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Ramatroban

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Ramatroban
Ramatroban.svg
Ramatroban
 
Formula
C21H21FN2O4S
CAS
116649-85-5
Mol weight
416.4658

 

(3R)-3-[[(4-Fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazole-9-propanoic acid
(+)-(3R)-3-(p-fluorobenzenesulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionic acid; (+)-3-(4-fluorophenylsulfonamido)-9-(2-carboxyethyl)-1,2,3,4-tetrahydrocarbazole
3-[(3R)-3-[(4-fluorophenyl)sulfonylamino]-1,2,3,4-tetrahydrocarbazol-9-yl]propanoic acid
Manufacturers’ Codes: Bay u 3405
  1. 3-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydro-9-carbazole propanoic acid
  2. BAY u 3405
  3. BAY u 3406
  4. BAY u-3405
  5. BAY u3405
  6. ramatroban
Trademarks: Baynas (Bayer)
MF: C21H21FN2O4S
MW: 416.47
Percent Composition: C 60.56%, H 5.08%, F 4.56%, N 6.73%, O 15.37%, S 7.70%
Properties: Crystals from ether, mp 134-135°. [a]D +70.1° (c = 1.0 in methanol).
Melting point: mp 134-135°
Optical Rotation: [a]D +70.1° (c = 1.0 in methanol)
Therap-Cat: Antiasthmatic; antiallergic.
Antiasthmatic (Nonbronchodilator); Thromboxane A2-Receptor Antagonist.

Ramatroban (INN) (also known as Bay-u3405)[1] is a thromboxane receptor antagonist.[2]

It is also a DP2 receptor antagonist.[3]

It is indicated for the treatment of coronary artery disease.[4] It has also been used for the treatment of asthma.[5]

It was developed by the German pharmaceutical company Bayer AG and is co-marketed in Japan by Bayer and Nippon Shinyaku Co. Ltd. under the trade name Baynas.

Ramatroban.png

SYN

Science 1976,193163-5

Proc Natl Acad Sci USA 1975,72(8),2994-8

 

The synthesis of Bay u 3405 was carried out as follows: Reductive amination of 3-oxo-1,2,3,4-tetrahydrocarbazole (I) with S-phenethylamine (II) afforded a mixture of diastereomeric amines, of which the desired isomer (III) crystallized in high diastereomeric purity as the hydrogensulfate. Cleavage of the phenethyl group by transfer hydrogenolysis with amminium formate and palladium on charcoal yielded the enantiomerically pure (3R)-3-amino-1,2,3,4-tetrahydrocarbazole (IV). Sulfonylation of (IV) with 4-fluorobenzenesulfonyl chloride (V) to the sulfonamide (VI) followed by addition of acrylonitrile and subsequent hydrolysis gave Bay u 3405.

 

SYN

J Label Compd Radiopharm 1994,34(12),1207

The synthesis of [14C]-labeled Bay-u-3405 by two closely related ways has been described: 1) [14C]-Labeled aniline (I) is diazotized and reduced with sodium sulfite, yielding the labeled hydrazine (II), which is condensed with the monoketal of cyclohexane-1,4-dione (III) under Fisher’s indole synthesis (ZnCl2) to afford the tetrahydrocarbazole (IV). The hydrolysis of (IV) with HCl in THF/water yields 1,2,3,4-tetrahydrocarbazol-3-one (V), which is submitted to a reductive condensation with (S)-1-phenylethylamine (VI) by means of tetrabutylammonium borohydride, yielding preferentially the secondary amine (VII), which, after purification, is dealkylated with ammonium formate and Pd/C to afford 1,2,3,4-tetrahydrocarbazole-3(R)-amine (VIII). The acylation of (VIII) with 4-fluorophenylsulfonyl chloride (IX) gives the corresponding sulfonamide (X), which is condensed with acrylonitrile by means of NaH, yielding 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]pro pionitrile (XI). Finally, this compound is hydrolyzed in the usual way. 2) The condensation of the sulfonamide (X) with methyl acrylate by means of NaH as before gives 3-[3(R)-(4-fluorophenylsulfonamido)-1,2,3,4-tetrahydrocarbazol-9-yl]propionic acid methyl ester (XII), which is finally hydrolyzed in the usual way.

……………………

 

http://pubs.rsc.org/en/content/articlelanding/2012/oc/c2oc90018a#!divAbstract

………………….

http://onlinelibrary.wiley.com/doi/10.1002/adsc.201300993/abstract

 
PATENT
 
CN 87100773 
DE 3631824
Arzneimittel-Forschung (1989), 39(12), 1519-21.
 
US 4988820 
EP 728743
PAPER
Journal of Organic Chemistry (2012), 77(10), 4842-4848. 
white solid: Rf (1% AcOH/40% EtOAc/hexane) 0.23; mp
135−137 °C; IR (KBr) ν 3276, 2926, 1712, 1591, 1494, 1467, 1153
cm−1
; 1
H NMR (CD3OD, 300.13 MHz) δ 1.87−2.09 (m, 2H14),
2.47−2.54 (m, 1H11), 2.67 (t, 3
JHH = 6.7 Hz, 2H2), 2.75−2.91 (m,
2H13+1H11), 3.61−3.71 (m, 1H12), 4.30 (t, 3
JHH = 6.7 Hz, 2H3), 6.96
(t, 3
JHH = 6.9 Hz, 1H7), 7.08 (t, 3
JHH = 7.1 Hz, 1H6), 7.21−7.31 (m,
2H18+H5+H7), 7.93−7.98 (m, 2H17); 13C NMR (CD3OD, 75.5 MHz)
δ 21.2 (C14), 29.7 (C11), 31.1 (C13), 35.8 (C2), 40.0 (C3), 51.5 (C12),
108.0 (C10), 110.2 (C5), 117.4 (d, 2
JCF= 23.3 Hz, 2C18), 118.7 (C8),
120.2 (C7), 122.4 (C6), 128.9 (C19), 131.0 (d, 3
JCF= 9.7 Hz, 2C17),
135.3 (C15), 138.0 (C4), 139.8 (d, 4
JCF= 3.5 Hz, C16), 166.6 (d, 1
JCF=
251.4 Hz, C19), 175.2 (C1); HRMS (ESI+, m/z) calcd for
(C21H22FN2O4S)+ (M + H)+ 417.1279, found 417.1273; [α]D
20=
+64.4 (c 1, MeOH) for 99% ee.
PATENT
 

This invention relates to 2-amino- tetrahydrocarbazole-propanoic acid and a new process for its synthesis .

2-Amino-tetrahydrocarbazole-propanoic acid is a key intermediate for the synthesis of Ramatroban, a thromboxaneA2 receptor (TP) antagonist with clinical efficacy in asthma and allergic rhinitis.

Figure imgf000002_0001

Ramatroban l-Amino-tetrahydrocarbazole-proanoic acid

US Patent 4988820 discloses the synthesis of this compound stating from compound 1, which is condensed with phenylhydrazine and ring-closed to give indole 2. Deprotection of 2 using acid provides ketone 3. Reductive amination of ketone with s-phenylethylamine in the presence of tetrabutylammonium borohydride provides compound 4, which undergoes palladium catalyzed hydrogenation to give key intermediate 5.

Figure imgf000003_0001

Ramatroban

Figure imgf000003_0002

The process, however, has disadvantages: the starting material 1 is relatively expensive, and the yield of the amination step is only 40% and needs expensive tetrabutylammonium borohydride as the reducing agent. And also the subsequent hydrogenation provides only 70% of the desired compound 5. [0006] US Patent 4988820 also describes an alternative synthesis of compound 5 starting from compound 6, which is oxidized by chromium trioxide to afford ketone 7. Condensation of compound 7 with phenylhydrazine and ring closure give indole 8. The subsequent hydrolysis using HCl provides indole 9. The intermediate 5 is obtained by resolution of racemic 9 using ( + ) -mandelic acid as the resolving agent.

Figure imgf000004_0001

9 5

However, this process has crucial disadvantages: the first step oxidation reaction needs the heavy metal reagent chromium trioxide, which is toxic and expensive, and the resolution of indole 9 using (+) -mandelic acid affords only -10 % of compound 5.

US Patent 5684158 discloses the synthesis of 2- amino-tetrahydrocarbazole-propanoic acid ethyl ester 10 by the alkylation of compound 5 in the presence of about 1 mol of alkali metal hydroxides and phase-transfer catalysts such as potassium hydroxide and benzyltriethylammonium chloride.

Figure imgf000004_0002

The problem with this reaction is that the insoluble material in the reaction mixture becomes very sticky during the reaction. The reaction mixture must be filtered in hot solvent in order to remove insoluble material during work up and the sticky material tents to block the filtration. [0010] Therefore, there is a great need for a new process for the synthesis of 2-amino-tetrahydrocarbazole- propanoic acid.

 ……………
Example 53

 

  •  
    9- (2-carboxyethyl) -4- (4-fluorphenylsulfonamidomethyl) -1,2,3,4-tetrahydrocarbazole

     

    Figure imgb0092
  •  
    0.91 g 9-(2-Cyanoethyl)-4-[N-(4-fluorphenylsulfonyl)-N-(2-cyanoethyl)aminomethyl]-1,2,3,4-tetrahydrocarbazol be hydrolyzed analogously to Example 7. One obtains 0.77 g (89% of theory) of crystalline product as the sodium salt.
  •  
    M.p .: 160 ° CR f = 0.57 CH 2 Cl 2: CH 3 0H = 9: 1
Example 69

 

    •  
      (+) – 3- (4-fluorophenylsulphonamido) -9- (2-carboxyethyl) -1,2,3,4-tetrahydrocarbazole

       

      Figure imgb0106
    •  
      5.8 g (0.0128 mol) of Example 67 are dissolved in 60 ml isopropanol, treated with 130 ml of 10% potassium hydroxide solution, after 16 hours heating under reflux, is cooled, diluted with water and extracted with ethyl acetate. The aqueous phase is concentrated in vacuo and then treated dropwise with vigorous stirring with conc.Hydrochloric acid. The case precipitated acid is filtered off, washed with water and dried thoroughly in vacuo.Obtained 4.4 g (86.6% of theory) of the product. .: Mp 85-95 ° C rotation [α] 20 = 42.55 ° (CHCl 3) D

Example 70

  •  
    (-) – 3- (4-fluorophenylsulphonamido) -9- (2-tarboxyethyl) -1,2,3,4-tetrahydrocarbazole

     

    Figure imgb0107
  •  
    The preparation of Example 70 from Example 68 is carried out analogously to the preparation of Example 69 from Example 67. m.p .: 85-95 ° C optical rotation: [α] 20 = -37.83 ° (CHCl 3) D
 
 
……………
 

Synthesis pathway

Synthesis of a)




Trade names

Country Trade name Manufacturer
Japan Baynas Bayer
Ukraine no no

Formulations

  • 50 mg tablet 75 mg

Reference

  • DE 3631824 (Bayer AG; appl. 19.9.1986; prior. 21.2.1986).
  • EP 728 743 (Bayer AG; appl. 14.2.1996; D-prior. 27.2.1995).
………….
Patent Submitted Granted
Phenylsulfonamid substituted pyridinealken- and aminooxyalkan-carboxylic-acid derivatives. [EP0471259] 1992-02-19 1995-05-17
Heterocyclic substituted cycloalkano(b)-indolesulfonamides. [EP0473024] 1992-03-04  
Cycloalkano[b]dihydroindoles and -indolesulphonamides substituted by heterocycles. [EP0451634] 1991-10-16 1994-03-09
Respiratory Drug Condensation Aerosols and Methods of Making and Using Them [US2009258075] 2009-10-15  
ANTITHROMBOTIC SUBSTITUTED CYCLOALKANO(B)DIHYDROINDOLE- AND -INDOLE-SULPHONAMIDES [US5096897] 1992-03-17  
Indolesulphonamide-substituted dihydropyridines [US5272161] 1993-12-21  
THERMODYNAMICALLY STABLE FORM OF (R)-3-[ [(4-FLUOROPHENYL) SULPHONYL]AMINO] -1,2,3,4- TETRAHYDRO -9H-CARBAZOLE -9-PROPANOIC ACID (RAMATROBAN) [WO9933803] 1999-07-08
DE1695703B2 * Mar 15, 1967 Nov 20, 1975 Sumitomo Chemical Co., Ltd., Osaka (Japan) Title not available
DE2125926A1 * May 25, 1971 Jan 27, 1972   Title not available
DE2226702A1 * May 25, 1972 Dec 13, 1973 Schering Ag Neue mittel zur behandlung des diabetes mellitus
FR1415322A *       Title not available
GB1487989A *       Title not available
US4235901 * May 14, 1979 Nov 25, 1980 American Home Products Corporation 1-Hydroxyalkanamine pyrano(3,4-b)indole compositions and use thereof

 

 
Ramatroban
Ramatroban structure.png
Systematic (IUPAC) name
3-((3R)-3-{[(4-fluorophenyl)sulfonyl]amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)propanoic acid
Clinical data
Legal status
  • Prescription only
Routes Oral
Identifiers
CAS number 116649-85-5
ATC code None
PubChem CID 123879
IUPHAR ligand 1910
ChemSpider 110413
UNII P1ALI72U6C Yes
ChEMBL CHEMBL361812
Chemical data
Formula C21H21FN2O4S 
Mol. mass 416.46 g/mol
Ramatroban
Ramatroban.svg
Clinical data
Trade names Baynas
AHFS/Drugs.com International Drug Names
Routes of
administration
Oral (tablets)
ATC code
  • None
Legal status
Legal status
  • Rx-only (JP)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.159.668 Edit this at Wikidata
Chemical and physical data
Formula C21H21FN2O4S
Molar mass 416.47 g·mol−1
3D model (JSmol)
 
References:
Thromboxane A2 receptor antagonist. Prepn: H. Böshagen et al., DE 3631824; eidem, US 4965258 (1988, 1990 both to Bayer);
Proc Natl Acad Sci USA1975,72,(8):2994-8
Science1976,193,():163-5
and absolute configuration: U. Rosentreter et al., Arzneim.-Forsch. 39, 1519 (1989).
Series of articles on pharmacology: ibid. 1522-1530.
Clinical evaluation in asthma: H. Aizawa et al., Chest 109, 338 (1996).

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DR ANTHONY CRASTO

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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 AFRICURE PHARMA as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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