallized from MeOH/EtOAc to give 1.9 g of a yellow solid.
Preparation of 6-(3-aminotetrahydrofuranyl)purine riboside. A mixture of 6-chloropurine riboside (0.5 gm, 1.74 mmol), 3-aminotetrahydrofuran
(0.325 gm, 2.6 mmol) and triethylamine (0.73 ml, 5.22 mmol) in methanol (10 ml) was heated to 80° C for 40 hours. The mixture was cooled, and concentrated. The residue was filtered through a short column of silica gel eluting with 90/10/1 (CH2Cl2/MeOH/PrNH2), the fractions containing the product were combined and concentrated. The residue was chromatorgraphed on the chromatotron (2 mm plate, 92.5/7.5/1 , CH2CL2/MeOH/P.NH2). The resulting white solid was recrystallized from MeOH/EtOAc to give 0.27 gm of white crystals (mp 128-130° C).
EXAMPLE 5
Resolution of 3-arninotetrahydrofuran hydrochloride
A mixture of 3-aminotetrahydrofuran hydrochloride (0.5 gm, 4 mmol) and
(S)-(+)-10-camphorsulfonyl chloride (1.1 gm, 4.4 mmol) in pyridine (10 ml) was stirred for 4 hours at room temperature and then concentrated. The residue was dissolved in EtOAc and washed with 0.5N HC1, sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated to give 1. 17 g of a brown oil (97%) which was chromatographed on silica gel (25% to 70% EtOAc/Hex). The white solid obtained was repeatedly recrystallized from acetone and the crystals and supernatant pooled until an enhancement of greater than 90% by 1H NMR was acheived.
Preparation of 3-(S)-aminotetrahydrofuran hydrochloride.
The sulfonamide (170 mg, 0.56 mmol) was dissolved in cone. HCl/AcOH (2 mL each), stirred for 20 hours at room temperature, washed three times with CH2C12 (10 ml) and concentrated to dryness to give 75 mg (qaunt ) of a white solid
Preparation of 6-(3-(S)-aminotetrahydrofuranyl)puπne riboside.
A mixture of 6-chloropurιne riboside (30 mg, 0.10 mmol),
3-(S)-amιnotetrahydrofuran hydrochloride (19 mg, 0.15 mmol) and triethylamine (45 ml, 0.32 mmol) in methanol
(0.5 ml) was heated to 80° C for 18 hours. The mixture was cooled, concentrated and chromatographed with 95/5 (CH2Cl /MeOH) to give 8 mg (24%) of a white solid.
| US7144871 * | 19 Feb 2003 | 5 Dec 2006 | Cv Therapeutics, Inc. | Partial and full agonists of A1 adenosine receptors |
| US7696181 * | 24 Aug 2006 | 13 Apr 2010 | Cv Therapeutics, Inc. | Partial and full agonists of A1 adenosine receptors |
Tioconazole UK-20349 an antifungal agent
Tioconazole;UK-20349;Trosyd;Trosyl;Vagistat-1
l-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole,
1-[2-(2-Chloro-3-thienylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
65899-73-2
Launched – 1983, Bristol-Myers Squibb
Tioconazole is an antifungal medication of the imidazole class used to treat infections caused by a fungus or yeast. It is marketed under the brand names Trosyd and Gyno-Trosyd (Pfizer). Tioconazole ointments serve to treat women’s vaginal yeast infections.[1]They are available in one day doses, as opposed to the 7-day treatments more common in use in the past.
Tioconazole topical (skin) preparations are also available for ringworm, jock itch, athlete’s foot, and tinea versicolor or “sun fungus”.
Side effects
Side effects (for the women’s formulas) may include temporary burning/irritation of the vaginal area, moderate drowsiness, headachesimilar to a sinus headache, hives, and upper respiratory infection. These side effects may be only temporary, and do not normally interfere with the patient’s comfort enough to outweigh the end result.
|
|
| Systematic (IUPAC) name | |
|---|---|
| (RS)-1-[2-[(2-Chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole | |
| Clinical data | |
| Trade names | Vagistat-1 |
| AHFS/Drugs.com | monograph |
| Legal status | |
| Routes | Topical |
| Identifiers | |
| CAS number | 65899-73-2 |
| ATC code | D01AC07 G01AF08 |
| PubChem | CID 5482 |
| DrugBank | DB01007 |
| KEGG | D00890 |
| Synonyms | Thioconazole |
| Chemical data | |
| Formula | C16H13Cl3N2OS |
| Mol. mass | 387.711 g/mol |
http://www.google.com/patents/EP0934279A1?cl=en
Imidazole derivatives, in particular, l-[2-(2-chloro-3-thienyl)methoxy]-2-(2,4- dichlorophenyl)ethyl]-lH-imidazole, commonly referred to as tioconazole, are known for their antifungal therapeutic properties. US 4,062,966 discloses a process for the preparation of l-aryl-2-(l -imidazolyl) alkyl ethers and thioethers which employs arylation of an appropriate 1 -aryl-2-(l -imidazolyl)alkanol or alkane thiol having the formula
wherein Rl to R4 are each H or C,^ alkyl, Ar is phenyl, or substituted phenyl wherein said substitutents are halogen, C,^ alkyl, C,_6 alkoxy, thienyl, or halothienyl, and, Z is oxygen or sulfur. In accordance with US’966, the reaction comprises converting the alcohol or thiol in a suitable solvent to its alkali metal derivative by treatment with a strong base, such as an alkali metal amide or hydride, and reacting with the appropriate aralkyl halide ofthe formula
X-(CH2)η-Y
where n is 1 or 2, Y is an aromatic heterocyclic group or substituted heterocyclic group, wherein substitutents are halogen, C,.6 alkyl, or C,.6 alkoxy atoms, thienyl or halothienyl group, and X is a halogen, preferably chlorine. Tetrahydrofuran (THF) is the preferred solvent taught in US ‘966. Reaction temperatures may range from about 0 °C to reflux temperature ofthe solvent and reaction times range from about 1 hour to about 24 hours. The product is isolated with water, extracted with ether, and may be purified as the free base or converted to a salt, e.g. the hydrochloride, and purified by recrystallization. A disadvantage ofthe process disclosed in US ‘966 is that THF is a peroxide generator which presents the potential for an explosion. From a commercial viewpoint, peroxide generators are not preferred due to the dangers associated therewith.
GB 1 522 848 discloses a process for the preparation of imidazoles useful as antifungal agents involving a labor intensive, multi-sequence reaction of an imidazole ether with a reactive ester. Like US ‘966, THF is employed presenting similar concerns in the synthesis ofthe desired imidazole product.
According to the Pharmaceutical Manufacturing Encyclopedia, tioconazole is prepared by dissolving l-(2,4-dichlorophenyl)-2-(l- imidazolyl)ethanol in THF and sodium hydride and heating to about 70 βC. The resulting mixture is then contacted with 2-chloro-3- chloromethylthiophene and heated to reflux (about 67 CC). The resulting product is filtered, saturated with hydrogen chloride, triturated and recrystallized to obtain the purified tioconazole hydrochloride product having a melting point of about 170 βC. This salt must then be freebased to form the product used in pharmaceutical formulations. This route, like those discussed above, also presents the dangers of a potential explosion. There is thus a continuing need for a commercially viable, synthetic route for the production of imidazoles, in particular tioconazole.
…………………….
see US 4062966
http://www.google.com/patents/US4062966
………………………….
References
- Tioconazole, Mayo Clinic
-
References1:
Gymer, G.E.; DE 2619381 .
References2:Hillier, K.; Blancafort, P.; Castaner, J.; Serradell, M.N.; Tioconazole. Drugs Fut 1980, 5, 10, 509.
- Growth quantification and rapid drug susceptibility testing of uropathogenic Candida albicans by isothermal microcalorimetry
28th Congr Eur Assoc Urol (March 15-19, Milan) 2013, Abst 618 - Difference in percutaneous absorption and intracutaneous distribution in guinea pigs among topical antifungal drugs (tioconazole solution, tioconazole cream, miconazole nitrate solution and bifonazole solution)
Biol Pharm Bull 2004, 27(9): 1428 - A randomized comparison of the nail surface remainder of three nail lacquers containing amorolfine 5%, ciclopirox 8%, or tioconazole 28% in healthy volunteers
63rd Annu Meet Am Acad Dermatol (AAD) (February 18-22, New Orleans) 2005, Abst P1805
Literature References:
Antimycotic imidazole derivative. Prepn: G. E. Gymer, BE 841309; idem, (1976, 1977 both to Pfizer).
Antifungal spectrum: S. Jevons, Antimicrob. Agents Chemother. 15, 597 (1979); F. C. Odds, J. Antimicrob. Chemother. 6,749 (1980).
Pharmacology: M. S. Marriott et al., Dermatologica 166, Suppl. 1, 1 (l983).
Clinical trial in dermatomycosis: Y. M. Clayton et al., Clin. Exp. Dermatol. 7, 543 (1982). Series of articles on pharmacology and clinical efficacy in gynecological use:Gynak. Rundsch. 23, Suppl. 1, 1-60 (l983).
Fosravuconazole in phase 1 for the treatment of fungal infections.
Fosravuconazole
Phosphoric acid 2(R)-[4-(4-cyanophenyl)thiazol-2-yl]-1(R)-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyoxymethyl monoester
(2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yll-2-(2,4-difluorophenyl)- 1 -(1 H- 1 ,2,4- triazol-l-yl)-2-[(dihydrogen phosphonoxy)methoxylbutane
BEF-1224
BMS-379224
E-1224
Phosphoric acid 2(R)-[4-(4-cyanophenyl)thiazol-2-yl]-1(R)-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyoxymethyl monoester bis(L-lysine) salt is used as drug
The azole antifungal agent E-1224 is a prodrug of ravuconazole. In 2009, originator Eisai licensed E-1224 to Drugs for Neglected Diseases Initiative for the treatment of American trypanosomiasis (Chagas disease) in Latin America and the Caribbean. DNDi was conducting phase II clinical trials with the prodrug for this indication, however, development of the compound has been discontinued due to lack of sustained efficacy. Ravuconazole was originally licensed by Eisai to Bristol-Myers Squibb (BMS). BMS developed the drug’s prodrug, referred to by BMS as BMS-379224. For strategic reasons, BMS did not pursue development of the compound. In 2010, E-1224 was licensed exclusively to Brain Factory for development, commercialization and sublicense in Japan for the treatment of fungal infections.
About Ravuconazole and Ravuconazole Prodrug
The compound on the left is ravuconazole; the compound on the right is the dihydrogen phosphonoxy methoxy derived ravuconazole prodrug which has improved solubility and bioavailability.
……………………………………………………………
WO 2001052852
http://www.google.com/patents/WO2001052852A1?cl=en
Triazole antifungal compounds are well known in the prior art. Of the several classes known, one particularly potent class contains a tertiary hydroxyl group. For example, U. S. Patent 5,648,372 discloses that (2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)- butan-2-ol has anti-fungal activity.
The utility of this class of compounds is limited by their low water solubility. For example, the solubility of the above triazole compound in water at pH 6.8 is 0.0006 mg/mL. This greatly impedes developing suitable parenteral dosage forms.
One method of addressing this problem was disclosed in European Patent Application 829478, where the water solubility of an azole antifungal agent was increased by attaching a linked amino-acid to the azole portion of the molecule
Alternatively, WO 97/28169 discloses that a phosphate moiety can be attached directly to the tertiary hydroxyl portion of the anti-fungal compound, e.g. the compound having the formula
U.S. Patent 5,707,977 and WO 95/19983 disclose water soluble prodrugs having the general formula
wherein X is OP(O)(OH)2 or an easily hydrolyzable ester OC(O)RNR l’rR>2.
WO 95/17407 discloses water-soluble azole prodrugs of the general formula
wherein X is P(O)(OH)2, C(O)-(CHR’)n-OP(O)(OH)2 or C(O)-(CHR’)π
-(OCHR,CHR1)mOR2.
WO 96/38443 discloses water-soluble azole prodrugs of the general formula
U.S. Patent 5,883,097 discloses water-soluble amino acid azole prodrugs such as the glycine ester
The introduction of the phosphonooxymethyl moiety into hydroxyl containing drugs has been disclosed as a method to prepare water-soluble prodrugs of hydroxyl containing drugs.
European Patent Application 604910 discloses phosphonooxymethyl taxane derivatives of the general formula
wherein at least one of R1 ‘, R2″, R3′, R6′ or R7′ is OCH2OP(O)(OH)2.
European Patent Application 639577 discloses phosphonooxymethyl taxane derivatives of the formula T-[OCH2(OCH2)mOP(O)(OH)2]n wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2- hydroxypropanoyloxy group; n is 1, 2 or 3; m is 0 or an integer from 1 to 6 inclusive, and pharmaceutically acceptable salts thereof. WO 99/38873 discloses O-phosphonooxymethyl ether prodrugs of a diaryl 1,3,4-oxadiazolone potassium channel opener.
Golik, J. et al, Bioorganic & Medicinal Chemistry Letters, 1996, 6:1837- 1842 discloses novel water soluble prodrugs of paclitaxel such as
EXAMPLE 1
(2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yll-2-(2,4-difluorophenyl)- 1 -(1 H- 1 ,2,4- triazol-l-yl)-2-[(dihydrogen phosphonoxy)methoxylbutane, sodium salt
(2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yll-2-(2,4-difluorophenyl)-l-(lH- 1 ,2,4-triazol- 1 -yl)-2-[(di-tert-butyl phosphonoxy)methoxy1butane
To a solution of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol, II, (8.74 g, 20 mmol) in THF (40 mL) under a nitrogen atmosphere was added sodium hydride (0.80 g, 60% in oil, 20 mmol) at rt. The resulting mixture was stirred at rt for 0.25 h and then di- tert-butyl chloromethyl phosphate, III (10.3 g, 40 mmol) was added. The reaction mixture was heated at 50 °C for 16 h. The reaction mixture was then allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in Et2O and was washed with H2O and brine. The organic layer was dried over MgSO4 and was concentrated under reduced pressure to obtain 17.0 g of crude subtitled compound. IV, as a gum. A small portion of this crude compound was purified by reverse phase chromatography on C- 18. The column was eluted with 30% CH3CN/H2O, 38% CH3CN/H2O, 45% CH3CN/H2O and then 50% CH3CN/Η2O. The product containing fractions were concentrated under reduced pressure in order to remove CH3CN. The resulting aqueous layer was then extracted with Et2O. The Et O layers were washed with brine, dried and concentrated under reduced pressure to afford purified subtitled compound, IV, as a white solid. 1H NMR (300 MHz, CDC13): δ 8.35 (s, 1H), 7.98 (d, 2H, J=9), 7.76 (s, 1H), 7.71 (d, 2H, J=9), 7.63 (s, 1H), 7.36-7.27 (m, 1H), 6.86-6.78 (m, 2H), 5.53 (dd, 1H, J=28,6), 5.53 (dd, 1H, J=9,6), 5.17 (d, 1H, J=15), 5.03 (d, 1H, J=15), 4.01 (q, 1H, J=7), 1.47 (s, 9H), 1.45 (s, 9H), 1.37 (d, 3H, J=7). MS [ESI+ (M+H)+] 660.2 obs. B. (2R,3R)-3-r4-(4-cyanoρhenyl)thiazol-2-yll-2-(2,4-difluorophenyl)-l-(lH- 1 ,2,4-triazol-l-yl)-2-[(dihydrogen phosphonoxy)methoxy]butane, sodium saltdeprotection
The crude (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluoropheny 1)- 1 -( 1 H- 1 ,2 ,4-triazol- 1 -y l)-2- [(di-tert-buty 1 phosphonoxy)methoxy]butane, IV, (17 g) was dissolved in CH C1 (100 mL). To this solution was added TFA (50 mL) and the reaction mixture was stirred at rt for 0.25 h. The reaction mixture was then concentrated under reduced pressure. To the residue was added H2O (200 mL), Et2O (100 mL) and EtOAc (100 mL). The pH of the aqueous layer was adjusted to 7.6 by addition of solid Na2CO3 and then the organic and aqueous layers were separated. The aqueous layer was then subjected to reverse phase chromatography on 400 g of C-18 eluted with H2O to 5% CH3CN/Η2O. The product containing fractions were concentrated under reduced pressure, frozen and lyophilized to afford 1.5 g of the subtitled compound, I, as a white solid. (1.5 g, 12% over two steps). Η NMR (500 MHz, D2O) δ 8.91 (s, IH), 7.92 (s, IH), 7.81 (d, 2H, J=8), 7.80 (s, IH), 7.77 (d, 2H, J=8), 7.21 (dd, IH, J=15,9), 6.99 (ddd, IH, J=9,9,2), 6.91 (ddd, IH, J=9,9,2), 5.35 (dd, IH, J=6,6), 5.29 (d, IH, J=15), 5.21 (dd, IH, J=6,6), 5.19 (d, IH, J=15), 3.86 (q, IH, J=7), and 1.35 (d, 3H, J=7); MS [(ESI“ (M-HV 546.1]; Anal. Calcd for C23Hi8F2N5θ5SιPι Na2/3.5 H2O: C, 42.21 : H, 3.85: N, 10.70: Na, 7.03. Found: C, 42.32: H, 3.83: N, 10.60: Na, 7.04.
Di-tert-butyl chloromethyl phosphate, III:
Di-tert-butyl chloromethyl phosphate, III, may be made by any of the following methods.
Method 1
Silver di-t-butyl phosphate (6.34 g, 20 mmol), which was prepared by mixing di- t-butyl phosphate (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971 , 27, 3163) with one equivalent of silver carbonate in 50% aqueous acetonitrile and by lyophilizing to dryness, was placed together with chloroiodomethane (35 g, 200 mmol) in benzene and stirred at room temperature for 18 hrs. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica and eluted with 2:1 hexanes-ethyl acetate. Appropriate fractions were concentrated to dryness to obtain the subtitled compound III (3.7 g, 71% yield): H NMR (CDCI3) δ 5.63 (d, 2H, J=17), 1.51 (s, 18H); MS (MH+ = 259).
Method 2
Tetrabutylammonium di-t-butyl phosphate was prepared by dissolving di-t-butyl phosphate [ 20g, 94 mmol (obtained from di-t-butyl phosphite by the method of Zwierzak and Kluba, Tetrahedron, 1971, 27, 3163)] in methanolic tetrabutylammonium hydroxide (47 mL of 1M solution, 47 mmol). The reaction mixture had a temperature of 23 °C and pH of 4.33. The pH of the reaction mixture was adjusted to 6.5-7.0 by addition of methanolic tetrabutylammonium hydroxide (48 mL of 1M solution, 48 mmol) over 0.2 h. The reaction mixture was stirred for 0.5 h at approximately 26 °C and then was concentrated under reduced pressure at a bath temperature below 40 °C. The crude residue was azeotroped three times by adding toluene (3×100 mL) and then the mixture was concentrated under reduced pressure. The crude residue was then triturated in cold hexanes (0°C) for 1 h and then the solid was collected by filtration, washed with a minimum amount of cold hexanes and dried to give a first crop of tetrabutylammonium di-t-butyl phosphate as a white solid. (24. Og). The mother liquor was concentrated under reduced pressure and then triturated in cold hexanes (20 mL) for 1 h. The solid was collected by filtration, washed with a minimum amount of cold hexanes and dried to give a second crop of tetrabutylammonium di-t-butyl phosphate as a white solid. [(8.5g), 32.5g total (77%)]. A solution of tetrabutylammonium di-t-butyl phosphate (218 g, 480 mmol) in benzene (200 mL) was added dropwise to stirred chloroiodomethane (800g, 4535 mmol) over 1.5 h at rt. The reaction mixture was stirred an additional 1.5 h at rt and then was concentrated under reduced pressure. The oily residue was dissolved in Et2O and filtered to remove white solids which had precipitated. The organic layer was washed with saturated NaHCO3 and H O/brine (1/1). The organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a red brown oil (320 g). The red brown oil was subjected to chromatography on silica gel (800g) eluted with 20% EtOAc/Hexanes, 25% EtOAc/Hexanes then 30% EtOAc/Hexanes. The product containing fractions were concentrated under reduced pressure to yield a golden oil. The oil was diluted with CH2C12 (30 mL) , concentrated under reduced pressure and then dried under vacuum to yield the subtitled compound III (61.3g, 49% yield). 1H NMR (Benzene-d6) δ 5.20 (2H, d, J=15), 1.22 (18H, s).
Method 3
Iodochloromethane (974 g, 402 mL, 5.53 mol) at 25°C was treated with tetrabutylammonium di-t-butylphosphate (250 g, 0.553 mol). The phosphate was added portion wise over 10 minutes. The heterogeneous mixture became a clear pink solution after approximately 15 minutes. The mixture was stirred for three hours, and the iodochloromethane was then removed by rotary evaporation with a bath temperature of <30°C. The residue was taken up in 1 L t-butyl methyl ether and stirred for 15 minutes to precipitate tetrabutylammonium iodide by-product. Tetrabutylammonium iodide was removed by vacuum filtration through a sintered glass funnel. The filtrate was concentrated by rotary evaporation to an oil which contained a 5:1 mixture of III and undesired dimer impurity
III”
The mixture can be purified by a silica gel chromatography to obtain III as pure compound in ~60% yield as an oil.
EXAMPLE 2
(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-l-(lH-l,2,4- triazol- 1 -yl)-2- (dihydrogen phosphonoxy)methoxy]butane
A. An oven dried, 1L round-bottom flask equipped with a mechanical stirrer, nitrogen inlet adapter, pressure-equalizing addition funnel fitted with a rubber septum and temperature probe was charged with sodium hydride (2.89 g, 0.069 mol, 60%) and THF (50 mL). To this stirred suspension, (2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)butan- 2-ol, II, (10 g, 0.023 mol) in 30 mL of THF was added dropwise over 20 minutes at room temperature. After stirring for 45 minutes, a solution of iodine (2.99 g, 0.0115 mol) in THF (30 mL)) was added dropwise over 10 minutes followed by dropwise addition of compound di tert butylchloromethyl phosphate, III (13.29 g, 0.035 mol, -68% purity) over 15 minutes. The reaction mixture was stirred for 4 hours at about 41 °C to complete the reaction. The completion of the reaction was judged by in-process HPLC. The reaction mixture was poured into ice cold water (100 mL). The aqueous phase was separated and extracted with ethyl acetate (3 x 50 mL) and the combined organic extract was washed with 10% sodium thiosulfite (50 mL), water (50 mL), brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give pale yellow oil (22.8 g, In-process HPLC: ~ 97% pure). The crude product was used “as is” in step B.
B. To a round-bottom flask equipped with magnetic stirrer, cooling bath, pH probe and N2 inlet-outlet was charged the product of Step A above (7.5 g) in CH2C12 (23 mL) and cooled to 0 °C. To this stirred solution, trifluoroacetic acid (8.8 mL) was added slowly and stirred for 3 h to complete the reaction. The completion of the reaction was judged by in-process HPLC. The reaction mixture was poured into a cold solution of 2N NaOH (64 mL). The reaction mixture was extracted with t-butyl acetate (2 x 65 mL) to remove all the organic impurities. The aqueous layer containing the title product as bis sodium salt was treated with activated charcoal (10 g) and filtered through a bed of Celite. The clear filtrate was acidified with IN HC1 to pH 2.5. The free acid, the title product, was extracted into ethyl acetate (2 x 50 mL). The combined organic layer was washed with water, dried over MgSO4) filtered, and the filtrate concentrated under reduced pressure to afford 3.39 g of crude title product.
EXAMPLE 3
Bis lysine salt of (2R,3R)-3-r4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4- difluorophenyl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)-2-[(dihydrogen phosphonoxy)methoxy]butane
The above obtained title product from Example 2 was dissolved in methanol (75 mL) and to this L-lysine (1.8 g) was added and heated at 60 °C for 4.5 h. The hot reaction mixture was filtered through a bed of Celite. The filtrate was concentrated to about 5 mL, mixed with ethanol (100 mL) and heated to 65 °C to crystallize the bis lysine salt. The salt was collected on a Buchner funnel and dried under vacuum to afford 3.71 g of the title compound as an off white crystalline solid.
About Eisai Co., Ltd.
Eisai Co., Ltd. is a research-based human health care (hhc) company that discovers, develops, and markets products throughout the world. Eisai focuses its efforts in three therapeutic areas: integrative neuroscience, including neurology and psychiatric medicines; integrative oncology, which encompasses oncotherapy and supportive-care treatments; and vascular and immunological reactions. Eisai contributes to the well-being of people around the world through a global network of research facilities, manufacturing sites and marketing subsidiaries. For more information about Eisai Co., Ltd., please visit http://www.eisai.co.jp/index-e.html.
ref
BMS-379224, a water-soluble prodrug of ravuconazole
42nd Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 27-30, San Diego) 2002, Abst F-817
| WO2000030655A1 * | Nov 17, 1999 | Jun 2, 2000 | Squibb Bristol Myers Co | Water soluble prodrugs of azole compounds |
| WO2006118351A1 | May 1, 2006 | Nov 9, 2006 | Eisai Co Ltd | Mono-lysine salts of azole compounds |
| WO2012060448A1 | Nov 4, 2011 | May 10, 2012 | Eisai R&D Management Co., Ltd. | Combined pharmaceutical composition as antifungal agent |
| CN101341160B | Dec 20, 2006 | Jan 25, 2012 | 卫材R&D管理有限公司 | Process for production of water-soluble azole prodrug |
| EP1345915A1 * | Oct 18, 2001 | Sep 24, 2003 | Bristol-Myers Squibb Company | Improved process for water soluble azole compounds |
| EP2291084A1 * | May 20, 2009 | Mar 9, 2011 | Neurogesx, Inc. | Carbonate prodrugs and methods of using the same |
| US7230023 | Aug 20, 2003 | Jun 12, 2007 | Sankyo Company, Limited | Triazole compound containing a phosphonate group |
| US8735376 | May 20, 2009 | May 27, 2014 | Acorda Therapeutics, Inc. | Carbonate prodrugs and methods of using the same |
some animations
RAVUCONAZOLE
- BMS 207147
- ER 30346
- Ravuconazole
- UNII-95YH599JWV
4-[2-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-thiazolyl]benzonitrile
 |
|
| Systematic (IUPAC) name | |
|---|---|
| 4-[2-[(2R,3R)-3-(2,4-Difluorophenyl)-3-hydroxy-4-(1,2,4-triazol-1-yl)butan-2-yl]-1,3-thiazol-4-yl]benzonitrile | |
| Clinical data | |
| Legal status |
PHASE 2 AS ON SEPT 2014
|
| Identifiers | |
| CAS number | 182760-06-1 |
| ATC code | None |
| PubChem | CID 467825 |
| NIAID ChemDB | 057176 |
| Chemical data | |
| Formula | C22H17F2N5OS |
| Mol. mass | 437.465086 g/mol |
DRUG PROCESS…do not miss this
http://www.drugprocess.com/pdf/Isavuconazole_DPLA_ProcessSummary.pdf =++++++++++++++++++++++
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Thiazole antifungals. III. Stereocontrolled synthesis of an optically active triazolymethyloxirane precursor to antifungal oxazolidine derivatives
Chem Pharm Bull 1991, 39(9): 2241
https://www.jstage.jst.go.jp/article/cpb1958/39/9/39_9_2241/_pdf
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Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and its stereoisomers
Chem Pharm Bull 1993, 41(6): 1035
https://www.jstage.jst.go.jp/article/cpb1958/41/6/41_6_1035/_pdf
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A novel route for chiral synthesis of the triazole antifungal ER-30346
Chem Pharm Bull 1998, 46(7): 1125
https://www.jstage.jst.go.jp/article/cpb1958/46/7/46_7_1125/_pdf
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ER-30346 is synthesized by thiazole ring formation of (2R, 3R) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1H-1,2,4-triazol-1-yl ) thiobutanamide (I) and 4-bromoacetylbenzonitrile (II) by means of reflux in methanol. The thioamide (I) is obtained with excellent yield from a chiral nitrile (III) by heating with diethyl dithiophosphate in aqueous medium.
The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-b: The starting material of this route is methyl (S) -3-hydroxy-2-methylpropionate (VIII ), which contains one additional carbon between the hydroxyl group and the 2-position carbon of (R) -lactate, the starting material of route-a. The hydroxyl group of (VIII) is protected by triphenylmethyl group. Then, 2,4 -difluorophenyl moiety is introduced to give the ketone (X). Direct conversion of the ketone (X) to the oxirane (XIV) by dimethylsulfoxonium methylide, the same condition for compound (IV) in route-a, does not proceed. The oxirane (XIV) having desired stereochemistry is obtained via oxidation reaction. The ketone (X) is converted to the exomethylene (XI) by Wittig reaction. The stereoselective oxidation of (XI) is achieved by means of osmium tetroxide in the presence of 4-methylmorpholine N-oxide to give the diol (XII) in 58% yield after separation of its epimer by column chromatography. After methanesulfonylation of the primary alcohol of (XII), a triazole moiety is introduced and the triphenylmethyl group is deprotected. Then, the primary hydroxyl group of (XVI) is oxidized under Swern oxidation condition to give the aldehyde (XVII), which is converted to the chiral nitrile intermediate (III) by means of heating with hydroxylamine-O-sulfonic acid.
The synthesis of (2S, 3S) -3- (2,4-difluorophenyl) -3-hydroxy-2-methyl-4- (1,2,4-triazol-1-yl) butyronitrile (XV), a key intermediate the synthesis of ER-30346 has been described: The tritylation of 3-hydroxy-2 (S) -methylpropionic acid methyl ester (I) with trityl chloride in hot pyridine gives the trityl ether (II), which is hydrolyzed with LiOH in H2O / THF / methanol yielding the free acid (III). The esterification of (III) with 2-mercaptopyridine (IV) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane gives the thioester (V), which is treated with 2,4-difluorophenylmagnesium bromide (VI) in THF yielding the propiophenone (VII), which by treatment with methyltriphenylphosphonium bromide / NaH in THF is converted into the methylene derivative (VIII). The oxidation of (VIII) with OsO4 and N-methylmorpholine oxide in acetone affords, after column chromatography, the chiral diol (IX), which is monomesylated with mesyl chloride / triethylamine in dichlormethane giving the monoester (X). The reaction of (X) with 1,2,4-triazol (XI) and NaH in DMF yields (2R, 3S) -2- (2,4-difluorophenyl) -3-methyl-1- (1,2,4-triazol-1-yl) -4- (triphenylmethoxy) -2-butanol (XII), which is detritylated with p-toluenesulfonic acid in methanol affording the diol (XIII). The oxidation of (XIII) with oxalyl chloride / DMSO in dichloromethane gives the aldehyde (XIV), which is finally treated with hydroxylamine-O-sulfonic acid in water yielding the desired bytyronitrile intermediate (XV) already referenced.
http://www.google.com/patents/WO2011042827A1?cl=en
Example 1
(2R,3R)-3-i4-(4-cvanophenyl)thiazol-2-yl1-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4-difluorophenyl)- butan-2-ol
To a solution of racemic 3-[4-(4-cyanophenyl)thiazol-2-yl]-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4- difluorophenyl)-butan-2-ol (43.7 g) in acetone (800 ml) a solution of (1 R)-10- camphorsulfonic acid (23 g) in methanol (300 ml) was added and the mixture was heated under reflux until a clear solution was obtained. The solution was slowly cooled to rt, seeded with crystals of the title enantiomeric salt and let overnight. The solid was collected by filtration, washed with acetone and dried to provide (2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl]-1 -(1 H-1 ,2,4-triazol-1 -yl)-2-(2,4-difluorophenyl)-butan-2-ol (1 R)- 10-camphorsulfonate as white solid. This crude salt was then taken up in methylenechloride (100 ml) and water (ca. 100 ml) and the mixture was basified with aqueous sodium hydroxide solution. The organic layer was separated and the aqueous phase washed twice with methylenechloride (50 ml) and combined. The organic phases were then washed twice with water (2×50 ml), dried with sodium sulfate, filtrated and the solvent removed under reduced pressure. The crude product was then mixed with isopropanol (ca. 150 ml), heated for 10 min, cooled to 0° C and stirred for ca. 2 hrs. The product was collected, washed with isopropanol and dried under reduced pressure to provide the enantiomerically pure title compound (17.5 g, 41 % yield, 99.1 % ee); m.p. 164-166° C; [a]=-30° (c=1 , methanol, 25° C); NMR (CDCI3): 1 .23(3H, d, J=8 Hz), 4.09(1 H, q, J=8Hz), 4.26(1 H, d, J=14Hz), 4.92(1 H, d, J=14Hz), 5.75(1 H, s), 6.75- 6.85(2H, m), 7.45-7.54(2H, m), 7.62(1 H, s), 7.69(1 H, s), 7.75(1 H, d, J=8Hz), 7.86(1 H, s), 8.03(1 H,d,J=8Hz). The analytical data were identical with published (US5648372 and Chem. Pharm. Bull. 1998, 46, 623-630).
…………………………
http://www.google.com/patents/WO1999045008A1?cl=en
Example 1
a) Preparation of (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-
2H-pyran-2-yloxy)-propiophenone A mixture of magnesium ( 7.25 g, 0.298 mol ) and iodine ( catalytic amount ) and l-bromo-2,5-difluorobenzene ( 20.0 g, 0.178 mol ) in THF ( 250ml ) was vigously stirred. The color of iodine was disappeared and the inner temperature rose up to 65°C. To this mixture was added additional l-bromo-2,5-difluorobenzene ( 30.0 g, 0.267 mol ) dropwise to maintain the inner temperature from 50 to 55°C over 45min. The resulting mixture was stirred at 55°C for 30min. then at r.t. for lhr. The – 21 –
mixture was cooled down to -5°C. To this mixture was added a solution of.4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl] morpholine ( 52.5 g, 0.216 mol ) in THF ( 150ml ) dropwise over 40min. And the resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was cooled down to 5°C and saturated NH4C1 aq. ( 100ml ) was added carefully. The whole was diluted with H20 ( 600ml ) and extracted with EtOAc ( 400ml + 200ml x 2 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel ( n-hexane : EtOAc = 10 :1 ~ 5 : 1 ) to give (2R)-2′,5′- Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-propiophenone (47.3 g,
81 % ) as pale yellow syrup.
Physical form : colorless oil; FAB-MS: m/z 271(M+H)+; Η-NMR(CDCl;j): 1.42~1.90(9H,m),3.32~3.40(lHxl/2,m),3.69~3.77(lHxl/2,m),3.86~3.94 (lHxl/2,m),4.66(lHxl/2,t,J=3.6Hz),4.75(lHxl/2,t,J=3.6Hz),4.87(lHxl/2, q,J=6.6Hz),5.11(lHxl/2,q,J=6.9Hz),7.08~7.25(2H,m),7.49~7.55(lH,m).
b) Preparation of 2-(2,5-Difluorophenyl)-2-[(lR)-l-(3,4,5,6,- tetr ahy dro-2H-pyran-2-yloxy ) ethyl] oxir ane To a stirred mixture of NaH ( 60% in oil, 9.1g, 0.228mol ) in DMSO
(300ml ) was added portionwise trimethylsulfoxonium iodide ( 53.9g, 0.245 mol ) at the inner teperature with the range from 15°C to 18°C. over 20min. The ice bath was removed and the mixtuer was stirred at r.t. for 3hrs. The mixture was cooled down to 10°C. To this mixture was added a solution of (2R)-2′,5′-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2- yloxy)-propiophenone ( 47.3 g , 0.175 mol ) in DMSO (150ml ) dropwise over 20min. The resulting mixture was stirred at r.t. for 4hrs. The reaction mixture was poured into ice-water ( 800ml ). The whole was extracted with EtOAc ( 400ml + 200ml x 2 ). The combined organic layer was washed with brine, dried over Na2S04 and concentrated in vacuo.
The residue was chromatograkkphed on silicagel ( n-hexane : EtOAc = – 22 –
8 : 1 ~ 5 : 1 ) to give 2-(2,5-Difluorophenyl)-2-[(lR)-l-(3,4,5,6,- tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 97 % ). Physical form : pale yellow syrup, EI-MS: m/z 284 (M)+ ; 1H-NMR(CDC13): 1.15(3Hxl/2,dd,J=6.6,1.3Hz), 1.24(3Hxl/2,dd, J=6.6,1.3Hz), 1.52-1.87 (6H,m),2.83~2,90(lH,m),3.07
(lHxl/2,d,J=5.3Hz),3.36(lHxl/2,d,J=5.6Hz), 3.48~3.56(lH,m),3.82~3.92 (lH,m),4.00~4.16(lH,m),4.73~4.92(lH,m), 6.96~7.02(lH,m),7.09~7.15 (lH,m).
c) Preparation of (3R)-2-(2,5-difluorophenyl)-3-(3,4,5,6- tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)-2-butanol
To a stirred suspension of NaH ( 60 % in oil, 21.0 g, 0.525 mol ) in DMF (300ml ) was added portionwise 1,2,4-triazole ( 43.3 g, 0.627 mol ) at the inner temperature from 2°C to 11°C over 30min. The resulting mixture was stirred at r.t. for l.δhrs. To this mixture was added a solution of 2-(2,5-Difluorophenyl)-2-[(lR)-l-(3,4,5,6-tetrahydro-2H- pyran-2-yloxy)ethyl]oxirane ( 48.3 g, 0.170 mol ) in DMF ( 50 ml ). The mixture was stirred at 60°C for lhr. and then at 65°C for 14hrs. The reaction mixture was cooled down to 10°C and then poured into ice- water (800 mL ). The resulting mixture was extracted with EtOAc
(400ml + 200ml x 2 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silicagel ( n-hexane : EtOAc = 4 : 1 ~ 1 : 5 ) to give (3R)-2-(2,5- difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-l-(lH-l,2,4- triazol-l-yl)-2-butanol ( 43.9 g, 73 % ) and recovered starting material
(13.2 g, 27 % ).
Physical form : colorless syrup ; FAB-MS: m/z 354 (M+H)+ ; Η- NMR(CDCl3): 1.00(3Hxl/2,d,J=6.6Hz),1.13(3Hxl/2,d,J=6.6Hz), 1.42~1.88(6H,m),3.38~3.60 (lH,m),3.80~4.00(lH,m),4.32~5.02(5H,m),6.83~6.99 (2H,m),7.14-7.21
(lH,m),7.73(lHxl/2,s),7.74(lHxl/2,s),7.92(lHxl/2,s),7.95(lHxl/2,s). – 23 –
d) Preparation of (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4- triazol-l-yl)-2,3-butanediol
A mixture of (3R)-2-(2,5-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H- pyran-2-yloxy)-l-(lH-l,2,4-triazol-l-yl)-2-butanol ( 43.9 g, 0.124 mol ) and PPTS ( 15.6 g, 62.1 mmol ) in EtOH ( 400ml ) was stirred at 55°C for 5hrs. The mixture was was evaporated to remove solvent down to 100ml. The residue was poured into ice-aqueous NaHC03 ( 500ml ). The whole was extracted with EtOAc ( 400ml + 200ml x 2 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silicagel (CH2C12 : MeOH = 20 : 1) to give (2R,3R)-2-(2,5-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-2,3- butanediol (18.0 g, 54 % ). Physical form : colorless syrup ; FAB-MS: m/z 270 (M+H)’ ; ‘H- NMR(CDC13): 0.99(3H,d,J=6.6Hz),2.61(lH,d,J=10.6Hz), 4.31-4.36
(lH,m),4.79,4.88
(2H,ABq,J=14.5Hz),4.84(lH,s),6.84~6.99(2H,m),7.13~7.19(lH,m),7.84(l H,s),7.85(lH,s).
e) Preparation of (2R,3S)-2-(2,5-Difluorophenyl)-3-methyl-2-
[ ( 1H- 1 ,2,4-triazol-l -yl) -methyl] -oxir ane
To a cold ( 0°C ) and stirred solution of (2R,3R)-2-(2,5-difluorophenyl)- l-(lH-l,2,4-triazol-l-yl)-2,3-butanediol ( 35.0 g, 0.130 mol ) and triethylamine ( 54.8 ml, 0.393 mol ) in CH2C12 ( 500ml ) was added a mesylchloride ( 12.1 ml, 0.156 mol ) dropwise over 5min. The resulting mixture was stirred at r.t. for l.δhrs. The reaction mixture was poured into ice-water ( 300ml ). The resulting mixture was shaken well and the organic layer was separated. The aqueous layer was further extracted with CH2C12 ( 150ml x 2 ). All the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give mesylate ( 46.7 g ) as crude syrup. The obtained mesylate was dissolved in MeOH ( 500ml ) – 24 –
and the solution was cooled down to 0°C. To this solution was added 28% NaOMe methanol solution (29.0 ml ). The mixture was stirred at 0°C for 50min. The reaction mixture was evaporated to reduce the volume of the solvent down to 150 ml. The residue was poured into ice- water ( 300ml ). The resulting mixture was extracted with ethylacetate (300ml + 200ml x 2 ). The combined organic layer was dried over Na.,S0 and concentrated in vacuo. The residue was cromatographed on silicagel (hexane : EtOAc = 1 : 3 ) to give (2R,3S)-2-(2,5-Difluorophenyl)- 3-methyl-2-[(lH-l,2,4-triazol-l-yl)-methyl]-oxirane (30.3 g, 93 %).
Physical form : white solid ; FAB-MS : m z 252 (M+H)+ ; ]H- NMR(CDC13): 1.64(3H,d,J=5.6Hz),3.19(lH,q,J=5.6Hz),4.42,4.97 (2H,ABq,J=14.8Hz), 6.75~6.81(lH,m),6.89~7.01(2H,m),7.83(lH,s),7.98 UH,s).
f) Preparation of (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-
2-methyl-4-[l,2,4]triazol-l-yl-butyronitrile
A mixture of (2R,3S)-2-(2,5-Difluorophenyl)-3-methyl-2-[(lH-l,2,4- triazol-l-yl)-methyl]-oxirane ( 30.3 g, 0.121 mol ), trimethylsilylcyanide ( 65.0 ml ) and MgO ( 24.5 g ) in o-xylene ( 400 ml ) was stirred at 130°C for lOhrs. To this mixture was added additional trimethylsilylcyanide (20.0 ml ) and MgO ( 8.5 g ) and the resulting mixture was stirred at 130°C further for 6hrs. The reaction mixture was cooled down to r.t. The precipitate was filtered off and washed with CH2C12. The filtrate was concentrated in vacuo to give crude brown syrup.
This crude syrup was dissolved in THF ( 600ml ) and the solution was cooled down to 0°C. To this mixture was added 1.0 M tetra n- butylammoniumfluoride THF solution ( 133ml, 0.133 mol ) dropwise over 5min. The mixture was stirred at r.t. for 50min. The solvent was removed under reduced pressure down to 150ml. The residue was poured into ice-water ( 400ml ). The resulting mixture was extracted – 25 –
with EtOAc ( 300ml + 200ml x 2 ). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silicagel ( n-hexane : EtOAc = 1 : 3 ) to give (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[l,2;4]triazol-l-yl- butyronitrile ( 30.5 g, 91 % ).
Physical form : colorless syrup ; FAB-MS : m/z 279 (M+H)+ ; Η- NMR(CDCl3): 1.19(3H,d,J=7.3Hz),3.33(lH,q,J=7.3Hz),4.82,5.00 (2H,ABq,J=13.9Hz), 5.56(lH,brs),6.89~7.04(2H,m),7.12~7.19(lH,m),7.85(lH,s),7.86(lH,s).
g) Preparation of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-
2-methyl-4- [ 1 ,2,4] triazol-1 -ylthiob tyramide
A mixture of (2S,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4- [l,2,4]triazol-l-yl-butyronitrile ( 30–5 S> O.llOmol ), diethyldithio- phospate ( 235 ml ) and H2O ( 110 ml ) was stirre at 80°C for 2hrs. The reaction mixture was cooled down to r.t. n-Hexane ( 400ml ) and water (200 ml ) was added. The whole was shaken well and the aqueous layer was separated. The remaining organic layer was further extracted with H20 ( 100ml x 3 ). All the aqueous layer was combined. Cooled down to
0°C and neutralized and basified ( PH8 ) with NaHC03. This basic(PH8) aqueous layer was extracted with EtOAc ( 300ml + 100ml x 3 ). The combined organic layer was dried over Na2S04 and concentrated in vacuo to give dark brown syrup. By addition of CH2C12 ( 100ml ) to this crude syrup, precipitate was formed. The precipitate was filtered and washed with CH2C12-hexane ( 5 : 1 mixture ) to give (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4-[l,2,4]triazol-l- ylthiobutyramide ( 19.2 g, 56 % ) as white powder. On the oter hand, the filtrate was concentrated in vacuo and the residue was chromatographed on silica gel ( Wako-gel C-300, CH2C12 : MeOH = 20 :
1 ) to give additional (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2- – 26 –
methyl-4-[l,2,4]triazol-l-ylthiobutyramide ( 7.46 g, 22 % ) as pale brown amorphous powder.
Physical form : White solid ; FAB-MS : m/z 313 (M+H)+ ; ‘H-NMR (CDC13): 1.12(3H,d,J=7.3Hz),3.74(lH,q,J=7.3Hz), 4.55,5.12 (2H,ABq,J=14.5Hz), 5.84(lH,s),6.85~7.02(2H,m),7.15-7.22(lH,m),7.80
(1H,S),7.89(1H,S), 7.89(lH,brs),8.43(lH,brs).
h) Preparation of 4-{2-[(lR,2R)-2-(2,5-Difluoro-phenyl)-2- hydroxy-l-methyl-3-[l,2,4]triazol-l-yl-propyl]-thiazol-4-yl}- benzonitrile
A mixture of (2R,3R)-3-(2,5-Difluoro-phenyl)-3-hydroxy-2-methyl-4- [l,2,4]triazol-l-ylthiobutyramide ( 26.7 g, 85.4 mmol ) and a-bromo-4′- cyano-acetophenone ( 24.0 g, 0.107 mol ) in EtOH ( 500ml ) was refluxed for lhr. The reaction mixture was cooled down to r.t. And the solvent was removed under reduced pressure down to 150ml. The residue was poured into in to cold ( 0°C ) saturated NaHC03 aq. ( 400ml ). The resulting mixture was extracted with EtOAc ( 300ml + 150 ml x 2 ). The combined organic layer was washed with brine (200ml ), dried over Na2S04 and concentrated in vacuo. The residue was chromatographed on silica gel ( Wako-gel C-300, Hexane : EtOAc = 1 : 2 ) to give 4-{2-
[(lR,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy-l-methyl-3-[l,2,4]triazol-l- yl-propyl]-thiazol-4-yl}-benzonitrile ( 32.0 g, 86 % ).
Physical form : colorless heavy syrup ; ESI-MS : m/z 437 (M)+ ; ‘H-
NMR(CDCl3): 1.25(3H,d,J=7.3Hz),4.12(lH,q,J=7.3Hz),4.26,4.96 (2H,Abq,J=14.5Hz), 5.75(lH,s),6.89~7.07(2H,m),7.23~7.29(lH,m),7.65
(lH,s),7.71(lH,s),7.75,8.02 (4H,Abq,J=8.6Hz),7.85(lH,s). – 27 –
i) Preparation of 4-{4-[(tert-Butoxycarbonyl-methyl-amino)- acetoxy]-3,5-dimethyl-benzyl}-l-[(2R,3R)-3-[4-(4-cyano-phenyl)- thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-lH- [l,2,4]triazol-4-ium bromide A mixture of 22.7mg of 4-{2-[(lR,2R)-2-(2,5-Difluoro-phenyl)-2-hydroxy- l-methyl-3-[l,2,4]triazol-l-yl-propyl]-thiazol-4-yl}-benzonitrile and 25.0mg of 4-tert-butoxycarbonyl-methyl-aminoacetoxy-3,5-dimethyl- benzyl bromide in CH3CN(1.5mL) was refluxed over 15hrs. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (Wakogel C-200, solvent:CH2Cl MeOH=10/l) to give 4-{4-[(tert-
Butoxycarbonyl-methyl-amino)-acetoxy]-3,5-dimethyl-benzyl}-l- [(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2- hydroxy-butyl]-lH-[l,2,4]triazol-4-ium bromide (36.0mg, 84% as colorless heavy syrup) ; FAB-MS : m/z 743 (M-Br)’ ; Η-NMR(CDC1S): 1.23(3H,d,J=7.3Hz),
1.47(9H,s),2.14(6H,s),3.03(3H,s),4.15(lH,q,J=7.3Hz),4.25(2H,s), 4.98,5.16(2H,ABq,J=13.9Hz),5.39~5.54(2H,m),6.27(lH,s),6.89-7.07(4H, m),7.24~7.27(lH,m),7.58(lH,s),7.73,8.06(4H,ABq,J=8.58),8.07(lH,s),ll. 26 (lH,s).
j) Preparation of l-{(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]- 2-(2,5-difluoro-phenyl)-2-hydroxy-butyl}-4-(3,5-dimethyl-4- methylaminoacetoxy-benzyl)-lH-[l,2,4]triazol-4-ium bromide To a solution of 36mg of 4-{4-[(tert-Butoxycarbonyl-methyl-amino)- acetoxy]-3,5-dimethyl-benzyl}-l-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-
2-yl]-2-(2,5-difluoro-phenyl)-2-hydroxy-butyl]-lH-[l,2,4]triazol-4-ium bromide in ethylacetate(2ml) was added dropwise 4N HC1 ethylacetate solution(lmL) and the mixture was stirred at r.t. for 4hrs.The precipitate was “filtered and washed with diethylether to give 1- {(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,5-difluoro-phenyl)-2- hydroxy-butyl}-4-(3,5-dimethyl-4-methylaminoacetoxy-benzyl)-lH- – 28 –
[l,2,4]triazol-4-ium bromide (24.5mg, 74% as HC1 salt and as white solid) ;
FAB-MS : m/z 643 (M-Br)+ ; Η-NMR(DMSO-d): 1.19(3H,d,J=7.3Hz), 2.11(6H,s),2.64(3H,s),4.15(lH,q,J=7.3Hz),4.41(2H,s),4.74,5.04(2H,ABq,J =14.5Hz),5.40(2H,s),6.76(lH,brs),7.10(2H,s),7.20~7.38(2H,m), 7.94,8.21
(4H,ABq,J=8.25),8.45(lH,s),9.07(lH,s),9.50(lH,brs),10.17(lH,s).
………………………
http://www.google.co.in/patents/US5648372
OR
http://www.google.co.in/patents/EP1394142A1
COMPD 21
- Example 88:Preparation of a compound of the structural formula:
-
-
2-(2,4-Difluorophenyl)-3-thioamide-1-(1H-1,2,4-triazol-1-yl)-2-butanol (the raw material 2) (156 mg) was dissolved in EtOH (2 ml), and 2-bromo-4′-cyanoacetophenone (the raw material 3) (224 mg) was added to the solution, followed by heating and refluxing for 1 hour. The liquid reaction mixture was neutralized with a saturated aqueous solution of NaHCO3 and subjected to extraction with AcOEt. After the extract was washed with H2O and then a saturated aqueous solution of NaCl and dried over MgSO4, AcOEt was distilled out. The resultant residue was purified by chromatography on silica gel (SiO2: 20 g, eluted with CH2Cl2 and then with 1% solution of MeOH in CH2Cl2), and then crystallized from IPE, thereby obtaining the intended compound (109 mg). Physical properties of this compound are described below.
- mp:
- 196-197°C.
- NMR:
- δ solvent (CDCl3)
1.23(3H,d,J=8.0Hz), 4.09(1H,q,J=8.0Hz), 4.26(1H,d,J=14.3Hz), 4.92(1H,d,J=14.3Hz), 5.74(1H,s), 6.78-6.85(2H,m), 7.48-7.54(1H,m), 7.64(1H,s), 7.69(1H,s), 7.75(1H,d,J=8.1Hz), 7.85(1H,s), 8.03(1H,d,J=8.1Hz). - MS:
- MH+ = 438.
References
- National Cancer Institute. Ravuconazole in Preventing Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2010 Feb 18]. Available from:http://clinicaltrials.gov/ct2/show/NCT00064311?term=ravuconazole&spons_ex=Y&rank=1 NLM Identifier: NCT00064311.
- The Aspergillus Website, Pasqualotto AC, Denning DW. Ravuconazole. Date accessed: 2010 Feb 18.
- Pasqualotto AC, Thiele KO, Goldani LZ (2010). “Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole”. Curr Opin Investig Drugs 11 (2): 165–74. PMID 20112166.
- Pfaller, M. A.; Messer, S. A.; Hollis, R. J.; Jones, R. N.; Sentry Participants, Group (2002). “Antifungal Activities of Posaconazole, Ravuconazole, and Voriconazole Compared to Those of Itraconazole and Amphotericin B against 239 Clinical Isolates of Aspergillus spp. and Other Filamentous Fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000”. Antimicrobial Agents and Chemotherapy46 (4): 1032. doi:10.1128/AAC.46.4.1032-1037.2002. PMC 127116. PMID 11897586.
Literature References:
Ergosterol biosynthesis inhibitor. Prepn (stereochemistry unspecified): T. Naito et al, EP 667346; eidem,US 5648372 (1995, 1997 both to Eisai); of optically acitve form: A. Tsuruoka et al., Chem. Pharm. Bull. 46, 623 (1998). Chiral synthesis: Y. Kaku et al., ibid. 1125.
In vitro comparative antifungal spectrum: J. C. Fung-Tomc et al., Antimicrob. Agents Chemother. 42, 313 1998. Antifungal activity in candidosis: K. V. Clemons, D. A. Stevens, ibid. 45, 3433 (2001); in aspergillosis: W. R. Kirkpatrick et al., J. Antimicrob. Chemother. 49, 353 (2002).
Clinical evaluation in onychomycosis: A. K. Gupta et al., J. Eur. Acad. Dermatol. Venereol. 19, 437 (2005).
Review of development and therapeutic potential: S. Arikan, J. H. Rex, Curr. Opin. Invest. Drugs 3, 555-561 (2002).
Extras you may need
http://www.google.com/patents/WO2011042827A1?cl=en
Scheme 1 :
The manufacturing process for Isavuconazole is similar: Since Isavuconazole differentiates from Ravuconazole by only another fluorine substitution on the aromatic ring (2,5- instead of 2,4-difluorophenyl), the identical synthesis has been used (US 6300353 from October 9, 2001 and Bioorg. & Med. Chem. Lett. 13, 191 (2003)). Consequently, also this manufacturing process, based on (R)-lactic acid, faces the same problems: to many steps, extremely low overall yield and in addition to US patent 6300353 claims even already known step as novel (claim 36).
Recent attempts to improve this concept as reported in WO 2007/062542 (Dec.1 , 2005), using less expensive, natural configured (S)-lactic acid, also failed: As already reported in US 6133485 and in US 2003/0236419, the second chiral center was formed from an optically active allyl alcohol prepared in a few steps from (S)-lactic acid. This allyl alcohol was subjected to Sharpless diastereoselective epoxidation providing first an opposite configured, epimeric epoxy alcohol which had to be then epimerized in an additional inversion step yielding finally the desired epoxy alcohol as the known precursor for Isavuconazole (US 6300353). It is obvious that this process using less expensive (S)- lactic acid makes the entire process with an inversion step even more complex than the original approach.
Elegant and more efficient process has been claimed in US 2004/0176432 from June 26, 2001 ) in which both chiral centers have been formed simultaneously, diastereo- and enantio-selectively pure in one single reaction step using chiral (R)-2-butynol as a chiral precursor in the presence of Pd(ll)-catalyst and diethyl zinc (Scheme 2).
Scheme 2:
Since water soluble, (R)-2-butynol is expensive, recently identical process has been published, in which instead of (R)-2-butynol less water soluble and therefore, less expensive (R)-4-phenyl-3-butyn-2-ol was used (Synthetic Commun. 39, 161 1 (2009)). Nevertheless, as incorrectly stated there, this process does not provide better diastereoselectivity than the original process using (R)-2-butynol: On the contrary disadvantage of this process is a very bad atom economy because huge phenyl group of (R)-4-phenyl-3-butyn-2-ol has to be “disposed” in oxidation step by the conversion of triple bond into carboxylic acid function.
……………………………
http://www.google.com/patents/WO2014023623A1?cl=en
The invention relates to a process for the manufacture of a
diastereomerically and enantiomerically enriched ester intermediate for isavuconazole or ravuconazole.
Isavuconazole and ravuconazole are triazole antifungal compounds. Processes for the manufacture of isavuconazole and ravuconazole were disclosed in patents WO99/45008, WO2007/062542 and WO03/002498 to Basilea. In WO2011/042827 a process for the manufacture of enantiomerically pure antifungal azoles such as ravuconazole and isavuconazole is disclosed, wherein a classical resolution of a racemic mixture is performed by the addition of an enantiopure chiral acid, then collection of the desired diastereomer followed by conversion of the salt into the enantiomerically pure form of the desired compound by treatment with a base or an ion-exchange resin. The disadvantages of using such classical resolution are that the chiral auxiliary needs to be applied in near stoichiometric amounts, and that additional process steps are required for recovery of these relatively high amounts of chiral reagent as well as for converting the salt into the free enantiopure product.
http://www.google.com/patents/US8076494
Reaction Scheme 1:
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New Drug Approvals 