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¹H-¹H COSY (COrrelated SpectroscopY) is a useful method for determining which signals arise from neighboring protons (usually up to four bonds). Correlations appear when there is spin-spin coupling between protons, but where there is no coupling, no correlation is expected to appear.

This method is very useful when the multiplets overlap or when is extensive second order coupling complicates the 1D spectrum.

There are many variants on the COSY pulse sequence. The most popular one in our laboratory is the gradient enhanced double quantum coherence (DQF-COSY) version. The ratio of gradient strengths is usually set to two to yield all COSY signals but may be set to three to yield only those correlations involving three protons, e.g., CH-CH₂. We use the gradient enhanced DQF-COSY pulse sequence shown in fig. 1.

The COSY spectrum as shown in fig. 2 for ethylbenzene (fig. 3) contains a diagonal and cross peaks (signals that are not on the diagonal and correspond to other signals on the same horizontal and vertical projections). The cross peaks indicate couplings between two mutliplets up to three, or occasionally four, bonds away. The diagonal consists of the 1D spectrum with single peaks suppressed.

The most apparent cross-peak in the spectrum is between H1′ and H2′ at 2.65 and 1.24 ppm. A much weaker four-bond correlation (see the figure below) appears between H1′ and H2 at 2.65 and 7.20 ppm. All the desired signals are antiphase. Half the multiplet is positive and half negative. In addition, artifacts (undesired signals) appear in the spectrum as vertical streaks (interference and f₁ noise) and along the inverted ‘V’ (fig. 4) whose tip is on the top axis of the sepctrum. These artifacts are rarely in phase with the desired signals and appear in specific locations.

For example, in 12,14-di^tbutylbenzo[g]chrysene (fig. 5), only a partial analysis of the regular ¹H-NMR spectrum is possible. COSY (fig. 6) provides extra information about the connectivity. No correlations (cross-peaks) are seen to the tbutyls because they are too many bonds away from the ring system.

The aromatic region of the spectrum (fig. 7) shows three bond correlations strongest. These can be used to determine which protons are neighbors. For example the proton at 8.17 ppm is next to the proton at 7.34 ppm, a fact that could not be easily determined from the 1D spectrum.

Four-bond and five-bond correlations are apparent when plotted to lower contours (fig. 8). These separate the spectrum into four groups of protons in a manner that is much clearer than the 1D spectrum.

Using horizontal and vertical lines, it is possible to separate each group and follow its connectivity (fig. 9). The blue group of four protons is connected in the order 8.62 ppm to 7.55 to 7.59 to 8.56, the green group of four protons in the order 8.54 to 7.34 to 7.44 to 8.17 and the red group or two protons, that correspond to H9 and 10 because they are the only group of two protons expected to have a three-bond coupling constant (8.9 Hz), are at 7.76 and 8.32 ppm. The yellow group of two protons correspond to H11 and 13 because the coupling constant is small (1.9 Hz) and consistent with a four bond correlation.

The multiplet structures in COSY are anti-phase for active couplings which leads to different patterns that for pure phase. A pure singlet (A) will not appear in a DQF-COSY spectrum because it is purely single quantum and a double-quantum filter is applied. This is true for deuterated solvent signals and for some protiated solvents such as water. Advantage of this is often taken for solvent suppression. A simple doublet appears in anti-phase. Many other combinations exist. The more common ones are listed in the table below and a few examples are shown.

Figs. 10-13 show expansions of COSY multiplets. The red contours are negative and the black ones are positive. The 1D projections are only representations (in practice the sum of the projection is zero).

Higher multiplicities in which all the couplings are active yield the patterns shown in table 1. For example the correlation between the CH₃ and CH₂ protons in ethylbenzene yield a 1 0 1 pattern in one direction and a 1 1 -1 – 1 pattern in the other direction (fig. 11).

When there are more than two multiplets coupled, then only one coupling is active in each cross-peak. This can be used to determine which coupling constant relates to which correlation, something that may not be obvious from the 1D spectrum. In figs. 12 and 13 for di^tbutylbenzo[g]chrysene, the active couplings are labeled. The top cross-peak between the protons at 7.34 and 8.17 ppm shows the largest active coupling of 8.1 Hz. The coupling pattern in the vertical (f₁) direction is 1 1 1 0 -1 -1 -1 and in the horizontal (f₂) direction it is 1 1 1 1 -1 -1 -1 -1. The multiplet below it has the smallest active coupling of 1.4 Hz. The f₁ coupling pattern is 1 -1 1 0 -1 1 -1 and the f₂ coupling pattern is 1 1 -1 -1 1 1 -1 -1. The bottom multiplet displays an active coupling of 7.0 Hz and the coupling pattern in both directions is 1 1 -1 0 1 -1 -1.

EXAMPLE

COSY spectra

• The information on the H that are coupling with each other is obtained by looking at the peaks inside the grid.  These peaks are usually shown in a contour type format, like height intervals on a map.
• In order to see where this information comes from, let’s consider an example shown below, the COSY of ethyl 2-butenoate 
• First look at the peak marked A in the top left corner.  This peak indicates a coupling interaction between the H at 6.9 ppm and the H at 1.8 ppm.  This corresponds to the coupling of the CH₃ group and the adjacent H on the alkene.
• Similarly, the peak marked B indicates a coupling interaction between the H at 4.15 ppm and the H at 1.25 ppm.  This corresponds to the coupling of the CH₂ and the CH₃ in the ethyl group.
• Notice that there are a second set of equivalent peaks, also marked A and Bon the other side of the diagonal.

The (H,H) COSY experiment establishes the connectivity of a molecule by giving cross peaks (these are the off diagnonal peaks) for pairs of protons that are in close proximity. For the example of Glutamic acid below, we obtain cross peaks for the proton pairs (2,3) and (3,4). We do not observe a crosspeak for the pair (2,4), because these protons are not directly adjacent.

A relayed COSY experiment goes one step beyond a COSY experiment by showing cross peaks not just for pairs of adjacent protons, but for triples as well. As a result, we observe additional cross peaks like the one for the pair 2,4 in Glutamic acid below. Relayed COSY experiments can give cross peaks for protons that are too distant to show coupling in the 1D NMR spectrum.500 MHz H-relayed (H,H) COSY Spectrum of Glutamic acid. 1-D spectra left and top. 10 mg of compound in 0.5 mL of D₂O, 5 mm sample tube, 256 spectra, digital resolution of 2.639 Hz/data point. Total measurement time ca. 3h.

500 MHz H-relayed (H,H) COSY Spectrum of Glutamic acid. 1-D spectra left and top. 10 mg of compound in 0.5 mL of D₂O, 5 mm sample tube, 256 spectra, digital resolution of 2.639 Hz/data point. Total measurement time ca. 3h.

With present hardware and pulse sequences, it is possible to repeat the relay step up to three times. This allows the correlation of of protons that are separated by up to six bonds (d-protons). The relaying nucleus is typically ¹H, but high abundance I =1/2 hetero-elements like ³¹P or ¹⁹F can be used as well.

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The heteronuclear multiple bond correlation NMR spectrum (400 MHz, CDCl3) of dimer 4 with the corresponding 1D ¹H NMR and ¹³C NMR traces exhibited ten acetylene carbon resonances, a duplication of the propargyl methylene proton resonances that coupled with four and six acetylene carbons, respectively, as well as two new olefin carbon resonances that coupled only with the propargyl methylene protons on the ‘shorter’ side of the molecule. The inset is a magnified view of the region of the acetylene cross-peaks. For a more detailed discussion, see the Supplementary Information.

SEE

http://www.nature.com/nchem/journal/v5/n4/extref/nchem.1575-s1.pdf

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Sucrose 2D NMR Spectra

The sugar sucrose can be used to illustrate  homonuclear 2D NMR experiment: the TOCSY.

Sucrose

Table sugar

Sucrose (“table sugar”) is a disaccharide derived from glucose and fructose.

The interesting element from an NMR spectroscopy viewpoint is that the two monomer units are completely separate spin systems and this can be visualised in the TOCSY spectrum.

HH COSY

The HH COSY shows the coupling network within the molecule.

HH TOCSY

The HH TOCSY spectrum shows correlations that belong together in contiguous spin systems: in the sucrose example, this means that the protons in the respective glucose and fructose units can be assigned.

HMQC

In the HMQC spectrum the one-bond direct HC couplings can be viewed as cross-peaks between the proton and carbon projections.

HMBC

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Relugolix (TAK-385)

1-[4-[1-(2,6-Difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea

N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N’-methoxyurea

CAS NO 737789-87-6

Relugolix (TAK-385)

…………….

http://www.google.co.in/patents/EP1591446A1?cl=en

(Production Method 1)

(Production method 2)

Example 83
http://www.google.co.in/patents/EP1591446A1?cl=en

Production of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N’-methoxyurea

• The similar reaction as described in Example 4 by using the compound (100 mg, 0.164 mmol) obtained in Reference Example 54 and methyl iodide (0.010 ml, 0.164 mmol) gave the title compound (17.3 mg, 17 %) as colorless crystals.
  ¹ H-NMR(CDCl₃) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s).

……………

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2011, 54(14): 4998. http://pubs.acs.org/doi/full/10.1021/jm200216q

1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b)

tak 385

http://pubs.acs.org/doi/suppl/10.1021/jm200216q/suppl_file/jm200216q_si_001.pdf

…………………….

new patent

WO-2014051164

Method for the production of TAK-385 or its salt and crystals starting from 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl) thieno[2,3-d] pyrimidine-2,4 (1H,3H)-dione or its salt. Takeda Pharmaceutical is developing relugolix (TAK-385), an oral LHRH receptor antagonist analog of sufugolix, for the treatment of endometriosis and uterine fibroids. As of April 2014, the drug is in Phase 2 trails. See WO2010026993 claiming method for improving the oral absorption and stability of tetrahydro-thieno[2,3-d]pyrimidin-6-yl]-phenyl)-N’-methoxy urea derivatives.

references

Discovery of TAK-385, a thieno[2,3-d]pyrimidine-2,4-dione derivative, as a potent and orally bioavailable nonpeptide antagonist of gonadotropin releasing hormone (GnRH) receptor
238th ACS Natl Meet (August 16-20, Washington) 2009, Abst MEDI 386

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2011, 54(14): 4998. http://pubs.acs.org/doi/full/10.1021/jm200216q

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LM11A-31-BHS

(2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide

2-Amino-3-methyl-N-[2-(4-morpholinyl)ethyl]-pentanamide dihydrochloride

• CAS Number 1214672-15-7
• Empirical Formula C12H25N3O2 · 2HCl
• Molecular Weight 316.27

LM11A-31 is a non-peptide ligand of the p75 neurotrophin receptor (p75NTR). LM11A-31 blocks pro-NGF induced cell death in neuronal cultures, and protects neuronal cells from the the cytotoxic effects of cisplatin or methotrexate. Oral administration of LM11A-31 promotes the survival of oligodendrocytes and myelinated axons in a mouse spinal cord injury model and improves function in both weight-bearing and non-weight bearing tests.Inhibits death of hippocampal neurons at 100–1,000 pM

http://amcrasto.wix.com/anthony-melvin-crasto/apps/blog/lm11a-31-new-drug-can-help-paralyzed

PharmatrophiX

 

LM11A-31, C12 H25 N3 O2, Pentanamide, 2-amino-3-methyl-N-[2-(4-morpholinyl)ethyl]- WO 2010102212 TO LONGO FRANK, PUB 10.09.2010 THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

PATENT LINK

http://patentscope.wipo.int/search/en/WO2010102212

Scientists have developed a pill which they claim could help paralyzed people walk again.

The new drug allowed mice with no movement in their lower limbs to walk with ‘well-coordinated steps’ and even to replicate swimming motions, researchers said.

The experimental drug, called LM11A-31, was developed by Professor Frank Longo, of Stanford University, California.

The researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42 day experimental period, the ‘Daily Mail’ reported.

In tests, the experimental medication did not increase pain in the mice and showed no toxic effects on the animals.

It also efficiently crossed the blood brain barrier, which protects the central nervous system from potentially harmful chemicals carried around in the rest of the bloodstream.

An injury to the spinal cord stops the brain controlling the body and this is the first time an oral drug has been shown to provide an effective therapy.

“This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model,” Professor Sung Ok Yoon, of Ohio State University, Columbus, said.

“So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement,” Yoon said.

The small molecule in the study was tested for its ability to prevent the death of cells called oligodendrocytes.

These cells surround and protect axons, long projections of a nerve cell, by wrapping them in a myelin sheath that protect the fibres.

In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon’s lab previously found p75 is linked to the death of these specialised cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

“Because we know oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons,” she said.

FULL TEXT – JOURNAL OF NEUROSCIENCE

http://www.jneurosci.org/content/26/20/5288.full

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death  in Journal of neuroscience, 26(20): 5288-5300; doi: 10.1523/​JNEUROSCI.3547-05.2006 by SM Massa – 2006 - Cited by 51 - Related articles
17 May 2006 – At 5 nm, LM11A-24 and -31 inhibit TUNEL staining to a degree … We further prioritized LM11A-31, because preliminary studies

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death

2010 SLIDE PRESENTATION RE P75 (E.G. LM11A-31) BY PHARMATROPHIX’S …

investorvillage.com/smbd.asp?mb=160&mn=440341…

3 Nov 2010 – 2010 slide presentation re p75 (e.g. LM11A-31) by PharmatrophiX’s founder. Longo is PharmatrophiX’s founder.

The experimental drug was developed by Prof Frank Longo from Stanford University

• Suppression of immunodeficiency virus-associated neural damage by the p75 neurotrophin receptor ligand, LM11A-31, in an in vitro feline model. Meeker RB, Poulton W, Feng WH, Hudson L, Longo FM. J Neuroimmune Pharmacol. 2012; 7 (2): 388-400

Prof Frank Longo from Stanford University publications

http://med.stanford.edu/profiles/cancer/frdActionServlet?choiceId=showFacPublications&fid=7249&

Patents

1 US2013005731  (A1) ― 2013-01-03

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2013005731A1&KC=A1&FT=D&ND=3&date=20130103&DB=worldwide.espacenet.com&locale=en_EP

2 WO2011150347  (A2) ― 2011-12-01

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=WO&NR=2011150347A2&KC=A2&FT=D&ND=3&date=20111201&DB=worldwide.espacenet.com&locale=en_EP

3 US2011230479  (A1) ― 2011-09-22

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2011230479A1&KC=A1&FT=D&ND=3&date=20110922&DB=worldwide.espacenet.com&locale=en_EP

<a href=”http://www.bloglovin.com/blog/4674983/?claim=hj3e8pdf2nd”>Follow my blog with Bloglovin</a>

………………..

http://www.google.com.mx/patents/US7723328

TABLE I
Structures of Compounds 1-6
Compound	Name
	Compound 1 (also referred to herein as “LM11A-28”)
	Compound 2 (also referred to herein as “LM11A-7”)
	Compound 3 (also referred to herein as “LM11A-24”, “24”, and “C24”)
	Compound 4 (also referred to herein as “LM11A-31” and “31”)
	Compound 5 (also referred to herein as “LM11A-36”, “36”, and “C36”)
	Compound 6 (also referred to herein as “LM11A-38” and “C38”)
	Compound 7

 

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http://www.google.co.in/patents/WO2010102212A2?cl=en

Table I. Structures of Compounds i-vii

 

Example 32: Preparation of enantiomerically pure 2-amino-3-methyl-N-(2- morpholino-ethyϊ)-pentanamide

[00332] 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by a method shown in Scheme 4 below. First, 2-aminoethanol (Compound IE) is transformed to its derivative with a leaving group (Compound 2E). Examples of the leaving group include halides and alkoxy or other activated hydroxyl group. Second, Compound 2E reacts with morpholine at a neutral or basic condition to yield 2-morpholinoethanamine (Compound 3E). The aforementioned two steps may also be performed continuously as one step with Compound 2E being generated in situ. For example, Compound 3 E can be prepared from Compound IE directly through a Mitsunobu reaction wherein the hydroxyl group of Compound IE is activated by diethyl azodicarboxylate (DEAD) before morpholine is added. The final product, 2-amino-3-methyl-N-(2-moipholinoethyl)-pentanamide (Compound 5E), can be obtained by coupling 2-morpholinoethanamine with 2-amino-3- methylpentanoic acid (Compound 4E) via a peptide coupling agent. Examples of the peptide coupling agent include l,r-carbonyldiimidazole (CDI), hydroxybenzotriazole (HOBT), 1,3-dicyclohexylcarbodiimide (DCC), 1- hydroxybenzo-7-azatriazole (HOAt), and the like. Scheme 4:

H2N^0H — H2N^ / LG , p , .

1 Ot= LG: a leaving group

1E zt

 

[00333] A chiral 2-amino-3-methyl-N-(2-moφholinoethyl)-pentanamide (Compound 5E) can be obtained by using the corresponding chiral 2-amino-3- methylpentanoic acid (Compound 4E) in the above coupling step. For example, (2S,3S)-2-amino-3-methyl-N-(2-moφholinoethyl)-pentanamide; (2R,3R)-2-amino- 3 -methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3 S)-2-amino-3 -methyl-N-(2- moφholinoethyl)-pentanamide; and (2S,3R)-2-ammo-3-methyl-N-(2- morpholinoethyl)-pentanamide can be obtained by using (2S,3S)-2-amino-3- methylpentanoic acid, i.e., L-isoleucine; (2R,3R)-2-amino-3-methylpentanoic acid, i.e., D-isoleucine; (2R,3S)-2-amino-3-methylpentanoic acid, i.e., D-alloisoleucine; and (2S,3R)-2-amino-3-methylpentanoic acid, i.e., L-alloisoleucine, respectively. [00334] The chiral purity, also known as, enantiomeric excess or EE, of a chiral Compound 5E can be determined by any method known to one skilled in the art. For example, a chiral Compound 5E can be hydrolyzed to Compound 3E and the corresponding chiral Compound 4E. Then, the chiral Compound 4E obtained through hydrolysis can be compared with a standard chiral sample of Compound 4E to determine the chiral purity of the chiral Compound 5E. The determination can be conducted by using a chiral HPLC.

……………….

http://www.google.co.in/patents/EP2498782A1?cl=en

Scheme A shows the chemical structures of the present compounds.

 

(2S,3S)-2-amino-3-methyl-/V-(2-mor holinoethyl)pentanamide

 

(2R,3R)-2-amin -3-methyl-A/-(2-morpholinoethyl)pentanamide

 

(2S,3R)-2-amino-3-meth l-A/-(2-morpholinoethyl)pentanamide

 

] Q (2R,3S)-2-amino-3-methyl-/ /-(2-morpholinoethyl)pentanamide

The free base compound of 2-amino-3-niethyl- -(2-morpholinoethyl)-pentanamide can be prepared from isoleucine by synthetic methods known to one skilled in the art.

Standard procedures and chemical transformation and related methods are well known to one skilled in the art, and such methods and procedures have been described, for example, in standard references such as Fiesers’ Reagents for Organic Synthesis, John Wiley and Sons, New York, NY, 2002: Organic Reactions, vols, 1-83, John Wiley and Sons, New York, NY, 2006; March J, and Smith M,, Advanced Organic Chemistry, 6th ed., John Wiley and Sons, New York, NY; and Larock R.C., Comprehensive Organic Transformations, Wiley-VCH Publishers, New York, 1999. All texts and references cited herein are incorporated by reference in their entirety. Other related synthetic methods can be found in U.S. Patent Application Publication Nos. 2006/024072 and 2007/0060526, the contents of which are herein incorporated by reference in their entirety for all purposes. The amorphous dihydrochloride (di-HCl) salt of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by mixing two molar ecjuivalents of HC1 with one molar equivalent of 2-amino- 3-methyl-N-(2-morpholinoethyl)~pentanamide in appropriate solvent(s) and then separating the di-HCl salt from the solvent(s) mixture.

The amorphous di-HCl salt of 2-aniino-3-methyl-N-(2-moi holinoethyl)-pentariamide was analyzed via the methods as described above. The XRD analysis indicated it was amorphous/low ordered as shown in Figure 1 , The DSC thermogram exhibited a broad endotherm with onset temperature 37 °C and peak temperature 74 °C and an enthalpy value of ΔΗ = 80 J/g. The TGA thermogram indicated the di-HCl salt is anhydrous and starts to decompose after about 200°C. An overlay of DSC and TGA thermograms are shown in Figure 2. The moisture sorption-desorpiion isotherm of the di-HC! salt (Figures 3 A and 3 B ) was collected using dynamic vapor sorption (DVS) analysis. The material did not adsorb much moisture from 0% to 20% RH, then it showed steady sorption up to 140 wt% moisture at 95% RH (likely deliquescence). This sample showed rapid desorption from 95% to 70% RH and then continues desorbing at a relatively slower pace to a mass about 5 wt% greater than the original value at 0% RH. This sample shows a small hysteresis between the sorption and desorption phase. O verall this material is quite hygroscopic. The crude solubility of the di-HCl salt in water was >30 mg/niL. The proton N MR spectrum of the amorphous di-HCl salt is shown in Figure 4. Example 2. Preparation of 2-amino-3-methyl- -(2-morpholinoethy[)-pentanamide (free base):

Five grams of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide di-HCl salt was dissolved in 150 mL of ethanol. Sodium bicarbonate (5.3 g), dissolved in 100 mL of HPLC water, was added to this solution. The mixed solution was sonicated for ~10 minutes. This solution was concentrated using a rotovap, and the residue was dissolved in 300 mL of methylene chloride. This solution was passed through a short plug of carbonate bonded silica gel. This solution was concentrated using rotovap and the residue was lyophilized to dry, resulting in 3.6 g of the free base as a white solid. Proton NMR, C-13 NMR and LC/MS confirmed the structure of this material as the free base of 2-amino-3-methyl-N-(2- morpholmoethyl)-pentanamide.

In the process of converting the di-HCl salt to free base, the sample was lyophilized to avoid formation of oil. XRD analysis of the lyophilized free base surprisingly re vealed it was crystalline, as shown in Figure 5. The DSC thermogram exhibited an endotherm with extrapolated onset temperature 51 °C and peak temperature 53 °C and an enthalpy value of Δ¾= 104 J/g. The TGA thermogram shows less than 0.6 wt% loss at 105 °C, suggesting it was solvent free. An overlay of the DSC and TGA thermograms can be seen in Figure 6. The crude solubility of free base in water was >30 mg/mL. The proton NMR was consistent with the free base. The NMR and Raman spectra are shown in Figures 7 and 8A and 8B, respectively. The moisture sorption-desorption isotherm (Figures 9 A and 9B) was collected using dynamic vapor sorption (DVS) analysis. The sample did not adsorb much moisture content from 0% to 45% RH under the experimental conditions. Above 45 %RH the sample appears to adsorb moisture of – 10 wt% from 45% to 50% RH followed by rapid sorption up to 96 wt% moisture at 95% RH. In the desorption phase, the free base shows a rapid desorption from 95% to 80°/» RH, then the sample desorbs at a relatively slow pace to the original weight at 0% RH. The sample may form a hydrate near 45 %>RH, The putative hydrate appears to deliquesce resulting in an amorphous glass by the end of the scan.

……………

new patent

WO-2014052659

Crystalline forms of neurotrophin mimetic compounds and their salts

Type II TNF receptor agonist; NGF receptor modulator

Crystalline forms of (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide (LM11A-31-BHS), useful for the treatment of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis. See WO2011066544 claiming deuterated compounds of LM11A-31-BHS, useful for treating neurodegenerative diseases. PharmatrophiX is investigating the p75 neutrophin receptor ligand, LM11A-31-BHS, for the oral treatment of AD. By March 2013, a phase I trial was planned. The drug was formerly being investigated in collaboration with Elan Corp and the deal was terminated by the fourth quarter of 2010.

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Cabotegravir, GSK 744,

(3S,11aR)-N-(2,4-Difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

3S, 1 1 aR)- N-[(2,4-difluorophenyl)methyl]-2,3,5,7, 1 1 , 1 1 a-hexahydro-6-hydroxy-3- methyl-5,7- dioxo-oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide

read at

http://newdrugapprovals.org/2014/04/10/cabotegravir-gsk-744-in-phase-2-for-hiv-infection/

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One of the most important applications of nanotechnology in medicine involves use of nanoparticles to deliver drugs, and other therapeutic substances to specific types of cells (such as cancer cells). Nanosized structures and devices are smaller than human cells which are around 10,000 nm in diameter and similar in size to biomolecules such as enzymes, proteins (hemoglobin is 5 nm in diameter). Due to their small size, nanoparticles can also penetrate the blood-brain barrier which is impervious to most therapeutic and imaging agents.

read at

http://trialx.com/curetalk/2012/10/nanotechnology-drug-delivery-systems-an-insight/

Varun Arora

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Targeted drug delivery is a popular area of research that melds together the disciplines of chemistry, medicine, and materials. The basic idea is to develop ways to give a person adose of medicine and somehow get that medicine to go to exactly the part of the body that needs it most – and preferably nowhere else. An article recently published in JACSdescribes a clever method of antibiotic delivery that involves fat blobs, gold particles, and their interaction with the toxins released by infectious bacteria.

read all

http://icanhasscience.com/bacteria/blinged-out-fat-blob-nanotrucks-for-targeted-drug-delivery/

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CERC-301 (MK-0657) MK-657, c-6161, AGN-PC-00887R

structure source….http://www.google.com/patents/WO2013156614A1?cl=en    my id is amcrasto@gmail.com

Treat depression; Treat major depressive disorder (MDD); Treat suicidality

808732-98-1 free form, C₁₉ H₂₃ F N₄ O₂

(-) (3S,4R) – 1-​Piperidinecarboxylic acid, 3-​fluoro-​4-​[(2-​pyrimidinylamino)​methyl]​-​, (4-​methylphenyl)​methyl ester, 

AND

1-​Piperidinecarboxylic acid, 3-​fluoro-​4-​[(2-​pyrimidinylamino)​methyl]​-​, (4-​methylphenyl)​methyl ester, (3S,​4R)​-

(-​)​-​(3S,​4R)​-​4-​Methylbenzyl 3-​fluoro-​4-​[(pyrimidin-​2-​ylamino)​methyl]​piperidine-​1-​carboxylate

(3S,4R)-4-methylbenzyl 3-fluor-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate              

cas no of       hydrochloride 808733-06-4

Company	Merck & Co. Inc.
Description	Small molecule NMDA receptor NR2B subtype (GRIN2B; NR2B) antagonist
Molecular Target	NMDA receptor NR2B subtype (GRIN2B) (NR2B)
Mechanism of Action	NMDA receptor antagonist

 

PLEASE NOTE THE + FORM

(+)​-​(3R,​4S)​-​4-​Methylbenzyl 3-​fluoro-​4-​[(pyrimidin-​2-​ylamino)​methyl]​piperidine-​1-​carboxylate HAS CAS NO…..808732-99-2 AND ITS HYDROCHLORIDE 808733-07-5

 

also NOTE

1-​Piperidinecarboxylic acid, 3-​fluoro-​4-​[(2-​pyrimidinylamino)​methyl]​-​, (4-​methylphenyl)​methyl ester, (3R,​4S)​-​rel-;

 cis-​4-​Methylbenzyl 3-​fluoro-​4-​[(pyrimidin-​2-​ylamino)​methyl]​piperidine-​1-​carboxylate

HAS CAS    NO      808733-05-3                        AND DELETED CAS 1221592-​28-​4

 MY email ID IS amcrasto@gmail.com

 

AGN-PC-00887R, (4-methylphenyl)methyl (3S,4R)-3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

Molecular Formula: C₁₉H₂₃FN₄O₂   Molecular Weight: 358.409923

https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=69053724

Cerecor is developing the selective NMDA receptor subunit 2B antagonist CERC-301 (MK-0657) for depression.

CERC-301 (formerly MK-0657) is an oral, selective NMDA receptor subunit 2B (NR2B) antagonist in phase II clinical trials as adjunctive treatment for major depressive disorder (MDD) at Cerecor.

The compound had been in early trials at the National Institute of Mental Health (NIMH) for the treatment of major depression and at Merck & Co. for the treatment of Parkinson’s disease; however, no recent development has been reported in either case.

In 2013, the product was acquired by Cerecor from Merck & Co. on a worldwide basis for development and commercialization.

A phase II trial began in November 2013 and later that month, the FDA granted fast track designation for major depressive disorder.

………………………………………………

wo 2004108705 or http://www.google.co.in/patents/EP1648882B1?cl=en

METHODS OF SYNTHESIS

EXAMPLES 1 AND 2EXAMPLE 1

(35,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylateEXAMPLE 2

(3R,4S)-4-methylbenzyl 3-fluor-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

Step 1

Preparation of 4-Methylbenzyl 4-oxopiperidine-1-carboxylate:

• 4-Methylbenzyl alcohol (37.6 g, 308 mmol) was added to a solution of 1,1′-carbonyldiimidazole (50.0 g, 308 mmol) in DMF at RT and stirred for 1 h. 4-Piperidone hydrate hydrochloride (commercially available from Sigma-Aldrich, 47.0 g, 308 mmol) was added, resulting in a reaction mixture that was then heated to 50°C and stirred for 15 h. The reaction mixture was diluted with EtOAc and washed with 0.1 M HCl, H₂O (four times), and brine, dried over Na₂SO₄, filtered and concentrated. Purification by silica gel chromatography (step gradient elution: 10%, 25%, 50% EtOAc in hexanes) produced the title compound (42.4 g, 85% yield) as a clear oil.
  ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 3.79 (t, 4 H), 2.45 (br s, 4 H) 2.31 (s, 3 H) ppm;
  HRMS (ES) m/z 248.1281 [(M+H)⁺; calcd for C₁₄H₁₈NO₃: 248.1287];
  Anal. C₁₄H₁₇NO₃: C, 68.03; H, 7.05; N, 5.59. Found: C, 68.00; H, 6.93; N, 5.66.

Step 2Preparation of (±)-4-methylbenzyl 3-fluoro-4-oxopiperidine-1-carboxylate:

• A solution of 4-methylbenzyl 4-oxopiperidine-1-carboxylate (21.2 g, 85.7 mmol) and diisopropylethylamine (71.3 mL, 428 mmol) in dichloromethane (425 mL) was cooled to 0 °C and stirred. TBSOTf (29.5 mL, 129 mmol) was added slowly, maintaining the internal temperature below 5 °C. Aqueous NaHCO₃ (20 mL) was added and the layers were separated. The organic layer was washed with NaHCO₃, H₂O (two times), and brine, dried over Na₂SO₄, filtered and concentrated to give the crude TBS enol ether.
• The crude TBS enol ether was dissolved in DMF (125 mL) at RT. Selectfluor® reagent (commercially available from Air Products and Chemicals, Inc., 30.4 g, 85.7 mmol) was added and the reaction mixture was stirred for 10 min. The reaction mixture was partitioned between EtOAc and H₂O and the organic layer was washed with H₂O (three times). The combined aqueous layers were extracted with EtOAc (two times) and the combined organics were dried over Na₂SO₄, filtered and concentrated. The entire reaction above was repeated and the resulting reaction products were combined to give the title compound (40 g), which was used in the next step without purification. NMR and mass spectral data suggest the ketone functionality in the product exists as a hydrate.
  ¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 2 H), 7.19 (m, 2 H), 5.18 (s, 2 H), 4.81 (br d, 1 H), 4.50(br d, 1 H), 4.23 (d, 1 H), 3.90 (m, 1 H), 3.60 (m, 1 H), 3.35 (t, 1 H), 2.58 (m, 2 H), 2.35 (s, 3 H) ppm;
  HRMS (ES) m/z 284.1292 [(M+H)⁺; calcd for C₁₄H₁₈FNO₄: 284.1293];
  Anal. C₁₄H₁₈FNO₄•1.2H₂O: C, 58.61; H, 6.46; N, 4.88. Found: C, 58.28; H, 6.06; N, 4.72.

Step 3Preparation of:

(±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate

 and

(±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate

• To a solution of (±)-4-methylbenzyl 3-fluoro-4-oxopiperidine-1-carboxylate (40 g, 150 mmol) in toluene (200 mL) at RT was added (carbethoxymethylene)triphenylphosphorane (63.0 g, 181 mmol) and the reaction mixture stirred for 1 h. The reaction mixture was concentrated and purified by silica gel chromatography (gradient elution: 10% to 20% EtOAc in hexanes) to give the olefins (±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate and (±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate (41.0 g, 78% yield, 3 steps) as a 3:1 E:Z mixture. This mixture was utilized directly in the next step. A small sample of the mixture was separated by silica gel chromatography for characterization purposes.
  (±)-4-methylbenzyl (E)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate: white solid, ¹H NMR (400 MHz, CDCl₃) δ 7.26 (d, 2 H), 7.17 (d, 2 H), 5.98 (s, 1 H), 5.11 (s, 2 H), 4.85 (m, 1 H), 4.18 (q, 2 H), 4.08 (br d, 1 H), 3.70 (m, 1 H), 3.55 (m, 1 H) 3.41 (m, 1 H), 3.33, (m, 1 H), 2.63 (br d, 1 H), 2.35 (s, 3 H), 1.29 (t, 3 H) ppm;
  HRMS (ES) m/z 358.1420 [(M+Na)⁺; calcd for C₁₈H₂₂FNO₄Na: 358.1425];
  Anal. C₁₈H₂₂FNO₄: C, 64.21; H, 6.58; N, 4.27. Found: C, 64.46; H, 6.61; N, 4.18.
• (±)-4-methylbenzyl (Z)-4-(2-ethoxy-2-oxoethylidene)-3-fluoropiperidine-1-carboxylate: white solid, ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 6.41(m, 1 H), 5.82 (s, 1 H), 5.11 (d, 2 H), 4.61 (m, 1H), 4.38 (br d, 1 H), 4.16 (q, 2 H), 3.05-2.95 (m, 1 H), 2.9-2.75 (m, 2 H), 2.33 (s, 3 H), 2.13 (m, 1 H), 1.27 (t, 3 H) ppm;
  HRMS (ES) m/z 358.1422 [(M+Na)⁺; calcd for C₁₈H₂₂FNO₄Na: 358.1425].

Step 4:Preparation of:

(±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate

and

(±)-trans 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate

• [0081]
  To a solution of the olefin mixture from Step 3 (10.0 g, 29.8 mmol) in toluene (160 mL) and CH₂Cl₂ (120 mL) was added diphenylsilane (5.53 mL, 29.8 mmol) and (R)-BINAP (1.86 g, 2.98 mmol). Sodium t-butoxide (0.29 g, 2.98 mmol) and CuCl (0.30 g, 2.98 mmol) were then added, the reaction mixture was protected from light and stirred for 15 h. Additional portions of diphenylsilane (2.76 mL), NaOtBu (0.29 g) and CuCl (0.30 g) were added and the reaction mixture was stirred at RT for 24h. The mixture was then filtered through celite and concentrated. Purification on silica gel (step gradient elution: 5%, 10%, 15%, 25%, 30% EtOAc in hexanes) gave recovered starting materials (3.5 g, 35% yield), (±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (5.0 g, 50% yield) and (±)-trans 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (1.2 g, 12% yield).
  (±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate: clear oil, ¹H NMR (400 MHz, CDCl₃) δ 7.25 (d, 2 H), 7.15 (d, 2 H), 5.10 (s, 2 H), 4.80-4.20 (m, 3 H), 4.15 (q, 2 H), 3.10-2.73 (m, 2 H), 2.52 (dd, 1 H), 2.35 (s, 3 H), 2.30 (dd, 1 H), 2.10 (m, 1 H), 1.72-1.48 (m, 2 H), 1.29 (t, 3 H) ppm;
  HRMS (ES) m/z 338.1689 [(M+H)⁺; calcd for C₁₈H₂₅FNO₄: 338.1762].
• (±)-trans 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate: clear oil, ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 4.50-3.95 (m, 3 H), 4.15 (q, 2 H), 2.81 (br t, 2 H), 2.70 (br d, 1 H), 2.35 (s, 3 H), 2.17 (m, 2 H), 1.89 (br d, 1 H), 1.25 (m, 1 H), 1.22 (t, 3 H) ppm;
  HRMS (ES) m/z 338.1699 [(M+H)⁺; calcd for C₁₈H₂₅FNO₄: 338.1762].

Step 5Preparation of (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid:

• To a solution of (±)-cis 4-methylbenzyl 4-(2-ethoxy-2-oxoethyl)-3-fluoropiperidine-1-carboxylate (10.0 g, 29.6 mmol) in THF (50 mL) was added aqueous NaOH (1M, 50 mL). The reaction mixture was stirred at RT for 5 h and then diluted with EtOAc and 1M HCl. The layers were separated and the aqueous extracted with EtOAc twice. The combined organics were washed with brine, dried over Na₂SO₄, filtered and concentrated to give the title compound (9.1 g) as a white solid which was used in the next step without further purification.
  ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 4.79-4.16 (m, 3 H), 3.05-2.75 (m, 2 H), 2.59 (dd, 1 H), 2.36 (dd, 1 H), 2.31 (s, 3 H), 2.20-2.02 (m, 1 H), 1.60 (m, 2 H) ppm;
  HRMS (ES) m/z 310.1457 [(M+H)⁺; calcd for C₁₆H₂₁FNO₄: 310.1449].
  Anal. C₁₆H₂₀FNO₄•0.15 H₂O: C, 62.13; H, 6.52; N, 4.53. Found: C, 61.55; H, 6.37; N, 4.41.

Step 6Preparation of (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate:

• To a suspension of crude acid (±)-((cis)-3-fluoro-1-{[(4-methylbenzyl)oxy]carbonyl}piperidin-4-yl)acetic acid (9.1 g, 29.4 mmol) in toluene (80 mL) was added triethylamine (10.2 mL, 73.5 mmol) and diphenylphosphoryl azide (9.52 mL, 44.1 mmol). The reaction mixture was heated to 70 °C and stirred for 20 min. A mixture of dioxane (80 mL) and 1 M NaOH (80 mL) was added and the reaction mixture was cooled to RT. The reaction mixture was concentrated to remove the dioxane and extracted with EtOAc three times, dried over Na₂SO₄, filtered and concentrated. The residue was suspended in CH₂Cl₂, stirred for 30 min, and the white preciptate filtered off. The filtrate was concentrated to give crude product (7.5 g) as a yellow oil, used directly in the next step. An analytical sample was purified by silica gel chromatography (gradient elution: CH₂Cl₂ to 80:20:2 CH₂Cl₂ : MeOH : NH₄OH) for characterization:
  ¹H NMR (400 MHz, CDCl₃) δ 7.24 (d, 2 H), 7.15 (d, 2 H), 5.08 (s, 2 H), 4.90-4.18 (m, 3 H), 2.95-2.75 (m, 2 H), 2.79 (dd, 1 H), 2.70 (dd, 1 H), 2.35 (s, 3 H), 1.59 (m, 3 H) ppm;
  HRMS (ES) m/z 281.1658 [(M+H)⁺; calcd for C₁₅H₂₂FN₂O₂: 281.1660].

Step 7

Preparation of:

(3S,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

and

(3R,4S)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate

• Two sealed tubes were each charged with a mixture of crude (±)-cis-4-methylbenzyl 4-(aminomethyl)-3-fluoropiperidine-1-carboxylate (Step 6, 3.7 g, 13.2 mmol) and 2-chloropyrimidine (1.51 g, 13.2 mmol) in n-butanol/diisopropyl-ethylamine (1:1, 13 mL). The tubes were sealed and the mixtures heated to 140 °C and stirred for 2 h. After cooling to RT, the reaction mixtures were combined and diluted with EtOAc and sat NaHCO₃. The layers were separated and the organic was washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated. Purification by silica gel chromatography (gradient elution: 1:1 hexanes:EtOAc to EtOAc) gave racemic cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 65% yield, 3 steps) as a white solid.
• The enantiomers were separated by preparative HPLC on a ChiralPak AD column (5 cm x 50 cm, 20µM) with MeOH:MeCN (15:85, 150 mL/min) as eluant. The HCl salt of Example 1 was prepared by dissolving (3S,4R)-cis-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate (6.9 g, 19.3 mmol) in iPrOH (100 mL) at 65 °C. A solution of HCl in iPrOH (1.608 M, 12.6 mL, 20.2 mmol) was added and the solution was slowly cooled to RT over 15 h. Et₂O (25 mL) was added, the mixture stirred for 3h, cooled to 0 °C, stirred for 1h and filtered to give (3S,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate hydrochloride as a white solid (7.0 g, 92% recovery).
• The hydrochloride salt of (3R,4S)-4-methylbenzyl-3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate was prepared using a similar procedure.

(3S,4R)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate•HCl:

• [α]_D -36.4° (c 0.17, MeOH);
  Melting Point 149-150 °C;
  ¹H NMR (400 MHz, CD₃OD) δ 8.58 (br s, 2 H), 7.21 (d, 2 H), 7.17 (d, 2 H), 6.99 (t, 1 H), 5.06 (s, 2 H), 4.79 (m, 1 H), 4.42 (t, 1 H), 4.21 (d, 1 H), 3.60 (dd, 1 H), 3.50 (dd, 1 H), 3.15-2.80 (m, 2 H), 2.30 (s, 3 H), 2.10 (m, 1 H), 1.61 (m, 2 H) ppm;
  HRMS (ES) m/z 359.1879 [(M+H)⁺; calcd for C₁₉H₂₄FN₄O₂: 359.1878];
  Anal. C₁₉H₂₃FN₄O₂•HCl•0.2 H₂O: C, 57.27; H, 6.17; N, 14.06. Found: C, 57.22; H, 6.37; N, 14.16.

(3R,4S)-4-methylbenzyl 3-fluoro-4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate •HCl:

• [α]_D +34.9° (c 0.18, MeOH);
  Melting Point 149-150 °C;
  ¹H NMR (400 MHz, CD₃OD) δ 8.58 (br s, 2 H), 7.21 (d, 2 H), 7.17 (d, 2 H), 6.99 (t, 1 H), 5.06 (s, 2 H), 4.79 (m, 1 H), 4.42 (t, 1 H), 4.21 (d, 1 H), 3.60 (dd, 1 H), 3.50 (dd, 1 H), 3.15-2.80 (m, 2 H), 2.30 (s, 3 H), 2.10 (m, 1 H), 1.61 (m, 2 H) ppm;
  HRMS (ES) m/z 359.1870 [(M+H)⁺; calcd for C₁₉H₂₄FN₄O₂: 359.1878].
  Anal. C₁₉H₂₃FN₄O₂•HCl•0.5H₂O: C, 56.50; H, 6.24; N, 13.87. Found: C, 56.68; H, 6.27; N, 13.80.

……………….

WO 2006069287

http://www.google.com/patents/WO2006069287A1?cl=en

Scheme 1:

,

4-MeBnOH CDI

Scheme 2:

R¹ X- R1

X” Rhodium metal precursor/

H I iiR² chiral phosphine ligand |_] p — R^:

14 13

Representative Examples include:

EXAMPLE 1

Step A:

¹¹ -’ .OH

A 5 L round bottom flask was charged with THF (1.87 L, KF< 50 ppm) and cooling to -75 ^°C was begun. When the temperature of THF had reached < – 20 ^°C, n-BuLi (11 M in hex, 123 mL) was added over 15 minutes in order to keep the solution temperature below -10 ^“C. When the solution reached -35 ^°C, controlled addition of diisopropylamine (197 mL, KF < 50 ppm) over 15 minutes was carried out so the exotherm did not cause the solution temperature to exceed -16 ^°C. The solution was then allowed to continue to cool until it reached -75 ^“C. 3-Fluoropyridine (compound 1 from Scheme 1) (125 g, KF < 150 ppm) was then added neat to this solution via addition funnel while maintaining the batch temperature below -70 ^°C.

Neat DMF (168 mL, KF < 50 ppm) was then added to the batch over 1 hour maintaining the temperature < -70 ^°C. After confirming complete formation of the aldehyde, the reaction was warmed to 0 ^“C, and H₂O (230 mL, 10 eq.) was added. NaBH₄ (48.4 g) was then added in two portions over 5 minutes at 0 ^°C. Addition of concentrated HCl (6 M, 1.17 L) was completed in 1 hour at temperatures between 0- 25^°C. The rection batch was then heated to 40 ^°C and kept at this temperature for 1 hour.

The reaction was then allowed to cool to room temperature. Then, to the aqueous layer 6 M NaOH (747 mL) was slowly added at 0-15 ^°C to adjust the pH to 12. Approximately 700 mL of H₂O was added to dissolve any precipitate in the aqueous layer. The aqueous layer was then extracted with IPAc (1 x 1.275 L, 2 x 800 mL). The organic layer was treated with 20 wt. % Darco-G60 carbon (based on product assay) and the solution was heated to 40 ^°C for 1 hour followed by filtration over solka floe. After filtration the organic layer was solvent switched from IPAc to IPAc:heptane (15-20% v/v IPAc:heptane). The product crystallized as a white solid. This solution was then cooled to 0 ^°C for 30 minutes and filtered. An additional 250 mL of heptane was cooled to 0 ^°C and used to wash the wet cake. Typical Yield = 79% (128.5 g).

Step B:

To a 2 L flask under N₂ atmosphere were charged compound 2 from Scheme 1 (50.0Ig), acetone (524 mL), and BnBr (50.0 mL). This homogenous solution was heated to reflux for ~ 12 h. The reaction mixture was cooled to room temperature and diluted with heptane (550 mL). The pyridinium salt (compound 3 from Scheme 1) was collected by filtration. The wet cake was then slurry washed at ambient temperature with 25% acetone/heptane (200 mL) and filtered. The wet cake was then dried under vacuum at ambient temperature exposed to the atmosphere, affording a slight-pinkish solid ca. 98% pure by 1 H NMR

Typical Yield – 93% (109.5 g)

Step C:

To a 2 L round bottom flask were charged compound 3 from Scheme 1 (100.30 g, 1.00 eq.) and methanol (960 mL). The homogenous solution was then cooled to 10⁰C. The NaBH₄ (19.10 g, 1.50 Eq) was added portion wise (using a solid addition funnel) while keeping the temperature < 0 ⁰C. The batch was diluted with IPAc (1.0 L), followed by addition of 1 L 11.25 wt% brine. The resulting mixture was aged 15 min, then allowed to separate into two clear layers. The lower brine layer was removed. The organic stream was then washed with 500 mL 15wt% brine, then allowed to separate into two clear layers. The lower brine layer was removed. The batch was adjusted to roughly 1:1 MeOHrIPAc (c = 100 g/L) and then treated with 25 wt% Ecosorb C-941 at 50 ⁰C in for ~ 2 h. This was then filtered through a plug of celite, while rinsing with 1 : 1 MeOH:IPAc (rinse was roughly 25% of total batch volume). The batch was then concentrated to a residue.

The batch was then dissolved in 5% MeOH in IPAc at ~ 100 g/L (~ 636 mL). The batch was warmed to 50 ⁰C, followed by addition of a solution of 4M HCl in dioxane (1.10 eq)) slowly over ~ 1 h. At this point, the batch was seeded with a small spatula tip full of seed. After complete addition of the HCl solution, the batch was allowed to cool to room temperature slowly overnight. The solids were isolated by filtration. A slurry cake wash was then performed with 5% MeOH/IPAc (200 mL), followed by a displacement wash of 5% MeOH/IPAc (200 mL). The batch was then dried under vacuum at ambient temperature exposed to the atmosphere to afford compound 4 as a white solid (77% yield).

This material, 66.1O g of crude 4, was dissolved in 450 mL MeOH to which was added 450 mL IPAc. This mixture was treated with 25wt% Ecosorb C-941 (16.53 g) and heated to 50 ⁰C for 2 h. The mixture was then filtered through a pad of celite, washing the Ecosorb C-941 with ~ 500 ml 25% MeOH in IPAc. The mixture was then solvent switched on a rotovap to roughly 10% MeOH in IPAc. During the solvent switch, after concentrating to roughly 60% of its original volume, a small spatula tip full of seed was introduced, causing instant crystal growth. This mixture was concentrated until the final volume was ~ 350 mL. The slurry was then isolated, using a slurry wash of- 200 mL 5% MeOH/IPAc. The solids were dried over night under vacuum, exposed to the atmosphere, affording 60.23 g of 4 (70% yield).

Typical Yield = 70% (60.2 g).

Step D:

In a N₂ atmosphere glovebox, (R,R)-Walphos (SL-W003-1) (60.1 mg, commercially available from Solvias, Inc., Fort Lee, New Jersey 07024) and [(COD)RhCl]₂ (20.3 mg) were dissolved in dichloromethane (3 mL, anhydrous, N₂ degassed) and aged for 45 min at room temperature. Compound 4 from Scheme 1 (15.0 g) was charged to a 6 oz. glass pressure vessel (Andrews Glass Co., Vineland, NJ) containing a magnetic stir bar. MeOH (69 mL, anhydrous, N₂ degassed) was added, followed by the catalyst solution and a dichloromethane (3 mL) rinse.

The reactor was degassed with H₂ (40 psig) and immersed in a preheated 50 ⁰C oil bath. After a few minutes, the vessel was further pressurized with H₂ to 85 psig and allowed to age for 18.75 h. After this time, the vessel was vented and cooled to room temperature. HPLC analysis indicated >99% conversion of the vinyl fluoride. HPLC analysis indicated 99.3% ee.

The reaction mixture from above was concentrated in vacuo to a dark brown oil, which was then diluted with 50 mL EtOAc, to which was added 50 mL saturated NaHCO₃ (aq). This biphasic mixture was stirred at room temperature for 30 min. This mixture was separated, the aqueous layer was extracted 3 x 10 mL EtOAc, then the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to a residue, which was purified by column chromatography (1 : 1 EtOAc:hexanes) to afford 9.45 g of free base compound 5 (74.4% isolated yield) as a pale yellow oil.

Typical Yield = 74% (9.5 g).

HC1 HN^>”^F

To a 100 mL round bottom flask was charged the free base compound 5 from Example Scheme 1 , (1.00 eq), the Pd(OH)₂/C (1.29g), MeOH (23 mL), and 6M HCl (3.89 mL, 1.00 eq.). This mixture was degassed three times, finally filling the vessel with H₂ (1 atm, balloon pressure). The reaction was stirred at room temperature for 18 h. The mixture was filtered through a plug of Celite 521, rinsed with 50 mL MeOH, then concentrated to a residue. The residue was redissolved in ~ 150 mL 1 : 1 MeOH:IPAc, then refiltered through a sintered glass funnel to remove inorganics. Theis resulting solution was then solvent switched to roughly 10% MeOH in IPAc, during which spontaneous crystallization of compound 6 from Scheme 1 was observed. The solids were isolated by vacuum, washed twice with ~ 10 mL 10% MeOH in IPAc, then dried under vacuum over night, affording a pale white, crystalline solid.

Typical Yield = 81% (3.2 g).

JV,iV -Carbonyldiimidazole, 2.39 g (1.00 eq) was charged to a 50 mL round bottom flask, to which was added the DMF (19.7 ml). Then, the 4- methylbenzyl alcohol (1.80 g 1.00 eq) was added as a solid. This mixture was stirred for 15 min. at room temperature, during which an exotherm was noted (ΔT = +6.1 ⁰C, 18.5 ⁰C to 24.6 ⁰C). The fluoroalcohol HCl salt 6, 2.50 g (1.00 eq) was then added as a solid to this mixture. This was heated to 50 ⁰C for 1O h, and then allowed to cool to room temperature over night. The resulting mixture was diluted with 40 mL EtOAc. This mixture was washed 2 x 25 mL 3M HCl and separated, then 1 x 25 mL 15wt% brine and separated. This was extracted with 1 x 15 mL EtOAc and combined with the previous organic stream. The organic stream was concentrated to a residue and subjected to column chromatography eluting with a gradient (0% to 50% EtOAc in hexanes, TLCs developed in 50% EtOAc:hexanes, visualizing with UV and KMnO₄), to afford 3.35 g of a clear colorless oil.

Typical Yield = 81 % (3.4 g).

Step G:

A solution of fluoro alcohol compound 7 from Scheme 1 (1.22 g) in CH₃CN was cooled to -20 ^°C and Hunig’s base (2.2 equiv., 1.66 mL) was added. To this, Tf₂O – (1.1 equiv., 0.81 mL) was slowly added while maintaining the internal temperature < -10^°C. Aqueous NH₄OH (15 equiv., 2.7 mL) was then added to the reaction mixture at low temperature (-20^°C) and then warmed up to room temperature and aged for Ih. After completion, toluene (15 mL) and 10% NaOH (10 mL) were added and the layers separated. After extraction, the organic layer was washed with H₂O (IO mL).

The toluene stream of the amine was dried (-400 μg/mL) and concentrated to 100 g/L. Methanol was then added to obtain an overall solvent composition of toluene/MeOH (95:5), followed by the slow addition of HCl (1.05 equiv, 1.12 ml) at 50 ^°C. The amine hydrochloride 8 from Scheme 1 crystallized immediately, and the reaction was aged 20 min. The light yellow salt was then filtered and washed with cold toluene (15 mL) to offer amine hydrochloride 8 in 82% as a white crystalline solid.

Into a 100-L round bottom flask were charged 1.67 kg amine HCl salt 8 from Scheme 1, 912.4 g chloropyrimidine, 4.6 L of diisopropylethyl amine and 25.78 L ethylene glycol. The resulting slurry gradually became a solution, which was degassed and stirred under a nitrogen atmosphere. The contents were heated to 100 ° C for 12 h. The heat was turned off and the reaction solution slowly cooled to room temperature, which resulted in the formation of a slurry. To the slurry was added 77.3 L water over 1 h period and the slurry was aged at room temperature for 3 h. The mixture was filtered and the cake was washed with additional 80 L. The wet cake was left under nitrogen to dry overnight. After drying, 1.90 kg of an off white solid was collected.

1.77 kg of the above solid was dissolved into 71 L EtOAc and treated with 531 g Darco G-60 carbon at room temperature for 3 h. Filtration through Solka Floe was followed by washing with 2 x 20 L EtOAc. A solvent switch to MeOH under reduced pressure resulted in a slurry, and the final MeOH volume was adjusted to 19 L. The slurry in MeOH was heated to ca. 60 °C. Gradually cooling to room temperature resulted in a slurry, to which 57 L GMP water was added over 1 h with cooling (exothermic mixing, temperature controlled below 30 “C). The mixture was aged at room temperature for 3 h and filtered to collect solid, the cake was washed with 30 L GMP water and left to dry under nitrogen. 1.55 kg dried product was collected. (89% yield).

Typical Yield = 89% (1.55 kg).

………….

European Journal of Medicinal Chemistry (2012), 53, 408-415

http://www.sciencedirect.com/science/article/pii/S0223523412002310

Two diastereoisomeric NR2B NMDA antagonists were radiolabelled with fluorine-18. ► The radiolabelling of 3-[¹⁸F]fluoro-1,4-substituted-piperidine pattern was achieved. ► In vitro study showed high specific and selective binding for NR2B NMDAR receptors. ► B_max/K_d ratios and logD_7.4 demonstrated appropriate properties for in vivo imaging.

………………………..

Organic & Biomolecular Chemistry (2012), 10(42), 8493-8500

http://pubs.rsc.org/en/content/articlelanding/2012/ob/c2ob26378e#!divAbstract

In order to develop a novel and useful building block for the development of radiotracers forpositron emission tomography (PET), we studied the radiolabelling of 1,4-disubstituted 3-[¹⁸F]fluoropiperidines. Indeed, 3-fluoropiperidine became a useful building block in medicinal chemistry for the pharmacomodulation of piperidine-containing compounds. The radiofluorination was studied on substituted piperidines with electron-donating and electron-withdrawing N-substituents. In the instance of electron-donating N-substituents such as benzylor butyl, configuration retention and satisfactory fluoride-18 incorporation yields up to 80% were observed. In the case of electron-withdrawing N-substituents leading to carbamate or amidefunctions, the incorporation yields depend on the 4-susbtitutent (2 to 63%). The radiolabelling of this building block was applied to the automated radiosynthesis of NR2B NMDA receptor antagonists and effected by a commercially available radiochemistry module. The in vivoevaluation of three radiotracers demonstrated minimal brain uptakes incompatible with the imaging of NR2B NMDA receptors in the living brain. Nevertheless, moderate radiometabolism was observed and, in particular, no radiodefluorination was observed which demonstrates the stability of the 3-position of the fluorine-18 atom. In conclusion, the 1,4-disubstituted 3-[¹⁸F]fluoropiperidine moiety could be of value in the development of other radiotracers for PET even if the evaluation of the NR2B NMDA receptor antagonists failed to demonstrate satisfactory properties for PET imaging of this receptor.

…………………….

WO 2013156614

The chemical structure of MK-0657 is as follows

http://www.google.com/patents/WO2013156614A1?cl=en

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(Boston) – Healthcare experts continue to regard probiotics as one of the most powerful tools in the management of everything from constipation and bloating to diarrhea and skin health.

Historically, yogurt has been a primary source of probiotics, but yogurt products loaded with sugar have their own health implications for the tens of millions of Americans who are trying to lose weight. Sales of the healthier Greek-style yogurt were up 50% in 2012, showing that Americans are looking for healthier probiotic options. Unfortunately, even most Greek yogurt is loaded with sugar and calories.

So, how is the weight-conscious American supposed to get their probiotics?

http://www.howlifeworks.com/health_beauty/A_Simple_Way_to_Lose_Pounds_and_Relieve_Gas_and_Bloating_458?ag_id=1505&wid=8DC8FAB4-7586-49C7-938A-93851D50A3B9&did=5484&cid=1005&si_id=4193&pubs_source=mpt&pubs_campaign=20140418-1505

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The role of modern drug discovery in the fight against neglected and tropical diseases

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A highly efficient and recyclable ligand-free protocol for the Suzuki coupling reaction of potassium aryltrifluoroborates in water

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• Author: Jonathan Faiz
• Published: 22 April 2014
• Copyright: Wiley-VCH Verlag GmbH & Co. KGaA
• Source / Publisher: Angewandte Chemie International Edition
• Associated Societies: Gesellschaft Deutscher Chemiker (GDCh), Germany
• read at

The pharmaceutical industry is facing economic and strategic pressures to remain productive and profitable, and those involved in basic research in academia are encountering difficulties as funding is shifting toward more applied areas. Thus, the field of drug design and development can benefit from academic−industrial partnerships. In his Editorial, K. C. Nicolaou, Rice University, Houston, TX, USA, discusses the challenges and opportunities for such collaborations.

http://www.chemistryviews.org/details/news/6104841/AcademicIndustrial_Partnerships_in_Drug_Discovery_and_Development.html

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READ AT

http://cen.acs.org/articles/86/i29/Piece-Piece.html

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The MERS virus.

MERS (Middle Earth Respiratory Virus)

A new spike in cases of a deadly respiratory virus, in Saudi Arabia and the United Arab Emirates, is prompting new fears of an outbreak when the area’s population spikes during the annual Hajj pilgrimage.

The syndrome, called Middle East Respiratory Syndrome (MERS), is caused by a relatively new-to-humans virus that’s a close cousin of SARS, a virus that infected thousands of people worldwide in 2002-2004.

read at

http://www.businessinsider.in/5-Things-You-Should-Know-About-MERS-The-Deadly-Virus-Thats-Now-Breaking-Out-In-Saudi-Arabia/articleshow/34169304.cms

Illustration: http://yvpc.sph.umich.edu/

Read More at inserbia.info/today/2013/06/mers-new-deadly-virus-spreading-from-middle-east/ © InSerbia News

http://medicmagic.net/mers-koronavirus-that-is-still-mysterious.html

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Regulators in Europe have given the green light to GlaxoSmithKline’s new chronic obstructive pulmonary disease drug Incruse.

Specifically, the European Commission has granted marketing authorisation for Incruse (umeclidinium) as a once-daily treatment to relieve symptoms in adults with COPD. The drug is a once-daily long-acting muscarinic antagonist (LAMA) delivered by GSK’s Ellipta inhaler.

Read more at: http://www.pharmatimes.com/Article/14-04-28/Europe_green_light_for_GSK_COPD_drug.aspx#ixzz30Lohff26
Follow us: @PharmaTimes on Twitter

read

http://www.pharmatimes.com/Article/14-04-28/Europe_green_light_for_GSK_COPD_drug.aspx

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Delamanid

Otsuka Pharmaceutical Co has been given the green light to sell its tuberculosis drug Deltyba in Europe.

Read more at: http://www.pharmatimes.com/Article/14-04-30/Otsuka_multi-drug_resistant_TB_drug_approved_in_Europe.aspx#ixzz30Sz3wf2k
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http://newdrugapprovals.org/2014/03/26/delamanid-an-experimental-drug-for-the-treatment-of-multi-drug-resistant-tuberculosis/

Delamanid

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

(2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole

2(R)-Methyl-6-nitro-2-[4-[4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl]phenoxymethyl]-2,3-dihydroimidazo[2,1-b]oxazole

(R) -2-methyl-6-nitro-2- { 4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl } -2 , 3- dihydroimidazo [2 , 1-b] oxazole

Imidazo[2,1-b]oxazole, 2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl]phenoxy]methyl]-, (2R)-

(R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

681492-22-8 cas no

Delamanid (USAN, codenamed OPC-67683) is an experimental drug for the treatment of multi-drug-resistant tuberculosis. It works by blocking the synthesis of mycolic acids in Mycobacterium tuberculosis, the organism which causes tuberculosis, thus destabilising its cell wall.[1][2][3]

In phase II clinical trials, the drug was used in combination with standard treatments, such as four or five of the drugs ethambutol, isoniazid,pyrazinamide, rifampicin, aminoglycoside antibiotics, and quinolones. Healing rates (measured as sputum culture conversion) were significantly better in patients who additionally took delamanid.[3][4]

The European Medicines Agency (EMA) recommended conditional marketing authorization for delamanid in adults with multidrug-resistant pulmonary tuberculosis without other treatment options because of resistance or tolerability. The EMA considered the data show that the benefits of delamanid outweigh the risks, but that additional studies were needed on the long-term effectiveness.[5]

Delamanid, an antibiotic active against Mycobacterium tuberculosis strains, has been filed for approval in the E.U. and by Otsuka for the treatment of multidrug-resistant tuberculosis. In 2013, a positive opinion was received in the E.U. for this indication. Phase III trials for treatment of multidrug-resistant tuberculosis are under way in the U.S. Phase II study for the pediatric use is undergone in the Europe.

The drug candidate’s antimycobacterial mechanism of action is via specific inhibition of the synthesis pathway of mycolic acid, which is a cell wall component unique to M. tuberculosis.

In 2008, orphan drug designation was received in Japan for the treatment of pulmonary tuberculosis.

Tuberculosis (TB), an airborne lung infection, still remains a major public health problem worldwide. It is estimated that about 32% of the world population is infected with TB bacillus, and of those, approximately 8.9 million people develop active TB and 1.7 million die as a result annually according to 2004 figures. Human immunodeficiency virus (HIV) infection has been a major contributing factor in the current resurgence of TB. HIV-associated TB is widespread, especially in sub-Saharan Africa, and such an infectious process may further accelerate the resurgence of TB.

Moreover, the recent emergence of multidrug-resistant (MDR) strains ofMycobacterium tuberculosis that are resistant to two major effective drugs, isonicotinic acid hydrazide (INH) and rifampicin (RFP), has further complicated the world situation.

The World Health Organization (WHO) has estimated that if the present conditions remain unchanged, more than 30 million lives will be claimed by TB between 2000 and 2020. As for subsequent drug development, not a single new effective compound has been launched as an antituberculosis agent since the introduction of RFP in 1965, despite the great advances that have been made in drug development technologies.

Although many effective vaccine candidates have been developed, more potent vaccines will not become immediately available. The current therapy consists of an intensive phase with four drugs, INH, RFP, pyrazinamide (PZA), and streptomycin (SM) or ethambutol (EB), administered for 2 months followed by a continuous phase with INH and RFP for 4 months. Thus, there exists an urgent need for the development of potent new antituberculosis agents with low-toxicity profiles that are effective against both drug-susceptible and drug-resistant strains of M. tuberculosis and that are capable of shortening the current duration of therapy.

………………………

US20060094767

(R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol

ARE THE INTERMEDIATES

Example 1884

Production of (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

4-[4-(4-Trifluoromethoxyphenoxy)piperidin-1-yl]phenol (693 mg, 1.96 mmol) was dissolved in N,N′-dimethylformamide (3 ml), and sodium hydride (86 mg, 2.16 mmol) was added while cooling on ice followed by stirring at 70-75° C. for 20 minutes. The mixture was cooled on ice. To the solution, a solution prepared by dissolving (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (720 mg, 2.75 mmol) in N,N′-dimethylformamide (3 ml) was added followed by stirring at 70-75° C. for 20 minutes. The reaction mixture was allowed to return to room temperature, ice water (25 ml) was added, and the resultant solution was extracted with methylene chloride (50 ml) three times. The organic phases were combined, washed with water 3 times, and dried over magnesium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1). Recrystallization from ethyl acetate/isopropyl ether gave (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (343 mg, 33%) as a light yellow powder.

…………………………

WO 2010021409 AND http://worldwide.espacenet.com/publicationDetails/biblio?CC=IN&NR=203704A1&KC=A1&FT=D

FOR 2, 4 DINITROIMIDAZOLE

…………………………………………

WO2011093529A1

These patent literatures disclose Reaction Schemes A and B below as the processes for producing the aforementioned 2, 3-dihydroimidazo [2, 1-b] oxazole compound.

Reaction Scheme A:

wherein R1 is a hydrogen atom or lower-alkyl group; R2 is a substituted pxperidyl group or a substituted piperazinyl group; and X1 is a halogen atom or a nitro group.

Reaction Scheme B:

wherein X2 is a halogen or a group causing a substitution reaction similar to that of a halogen; n is an integer from 1 to 6; and R1, R2 and X1 are the same as in Reaction Scheme A.

An oxazole com ound represented by Formula (la) :

, i.e., 2-methyl-6-nitro-2-{4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl }-2, 3- dihydroimidazo [2, 1-b] oxazole (hereunder, this compound may be simply referred to as “Compound la”) is produced, for example, by the method shown in the Reaction Scheme C below (Patent

Literature 3) . In this specification, the term “oxazole compound’ means an oxazole derivative that encompasses compounds that contain an oxazole ring or an oxazoline ring (dihydrooxazole ring) in the molecule.

Reaction Scheme C:

However, the aforementioned methods are unsatisfactory in terms of the yield of the objective compound. For example, the method of Reaction Scheme C allows the objective oxazole Compound (la) to be obtained from Compound (2a) at a yield as low as 35.9%. Therefore, alternative methods for producing the compound in an industrially advantageous manner are desired. Citation List

Patent Literature

PTL 1: WO2004/033463

PTL 2: WO2004/035547

PTL 3: WO2008/140090

Example 9

Production of (R) -2-methyl-6-nitro-2- { 4- [4- (4- trifluoromethoxyphenoxy) piperidin-l-yl] phenoxymethyl } -2 , 3- dihydroimidazo [2 , 1-b] oxazole

{R) -1- [ - {2 , 3-epoxy-2-methylpropoxy ) phenyl] -4- [4- ( trifluoromethoxy ) phenoxy ] piperidine (10.0 g, 23.6 mmol, optical purity of 94.3%ee), 2-chloro-4-nitroimidazole (4.0 g, 27.2 mmol), sodium acetate (0.4 g, 4.9 mmol), and t- butyl acetate (10 ml) were mixed and stirred at 100°C for 3.5 hours. Methanol (70 ml) was added to the reaction mixture, and then a 25% sodium hydroxide aqueous solution (6.3 g, 39.4 mmol) was added thereto dropwise while cooling with ice. The resulting mixture was stirred at 0°C for 1.5 hours, and further stirred at approximately room

temperature for 40 minutes. Water (15 ml) and ethyl acetate (5 ml) were added thereto, and the mixture was stirred at 45 to 55°C for 1 hour. The mixture was cooled to room temperature, and the precipitated crystals were collected by filtration. The precipitated crystals were subsequently washed with methanol (30 ml) and water (40 ml) . Methanol (100 ml) was added to the resulting

crystals, followed by stirring under reflux for 30 minutes. The mixture was cooled to room temperature. The crystals were then collected by filtration and washed with methanol (30 ml) . The resulting crystals were dried under reduced pressure, obtaining 9.3 g of the objective product (yield: 73%) .

Optical purity: 99.4%ee.

……………….

Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles
J Med Chem 2006, 49(26): 7854

http://pubs.acs.org/doi/abs/10.1021/jm060957y

(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (19,  DELAMANID).

To a mixture of 27 (127.56 g, 586.56 mmol) and 4-[4-(4-trifluoromethoxyphenoxy)piperidin-1-yl]phenol (28g) (165.70 g, 468.95 mmol) in N,N-dimethylformamide (1600 mL) was added 60% sodium hydride (22.51 g, 562.74 mmol) at 0 °C portionwise. After the mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, the reaction mixture was cooled in an ice bath and carefully quenched with ethyl acetate (230 mL) and ice water (50 mL). The thus-obtained mixture was poured into water (3000 mL) and stirred for 30 min. The resulting precipitates were collected by filtration, washed with water, and dried at 60 °C overnight. This crude product was purified by silica gel column chromatography using a dichloromethane and ethyl acetate mixture (5/1) as solvent. The appropriate fractions were combined and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate (1300 mL)−isopropyl alcohol (150 mL) to afford 19 (119.11 g, 48%) as a pale yellow crystalline powder.

Mp 195−196 °C.

1H NMR (CDCl3) δ 1.77 (3H, s), 1.87−2.16 (4H, m), 2.95−3.05 (2H, m), 3.32−3.41 (2H, m), 4.02 (1H, d, J = 10.2 Hz), 4.04 (1H, d, J = 10.2 Hz), 4.18 (1H, J = 10.2 Hz), 4.36−4.45 (1H, m), 4.49 (1H, d, J = 10.2 Hz), 6.76 (2H, d, J = 6.7 Hz), 6.87−6.94 (4H, m), 7.14 (2H, d, J = 8.6 Hz), 7.55 (1H, s).

[α  −9.9° (c 1.01, CHCl3).

MS (DI) m/z 535 (M+ + 1). Anal. (C25H25F3N4O6) C, H, N.

http://pubs.acs.org/doi/suppl/10.1021/jm060957y/suppl_file/jm060957ysi20061113_095044.pdf

References