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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

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 amcrasto@gmail.com, 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......https://newdrugapprovals.wordpress.com/ , 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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Beperminogene perplasmid, ベペルミノゲンペルプラスミド


1gctgcttcgc gatgtacggg ccagatatac gcgttgacat tgattattga
51ctagttatta atagtaatca attacggggt cattagttca tagcccatat
101atggagttcc gcgttacata acttacggta aatggcccgc ctggctgacc
151gcccaacgac ccccgcccat tgacgtcaat aatgacgtat gttcccatag
201taacgccaat agggactttc cattgacgtc aatgggtgga gtatttacgg
251taaactgccc acttggcagt acatcaagtg tatcatatgc caagtacgcc
301ccctattgac gtcaatgacg gtaaatggcc cgcctggcat tatgcccagt
351acatgacctt atgggacttt cctacttggc agtacatcta cgtattagtc
401atcgctatta ccatggtgat gcggttttgg cagtacatca atgggcgtgg
451atagcggttt gactcacggg gatttccaag tctccacccc attgacgtca
501atgggagttt gttttggcac caaaatcaac gggactttcc aaaatgtcgt
551aacaactccg ccccattgac gcaaatgggc ggtaggcgtg tacggtggga
601ggtctatata agcagagctc tctggctaac tagagaaccc actgcttact
651ggcttatcga aattaatacg actcactata gggagaccca agctggctag
701cgtttaaact taagcttggt accgagctcg gatccgccag cccgtccagc
751agcaccatgt gggtgaccaa actcctgcca gccctgctgc tgcagcatgt
801cctcctgcat ctcctcctgc tccccatcgc catcccctat gcagagggac
851aaaggaaaag aagaaataca attcatgaat tcaaaaaatc agcaaagact
901accctaatca aaatagatcc agcactgaag ataaaaacca aaaaagtgaa
951tactgcagac caatgtgcta atagatgtac taggaataaa ggacttccat
1001tcacttgcaa ggcttttgtt tttgataaag caagaaaaca atgcctctgg
1051ttccccttca atagcatgtc aagtggagtg aaaaaagaat ttggccatga
1101atttgacctc tatgaaaaca aagactacat tagaaactgc atcattggta
1151aaggacgcag ctacaaggga acagtatcta tcactaagag tggcatcaaa
1201tgtcagccct ggagttccat gataccacac gaacacagct ttttgccttc
1251gagctatcgg ggtaaagacc tacaggaaaa ctactgtcga aatcctcgag
1301gggaagaagg gggaccctgg tgtttcacaa gcaatccaga ggtacgctac
1351gaagtctgtg acattcctca gtgttcagaa gttgaatgca tgacctgcaa
1401tggggagagt tatcgaggtc tcatggatca tacagaatca ggcaagattt
1451gtcagcgctg ggatcatcag acaccacacc ggcacaaatt cttgcctgaa
1501agatatcccg acaagggctt tgatgataat tattgccgca atcccgatgg
1551ccagccgagg ccatggtgct atactcttga ccctcacacc cgctgggagt
1601actgtgcaat taaaacatgc gctgacaata ctatgaatga cactgatgtt
1651cctttggaaa caactgaatg catccaaggt caaggagaag gctacagggg
1701cactgtcaat accatttgga atggaattcc atgtcagcgt tgggattctc
1751agtatcctca cgagcatgac atgactcctg aaaatttcaa gtgcaaggac
1801ctacgagaaa attactgccg aaatccagat gggtctgaat caccctggtg
1851ttttaccact gatccaaaca tccgagttgg ctactgctcc caaattccaa
1901actgtgatat gtcacatgga caagattgtt atcgtgggaa tggcaaaaat
1951tatatgggca acttatccca aacaagatct ggactaacat gttcaatgtg
2001ggacaagaac atggaagact tacatcgtca tatcttctgg gaaccagatg
2051caagtaagct gaatgagaat tactgccgaa atccagatga tgatgctcat
2101ggaccctggt gctacacggg aaatccactc attccttggg attattgccc
2151tatttctcgt tgtgaaggtg ataccacacc tacaatagtc aatttagacc
2201atcccgtaat atcttgtgcc aaaacgaaac aattgcgagt tgtaaatggg
2251attccaacac gaacaaacat aggatggatg gttagtttga gatacagaaa
2301taaacatatc tgcggaggat cattgataaa ggagagttgg gttcttactg
2351cacgacagtg tttcccttct cgagacttga aagattatga agcttggctt
2401ggaattcatg atgtccacgg aagaggagat gagaaatgca aacaggttct
2451caatgtttcc cagctggtat atggccctga aggatcagat ctggttttaa
2501tgaagcttgc caggcctgct gtcctggatg attttgttag tacgattgat
2551ttacctaatt atggatgcac aattcctgaa aagaccagtt gcagtgttta
2601tggctggggc tacactggat tgatcaacta tgatggccta ttacgagtgg
2651cacatctcta tataatggga aatgagaaat gcagccagca tcatcgaggg
2701aaggtgactc tgaatgagtc tgaaatatgt gctggggctg aaaagattgg
2751atcaggacca tgtgaggggg attatggtgg cccacttgtt tgtgagcaac
2801ataaaatgag aatggttctt ggtgtcattg ttcctggtcg tggatgtgcc
2851attccaaatc gtcctggtat ttttgtccga gtagcatatt atgcaaaatg
2901gatacacaaa attattttaa catataaggt accacagtca tagctgttaa
2951cccgggtcga agcggccgct cgagtctaga gggcccgttt aaacccgctg
3001atcagcctcg actgtgcctt ctagttgcca gccatctgtt gtttgcccct
3051cccccgtgcc ttccttgacc ctggaaggtg ccactcccac tgtcctttcc
3101taataaaatg aggaaattgc atcgcattgt ctgagtaggt gtcattctat
3151tctggggggt ggggtggggc aggacagcaa gggggaggat tgggaagaca
3201atagcaggca tgctggggat gcggtgggct ctatggcttc tactgggcgg
3251ttttatggac agcaagcgaa ccggaattgc cagctggggc gccctctggt
3301aaggttggga agccctgcaa agtaaactgg atggctttct tgccgccaag
3351gatctgatgg cgcaggggat caagctctga tcaagagaca ggatgaggat
3401cgtttcgcat gattgaacaa gatggattgc acgcaggttc tccggccgct
3451tgggtggaga ggctattcgg ctatgactgg gcacaacaga caatcggctg
3501ctctgatgcc gccgtgttcc ggctgtcagc gcaggggcgc ccggttcttt
3551ttgtcaagac cgacctgtcc ggtgccctga atgaactgca agacgaggca
3601gcgcggctat cgtggctggc cacgacgggc gttccttgcg cagctgtgct
3651cgacgttgtc actgaagcgg gaagggactg gctgctattg ggcgaagtgc
3701cggggcagga tctcctgtca tctcaccttg ctcctgccga gaaagtatcc
3751atcatggctg atgcaatgcg gcggctgcat acgcttgatc cggctacctg
3801cccattcgac caccaagcga aacatcgcat cgagcgagca cgtactcgga
3851tggaagccgg tcttgtcgat caggatgatc tggacgaaga gcatcagggg
3901ctcgcgccag ccgaactgtt cgccaggctc aaggcgagca tgcccgacgg
3951cgaggatctc gtcgtgaccc atggcgatgc ctgcttgccg aatatcatgg
4001tggaaaatgg ccgcttttct ggattcatcg actgtggccg gctgggtgtg
4051gcggaccgct atcaggacat agcgttggct acccgtgata ttgctgaaga
4101gcttggcggc gaatgggctg accgcttcct cgtgctttac ggtatcgccg
4151ctcccgattc gcagcgcatc gccttctatc gccttcttga cgagttcttc
4201tgaattatta acgcttacaa tttcctgatg cggtattttc tccttacgca
4251tctgtgcggt atttcacacc gcatcaggtg gcacttttcg gggaaatgtg
4301cgcggaaccc ctatttgttt atttttctaa atacattcaa atatgtatcc
4351gctcatgaga caataaccct gataaatgct tcaataatag cacgtgctaa
4401aacttcattt ttaatttaaa aggatctagg tgaagatcct ttttgataat
4451ctcatgacca aaatccctta acgtgagttt tcgttccact gagcgtcaga
4501ccccgtagaa aagatcaaag gatcttcttg agatcctttt tttctgcgcg
4551taatctgctg cttgcaaaca aaaaaaccac cgctaccagc ggtggtttgt
4601ttgccggatc aagagctacc aactcttttt ccgaaggtaa ctggcttcag
4651cagagcgcag ataccaaata ctgttcttct agtgtagccg tagttaggcc
4701accacttcaa gaactctgta gcaccgccta catacctcgc tctgctaatc
4751ctgttaccag tggctgctgc cagtggcgat aagtcgtgtc ttaccgggtt
4801ggactcaaga cgatagttac cggataaggc gcagcggtcg ggctgaacgg
4851ggggttcgtg cacacagccc agcttggagc gaacgaccta caccgaactg
4901agatacctac agcgtgagct atgagaaagc gccacgcttc ccgaagggag
4951aaaggcggac aggtatccgg taagcggcag ggtcggaaca ggagagcgca
5001cgagggagct tccaggggga aacgcctggt atctttatag tcctgtcggg
5051tttcgccacc tctgacttga gcgtcgattt ttgtgatgct cgtcaggggg
5101gcggagccta tggaaaaacg ccagcaacgc ggccttttta cggttcctgg
5151ccttttgctg gccttttgct cacatgttct t

Beperminogene perplasmid

ベペルミノゲンペルプラスミド

HGF plasmid

  • DNA (human hepatocyte growth factor plasmid pVAX1 cDNA)
  • DNA (plasmid pVAX1HGF/MGBI)
  • AMG-0001
    DS-992

Nucleic Acid Sequence

Sequence Length: 51811342 a 1223 c 1314 g 1302 t

APPROVED, japan 2019, Collategene, 2019/3/29

Antiparkinsonian, Angiogenesis inducing agent

CAS: 627861-07-8

  • Originator AnGes MG
  • Developer AnGes MG; Osaka University Hospital
  • Class Antiparkinsonians; Gene therapies; Ischaemic heart disorder therapies; Vascular disorder therapies
  • Mechanism of Action Angiogenesis inducing agents; Gene transference; Hepatocyte growth factor expression stimulants
  • Available For Licensing Yes – Ischaemic heart disorders; Lymphoedema; Parkinson’s disease
  • Registered Peripheral arterial disorders
  • Phase I/II Lymphoedema
  • No development reported Arteriosclerosis obliterans; Ischaemic heart disorders; Parkinson’s disease; Thromboangiitis obliterans
  • 26 Mar 2019 Registered for Peripheral arterial disorders in Japan (IM)
  • 21 Feb 2019 The Pharmaceutical Affairs and Food Sanitation Council recommends conditional and time-limited approval of beperminogene perplasmid for the improvement of ulcers associated with chronic peripheral arterial disease
  • 21 Feb 2019 AnGes plans a clinical study to assess the efficacy of beperminogene perplasmid in improvement of pain at rest in chronic peripheral arterial disorders
  • In 2010, the product received fast track designation in the U.S. for the treatment of critical limb ischemia

HGF Plasmid (Beperminogene Perplasmid)Critical Limb Ischemia (Arteriosclerosis Obliterans & Buerger’s Disease) AMG0001 Injection, JAPAN AND US  ALLIANCE Mitsubishi Tanabe Pharma

PATENT

WO 2017126488

US 20170283446

Expert Review of Cardiovascular Therapy (2014), 12(10), 1145-1156.

////////////Beperminogene perplasmid,  japan 2019, ベペルミノゲンペルプラスミド , AnGes MG, Osaka University Hospital, Critical Limb Ischemia, Arteriosclerosis Obliterans,  Buerger’s Disease, AMG0001, AMG-0001, DS-992 , HGF plasmid ,  fast track designation

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Ferric carboxymaltose , カルボキシマルトース第二鉄


Chemical structure

Ferric carboxymaltose

カルボキシマルトース第二鉄

CAS: 9007-72-1

Molecular Formula, C24H44FeO25
Molecular Weight, 788.43616  g/mol

(2S,3S,4S,5R)-4-[(2R,3R,4R,5S,6R)-5-[(2R,3R,4R,5S,6R)-3,4-dihydroxy-6-(hydroxymethyl)-5-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2,3,5,6-tetrahydroxyhexanoate;iron(3+);oxygen(2-);hydroxide;hydrate

Iron dextri-maltose
Iron(3+) hydroxide oxide poly-(1–4)-alpha-D-glucopyranosyl-(1–4)-D-gluconate hydrate
Polynuclear iron (III)-hydroxide 4(R)-(poly-(1–4)-O-alpha-D-glucopyranosyl)-oxy-2(R),3(S),5(R),6-tetrahydroxy-hexanoate
Poly[D-glucopyranosyl(1–4)]-D-gluconic acid complex of hydrated iron(III) oxide

japan pmda approved, 2019/3/26, Ferinject

Treatment of patients with iron deficiency anemia

Hematinic, Supplement (iron)

LAUNCHED, 2007, Vifor Pharma, Anemia, iron deficiency

1 Injectafer

2. Ferinject

3. Iron Dextri-maltose

4. Unii-6897gxd6oe

5. Vit 45

6. Vit-45

7. Ferric Carboxymaltose [usan:inn:ban]

8. Iron(3+) Hydroxide Oxide Poly-(1?4)-alpha-d-glucopyranosyl-(1?4)-d-gluconate Hydrate

9. 889138-31-2

10. 9007-72-1

11 Z-213

In 2013, Vifor Pharma and Zeria Pharmaceutical signed an exclusive licensing agreement for the product’s development and commercialization in Japan for the treatment of iron deficiency anemia.

Ferric carboxymaltose is an intravenously-administered iron complex which was first launched in Germany following E.U. approval in 2007 for the treatment of iron deficiency anemia (IDA)

PATENT

WO 2011055374

US 20120214986

IN 2011MU03463

IN 2013CH03474

WO 2016181195

IN 2015CH02360

CN 106236707

CN 106977621

EP 3339329

PATENT

WO2016181195

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=0CD65F382B1D233E8FC0BB3C2CCB28D7.wapp1nA?docId=WO2016181195&tab=PCTDESCRIPTION&maxRec=1000

Iron deficiency anaemia (IDA) is a common haematological complication with potentially serious clinical consequences that may require intravenous iron therapy.

Ferric carboxymaltose (FCM) is a stable, non-dextran iron formulation administered intravenously in large single doses to treat IDA. It is an iron complex that consists of a ferric hydroxide core stabilized by a carbohydrate shell. It is commercially available in the market under the trade name Ferinject®

Ferric carboxymaltose has been designed to provide high iron utilisation and to have a better benefit to risk profile than iron dextran and iron sucrose therapy. In the case of iron dextran, a key risk is the reaction with anti-dextran antibodies leading to the well known dextran induced anaphylactic reactions. In the case of iron sucrose, the negative characteristics include high pH, high osmolarity, low dosage limits and the long duration of administration.

Ferric carboxymaltose allows for controlled delivery of iron within the cells of the reticuloendothelial system and subsequent delivery to the iron-binding proteins ferritin and transferrin, with minimal risk of release of large amounts of ionic iron in the serum.

U.S. Pat. No. 3,076,798 discloses a process for the preparation of iron(III)-polymaltose complex compounds. The iron(III)-polymaltose complex compound

preferably has a molecular weight in the range from 20,000 to 500,000 daltons, preferably from 30,000 to 80,000 daltons.

U.S. Patent No. 7,612,109 discloses water-soluble iron carbohydrate complexes (ferric carboxymaltose complexes) obtainable from an aqueous solution of an iron (III) salt, preferably iron (III) chloride, and an aqueous solution of the oxidation product of one or more maltodextrins using an aqueous hypochlorite solution.

PCT application No.WO2011/055374, discloses a process for the preparation of iron (III) carboxymaltose complex using ferric hydroxide.

In Netherlands article, starch 41 (1989) Nr .8, S. 303-309 transition metal ions enhance the selectivity of oxidations by H2O2 to produce polysaccharides to polydicarbonates by glycol cleavage of the C2-C3 vicinal diol moiety.

Even though many prior art processes reported methods for the preparation of Iron(III) carboxymaltose, each process has some limitations with respect to yield, purity and scale-up etc.

EXAMPLES

Example- 1: Preparation of trivalent iron carboxymaltose

Step (i)

20grams of anhydrous iron(III)chloride was dissolved in 50ml of purified water at room temperature for 10 minutes stirring. To this 2gm of maltodextrin (13-17 dextrose equivalents) was added and stirred for 10 minutes at room temperature. The obtained brownish-yellow clear solution was cooled to 0-5°C and the pH of the reaction mixture was adjusted to 7.0 by adding 20% aqueous sodium hydroxide solution. A brown colour precipitate obtained was maintained for 1 hour at 0-5°C and collected through filtration (Wet cake wt. ~ 65. Og). The cake was suck dried and used for next step.

Step (ii)

20grams of maltodextrin having a dextrose equivalents of 13-17 were dissolved in 50ml of purified water and the solution was metered in the course of 20 minutes to a stirred mixture of 2.66gm of Starks catalyst (methyl trioctyl ammonium hydrogen sulfate prepared in-situ from 2gm of Aliquat 336 and 0.66gm of NaHSO4.H2O), 0.8gm of sodium tungstate dihydrate and 0.37gm of TEMPO at RT. 31.12gm of hydrogen peroxide solution (50-55% w/v) was then added drop wise over a period of 40 minutes at 25-30°C and raised the temperature to90-95°C and stirred for 3 hours. After cooling to room temperature, a second portion of 15.5gm of H2O2 solution was metered in the course of 15 minutes at 25-30°C and the resulting solution was again refluxed at 90-95°C for 1 hour. After cooling to 35-40°C, wet cake of step (i) (ferric hydroxide maltodextrin complex) was added, with stirring. 14.0ml of 20% aqueous sodium hydroxide solution was added to adjust the reaction mass pH to 10- 10.5 and the slurry was heated to 50°C, stirred for 30 minutes. Then the reaction mixture was acidified to pH 5.5 by adding hydrochloric acid solution and the mixture was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 14 hours. Then the reaction mixture was cooled to room temperature and filtered through a celite pad. Thereafter, the iron(III)complex was isolated by precipitation by adding ethanol (237. Og) drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 202 kDa. Iron content = 23.38% w/w

Example-2:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst and 0.2gm of Na2WO4.2H2O at room temperature in the course of 20 minutes. 24grams of H2O2 solution was metered in the course of 45 minutes at 25-30°C and raised the temperature to 90-95°C and stirred for 2 hours and cooled to room temperature.

The solution was added to another portion of a stirred mixture of 1.33gm of Starks catalyst and 0.2gm of Na2WO4.2H2O at room temperature. Thereafter, 12gm of

H2O2solution was added drop wise over a period of 20 minutes at 25-30°C and the resulting reaction mixture was again refluxed at 90-95°C for 2 hours. After cooling to 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. 14ml of 20% NaOH solution was added to adjust the reaction mass pH to 10- 10.5 and the slurry was heated to 50°C, stirred for 30 minutes. Then the mixture was acidified to pH 5.5 by adding hydrochloric acid solution and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 13 hours. Then the reaction solution was cooled to room temperature, adjusted pH to 5.5 to 6.0 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (331.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 200 kDa. Iron content = 25.57 % w/w

Example-3:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 100ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2solution was added drop wise in the course of 1 hour at 25-30°C and raised the temperature to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the reaction mixture was acidified to pH 5.5 with hydrochloric acid addition and the mixture was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 14 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (343.0g) addition drop wise at room temperature. The obtained brown

amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 260 kDa. Iron content = 23.67 % w/w

Example-4:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37g of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2 solution was added drop wise over a period of 1 hour at 55-60°C and the temperature was raised to 90-95 °C, stirred for 3 hours and cooled to room temperature. After cooling to 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the reaction mixture was acidified to pH 5.5 with hydrochloric acid addition and was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (343.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 261 kDa. Iron content = 22.85 % w/w

Example-5:

Step (i)

16grams of anhydrous iron(III)chloride was dissolved in 50ml of purified water at room temperature for 10 min stirring. The obtained brownish-yellow clear solution was cooled to 0-5°C and the pH was adjusted to 7.0 first by adding aqueous sodium carbonate solution (21gm of Na2CO3dissolved in 102 ml of purified water) and then by adding 20% NaOH solution. A brown colour precipitate obtained was maintained for 1 hour at 0-5°C and collected through filtration (Wet wt. ~54.0g). The cake was suck dried and used for next step.

Step (ii)

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30gm of H2O2solution was added drop wise over a period of 1 hour at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) added and stirred for 10 minutes. 20% NaOH solution was added drop wise to adjust the reaction mass pH tolO-10.5 and the slurry was heated to 50°C, stirred for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was kept at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (315.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 236 kDa. Iron content = 22.35 % w/w

Example-6:

Step (i)

20grams of anhydrous ferric chloride was dissolved in 50ml of purified water at room temperature for 10 min stirring. The obtained brownish-yellow clear solution was cooled to 0-5°C and the pH was adjusted to 7.0 by adding 20% NaOH solution. A brown colour precipitate obtained was stirred for 1 hour at 0-5°C and collected through filtration. The cake was suck dried and used for next step.

Step (ii)

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37g of TEMPO at room temperature over a

period of 15 minutes. 36gm of H2O2 solution was metered in the course of 1 hour at 25-30°C and the resulting solution was heated to 90-95°C, stirred for 3 hours and cooled to room temperature.

After cooling to 25-30°C, wet cake of step (i) was added and stirred for 10 min. 12ml of 20% NaOH solution was added drop wise to adjust the reaction mass pH to 10-10.5 and the slurry was heated to 50°C, kept at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (315.0g) addition at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 365 kDa. Iron content = 23.93 % w/w

Example-7:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.2gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30gm of H2O2 solution was added drop wise in the course of 1 hour at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example-6 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12.0ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was kept at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature; pH was adjusted to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (276.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 366 kDa. Iron content = 21.2 % w/w

Example-8:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst and 0.8gm of Na2WO4.2H2O at room temperature over a period of 15 minutes. 30grams of H2O2 solution was metered in the course of 1 hour at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example-6 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to 25-30°C, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (315.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 340 kDa. Iron content = 23.28 % w/w

Example-9:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2 solution was added drop wise over a period of 1 hour at 25-30°C and the resulting solution was heated to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. A pH of 10-10.5 was established by adding 12ml of 20% NaOH solution and the slurry was heated to 50°C, stirred at this temperature for 30 minutes. Then the solution was acidified to pH 5.5 with hydrochloric acid addition and the solution was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was isolated by precipitating with ethanol (304.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried under vacuum at 50°C for 2-3 hours. Molecular weight = 352 kDa. Iron content = 23.0 % w/w

Example-10:

20grams of maltodextrin (13-17 dextrose equivalents) were dissolved in 50ml of purified water and the solution was added to a stirred mixture of 2.66gm of Starks catalyst, 0.8gm of Na2WO4.2H2O and 0.37gm of TEMPO at room temperature over a period of 15 minutes. 30grams of H2O2 solution was added drop wise in the course of 60 minutes at 25-30°C and the temperature was raised to 90-95°C, stirred for 3 hours and cooled to room temperature.

At 25-30°C, wet cake of step (i) from example- 1 was added and stirred for 10 minutes. 12ml of 20% NaOH solution was added drop wise to adjust the reaction mixture pH to 10-10.5 and the temperature of the slurry was raised to 50°C, stirred at this temperature for 30 minutes. Then the reaction mixture was acidified to pH 5.5 with hydrochloric acid addition and was maintained at 50°C for another 30 minutes. Further temperature was raised to 95-100°C and stirred for 12 hours. The reaction mixture was allowed to cool to room temperature, adjusted pH to 6.0 to 6.5 with 20% NaOH solution and filtered through a celite pad. Then the iron(III)complex was

isolated by precipitating with ethanol (276.0g) addition drop wise at room temperature. The obtained brown amorphous solid was dried in vacuum at 50°C for 2-3 hours. Molecular weight = 348 kDa. Iron content = 24.6 % w/w

/////////Ferric carboxymaltose , カルボキシマルトース第二鉄 ,Injectafer, Ferinject, Iron dextri-maltose, Unii-6897gxd6oe, Vit 45, Vit-45, japan 2019, Z-213

C(C1C(C(C(C(O1)OC2C(OC(C(C2O)O)OC3C(OC(C(C3O)O)OC(C(CO)O)C(C(C(=O)[O-])O)O)CO)CO)O)O)O)O.O.[OH-].[O-2].[Fe+3]

Peficitinib hydrobromide, ペフィシチニブ臭化水素酸塩


1353219-05-2.png

Structure of PEFICITINIB HYDROBROMIDE

img

ChemSpider 2D Image | PEFICITINIB HYDROBROMIDE | C18H23BrN4O2

Peficitinib hydrobromide

ペフィシチニブ臭化水素酸塩

ASP015K,

Rheumatoid Arthritis

1H-Pyrrolo(2,3-b)pyridine-5-carboxamide, 4-((5-hydroxytricyclo(3.3.1.13,7)dec-2-yl)amino)-, hydrobromide (1:1), stereoisomer

4-{[(1R,2s,3S,5r)-5-Hydroxyadamantan-2-yl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide hydrobromide (1:1)

1H-Pyrrolo[2,3-b]pyridine-5-carboxamide, 4-[[(1R,3S)-5-hydroxytricyclo[3.3.1.13,7]dec-2-yl]amino]-, hydrobromide (1:1)

U55XHZ5X6P

Formula
C18H22N4O2. HBr
CAS
1353219-05-2 HBR
944118-01-8 BASE
Mol weight
407.3048

PMDA, 2019/3/26 JAPAN APPROVED, Smyraf

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Peficitinib hydrobromide is used in the treatment of Psoriasis and Rheumatoid Arthritis

Peficitinib (formerly known as ASP015K) is a pyrrolo[2,3-b]pyridine derivative orally administered once-daily JAK inhibitor in development for the treatment of Rheumatoid Arthritis. In preclinical studied Peficitinib inhibited JAK1 and JAK3 with IC50 of 3.9 and 0.7 nM, respectively. Peficitinib also inhibited IL-2-dependent T cell proliferation in vitro and STAT5 phosphorylation in vitro and ex vivo. Furthermore, Peficitinib dose-dependently suppressed bone destruction and paw swelling in an adjuvant-induced arthritis model in rats via prophylactic or therapeutic oral dosing regimens.In clinical trials, Peficitinib treatment prescribed at 50, 100 and 150 mg amounts each showed statistically significantly higher ACR20 response rates compared to the placebo and response rates increased up to the 150 mg dosage. Adverse events included neutropenia, headache, and abdominal pain. The treatment-emergent adverse events occurring more frequently in the Peficitinib group compared with the placebo group included diarrhea, nasopharyngitis, and increased serum creatine phosphokinase activity. No cases of serious infections were reported. Herpes zoster occurred in four patients (two each in the peficitinib 25 and 100 mg cohorts). The authors concluded that treatment with peficitinib as monotherapy for 12 weeks in Japanese patients with moderate to severe RA is efficacious and showed an acceptable safety profile.

SYN

CLIP

Bioorganic & Medicinal Chemistry

Volume 26, Issue 18, 1 October 2018, Pages 4971-4983

Discovery and structural characterization of peficitinib (ASP015K) as a novel and potent JAK inhibitor

Abstract

Janus kinases (JAKs) are considered promising targets for the treatment of autoimmune diseases including rheumatoid arthritis (RA) due to their important role in multiple cytokine receptor signaling pathways. Recently, several JAK inhibitors have been developed for the treatment of RA. Here, we describe the identification of the novel orally bioavailable JAK inhibitor 18, peficitinib (also known as ASP015K), which showed moderate selectivity for JAK3 over JAK1, JAK2, and TYK2 in enzyme assaysChemical modification at the C4-position of lead compound 5 led to a large increase in JAK inhibitory activity and metabolic stability in liver microsomes. Furthermore, we determined the crystal structures of JAK1, JAK2, JAK3, and TYK2 in a complex with peficitinib, and revealed that the 1H-pyrrolo[2,3–b]pyridine-5-carboxamide scaffold of peficitinib forms triple hydrogen bonds with the hinge region. Interestingly, the binding modes of peficitinib in the ATP-binding pockets differed among JAK1, JAK2, JAK3, and TYK2. WaterMap analysis of the crystal structures suggests that unfavorable water molecules are the likely reason for the difference in orientation of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide scaffold to the hinge region among JAKs.

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Image result for Peficitinib hydrobromide

PATENT

WO 2011162300

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2011162300&tab=FULLTEXT&queryString=%28PA%2FAstellas%29+&recNum=126&maxRec=386

Diseases that have good JAK3 inhibitory activity and are caused by undesired cytokine signaling (eg rejection in living transplantation, rheumatism, psoriasis, autoimmune diseases, asthma, atopic dermatitis, Alzheimer’s disease, atherosclerosis etc. Patent Document 1 discloses fused heterocyclic compounds and salts thereof which are useful as therapeutic agents and / or prophylactic agents for diseases (eg, cancer, leukemia, etc.) caused by abnormal cytokine signaling. Among them, 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo represented by the following formula (I) disclosed in the example compound Ex121 [2,3-b] pyridine-5-carboxamide exhibits good activity, and is particularly a compound expected as a therapeutic agent for suppressing rejection during organ / tissue transplantation, rheumatism, psoriasis and the like.
[Chemical formula 1]
 The solid stability of a compound which has become a drug development candidate is an important factor both in industrial operation and in maintaining quality. In the stability of the drug substance itself, it is necessary to evaluate the stability of the quality necessary to maintain the efficacy and safety of the drug, and to obtain the information necessary for setting the storage method and the shelf life of the drug. For this reason, the stability test is considered to be one of the most important tests in the manufacture of pharmaceuticals (Heat measurement, 2004, 31 (2), pp. 80-86).
 Patent Document 1 discloses the free form of the compound of the formula (I) but does not disclose as a crystal. There is a need for a drug substance which is more suitable for formulation, and is physically and chemically stable from the viewpoint of quality assurance.
Example 1
(Production Method of Hydrobromide Salt Form B 45)
(In the Case of Addition of Seed Crystals )
After nitrogen substitution, the reaction vessel was charged with 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy- 2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (145.0 kg), water (377 L), EtOH (1508 L), 48% hydrobromic acid (74.9 kg) It charged sequentially at room temperature and started stirring. 48% hydrobromic acid was added, taking care that the pH was in the range of 1.5 to 1.9. The reaction mixture was heated and stirred until the internal temperature reached 70 ° C. or higher. After confirming that the solution was completely dissolved, the solution was stirred for 5 minutes or more, and the solution was subjected to clear filtration at an internal temperature of 70 ° C. or higher, and the pot and line were washed with warm EtOH (290 L). At an internal temperature of about 50 ° C., 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide odor Hydrochloric acid salt seed crystals (B45, 145 g) were added, and the mixture was ripened and stirred overnight at an internal temperature of 40 to 50 ° C. Subsequently, the mixture was cooled to an internal temperature of 20 to 30 ° C. over 1 hour or more, and the mixture was aged and stirred at the same temperature for 1 hour or more. At an internal temperature of 20 to 30 ° C., EtOAc (4350 L) was added dropwise over 1 hour, and the mixture was aged and stirred overnight at the same temperature. The precipitated crystals were filtered. The wet crystals were washed with a solution of EtOH / EtOAc (145 L / 290 L). The wet crystals are dried under reduced pressure at an external temperature of 40 ° C. overnight under reduced pressure to give 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3 -b] Pyridine-5-carboxamide hydrobromide crystal (B45, 161 kg) was obtained.

[0037]
(Another method of producing hydrobromide salt B45 type crystal)
(In the case of no addition of seed crystals) After
sufficiently drying the reaction vessel and replacing with nitrogen, water (585 L) is charged and subsequently 4- {[ (1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (225 kg), EtOH (2250 L) was charged Stirring was started. The internal temperature was adjusted to 25 ° C., and 48% hydrobromic acid (127.8 kg) was charged at the same temperature, and the vessel and kettle wall were washed with EtOH (90 L). After the completion of the charging, it was confirmed that the reaction solution had been dissolved, the pH was measured, and the pH was confirmed to be in the range of 1.5 to 1.9. When the pH was out of the range, the pH was adjusted to a predetermined pH using 48% hydrobromic acid (48% hydrobromic acid: about 11.6 kg). The temperature was raised until the internal temperature reached 70 ° C., and after confirmation of dissolution, the mixture was stirred for 5 minutes or more. The solution was subjected to clear filtration while maintaining the internal temperature at 60 ° C. or higher, and washed through a filter from a dissolution vessel with warm EtOH (450 L) preheated to 50 ° C. or higher. The clarified filtrate was gradually cooled to an internal temperature of 45 ° C., and filtered EtOAc (6750 L) was added dropwise over 6 hours at an internal temperature of 45 ° C. After the dropping was completed, the mixture was stirred at an internal temperature of 45 ° C. for 10 hours or more. Subsequently, it was cooled to an internal temperature of 25 ° C. using a follow-up temperature control cooler, and stirred at an internal temperature of 25 ° C. for 3 hours. The predetermined supernatant concentration and the crystal form of the precipitated crystals were confirmed and filtered. A mixed solvent of EtOH / EtOAc (225 L / 450 L) was prepared and cake washed using this mixed solvent. The obtained wet crystals are dried under reduced pressure at an external temperature of 40 ° C. for 10 hours or more, and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [ 2,3-b] pyridine-5-carboxamido hydrobromide crystal (B45, 250 kg) was obtained.

[0038]
1 H-NMR (600 MHz, d 6 -DMSO) δ: 1.49 (2 H, m), 1. 68 (2 H, m), 1.71 (2 H, m), 1. 80 (2 H, m), 1. 91 (2 H, m), 2.10 (1H, m), 2.20 (2 H, m), 3. 70-4.00 (1 H, brs), 4. 28 (1 H, m), 6. 66 (1 H, m), 7. 39 (1 H, m), 7. 75 (1 H, brs), 8. 38 (1 H, brs), 8.5 5 (1 H, s), 11. 17 (1 H, d, 7.8 Hz), 12.5 (1 H, brs), 14. 17 (1 H, brs)
Elemental analysis: theoretical value: C 53.08%, H 5.69% , N 13.76%, O 7.86% , Br 19.62%;
Found:. C 53.02%, H 5.74 %, N 13.73%, Br 19.42%
molecular composition: C 18 H 22 N 4 O . HBr
MS: 327.0 (M From the result of + H) +
elemental analysis, 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5 The carboxamido hydrobromide was a monohydrobromide.

[0039]
Example 2
(hydrobromide A87 crystal)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] Pyridine-5-carboxamide (6.0 g) was charged in EtOH / water (57.6 mL / 14.4 mL). At 50-60 ° C., 48% hydrobromic acid was added, stirred for 15 minutes more, and washed with EtOH (18 mL). At 45 ° C.-55 ° C. EtOAc (180 mL) was added dropwise over 30 minutes. Crystals were precipitated upon stirring at 15 ° C to 25 ° C. The crystals were collected by filtration and washed with a mixed solvent of EtOH / EtOAc (6 mL / 12 mL). The crystals are dried under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide odor Seed crystals of hydrofluoride (Form A87, 6.11 g) were obtained.
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide (3.0 g), EtOH (24 mL), water (6 mL), and 48% hydrobromic acid (1.55 g) were charged sequentially at room temperature. After charging, the mixture was heated to an internal temperature of 60 ° C. or higher and stirred. After confirming that the solution was completely in solution, the solution was subjected to clear filtration at an internal temperature of 60 ° C. or higher, and washed with warm EtOH (9 mL). EtOH (21 mL) is added dropwise at an internal temperature of 70 ° C. or higher, and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H at an internal temperature of 70 ° C. Seed crystals (A87, 30 mg) of pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide were added, and the mixture was ripened and stirred overnight at an internal temperature of 65 to 70 ° C. Subsequently, it was cooled to an internal temperature of 20 to 30 ° C., and ripening stirring was carried out at the same temperature overnight. At an internal temperature of 20 to 30 ° C., EtOAc (90 mL) was added dropwise over 1 hour, and the mixture was aged and stirred at the same temperature for 1 hour or more. The precipitated crystals were collected by filtration. The wet crystals were washed with a solution of EtOH / EtOAc (3 mL / 12 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide crystal (Form A87, 3.09 g) was obtained.

[0040]
Example 3
(hydrobromide A61 crystal)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] Pyridine-5-carboxamide (5.0 g), EtOH (48 mL), water (12 mL), and 48% hydrobromic acid (2.58 g) were charged sequentially at room temperature. After charging, the mixture was heated to an internal temperature of 70 ° C. and stirred. After confirming complete dissolution, the solution was clarified by filtration at an internal temperature of 70 ° C., and washed with warm EtOH (15 mL). The internal temperature was cooled to 50 to 60 ° C., and EtOAc (150 mL) was added dropwise over 1 hour at the same temperature. After the addition was completed, the solution was gradually cooled to 20 to 30 ° C., and the mixture was aged and stirred at the same temperature for 1 hour or more. The precipitated crystals were collected by filtration. The wet crystals were washed with a solution of EtOH / EtOAc (5 mL / 10 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide crystal (Form A61, 5.19 g) was obtained.

[0041]
Example 4
(hydrobromide A36 type crystal)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] To a suspension of pyridine-5-carboxamide (500 mg) in EtOAc, 48% hydrobromic acid (258 μL) was added, and the mixture was stirred with heating under reflux for 1 hour, and further allowed to cool to room temperature. The precipitated crystals were collected by filtration and washed with EtOAc. The resulting crystals are dried at 60 ° C. under reduced pressure to give 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-]. b] Pyridine-5-carboxamide monohydrobromide crystal (Form A36, 625 mg) was obtained.

[0042]
Example 5
(B11-type crystal of hydrobromide monohydrate)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2 , 3-b] Pyridine-5-carboxamide (5.0 g), EtOH (48 mL), water (12 mL), 48% hydrobromic acid (2.58 g) were sequentially charged at room temperature. After charging, the mixture was heated to an internal temperature of 70 ° C. or higher and stirred. After confirming that the solution had completely dissolved, the solution was subjected to clear filtration at an internal temperature of 70 ° C. or higher, and washed with warm EtOH (15 mL). 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide odor at an internal temperature of about 35 ° C. Hydrochloric acid salt seed crystals (A87, 49.0 mg) were added, and the mixture was aged with an internal temperature of 30 to 40 ° C. for 4 hours. Subsequently, the mixture was cooled to an internal temperature of 20 to 30 ° C., and aged and stirred overnight at the same temperature. At an internal temperature of 20-25 ° C., EtOAc (150 mL) was added dropwise over 1 hour, and the mixture was aged and stirred at the same temperature for 30 minutes or longer. The precipitated crystals were collected by filtration. The wet crystals were washed with a solution of EtOH / EtOAc (5 mL / 10 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide monohydrate crystal (Form B11, 5.24 g) was obtained.

[0043]
Example 6
(B21-type crystal of hydrobromide dihydrate)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2 , 3-b] Pyridine-5-carboxamide (5.0 g), EtOH (18 mL), water (12 mL), 48% hydrobromic acid (2.58 g) were sequentially charged at room temperature. After charging, the mixture was heated to an internal temperature of 60 ° C. or higher and stirred. After confirming that the solution was completely dissolved, the solution was subjected to clear filtration at an internal temperature of 60 ° C. or higher, and washed with warm EtOH (10 mL). The mixture was cooled to an internal temperature of about 45 to 50 ° C. and aged for 2 hours while stirring. Subsequently, the reaction solution is cooled to an internal temperature of 20 to 30 ° C., and aged at the same temperature and stirred overnight. At an internal temperature of 20 to 30 ° C., EtOAc (160 mL) was added dropwise over 1 hour, and the mixture was aged and stirred for 1 hour or more at the same temperature. The precipitated crystals were filtered. The wet crystals were washed with a solution of EtOH / EtOAc (3 mL / 12 mL). The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide dihydrate crystals (Form B21, 6.05 g) were obtained.

[0044]
Example 7
(Tautomerism of each crystal)

[0045]
Example 7-1
(Crystal form conversion; hydrobromide B21 → A61)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- Pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide dihydrate (Form B21, 300 mg) and EtOH (3 mL) were sequentially charged at room temperature and suspended overnight. After suspension, the crystals were collected by filtration at room temperature and the wet crystals were washed with EtOH. The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide crystal (Form A61, 258 mg) was obtained.

[0046]
Example 7-2
(Crystal form conversion; hydrobromide B11 → B21)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- Pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide monohydrate (form B11, 2.0 g), EtOH (7 mL), water (3 mL) were sequentially charged at room temperature and suspended overnight. It became cloudy. After suspension, the crystals were collected by filtration at room temperature and the wet crystals were washed with 70% aqueous EtOH. The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide dihydrate crystals (Form B21, 1.54 g) were obtained.

[0047]
Example 7-3
(Crystal form conversion; hydrobromide A61 form → B21 form)
4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- Pyrrolo [2,3-b] pyridine-5-carboxamide hydrobromide (form A61, 1.0 g), EtOH (3.5 mL) and water (1.5 mL) were sequentially charged at room temperature and suspended overnight. After suspension, the crystals were filtered at room temperature and the wet crystals were washed with 70% aqueous EtOH. The wet crystals are dried overnight under vacuum and 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide Hydrobromide dihydrate crystals (Form B21, 827 mg) were obtained.

[0048]
Reference Example 1
( Example of Preparation of Monohydrate Crystalline Compound (I) Free Form)
4-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carboxamide (44.5 g) under nitrogen atmosphere 1s, 3R, 4s, 5S) -4-aminoadamantan-1-ol (57.0 g) and tributylamine (162.6 mL) were charged in NMP (222.5 mL), and heated and stirred at a bath temperature of 200 ° C. for 2.5 hours. The reaction solution was allowed to cool, and then the reaction solution was added dropwise while stirring in water / Et 2 O (6 L / 0.5 L), followed by stirring for 30 minutes. The obtained solid was collected by filtration, washed twice with water (400 mL), washed twice with Et 2 O (300 mL), and dried. The resulting solid was warmed to dissolve in MeOH (1.8 L) and filtered hot. The resulting mother liquor was concentrated under reduced pressure and MeOH (1.8 L) was added to the residue and heated to dissolve. The resulting solution was allowed to cool and stir, and then stirred at room temperature and aged overnight. The precipitated solid was collected by filtration, washed with EtOH and dried under reduced pressure. The resulting solid was suspended in EtOH (250 mL) and stirred at room temperature for 1 h. The solid was collected by filtration, washed with EtOH and dried under reduced pressure. The obtained solid was suspended in water (900 mL) and stirred at a bath temperature of 70 ° C. for 2 hours. The solid was collected by filtration, washed with water and dried under reduced pressure. Furthermore, the solid was suspended in water (900 mL) and stirred at a bath temperature of 70 ° C. for 2 hours. The solid is collected by filtration, washed with water and then dried under reduced pressure to give 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2 , 3-b] Pyridine-5-carboxamide monohydrate crystal (Form A01, 44 g) was obtained.

REFERENCES

1: D’Amico F, Fiorino G, Furfaro F, Allocca M, Danese S. Janus kinase inhibitors for the treatment of inflammatory bowel diseases: developments from phase I and phase II clinical trials. Expert Opin Investig Drugs. 2018 Jul;27(7):595-599. doi: 10.1080/13543784.2018.1492547. Epub 2018 Jul 6. Review. PubMed PMID: 29938545.

2: Sands BE, Sandborn WJ, Feagan BG, Lichtenstein GR, Zhang H, Strauss R, Szapary P, Johanns J, Panes J, Vermeire S, O’Brien CD, Yang Z, Bertelsen K, Marano C; Peficitinib-UC Study Group. Peficitinib, an Oral Janus Kinase Inhibitor, in Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2 Study. J Crohns Colitis. 2018 Jun 15. doi: 10.1093/ecco-jcc/jjy085. [Epub ahead of print] PubMed PMID: 29917064.

3: Veale DJ, McGonagle D, McInnes IB, Krueger JG, Ritchlin CT, Elewaut D, Kanik KS, Hendrikx T, Berstein G, Hodge J, Telliez JB. The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis. Rheumatology (Oxford). 2018 Apr 3. doi: 10.1093/rheumatology/key070. [Epub ahead of print] PubMed PMID: 29618084.

4: Cline A, Cardwell LA, Feldman SR. Advances in treating psoriasis in the elderly with small molecule inhibitors. Expert Opin Pharmacother. 2017 Dec;18(18):1965-1973. doi: 10.1080/14656566.2017.1409205. Epub 2017 Nov 27. Review. PubMed PMID: 29171774.

5: Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann Rheum Dis. 2018 Feb;77(2):175-187. doi: 10.1136/annrheumdis-2017-211555. Epub 2017 Aug 1. Review. PubMed PMID: 28765121.

6: Zhu T, Howieson C, Wojtkowski T, Garg JP, Han D, Fisniku O, Keirns J. The Effect of Verapamil, a P-Glycoprotein Inhibitor, on the Pharmacokinetics of Peficitinib, an Orally Administered, Once-Daily JAK Inhibitor. Clin Pharmacol Drug Dev. 2017 Nov;6(6):548-555. doi: 10.1002/cpdd.344. Epub 2017 Mar 16. PubMed PMID: 28301084.

7: Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, Shay K, Wang X, Garg JP, Cardiel MH. Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease-Modifying Antirheumatic Drugs in the Treatment of Moderate-to-Severe Rheumatoid Arthritis. Arthritis Rheumatol. 2017 May;69(5):932-942. doi: 10.1002/art.40054. PubMed PMID: 28118538.

8: Ito M, Yamazaki S, Yamagami K, Kuno M, Morita Y, Okuma K, Nakamura K, Chida N, Inami M, Inoue T, Shirakami S, Higashi Y. A novel JAK inhibitor, peficitinib, demonstrates potent efficacy in a rat adjuvant-induced arthritis model. J Pharmacol Sci. 2017 Jan;133(1):25-33. doi: 10.1016/j.jphs.2016.12.001. Epub 2016 Dec 23. PubMed PMID: 28117214.

9: Zhu T, Parker B, Wojtkowski T, Nishimura T, Garg JP, Han D, Fisniku O, Keirns J. Drug Interactions Between Peficitinib, an Orally Administered, Once-Daily Janus Kinase Inhibitor, and Rosuvastatin in Healthy Subjects. Clin Pharmacokinet. 2017 Jul;56(7):747-757. doi: 10.1007/s40262-016-0474-4. PubMed PMID: 27878567.

10: Semerano L, Decker P, Clavel G, Boissier MC. Developments with investigational Janus kinase inhibitors for rheumatoid arthritis. Expert Opin Investig Drugs. 2016 Dec;25(12):1355-1359. Epub 2016 Oct 31. PubMed PMID: 27748152.

11: Kivitz AJ, Gutierrez-Ureña SR, Poiley J, Genovese MC, Kristy R, Shay K, Wang X, Garg JP, Zubrzycka-Sienkiewicz A. Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate. Arthritis Rheumatol. 2017 Apr;69(4):709-719. doi: 10.1002/art.39955. PubMed PMID: 27748083.

12: Lam S. JAK inhibitors: A broadening approach in rheumatoid arthritis. Drugs Today (Barc). 2016 Aug;52(8):467-469. PubMed PMID: 27722215.

13: Roskoski R Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res. 2016 Sep;111:784-803. doi: 10.1016/j.phrs.2016.07.038. Epub 2016 Jul 26. Review. PubMed PMID: 27473820.

14: Iwata S, Tanaka Y. Progress in understanding the safety and efficacy of Janus kinase inhibitors for treatment of rheumatoid arthritis. Expert Rev Clin Immunol. 2016 Oct;12(10):1047-57. doi: 10.1080/1744666X.2016.1189826. Epub 2016 Jun 6. Review. PubMed PMID: 27253519.

15: Cao YJ, Sawamoto T, Valluri U, Cho K, Lewand M, Swan S, Lasseter K, Matson M, Holman J Jr, Keirns J, Zhu T. Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects. Clin Pharmacol Drug Dev. 2016 Nov;5(6):435-449. doi: 10.1002/cpdd.273. Epub 2016 Jun 30. PubMed PMID: 27162173.

16: Nielsen OH, Seidelin JB, Ainsworth M, Coskun M. Will novel oral formulations change the management of inflammatory bowel disease? Expert Opin Investig Drugs. 2016 Jun;25(6):709-18. doi: 10.1517/13543784.2016.1165204. Epub 2016 Mar 28. Review. PubMed PMID: 26967267.

17: Yiu ZZ, Warren RB. Novel Oral Therapies for Psoriasis and Psoriatic Arthritis. Am J Clin Dermatol. 2016 Jun;17(3):191-200. doi: 10.1007/s40257-016-0179-3. Review. PubMed PMID: 26923915.

18: Takeuchi T, Tanaka Y, Iwasaki M, Ishikura H, Saeki S, Kaneko Y. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016 Jun;75(6):1057-64. doi: 10.1136/annrheumdis-2015-208279. Epub 2015 Dec 15. PubMed PMID: 26672064; PubMed Central PMCID: PMC4893099.

19: Oda K, Cao YJ, Sawamoto T, Nakada N, Fisniku O, Nagasaka Y, Sohda KY. Human mass balance, metabolite profile and identification of metabolic enzymes of [¹⁴C]ASP015K, a novel oral janus kinase inhibitor. Xenobiotica. 2015;45(10):887-902. doi: 10.3109/00498254.2015.1026864. Epub 2015 May 19. PubMed PMID: 25986538.

20: Nakada N, Oda K. Identification and characterization of metabolites of ASP015K, a novel oral Janus kinase inhibitor, in rats, chimeric mice with humanized liver, and humans. Xenobiotica. 2015;45(9):757-65. doi: 10.3109/00498254.2015.1019594. Epub 2015 Jun 12. PubMed PMID: 25869242.

/////////////////Peficitinib hydrobromide, Smyraf, JAPAN 2019, ペフィシチニブ臭化水素酸塩  , ASP015K, Rheumatoid Arthritis

O=C(C1=CN=C(NC=C2)C2=C1N[C@@H]3[C@]4([H])C[C@@]5([H])C[C@](C4)(O)C[C@]3([H])C5)N.[H]Br

Romosozumab, ロモソズマブ (遺伝子組換え)


Image result for Romosozumab

Romosozumab

ロモソズマブ (遺伝子組換え)

AMG 785

Immunoglobulin G2, anti-(human sclerostin) (human-mouse monoclonal 785A070802 heavy chain), disulfide with human-mouse monoclonal 785A070802 κ-chain, dimer

  • Immunoglobulin G2, anti-(human sclerostin) (humanized monoclonal 785A070802 heavy chain), disulfide with humanized monoclonal 785A070802 κ-chain, dimer
Formula
C6452H9926N1714O2040S54
CAS
909395-70-6
Mol weight
145875.6186

Monoclonal antibody
Treatment of osteoporosis

Osteoporosis agent, Sclerostin activity inhibitor

JAPAN APPROVED 2019/1/8, Evenity

Romosozumab (AMG 785) is a humanized monoclonal antibody that targets sclerostin for the treatment of osteoporosis.[1]

Romosozumab was originally discovered by Chiroscience,[2] which was acquired by Celltech (now owned by UCB).[3] Celltech entered in a partnership with Amgen in 2002 for the product’s development.[4]

In 2016 results from 12 months of a clinical study were reported.[5]

Some results from the FRAME[6] and ARCH clinical studies were reported on in 2017.[7]

Japan’s Ministry of Health, Labor and Welfare has granted a marketing authorization for romosozumab (EVENITY) for the treatment of osteoporosis in patients at high risk of fracture. Developed by Amgen and UCB, romosozumab is a humanized IgG2 monoclonal antibody that targets sclerostin. The approval in Japan is based on results from the Phase 3 FRAME and BRIDGE studies, which included 7,180 postmenopausal women with osteoporosis and 245 men with osteoporosis, respectively.

A biologics license application (BLA) for romosozumab as a treatment of osteoporosis in postmenopausal women at high risk for fracture was submitted to the U.S. Food and Drug Administration (FDA) in July 2016, but additional safety and efficacy data was requested in the FDA’s complete response letter, as announced by Amgen and UCB in July 2017. In July 2018, Amgen and UCB announced that the BLA had been resubmitted. In addition to data from early-stage clinical studies, the original BLA included data from the Phase 3 FRAME study. The resubmitted BLA includes results from the more recent Phase 3 ARCH study, an alendronate-active comparator trial including 4,093 postmenopausal women with osteoporosis who experienced a fracture, and the Phase 3 BRIDGE study. The FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee is scheduled to review data supporting the BLA for romosozumab at a meeting on January 16, 2019.

The European Medicines Agency is also currently reviewing a marketing application for romosozumab.

US 20170305999

Commercial production of cell culture-derived products (for example, protein-based products, such as monoclonal antibodies (mAbs)), requires optimization of cell culture parameters in order for the cells to produce enough product to meet clinical and commercial demands. However, when cell culture parameters are optimized for improving productivity of a protein product, it is also necessary to maintain desired quality specifications of the product such as glycosylation profile, aggregate levels, charge heterogeneity, and amino acid sequence integrity (Li, et al., 2010 , mAbs., 2(5):466-477).
      For instance, an increase of over 20% volumetric titer results in a significant improvement in large-scale monoclonal antibody production economics. Additionally, the ability to control the glycan forms of proteins produced in cell culture is important. Glycan species have been shown to significantly influence pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic proteins such as mAbs. Moreover, the ability to modulate the relative percentage of various glycan species can have drastic results over the behavior of a protein in vivo. For example, increased mannose-5-N-acetylglycosamine-2 (“Man5”) and other high-mannose glycan species have been shown to decrease mAb in vivo half-life (Liu, 2015 , J Pharm Sci., 104(6):1866-84; Goetze et al., 2011 , Glycobiology, 21(7):949-59; and Kanda et al. 2007 , Glycobiology, 17(1):104-18). On the other hand, glycosylated mAbs with mannose-3-N-acetylglycosamine-4 (“G0”) glycan species have been shown to impact antibody dependent cellular cytotoxicity (ADCC).
      Bioreactors have been successfully utilized for the cell-based production of therapeutic proteins using fed-batch, immobilized, perfusion and continuous modes. Strategies, such as the use of temperature, media formulation, including the addition of growth inhibitors, autocrine factors or cyclic mononucleotides, and hyperstimulation by osmolarity stress, have been used to enhance protein production by cells in culture. To the extent that they have worked at all, these approaches have shown only marginal success.
      As such, there is a particular need for improved compositions for use in cell culture for the production of medically or industrially useful products, such as antibodies. Ideally, such compositions and methods for utilizing the same would result in higher titers, modulated (e.g. decreased) high and low molecular weight species, as well as a more favorable glycosylation profile of the derived products in cell culture.
      Throughout this specification, various patents, patent applications and other types of publications (e.g., journal articles, electronic database entries, etc.) are referenced. The disclosure of all patents, patent applications, and other publications cited herein are hereby incorporated by reference in their entirety for all purposes.

References

  1. ^ “Statement On A Nonproprietary Name Adopted By The USAN Council: Romosozumab” (PDF)American Medical Association.
  2. ^ Quested, Tony (June 7, 2015). “Cream of life science entrepreneurs’ first venture was selling doughnuts”Business Week. Cambridge, England: Q Communications. Retrieved December 24, 2018.
  3. ^ Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 2003 Dec 1;22(23):6267-76.
  4. ^ Celltech group Annual Report and Accounts 2002
  5. ^ Cosman; et al. (2016). “Romosozumab Treatment in Postmenopausal Women with Osteoporosis”. The New England Journal of Medicine375: 1532–1543. doi:10.1056/NEJMoa1607948PMID 27641143.
  6. ^ Efficacy and Safety of Romosozumab Treatment in Postmenopausal Women With Osteoporosis (FRAME)
  7. ^ Bone Loss Drug Effective, But is it Safe? Oct 2017
Romosozumab
Monoclonal antibody
Type Whole antibody
Source Humanized (from mouse)
Target Sclerostin
Clinical data
ATC code
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
ChemSpider
  • none
KEGG
Chemical and physical data
Formula C6452H9926N1714O2040S54
Molar mass 145.9 kg/mol

///////////Romosozumab, ロモソズマブ (遺伝子組換え)  , JAPAN 2019, Monoclonal antibody, Osteoporosis, AMG 785

Esaxerenone エサキセレノン , эсаксеренон , إيساكسيرينون , 艾沙利 酮 ,


Esaxerenone.svg

1632006-28-0.png

ChemSpider 2D Image | esaxerenone | C22H21F3N2O4S

img

Esaxerenone

エサキセレノン , эсаксеренон إيساكسيرينون 艾沙利  酮 

CS-3150XL-550

Formula
C22H21F3N2O4S
CAS
1632006-28-0
Mol weight
466.4734

Pmda approved japan, 2019/1/8, Minebro

Antihypertensive, Aldosterone antagonist

N62TGJ04A1
UNII:N62TGJ04A1
эсаксеренон [Russian] [INN]
إيساكسيرينون [Arabic] [INN]
艾沙利酮 [Chinese] [INN]
1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
10230
1632006-28-0 [RN], 880780-76-7, 1072195-82-4 (+ isomer)   1072195-83-5 (- isomer)
1H-Pyrrole-3-carboxamide, 1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-
  • Originator X-Ceptor Therapeutics
  • Developer Daiichi Sankyo Company
  • Class Antihyperglycaemics; Antihypertensives; Pyrroles; Small molecules; Sulfones
  • Mechanism of Action Mineralocorticoid receptor antagonists
  • Registered Hypertension
  • Phase III Diabetic nephropathies
  • No development reported Cardiovascular disorders; Heart failure
  • 09 Jan 2019 Registered for Hypertension in Japan (PO) – First global approval
  • 27 Nov 2018 Daiichi Sankyo completes a phase III trial in Diabetic nephropathies in Japan (PO) (JapicCTI-173696)
  • 08 Jun 2018 Efficacy and adverse events data from the phase III ESAX-HTN trial in Essential hypertension presented 28th European Meeting on Hypertension and Cardiovascular Protection (ESH-2018)

CS 3150, angiotensin II receptor antagonist,  for the treatment or prevention of such hypertension and heart disease similar to olmesartan , losartan, candesartan , valsartan,  irbesartan,  telmisartan, eprosartan,

 Cas name 1H-Pyrrole-3-carboxamide, 1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-, (5S)-

CAS 1632006-28-0 for S conf

MF C22 H21 F3 N2 O4 S

MW 466.47

(S)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

CAS 1632006-28-0 for S configuration

1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide

(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide, CAS 880780-76-7

(+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-82-4

(-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide..1072195-83-5

How to synthesis Esaxerenone 1632006-28-0 – YouTube

Oct 31, 2018 – Uploaded by EOS Med Chem

Esaxerenone 1632006-28-0, FDA approved new drug will be a big potential drug. Original Route of Synthesis …

Esaxerenone, also known as CS-3150, XL-550, is a nonsteroidal antimineralocorticoid which was discovered by Exelixis and is now under development by Daiichi Sankyo Company for the treatment of hypertension, essential hypertension, hyperaldosteronism, and diabetic nephropathies. It acts as a highly selective silent antagonist of the mineralocorticoid receptor (MR), the receptor for aldosterone, with greater than 1,000-fold selectivity for this receptor over other steroid hormone receptors, and 4-fold and 76-fold higher affinity for the MR relative to the existing antimineralocorticoids spironolactone and eplerenone.
Image result for Esaxerenone SYNTHESIS

Esaxerenone (INN) (developmental code names CS-3150XL-550) is a nonsteroidal antimineralocorticoid which was discovered by Exelixis and is now under development by Daiichi Sankyo Company for the treatment of hypertensionessential hypertensionhyperaldosteronism, and diabetic nephropathies.[1][2][3] It acts as a highly selective silent antagonist of the mineralocorticoid receptor(MR), the receptor for aldosterone, with greater than 1,000-fold selectivity for this receptor over other steroid hormone receptors, and 4-fold and 76-fold higher affinity for the MR relative to the existing antimineralocorticoids spironolactone and eplerenone.[1][2][3] As of 2017, esaxerenone is in phase III clinical trials for hypertension, essential hypertension, and hyperaldosteronism and is in phase IIclinical trials for diabetic nephropathies.[1]

  • Mechanism of Action Mineralocorticoid receptor antagonists 

JAPAN PHASE 2……….Phase 2 Study to Evaluate Efficacy and Safety of CS-3150 in Patients with Essential Hypertension

http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-121921

Phase II Diabetic nephropathies; Hypertension

  • 01 Jan 2015 Daiichi Sankyo initiates a phase IIb trial for Diabetic nephropathies in Japan (NCT02345057)
  • 01 Jan 2015 Daiichi Sankyo initiates a phase IIb trial for Hypertension in Japan (NCT02345044)
  • 01 May 2013 Phase-II clinical trials in Diabetic nephropathies in Japan (PO)
  •  Currently, angiotensin II receptor antagonists and calcium antagonists are widely used as a medicament for the treatment or prevention of such hypertension or heart disease.
     Mineralocorticoid receptor (MR) (aldosterone receptor) has been known to play an important role in the control of body electrolyte balance and blood pressure, spironolactone having a steroid structure, MR antagonists such as eplerenone, are known to be useful in the treatment of hypertension-heart failure.
     Renin – angiotensin II receptor antagonists are inhibitors of angiotensin system is particularly effective in renin-dependent hypertension, and show a protective effect against cardiovascular and renal failure. Also, the calcium antagonists, and by the function of the calcium channel antagonizes (inhibits), since it has a natriuretic action in addition to the vasodilating action, is effective for hypertension fluid retention properties (renin-independent) .
     Therefore, the MR antagonist, when combined angiotensin II receptor antagonists or calcium antagonists, it is possible to suppress the genesis of multiple hypertension simultaneously, therapeutic or prophylactic effect of the stable and sufficient hypertension irrespective of the etiology is expected to exhibit.
     Also, diuretics are widely used as a medicament for the treatment or prevention of such hypertension or heart disease. Diuretic agent is effective in the treatment of hypertension from its diuretic effect. Therefore, if used in combination MR antagonists and diuretics, the diuretic effect of diuretics, it is possible to suppress the genesis of multiple blood pressure at the same time, shows a therapeutic or prophylactic effect of the stable and sufficient hypertension irrespective of the etiology it is expected.
     1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (hereinafter, compound ( I)) is, it is disclosed in Patent Documents 1 and 2, hypertension, for the treatment of such diabetic nephropathy are known to be useful.

CS-3150 (XL550) is a small-molecule antagonist of the mineralocorticoid receptor (MR), a nuclear hormone receptor implicated in a variety of cardiovascular and metabolic diseases. MR antagonists can be used to treat hypertension and congestive heart failure due to their vascular protective effects. Recent studies have also shown beneficial effects of adding MR antagonists to the treatment regimen for Type II diabetic patients with nephropathy. CS-3150 is a non-steroidal, selective MR antagonist that has the potential for the treatment of hypertension, congestive heart failure, or end organ protection due to vascular damage.

Useful as a mineralocorticoid receptor (MR) antagonist, for treating hypertension, cardiac failure and diabetic nephropathy. It is likely to be CS-3150, a non-steroidal MR antagonist, being developed by Daiichi Sankyo (formerly Sankyo), under license from Exelixis, for treating hypertension and diabetic nephropathy (phase 2 clinical, as of March 2015). In January 2015, a phase II trial for type 2 diabetes mellitus and microalbuminuria was planned to be initiated later that month (NCT02345057).

Exelixis discovered CS-3150 and out-licensed the compound to Daiichi-Sankyo. Two phase 2a clinical trials, one in hypertensive patients and the other in type 2 diabetes with albuminuria, are currently being conducted in Japan by Daiichi-Sankyo.

Mineralocorticoid receptor (MR) (aldosterone receptor) has been known to play an important role in the control of body electrolyte balance and blood pressure, spironolactone having a steroid structure, MR antagonists such as eplerenone, are known to be useful in the treatment of hypertension-heart failure.

CS-3150 (XL550) is a small-molecule antagonist of the mineralocorticoid receptor (MR), a nuclear hormone receptor implicated in a variety of cardiovascular and metabolic diseases. MR antagonists can be used to treat hypertension and congestive heart failure due to their vascular protective effects. Recent studies have also shown beneficial effects of adding MR antagonists to the treatment regimen for Type II diabetic patients with nephropathy. CS-3150 is a non-steroidal, selective MR antagonist that has the potential for the treatment of hypertension, congestive heart failure, or end organ protection due to vascular damage.

Exelixis discovered CS-3150 and out-licensed the compound to Daiichi-Sankyo. Two phase 2a clinical trials, one in hypertensive patients and the other in type 2 diabetes with albuminuria, are currently being conducted in Japan by Daiichi-Sankyo.

Daiichi Sankyo (formerly Sankyo), under license from Exelixis, is developing CS-3150 (XL-550), a non-steroidal mineralocorticoid receptor (MR) antagonist, for the potential oral treatment of hypertension and diabetic nephropathy, microalbuminuria ,  By October 2012, phase II development had begun ; in May 2014, the drug was listed as being in phase IIb development . In January 2015, a phase II trial for type 2 diabetes mellitus and microalbuminuria was planned to be initiated later that month. At that time, the trial was expected to complete in March 2017 .

Exelixis, following its acquisition of X-Ceptor Therapeutics in October 2004 , was investigating the agent for the potential treatment of metabolic disorders and cardiovascular diseases, such as hypertension and congestive heart failure . In September 2004, Exelixis expected to file an IND in 2006. However, it appears that the company had fully outlicensed the agent to Sankyo since March 2006 .

Description Small molecule antagonist of the mineralocorticoid receptor (MR)
Molecular Target Mineralocorticoid receptor
Mechanism of Action Mineralocorticoid receptor antagonist
Therapeutic Modality Small molecule

In January 2015, a multi-center, placebo-controlled, randomized, 5-parallel group, double-blind, phase II trial (JapicCTI-152774;  NCT02345057; CS3150-B-J204) was planned to be initiated later that month in Japan, in patients with type 2 diabetes mellitus and microalbuminuria, to assess the efficacy and safety of different doses of CS-3150 compared to placebo. At that time, the trial was expected to complete in March 2017; later that month, the trial was initiated in the Japan

By October 2012, phase II development had begun in patients with essential hypertension

By January 2011, phase I trials had commenced in Japan

Several patents WO-2014168103,

WO-2015012205 and WO-2015030010

XL-550, claimed in WO-2006012642,

PATENT

http://www.google.co.in/patents/EP2133330A1?cl=en

(Example 3)(+/-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide

  • After methyl 4-methyl-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxylate was obtained by the method described in Example 16 of WO 2006/012642 , the following reaction was performed using this compound as a raw material.
  • Methyl 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate (1.4 g, 4.9 mmol) was dissolved in methanol (12 mL), and a 5 M aqueous sodium hydroxide solution (10 mL) was added thereto, and the resulting mixture was heated under reflux for 3 hours. After the mixture was cooled to room temperature, formic acid (5 mL) was added thereto to stop the reaction. After the mixture was concentrated under reduced pressure, water (10 mL) was added thereto to suspend the resulting residue. The precipitated solid was collected by filtration and washed 3 times with water. The obtained solid was dried under reduced pressure, whereby 4-methyl-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylic acid (1.1 g, 83%) was obtained as a solid. The thus obtained solid was suspended in dichloromethane (10 mL), oxalyl chloride (0.86 mL, 10 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 2 hours. After the mixture was concentrated under reduced pressure, the residue was dissolved in tetrahydrofuran (10 mL), and 4-(methylsulfonyl)aniline hydrochloride (1.0 g, 4.9 mmol) and N,N-diisopropylethylamine (2.8 mL, 16 mmol) were sequentially added to the solution, and the resulting mixture was heated under reflux for 18 hours. After the mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and acetonitrile (10 mL) and 3 M hydrochloric acid (100 mL) were added to the residue. A precipitated solid was triturated, collected by filtration and washed with water, and then, dried under reduced pressure, whereby 4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (1.4 g, 89%) was obtained as a solid.
    1H-NMR (400 MHz, DMSO-d6) δ11.34 (1H, brs,), 9.89 (1H, s), 7.97 (2H, d, J = 6.6 Hz), 7.87-7.81 (3H, m), 7.73 (1H, t, J = 7.4 Hz), 7.65-7.61 (2H, m), 7.44 (1H, d, J = 7.8 Hz), 3.15 (3H, s), 2.01 (3H, s).
  • Sodium hydride (0.12 g, 3 mmol, 60% dispersion in mineral oil) was dissolved in N,N-dimethylformamide (1.5 mL), and 4-methyl -N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide (0.47 g, 1.1 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (0.14 g, 1.2 mmol) was added thereto, and the resulting mixture was stirred at room temperature. After 1 hour, sodium hydride (40 mg, 1.0 mmol, oily, 60%) was added thereto again, and the resulting mixture was stirred for 30 minutes. Then, 1,3,2-dioxathiolane-2,2-dioxide (12 mg, 0.11 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the mixture was concentrated under reduced pressure, methanol (5 mL) was added to the residue and insoluble substances were removed by filtration, and the filtrate was concentrated again. To the residue, tetrahydrofuran (2 mL) and 6 M hydrochloric acid (2 mL) were added, and the resulting mixture was stirred at 60°C for 16 hours. The reaction was cooled to room temperature, and then dissolved in ethyl acetate, and washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate), whereby the objective compound (0.25 g, 48%) was obtained.
    1H-NMR (400 MHz, CDCl3) δ: 7.89-7.79 (m, 6H), 7.66-7.58 (m, 2H), 7.49 (s, 1H), 7.36 (d, 1H, J = 7.4Hz), 3.81-3.63 (m, 4H), 3.05 (s, 3H), 2.08 (s, 3H).
    HR-MS (ESI) calcd for C22H22F3N2O4S [M+H]+, required m/z: 467.1252, found: 467.1246.
    Anal. calcd for C22H21F3N2O4S: C, 56.65; H, 4.54; N, 6.01; F, 12.22; S, 6.87. found: C, 56.39; H, 4.58; N, 5.99; F, 12.72; S, 6.92.

(Example 4)

Optical Resolution of Compound of Example 3

  • Resolution was performed 4 times in the same manner as in Example 2, whereby 74 mg of Isomer C was obtained as a solid from a fraction containing Isomer C (tR = 10 min), and 71 mg of Isomer D was obtained as a solid from a fraction containing Isomer D (tR = 11 min).
  • Isomer C: (+)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
    [α]D 21: +7.1° (c = 1.0, EtOH) .
    1H-NMR (400 MHz, CDCl3) δ: 7.91 (s, 1H), 7.87-7.79 (m, 5H), 7.67-7.58 (m, 2H), 7.51 (s, 1H), 7.35 (d, 1H, J = 7.0 Hz), 3.78-3.65 (m, 4H), 3.05 (s, 3H), 2.07 (s, 3H).
    HR-MS (ESI) calcd for C22H22F3N2O4S [M+H]+, required m/z: 467.1252, found: 467.1260.
    Retention time: 4.0 min.
  • Isomer D: (-)-1-(2-hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl)phenyl]-5-[2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide
    [α]D 21: -7.2° (c = 1.1, EtOH) .
    1H-NMR (400 MHz, CDCl3) δ: 7.88-7.79 (m, 6H), 7.67-7.58 (m, 2H), 7.50 (s, 1H), 7.36 (d, 1H, J = 7.5 Hz), 3.79-3.65 (m, 4H), 3.05 (s, 3H), 2.08 (s, 3H).
    HR-MS (ESI) calcd for C22H22F3N2O4S [M+H]+, required m/z: 467.1252, found: 467.1257.
    Retention time: 4.5 min.

……………………………………………….

WO 2014168103

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014168103

 Step B: pyrrole derivative compounds (A ‘)
[Of 16]
(Example 1) 2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1-one
[Of 19]
 1- [2- (trifluoromethyl) phenyl] propan-1-one 75 g (370 mmol) in t- butyl methyl ether (750 mL), and I was added bromine 1.18 g (7.4 mmol). After confirming that the stirred bromine color about 30 minutes at 15 ~ 30 ℃ disappears, cooled to 0 ~ 5 ℃, was stirred with bromine 59.13 g (370 mmol) while keeping the 0 ~ 10 ℃. After stirring for about 2.5 hours, was added while maintaining 10 w / v% aqueous potassium carbonate solution (300 mL) to 0 ~ 25 ℃, was further added sodium sulfite (7.5 g), was heated to 20 ~ 30 ℃. The solution was separated, washed in the resulting organic layer was added water (225 mL), to give t- butyl methyl ether solution of the title compound and the organic layer was concentrated under reduced pressure (225 mL).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.91 (3H, D, J = 4.0 Hz), 4.97 (1H, Q, J = 6.7 Hz), 7.60 ~ 7.74 (4H, M).
(Example 2) 2-cyano-3-methyl-4-oxo-4- [2- (trifluoromethyl) phenyl] butanoate
[Of 20]
 2-bromo-1- [2- (trifluoromethyl) phenyl] propan-1 / t- butyl methyl ether solution (220 mL) in dimethylacetamide (367 mL), ethyl cyanoacetate obtained in Example 1 53.39 g (472 mmol), potassium carbonate 60.26 g (436 mmol) were sequentially added, and the mixture was stirred and heated to 45 ~ 55 ℃. After stirring for about 2 hours, 20 is cooled to ~ 30 ℃, water (734 mL) and then extracted by addition of toluene (367 mL), washed by adding water (513 mL) was carried out in the organic layer (2 times implementation). The resulting organic layer was concentrated under reduced pressure to obtain a toluene solution of the title compound (220 mL).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.33 ~ 1.38 (6H, M), 3.80 ~ 3.93 (2H, M), 4.28 ~ 4.33 (2H, M), 7.58 ~ 7.79 (4H, M).
(Example 3) 2-chloro-4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl
[Of 21]
 The 20 ~ 30 ℃ 2-cyano-3-methyl-4-oxo-4 was obtained [2- (trifluoromethyl) phenyl] butanoate in toluene (217 mL) by the method of Example 2 ethyl acetate (362 mL) Te, after the addition of thionyl chloride 42.59 g (358 mmol), cooled to -10 ~ 5 ℃, was blown hydrochloric acid gas 52.21 g (1432 mmol), further concentrated sulfuric acid 17.83 g (179 mmol) was added, and the mixture was stirred with hot 15 ~ 30 ℃. After stirring for about 20 hours, added ethyl acetate (1086 mL), warmed to 30 ~ 40 ℃, after the addition of water (362 mL), and the layers were separated. after it separated organic layer water (362 mL) was added for liquid separation, and further 5w / v% was added for liquid separation aqueous sodium hydrogen carbonate solution (362 mL).
 Subsequently the organic layer was concentrated under reduced pressure, the mixture was concentrated under reduced pressure further added toluene (579 mL), was added toluene (72 mL), and cooled to 0 ~ 5 ℃. After stirring for about 2 hours, the precipitated crystals were filtered, and washed the crystals with toluene which was cooled to 0 ~ 5 ℃ (217 mL). The resulting wet goods crystals were dried under reduced pressure at 40 ℃, the title compound was obtained (97.55 g, 82.1% yield).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.38 (3H, t, J = 7.1 Hz), 2.11 (3H, s), 4.32 (2H, Q, J = 7.1 Hz), 7.39 (1H, D, J = 7.3 Hz), 7.50 ~ 7.62 (2H, m), 7.77 (1H, d, J = 8.0 Hz), 8.31 (1H, br).
(Example 4) 4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl
[Of 22]
 Example obtained by the production method of the three 2-chloro-4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylate 97.32 g (293 mmol) in ethanol (662 mL), tetrahydrofuran (117 mL), water (49 mL), sodium formate 25.91 g (381 mmol) and 5% palladium – carbon catalyst (water content 52.1%, 10.16 g) was added at room temperature, heated to 55 ~ 65 ℃ the mixture was stirred. After stirring for about 1 hour, cooled to 40 ℃ less, tetrahydrofuran (97 mL) and filter aid (KC- flock, Nippon Paper Industries) 4.87 g was added, the catalyst was filtered and the residue using ethanol (389 mL) was washed. The combined ethanol solution was used for washing the filtrate after concentration under reduced pressure, and with the addition of water (778 mL) was stirred for 0.5 hours at 20 ~ 30 ℃. The precipitated crystals were filtered, and washed the crystals with ethanol / water = 7/8 solution was mixed with (292 mL). The resulting wet goods crystals were dried under reduced pressure at 40 ℃, the title compound was obtained (86.23 g, 98.9% yield).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.35 (3H, t, J = 7.1 Hz), 2.18 (3H, s), 4.29 (2H, M), 7.40 ~ 7.61 (4H, M), 7.77 (1H, d, J = 7.9 Hz), 8.39 (1H, br).
(Example 5) (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl
[Of 23]
 N to the fourth embodiment of the manufacturing method by the resulting 4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylate 65.15 g (219 mmol), N- dimethylacetamide ( 261 mL), ethylene carbonate 28.95 g (328.7 mmol), 4- dimethylaminopyridine 2.68 g (21.9 mmol) were sequentially added at room temperature, and heated to 105 ~ 120 ℃, and the mixture was stirred. After stirring for about 10 hours, toluene was cooled to 20 ~ 30 ℃ (1303 mL), and the organic layer was extracted by adding water (326 mL). Subsequently, was washed by adding water (326 mL) to the organic layer (three times). The resulting organic layer was concentrated under reduced pressure, ethanol (652 mL) was added, and was further concentrated under reduced pressure, ethanol (130 mL) was added to obtain an ethanol solution of the title compound (326 mL).
 1 H NMR (400 MHz, CDCl 3 ) delta: 1.35 (3H, t, J = 7.1 Hz), 1.84 (1H, Broad singlet), 2.00 (3H, s), 3.63 ~ 3.77 (4H, M), 4.27 (2H , m), 7.35 ~ 7.79 (5H, m).
(Example 6) (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid
[Of 24]
 Obtained by the method of Example 5 (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid ethyl / ethanol (321 mL) solution in water (128.6 mL), was added at room temperature sodium hydroxide 21.4 g (519 mmol), and stirred with heating to 65 ~ 78 ℃. After stirring for about 6 hours, cooled to 20 ~ 30 ℃, after the addition of water (193 mL), and was adjusted to pH 5.5 ~ 6.5, while maintaining the 20 ~ 30 ℃ using 6 N hydrochloric acid. was added as seed crystals to the pH adjustment by a liquid (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid 6.4 mg , even I was added to water (193mL). Then cooled to 0 ~ 5 ℃, again, adjusted to pH 3 ~ 4 with concentrated hydrochloric acid and stirred for about 1 hour. Then, filtered crystals are precipitated, and washed the crystals with 20% ethanol water is cooled to 0 ~ 5 ℃ (93 mL). The resulting wet product crystals were dried under reduced pressure at 40 ℃, to give the title compound (64.32 g, 95.0% yield). 1 H NMR (400 MHz, DMSO-D 6 ) delta: 1.87 (3H, s), 3.38 ~ 3.68 (4H, M), 7.43 ~ 7.89 (5H, M).
(Example 7)
(S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid quinine salt
(7-1) (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid quinine salt
obtained by the method of Example 6 the (RS) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid 50.00 g (160 mmol), N, N- dimethylacetamide (25 mL), ethyl acetate (85 mL) was added and dissolved at room temperature (solution 1).

 Quinine 31.05 g (96 mmol) in N, N- dimethylacetamide (25 mL), ethyl acetate (350 mL), was heated in water (15 mL) 65 ~ 70 ℃ was added, was added dropwise a solution 1. After about 1 hour stirring the mixture at 65 ~ 70 ℃, and slowly cooled to 0 ~ 5 ℃ (cooling rate standard: about 0.3 ℃ / min), and stirred at that temperature for about 0.5 hours. The crystals were filtered, 5 ℃ using ethyl acetate (100 mL) which was cooled to below are washed crystals, the resulting wet product crystals was obtained and dried under reduced pressure to give the title compound 43.66 g at 40 ℃ (Yield 42.9%). Furthermore, the diastereomeric excess of the obtained salt was 98.3% de. 1 H NMR (400 MHz, DMSO-D 6 ) delta: 1.30 ~ 2.20 (10H, M), 2.41 ~ 2.49 (2H, M), 2.85 ~ 3.49 (6H, M), 3.65 ~ 3.66 (1H, M), 3.88 (3H, s), 4.82 (1H, broad singlet), 4.92 ~ 5.00 (2H, m), 5.23 ~ 5.25 (1H, m), 5.60 (1H, br), 5.80 ~ 6.00 (1H, m), 7.36 ~ 7.92 (9H, M), 8.67 (1H, D, J = 4.6 Hz) (7-2) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3 diastereomeric excess of the carboxylic acid quinine salt HPLC measurements (% de)  that the title compound of about 10 mg was collected, and the 10 mL was diluted with 50v / v% aqueous acetonitrile me was used as a sample solution.

 Column: DAICEL CHIRALPAK IC-3 (4.6 mmI.D. × 250 mm, 3 μm)
mobile phase A: 0.02mol / L phosphorus vinegar buffer solution (pH 3)
mobile phase B: acetonitrile
solution sending of mobile phase: mobile phase A and I indicates the mixing ratio of mobile phase B in Table 1 below.
[Table 1]
  Detection: UV 237 nm
flow rate: about 0.8 mL / min
column temperature: 30 ℃ constant temperature in the vicinity of
measuring time: about 20 min
Injection volume: 5 μL
diastereomeric excess (% de), the title compound (retention time about 12 min), was calculated by the following equation using a peak area ratio of R-isomer (retention time of about 13 min).
% De = {[(the title compound (S body) peak area ratio) – (R body peak area ratio)] ÷ [(the title compound (S body) peak area ratio) + (R body peak area ratio)]} × 100
(Example 8)
(S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A))
(8-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3 – carboxylic acid
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 40.00 g (63 mmol) in ethyl acetate (400 mL), was added 2N aqueous hydrochloric acid (100 mL) was stirred at room temperature and separated . The resulting organic layer was concentrated under reduced pressure (120 mL), and added ethyl acetate (200 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (120 mL).
(8-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl
ethyl acetate (240 mL), was mixed tetrahydrofuran (80 mL) and oxalyl chloride 20.72 g (163 mmol), and cooled to 10 ~ 15 ℃ was. Then the resulting solution was added while keeping the 10 ~ 15 ℃ Example (8-1) and stirred for about 1 hour by heating to 15 ~ 20 ℃. After stirring, acetonitrile (120 mL) and pyridine 2.46 g (31 mmol) was added and the reaction mixture was concentrated under reduced pressure (120 mL), acetonitrile (200 mL) was added and further concentrated under reduced pressure (120 mL).
 After completion concentration under reduced pressure, acetonitrile (200 mL) was added and cooled to 10 ~ 15 ℃ (reaction 1).
 Acetonitrile (240mL), pyridine 12.39 g (157 mmol), 4- were successively added (methylsulfonyl) aniline 26.85 g (157 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.
 The resulting reaction solution in acetonitrile (40 mL), 2 N hydrochloric acid water (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. Again, 2N aqueous hydrochloric acid to the organic layer (120 mL), was added sodium chloride (10.0 g) was stirred, and the layers were separated. After filtering the resulting organic layer was concentrated under reduced pressure (400 mL). Water (360 mL) was added to the concentrated liquid, after about 1 hour stirring, the crystals were filtered, washed with 50v / v% aqueous acetonitrile (120 mL), wet product of the title compound (undried product, 62.02 g) and obtained. 1 H NMR (500 MHz, DMSO-D 6 ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H)
(8-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A))  ( the resulting wet product crystals 8-2), t- butyl methyl ether (200 mL), acetonitrile (40 mL), 48w / w potassium hydroxide aqueous solution (16 g) and water (200 mL) was added, I was stirred for about 2 hours at 25 ~ 35 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (120 mL), ethanol (240 mL) was added and further concentrated under reduced pressure (120 mL). After completion concentration under reduced pressure, ethanol (36 mL), and heated in water (12 mL) was added 35 ~ 45 ℃, while maintaining the 35 ~ 45 ℃ was added dropwise water (280 mL), and was crystallized crystals. After cooling the crystal exudates to room temperature, I was filtered crystal. Then washed with crystals 30v / v% aqueous ethanol solution (80 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystalline (26.26 g, 89.7% yield). Moreover, the enantiomers of the resulting crystals was 0.3%.
1 H NMR (400 MHz, CDCl 3 ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, M), 7.77 ~ 7.90 (6H, M).
(8-4) (S)-1-(2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole -3- HPLC method for measuring the amount enantiomer carboxamide (%)  and collected the title compound of about 10 mg is, what was the 10 mL was diluted with 50v / v% aqueous acetonitrile to obtain a sample solution.
see
(Example 12) (S) -1- (2- hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxamide (Compound (A)) Preparation of 2
(12-1) (S)-1-(2-hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H – pyrrole-3-carboxylic acid
obtained by the method of Example 7 (S) -1- (2- hydroxyethyl) -4-methyl-5- [2- (trifluoromethyl) phenyl] -1H- pyrrole 3-carboxylic acid (8α, 9R) -6′- methoxycinnamate Conan-9-ol 10.00 g (16 mmol) in t- butyl methyl ether (90 mL), water (10 mL) 36w / w% aqueous hydrochloric acid ( 5 mL) was added and stirring at room temperature and separated. The resulting organic layer was concentrated under reduced pressure (30 mL), was added ethyl acetate (50 mL), and further concentrated under reduced pressure to obtain a solution containing the title compound (30 mL).
(12-2) N – {[4- (methylsulfonyl) phenyl] amino} oxamic acid 2 – ((S) -3- methyl-4 – {[4- (methylsulfonyl) phenyl] carbamoyl} -2- [ 2- (trifluoromethyl) phenyl] -1H- pyrrol-1-yl) ethyl
ethyl acetate (50 mL), was mixed with tetrahydrofuran (20 mL) and oxalyl chloride 5.18 g (41 mmol), and cooled to 0 ~ 5 ℃ was.Then the resulting solution was added in Examples while maintaining the 0 ~ 5 ℃ (12-1), and the mixture was stirred for 6 hours at 0 ~ 10 ℃. After stirring, acetonitrile (30 mL) and pyridine 0.62 g (8 mmol) was added and the reaction mixture was concentrated under reduced pressure (30 mL), acetonitrile (50 mL) was added, and further concentrated under reduced pressure (30 mL).
 After concentration under reduced pressure end, is added acetonitrile (10 mL) and oxalyl chloride 0.10 g (1 mmol), and cooled to 0 ~ 5 ℃ (reaction 1).
 Acetonitrile (30mL), pyridine 3.15 g (40 mmol), 4- were successively added (methylsulfonyl) aniline 6.71 g (39 mmol), the reaction solution 1 was added while maintaining the 10 ~ 15 ℃, the 20 ~ 25 ℃ and the mixture was stirred and heated to about 1 hour.
 Insolubles from the resulting reaction solution was filtered, washed with acetonitrile (10 mL), and stirred for about 2 hours the addition of water (15 mL), followed by dropwise addition of water (75 mL) over about 1 hour . After about 1 hour stirring the suspension was filtered crystals were washed with 50v / v% aqueous acetonitrile (20 mL), wet product of the title compound (undried product, 15.78 g) to give a. 1 H NMR (500 MHz, DMSO-D 6 ) delta: 1.94 (s, 3H), 3.19 (s, 3H), 3.20 (s, 3H), 3.81 (t, 1H), 4.12 (t, 1H), 4.45 ( t, 2H, J = 5.81 Hz), 7.62 (t, 1H, J = 4.39 Hz), 7.74 (t, 2H, J = 3.68 Hz), 7.86 (dd, 3H), 7.92 (dd, 3H, J = 6.94 , 2.13 Hz), 7.97 (DD, 2H, J = 6.80, 1.98 Hz), 8.02 (DD, 2H), 10.03 (s, 1H), 11.19 (s, 1H)
(12-3) (S)-1- (2-hydroxyethyl) -4-methyl -N- [4- (methylsulfonyl) phenyl] -5- [2- (trifluoromethyl) phenyl] -1H- pyrrole-3-carboxamide (Compound (A))  ( the resulting wet product crystals 12-2), t- butyl methyl ether (50 mL), acetonitrile (10 mL), 48w / w potassium hydroxide aqueous solution (4 g) and water (50 mL) was added, 15 I was about 2 hours of stirring at ~ 25 ℃. After stirring, and the mixture is separated, the resulting organic layer was concentrated under reduced pressure (30 mL), was added ethanol (60 mL), was further concentrated under reduced pressure (30 mL). After completion concentration under reduced pressure, ethanol (14 mL), after addition of water (20 mL), was added a seed crystal, and was crystallized crystals. After dropwise over about 1 hour water (50 mL), and about 1 hour stirring, and crystals were filtered off. Then washed with crystals 30v / v% aqueous ethanol solution (10 mL), where it was dried under reduced pressure at 40 ℃, the title compound was obtained in crystal (6.36 g, 87.0% yield). Moreover, the enantiomers of the resulting crystals was 0.05%. Enantiomers amount, I was measured by the method of (Example 8-4). 1 H NMR (400 MHz, CDCl 3 ) delta: 1.74 (1H, Broad singlet), 2.08 (3H, s), 3.04 (3H, s), 3.63 ~ 3.80 (4H, M), 7.36 (1H, D, J = 7.2 Hz), 7.48 (1H, s), 7.58 ~ 7.67 (2H, m), 7.77 ~ 7.90 (6H, m).

Patent literature

Patent Document 1: International Publication WO2006 / 012642 (US Publication US2008-0234270)
Patent Document 2: International Publication WO2008 / 056907 (US Publication US2010-0093826)
Patent Document 3: Pat. No. 2,082,519 JP (US Patent No. 5,616,599 JP)
Patent Document 4: Pat. No. 1,401,088 JP (US Pat. No. 4,572,909)
Patent Document 5: US Pat. No. 3,025,292

Angiotensin II receptor 桔抗 agent

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015012205&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=FullText

Angiotensin II receptor 桔抗 agent used as the component (A), olmesartan medoxomil, olmesartan cilexetil, losartan, candesartan cilexetil, valsartan, biphenyl tetrazole compounds such as irbesartan, biphenyl carboxylic acid compounds such as telmisartan, eprosartan, agile Sultan, and the like, preferably, a biphenyl tetrazole compound, more preferably, olmesartan medoxomil, is losartan, candesartan cilexetil, valsartan or irbesartan, particularly preferred are olmesartan medoxomil, losartan or candesartan cilexetil, Most preferably, it is olmesartan medoxomil.
 Olmesartan medoxomil, JP-A-5-78328, US Patent No. 5,616,599
is described in Japanese or the like, its chemical name is (5-methyl-2-oxo-1,3-dioxolen-4-yl ) methyl 4- (1-hydroxy-1-methylethyl) -2-propyl-1 – in [2 ‘(1H- tetrazol-5-yl) biphenyl-4-ylmethyl] imidazole-5-carboxylate, Yes, olmesartan medoxomil of the present application includes its pharmacologically acceptable salt.
Olmesartan.pngOLMESARTAN
 Losartan (DUP-753) is, JP 63-23868, is described in US Patent No. 5,138,069 JP like, and its chemical name is 2-butyl-4-chloro-1- [2 ‘ – The (1H- tetrazol-5-yl) biphenyl-4-ylmethyl] -1H- is imidazol-5-methanol, application of losartan includes its pharmacologically acceptable salt (losartan potassium salt, etc.).
Skeletal formula
 LOSARTAN
 Candesartan cilexetil, JP-A-4-364171, EP-459136 JP, is described in US Patent No. 5,354,766 JP like, and its chemical name is 1- (cyclohexyloxycarbonyloxy) ethyl-2 ethoxy-1- [2 ‘one (1H- tetrazol-5-yl) -4-Bife~eniru ylmethyl] -1H- benzimidazole-7-carboxylate is a salt application of candesartan cilexetil, which is a pharmacologically acceptable encompasses.
 Valsartan (CGP-48933), the JP-A-4-159718, are described in EP-433983 JP-like, and its chemical name, (S) -N- valeryl -N- [2 ‘- (1H- tetrazol – It is a 5-yl) biphenyl-4-ylmethyl) valine, valsartan of the present application includes its pharmacologically acceptable ester or a pharmacologically acceptable salt thereof.
 Irbesartan (SR-47436), the Japanese Patent Publication No. Hei 4-506222, is described in JP WO91-14679 publication, etc., its chemical name, 2-N–butyl-4-spiro cyclopentane-1- [2′ The (tetrazol-5-yl) biphenyl-4-ylmethyl] -2-imidazoline-5-one, irbesartan of the present application includes its pharmacologically acceptable salts.
 Eprosartan (SKB-108566) is described in US Patent No. 5,185,351 JP etc., the chemical name, 3- [1- (4-carboxyphenyl-methyl) -2-n- butyl – imidazol-5-yl] The 2-thienyl – methyl-2-propenoic acid, present in eprosartan, the carboxylic acid derivatives, pharmacologically acceptable ester or a pharmacologically acceptable salt of a carboxylic acid derivative (eprosartan mesylate, encompasses etc.).
 Telmisartan (BIBR-277) is described in US Patent No. 5,591,762 JP like, and its chemical name is 4 ‘- [[4 Mechiru 6- (1-methyl-2-benzimidazolyl) -2 – is a propyl-1-benzimidazolyl] methyl] -2-biphenylcarboxylic acid, telmisartan of the present application includes its carboxylic acid derivative, a pharmacologically acceptable ester or a pharmacologically acceptable salt thereof of carboxylic acid derivatives .
 Agile Sultan, is described in Patent Publication No. 05-271228 flat JP, US Patent No. 5,243,054 JP like, and its chemical name is 2-ethoxy-1 {[2 ‘- (5-oxo-4,5-dihydro 1,2,4-oxadiazole-3-yl) biphenyl-4-yl] methyl} -1H- benzo [d] imidazole-7-carboxylic acid (2-Ethoxy-1 {[2 ‘- (5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] is a methyl} -1H-benzo [d] imidazole-7-carboxylic acid).

References

  1. Jump up to:a b c http://adisinsight.springer.com/drugs/800021527
  2. Jump up to:a b Yang J, Young MJ (2016). “Mineralocorticoid receptor antagonists-pharmacodynamics and pharmacokinetic differences”. Curr Opin Pharmacol27: 78–85. doi:10.1016/j.coph.2016.02.005PMID 26939027.
  3. Jump up to:a b Kolkhof P, Nowack C, Eitner F (2015). “Nonsteroidal antagonists of the mineralocorticoid receptor”. Curr. Opin. Nephrol. Hypertens24 (5): 417–24. doi:10.1097/MNH.0000000000000147PMID 26083526.

External links

Esaxerenone
Esaxerenone.svg
Clinical data
Routes of
administration
Oral
Drug class Antimineralocorticoid
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C22H21F3N2O4S
Molar mass 466.475 g/mol
3D model (JSmol)

///////////JAPAN 2019, Esaxerenone, Minebro, エサキセレノン ,Phase III, Diabetic nephropathies, HYPERTENSION. PHASE 3, N62TGJ04A1, UNII:N62TGJ04A1, эсаксеренон إيساكسيرينون 艾沙利  酮 CS-3150XL-550, CS 3150, XL 550

Relugolix レルゴリクス


Relugolix structure.png

ChemSpider 2D Image | Relugolix | C29H27F2N7O5S

737789-87-6.png

Relugolix (TAK-385), RVT 601

レルゴリクス

Formula
C29H27F2N7O5S
CAS
737789-87-6
Mol weight

UNII

623.6304
UNII-P76B05O5V6

2019/1/8  PMDA JAPAN APPROVED, Relumina

1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea
Urea, N-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-1,2,3,4-tetrahydro-3-(6-methoxy-3-pyridazinyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-N’-methoxy- 
737789-87-6 [RN]
9628
P76B05O5V6
Image result for Relugolix
  • Originator Takeda
  • Developer Myovant Sciences; Takeda; Takeda Oncology
  • Class Analgesics; Antineoplastics; Ketones; Pyrimidines; Small molecules
  • Mechanism of Action LHRH receptor antagonists
  • Preregistration Uterine leiomyoma
  • Phase III Pain; Prostate cancer
  • No development reported Solid tumours
  • 08 Nov 2018 Myovant announces intention to submit NDA for Uterine leiomyoma in Q3 of 2019
  • 08 Nov 2018 Myovant Sciences completes enrollment in the phase III LIBERTY 1 trial for Uterine leiomyoma (Combination therapy) in USA (PO)(NCT03049735)
  • 25 Oct 2018 Myovant Sciences completes enrolment in its phase III HERO trial for Prostate cancer (Late-stage disease) in Denmark, Australia, Austria, Belgium, Canada, United Kingdom, USA, Japan, Taiwan, Sweden, Spain, Slovakia, New Zealand, Netherlands, South Korea, Germany, France and Finland (PO) (NCT03085095)

Image result for Relugolix

Relugolix has been used in trials studying the treatment of Endometriosis, Prostate Cancer, Uterine Fibroids, and Androgen Deprivation Treatment-naïve Nonmetastatic Prostate Cancer.

Relugolix (developmental code names RVT-601TAK-385) is a gonadotropin-releasing hormone antagonist (GnRH antagonist) medication which is under development by Myovant Sciences and Takeda for the treatment of endometriosisuterine fibroids, and prostate cancer.[1][2][3][4][5][6][7] Unlike most other GnRH modulators, but similarly to elagolix, relugolix is a non-peptide and small-molecule compound and is orally active.[6][7] As of July 2018, it is in the pre-registration phase of development for uterine fibroids and is in phase III clinical trials for endometriosis and prostate cancer.[1]

Pharmacology

Pharmacodynamics

Relugolix is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR) (IC50 = 0.12 nM).[6][7][8]

A single oral administration of relugolix at a dose of 3 mg/kg has been found to suppress luteinizing hormone (LH) levels for more than 24 hours in castrated cynomolgus monkeys, indicating a long duration of action.[6] The drug (80–160 mg/day) has been found to reduce testosterone levels to sustained castrate levels in men with once-daily administration.[8] Lower dosages (10–40 mg/day) are being studied in the treatment of endometriosis and uterine fibroids to achieve partial sex hormone suppression.[4] The reasoning behind partial suppression for these conditions is to reduce the incidence and severity of menopausal symptoms such as hot flushes and to avoid bone mineral density changes caused by estrogen deficiency that can eventually lead to osteoporosis.[4][9]

History

Relugolix was first described in 2004.[10][6] It superseded sufugolix, which was developed by the same group.[6]

Society and culture

Generic names

Relugolix is the generic name of the drug and its INN and USAN.[11] It is also known by its developmental code names RVT-601 and TAK-385.[1][11]

SYN

Journal of Medicinal Chemistry, 54(14), 4998-5012; 2011

PATENT

http://www.google.co.in/patents/EP1591446A1?cl=en

(Production Method 1)

  • Figure 00120001
    (Production method 2)

  • Figure 00130001
      • Example 83

http://www.google.co.in/patents/EP1591446A1?cl=en

    Production of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N’-methoxyurea
  • Figure 01690002
  • The similar reaction as described in Example 4 by using the compound (100 mg, 0.164 mmol) obtained in Reference Example 54 and methyl iodide (0.010 ml, 0.164 mmol) gave the title compound (17.3 mg, 17 %) as colorless crystals.
    1 H-NMR(CDCl3) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s).

PAPER

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2011, 54(14): 4998. http://pubs.acs.org/doi/full/10.1021/jm200216q

1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b)

Compound 16b was prepared in 44% yield from 15j by a procedure similar to that described for16a as colorless crystals, mp 228 °C (dec). 1H NMR (CDCl3): δ 2.15 (6H, s), 3.60–3.80 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.20–7.65 (7H, m), 7.69 (1H, s). LC–MS m/z: 624.0 [M + H+], 621.9 [M + H]. Anal. (C29H27F2N7O5S) C, H, N.

Abstract Imagetak 385

http://pubs.acs.org/doi/suppl/10.1021/jm200216q/suppl_file/jm200216q_si_001.pdf

PATENT

WO-2014051164

Method for the production of TAK-385 or its salt and crystals starting from 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl) thieno[2,3-d] pyrimidine-2,4 (1H,3H)-dione or its salt. Takeda Pharmaceutical is developing relugolix (TAK-385), an oral LHRH receptor antagonist analog of sufugolix, for the treatment of endometriosis and uterine fibroids. As of April 2014, the drug is in Phase 2 trails. See WO2010026993 claiming method for improving the oral absorption and stability of tetrahydro-thieno[2,3-d]pyrimidin-6-yl]-phenyl)-N’-methoxy urea derivatives.

PATENT

https://patents.google.com/patent/WO2015062391A1/en

Endometriosis is a common estrogen-dependent gynecological diseases, often occurs in women during their childbearing years, and its mechanism is unclear. Complex and difficult to diagnose the cause of the symptoms of endometriosis is unknown, serious block to the discovery of effective therapies. Currently, endometriosis primarily by laparoscopy diagnosis, and treatment by surgery, or pill, or progesterone receptor agonists of GnRH reduce estrogen levels to control.

Currently the high incidence of endometriosis, Datamonitor 2009 year data show that only two countries, India and China, the number of female patients suffering from endometriosis had more than 68 million (31,288,000 India, China 3753.5 million) passengers, while the national prevalence of the number seven major markets have more than 17 million. Datamonitor expects 2009 to 2018, endometriosis market from 2009 to $ 764 million (US $ 596 billion and the EU $ 117 million, Japan US $ 051 million) in 2018 increased to US $ 1.156 billion (US 8.44 billion dollars, 206 million US dollars the European Union, Japan $ 106 million), while the Chinese market will have more room for growth.

Gonadotropin-releasing hormone (Gonadoliberin; gonadotropin releasing hormone; GnRH), also known as luteinizing hormone releasing hormone (LHRH), is synthesized by neuroendocrine cells of the hypothalamus hormones decapeptide (pGlu-His-Trp-Ser-Tyr-Gly- Leu-Arg-Pro-Gly-NH2), a central regulator of reproductive endocrine system. Which conveys the circulatory system through hypothalamus-pituitary portal to the pituitary, bind to the cells of the anterior pituitary GnRH receptor, such as gonadotropin luteinizing hormone (Luteinizing Hormone, LH) and FSH (Follicle-Stimulating Hormone, FSH ) secretion and release, regulation of normal development and corpus luteum of the ovary, hypothalamic – pituitary – gonadal axis plays an important role. GnRH receptors capable of activating the G protein coupled calcium phosphatidylinositol second messenger system exert their regulatory role, and LH is adjusted to produce steroids, FSH regulating development of the male and female follicle spermatogenesis.

LH and FSH are released into the circulation, and combined with the ovaries or testes specific cell receptors, stimulating the production of steroids. The presence of sex steroids, diseases such as endometriosis, uterine fibroids, prostate cancer and exacerbations, to be given long-acting GnRH receptor agonists and antagonists for treatment control peptides.

Peptide GnRH receptor antagonists include linear peptides (US 5,171,835) GnRH-derived, cyclic hexapeptide derivatives (US 2002/0065309), a bicyclic peptide derivative (Journal of Medicinal Chemistry, 1993; 36: 3265-73), etc. ; and GnRH receptor peptide agonists include leuprolide (leuprorelin, pGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt). However, there are many problems including oral absorbability, dosage form, dose volume, drug stability, sustained action, and metabolic stability of the peptide-type compound to be resolved. But the main reason small molecule GnRH receptor antagonists of peptide-based therapy is superior to the existing method is that small molecule GnRH receptor antagonist may be orally administered directly, convenient. Studies have shown that small molecule antagonists of endometriosis, precocious puberty, prostate cancer and other hormone-dependent diseases having a significant effect.

GnRH receptor agonist mediated indirect mechanisms of tumor suppression by long-term effects on the hypothalamic – pituitary – gonadal axis, leading to pituitary gonadotropins (FSH, LH) is reduced, thereby reducing the secretion of sex hormones and indirectly inhibit growth of tumor cells. And a GnRH receptor antagonist directly to inhibit the release of the pituitary gonadotropins, thereby inhibiting tumor cell growth.

Given the limitations of peptide GnRH receptor antagonists, non-peptide GnRH receptor antagonists have been proposed and into the development, clinical trials and launch phase, such as Elagolix (NBI-56418, or also known as ABT-620) is a Abbott and Neurocrine Biosciences Inc company co-developed small molecule GnRH receptor antagonist, is currently in phase III clinical stage, mainly used in the treatment of endometriosis (III phase) and uterine fibroids (II period). June 2012, data released results of a Phase II clinical endometrial endometriosis Houston, the 94th annual meeting of the Endocrine Society: 131 accepts elagolix (150 or 250mg qd), leuprorelin depot (3.75mg sc in, once a month, female patients with endometriosis endometrium 12 weeks) or placebo treatment, elagolix treatment groups in patients with serum hormone estrogen compared to leuprorelin therapy group and the placebo group was significantly reduced. At the same time, elagolix safety and tolerability have been well verified.

Relugolix also known as TAK-385, is a GnRH by the Japanese Takada Pharmaceutical company developed an oral small molecule receptor antagonist, for the treatment of endometriosis, uterine fibroids and prostate. 2011 entered endometriosis and uterine fibroids clinical phase II study, carried out a clinical study of prostate cancer in the same year.

It disclosed a series of current small molecule GnRH receptor antagonists including patent WO2006096785, WO2010026993, WO2011076687, WO2012175514 like.

Despite the large number of interesting studies have been conducted in this field, there remains a need to continue research and development of more effective small molecule GnRH receptor antagonists, the present invention provides a novel GnRH receptor antagonist structure, and found to have such a structure compounds having good activity, reproductive endocrine system effective to treat the disease.

PATENT

US 20120071486,  https://patentscope.wipo.int/search/en/detail.jsf?docId=US73518712&redirectedID=true

Example 83

Production of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea

      The similar reaction as described in Example 4 by using the compound (100 mg, 0.164 mmol) obtained in Reference Example 54 and methyl iodide (0.010 ml, 0.164 mmol) gave the title compound (17.3 mg, 17%) as colorless crystals.
       1H-NMR (CDCl 3) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J=8.2 Hz), 7.12 (1H, d, J=8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s).

References

Discovery of TAK-385, a thieno[2,3-d]pyrimidine-2,4-dione derivative, as a potent and orally bioavailable nonpeptide antagonist of gonadotropin releasing hormone (GnRH) receptor
238th ACS Natl Meet (August 16-20, Washington) 2009, Abst MEDI 386

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2011, 54(14): 4998. http://pubs.acs.org/doi/full/10.1021/jm200216q

References

  1. Jump up to:a b c http://adisinsight.springer.com/drugs/800028257
  2. ^ Goenka L, George M, Sen M (June 2017). “A peek into the drug development scenario of endometriosis – A systematic review”. Biomed. Pharmacother90: 575–585. doi:10.1016/j.biopha.2017.03.092PMID 28407578.
  3. ^ Dellis A, Papatsoris A (October 2017). “Therapeutic outcomes of the LHRH antagonists”. Expert Rev Pharmacoecon Outcomes Res17 (5): 481–488. doi:10.1080/14737167.2017.1375855PMID 28870102.
  4. Jump up to:a b c Streuli I, de Ziegler D, Borghese B, Santulli P, Batteux F, Chapron C (March 2012). “New treatment strategies and emerging drugs in endometriosis”. Expert Opin Emerg Drugsdoi:10.1517/14728214.2012.668885PMID 22439891.
  5. ^ Elancheran, R.; Maruthanila, V. L.; Ramanathan, M.; Kabilan, S.; Devi, R.; Kunnumakara, A.; Kotoky, Jibon (2015). “Recent discoveries and developments of androgen receptor based therapy for prostate cancer”. Med. Chem. Commun6 (5): 746–768. doi:10.1039/C4MD00416GISSN 2040-2503.
  6. Jump up to:a b c d e f Miwa K, Hitaka T, Imada T, Sasaki S, Yoshimatsu M, Kusaka M, Tanaka A, Nakata D, Furuya S, Endo S, Hamamura K, Kitazaki T (July 2011). “Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor”. J. Med. Chem54 (14): 4998–5012. doi:10.1021/jm200216qPMID 21657270.
  7. Jump up to:a b c Nakata D, Masaki T, Tanaka A, Yoshimatsu M, Akinaga Y, Asada M, Sasada R, Takeyama M, Miwa K, Watanabe T, Kusaka M (January 2014). “Suppression of the hypothalamic-pituitary-gonadal axis by TAK-385 (relugolix), a novel, investigational, orally active, small molecule gonadotropin-releasing hormone (GnRH) antagonist: studies in human GnRH receptor knock-in mice”. Eur. J. Pharmacol723: 167–74. doi:10.1016/j.ejphar.2013.12.001PMID 24333551.
  8. Jump up to:a b MacLean D, Shi H, Suri A, Faessel H, and Saad F (2013). “Safety and Testosterone-Lowering Effects of the Investigational, Oral, GnRH Antagonist, TAK-385 in Healthy Male Volunteers: Results of a Phase 1 Inpatient/Outpatient Study”doi:10.1210/endo-meetings.2013.CN.1.SAT-318.
  9. ^ Struthers RS, Nicholls AJ, Grundy J, Chen T, Jimenez R, Yen SS, Bozigian HP (February 2009). “Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix”J. Clin. Endocrinol. Metab94 (2): 545–51. doi:10.1210/jc.2008-1695PMC 2646513PMID 19033369.
  10. ^ https://patents.google.com/patent/US7300935/
  11. Jump up to:a b https://chem.nlm.nih.gov/chemidplus/rn/737789-87-6
Relugolix
Relugolix structure.png
Relugolix molecule ball.png
Clinical data
Synonyms RVT-601; TAK-385
Routes of
administration
By mouth
Drug class GnRH antagonist
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C29H27F2N7O5S
Molar mass 623.630 g/mol
3D model (JSmol)

External links

///////////Relugolix, TAK-385, JAPAN 2019, Relumina, レルゴリクス , PHASE 3

CONC(=O)NC1=CC=C(C=C1)C1=C(CN(C)C)C2=C(S1)N(CC1=C(F)C=CC=C1F)C(=O)N(C2=O)C1=CC=C(OC)N=N1

Metyrosine, Metirosine メチロシン метирозин , ميتيروسين , 甲酪氨酸 ,


Skeletal formula

ChemSpider 2D Image | Metirosine | C10H13NO3

Metyrosine, Metirosine

メチロシン  метирозин ميتيروسين 甲酪氨酸 

Metyrosine (USP);
Metirosine (JAN/INN);
Demser (TN)

CAS 672-87-7

  • Molecular FormulaC10H13NO3
  • Average mass195.215 Da

APPROVED P[MDA JAPAN 2019/1/8

  • (-)-alpha-Methyl-L-tyrosine
  • (–)-α-methyl-L-tyrosine
  • (S)-alpha-Methyltyrosine
  • Methyltyrosine

Synthesis ReferenceUS2868818

α-Methyl-p-tyrosine
метирозин [Russian] [INN]
ميتيروسين [Arabic] [INN]
甲酪氨酸 [Chinese] [INN]
(-)-(S)-2-Amino-3-(4-hydroxyphenyl)-2-methylpropionsaeure
(-)-α-Methyl-L-tyrosine
(2S)-2-amino-3-(4-hydroxyphenyl)-2-methylpropanoic acid
211-599-5 [EINECS]
3929
672-87-7 [RN]
a-Methyl-3-(p-hydroxyphenyl)alanine
a-methyl-L-tyrosine
a-Methyl-p-tyrosine
a-MPT
Demser [Trade name]
DOQ0J0TPF7
L 588357-0
L-2-Methyl-3-(4-hydroxyphenyl)alanine
L-a-MT
L-tyrosine, a-methyl-
OPTICAL RoT -0.24 °, hydrochloric acid; Wavlenght 589.3 nm;  25 °C
mp 319 °C (decomp) JP 45006008

An inhibitor of the enzyme tyrosine 3-monooxygenase, and consequently of the synthesis of catecholamines. It is used to control the symptoms of excessive sympathetic stimulation in patients with pheochromocytoma. (Martindale, The Extra Pharmacopoeia, 30th ed)

Metirosine (INN and BANα-MethyltyrosineMetyrosine USANAMPT) is an antihypertensive drug. It inhibits the enzyme tyrosine hydroxylase and, therefore, catecholamine synthesis, which, as a consequence, depletes the levels of the catecholamines dopamineadrenaline and noradrenaline in the body.

For use in the treatment of patients with pheochromocytoma, for preoperative preparation of patients for surgery, management of patients when surgery is contraindicated, and chronic treatment of patients with malignant pheochromocytoma.

Image result for metyrosine

Pharmacodynamics

In patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine, administration of one to four grams of metyrosine per day has reduced catecholamine biosynthesis from about 35 to 80 percent as measured by the total excretion of catecholamines and their metabolites (metanephrine and vanillylmandelic acid). The maximum biochemical effect usually occurs within two to three days, and the urinary concentration of catecholamines and their metabolites usually returns to pretreatment levels within three to four days after metyrosine is discontinued. Most patients with pheochromocytoma treated with metyrosine experience decreased frequency and severity of hypertensive attacks with their associated headache, nausea, sweating, and tachycardia. In patients who respond, blood pressure decreases progressively during the first two days of therapy with metyrosine; after withdrawal, blood pressure usually increases gradually to pretreatment values within two to three days.

Mechanism of action

Metyrosine inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step, blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines and their synthesis. This consequently, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in the body,usually measured as decreased urinary excretion of catecholamines and their metabolites. One main end result of the catecholamine depletion is a decrease in blood presure

Clinical use

Metirosine has been used in the treatment of pheochromocytoma.[1] It is contra-indicated for the treatment of essential hypertension.

However it is now rarely used in medicine, its primary use being in scientific research to investigate the effects of catecholamine depletion on behaviour.[2] Info on how catecholamine depletion from this medicine affects behavior needed in this srticle.

SYN

Image result for metyrosine SYNTHESIS

Image result for metyrosine

PAPER

Saito, Hiroyuki; Agricultural and Biological Chemistry 1988, 52(9), PG 2349-50 

PATENT

https://patents.google.com/patent/WO2011053835A1

Metyrosine, which has the structure of Formula:

Figure imgf000002_0001

is useful in reducing elevated levels of catecholamines associated with pheochromocytoma, and preventing hypertension. Metyrosine, as shown, is a chiral compound. The synthesis of metyrosine in pure or substantially pure enantiomeric form requires a process that involves using substantially diastereomerically and/or enantiomerically pure intermediates. The Applicant has discovered, surprisingly, certain compounds that are substantially

diastereomerically or enantiomerically pure and processes to prepare them, and which compounds may be converted to metyrosine.

Scheme 1

Figure imgf000020_0001
Figure imgf000021_0001

Lower diastereomeric purity Higher diastereomeric purity

Figure imgf000021_0002

Example 1. (R)-Phenylglycinamide«HCl

Figure imgf000034_0001

[0091] To a 500 mL flask were charged (i?)-phenylglycinamide (20.0 g, 133 mmol, 1 eq. Amplachem ref: Aa-33365) and MeOH (160 mL). 4 M HCl/dioxane (50 mL, 200 mmol, 1.5 eq.) was then added dropwise resulting in the formation of a white precipitate. The mixture was stirred for 30 min, was filtered and was washed with MeOH (20 mL) and diethyl ether (20 mL). Drying in vacuo provided (i?)-phenylglycinamide.HCl (21.9 g, 89%) as a white solid. Ή NMR (D20, 400 MHz) 4.97 (s, 1 H); 7.36-7.41 (m, 5 H).

[0092] Example 2. 2-[l-(S)-Cyano-2-(4-methoxyphenyl)-l-methylethylamino]-2-

(R)-phenylacetamide 2

Figure imgf000034_0002

[0093] Method A. To a 500 mL flask were charged (j )-phenylglycinamide’HCl

(15.0 g, 80.6 mmol, 1 eq.), MeOH (104 mL), H20 (17 mL) and -methoxyphenylacetone (12.4 mL, 80.6 mmol, 1 eq, Aldrich, ref: 19917-6). To this mixture was added a solution of NaCN (3.95 g, 80.6 mmol, 1 eq.) in H20 (10 mL). The resulting solution was stirred for 4 days at room temperature while a white precipitate formed. The precipitate was filtered and washed with H20/MeOH (7:3) to provide 2-[l-(5)-cyano-2-(4-methoxyphenyl)-l- methylethylamino]-2-(i?)-phenylacetamide 2 (11 ,0 g) as a white solid. The filtrate was stirred for 3 d more at room temperature and the solid formed was filtered to provide 2 (3.30 g). The filtrate was stirred for 1 d more to provide 2 (1.70 g). The filtered solids were combined and dried in vacuo to provide 2 (16.0 g, 61 %, dr 98/2) as a white solid.

[0094] Method B. In a sealed tube were charged (i?)-phenylglycinamide.HCl (1.2 g,

6.45 mmol, 1 eq.), MeOH (4 mL), H20 (7 mL) and 7-methoxyphenylacetone (991 μL, 6.45 mmol, 1 eq.). A solution of NaCN (316 mg, 6.45 mmol, 1 eq.) in H20 (1 mL) was added. The mixture was stirred for 20 hours at 40°C resulting in the formation of a white precipitate. The precipitate was filtered, was washed with H20/MeOH (7:3 v/v, 2 x 2 mL) and was dried in vacuo to provide 2 (1.59 g, 76%, dr 98/2) as a white solid. Ή NMR (CDC13, 400 MHz) 1.14 (s, 3 H); 2.90 (d, J= 13.6 Hz, 1 H); 2.99 (d, J= 13.6 Hz, 1 H); 3.20 (bs, 1 H); 3.80 (s, 3 H); 4.51 (s, 1 H); 5.45 (bs, 1 H); 5.75 (bs, 1 H); 6.90 (d, J= 8.6 Hz, 2 H); 7.27 (d, J= 8.6 Hz, 2 H); 7.30-7.50 (m, 5 H). dr determination: Ή NMR comparing integration of peaks of 2 at 2.90/2.99 (1.98 H, formally 2 H) with those of its diastereoisomer or diastereomer

(prepared from racemic phenylglycinamide) at 2.82/2.85 (0.04 H, formally 2 H). Ή NMR diastereoisomer of 2 (CDC13, 400 MHz) 1.49 (s, 3 H); 2.82 (d, J = 13.8 Hz, 1 H); 2.85 (d, J = 13.8 Hz, 1 H); 3.78 (s, 3 H); 4.52 (s, 1 H); 5.55 (bs, 1 H); 6.60 (bs, 1 H); 6.84 (d, J = 8.6 Hz, 2 H); 7.17 (d, J = 8.6 Hz, 2 H); 7.30-7.40 (m, 5 H).

[0095] Example 3. 2-[(R)-(Carbamoylphenylmethyl)-amino]-3-(4- methoxyphenyl)-2-(S)-methylpropionamide 3

Figure imgf000036_0001

[0096] To a 500 mL flask were added nitrile 2 (10.0 g, 30.95 mmol) and CH2C12(130 mL). The solution was cooled to -10°C and H2S04 (10 mL) was added dropwise over 15 min. The mixture was stirred for 2 h at 0°C. Ice (200 g) was added and the mixture was stirred for 1 h. The mixture was basified with 32% aq NH3 to pH 8-9, EtOAc (400 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 250 mL). The combined organic phases were dried over MgS04 and were concentrated to provide 3 (1 1.1 g (9.99 g theoretical, the sample contains 10% w/w of EtOAc by NMR) 94%, 92.9% chemical purity, 97% de by HPLC/MS) as a white solid. HPLC/MS tR – 3.04 min; m/z = 342.1 (M+l) de determination: HPLC/MS comparing integration of peaks at tR = 3.04 min (98.5 area%) and tR = 2.92 min (1.5 area% the other diastereoisomer of 3) HPLC/MS diastereoisomer of 3 tR = 2.92 min; m/z = 342.1 (M+l)

[0097] Example 4. Purification of 3 by Crystallization. Amide 3 (8.10 g, 23.7 mmol) and methyl isobutyl ketone (124 mL) were heated to reflux temperature until the solid was dissolved and the solution was cooled to room temperature. The solid formed was filtered, was washed with methyl isobutyl ketone (2 x 20 mL) and was dried in vacuo to provide 3 (5.45 g, 67%, >99.5% purity by HPLC/MS) as a white solid. 1H NMR (DMSO, 200 MHz) 1.00 (3H, s); 2.35 (bs, 1 H); 2.75 (d, J = 13.3 Hz, 1 H) 2.85 (d, J = 13.3 Hz, 1 H); 3.61 (s, 3 H); 4.17 (s, 1 H); 6.60 (d, J= 8.4 Hz, 2 H); 691 (d, J= 8.4 Hz, 2 H); 6.93 (bs, 1 H), 7.01 bs (1 H); 7.20-7.50 (m, 6 H); 7.6 (bs, 1 H). HPLC/MS m z = 342.1 (M+l ) Example 5. 2-(S)-Amino-3-(4-methoxyphenyl)-2-methyIpropionamide 4

Figure imgf000037_0001

[0099] Method A, Hydro genolysis: Amine 3 (6.00 g, 17.6 mmol, 1 eq) was dissolved in MeOH (60 mL) and 10% Pd/C (2.15 g, 56% moisture content, 16 wt%) was added. The mixture was stirred under H2 (3 bar) at 50°C for 16 h. The mixture was filtered through Celite, the filter pad was washed with MeOH (20 mL) and the filtrates were concentrated to provide 5.50 g of a 1 : 1 mixture of 4 (3.37 g, 91%) and phenylacetamide as a white solid.

[0100] Method B, Transfer hydrogenolysis: Amine 3 (500 mg, 1 ,47 mmol, 1 eq) was dissolved in i-PrOH (5 mL) under Argon. 10% Pd/C (200 mg, 56% moisture content, 18 wt%) and ammonium formate (601 mg, 9,56 mmol, 6.5 eq.) were added. The mixture was stirred at reflux temperature for 1 h. The mixture was filtered through Celite, the filter pad was washed with EtOH (10 mL) and the filtrates were concentrated to provide 480 mg of a 1 : 1 mixture of desired compound (293 mg, 96%) and phenylacetamide as a white solid. Ή NMR (DMSO, 400 MHz) 1.14 (s, 3 H); 2.10 (bs, 2 H); 2.50 (d, J= 13.1 Hz, 1 H); 2.95 (d, J = 13.1 Hz, 1 H); 3.69 (s, 3 H); 6.80 (d, J = 8.5 Hz, 2 H); 6.81 (bs, 1 H); 6.90 (bs, 1 H); 7.09 (d, J= 8.5 Hz, 2 H). (Phenylacetamide 3.34 (s, 2 H); 7.15-7.28 (m, 6 H); 7.42 (bs, 1 H).). HPLC/MS 4 tR = 1.96 min. MS (ESI (+)) m/z = 164.2 (M-CONH2). (Phenylacetamide tR = 1.76 min. MS (ESI (+)) m/z = 136.2 (M+l)).

[0101] Example 6. Metyrosine 1

Figure imgf000037_0002

[0102] To a 100 mL flask with a reflux condenser was charged amide 4 (5.50 g of a mixture containing 4 (3.37 g, 16.1 mmol) and phenylacetamide (2.13 g)) and 48% HBr (30 mL). The solution was heated for 5 h at 120 °C and was cooled to room temperature. H20 (60 mL) was added and the solution was washed with EtOAc (3 35 mL). The aqueous phase was concentrated in vacuo to provide a beige paste. The paste was dissolved in H20 (15 mL) and the resulting mixture was heated to 65 °C. Activated carbon (300 mg, Type NORIT SX) was added and the mixture was stirred for 15 min, was filtered and the filter pad was washed with water (2 4 mL). The combined filtrates were heated to 55 °C and the pH was adjusted to 5-6 using 32% aq. NH3. The mixture was cooled to 0 °C, was stirred for 15 min and was filtered. The collected solids were washed with cold water (2 x 5 mL) and were dried in vacuo to provide (-)-Q!-methyl-L-tyrosine (or metyrosine) 1 (2.65 g, 84%) as a white solid. HPLC (Zorbax C18, NaH2P04 10 mM pH = 3 / MeCN (100:0) 10 min, (100:0) to (0: 100) 15 min, 0: 100 5 min) tR = 10.1 min. Chiral HPLC (Nucleosil Chiral-1, CuS04 10 mM / MeCN 10:1) tR = 16.9 min. m.p. – 320-321°C. [a]5 6 = +201° (c – 0.5 Copper complex solution)(lit.2 + 185-190°) Copper complex solution preparation: Solution A

(anhydrous NaOAc dissolved in H20 (150 mL) in 250 mL volumetric flask, glacial acetic acid (50 mL) added and diluted to volume with H20) mixed with Solution B (cupric sulfate (62.5 g) diluted to volume with H20 in a 200 mL volumetric flask) in a 1 L volumetric flask and was diluted to volume with H20. Metyrosine solution (5 mg/mL) was prepared in this solution.

[0103] To obtain an NMR spectrum (taking into account the low solubility of the product), a small sample (10 mg) was transformed into its HC1 salt. The sample was dissolved in 2 M HC1 and the solution was evaporated to dryness. Ή NMR (D20, 400 MHz) 1.49 (s, 3 H); 2.90 (d, J= 14.5 Hz, 1 H); 3.16 (d, J = 14.5 Hz, 1 H); 6.75 (d, J= 8.2 Hz, 2 H), 7.01 ((d, J= 8.2 Hz, 2 H). 13C NMR (D20, 100.6MHz) 21.6; 41.6; 61.0; 116.0, 125.0; 131.7; 155.5; 173.8. [0104] Preparation of Metyrosine using (S)-phenylethylamine

Scheme 4

Figure imgf000039_0001

(S)~Phenylethy la mine. HCl

Figure imgf000039_0002
Figure imgf000039_0003

[0105] Example 7. (S)-Phenylethylamine hydrochloride.

Figure imgf000039_0004

[0106] To a 500 mL flask were added (5)-phenylethylamine (BASF, ref: UN2735,

40.0 g, 333 mmol, 1 eq.) and MeOH (160 mL). The solution was cooled to 0 °C and 37% HCl (40 mL, 480 mmol, 1.44 eq.) were added dropwise. Concentration of the reaction mixture gave a white solid. Diethyl ether (300 mL) was added and the suspension was stirred for 15 min. The solid was filtered and was washed with diethyl ether (2 x 60 mL) to provide (^-phenylethylamine hydrochloride (39.1 g, 75%) as a white solid. Ή NMR (D20, 400 MHz) 1.52 (d, J= 7.2 Hz, 3 H); 4.42 (q, J= 7.2 Hz, 1 H); 7.35-7.40 (m, 5 H).

Example 8. 3-(4-Methoxyphenyl)-2-methyl-2-(l-(S)-phenylethylamino)-

Figure imgf000040_0001

To a 500 mL flask were added (^-phenylethylamine.HCl (25.0 g, 159.2 mmol, 1 eq.), MeOH (125 mL), NaCN (7.80 g, 159.2 mmol, 1 eq.) and 4-methoxyphenylacetone (Aldrich, ref: 19917-6. 24.5 mL, 159.2 mmol, 1 eq.). The mixture was stirred for 14 h at room

temperature. The mixture was filtered, the filter cake was washed with MeOH (30 mL) and the filtrates were concentrated to an oil which was dissolved in CH2C12(370 mL) and washed with water (250 mL). The organic phase was dried (MgS04) and concentrated in vacuo to provide 3-(4-methoxyphenyl)-2-methyl-2-(l-(5 -phenylethylamino)-propionitrile (47.2 g, 100% as a 6/4 mixture of diastereoisomers (S,S)/(R,S)), containing 5% of 4- methoxyphenylacetone) as a yellow oil. Ή NMR (CDC13, 400 MHz) 1 ,05 (s, 0.62 x 3 H); 1.27 (d, J- 6.4 Hz, 0.6 x 3 H); 1.40-1.44 (m, 0.4 x 6 H); 2.47 (d, J= 13.6 Hz, 0.4 x 1 H); 2.74 (d, J= 13.6 Hz, 0.4 x 1 H); 2.84 (d, J= 14 Hz, 0.6 x 1 H) 2.94 (d, J= 14 Hz, 0.6 x 1 H); 3.78 (s, 0.4 x 3 H); 3.82 (s, 0.6 x 3 H); 4.02 (q, J= 6.4 Hz, 0.6 x 1 H); 4.16 (q, J= 6, 4 Hz, 0.4 x 1 H); 6.80-7.40 (m, 9H). [0108] Example 9. 3-(4-Methoxyphenyl)-2-methyl-2-(l-(S)-phenylethylam o)- propionamidc 6.

Figure imgf000041_0001

[0109] Method A. To a 1 L flask with mechanical stirring under argon was added 3-

(4-methoxyphenyl)-2-methyl-2-(l-(5)-phenylethylamino)-propionitrile 5 (40.0 g, 136.1 mmol) dissolved in CH2C12 (400 mL). The solution was cooled to -5 °C (using an ice salt bath) and cone. H2S04 (40 mL) was added dropwise maintaining the temperature between – 5°C and 5°C. The mixture was warmed to RT over 2 h and was stirred for 16 h. Ice (400 g) was added and the mixture was stirred for 40 min. The two phases were separated and the aqueous phase was neutralized to pH 8-9 with 32% aq. NH3. The aqueous phase was extracted with EtOAc (3 x 350 mL). The combined organic layers were dried (MgS04) and were concentrated in vacuo to provide 6 (14.2 g, 34%, 98% chemical purity by HPLC/MS) as a 6/4 mixture of diastereoisomers (S,S)/(R, S)) as a yellow oil.

[01 10] Method B. In a 250 mL flask was dissolved 3-(4-methoxyphenyl)-2-methyl-

2-(l-(«S -phenylethylamino)-propionitrile 5 (5.0 g, 17.0 mmol) in CH2C12 (50 mL). The solution was cooled to 0°C and cone. H2S04 (2.5 mL) was added dropwise. The mixture was stirred at 40 °C for 28 h, was cooled to RT and ice (50 g) was added. The mixture was stirred for 1 h and the phases separated. The aqueous phase was basified to pH 8-9 using 32% aq. NH3 and was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgS04) and concentrated in vacuo to provide 6 (3.32 g, 62%, 97% purity by HPLC/MS) as a 6/4 mixture of diastereoisomers (S,S)/(R,S)) as a yellow oil. Ή NMR (CDC13, 400 MHz) 1.13 (s, 0.4 x 3 H); 1.15 (s, 03 x 3 H) 1.24 (d, J= 6.6 Hz, 0.4 x 3 H); 1.30 (d, J = 6.6 Hz 0.6 x 3 H); 2.75 (d, J= 13.4 Hz, 0.6 x 1 H); 2.78 (d, J= 13.6 Hz, 0.4 x 1 H); 2.84 (d, J= 13.4 Hz, 0.6 x 1 H) 3.32 (d, J = 13.6 Hz, 0.4 x 1 H); 3.78 (s, 0.6 x 3 H); 3.80 (s, 0.4 x 3 H); 3.85 (q, J = 6.6 Hz, 0.6 x 1 H); 4.16 (q, J = 6.6 Hz, 0.4 x 1 H); 6.80-7.40 (m, 9 H). HPLC/MS tR = 4.21 min [(S,S)-6 MS (ESI (+)) m/z 313.2 (M+l )] and 4.34 min [(R,S)-6 MS (ESI (+)) m/z 313.2 (M+l)].

[01 1 1 ] Example 10. 3-(4-Methoxyphenyl)-2-(5)-methyl-2-(l-(S)- phenylethylamino)-propionamide hydrochloride.

Figure imgf000042_0001

[01 12] In a 500 mL flask was dissolved amide 6 (14.2 g, 45.5 mmol, 1 eq.) in z-PrOH

(140 mL). Cone. HCl (5.7 mL, 68.3 mmol, 1.5 eq.) was added dropwise and the mixture was stirred for 20 min. The solvent was evaporated in vacuo and methyl isobutyl ketone (200 mL) was added. The mixture was heated to reflux temperature, was cooled to room temperature and was stirred for 72 h. The solids were collected by filtration, washed with methyl isobutyl ketone (20 mL) and dried in vacuo to provide 6«HC1 (13.6 g, 86%, diasteremeric ratio (dr) 63/37( i.e., 63% diastereomeric purity of the S,S diastereomer)) as a white solid.

[01 13] Example 11. Purification (Enhancing Diastereomeric Purity) of 6.HC1 by

Crystallization. In a 250 mL flask were placed amide hydrochloride 6·ΗΟ (13.6 g, dr 37/63) and /-BuOH (136 mL). The mixture was heated to reflux temperature and z-BuOH (95 mL) was distilled. The mixture was cooled to room temperature and was stirred overnight. The solids were collected by filtration and were washed with z-BuOH to provide 6»HC1 (1 1.6 g, 85%, dr 73/27 as a white solid.

[01 14] This solid was dissolved in /-BuOH (139 mL) and was heated to reflux temperature. z-BuOH (70 mL) was distilled and the mixture was cooled to room temperature and was stirred for 3 h. Filtration provided 6»HC1 (7.5 g, 65%, dr 88/12) as a white solid. [01 15] This solid was dissolved in /-BuOH (130 mL) and was heated to reflux temperature. z-BuOH (65 mL) was distilled and the mixture was cooled to room temperature and was stirred for 3 h. Filtration provided 6·ΗΟ (6.0 g, 80%, dr 99/1) as a white solid.

[01 16] This solid was dissolved in z-BuOH (105 mL) and was heated to reflux temperature. z-BuOH (53 mL) was distilled and the mixture was cooled to room temperature and was stirred for 16 h. Filtration provided 6·ΗΟ (5.4 g, 90%, dr >99/l, 100% purity by HPLC/MS, 40% overall yield (67% theoretical yield)) as a white solid. Ή NMR (DMSO, 400 MHz) 1.06 (s, 3 H); 1.57 (d, J= 6.4 Hz, 3 H); 2.84 (d, J= 13.2 Hz, 1 H); 3.27 (d, J = 13.2 Hz, 1 H); 3. 69 (s, 3 H) 4.40 (bs, 1 H); 6.83 (d, J= 8.4 Hz, 2 H); 6.98 (d, J= 8.4 Hz, 2 H); 7.37-45 (m, 2 H); 7.50-7,65 (m, 2 H); 7.80 (bs, 1 H); 9.40 (bs, 2 H). HPLC/MS tR = 4.21 min [(S,S)- 6»HC1. MS (ESI (+)) m z 313.2 (M+l)].

Example 12. 2-(S)-Amino-3-(4-methoxyphenyl)-2-methyl-propionamide

Figure imgf000043_0001

[01 18] Amine 6-HC1 (5.40 g, 15.5 mmol, 1 eq) was dissolved in MeOH (60 mL) and

10%Pd/C (2.0 g, 56% moisture content, 16% w/w) was added. The mixture was stirred under H2 (3 bar) at 50 °C for 80 min. The mixture was filtered through celite and the filter pad was washed with MeOH (20 mL). The filtrates were concentrated in vacuo to provide 2-(S)- amino-3-(4-methoxyphenyl)-2-methyl-propionamide hydrochloride (3.80 g, 100%, 99.5% purity by HPLC/MS) as a yellow solid. Ή NMR (DMSO, 400 MHz) 1.46 (s, 3 H); 3.02 (d, J = 14 Hz, 1 H); 3.10 (d, J- 14 Hz, 1 H), 3.72 (s, 3 H); 6.87 (d, J= 8.8 Hz, 2 H); 7.15 (d, J = 8.8 Hz, 2 H); 7.64 (s, 1 H); 7.94 (s, 1 H); 8.08 (bs, 2 H). HPLC/MS tR = 1.95 min. MS (ESI (+)) m z = 164.2 (M – CONH2). [01 19] Example 13. Metyrosine 1

Figure imgf000044_0001

[0120] To a 100 mL flask with a reflux condenser were added 2-(iS -amino-3-(4- methox phenyl)-2-methyl-propionamide hydrochloride (3.80 g, 15.6 mmol) and 48% HBr (20 mL). The solution was heated for 4 h at 120 °C, was cooled to room temperature and was concentrated in vacuo to give a beige paste. The paste was dissolved in water (15 ml) and the solution was again concentrated under vacuum. The paste was dissolved in H20 (15 mL), the solution was heated to 65 °C and 300 mg of activated carbon were added. The mixture was stirred for 15 min, was filtered and the filter pad was washed with water (2 x 4 mL). The solution was heated to 55 °C and the pH was adjusted to 5-6 using 32% aq. NH3. The mixture was cooled to 0 °C and was stirred for 15 min. Filtration, washing with cold water (2 x 5 mL) and drying in vacuo provided Metyrosine 1 (2.55 g, 83% yield, 99.6% HPLC purity, >99,5% ee) as a white solid. HPLC ((Zorbax C18, NaH2P04 10 mM pH = 3/MeCN (100:0) 10 min, (100:0) to (0: 100) 15 min, 0: 100 5 min), tR = 10.1 min. Chiral HPLC (Nucleosil Chiral-1, CuS04 10 mM/MeCN 10: 1), tR = 16.9 min. m.p. = 321-322 °C. [α]546 = +187° (c = 0.5, Copper complex solution) Copper complex solution preparation: Solution A (anhydrous NaOAc dissolved in H20 (150 mL) in 250 mL volumetric flask, glacial acetic acid (50 mL) added and diluted to volume with H20) mixed with Solution B (cupric sulfate (62.5 g) diluted to volume with H20 in a 200 mL volumetric flask) in a 1 L volumetric flask and diluted to volume with H20. Sample prepared 5 mg/mL in this solution.

[0121] In order to obtain an NMR spectrum and taking into account the low solubility of the product, a small sample (10 mg) was transformed into its HC1 salt. The sample was dissolved in 2 M HC1 and the solution was evaporated to dryness. Ή NMR (D20, 400 MHz) 1.49 (s, 3 H); 2.90 (d, J= 14.5 Hz, 1 H); 3.16 (d, J= 14.5 Hz, 1 H); 6.75 (d, J- 8.2 Hz, 2 H), 7.01 (d, J= 8.2 Hz, 2 H). [0122] Preparation of Metyrosine using L-alanine tert-butyl ester:

Scheme 5

Figure imgf000045_0001

[0123] Example 14. Synthesis of Aldimine. 4-Chlorobenzaldehyde (3.87 g, 27.5 mmol) was dissolved in methanol (50 mL) and treated with triethylamine (3.87 g, 38.3 mmol, 1.39 equiv). The mixture was stirred for 7 min at ambient temperature followed by addition of L-alanine tert-butyl ester hydrochloride (5.00 g, 27.5 mmol). Magnesium sulfate (6.63 g, 55.1 mmol, 2 equiv) was added to this solution and the slurry was stirred for 17 h at ambient temperature. The solid was filtered and washed with methanol (6 mL). The filtrate was evaporated to dryness to result in an oily solid. This solid was dissolved in a biphasic MTBE/water (70 mL/20 mL) mixture. The organic phase was separated and washed with water (20 mL). The organic phase was dried over MgS04, the solid was filtered, and the filtrate was evaporated to dryness to afford aldimine 7 [7.09 g; 96.2%] as a clear oil, which became a solid when stored in a refrigerator. 1H NMR (500 MHz, CDC13): δ 8.25 (br. s, 1H, ArCH), 7.71 (d, J= 8.5 Hz, 2H, Ar), 7.38 (d, J= 8.5 Hz, 2H, Ar), 4.04 (dq, J, = 0.6 Hz, J2 = 6.8 Hz, 1H, CH), 1.48 (d, J= 6.8 Hz, 3H, CH3), 1.47 (s, 9H, 3 CH3).

[0124] Example 15. Synthesis of ferf-Butyl 2-Amino-3-(4-methoxyphenyl)-2- methylpropanoate. Aldimine (2.00 g, 7.47 mmol) and O-allyl-N-benzylcinchonidinium bromide (0.38 g, 0.75 mmol, 0.10 equiv) were mixed with toluene (20 mL) at ambient temperature. The mixture was stirred for 30 min and then was cooled to 0°C. Powdered KOH (2.10 g, 37.35 mmol, 5 equiv) was added at once to convert the thin slurry into a yellow solution. The mixture was stirred for 5 min and 4-methoxybenzyl bromide (7.51 g, 37.35 mmol, 5 equiv) was added at 0 to 1°C. The solution was allowed to warm and was stirred at ambient temperature for 16 h. The reaction mixture was sequentially washed with water (20 mL) and brine (20 mL), separated, and treated with a 5-6 N HC1 solution in IPA (7 mL) for 1 h at ambient temperature. The reaction mixture was washed with water (20 mL). The aqueous phase was separated and treated with toluene (20 mL). The aqueous phase was separated, treated with a 2 N NaOH solution until basic, and the product was extracted with toluene (20 mL). The toluene phase was washed with brine (20 mL), separated, and dried over Na2S04. The solid was filtered and the solvent was stripped to dryness to afford tert- butyl 2-amino-3-(4-methoxyphenyl)-2-methylpropanoate; 1.70 g; 85.8% as a clear oil. Ή NMR (500 MHz, CDC13): δ 7.13 (d, J= 8.7 Hz, 2H, Ar), 6.81 (d, J= 8.7 Hz, 2H, Ar), 3.78 (s, 3H, CH3), 3.05 (d, J= 13.3 Hz, 1H, CH2), 2.71 (d, J- 13.3 Hz, 1H, CH2), 1.62 (br. s, 2H, NH2), 1.45 (s, 9H, 3xCH3), 1.32 (s, 3H, CH3). Ή NMR analysis, carried out in the presence of 1.2 equiv of BINOL, resulted in 47.6% ee. Optical rotation (Q?5D, chloroform, c = 1.38): – 9.06°.

[0125] Example 16. Synthesis of 2-Amino-3-(4-methoxyphenyl)-2- methylpropanoic Acid Hydrochloride. Intermediate

Figure imgf000046_0001

2-amino-3-(4- methoxyphenyl)-2-methylpropanoate (0.60 g, 2.26 mmol) was mixed with toluene (6 mL) and a 5-6 N HC1 solution in IPA (2 mL). A clear yellow solution was heated to reflux and kept at that temperature for 7 h. The resulting slurry was cooled to ambient temperature and filtered. The solid was washed with toluene (3 mL) on a filter and air-dried to afford 2- amino-3-(4-methoxyphenyl)-2-methylpropanoic acid hydrochloride [0.37 g; 67%] as a white solid [HPLC 71.8% (AUC; ¾= 3.71 ]. Ή NMR (500 MHz, DMSO-i¾): <5 13.96 (br. s, 1H, COOH), 8.44 (br. s, 3H, NH3), 7.16 (d, J= 8.7 Hz, 2H, Ar), 6.90 (d, J= 8.7 Hz, 2H, Ar), 3.74 (s, 3H, CH3), 3.08 (s, 2H, CH2), 1.48 (s, 3H, CH3). Optical rotation (Λ, DMSO, c = 1.10) +7.27°. [0126] Example 17. Synthesis of Metyrosine 1. tert-Butyl 2-amino-3-(4- methoxyphenyl)-2-methylpropanoate (0.30 g, 1.13 mmol) was dissolved in CH2C12(3 mL) and BBr3 (0.85 g, 3.39 mmol, 3 equiv) was added at room temperature. The reaction mixture was stirred for 1.5 h and treated with a NaHC03 solution to a basic pH. The aqueous phase was isolated. Solid started to precipitate in the aqueous phase in 30 min. Solid was filtered in 16 h and was washed on a filter with CH2C12(2 mL) and water (2 mL). The solid was air- dried to afford metyrosine [0.10 g; 45.4%] as a white solid [HPLC 80.7% (Metyrosine; AUC; fR= 2.32 & 2.57]. Ή NMR (500 MHz, TFA-d): δ 8.60 (d, J= 8.7 Hz, 2H, Ar), 8.39 (d, J = 8.7 Hz, 2H, Ar), 4.91 (d, J= 15.0 Hz, 1H, CH2), 4.67 (d, J= 15.0 Hz, 1H, CH2), 3.30 (s, 3H, CH3). Optical rotation (ο?0ο, c = 1.080, 1 = 10 mm, NaOAc/CuS04/H20/AcOH) +148.1.

[0127] Larger scale (e.g. >100 g) Synthesis Metyrosine using (R)- phenylglycinamide (Examples 18-24). Scheme 6 provides the general synthetic outline.

Scheme 6

Figure imgf000048_0001

l) NaCN, MeOH/H20, 24 h, 44 °C; 2) H2S04 cone, DCM, 15 °C to RT, 1.25 h: 3) a. 3 atm H2 6 wt% 10% Pd/C, MeOH, 55 °C, 16 h, b. HBr aq; 4) HBr 48%, 105 °C, 17 h; 5) NaOH aq; 6) 5 wt% 10% Pd/C, HC02H/H20 MeOH, 55 °C, 6 h

[0128] Example 18. 2-[l-(S)-Cyano-2-(4-methoxyphenyl)-l-methylethylamino]-

2-(R)-phenylacetamide 2. In a 5 L reactor equipped with anchor stirrer were charged (i?)-phenylglycinamide»HCl (330 g, 1.77 mol, 1 eq.), MeOH (1.1 L), H20 (1.9 L) and

7-methoxyphenylacetone (290 g, 1.77 mol, 1 eq.). A solution of NaCN (86.7 g, 1.77 mol, 1 eq.) in H20 (300 mL) was added over 15 min at room temperature. The mixture was stirred for 24 hours at 44 °C resulting in the formation of a yellow precipitate. The mixture was cooled to room temperature. The precipitate was filtered, was washed with H20/MeOH (7:3 v/v, 2 x 750 mL) and -PrOH (2 x 500 mL). The solid was dried in vacuo (3 days) at 35°C to provide 2-[l-(5)-Cyano-2-(4-methoxyphenyl)-l-methylethylamino]-2-( ?)-phenylacetamide 2 (460 g, 80%, dr 97/3) as a yellow solid. Ή NMR (400 MHz, CDC13) 1.14 (s, 3 H), 2.90 (d, J = 13.6 Hz, 1 H), 2.99 (d, J = 13.6 Hz, 1 H), 3.20 (bs, 1 H), 3.80 (s, 3 H), 4.51 (s, 1 H), 5.45 (bs, 1 H), 5.75 (bs, 1 H), 6.90 (d, J= 8.6 Hz, 2 H), 7.27 (d, J= 8.6 Hz, 2 H), 7.30-7.50 (m, 5 H). Ή NMR (R,R and S^-diastereoisomers of 2 (400 MHz, CDC13) 1.49 (s, 3 H), 2.82 (d, J = 13.8 Hz, 1 H), 2.85 (d, J= 13.8 Hz, 1 H), 3.78 (s, 3 H), 4.52 (s, 1 H), 5.55 (bs, 1 H), 6.60 (bs, 1 H), 6.84 (d, J = 8.6 Hz, 2 H), 7.17 (d, J= 8.6 Hz, 2 H), 7.30-7.40 (m, 5 H). dr determination: Ή NMR comparing integration of peaks of 2 at 2.90/2.99 (1.00 H, formally 2 H) with those of its (^.ii/S’^-diastereoisomeric pair (prepared from nearly rac- phenylglycinamide) at 2.82/2.85 (0.03 H, formally 2 H).

[0129] Example 19. 2-[(R)-(Carbamoylphenylmethyl)-amino]-3-(4- methoxyphenyl)-2-(S)-methylpropionamide 3. Into a 10 L reactor equipped with anchor stirrer was charged CH2C12 (1.64 L). The solvent was cooled to 15°C, then 95% H2S04 (492 mL) and 2-[l-(5)-cyano-2-(4-methoxyphenyl)-l-methylethylamino]-2-( ?)-phenylacetamide 2 (410 g, 1.27 mol) were added alternately in 9 portions over approximately 45 min

(specifically: 164 mL of H2S04 then 82 g of 2; subsequently, at approximately 5 min intervals, 8 x [41 mL of H2S04 then immediately 41 g of 2]). On addition of each portion, the suspension of 2 in the dense oily phase slowly dissolved (1-2 min) to provide a biphasic mixture. The resulting biphasic mixture (a red-brown dense oil with a pale yellow

supernatant CH2C12 layer) was stirred for 0.5 h at 25°C. Ice-cold water (4.1 L) was added over 30 min, very slowly initially (200 mL dropwise over 15 min) due to a violent exotherm, and the biphasic mixture was stirred for 0.5 h. The phases were separated and the organic phase discarded. The combined aqueous phases were washed with CH2C12 (450 mL), and residual CH2C12 was stripped from the aqueous phase by distillation under vacuum at 55°C (20-30 mBar). The aqueous solution was then cooled to 20°C and was basified with 32% aq NH3 (1 150 mL) to pH 8-9 at such a rate that the temperature was kept below 28°C

(approximately 120 min). The suspension was stirred for 30 min to ascertain a stable pH. The white solid which formed was separated by filtration, washed with H20 (2 x 2050 mL), and was thoroughly drained of water (but was not dried) to provide 2-[(R)- (carbamoylphenylmethyl)-amino]-3-(4-methoxyphenyl)-2-(5)-methylpropionarnide 3 (1087 g (391 g theoretical, the sample contains 64% w/w of H20), yield 90%, 97% HPLC purity, 96% de) as a wet white solid. HPLC (Luna C18, H20 / MeCN 95:5 to 0: 100 30 min, 254 nm, sample 2 mg/mL in MeOH). tR (3) = 15.3 min, 96% de. (2 degrades under these conditions: 3 peaks are detected at 17.7, 18.9 and 19.9 min). HPLC (#R/S,S)-diastereoisomer of 3, tR = 1 5.0 min. de determination: HPLC comparing integration of peaks at tR = 15.3 min (97.3 area% 3) and tR = 15.0 min (1 .6 area% ( ?, ?)-diastereoisomer of 3 (reference (R,R/S,S) prepared from nearly rac-phenylglycinamide).

[0130] Example 20. Purification of 2-[(R)-(carbamoylphenylmethyl)-amino]-3-

(4-methoxyphenyl)-2-(S)-methylpropionamide 3. 2-[( ?)-(Carbamoylphenylmethyl)- amino]-3-(4-methoxyphenyl)-2-(5)-methylpropionamide 3 (321 g, 941 mmol) and methyl isobutyl ketone (4173 mL) were heated to 72°C until the solid was dissolved and the biphasic mixture (the minor lower aqueous layer is only visible on stopping stirring) was allowed to cool to room temperature with constant stirring. Stirring was maintained for 2 h. The solid formed was filtered at room temperature, was washed with methyl isobutyl ketone (2 x 320 mL) and was dried in vacuo to provide 2-[( ?)-(carbamoylphenylmethyl)-amino]-3-(4- methoxyphenyl)-2-(5 methylpropionamide 3 (268 g, 84%, >99.5% purity by HPLC) as a white solid. Ή NMR (400 MHz, DMSO-d6) 1.04 (s, 3H), 2.35 (bs, 1 H), 2.79 (d, J- 12.8 Hz, 1 H), 2.95 (d, J = 12.8 Hz, 1 H), 3.65 (s, 3 H), 4.22 (s, 1 H), 6.65 (d, J – 8.4 Hz, 2 H), 6.96 (d, J = 8.4 Hz, 2 H), 7.02 (bs, 1 H), 7.05 (bs, 1 H), 7.33-7.30 (m, 3 H), 7.48 (d, J= 7.2 Hz, 2 H), 7.52 (bs, 1 H), 7.64 (bs, 1 H). HPLC (Luna CI 8, H20 / MeCN 95:5 to 0: 100 30 min, 254 nm, sample 2 mg/mL in MeOH) tR = 15.3 min, >99.5% purity. Mp: 106-108°C.

[0131 ] Example 21. Hydrogenolysis to provide 2-(S)-Amino-3-(4- methoxyphenyl)-2-methyl-propionamide hydrogen bromide salt 4»HBr. To a 1 L hydrogenation reactor were added 2-[( ?)-(carbamoylphenylmethyl)-amino]-3-(4- methoxyphenyl)-2-(5)-methylpropionarnide 3 (183.0 g, 537 mmol, 1 eq), MeOH (549 mL) and 10% Pd/C (19.4 g, 5 wt%). The mixture was stirred under H2 (3 bar) at 51 °C for 8 h. Further 10% Pd/C (3,88 g, 1 wt%) was added and the mixture was stirred for a further 8 h at 53°C. The mixture was cooled to room temperature, was filtered through Celite and the filter pad was washed with MeOH (2 x 50 mL). The combined filtrates were concentrated at 30°C under reduced pressure (rotary evaporator) to a dense white “stirrable” paste (250 mL) containing 2-(,S)-amino-3-(4-methoxyphenyl)-2-methyl-propionamide 4 and 5.

[0132] H20 (75 mL) and 48% HBr (75 mL, 667 mmol, 1 ,25 eq.) were then added resulting in a white suspension. Residual MeOH was stripped from the mixture (45 mL distilled) by distillation at 100°C (bath temperature) at reduced pressure (20-30 mBar). The resulting aqueous solution was cooled to room temperature and filtered; the solid was washed with H20 (50 mL). The white solid was discarded (containing phenylacetamide 5 and 4% 4-HBr by NMR) and the resulting solution of 4»HBr (approximately 400 mL, containing 23% 5 with respect to 4 by NMR) was used directly. 1H NMR (400 MHz, DMSO-6d) 4 1.14 (s, 3 H), 2.10 (bs, 2 H), 2.50 (d, J= 13.1 Hz, 1 H), 2.95 (d, J= 13.1 Hz, 1 H), 3.69 (s, 3 H), 6.80 (d, J= 8.5 Hz, 2 H), 6.81 (bs, 1 H), 6.90 (bs, 1 H), 7.09 (d, J- 8.5 Hz, 2 H).

Phenylacetamide 5 3.34 (s, 2 H), 7.15-7.28 (m, 6 H), 7.42 (bs, 1 H). HPLC (Kromasil C8, H2O/0.1 % TFA / MeCN/0.07% TFA 95:5 to 0: 100 30 min, 254 nm, 1 mg/mL in MeOH) phenylacetamide 5 tR = 1 1.21 min. 4 tR = 9.10 min. (3 tR = 1 1 ,95 min.).

[0133] Example 22. (-)-a-Methyl-L-tyrosine, Metyrosine 1. To a 2 L flask equipped with an anchor stirrer was charged the 4»HBr solution (519 mmol obtained from hydrogenolysis) and 48% HBr (648 mL) was added. The solution was heated for 17 h at 105°C and was cooled to room temperature. The solution was washed with CH2C12 (8 x 80 mL, to remove traces of phenylacetic acid) and the aqueous phase was stripped of residual CH2C12 by distillation at 65°C at reduced pressure (20-30 mBar). Activated carbon (10.5 g) was added and the mixture was stirred for 30 min at 60°C, was filtered at 60°C and the filter pad was washed with water (2 x 35 mL) at RT. The combined filtrates were cooled to room temperature and were basified with 12.5 M NaOH (430 mL) to pH 6-7 at such a rate as to maintain the temperature below 30°C (over approximately 2 h). The white solid formed was separated by filtration, was washed with H20 (2 x 315 mL) and was dried in vacuo to provide (-)-a-methyl-L-tyrosine, metyrosine 1 (87 g, 86%, >99.9% HPLC purity, no impurities detected, >99.9% ee the other enantiomer is not detected) as a white solid. HPLC (Zorbax CI 8, NaH2P04 10 mM pH = 3 / MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0: 100 5 min, , 225 nm, sample 1 mg/mL in 0.1 M HC1) tR (1) = 7.6 min, tR (4) = 13,95 min. Chiral HPLC (Nucleosil Chiral-1 , CuS04 10 mM / MeCN 9: 1 , 254 nm, sample 1 mg/mL in eluant) tR = 14.4 min. tR enantiomer = 8.4 min. Mp: 309-313°C.

[0134] In order to obtain an NMR spectrum (taking into account the low solubility of the product), a small sample (10 mg) was transformed into its HC1 salt. The sample was dissolved in 2 M HC1 and the solution was evaporated to dryness. Ή NMR (400 MHz, D20) 1.49 (s, 3 H), 2.90 (d, J = 14.5 Hz, 1 H), 3.16 (d, J = 14.5 Hz, 1 H), 6.75 (d, J = 8.2 Hz, 2 H), 7.01 (d, J = 8.2 Hz, 2 H).

[0135] Example 23. Transfer hydrogenolysis to provide 2-(S)-Amino-3-(4- methoxyphenyl)-2-methylpropionamide formic acid salt 4-HCOOH. In a 5 L reactor equipped with anchor stirrer and oil bubbler, 2-[(i?)-(carbamoylphenylmethyl)-amino]-3-(4- methoxyphenyl)-2-(5)-methylpropionamide 3 (261.8 g, 766.8 mmol) was dissolved in MeOH (1570 mL). A first batch of 10% Pd/C (22.2 g, 4% w/w) was added and the mixture was heated to 56 °C. HCOOH (217 mL, 5.75 mol) was dissolved in H20 (393 mL) and 480 mL of the resulting solution were added to the mixture dropwise over 4.5 h, and the temperature was maintained between 54 and 60°C. When gas development ceased (as determined from the oil bubbler, approximately 30 min after complete addition of HC02H aq), the mixture was cooled to room temperature and a second batch of 10% Pd/C (5.6 g, 1 % w/w) was added. The mixture was heated again to 55°C and the remaining HCOOH solution (130 mL) was added dropwise over 45 min. Stirring was maintained for a further 30 min. The mixture was cooled to room temperature, was filtered over a pad of Celite and the filter pad was washed with MeOH (2 x 100 mL). The combined filtrates were concentrated under reduced pressure (rotary evaporator) to a white “stirrable” paste (approximate volume 300 mL) containing 4’HCOOH and phenylacetamide 5.

[0136] H20 (100 mL) was added and residual MeOH was stripped by distillation at reduced pressure (20-30 mBar) at 70 °C. The resulting solution (approximately 360 mL) was filtered and was washed with 100 mL of H20. The white solid (5 containing 1 % of

4«HCOOH by NMR) was discarded and the resulting solution of 4»HCOOH (containing 13% of 5 with respect to 4 by NMR) was used directly. Ή NMR (400 MHz, DMSO-d6) 1.43 (s, 3 H), 2.93 (d, J = 13.6 Hz, 1 H), 3.08 (d, J = 13.6 Hz, 1 H), 3.73 (s, 3 H), 6.88 (d, J = 8.8 Hz, 2 H), 7.17 (d, J = 8.8 Hz, 2 H), 7.56 (s, 1 H), 7.83 (s, 1 H). Phenylacetamide 5 (200 MHz, DMSO-d6) 3.36 (s, 2 H), 6.87 (bs, 1 H), 7.20-7.33 (m, 5 H), 7.45 (bs, 1 H). HPLC (Kromasil C8, H2O/0.1% TFA / MeCN/0.07% TFA 95:5 to 0:100 30 min, 254 nm, 1 mg/mL in MeOH) Phenylacetamide 5 tR = 1 1.38 min. 4.HC02H tR = 9.11 min. (3 tR = 11,95 min).

[0137] Example 24. (-)-a-Methyl-L-tyrosine, Metyrosine 1. Into a 2 L reactor equipped with anchor stirrer, a solution of 4»HCOOH (760 mmol from transfer

hydrogenolysis) and H20 (200 mL) was mixed with 48% aqueous HBr (948 mL, 8.43 mol). The resulting solution was heated to 105°C for 17 h. The mixture was cooled to room temperature and was washed with CH2C12 (6 x 125 mL, to remove traces of phenylacetic acid), the aqueous phase was stripped of residual CH2C12 at 60 °C at reduced pressure (20-30 mBar). The solution was mixed with activated carbon (15.6 g, 10% w/w) and was heated to 60°C for 30 min. The mixture was filtered at 60°C and the residue was rinsed with H20 (2 x 60 mL). The combined filtrates were cooled to 15°C and were basified with 12.5 M NaOH (730 mL) to pH 6-7 at such a rate as to maintain the temperature below 30°C (over approximately 100 min). The white solid formed was separated by filtration, was washed with H20 (2 x 460 mL) and IPA (490 mL and 245 mL) and was dried to provide (-)-ot- methyl-L-tyrosine, Metyrosine 1 (121.1 g, 82%, >99.9% HPLC no impurities >0.1% detected; >99.9% ee., the other enantiomer is not detected) as a white solid. HPLC (Zorbax CI 8, NaH2P04 10 mM pH = 3 / MeCN (100:0) 10 min, (100:0) to (0:100) 15 min, 0: 100 5 min, 225 nm, sample 1 mg/mL in 0.1 M HC1) tR (1) = 7.6 min; t (4) = 13,95 min. Chiral HPLC (Nucleosil Chiral-1, CuS04 10 mM / MeCN 9:1, 254 nm, sample 1 mg/mL in eluant) tR – 14.3 min. tR enantiomer = 8.4 min. Mp: 308-313 °C.

Patent

IN 2010/CHE/1204, IN 1204/CHE/2010,

EXAMPLE-1:
Step- (a): Preparation of (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester(32).
Dissolved N-BOC-L-AIanine (200 gm, 1.057 mol) in methylene chloride (800 ml) under stirring. Cooled the resulting reaction mixture to -15 to -10°C, added N-methyl morpholine (128.3 gm, 1.268 mol) then further cooled to -35°C, added ethylchloroformate (131.9 gm, 1.215 mol) followed by 3,5-dichloroaniline (171.2 gm, 1.057 mol). Stirred the above reaction mixture at 0 to 5°C for a period of 16-18 hours. Quenched the reaction mixture with water (500 ml), stirred for 10-15 minutes and separated the organic layer. The organic Iayerwas washed with water (2×200 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, added hexane (400 ml) and stirred for 30 minutes at 0-5°C. Filtered the resulting solid and washed with hexane (100ml). Dried until constant weight is reached. Dry weight of obtained (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester is 300.0 gm.
Yield: 85.1%;
Melting point of the resulting compounds ranges from 138.1-140.5°C;
IR spectra (cm’1): 3321, 2981, 1671, 1589, 1539,1446, 1317, 1255, 1165, 1117, 1072, 858, 802;

capture
32

1H NMR (400 MHz, CDCI3): 59.27(br.s, 1H), 7.37(s, 2H), 6.96(s, 1H), 5.42 (br.d, J=5.16HZ, 1H), 4.39(br.s, 1H),1.47 (s, 9H), 1.41(d, J=7.00HZ, 3H).
Mass (m/z): 334.2 [M+H]+.
Step- (b): Preparation of (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide (33).

capture
Dissolved (S)- [1-(3,5-Dichloro-phenylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (200.0 gm, 0.599 mol) obtained from step-(a) in methanol (300 ml). To the resulting mixture Cone, hydrochloric acid (500 ml) and water (320 ml) are added at 20-25°C. The resulting reaction mixture was stirred for 16-18 hours at 20-25°C. Added water (200 ml) and toluene (400 ml), cooled to 5-100C1 then basified with 50% sodium hydroxide solution. Stirred for 15 minutes and separated the layers. Aqueous layer was washed with toluene (3x200ml). Combined organic layers and washed with water, dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure to get the title compound as brown colored syrup. Weight: 135.0 gm.
Yield: 96.4%;
IR spectra (cm-1): 3281, 2969, 2930, 1681, 1585, 1515, 1445, 1409, 1372, 1258, 1185, 1112, 925, 843, 798, 669;\

1H NMR (400 MHz, CDCI3) : 59.67(br.s, 1H), 7.50(s, 2H), 7.00(s, 1H), 3.51 (q,J=7.03HZ, 1H), 1.65(br.s, 2H),1.34(d, J=7.04HZ, 3H).
Mass (m/z): 234.09 [M+H]+.
Step- (c): Preparation of (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one(34).

capture
Dissolved (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide (135 gm, 0.579 mol) obtained in step-(b) in toluene (925 ml) under stirring. Cooled the resulting reaction mixture to 20°C, added isobutyraldehyde (83.5 gm, 1.157mol) over a period of 50 to 60 minutes. Stirred the above reaction mass at 50 to 55°C for a period of 18-19 hours. The organic layer was distilled off under reduced pressure, added hexane (270 ml) and stirred for 1.45 hours at 0-5°C. Filtered the resulting solid and washed with hexane (50ml). Dried until constant weight is reached. Dry weight of obtained (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one is 138.0 gm.
Yield: 82.98%;
Melting point ranges from 128.9-131.8°C;
IR spectra (cm”1): 3305, 3051, 2962, 2877, 1689, 1587, 1450, 1383, 1278, 1223, 1055, 846, 798, 743;

1H NMR (400 MHz, CDCI3) : 57.40 (s, 2H), 7.15 (s, 1H), 5.00 (s, 1H), 3.68 (q, J=6.83HZ, 1H), 1.98 (br.s, 1H), 1.35 (d, J=6.84HZ, 3H), 0.96(d, J=6.87HZ, 3H), 0.76 (d, J=6.70HZ, 3H).
Mass (m/z): 288.1 [M+H]+.
Step- (d): Preparation of (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1 -(2,2,2-trifluoroacetyl)-imidazolidin-4-one (35).

capture
Dissolved (S)-3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one (135 gm, 0.470 mol) obtained in step-(c) in methylene chloride (1080 ml) under stirring. Cooled the resulting reaction mixture to 0 to 5°C, added triethyl amine (66.48 gm, 0.658 mol) followed by trifluoroacetic anhydride (132.3 gm, 0.658 mol) over a period of 30 minutes. Stirred the above reaction mass at 0 to 5°C for a period of 2-3 hours. Quenched the reaction mixture with water (405 ml), stirred for 20-25 minutes and separated the organic layer. The organic layer was washed with water (2×270 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, to get crude product as semi solid. The obtained semi solid mass was recrystalised using isopropyl alcohol to get pure product. Dried until constant weight is reached. Dry weight of obtained (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one is 153.0 gm.
Yield: 84.93%;

Step- (c): Preparation of (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one (34).
Dissolved (S)- 2-Amino-N-(3,5-dichloro-phenyl)-propionamide (104 gm, 0.446 mol) obtained in step-(b) in toluene (715 ml) under stirring. Cooled the resulting reaction mixture to 20°C, added isobutyraldehyde (64.34 gm, 0.892mol) over a period of 50 to 60 minutes. Stirred the above reaction mass at 50 to 55°C for a period of 18-19 hours. The organic layer was distilled off under reduced pressure, added hexane (200 ml) and stirred for 3 hours at 0-5°C. Filtered the resulting solid and washed with hexane (25ml). Dried until constant weight is reached. Dry weight of obtained (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one is 101.0 gm. Yield: 78.90%;
Step- (d): Preparation of (2R, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-imidazolidin-4-one (35).
Dissolved (S)- 3-(3,5-Dichloro-phenyl)-2-isopropyl-5-methyl-imidazolidin-4-one (100 gm, 0.348 mol) obtained in step-(c) in methylene chloride (800 ml) under stirring. Cooled the resulting reaction mixture to 0 to 5°C, added triethyl amine (42.28 gm, 0.417 mol) followed by trifluoroacetic anhydride (87.73 gm, 0.417 mol) over a period of 30 minutes. Stirred the above reaction mass at 0 to 5°C for a period of 2-3 hours. Quenched the reaction mixture with water (300 ml), stirred for 20-25 minutes and separated the organic layer. The organic layer was washed with water (2×200 ml), dried with anhydrous sodium sulfate and filtered. The organic layer was distilled off under reduced pressure, to get crude product as semi solid. The obtained semi solid mass was recrystalised using isopropyl alcohol to get pure product. Dried until constant

reached. Dry weight of obtained (2S, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1-(2,2,2-trifluoroacetyl)-5-(4-methoxy benzyl)-imidazolidin-4-one is 6.6 gm.
Yield: 61.10%;
Melting point ranges from 114.2-116.4°C;
IR spectra (cm’1): 2977, 1731, 1692, 1609, 1585, 1572, 1513, 1426, 1348, 1250, 1197, 1048, 890, 748;
1H NMR (400 MHz, CDCI3) : 57.29 (s,1H), 6.84(d, J=8.5HZ, 2H), 6.80(d, J=1.5HZ, 2H), 6.73(d, J=8.1HZ, 2H), 5.07(s, 1H), 3.99(q, J=6.9Hz, 2H), 3.66(d, J=13.8HZ, 1H), 2.99(d, J=13.8HZ, 1H), 2.05(t, J=6.94HZ, 1H), 1.95(s, 3H), 1.41 (t, J=6.94HZ, 3H), 0.91 (d, J=6.61HZ, 3H), 0.52(d, J=7.30HZ, 3H).
Mass (m/z): 517.3 [M+H]+.

Step- (f): Preparation of (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-ethoxy phenyi)-propionamide (45).

str1

To the suspension of potassium hydroxide (1.12 gm, 0.0169 mol) in isopropyl alcohol (25 ml) , (2S, 5S)-2-isopropyl-3-(3,5-Dichloro-phenyl)-5-methyl-1 -(2,2,2-trifluoroacetyl)- 5-(4-ethoxy benzyl)-imidazolidin-4-one (5.0 gm, 0.009 mol) obtained in step-(e) was added at 25 to 30°C under stirring. The resulting reaction mixture was stirred at 40 to Cl 45 45°C for 3-4 hours. Cooled to 10 to 15°C,added 3M sulfuric acid (15 ml) over a period of 30 minutes. The resulting reaction mixture was heated to 70 to 75°C, stirred for 2 to 3 hours at same temperature. Distilled solvent completely under reduced pressure, added water (25 ml) and ethyl acetate (50 ml). Stirred for 15 minutes and basified with 20% sodium hydroxide solution. Stirred for 15 minutes at 25 to 30°C, separated the organic layer. Aqueous layer washed with ethyl acetate (50 ml). Combined the organic layers and washed with saturate sodium chloride solution (25 ml), dried over anhydrous sodium sulfate, filtered. Removed solvent completely under reduced pressure to get the title compound as brown colored syrup. Weight of (S)-2-amino-N-(3,5-Dichloro-phenyl)- 2-methyl-3-(4-ethoxy phenyl)-propionamide is 2.8 gm. Yield: 79.0%; IR spectra (cm”1 ): 2981, 1732, 1689, 1682, 1575, 1513, 1446, 1302, 1244, 1179, 1116, 1048, 843; 1H NMR (400 MHz, CDCI3) : 59.79(br.s, 1H), 7.52(s, 2H), 7.05(d, J=8.68HZ, 3H), 6.79(d, J=8.53HZ, 2H), 3.94(q, J=6.98, 2H), 3.38(d, J=13.25HZ, 1H), 2.57(d, J=13.56HZ, 1H), 2.03(s, 1H), 1.58(br.s, 2H), 1.43(s, 3H),1.39(t, J=5.42HZ, 3H), Mass (m/z): 368.2 [M+H]+ .

Step- (g): Preparation of (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine). Dissolved the (S)-2-amino-N-(3,5-Dichloro-phenyl)-2-methyl-3-(4-ethoxy phenyl)- propionamide (2.8 gm, 0.007 mol) obtained in step-(f) in aqueous HBr (50 ml) under stirring. The resulting reaction mixture was heated to 120-125°C and stirred for 24 hours. Cooled to 50°C, added water (100 ml) stirred for 15 minutes then further cooled 54 to 10-15°C , pH adjusted to 5-6 with ammonium hydroxide solution. Stirred for 30 minutes at 10-15°C, filtered and cake washed with water (2×5 ml). Dried until constant weight is reached. Dry weight of obtained crude (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine) of formula-1 is 1.8 gm.

Step- (h): Purification of (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine). The crude (2S)-2-amino-3-(4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine) obtained in step ( g) 1.8 gm) was dissolved in water (180 ml) by heating the reaction mixture to 90°C. Darco (Charcoal) was added and stirred for 10-15 minutes at same temperature. The resulting reaction mixture was filtered through celite bed. The filtered reaction mass concentrated up to half volume reached under reduced pressure. Cooled to IO0C and stirred for a period of 30 minutes at same temperature. Filtered the resulting solid, washed with water. Dried until constant weight is reached. Dry weight of obtained pure (2S)-2-amino-3- (4-hydroxy phenyl)-2-methyl propanoic acid (Metyrosine) of formula-1 was 0.8 gm. The product is matching in all respects with compounds of Metyrosine obtained from EXAMPLE-1 (Step-h). Purity: 99.98%. Chiral purity by HPLC: 100.0%.

IR FROM NET

13 C NMR

References

  1. ^ Green KN, Larsson SK, Beevers DG, Bevan PG, Hayes B (August 1982). “Alpha-methyltyrosine in the management of phaeochromocytoma”Thorax37 (8): 632–3. doi:10.1136/thx.37.8.632PMC 459390PMID 7179194.
  2. ^ O’Leary OF, Bechtholt AJ, Crowley JJ, Hill TE, Page ME, Lucki I. Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology. 2007 Jun;192(3):357-71. PMID 17318507
Metirosine
Skeletal formula
Ball-and-stick model of metirosine as a zwitterion
Clinical data
Trade names Demser
AHFS/Drugs.com Consumer Drug Information
ATC code
Pharmacokinetic data
Elimination half-life 3.4–3.7 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
ECHA InfoCard 100.010.546 Edit this at Wikidata
Chemical and physical data
Formula C10H13NO3
Molar mass 195.215 g/mol
3D model (JSmol)
Title: Metyrosine
CAS Registry Number: 672-87-7
CAS Name: a-Methyl-L-tyrosine
Additional Names: a-methyl-p-tyrosine; a-methyltyrosine; 4-hydroxy-a-methylphenylalanine; a-methyl-3-(p-hydroxyphenyl)alanine; metirosine; L-a-MT; a-MPT
Manufacturers’ Codes: MK-781
Trademarks: Demser (Merck & Co.)
Molecular Formula: C10H13NO3
Molecular Weight: 195.22
Percent Composition: C 61.52%, H 6.71%, N 7.17%, O 24.59%
Literature References: An inhibitor of the first and rate-limiting reaction in catecholamine biosynthesis, the hydroxylation of tyrosine to dopa. Prepn: NL 6607757 (1966 to Merck & Co.), C.A. 67, 91108p (1967). Prepn of DL-form: Stein et al., J. Am. Chem. Soc. 77, 700 (1955); Potts, J. Chem. Soc. 1955, 1632; Pfister, Stein, US 2868818 (1959 to Merck & Co.); Saari, J. Org. Chem. 32,4074 (1967). Metabolism and biochemical and pharmacologic effects in man: Engelman et al., J. Clin. Invest. 47, 568, 577 (1968). Review of pharmacology and clinical use: R. N. Brogden et al., Drugs 21, 81-89 (1981).
Properties: Crystals, mp 310-315°.
Melting point: mp 310-315°
Derivative Type: DL-Form
CAS Registry Number: 620-30-4
Properties: Crystals from water, dec 320° (Stein et al., loc. cit.), also reported as dec 330-332° (Potts, loc. cit.). Soly in water at room temp: 0.57 mg/ml.
Therap-Cat: Tyrosine hydroxylase inhibitor; as antihypertensive in pheochromocytoma.
Keywords: Antipheochromocytoma.

////////////Metyrosine, Metirosine, Demser, メチロシン , JAPAN 2019, α-Methyl-p-tyrosine, метирозин ميتيروسين 甲酪氨酸 

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