Benazepril Synthesis by Dr Anthony Crasto


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BENAZEPRIL HYDROCHLORIDE SYNTHESIS BY DR ANTHONY CRASTO, WORLD DRUG TRACKER...............DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, NO ADVERTISEMENTS , ACADEMIC , NON COMMERCIAL SITE, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution,

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Benazepril Synthesis by Dr Anthony Crasto

  1. 1.
  2. 2.   is the link to my blog which tracks drugs worldwide  US, CANADA, JAPAN, EU CHINA ETC
  3. 3. He was only in first standard in school (Dec 2007) when I was Paralysed head to toe. His smiling face sees me through day in and day out. Vast readership from academia and industry motivates me, and keeps me going. Helping millions with free advertisement free websites and has million hits on google Thanks for helping me to keep lionel smiling
  4. 4.  Your own will power and determination will reach you to the shore even if you are drowned in the middle of a storm
  5. 5.  ACE Inhibitors are medications that belong in the class of medications known as antihypertensive medications.  ACE Inhibitors work on the Renin- Angiotensin-Aldosterone System
  6. 6.  Benazepril, brand name Lotensin (Novartis), is a medication used to treat high blood pressure (hypertension), congestive heart failure, and chronic renal failure. Upon cleavage of its ester group by the liver, benazepril is converted into its active form benazeprilat, a non-sulfhydryl angiotensin- converting enzyme (ACE) inhibitor.
  7. 7.  ACE Inhibitors work in the lungs to inhibit Angiotensin Converting Enzyme from turning Angiotensin I into Angiotensin II.  These medications cause an increase of bradykinin, which inhibits kinase II, another name for Angiotensin Converting Enzyme. (Lehne, 2007, pg. 464)  Blood Pressure is decreased due to a decrease in blood volume, peripheral resistance, and cardiac load.  ACE Inhibitors, inhibit vasoconstriction and release of aldosterone which inhibits the retention of sodium and water.
  8. 8. Generic Name Trade Name  benazepril  captopril  enalapril  enalaprilat  fosinopril  lisinopril  moexipril  perinodopril  quinapril  ramipril  Lotensin  Capoten  Vasotec  Vasotec IV  Monopril  Prinivil, Zestril  Univasc  Aceon  Accupril  Altace
  9. 9.  is also known as (3S)-3-(((1S)-1-Carboxy-3- phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-1H-1- benzazepine-1-acetic acid, 3-ethyl ester, monohydrochloride; Benazepril HCl; Cibacen; Cibacen CHF; Labopol.  It belongs to the product categories of Intermediates & Fine Chemicals; Pharmaceuticals; Amines; Aromatics; Heterocycles.  This chemical’s molecular formula is C24H29ClN2O5 and molecular weight is 460.96. What’s more, its IUPAC name 2-[(3S)-3-[[(2S)- 1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5- dihydro-3H-1-benzazepin-1-yl]acetic acid hydrochloride. In addition, Benazepril hydrochloride (CAS 86541-74-4) is crystalline solid which is soluble in DMSO.  It is used in high blood pressure and congestive heart failure. When you are using this chemical, you should not breathe dust and avoid contact with skin and eyes.
  10. 10. Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin 1-Carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-1- benzazepin-2-one monohydrochloride; 3(S)-[1(S)-Ethoxycarbonyl-3-phenylpropylamino]-2-oxo- 2,3,4,5-tetrahydro-1-benzazepine-1-acetic acid monohydrochloride 【CAS】 86541-74-4, 86541-75-5 (free base) MF C24-H28-N2-O5.Cl-H MW 460.9551rot–[Alpha] 20 D -141.0 °. (C = 0.9, ethanol) Cardiovascular Drugs, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors Launched-1990 Novartis (Originator), Pierre Fabre (Licensee), Andrx (Generic), Eon Labs (Generic), KV Pharmaceutical (Generic), Mylan (Generic)
  11. 11.  EARLIER Preparation of Benazepril hydrochloride (CAS 86541-74-4): The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.
  12. 12. ABOVE SCHEME-EP 1891014 B1
  13. 13.  Benazepril (CAS REGISTRY No. 86541-75-5) first disclosed inUS 4,410,520 is one of the well-known ACE inhibitors and is used for the treatment of hypertension.  Chemically, Benazepril, is (3S)-1-(carboxymethyl-[[(1(S)-1- (ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro- 1H-[1]benzazepine-2-one.  Benazepril is administered orally in the form of hydrochloride salt (CAS REGISTRY No. 86541-74-4) represented by formula (I).  The preparation of benazepril disclosed in US 4,410,520 , J. Med. Chem. 1985, 28, 1511-1516, and Helvetica Chimica Acta (1988) 71, 337-342, as given in scheme 1, NEXT SLIDE involves reductive amination of ethyl 2-oxo-4-phenyl butyrate (IV) with sodium salt of (3S)-3-amino-1-carboxymethyl-2,3,4,5- tetrahydro-1 H-benzazepin-2-one (III).
  14. 14.  In example 12 of US 4,410,520 , the crude benazepril (II) obtained in a diastereomeric ratio of SS: SR=70:30 was dissolved in dichloromethane and treated with HCl gas to obtain benazepril hydrochloride. The benazepril hydrochloride of formula (I) obtained as a foam was crystallized from methyl ethyl ketone to obtain in a SS: SR=95:5 diastereomeric ratio. Benazepril hydrochloride was further purified by recrystallization from a mixture of 3-pentanone/methanol (10:1), melting point: 188-190 °C.  Alternatively, in example 27 of US 4,410,520 , benazepril hydrochloride was purified by refluxing in chloroform, filtering, and washing first with chloroform and then with diethyl ether. The melting point of benazepril hydrochloride obtained as per this example is 184-186 °C.
  15. 15.  An alternative process disclosed in US 4,785,089 involves nucleophilic substitution of (3S)-3-amino-1-t- butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H- benzazepine-2-one (V), using the chiral substrate ethyl (2R)-2-(4-nitrobenzenesulfonyl)-4-phenyl butyrate (VI) in presence of N-methylmorpholine (scheme 2). NEXT SLIDE  The benazepril t-butyl ester (IIa) obtained in a diastereomeric ratio of SS: SR=96:4 was hydrolyzed to benazepril (II) and converted to hydrochloride salt by treating with HCl gas in ethyl acetate.  The crystalline suspension of benazepril hydrochloride in ethyl acetate was diluted with acetone and filtered to obtain in a diastereomeric ratio of SS: SR=99.1:0.9. Further purification by refluxing in ethyl acetate afforded benazepril hydrochloride in a diastereomeric ratio of SS: SR=99.7:0.3, melting point of 181 °C.
  16. 16.  The Merck Index., 12th edition reports benazepril hydrochloride crystals obtained from 3- pentanone+methanol (10:1), melting point 188-190 °C  The crystallization methods taught in the prior art does not consistently produce a constant diastereomeric composition of SS:SR diastereomer. This is evident from the variation in the melting points of the benazepril hydrochloride reported in three different working examples, which varies between 181 to 190°C.  The variation in diastereomeric composition of a pharmaceutical substance is not desirable as it would affect its efficacy. Hence there is a need for a crystallization process that consistently produce a constant diastereomeric composition of SS diastereomer in greater than 99.8%.
  17. 17.  Coming to the crystalline form, it is well known in the art that the solid form of a pharmaceutical substance affect the dissolution rate, solubility and bioavailability. The solid form may be controlled by process employed for the manufacture of the pharmaceutical substance. In particular the process of purification of the solid substance by crystallization is used to control the solid form (Organic Process Research & Development, 2003, 7, 958-1027).  It has been found that the crystalline form of benazepril hydrochloride obtained from processes of prior art documents is designated as crystalline Form A as evident from the following documents.
  18. 18.  In a monograph published by Al-badar et al in Profiles of Drug Substances, Excipients, and Related Methodology, Vol. 31, 2004, p117-161; benazepril hydrochloride prepared by the process disclosed in US 4,410,520 , and J. Med. Chem. 1985, 28, 1511- 1516, has been characterized by powder X-ray diffraction pattern having 2θ peaks at 6.6, 9.9, 11.9, 13.7, 14.0, 14.9, 15.3, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 22.2, 25.2, 25.5, 26.4, 26.6, 27.1, 27.9, 29.8, 30.4, 31.0, 32.6, 33.3, 33.8, 34.4, 35.5, 38.2, 39.9, 43.9, 48.9.  The major peaks are at 6.6, 9.9, 11.9, 13.7, 14.9, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 25.2, 25.5, 26.4, 26.6, 27.9, 31.0, and 32.6.  WO 2004/013105 A1 also discloses that by following the processes of the prior art mentioned above, crystalline benazepril hydrochloride is isolated in a form designated as Form A having a powder X-ray diffraction pattern with 2θ values at 6.7, 10.1, 12.0, 13.8, 15.1, 16.4, 17.4, 19.0, 19.6, 20.2, 20.9, 21.0, 25.3, 25.5, 26.4, 26.6, 27.6, 28.0, 31.0, 32.7.
  19. 19.  WO 2004/013105 A1 discloses that benazepril hydrochloride Form A may be prepared from a concentrated solution of the benazepril hydrochloride in a solvent selected from C1-C10 alcohol, N,N- dimethylformamide, N-methylpyrrolidone by adding an anti-solvent selected from C4-C12 alkane or C1- C10 acetate, preferably, hexane or ethyl acetate.  WO 2004/013105 A1 in Example 5 describes a process of making crystalline form A of benazepril hydrochloride by passing HCl gas into a solution of benazepril free base in diethyl ether and filtering the resulting suspension.  Similarly, in Example 6, the benazepril hydrochloride was dissolved in water free ethanol and the resulting solution was added to heptane at 20° C to obtain the crystalline Form A.
  20. 20.  Further, WO 2004/013105 A1 , mentions a list of solvents and anti-solvents that can be used to make benazepril hydrochloride crystalline Form A. However, there is no enabling disclosure and the document is silent on the diastereomeric purity of the crystalline form A obtainable by the process disclosed.  The processes of crystallization and/or recrystallization disclosed in the prior art do not consistently produce benazepril hydrochloride with constant diasteromeric content as evident from the variation in the melting point of the crystalline benazepril hydrochloride obtained from crystallization from various solvents.
  21. 21. Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use Watthey, J.W.H. (Novartis AG) EP 0072352; GB 2103614; JP 8338260 SYNTHETIC SCHEMES
  22. 22.  The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro- 1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3- chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido- 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5- tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1- (benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H- (1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino- 1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3- benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.
  23. 23. Process for the preparation of benazepril Kumar, Y.; De, S.; Thaper, R.K.; Kumar, D.S.M. (Ranbaxy Laboratories Ltd.) WO 0276375
  24. 24.  The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.
  25. 25. Synthesis of 14C-labeled 3-([1- ethoxycarbonyl-3-phenyl-(1S)- propyl]amino)-2,3,4,5-tetrahydro-2- oxo-1H-1-(3S)-benzazepine-1- acetic acid hydrochloride ([14C]CGS 14824A) Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S. J Label Compd Radiopharm 1987,24(10),1177-84
  26. 26.  A new synthesis of CGS-14824A is given: The reaction of 3- bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1- tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5- tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII).  The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N- alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4- phenylbutyrate (XIII) by means of sodium cyanoborohydride.
  27. 27. US 6548665 B2– above
  28. 28.  see translated version————-First, 2,3,4,5 – tetrahydro-1H-[1] azepin-2 phenyl – one (2) Preparation of the dry reaction flask, add α- tetralone 20g (0.137mol), stacked acid 7.36g (0.171mol) and chloroform 140ml, was stirred at 40 ℃ in 1h concentrated sulfuric acid was slowly added dropwise 36ml, acid layer was separated and poured into 900ml water to give a creamy solid. Recrystallization with hot water to give white crystals (2) 15.5g (70%), mp141 ℃. (Acidic filtrate and after a small amount of product can be obtained.) Second, 3,3 – dichloro-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (3) of the prepared in a dry reaction flask, (2) 48.3g (0.3mol) and xylene solution of 1300ml, phosphorus pentachloride 188g (0.9mol), stirred and gradually heated to at 0.5h 90 ℃, (Caution! When phosphorus pentachloride dissolved hydrogen chloride gas had severe.) 90 ℃ the reaction was continued for 0.5h, filtered to remove a small amount of suspended solids, solvent recovery under reduced pressure, to the residue was added saturated sodium bicarbonate solution, 100ml, stirred until a solid precipitate complete, filtered and the cake washed with ethanol (100ml × 2), diethyl ether (50ml) and dried to give (3) 69.0g (90%), mp185 ~ 187 ℃. III.3 – chloro-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (4) Preparation of the reaction flask (3) 10g (0.087mol), Sodium acetate 77g (0.11mol), acetic acid 460ml and 5% Pd-C 0.86g, under atmospheric pressure at room temperature to a hydrogen-absorbing up total of 950ml (about 0.5h). Filtration, recycling the catalyst recovered solvent, the residue was dried under reduced pressure, and then added 900ml of 10% sodium bicarbonate solution and dichloromethane 300ml, stirring, standing, the organic layer was separated and the aqueous layer extracted with dichloromethane (300ml × 3) extracted organic layers were combined, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure. Diethyl ether was added to the cured 350ml, and mashed, filtered and dried to give (4) 8.19g (95%), mp163 ~ 167 ℃.
  29. 29.  4 (3) – azido-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (5) Preparation of the dry reaction flask (4) 15.9g ( 0.08mol), sodium azide 6.4g (0.10mol) and 320ml solution of dimethyl sulfate, the reaction was stirred at 80 ℃ 3h, cooled to room temperature, poured into ice-water (1L) to precipitate a pale yellow solid , filtered and dried under reduced pressure at 75 ℃ to give (5) 14.7g (90%), mp142 ~ 145 ℃. V.3 – azido-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (6) Preparation of the dry reaction flask, (5) 3.0g (0.015mol), tetrabutylammonium bromide, 0.5g (0.0015 mol), powdered potassium hydroxide 1.1g (0.016mol) and 30ml of tetrahydrofuran solution of ethyl bromoacetate was added 1.9ml ( 0.016mol), stirred rapidly at room temperature for 1.5h (nitrogen). Water was added: dichloromethane (50:100 ml), stirred, allowed to stand, the organic layer separated. Washed with water, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure to give a pale yellow oil (6) 4.1g (96%) (can be used directly in the next step).
  30. 30.  VI.3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (7) Preparation of the dry reaction flask, (6 ) 20.0g (0.070mol), ethanol 100ml, 10% Pd-C 1.0g stirring, at room temperature, 303.9kPa hydrogenated under a hydrogen pressure 1.5h, intermittent deflated to remove the generated nitrogen gas, after the reaction was collected by filtration Pd / C, recovery of solvents under reduced pressure to give a yellow oil, add ether l00ml, mashed, filtered and dried to give a white solid (7) 17.0g (93%) mp101 ~ 102 ℃. Seven, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (8) Preparation of the reaction flask, adding (7) 25.1g (0.096mol), L – tartaric acid 14.4g (0.096mol) and hot ethanol 200ml, stirring to dissolve, cooled at room temperature overnight, filtered and dried under reduced pressure to give a white powder 30.7g, with ethanol Recrystallization twice (each 200ml), to give (8) tartaric acid salt of 13.6g (34%), mp168 ~ 169 ℃, with 10% ammonium hydroxide, to give a white solid (8) 8.0g (95%) mp104 ~ 106 ℃. Eight, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (9)
  31. 31.  Preparation of the reaction flask, (8) 4.0g (0.056mol) and 150ml of methanol solution of sodium hydroxide 2.1g (0.056moI) and a solution of 5ml of water, stirred at room temperature for 2h, the solvent recovered under reduced pressure, the residue was dried and diethyl ether was added 100ml, trace broken, filtered, and dried to give (9) 12.9g (89%) (used directly in the next step). IX benazepril (1) Synthesis of the reaction flask (9) 12.9g (0.050mol), 2 – oxo-4 – phenylbutyrate 31.0g (0.15mol), acetic acid and 100ml methanol 75ml, the reaction was stirred at room temperature for 1h (nitrogen). Of sodium borohydride cyanide was slowly added dropwise 3.8g (0.062mol) and 30ml of methanol solution of (4h was completed within), stirred overnight, heat. Concentrated hydrochloric acid 10ml, 1h stirring at room temperature, the solvent was recovered under reduced pressure, water was added to the residue and diethyl ether 400ml l00ml, dissolved with concentrated ammonium hydroxide and the pH adjusted to 9.3, the organic layer was separated and the aqueous layer acidified with concentrated hydrochloric to pH 4.3, extracted with ethyl acetate (100ml × 3) extracted organic layers were combined,
  32. 32.  dried over anhydrous magnesium sulfate, the solvent recovered under reduced pressure, to the residue was added methylene chloride (150ml) to dissolve. And pass into dry hydrogen chloride after 5min recovered solvent under reduced pressure, to the residue was added hot ethyl ketone 100ml, stirring to dissolve, cooled and precipitated solid was filtered to give crude product (1). A 3 – amyl ketone / methanol (volume ratio 10:1) (110ml) was recrystallized (1) 5.8 g, mp 188 ~ 190 ℃, [alpha] D 20 -141.0 (C = 0.9, C 2 H 5 OH ) [Spectral Data] (free base) [2] MS: m / Z (%) 424 (M + , 2), 351 (100), 190 (22), 91 (65) ] [other synthetic routes described in the reference literature.  [References] [1] Briggs LH et al. J Chem Soc, 1937, 456 [2] Watthey WH et al. J Med Clmm, 1985, 28:1511 [3] EP 1986, 206933 (CA, 1987, 107: 77434e) [4] EP 1983, 72352 (CA, 1983, 99:53621 d) [5] package insert: Lotensin [6] property protection case I: Lotensin [7] property protection case II: Lotensin [8] Drug Monograph information: BENAZEPRIL 
  33. 33.  more info  Benazepril M.p. 148.5°.  Proprietary names. Briem; Cibace; Cibacen; Cibacene; Labopal; Lotensin; Tensanil; Zinandril.  C24H28N2O5,HCl=461.0  CAS—86541–74–4  A white to off–white crystalline powder. It is soluble in water, ethanol and methanol.  Partition Coefficient.  Log P(octanol/water), 3.50.  Gas Chromatography.  System GP—RI 3030 (benazepril-ME); RI 2985 (M (benazeprilate)-ME3).  Column: 3% OV-101 on Gaschrom Q, 80–100 mesh (Ciba-Geigy), pyrex glass (1.5 m × 2 mm i.d.). Column and injector port temperature: 275°. Carrier gas: helium, flow rate 30 mL/min. MS detection (EI, SIM). Retention times: benazepril (methyl ester derivative) 2.55 min; benazeprilat (derivative) 2.3 min. [G. Kaiser et al.,J. Chromatogr.,1987, 419, 123–133].
  34. 34.  High Performance Liquid Chromatography.  System HAA—retention time 17.0 min.  Column: C18 (RP-BDS, 5 μm packing, 250 × 3 mm i.d.). Mobile phase: sodium dihydrogen phosphate (0.025 M, pH 4.8):acetonitrile (55:45). 0.4 mL/min flow rate. UV detection (λ=250 nm). Retention time: benazepril hydrochloride, 4.95 min. [I. E. Panderi and M. Parissi-Polou,J. Pharm. Biomed. Anal.,1999, 21, 1017– 1024].  Column: Hypersil ODS (5 μm, 250 × 4.5 mm). Mobile phase: sodium heptanesulfonate (20 mM, pH 2.5):acetonitrile (5% THF) (52:48 v/v), 1.0 mL/min flow rate. UV detection (λ=215 nm). Retention time: 15 min. [D. Bonazzi et al.,J. Pharm. Biomed. Anal.,1997, 16, 431–438].
  35. 35.  Ultraviolet Spectrum.  Aqueous acid (0.2 M NH2SO4)—237 nm; basic— 241 nm; aqueous acid (0.1 M hydrochloric acid)— 237.2 nm (hydrochloride salt).  Reference(s): Clarke’s Analysis of Drugs and Poisons Watthey, J.W.H. et al.: J. Med. Chem. (JMCMAR) 28, 1511 (1985). US 4 410 520 (Ciba-Geigy; 18.10.1983; prior. 11.8.1981, 9.11.1981, 19.7.1982). EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA- prior. 11.8.1981, 9.11.1981).
  36. 36. DR ANTHONY MELVIN CRASTO Ph.D MOBILE-+91 9323115463 GLENMARK SCIENTIST , NAVIMUMBAI, INDIA web link --my-own-on-the-net Congratulations! Your presentation titled "Anthony Crasto Glenmark scientist, helping millions with websites" has just crossed MILLION views.