ENDO EXO STORY.......cis-norborene-5,6-endo-dicarboxylic anhydride

You will react cyclopentadiene with maleic anhydride to form the Diels-Alder product below. This Diels-Alder reaction produces almost solely the endo isomer upon reaction at ambient temperature.




The preference for endo–stereochemistry is “observed” in most Diels-Alder reactions. The fact that the more hindered endo product is formed puzzled scientists until Woodward, Hoffmann, and Fukui used molecular orbital theory to explain that overlap of the p orbitals on the substituents on the dienophile with p orbitals on the diene is favorable, helping to bring the two molecules together.

Hoffmann and Fukui shared the 1981 Nobel Prize in chemistry for their molecular orbital explanation of this and other organic reactions. In the illustration below, notice the favorable overlap (matching light or dark lobes) of the diene and the substituent on the dienophile in the formation of the endo product:






Oftentimes, even though the endo product is formed initially, an exo isomer will be isolated from a Diels-Alder reaction. This occurs because the exo isomer, having less steric strain than the Endo , is more stable, and because the Diels-Alder reaction is often reversible under the reaction conditions. In a reversible reaction, the product is formed, reverts to starting material, and forms again many times before being isolated.

The more stable the product, the less likely it will be to revert to the starting material. The isolation of an exo product from a Diels-Alder reaction is an example of an important concept: thermodynamic vs kinetic control of product composition. The first formed product in a reaction is called the kinetic product. If the reaction is not reversible under the conditions used, the kinetic product will be isolated. However, if the first formed product is not the most stable product and the reaction is reversible under the conditions used, then the most stable product, called the thermodynamic product, will often be isolated.



The NMR spectrum of cis-5-norbornene-2,3-endo-dicarboxylic anhydride is given below:





Cis-Norbornene-5,6-endo-dicarboxylic anhydride 
Cyclopentadiene was previously prepared through the cracking of dicyclopentadiene and kept under cold conditions.  In a 25 mL Erlenmeyer flask, maleic anhydride (1.02 g, 10.4 mmol) and ethyl acetate (4.0 mL) were combined, swirled, and slightly heated until completely dissolved.  To the mixture, ligroin (4 mL) was added and mixed thoroughly until dissolved.  Finally, cyclopentadiene (1 mL, 11.9 mmol) was added to the mixture and mixed extensively.  The reaction was cooled to room temperature and placed into an ice bath until crystallized.  The crystals were isolated through filtration in a Hirsch funnel.  The product had the following properties: 0.47 g (27.6% yield) mp: 163-164 °C (lit: 164 °C).  ¹H NMR (CDCl₃, 300 MHz) δ: 6.30 (dd, J=1.8 Hz, 2H), 3.57 (dd, J=7.0 Hz, 2H), 3.45 (m, 2H), 1.78 (dt, J=9.0,1.8 Hz, 1H), 1.59 (m, 1H) ppm.  ¹³C NMR (CDCl₃, 75Hz) δ: 171.3, 135.5, 52.7, 47.1, 46.1 ppm.  IR 2982 (m), 1840 (s), 1767 (s), 1089 (m) cm^-1.

Reaction Mechanism The scheme below depicts the concerted mechanism of the Diels-Alder reaction of cyclopentadiene and maleic anhydride to formcis-Norbornene-5,6-endo-dicarboxylic anhydride.

Results and Discussion 
When combining the reagents, a cloudy mixture was produced and problems arose in the attempt to completely dissolve the mixture.  After heating for about 10 minutes and magnetically stirring, tiny solids still remained. The undissolved solids were removed form the hot solution by filtration and once they cooled, white crystals began to form. Regarding the specific reaction between cyclopentadiene and maleic anhydride, the endo isomer, the kinetic product, was formed because the experiment was directed under mild conditions.   The exo isomer is the thermodynamic product because it is more stable.3

A total of 0.47 g of the product was collected; a yield of 27.6%. The melting point was in the range of 163-164 °C which indicates the absence of impurities because the known melting point of the product is 164 °C.

The ¹H NMR spectrum of the product revealed a peak in the alkene range at 6.30 ppm, H-2 and H-3 (Figure 1).  In addition, it exhibited two peaks at 3.57 and 3.45 ppm because of the proximity of H-1, H-4, H-5, and H-6 to an electronegative atom, oxygen.  Finally, two peaks at 1.78 and 1.59 ppm corresponded to the sp³ hydrogens, Hb and Ha, respectively.  Impurities that appeared included ethyl acetate at 4.03, 2.03, and 1.31 ppm as well as acetone at 2.16 ppm.

Regarding the ¹³C NMR, a peak appeared at 171.3 ppm, accounting for the presence of two carbonyl functional groups, represented by C-7 and C-8 in Figure 1.  The alkene carbons, C-2 and C-3, exhibited a peak at 135.5 ppm, while the sp³ carbons close to oxygen, C-5 and C-6, displayed a peak at 52.7 ppm.  Finally, peaks at 46.1 and 47.1 ppm accounted for the sp³ carbons, C-1 and C-4, and C-9.  Impurities of ethyl acetate appeared at 46.6, 25.8, and 21.0 ppm accompanied with acetone at 30.9 ppm.

The IR spectrum revealed a peak at 2982 cm^-1 representing the C-H stretches.  A peak at 1840 cm^-1 accounted for the carbonyl functional group, while a peak at 1767 cm^-1 accounted for the alkene bond.  A peak at 1089 cm^-1 represented the carbon-oxygen functional group.

In order to distinguish between the two possible isomers, properties such as melting point and spectroscopy data were analyzed.  The exo product possessed a melting point in the range of 140-145 °C which is significantly lower than the endo product.  The observed melting point in this experiment supported the production of the endo isomer. 
The ¹H NMR spectum exhibited a doublet of doublets at 3.57 ppm for the endo isomer.  The exo isomer would possess a triplet around 3.50 ppm due to the difference in dihedral angle between the hydrogen molecules of H-1 and H-4, and H-5 and H-6 (Figure 1).  A peak at 3.00 ppm would appear in the exo isomer spectra as opposed to a peak at 3.60 ppm as shown in the observed endo product.³ This is because of the interaction and coupling with the H-5 and H-6, as displayed in Figure 1.

Conclusion 
Through the Diels-Alder reaction, 27.6% yield of cis-Norbornene-5,6-endo-dicarboxylic anhydride was produced. The distinction of the presence of the endo isomer was proven by analyzing physical properties of both possible isomers.

Martin, J.; Hill, R.; Chem Rev, 1961, 61, 537-562.

2 Pavia, L; Lampman, G; Kriz, G; Engel, R. A Small Scale Approach to Organic Laboratory   Techniques, 2011, 400-409.

3 Myers, K.; Rosark, J. Diels-Alder Synthesis, 2004, 259-265.
link 
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PIPERONAL

HNMR peaks  Piperonal.

As I assigned number 1-5, i have identified 5 different types of hydrogens that are going to show the five different peaks on the HNMR spectrum. Hydrogens labeled as number are equivalent so there are no coupling and are going to show a singlet but with the height of 2H. (S,2H). 

Hydrogen labelled as 2 is going to show a doublet (d,1H) because of spin-spin splitting with Hydrogen 3 on the same aromatic ring. Hydrogen 2 and 3 are adjacent to each other which makes them have the spin-spin splitting. the J constant for this Hydrogen is about 8Hz which we can calculate by the difference of the ranges in PPM an multiplying by 300 . 

and after the calculation i have found it to be about 7.2 which is close to 8 is valid for out argument. Hydrogen 3 show two spin-spin splitting because it it adjacent to Hydrogen 2 and meta relation to Hydrogen 5 on the aromatic ring. so Hydrogen 3 has (d,d,1H) two doublets next to each other. Hydrogen 4 is an aldehyde and had no coupling effect from the aromatic ring and therefore shows only a singlet (S,1H). also we know it is going to lie between the ranges of 9-10 because it's an aldehyde.

 As i mentioned before Hydrogen 5 is experiencing meta coupling effect because of Hydrogen 3 on the aromatic ring so it is going to show a doublet (d,1H). Hydrogens 2,3,and 5 all lie between the ranges of about 7-8. Also Hydrogen 5 is going to have a J constant of about 2Hz. After the integration we see that our assumptions are correct and the length of the integration lines correlates to the numbers of hydrogen.


IR




Piperonal (1,3-benzenodioxole-5-carbaldehyde)




The C=O double bond can be found in the range from 165 to 210 ppm. The C=O bond in this molecule shows up at about 190 ppm. A C-O single bond lies between 55 and 90 ppm and can be found for piperonal at about 78 ppm. The remaining carbons in the piperonal molecule are part of a benzene ring.

Aromatic carbons have a chemical shift of 115 to 150 ppm. As can be seen below, there are numerous peaks that fall in this range. It can be expected that the carbons bonded to the oxygen atoms have a stronger chemical shift due to the electronegativity of the oxygen. 

The peaks for these two carbons could fall in the 145 to 160 ppm range. The carbon attached to the carbonyl group would also have a greater chemical shift, and could be estimated to be in a range from 120 to 135 ppm.


MASS

3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one

Step 1: Synthesis of 3,4,5-tris(trimethylsilyloxy)-6-trimethylsilyloxymethyl-tetrahydropyran-2-one

To a solution of D-(+)-glucono-1,5-lactone (7.88 kg) and N-methylmorpholine (35.8 kg) in tetrahydrofuran (70 kg) was added trimethylsilyl chloride (29.1 kg) at 40° C. or below, and then the mixture was stirred at a temperature from 30° C. to 40° C. for 2 hours. After the mixture was cooled to 0° C., toluene (34 kg) and water (39 kg) were added thereto. The organic layer was separated and washed with an aqueous solution of 5% sodium dihydrogen phosphate (39.56 kg×2) and water (39 kg×1). The solvent was evaporated under reduced pressure to give the titled compound as an oil. The product was used in the next step without further purification.

¹H-NMR (CDCl₃) δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74-3.83 (3H, m), 3.90 (1H, t, J=8.0 Hz), 3.99 (1H, d, J=8.0 Hz), 4.17 (1H, dt, J=2.5, 8.0 Hz).

http://www.google.com.au/patents/WO2009154276A1?cl=en

Benzene dibromo-1 - 2,4 - (methyl ethoxy methyl - 1 - methoxy-1)

LEARN NMR


Benzene dibromo-1 - 2,4 - (methyl ethoxy methyl - 1 - methoxy-1)

Step 2:




Under a nitrogen atmosphere, 2,4 - tetrahydrofuran solution (40g, 0.15mol) of the (300ml), 2 dibromo benzyl alcohol - was added at room temperature (144ml, 1.5mol) methoxypropene, and cooled to 0 ℃. At 0 ℃, was added (75mg, 0.30mmol) and pyridinium p-toluenesulfonate, followed by stirring for 1 hour at the same temperature. Subsequently, in addition to saturated sodium hydrogen carbonate aqueous solution was cooled to 0 ℃, the reaction mixture was extracted with toluene. Was washed with brine and the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain quantitatively the title compound as an oil. The product was used in the next step without further purification.


A FANTASTIC EXAMPLE TO LEARN NMR

1 H-NMR (CDCl 3)
δ: 1.44 (6H, s),            6H OF GEM DIMETHYL GROUP
3.22 (3H, s),                -OCH3
4.48 (2H, s),                -OCH2-AR
7.42 (1H, d, J = 8.0Hz ), AR-H ORTHO TO SUBS, 8 HZ IS ONLY ORTHO COUPLING
7.44 (1H, dd, J = 1.5,8.0 Hz), AR-H META TO SUBS
7.68 (1H, d, J = 1.5Hz).  AR-H SANDWICHED BETWEEN 2 BROMO, 1.5 HZ INDICATES META COUPLING

SEE

http://www.google.com.au/patents/WO2009154276A1?cl=en

SPIRO COMPD EXAMPLE FOR NMR INTERPRETATION

(1S, 3'R, 4'S, 5'S, 6'R) -3 ', 4', 5 ', 6'-tetrahydro -6,6' - bis (hydroxymethyl) - spiro [ (3H), 2'-[2H] pyran] -3 ', 4', 5'-

Preparation of triol isobenzofuran-1

Crude 2 obtained in Step 4 - [2,5 - [bis (1 - methoxy-1 - methyl) ethoxy methyl] phenyl] -3,4,5 - tris (trimethylsilyloxy)-6 - trimethylsilyloxy methyl - tetrahydro pyran-2 - is cooled to -25 ℃ the methanol THF ol (theoretical 75.3mol) and (104.13kg) of (52.0kg) in a nitrogen stream, p-toluenesulfonic acid (2.9kg , I added a 15.6mol). For 3 hours 30 minutes of stirring at room temperature, it was confirmed the precipitation of a white solid. Was added methyl tert-butyl ether (108.7kg) the reaction mixture was stirred for 1 hour and cooled to 10 ℃. The solid was collected by filtration precipitated, washed with methanol with (104kg), to give (24.08kg) wet white powder. Was suspended in methanol (42.9kg) in the powder, and heated to 48 ℃ over 30 minutes, followed by stirring for 1 hour at 48 ℃. Was then stirred for 1 hour and cooled to 10 ℃. The solid was collected by filtering the suspension, washed with methanol (10.0kg), methyl tert-butyl ether by (10.0kg), to give (19.78kg) wet powder. And dried at reduced pressure below 40 ℃ This powder was obtained as white crystals (14.71kg, 63.4% 2 steps yield) of the title compound.

¹ H-NMR _(CD 3 OD) ^δ :3.47-3 .50 (1H, m) ,3.63-3 .69 (1H, m) ,3.75-3 .85 (4H, m), 4.63 (2H, s), 5.12 (1H, d, J = 12.6Hz), 5.18 (1H, d, J = 12.6Hz) ,7.23-7 .37 (3H, m ).
MS ^{(ESI +):} 299 [M ^+1] + 

http://www.google.com.au/patents/WO2011074675A1?cl=en

NEED HELP

(3R, 4S, 5R, 6R) -3,4,5 - tris (trimethylsilyloxy)-6 - trimethylsilyloxy methyl - tetrahydropyran-2: Step 3

Glucono -1,5 - - D-(+) in tetrahydrofuran (70kg) in the solution (35.8kg, 353.9mol) of N-methylmorpholine (7.88kg, 44.23mol) and lactone, chlorotrimethylsilane ( was added at 40 ℃ less 29.1kg, and 267.9mol), and the mixture was stirred for 2 hours at 30 ~ 40 ℃ resulting mixture. Was cooled to 0 ℃ the reaction mixture was added toluene (34kg) water (39kg), and the organic layer was separated. Twice sodium dihydrogen phosphate aqueous solution (5 wt%, 39.56kg) in, washed once with water (39kg) the organic layer the solvent was evaporated under reduced pressure. Was dissolved in toluene (34.6kg) and the residue obtained was obtained as a toluene solution of the title compound.

¹ H-NMR (CDCl ₃₎ ^δ: 0.13 (9H, s), 0.17 (9H, s), 0.18 (9H, s), 0.20 (9H, s), 3.74- 3.83 (3H, m), 3.90 (1H, t, J = 8.0Hz), 3.99 (1H, d, J = 8.0Hz), 4.17 (1H, dt, J = 2 .5,8.0 Hz).

MORE HELP

¹ H-NMR _{(DMSO-d 6)} ^δ: 4.49 (4H, t, J = 5.8Hz), 5.27 (1H, t, J = 5.8Hz), 5.38 (1H, t, J = 5.8Hz), 7.31 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 7.5Hz), 7.50 (1H, s).

Benzene (ethoxy methyl - methyl - - methoxy-1 1) - bromo-1 ,4 - 2:2 process bis.......EXAMPLE FOR NMR INTERPRETATION

 Benzene (ethoxy methyl - methyl - - methoxy-1 1) - bromo-1 ,4 - 2:2 process bis

(- Bromo-4 - 2-hydroxyethyl methyl phenyl) in tetrahydrofuran (57kg) in the solution (8.0kg, 36.9mol) of methanol, I added (185.12g, 0.74mol) of pyridinium p-toluenesulfonate. After cooling to -15 ℃ below the mixture, 2 - was added at -15 ℃ or less (7.70kg, 106.8mol) methoxy propene, and the mixture was stirred 1 h at -15 ~ 0 ℃. 

Was added aqueous potassium carbonate (25 wt%, 40kg) and the reaction mixture was warmed to room temperature and separate the organic layer was added toluene (35kg).

After washing with water (40kg) The organic layer was evaporated under reduced pressure. Was dissolved in toluene (28kg) and the residue obtained was obtained as a toluene solution of the title compound.

¹ H-NMR (CDCl ₃₎ ^δ: 1.42 (6H, s), 1.45 (6H, s), 3.24 (3H, s), 3.25 (3H, s), 4.45 ( 2H, s), 4.53 (2H, s), 7.28 (1H, dd, J = 1.5,8.0 Hz), 7.50 (1H, d, J = 8.0Hz), 7. 54 (1H, d, J = 1.5Hz).
MS ^(ESI +): 362 [M ^+2] +.

http://www.google.com.au/patents/WO2011074675A1?cl=en

NEED HELP IN INTERPRETATION

Preparation of methanol (2 - hydroxymethyl-phenyl - bromo-4)

To the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.1kg) in - bromoterephthalic was added at below 30 ℃ solution (7.5kg, 30.6mol) of the acid, and the mixture was stirred for 1 hour at 25 ℃. Then cooled to 19 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). In addition to methanol (15.0kg) in the mixture was kept for a while.

Again, to the mixing solution (1mol / L, 78.9kg, 88.4mol) of borane-tetrahydrofuran complex in tetrahydrofuran (6.34kg, 61.0mol) and, trimethoxyborane, two tetrahydrofuran (33.0kg) in - was added at below 30 ℃ solution (7.5kg, 30.6mol) of bromo terephthalic acid, and the reaction was carried out for 1 hour at 25 ℃. Then cooled to 18 ℃ The reaction mixture was stirred for 30 minutes and added a mixed solution of tetrahydrofuran and methanol (3.0kg) of (5.6kg). After addition of methanol (15.0kg) in the mixture is combined with the reaction mixture obtained in the previous reaction, and then the solvent was distilled off under reduced pressure. After addition of methanol (36kg) residue was obtained, and the solvent was evaporated under reduced pressure. 

Furthermore, (54 ℃ dissolved upon confirmation) which was dissolved by warming was added to methanol (36kg) to the residue. After cooling to room temperature the solution was stirred for 30 minutes added water (60kg). After addition of water (165kg) In addition to this mixture was cooled to 0 ℃, and the mixture was stirred for one hour. Centrifuge the obtained crystals were washed twice with water (45kg), and dried for 2 hours under reduced pressure to give (11.8kg, 54.4mol, 89% yield) of the title compound.

¹ H-NMR _{(DMSO-d 6)} ^δ: 4.49 (4H, t, J = 5.8Hz), 5.27 (1H, t, J = 5.8Hz), 5.38 (1H, t, J = 5.8Hz), 7.31 (1H, d, J = 7.5Hz), 7.47 (1H, d, J = 7.5Hz), 7.50 (1H, s).

Preparation of bromo terephthalic acid dimethyl ester - 1:2 process

Under a nitrogen stream, 2 - and cooled to about 5 ℃ a methanol suspension (30.0kg, 122.4mol) of the (95kg) bromo terephthalic acid was added dropwise (33.0kg) 98 wt% sulfuric acid under stirring . After that, I was stirred for 6 hours at about 60 ℃. After confirming by TLC of the reaction finished, the reaction mixture was cooled to room temperature, was added (220.0kg) methyl tert-butyl ether. The brine water (180.0kg), ₃ aqueous solution NaHCO (8 weight%, 180.0kg) and (24 wt%, 180.0kg) in the organic layer, anhydrous magnesium sulfate at (6.0kg) dried, and concentrated under reduced pressure, was obtained as a pale yellow crystal (30.40kg, 92.0% yield) of the title compound.

¹ H-NMR (CDCl ₃₎ ^δ: 3.94 (3H, s), 3.95 (3H, s), 7.79 (1H, d, J = 7.5Hz), 7.99 (1H, dd , J = 8.1Hz, 1.5Hz), 8.30 (1H, d, J = 1.5Hz). 

Zopolrestat

Zopolrestat

CAS : 110703-94-1

110765-49-6 (Na salt)

3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazineacetic acid

2- [4-Oxo-3- [5- (trifluoromethyl) benzothiazol-2-ylmethyl] -3,4-dihydrophthalazin-1-yl] acetic acid

3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate

Pfizer Inc. INNOVATOR

2-[4-oxo-3-[5-(trifluoromethyl)benzothiazol-2-ylmethyl]-3,4-dihydrophthalazin-1-yl]acetic acid

Manufacturers' Codes: CP-73850

MF: C19H12F3N3O3S

MW: 419.38

C 54.41%, H 2.88%, F 13.59%, N 10.02%, O 11.45%, S 7.65%

 Crystals, mp 197-198°. pKa (dioxane/water): 5.46 (1:1); 6.38 (2:1). Log P (n-octanol/water): 3.43.

 mp 197-198°

pKa: pKa (dioxane/water): 5.46 (1:1); 6.38 (2:1)

Log P: Log P (n-octanol/water): 3.43

Therap-Cat: Treatment of diabetic complications.

Keywords: Aldose Reductase Inhibitor.

................................

synthesis

http://www.google.com/patents/US20140228319

2-(8-oxo-7-((5-trifluromethyl)-1H-benzo[d]imidazol-2-yl)methyl)7,8-dihydropyrazin[2,3-d]pyridazin-5-yl)acetic acid and [4-oxo-(5-trifluoromethyl-benzothaiazol-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid (also known as zopolrestat), pharmaceutical compositions thereof and methods of treating diabetic complications in mammals comprising administering to mammals these salt and compositions. 2-(8-oxo-7-((5-trifluromethyl)-1H-benzo[d]imidazol-2-yl)methyl)8-dihydropyrazin[2,3-d]pyridazin-5-yl) acetic acid (formula II), is disclosed in WO 2012/009553 A1. Zopolrestat (formula III) is disclosed in U.S. Pat. No. 4,939,140.

Each of the patents, applications, and other references referred to herein are incorporated by reference. The diabetic complications include neuropathy, nephropathy, retinopathy, cataracts and cardiovascular complications, including myocardial infarction and cardiomyopathy. This invention is also directed to combinations of these salts and antihypertensive agents. These combinations are also useful in treating diabetic complications in mammals.

2-(8-oxo-7-((5-trifluoromethyl)-1H-benzo[d]imidazol-2-yl)methyl)8-dihydropyrazin[2,3-d]pyridazin-5-yl)acetic acid is prepared as disclosed in WO 2012/009553 A1, which is incorporated herein by reference. Zopolrestat is prepared as disclosed in U.S. Pat. No. 4,939,140.

..............................

Zopolrestat can be obtained by several different ways: 1) The reaction of 2- (4-oxo-3,4-dihydrophthalazin-1-yl) acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2- [3- (cyanomethyl) -4-oxo-3,4-dihydrophthalazin-1-yl] acetic acid ethyl ester (II), which is cyclized with 2-amino-4- (trifluoromethyl) thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV). Finally, this compound is hydrolyzed with KOH in methanol / water / THF. 2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride . (V) in hot DMF saturated with H2S 3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2- [3- (hydroxymethyl) -4-oxo-3,4 -dihydrophthalazin-1-yl] acetic acid ethyl ester (VI), which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII). Finally, this compound is treated with potassium cyanide and KI in acetone / water.

http://dmd.aspetjournals.org/content/26/11/1149/F2.expansion.html

............................

http://www.google.com/patents/EP0222576A2?cl=en

5=CF3 IS SUBS

EXAMPLE 7

• [0051]
  In accordance with Example 6, the following compounds are prepared:

  

  

  

..........................

http://www.google.com/patents/US4939140

EXAMPLE 18 Sodium 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetateSodium methoxide (54 mg) was added to 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.4 g) in methanol 10 ml) at room temperature. After the addition was complete, a clear solution was obtained which was stirred for 15 minutes at room temperature. The excess methanol was evaporated. The residue was triturated with ether (20 ml) and filtered to obtain the product (0.43 g; m.p. 300° C.).EXAMPLE 19 3-(5-Trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-3H-phthalazin-1-ylacetate, dicyclohexylamine saltTo a mixture of 3-(5-trifluromethylbenzothiazol-2ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (0.42 g) in methanol (10 ml) was added dicyclohexylamine (0.2 g) in methanol (5 ml). The resulting clear solution was stirred at room temperature for 15 minutes and then evaporated to dryness. Trituration of the residue with ether (30 ml) gave a white solid (0.38 g; m.p. 207° C.).EXAMPLE 20 3-(5-Trifluoromethylbenzothiazol-2ylmethyl)-4-oxo-3H-phthalazin-1-ylacetic acid, meglumine saltA solution of 3-(5-trifluoromethylbenzothiazol-2-ylmethyl)-4-oxo-phthalazin-1-ylacetic acid (419 mg) and meglumine (196 mg) in methanol (50 ml) was stirred at room temperature for an hour and then evaporated to dryness. The residue was triturated with ether (25 ml), filtered and the collected solid was air dried (610 mg; m.p. 157° C.).................................

J. Med. Chem., 1991, 34 (1), pp 108–122

DOI: 10.1021/jm00105a018

http://pubs.acs.org/doi/abs/10.1021/jm00105a018

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Mylari, Banavara L.; Zembrowski, William J.; Beyer, Thomas A.; Aldinger, Charles E.; Siegel, Todd W.
Journal of Medicinal Chemistry, 1992 ,  vol. 35,   12  p. 2155 - 2162

......................................

Mylari; Beyer; Scott; Aldinger; Dee; Siegel; Zembrowski
Journal of Medicinal Chemistry, 1992 ,  vol. 35,   3  p. 457 - 465

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Literature References:

Aldose reductase inhibitor. Prepn: B. L. Mylari et al., EP 222576; E. R. Larson, B. L. Mylari, US 4939140(1987, 1990 both to Pfizer);

B. L. Mylari et al. J. Med. Chem. 34, 108 (1991).

Pharmacology: B. Tesfamariam et al., J. Cardiovasc.Pharmacol. 21, 205 (1993); B. Tesfamariam et al., Am. J. Physiol. 265, H1189 (1993).

Clinical pharmacokinetics: P. B. Inskeep et al., J. Clin. Pharmacol. 34, 760 (1994).

Zopolrestat < Rec INN; BAN; USAN >
Drugs Fut 1995, 20(1): 33

Synthesis of aldose reductase inhibitor, 3, 4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid
J Label Compd Radiopharm 1991, 29(2): 143

EP0222576	3-19-1992	HETEROCYCLIC OXOPHTHALAZINYL ACETIC ACIDS
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US4939140	7-4-1990	Heterocyclic oxophthalazinyl acetic acids

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