Pharmaceutical Substances Syntheses, Patents, Applications - Part 184 potx

monoperoxyphtholic acid phenylboronic ethyl brornoacetote ethyl 2-phenylocetoxy- ocetote VllI... K,SO, "oxone- synthesis of 4-rnethylthiophenylboronic ocid triisopropyl borate Re

Rofecoxib R 1831

H202, 5 mo1Z No2W04

0

1

hydrogen peroxide, H~c-", bromine in

4'-(methylsulfonyl)- acetophenone (11)

DMF

*

phenylocetic ocid sodium salt

H

H 3 C y y C H 3 , DMF

CH3CH3

IV

Rofecoxib

I

magnesium monoperoxyphtholote

(MMPP)

OBU (1 ,a-diozobicyclo- phenylocetic

[5.4.0]undec-7-ene) ocid (N)

Rofecoxib

1

1832 R Rofecoxib

4-brorno-

thioonisole (V)

2(5H)- furonone

1 pollodium(1l) acetote

2 iodine, pyridine

r

1 tert-butyllithium

2 trirnethylsilyl chloride

4-[4-(rnethylthi0)- phenyl]-2(5~)- furanone (Vl)

2

Rofecoxib

2 monoperoxyphtholic acid phenylboronic

ethyl

brornoacetote

ethyl 2-(phenylocetoxy)- ocetote (VllI)

Rolitetracycline R 1833

1 LiBr or LiCl

2 x , NO,CO,, P ~ ( P P ~ , ) ,

b

0 4-(rnethylthi~)~henylboronic ocid (X)

H3C-S

2 KHSO, - KHSO, K,SO,

"oxone-

synthesis of 4-(rnethylthio)phenylboronic ocid

triisopropyl borate

Reference (s):

b WO 9 613 483 (Merck Frosst Canada; appl 2.10.1994; USA-pr~or 27.10.1994)

e WO 9 608 482 (Merck & Co.; appl 12.9.1995; USA-prior 16.9.1994)

a-e WO 9 500 501 (Merck Frosst Canada Inc.; appl 15.5.1995; USA-prior 24.6.1993, 10.1.1994)

The discovery of rofecoxib:

Prasit, P et al.: Bioorg Med Chem Lett (BMCLES) 9 (13), 1773 (1999)

alternative syntheses:

WO 9 636 623 (Merck Frosst Canada; appl 15.5.1996; USA-prior 18.5.1995)

GB 2 294 879 (Merck & Co.; appl 9.10.1995; USA-prior 19.10.1994)

W09 619 469 (Merck Frosst Canada; appl 18.12.1995; USA-prior 21.12.1994)

Trade Name(s):

D: Vioxx (Merck Sharp & GB: Vioxx (Merck Sharp & USA: Vioxx (Merck Sharp &

Rolitetrac ycline ATC: JOlAA09

Use: antibiotic, antibacterial RN: 751-97-3 MF: C,H,,N,O, MW: 527.57 EINECS: 212-031-9

LD,,: 75 mgkg (M, i.v.); 1320 mgkg (M, p.0.);

93 mglkg (dog, i.v.)

pentahydroxy-6-methyl-l,11-dioxo-N-(l-pyrrolidinylmethyl)-2-naphthacenecarboxamide

1834 R Romurtide

Reference(s):

DE 1 044 806 (Hoechst; appl 3.10.1956)

DE 1 063 598 (Hoechst; appl 14.2.1957)

1JS 3 104 240 (Bristol-Myers; 17.9.1963; prior 18.8.1958)

Gottstein, W.J eta].: J Am Chem Soc (JACSAT) 81, 1198 (1959)

tetracycline paraform- pyrrolidine

aldehyde

Trade Name(s):

GB: Tetrex PMT (Bristo1)- J: Bristacin (Rristre-Banyu) IJSA: Syntetrin (Bristol); wfm comb.; wfm

Ralitetracycline

Romurtide ATC: L03AX

denvative, treatment of leukopenia associated with cancer radiotherapy RN: 781 13-36-7 MF: C43H7RN6013 MW: 887.13

LD,,,: >600 mglkg (M, p.0.); 436 mgkg (Mm, s.c.); 625 mglkg (Mf, s.c.);

>90 mglkg (R, I.v.); >600 mglkg (R, p.0.); 761 mg/kg (Rm, s.c.); 801 mgkg (Rf, s.c.):

>200 mglkg (dog, s.c.)

CN: @-[@-[N-(N-acetylmuramoyl)-~-alanyl]-~-a-glutaminyl]-~-(l-oxooctadecyl)-~-lysine

H

X K Y

0 N-hydroxy-

succinimide

N-tert-butoxycarbonyl- benzyl D-iso-

L-alonine glulorninote

0

cIcocc,H, N ( ~ ~ H ~ ) ~

Hz Pd-C

I

C O ~ H N6-(benzylaxycarbonyl)- ethyl

b 11

F

Romurtide R 1835

0

L-olonyl-D-isoglutaminyl-Nz-(benzyl- oryc0rbonyl)-L-lysine benzyl ester (Ill)

X O

1 -0-benzyl-4.6-0-benzylidene

N-ocetylmuramic acid

1836 R Ronifibrate

Rornurtide

Keference(s):

EP 21 367 (Daiichi; appl 20.6.1980; J-prior 21.6.1979)

US 4 317 771 (Daiichi; 2.3.1982; appl 23.6.1980; J-prior 21.6.1979)

medical use for treatment of thromboperiia:

EP 331 756 (Daiichi; appl 2.9.1988; J-prior 2.9.1987)

JP 63 093 724 (Daiichi; appl 9.10.1986)

Trade Name(s):

Ronifibrate ATC: ClOAB07

Use: antihyperlipoproteinemic, fibrate serum antihyperlipidemic RN: 42597-57-9 MF: C19H,oClN05 MW: 377.82

LD,,: 3100-4080 mgkg (M, p.0.)

CN: 3-pyridinecarboxylic acid 3-[2-(4-ch1orophenoxy)-2-methyl-1 -oxopropoxy]propyl ester

hydrochloride

RN: 42749-78-0 MI;: C19HmCIN0, HCI MW: 414.29

sodium 2-(4-chloro-

phenoxy)-Emethyl-

propionate

nicotinoyl Ronifibrote

B

Ropinirole R 1837

Reference (s):

JP49 030 377 (Kowa; appl 19.7.1972); C.A (CHABA8) 81,135984s

JP 4 840 777 (Yamanouchi; appl 5.10.1971); C.A (CHABA8) 7 9 , 6 6 1 8 0 ~ (1973)

Fomulation(s): cps 250 mg, 500 mg

Trade Name(s):

I: Cloprane (Sankyo Pharma)

Ropinirole

(SK&F-101468; SK & F-101468A)

ATC: N04BC04 Use: dopamine-D,-agonist, antiparkinsonian RN: 91374-21-9 MF: C,,H,N,O MW: 260.38

hydrochloride

RN: 91374-20-8 MF: C,6H,N,0 HCI MW: 296.84

chloride

2-chlorornethylphenethyl

benzoote (I)

2 HsC-COOH

3 Na2S,0,

I

1 hexornethylene-

2-forrnylphenethyl

benzoate (Il)

1 NaOCHs CH30H

2 H20 HCI

+ H3C-NO2 - q0pN02

0

1838 R Ropivacaine hydrochloride

dipropylornine Ropinirole

WO 9 116 306 (Smith Kline & French; appl 15.4.1991; GB-prior 17.4.1990)

EP 113 964 (Smith Kline & French; appl 30.11.1983; USA-prior 7.12.1982)

Hayler, J.D et al.: Org Process Res Dev (OPRDFK) 2, 3 (1998)

Hayler, H.D.; Howie, S.L.B.; Negus, A.; Oxley, P.W.: J Heterocycl Chem (JHTCAD) 32 (3), 875 (1995)

dihydroindolinones as cardiovascular agents:

EP 300 6 14 (Smith Kline & French; appl 16.6.1988; GB-prior 19.6.1987)

AU 8 777 61 5 (Smith Kline & French; appl 25.1.1989; GB-prior 30.8.1986)

US 4 452 808 (Smith Kline & French; appl 5.6.1984; USA-prior 7.12.1982)

WO 9 415 918 (Smith Kline & French; appl 21.7.1994; GB-prior 8.1.1993)

use for treatment of Parkinson k disease:

EP 299 602 (Smith Kline & French; appl 18.1.1989; GB-prior 21.5.1987)

W O 9 71 1 696 (Cygnus Inc.; appl 6.9.1996; USA-prior 29.9.1995,4.9.1996)

WO 9 639 136 (SmithKline Beecham; appl 12.12.1996; GB-prior 6.6.1995)

WO 9 323 035 (SmithKline Beecham; appl 25.11.1993; GB-prior 18.5.1992)

WO 9 200 735 (SmithKline Beecham; appl 8.7.199 1 ; GB-prior 9.7.1990)

WO 9 706 786 (Scherer Ltd.; appl 16.8.1996; GB-prior 18.18.1995)

Trade Name(s):

Ropivacaine hydrochloride

(LEA- 103)

ATC: NOlBBOS) Use: local anesthetic

RN: 98717-15-8 MF: C17H,N20 HCI MW: 310.87

monohydrate

RN: 1321 12-35-7 MF: C,,H,,N,O HCI H 2 0 MW: 328.88

base

RN: 84057-95-4 MF: C,,H,,N,O MW: 274.41

Rosiglitazone R 1839

L-pipecolic

acid

L-pipecoloyl chloride

Ropivocoine hydrochloride

Reference(s):

WO 8 500 599 (Apothekemes Lab., Astra; WO-prior 1.8.1983)

WO 9 61 1 185 (Chiroscience; appl 9.10.1995; GB-prior 7.10.1994)

slorage stable optically pure hydrochloride monohydrate:

AU 8 666 449 (Astra, Nissan; appl 12.12.1986; S-prior 3.1.1986)

WO 9 636 606 (Astra; appl 30.4.1996; S-prior 16.5.1995)

composition with long/medium chain triglycerides:

EP 770 387 (Braun Melsungen; prior 28.10.1995)

sustained release formulation:

WO 9 641 616 (Euroceltique; USA-prior 9.6.1996)

combination with P-blocker:

WO 9 527 51 1 (Astra; appl 24.3.1995; S-prior 7.4.1994)

WO 9 505 198 (F M Borgbjerg; appl 16.8.1994; DK-prior 17.8.1993)

injection suspension:

WO 9 401 087 (Astra; appl 24.6.1993; S-prior 9.7.1992)

Trade Name(s):

Rosiglitazone

(BRL 49653)

Use: antidiabetic, insulin enhancer RN: 122320-73-4 MF: C,,H,,N,O,S MW: 357.43

(R)-(+)-form

RN: 163860-1 6-0 MF: CI8H,,N,O3S MW: 357.43

maleate

RN: 155141-29-0 MF: C,,H,,N3O3S C4H40 MW: 425.51

1840 R Rosiglitazone

F

1 2 0 ° C

ncnO

benzoldehyde 2-chloro- 2-(methylamino)- 2-(methyl-2-pyri-

pyridine ethanol

4-[2-(methyl-2-pyridlnyl-

arnino)ethoxy]benzoldehyde (I)

(52)-5-[[4-[2-(methyl-2

pyridinylamlno)ethoxy]-

phenyl]methylene]-2.4-

thiazolidinedione (11)

0

2.4-thiozo- lidinedione

Mg I* CHJOH

_)

Rosiglitozone

@ alternative biocatolytic reduction of 11 ond synthesis of the (R)-(+)-enontiomcr

Rosiglitazone

El

Rhodotorulo rubro CBS 6969, dioxone

w

Li+

H J C / Y H ~ C H , 1HF

C H J C H ,

FH3 m s g O o

Rosiglitozone

1

lithium tri-sec-butylborohydride