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RG-1577, EVT 302, Sembragiline, RO-4602522



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RG-1577, EVT 302, Sembragiline, RO-4602522

Hoffmann La Roche

CAS 676479-06-4, MW 342.36

  • C19 H19 F N2 O3
  • Acetamide, N-​[(3S)​-​1-​[4-​[(3-​fluorophenyl)​methoxy]​phenyl]​-​5-​oxo-​3-​pyrrolidinyl]​-

UNII-K3W9672PNJ2D chemical structure of 676479-06-4

RG-1577, a selective and reversible monoamine oxidase B inhibitor, for treating AD (phase 2 clinical, as of May 2015).

Family members of the product case for RG-1577 (WO2004026825) hold protection in EU until 2023 and expire in US in 2024 with US154 extension. Follows on from WO2006097197, claiming a process for preparing RG-1577.

Alzheimers Disease is a brain disease that slowly destroys memory and thinking skills, up to loss of the ability to carry out the simplest tasks. It is the most common cause of dementia among older people. Mild Alzheimers Disease manifests itself in memory loss and small changes in other cognitive abilities, e.g getting lost, trouble handling money and managing daily tasks, having some mood and personality changes, etc.

In the stage of Moderate Alzheimers Disease, the control of language, reasoning, sensory processing, and conscious thought are impacted. Memory loss and con usion grow worse, e.g patients have problems recognizing family and friends and become unable to learn new things, etc. hallucinations, delusions, and paranoia may occur. .Severe Alzheimers Disease is the final stage. Patients cannot communicate anymore and are completely dependent.

N-[(3S)-l-[4-[(3-fluorophenyl)methoxy]phenyl]-5-oxo-pyrrolidin-3-yl]acetamide has previously been described in the art. 1 WO 2006/097197 2 and WO 2006/0972703 relate to methods for preparing enantiomerically pure 4-pyrrolidinophenylbenzyl ether derivatives.

The processes of the prior art hamper from several drawbacks (e.g. long reaction sequence, low overall yield also due to loss of half of the product in the classical resolution step, the need for a chromatographic purification to remove by-products formed in the Mitsunobu reaction) and are therefore less suitable for the preparation of N-[(3S)-l-[4-[(3-fluorophenyl) methoxy]phenyl]-5-oxo-pyrrolidin-3-yl]acetamide on large scale.


Most Recent Events

  • 01 Aug 2014Roche completes a phase I trial in volunteers in USA (NCT02104648)
  • 14 May 2014Roche completes enrolment in the MAyflOwer RoAD trial for Alzheimer’s disease (combination therapy, adjunctive treatment) in Australia, Canada, Czech Republic, France, Germany, Italy, Poland, South Korea, Spain, Sweden the United Kingdom and the USA (NCT01677754)
  • 01 Apr 2014Roche initiates enrolment in a phase I trial in healthy volunteers in USA (NCT02104648)







WO 2015063001;jsessionid=82F2EFFC078602A9E3061C7CF658B36C.wapp2nA?docId=WO2015063001&recNum=37&office=&queryString=&prevFilter=%26fq%3DOF%3AWO%26fq%3DICF_M%3A%22C07D%22&sortOption=%E5%85%AC%E9%96%8B%E6%97%A5%EF%BC%88%E6%96%B0%E3%81%97%E3%81%84%E9%A0%86%EF%BC%89&maxRec=57119

Novel, crystalline polymorphic forms A and B of a pyrrolidone derivative ie RG-1577, useful for treating Alzheimer’s disease (AD). Roche and its Japanese subsidiary Chugai, under license from Evotec, which previously licensed the drug from Roche, are developing RG 1577


formula 1 via the following routes

In a certain embodiment, present invention relates to a synthesis of a compound of formula he following route A


In a certain embodiment, present invention relates to a synthesis of a compound of formula he following route B

In a certain embodiment, present invention relates to a crystalline polymorph of a compound of formula 1.


synthesize a compound of formula 1 from a compound of formula 7


compound of formula 6 to a compound of formula 7

In a certain embodiment, present invention relates to a process to synthesize a compound of formula 1 as described herein, further comprising reacting a compound of formula 6 via the intermediate 6a to a compound of formula 7


further comprising reacting a compound of formula 3 with a compound of formula 5 to a compound of formula 6



comprising reacting a compound of formula 2 to a compound of formula 3

2 3


In a certain embodiment, present invention relates to a process to synthesize a compound of formula 1 as described herein, further comprising reacting a compound of formula 10 to a compound of formula 6


eacting a compound of formula 9 with a compound of formula 5 to a compound of formula 10


In a certain embodiment, present invention relates to a process to synthesize a compound of formula 1 as described herein, further comprising reacting a compound of formula 8 to a compound of formula 9


(lS’)-N-[l-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl-]acetamide (1)

To a suspension of chloride (7) (37.9 g, 100 mmol) in 2-methyltetrahydrofurane (600 ml) was added under vigorous stirring at 0°C 1.65 M potassium ie/t-butoxide in THF (75.5 ml, 125 mmol, ACROS) over 2.5 h. After additional stirring at 0°C for 1 h, the cold suspension was hydrolyzed with 0.1 M HCl (600 ml) and the reaction mixture was stirred at 30°C for 0.5 h. The organic layer was washed with water (300 ml), dried (Na2S04) and filtered. Removal of the solvent by rotary evaporation (50°C/>10 mbar) afforded 32.1 g crystalline residue, which was dissolved in 2-butanone (400 ml) at ca. 95°C and hot filtered. Crystallization, which was induced by seeding and cooling to room temperature and 0°C (4 h) afforded 25.4 g (74.2%) of the titled compound (1) as an off-white, crystalline powder,

Mp. 162-164°C (polymorph B).

Ee >99.8%, [cc]D20 = – 17.8 (DMF; c = 1).

1H NMR (400 MHz, DMSO- 6) δ ppm 1.82 (s, 3H), 2.34 (dd, J1=n. l, J2=3.9, 1H), 2.84 (dd, J/=17.1, J2=8.2, 1H), 3.55 (dd, J/=10.2, J2=3.2, 1H), 4.07 (dd, J/=10.2, J2=6.7, 1H), 4.32-4.41 (m, 1H), 5.13 (s, 2H), 7.02 & 7.55 (d, J=9.1, each 1H), 7.11-7.19 (m, 1H), 7.24-7.31 (m, 1H), 7.40-7.47 (m, 1H), 8.40 (d, J=6.4, 1H).

ESI-MS (m/z) 343 [M+H]+, 365 [M+Na]\. Anal.Calcd for Ci9H19FN203 (342.37): Calcd. C, 66.66; H, 5.59; N, 8.18; F, 5.02; O, 14.02. Found C, 66.76; H, 5.48; N, 8.13; F, 5.03; O, 13.99.

Crystallized (1) form previous step (9.5 g, 0.028 mol) was dissolved in 2-butanone (290 mL) upon heating. The hot solution was filtered over charcoal. The solution was concentrated by removal of 2-butanone (200 mL) by distillation prior to seeded cooling crystallization. Filtration, washing with chilled 2-butanone and drying at 50°C/25 mbar/16h afforded 9.18 g (93.9% corrected yield) of the title compound (1) as a crystalline powder of polymorphic form B with an assay of 100.4 %(w/w) and a purity of 99.97 %(area) (by HPLC).

Alternatively, to a stirred suspension of hydroxyamide (6) (30.0 g, 0.083 mol) in toluene (500 ml) was added at 50°C within 45 minutes thionyl chloride (10.40 g, 0.087 mol) and the resulting mixture was stirred for 3h at 50°C. The mixture was then heated up to 92°C and subsequently stirred at this temperature for 15 h. The Suspension was then cooled to 50°C and toluene was removed by distillation under reduced pressure. The distillation residue was cooled to ambient temperature and treated with N-methylpyrrolidone (210 ml) to obtain an almost clear solution. This solution was then cooled to -10°C and subsequently treated at this temperature within 2h with a solution of potassium iert-butoxide (12.40 g, 0.111 mol) in THF (60 g). The resulting mixture was stirred for another 60 minutes at -10°C, then warmed up to room temperature within 60 minutes and subsequently stirred at room temperature for 6 h. The reaction mixture was quenched with water (150 g) and the pH was adjusted with acetic acid (approx. 1.8 g) to pH 7-8. The mixture was then heated to 30-45°C and THF and toluene were distilled off under reduced pressure (<200 mbar) to obtain a clear NMP/water mixture (400 ml). This mixture was heated to 45°C and 260 mg of seed crystals were added. Water (320 ml) was then added within 3 h whereby the product crystallized. The resulting suspension was cooled to room temperature within 3 h and subsequently stirred at this temperature for 2 h. Filtration and washing of the filter cake with a mixture of water (100 ml) and N-methylpyrrolidone (20 ml) and subsequently only with water (150 ml) afforded after drying (70°C/10 mbar/20 h) 26.2 g (92%) of the title compound (1) as a crystalline powder with an assay of 99.6 %(w/w) and a purity of 99.7 %(area) (by HPLC).


Purity (HPLC): Column: XSelect Phenyl Hexyl x2, 150 x 4.6mm, 3.5um. Starting

Pressure: 226 bar; temp.: 50°C. Inj. vol.: 2.0 μΐ^ + wash. Flow: 1.0 ml/min. Det: 204 nm. A: Water + 5% ACN, 77-2% in 7 min., hold for 1 min.; B: 0.1% HCOOH, 18% isocratic; C: MeOH, 5-80% in 7 min., hold for 1 min. Sample prep.: 2 mg/ml ACN. Retention times: β-acid 5.93 min., diacid 6.18 min., cc-acid 6.89 min., diester 6.96 min.

ee determination(HPLC): Column: Chiralpak IA-3 100 x 4.6mm, 3um; 91 bar, 2ml/min; temp.: 30°C. Inj. vol.: 10.0 μL· Det.: 206 nm. A: n-heptane, 80%; B: EtOH, 20%. Sample prep.: 4 mg/ml EtOH. Retention times: D-enantiomer 2.21 min., L-enantiomer 2.71 min


US 20050065204


Preparation of (S)-1-(4-Hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic Acid

8.00 g Polyethyleneglycol 6000 was dissolved in 150 mL (100 mM) magnesium acetate buffer pH 6.0 under stirring, and the solution added to a stirred suspension of 10.00 g (42.51 mmol) (RS)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (99.7%) in 40 mL methylcyclohexane. The mixture was heated to 28° C. and the pH readjusted to 6.0 with 2 M NaOH. The reaction was started by adding 33.2 mg Candida cylindraceae cholesterase (16.88 kU/g), and the pH was maintained at 6.0 by the controlled addition of 1.0 M NaOH solution under stirring. After a total consumption of 20.35 mL (20.35 mmol) 1.0 M sodium hydroxide solution (after 17.1 h; 47.9% conversion) the reaction mixture was passed through a sintered glass filter. The filtrate spontaneously separated into an aqueous and an organic phase.The aqueous phase was washed with 2×200 mL ethyl acetate to remove uncleaved ester. The aqueous phase was set to pH 4.0 with 25% sulfuric acid and concentrated in vacuo to a volume of ca. 80 mL (bath 60° C.). The solution was cooled to 1° C. (formation of white precipitate/crystals) and the pH set to 1.5 with 25% sulfuric acid. The precipitate/crystals were stirred overnight at 1° C., filtered off on a sintered glass filter (washed with a minimum amount of water) and dried overnight on high vacuum (RT, 6×10−2 mbar) to give 4.32 g (19.53 mmol; 45.9%) (S)-1-(4-hydroxyphenyl)-5-oxo-pyrrolidine-3-carboxylic acid. Analysis: HPLC (area A226nm): 99.3%, 0.7% ester. 98.9%ee. The product contains 5.3% water (according to Karl Fischer determination) and 2.1% (w/w) PEG (according to NMR).


Company Evotec AG
Description Small molecule monoamine oxidase B (MAO-B) inhibitor
Molecular Target Monoamine oxidase B (MAO-B)
Mechanism of Action Monoamine oxidase B (MAO-B) inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Alzheimer’s disease (AD)
Indication Details Treat Alzheimer’s disease (AD)
Regulatory Designation

Chugai Pharmaceutical Co. Ltd.; Roche


Chūō, japan

Map of chuo-ku tokyo


A Chūō Line (Rapid) E233 series (right) and A Chūō-Sōbu Line E231 series (June 2007)

Chuo Dori street on a weekend afternoon


  1. Hello!

    Can you explain what these report exactly mean?
    Is the Drug EVT302 approved?

    Best Regards


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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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