Ospemifene Оспемифен أوسبيميفان 奥培米芬 spectral visit

Ospemifene or (Z)-2-[4-(4-chloro- 1 ,2-diphenyl-but- 1 -enyl)phenoxy]ethanol is represented by formula (I):

Ospemifene is an estrogen receptor agonist/antagonist currently investigated e.g. for the treatment of vulvar and vaginal atrophy due to menopause.
Preparation of ospemifene starting from Z-4-(4-hydroxy-l,2-diphenyl-but-l- enyl)phenol has been described in WO 96/07402. Use of McMurry coupling reaction for the manufacture of ospemifene has been described in WO 2008/099059 and WO 2011/089385. These methods suffer from the drawback that large amounts of expensive reagents or solvents, such as titanium tetrachloride, LiAlH₄, and 2-Me- THF, are needed.

^Actuals...WO2014060639
1H-NMR (400 MHz, CDC1₃) δ (ppm): 
7.37 (2H, t, 7=8Hz, ArH), 
7.29 (3Η, t, J=7.2Hz, ArH), 
7.20 (2Η, t,7=7.6Hz, ArH), 
7.16-7.13 (3Η, m, ArH), 
6.80 (2Η, d, J=8.8Hz, ArH), 
6.57 (2Η, d, 7=8.8Hz, ArH), 
3.94 (2Η, t, y=4.4Hz, ArOCH₂CH₂OH), 
3.87 (2H, m, ArOCH₂CH OH), 
3.42 (2H, t, J=7.2Hz, C1CH₂CH₂), 
2.92 (2H, t, 7=7.2Hz, C1CH₂CH₂),
 1.95 (1Η, t, 7=6.4Hz, OH).  


^{'
1H NMR PREDICT}

^{ACTUALS 13C NMR.....}WO2014060639
¹³C- NMR (100 MHz, CDC1₃) δ (ppm): 
157.2, 143.2, 142.1 , 141.3, 2 x 135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.


^{13C NMR PREDICT}

^COSY

^PATENT
http://www.google.com/patents/WO2014060639A1?cl=en

EXAMPLE 5. Preparation of (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)- phenoxy]ethanol (ospemifene) by base hydrolysis of pivaloyl-groiip
_; . (Z)-2-(4-(4-Chloro- l ,2-diphenylbut-l-en- l-yl)phenqxy)ethyl pivalate ( 1 g, 2.16 mmol) was dissolved in THF (8 ml) followed by addition of MeOH (1 ml) and water (1 ml). Sodium hydroxide (0.1 g, 2.5 mmol) was added in orie portion and the reaction was stirred at room temperature for 12 h. After completion of the reaction the mixture was partitioned between water (20 ml) and EtOAc (20 ml). Organic phase was washed with water (20 ml) and brine (20 ml); dried (Na₂S0₄), filtered, and concentrated: The residue was crystallized from -PrOH yielding ospernifene (0:29 g, 35 %) as a white solid.

1H-NMR (400 MHz, CDC1₃) δ (ppm): 7.37 (2H, t, 7=8Hz, ArH), 7.29 (3Η, t, J=7.2Hz, ArH), 7.20 (2Η, t,7=7.6Hz, ArH), 7.16-7.13 (3Η, m, ArH), 6.80 (2Η, d, J=8.8Hz, ArH), 6.57 (2Η, d, 7=8.8Hz, ArH), 3.94 (2Η, t, y=4.4Hz, ArOCH₂CH₂OH), 3.87 (2H, m, ArOCH₂CH OH), 3.42 (2H, t, J=7.2Hz, C1CH₂CH₂), 2.92 (2H, t, 7=7.2Hz, C1CH₂CH₂), 1.95 (1Η, t, 7=6.4Hz, OH).  

¹³C- NMR (100 MHz, CDC1₃) δ (ppm): 157.2, 143.2, 142.1 , 141.3, 2 x 135.7, 132.2, 130.0, 129.8, 128.8, 128.7, 127.4, 127.0, 113.9, 69.3, 61.8, 43.3, 39.0.



EXAMPLE 6. Preparation of (Z)-2-[4-(4-chloro-l,2-diphenyl-but-l-enyl)- phenoxy]ethanol (ospernifene) by reductive cleavage of pivaloyl-grou
(Z)-2-(4-(4-Chloro- 1 ,2-diphenylbut- 1 -en- 1 -yl)phenoxy)ethyl pivalate (3.5 g, 7.56 mmol) was dissolved in toluene (35 ml) and stirred under nitrogen for 5 min at room temperature. Lithium aluminium hydride solution (1 M in THE) (7.56 ml, 7.56 n mbi) was added dropwise to the reaction and the mixture was stirred at room temperature for 30 min. After HPLC indicated completion, the reaction was quenched by addition of saturated NH₄Cl-sblution (75 ml). Additional amount of toluene (30 ml) was added and the phases were separated. The organic phase was washed with water (50 ml), brine (50 ml), dried (Na₂S0₄), filtered and concentrated in vacuo. The residue was crystallized from 90 % MeOH yielding ospernifene (1 ,75 g, 61 9c) as a white solid.


1H NMR PREDICT

13C NMR PREDICT

Patent

	Filing date	Publication date	Applicant	Title
WO1996007402A1	Sep 6, 1995	Mar 14, 1996	Michael Degregorio	Triphenylethylenes for the prevention and treatment of osteoporosis
WO2008099059A1	Feb 13, 2008	Aug 21, 2008	Hormos Medical Ltd	Method for the preparation of therapeutically valuable triphenylbutene derivatives
WO2011089385A1	Jan 19, 2011	Jul 28, 2011	Cambrex Karlskoga Ab	New processes for producing benzophenone derivatives

Reference
1	*	ZHANG, DAN ET AL: "Two-step synthesis technology of ospemifene", XIANDAI YAOWU YU LINCHUANG , 27(4), 351-352 CODEN: XYYLAW; ISSN: 1674-5515, [Online] vol. 27, no. 4, 29 March 2012 (2012-03-29) , pages 351-352, XP002719433, Retrieved from the Internet: URL:http://www.tiprpress.com/xdywlc/ch/reader/create_pdf.aspx?file_no=201204004&flag=1&journal_id=xdywlc&year_id=2012> [retrieved on 2014-01-29] & DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; ZHANG, DAN ET AL: "Two-step synthesis technology of ospemifene", XP002719430, retrieved from STN Database accession no. 2013:1491112

H-NMR spectral analysis

CAS NO. 128607-22-7, 2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethanol H-NMR spectral analysis

C-NMR spectral analysis

CAS NO. 128607-22-7, 2-[4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenoxy]ethanol C-NMR spectral analysis

PATENT ON IMPURITIES
http://www.google.com/patents/CN104030896A?cl=en

Ospemifene olefins having molecular structure, W02011 / 89385 by the use of 4-hydroxy-benzophenone (2) and 2-bromoethanol in DMF to give 4-hydroxyethoxy-phenyl benzophenone ( 3), then by (3) and 3-chloro-acetone titanium tetrachloride - zinc catalytic reactions occur McMurry generated directly ospemifene.

[0007]

[0008] The method or W02008 / 099059 uses, hydroxy benzophenone 4_ 3_ chlorobenzene first with acetone to give compound by McMurry reaction of 5-chloro-1,2-diphenyl-1- (4-hydroxyphenyl ) -1_ pentene (4), and then the reaction Williams (5)

And to protect the reaction of ospemifene.

[0009]

The key step [0010] The method is to generate two ketone double bond coupling reaction, called McMurry reaction. This reaction of aldehydes and ketones in the reducing metal (Li, Na, Mg, Zn, LiAlH4, Zn-Cu) and a lower valence state titanium (TiCl3, TiCl4) role two carbonyl groups condensation-deoxy get olefins. Although McMurry reaction step is relatively simple, but the reaction conditions are harsh, self-conjugated cis-trans isomerization is difficult to avoid. Thus prepared ospemifene process, McMurry reaction prone plurality of side reaction products, the quality of which will affect the final product. States pharmacopoeia of a single impurity API has very strict limits, generally require less than 0.1%. In ospemifene of technology and quality research, separation and identification of impurities may have produced, then the structure of impurity, presumably causes and pathways that may arise in the process be avoided. And if the impurity has been generated, depending on the nature of impurities using a good method to remove them, for the preparation of high purity ospemifene has a very big help.

 Referring to W02008 / 099059 ospemifene obtained crude product by column chromatography using ethyl acetate: petroleum ether = 1: 3 as eluent to give a white solid. HPLC mobile phase: 0.5% triethylamine (adjusted with phosphoric acid to pH 3.0) - acetonitrile = 60: 40; flow rate: 1.0ml.mirT1; detection wavelength was 277nm. 1HNMR = L 90 (t, 1H, OH), 3.85 (q, 2H, CH2), 3.93 (m, 2H, -CH2), 4.65 (s, 1H,), 6.65 (d, 2H, benzene ring), 6.90 ~ 7.24 (m, 7H, phenyl ring). Elemental analysis = C15H16O3 Calculated C73.75%, H6.60%; Found C73.55%, H6.24%.

[0049] Example 9 ospemifene passivation

[0050] The ospemifene crude 20g added hexane 10ml, 40 ° C with stirring 30min, coolish, standing Ih pour out the liquid, then added hexane 10ml, repeat the above operation. The remaining solvent was evaporated under reduced pressure, the residue was added 160ml of methanol and ethanol were heated and dissolved, cooled to 40 ° C, maintaining the temperature was allowed to stand seeding crystallization. After crystallization, crystallization continued cooling and stirring, and then place the frozen _25 ° C. Filtered to give a white solid 15.2g, yield 76%, HPLC mobile phase: 0.5% triethylamine (adjusted with phosphoric acid to pH 3.0) - acetonitrile = 60: 40; flow rate: 1.0ml.mirT1; detection wavelength was 277nm The content of 99.92%.

10 ospemifene purification Example [0051] Example

[0052] The ospemifene crude 20g cyclohexane 100ml, stirred at room temperature 30min, cooled to (TC, standing Ih pour out the liquid, then cyclohexane 60ml, repeat the operation. Evaporated under reduced pressure The remaining solvent, the residue was added ethanol 200ml dissolved by heating and cooled to 40 ° C, slowly dropping water 20ml, maintaining the temperature was allowed to stand seeding crystallization. After crystallization, crystallization continued cooling and stirring at room temperature 25 ° C place. Filtering to give a white solid 14.8g, yield 74%, HPLC mobile phase:

0.5% triethylamine (adjusted with phosphoric acid to pH 3.0) - acetonitrile = 60: 40; flow rate: 1.0ml.mirT1; detection wavelength was 277nm, the content of 99.89%. [0053] Example 11 ospemifene passivation

[0054] The ospemifene crude 20g heptane was added 50ml, room temperature for 30min, cooled at room temperature, the liquid was decanted standing Ih, then heptane was added 20ml, repeat the above operation. The remaining solvent was distilled off under reduced pressure, the residue was added 160ml of isopropanol was heated to dissolve, cooled to 30 ° C, water was slowly added dropwise 16ml, maintaining the temperature was allowed to stand seeding crystallization. After crystallization, continue stirring and cooled to 0 ° C crystallization, at room temperature. Filtered to give a white solid 15.8g, Yield 79%, HPLC mobile phase:

0.5% triethylamine (adjusted with phosphoric acid to pH 3.0) - acetonitrile = 60: 40; flow rate: 1.0ml.mirT1; detection wavelength was 277nm, the content of 99.85%.

[0055] Example 12 ospemifene passivation

[0056] The above operation ospemifene crude 20g cyclohexane 40ml, room temperature for 30min, cooled at room temperature, the liquid was decanted standing Ih, then cyclohexane 20ml, repeat. The remaining solvent was distilled off under reduced pressure, the residue was added 200ml methanol was dissolved by heating, cooled to 30 ° C, water was slowly added dropwise 20ml, maintaining the temperature was allowed to stand seeding crystallization. After crystal precipitation, continue stirring and cooled to 0 ° C crystallization. Filtered to give a white solid 16.2g, Yield 81%, HPLC mobile phase: 0.5% triethylamine (adjusted with phosphoric acid to pH 3.0) - acetonitrile = 60: 40; flow rate: 1.0ml.mirT1; detection wavelength was 277nm The content of 99.90% ο

[0057] Example 13 ospemifene passivation

[0058] The ospemifene crude 20g of n-hexane was added 200ml, stirred at room temperature 30min, cooled at room temperature, the liquid was decanted standing Ih and then added hexane 20ml, repeat the above operation. The remaining solvent was evaporated under reduced pressure, the residue is added methanol, ethanol and isopropanol mixture was stirred at room temperature 300ml lh, maintaining the temperature was allowed to stand seeding crystallization. Filtered to give a white solid 12.4g, Yield 62%, HPLC mobile phase: 0.5% triethylamine (adjusted with phosphoric acid to pH 3.0) - acetonitrile = 60: 40; flow rate: 1.0ml.mirT1; detection wavelength was 277nm The content of 99.93%.

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ARTICLE

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 H-NMR（400 MHZ，CDCl3）δ：2.98（t， 2H，=CH2CH2Cl），3.45（t，2H，=CH2CH2Cl），3.85 （t，2H，-OCH2CH2OH），3.95（t，2H，-OCH2CH2OH）， 6.58（d，2H，羟基苯邻位），6.80（d，2H，羟基苯 间位），7.10～7.43（m，10H，苯环）。

13C-NMR（100 MHZ，CDCl3）δ：38.55（C-9），42.80（C-10），61.40 （C-1），68.88（C-2），113.48（C-4），126.95（C-5）， 128.20（C-17），128.34（C-13），129.36（C-16）， 129.51（C-12），131.73（C-14），135.26（C-8），135.34 （C-7），140.93（C-15），141.65（C-11），142.80（C-6）， 156.79（C-3）。合成路线见图 1。

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सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
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////////////

Isotopes: Br and Cl

There are other cases in which knowledge of isotopes can be crucial. For example, bromoethane should display a peak for the molecular ion at m/z = 109. However, the farthest large peak to the right in its mass spectrum is at 110. There is another large peak at 108.

Figure MS4. Mass spectrum of bromoethane. Source: SDBSWeb : http://riodb01.ibase.aist.go.jp/sdbs/ (National Institute of Advanced Industrial Science and Technology of Japan, 22 August 2008)

• In the periodic table, the atomic mass of bromine is listed as 80, but that is just an average.
• Bromine is really about 50% ⁷⁹Br and 50% ⁸¹Br.
• As a result, two molecular ion peaks of equal intensity two units apart, M+ and M+2, are observed.
• This pattern of molecular ions is a good indication that there is a bromine present in the molecule.

Similarly, chlorobenzene should display M+ at m/z =112, provided you take into account that most chlorine atoms have an atomic weight of 35 amu. The periodic table lists an atomic weight for chlorine of 35.453 amu, though. That's because about 25% of chlorine atoms are actually ³⁷Cl. The mass spectrum of chlorobenzene actually shows an additional molecular ion at 114 amu.

Figure MS5. Mass spectrum of chlorobenzene.

Source: SDBSWeb : http://riodb01.ibase.aist.go.jp/sdbs/ (National Institute of Advanced Industrial Science and Technology of Japan, 22 August 2008)

• Chlorinated compounds show an M+2 peak that is 1/3 as large as the M+ peak.

Note also that halogens are easily lost during mass spectrometry.  If you subtract the mass of the halogen from the molecular ion mass, you will often find a peak that corresponds to the remainder of the structure.

Problem MS4. 

Draw one possible structure for the compound in each of the following mass spectra.

Source: SDBSWeb : http://riodb01.ibase.aist.go.jp/sdbs/ (National Institute of Advanced Industrial Science and Technology of Japan, 25 August 2008)

Problem MS5. 

In the following mass spectrum, more than one halogen atom is present.

1. What is a possible structure of the compound?
2. Show why this pattern of molecular ions is observed.

Source: SDBSWeb : http://riodb01.ibase.aist.go.jp/sdbs/ (National Institute of Advanced Industrial Science and Technology of Japan, 25 August 2008)

Isotopes
Since a mass spectrometer separates and detects ions of slightly different masses, it easily distinguishes different isotopes of a given element. This is manifested most dramatically for compounds containing bromine and chlorine, as illustrated by the following examples. Since molecules of bromine have only two atoms, the spectrum on the left will come as a surprise if a single atomic mass of 80 amu is assumed for Br. The five peaks in this spectrum demonstrate clearly that natural bromine consists of a nearly 50:50 mixture of isotopes having atomic masses of 79 and 81 amu respectively. Thus, the bromine molecule may be composed of two ⁷⁹Br atoms (mass 158 amu), two ⁸¹Br atoms (mass 162 amu) or the more probable combination of ⁷⁹Br-⁸¹Br (mass 160 amu). Fragmentation of Br₂ to a bromine cation then gives rise to equal sized ion peaks at 79 and 81 amu.

bromine		vinyl chloride		methylene chloride

The center and right hand spectra show that chlorine is also composed of two isotopes, the more abundant having a mass of 35 amu, and the minor isotope a mass 37 amu. The precise isotopic composition of chlorine and bromine is:
        Chlorine:   75.77% ³⁵Cl and 24.23% ³⁷Cl
        Bromine:   50.50% ⁷⁹Br and 49.50% ⁸¹Br

The presence of chlorine or bromine in a molecule or ion is easily detected by noticing the intensity ratios of ions differing by 2 amu. In the case of methylene chloride, the molecular ion consists of three peaks at m/z=84, 86 & 88 amu, and their diminishing intensities may be calculated from the natural abundances given above. Loss of a chlorine atom gives two isotopic fragment ions at m/z=49 & 51amu, clearly incorporating a single chlorine atom. Fluorine and iodine, by contrast, are monoisotopic, having masses of 19 amu and 127 amu respectively. It should be noted that the presence of halogen atoms in a molecule or fragment ion does not change the odd-even mass rules given above.

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Two other common elements having useful isotope signatures are carbon, ¹³C is 1.1% natural abundance, and sulfur, ³³S and ³⁴S are 0.76% and 4.22% natural abundance respectively. For example, the small m/z=99 amu peak in the spectrum of 4-methyl-3-pentene-2-one (above) is due to the presence of a single ¹³C atom in the molecular ion. Although less important in this respect, ¹⁵N and ¹⁸O also make small contributions to higher mass satellites of molecular ions incorporating these elements.

The calculator on the right may be used to calculate the isotope contributions to ion abundances 1 and 2 amu greater than the molecular ion (M). Simply enter an appropriate subscript number to the right of each symbol, leaving those elements not present blank, and press the "Calculate" button. The numbers displayed in the M+1 and M+2 boxes are relative to M being set at 100%.

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सुकून उतना ही देना प्रभू, जितने से
जिंदगी चल जाये।
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///////

The Molecular Ion (M+) Peak

This page explains how to find the relative formula mass (relative molecular mass) of an organic compound from its mass spectrum. It also shows how high resolution mass spectra can be used to find the molecular formula for a compound.

Using a mass spectrum to find relative formula mass

The formation of molecular ions

When the vaporised organic sample passes into the ionisation chamber of a mass spectrometer, it is bombarded by a stream of electrons. These electrons have a high enough energy to knock an electron off an organic molecule to form a positive ion. This ion is called the molecular ion.

The molecular ion is often given the symbol M⁺ or - the dot in this second version represents the fact that somewhere in the ion there will be a single unpaired electron. That's one half of what was originally a pair of electrons - the other half is the electron which was removed in the ionisation process.

The molecular ions tend to be unstable and some of them break into smaller fragments. These fragments produce the familiar stick diagram. Fragmentation is irrelevant to what we are talking about on this page - all we're interested in is the molecular ion.

Using the molecular ion to find the relative formula mass

In the mass spectrum, the heaviest ion (the one with the greatest m/z value) is likely to be the molecular ion. A few compounds have mass spectra which don't contain a molecular ion peak, because all the molecular ions break into fragments. That isn't a problem you are likely to meet at A'level.

For example, in the mass spectrum of pentane, the heaviest ion has an m/z value of 72.

Because the largest m/z value is 72, that represents the largest ion going through the mass spectrometer - and you can reasonably assume that this is the molecular ion. The relative formula mass of the compound is therefore 72.

Finding the relative formula mass (relative molecular mass) from a mass spectrum is therefore trivial. Look for the peak with the highest value for m/z, and that value is the relative formula mass of the compound. There are, however, complications which arise because of the possibility of different isotopes (either of carbon or of chlorine or bromine) in the molecular ion. These cases are dealt with on separate pages.

Using a mass spectrum to find a molecular formula

So far we've been looking at m/z values in a mass spectrum as whole numbers, but it's possible to get far more accurate results using a high resolution mass spectrometer. You can use that more accurate information about the mass of the molecular ion to work out the molecular formula of the compound.

Accurate isotopic masses

For normal calculation purposes, you tend to use rounded-off relative isotopic masses. For example, you are familiar with the numbers:

1H		1
12C		12
14N		14
16O		16

To 4 decimal places, however, these are the relative isotopic masses:

1H		1.0078
12C		12.0000
14N		14.0031
16O		15.9949

The carbon value is 12.0000, of course, because all the other masses are measured on the carbon-12 scale which is based on the carbon-12 isotope having a mass of exactly 12.

Using these accurate values to find a molecular formula

Two simple organic compounds have a relative formula mass of 44 - propane, C₃H₈, and ethanal, CH₃CHO. Using a high resolution mass spectrometer, you could easily decide which of these you had. On a high resolution mass spectrometer, the molecular ion peaks for the two compounds give the following m/z values:

C3H8		44.0624
CH3CHO		44.0261

You can easily check that by adding up numbers from the table of accurate relative isotopic masses above.

Example 1

A gas was known to contain only elements from the following list: 1H 1.0078 12C 12.0000 14N 14.0031 16O 15.9949 The gas had a molecular ion peak at m/z = 28.0312 in a high resolution mass spectrometer. What was the gas? SOLUTION After a bit of playing around, you might reasonably come up with 3 gases which had relative formula masses of approximately 28 and which contained the elements from the list. They are N2, CO and C2H4. Working out their accurate relative formula masses gives: N2 28.0062 CO 27.9949 C2H4 28.0312 The gas is obviously C2H4.

The Utilization of Gas Chromatography/Mass Spectrometry in the Profiling of Several Antioxidants in Botanicals

.

 Spectrum of silylated epigallocatechin (EGC) (from standard compound), ret. time 65.18 min, MW = 738.31 (Note: The molecular weight does not consider the natural isotope distribution of elements and it is based only on the nuclidic masses of a single isotope).

 http://www.intechopen.com/books/advances-in-gas-chromatography/the-utilization-of-gas-chromatography-mass-spectrometry-in-the-profiling-of-several-antioxidants-in-


 By Serban Moldoveanu
DOI: 10.5772/57292