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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