Pharmaceutical Substances Syntheses, Patents, Applications - Part 141 docx

improved racemate resolution with cinchonidine: DAS 2 319 245 Syntex; appl... preparation of 2-propionylnaphthalene: EP 176 142 Blaschim; appl.. resolution with dehydroabietylaminc: DAS

Naproxen N 1401

(5)-2-(5-bromo-6-

methoxy-2-nophthyl)

propanoic acid (XII)

@ Stereospecific Syntex process:

1 NaOH

ethyl (5)-loctate mesyl

II

Ms: -S-CH3

II

0

(IRC-50s resin), 115- 120 OC c H 3 H3C

process review:

Harrington, P.J.; Lodewijk, E.: Organic Process Res & Dev 1 , 7 2 (1997)

Harrison, J.T et al.: J Med Chem (JMCMAR) 13, 203 (1970)

a US 3 896 157 (Syntex; 22.7.1975; prior 13.1.1967,7.12.1967,4.11.1971)

US 3 904 682 (Syntex; 9.9.1975; prior 13.1.1967, 7.12.1967,24.3.1969, 31.8.1971, 21.6.1973)

US 3 978 116 (Syntex; 31.8.1976; prior 13.1.1967,7.12.1967,4.11.1971)

US 3 978 124 (Syntex; 31.8.1976; prior 13.1.1967,7.12.1967,4.11.1971)

US 3 998 966 (Syntex; prior 4.1 1.1971)

US 4 001 301 (Syntex; 4.1.1977; prior 4.11.1971)

US 4 009 197 (Syntex; 22.2.1977; prior 13.1.1967)

DAS 1 668 654 (Syntex; appl 8.1.1968; USA-prior 13.1.1967; 7.12.1967)

improved racemate resolution with cinchonidine:

DAS 2 319 245 (Syntex; appl 16.4.1973; USA-prior 21.4.1972, 11.4.1973)

DAS 2 008 272 (Syntex; appl 23.2.1970; USA-prior 24.3.1969)

US 3 663 584 (Syntex; 16.5.1972; appl 4.12.1970)

similar process with Cu-compound:

US 3 658 863 (Syntex; 25.4.1972; appl 30.9.1969)

similar process with Cd-compound:

IJS 3 694 476 (Syntex; 26.9.1972; appl 4.12.1970)

DOS 2 805 488 (Syntex; appl 9.2.1978; USA-prior 16.2.1977, 19.12.1977)

resolution with N-alkyl-D-glucamines:

US 4 515 81 1 (Syntex; 7.5.1985; USA-prior 6.7.1979, 26.11.1979)

EP 7 116 (Syntex; appl 17.7.1979; CH-prior 19.7.1978)

DOS 3 025 448 (Syntex; appl 4.7.1980; USA-prior 6.7.1979, 26.1 1.1979)

Ohta, T et al.: J Org Chem (JOCEAH) 52, 3174 (1987)

DOS 2 919 919 (Montedison; appl 17.5.1979; I-prior 22.5.1978)

US 4 239 9 14 (Montedison; 16.12.1980; I-prior 22.5.1978)

electrocurboxylation of 2-acetyl-6-methoxynaphthalene:

Chan, A S et al.: J Org Chem (JOCEAH) 60,742 (1995)

naphthacrylic acid via corresponding cyanohydrins:

US 3 637 767 (Syntex; 25.1.1972; appl 30.7.1968)

Giordano, C et al.: Tetrahedron (TETRAB) 45,4243 (1989)

US 4 579 968 (Zambon; 1.4.1986; I-prior 24.2.1984)

US 4 697 036 (Zambon; 29.9.1987; I-prior 6.8.1984)

US 4 810 819 (Zambon; 7.3.1989; appl 5.8.1987; USA-prior 5.4.1985)

US 4 855 464 (Zambon; 29.9.1987; I-prior 6.8.1984)

US 4 888 433 (Zambon; 29.9.1987; I-prior 6.8.1984)

preparation of 2-propionylnaphthalene:

EP 176 142 (Blaschim; appl 16.9.1985; I-prior 24.9.1984, 17.5.1985)

E P 301 31 1 (Zambon; appl 12.7.1988; I-prior 28.7.1987)

US 4 605 758 (Syntex; 12.8.1986; prior 11.12.1981, 23.4.1984)

US 4 749 804 (Syntex; 7.6.1988; prior 11.12.1981, 23.4.1984, 10.6.1986)

US 4 912 254 (Syntex; 27.3.1990; prior 11.12.1981,23.4.1984, 10.6.1986, 6.5.1988)

alternative syntheses:

DAS 1 934 460 (Syntex; appl 8.7.1969; USA-prior 30.7.1968)

US 3 637 767 (Syntex; 25.1.1972; appl 30.7.1968)

DAS 1 793 825 (Syntex; appl 8.1.1968; USA-prior 13.1.1967,7.12.1967)

resolution with dehydroabietylaminc:

DAS 2 339 765 (Syntex; appl 6.8.1973; USA-prior 10.8.1972)

resolution with (S)-a-phenylethylamine:

US 4 546 201 (Blaschim; 8.10.1985; I-prior 27.7.1983)

enzymatic cleavage of esters of racemic naproxen:

US 4 857 462 (Boehringer Mannh.; 15.8.1989; D-prior 16.12.1983)

EP 195 717 (Montedison; appl 17.3.1986; I-prior 22.3.1985)

EP 233 656 (Gist-Brocades; appl 6.1.1987; GB-prior 7.1 l986)

EP 330 217 (1st Guido Donegani; appl 24.2.1989; I-prior 25.2.1988,29.7.1988)

Formulation(s): f c tabl 250 mg, 500 mg, 1000 mg; suppos 250 mg, 500 mg; susp 125 mg15 ml,

250 mg/5 ml; tabl 250 mg, 375 mg, 500 mg, 750 mg (as acid); f c tabl 550 mg; tabl 275 mg,

550 mg, 375 mg, 500 mg (as sodium salt)

Trade Namefs):

D: Apranax (Roche; Syntex) Naprosyne (Cipharm; I: Aperdan (ABC

Proxen (Roche; Syntex; Naprosyn (Roche; 1973) Euroter.)

Naratriptan N 1403 Axer Alfa (Alfa

Wassermann; as sodium

salt)

Floginax (Teofarma)

Flogogin (Angelini; as

sodium salt)

Floxalin (Salus Research;

as sodium salt)

Gibinap (Metafarm)

Gibixen (Metafarm)

Laser (Tosi-Novara)

Leniartril (Sancarlo)

Naprius (Aesculapius-Rs) Naprorex (Lampugnani) Naprosyn (Recordati) Neoblimon (Guidotti) Nitens (Pulitzer)-comb

Numidan (Therabel Pharma)-comb

Piproxen (Nuovo ISM)- J:

Prexan (Lafare) Primeral (Master Pharma;

as sodium salt)

Proxine (Del Saz &

Filippini) Synalgo (Geymonat) Synflex (Recordati; as sodium salt)

Ticoflex (Farma Uno) Xenar (Alfa Wassermann) Naixan (Tanabe) Anaprox (Roche) Naprosyn (Roche; 1976) generics

Naratriptan

(GR-85548)

ATC: N02CC02 Use: antimigraine agent, 5-HT,-agonist RN: 121 679-13-8 MF: C,,HzsN30zS MW: 335.47

CN: N-methyl-3-(l-methyl-4-piperidinyl)-lH-indole-5-ethanesulfonamide

hydrochloride

RN: 121 679- 19-4 MF: C,,H,,N,O,S xHC1 MW: unspecified

monohy drochloride

RN: 143388-64-1 MF: C,,H2,N302S HCl MW: 371.93

0

KOH, CHJOH 20 "C

1 -methyl-4- piperidone (11)

"

\\ A \ DMF 110 "C

111 + H 3 C @ S \ C H ,

u n pollodium ocetote (V)

, I -

tri-p-tolylphosphine (VI)

N-methylvinyl-

Hz Pd-C DMF, HzO

1 N v VI

DMF 110 "C

2 H,, Pd-C

or:

H 0

KOH CH,OH, A

I-hydroxy-

1 -methyl-

piperidine

H 1 11 KOH, A

IV v VI

I -b

1 potassium hydroxide

Natamycin N 1405

1 2N HCI, 20 OC

polyphosphate ester

CH3

2-(4-hydrazinophenyl)- 2-(1 -methyl-

N-methylethanesulfon- 4-piperidinyl)

wo 9 509 166 (Glaxo; appl 6.4.1995; GB-prior 29.9.1993)

EP 303 507 (Glaxo; appl 15.2.1989; GB-prior 13.8.1987, 14.6.1988, 17.6.1988)

Fomtulation(s): tabl 2.5 mg (as monohydrochloride)

Trade Name(s):

D: Naramig (Glaxo Wellcornel

Cascan)

Natamycin

(Pimaricin)

ATC: A01 AB 10; A07AA03; DOlAA02;

G01AA02; S01AA10 Use: fungicidal antibiotic RN: 7681-93-8 MF: C,,H,,NO,, MW: 665.73 EINECS: 231-683-5

LD,,: >5 g k g (M, i.v.); 1500 m g k g (M, p.0.);

36 mglkg (R, i.v.); 2730 m g k g (R, p.0.);

18 mgkg (dog, i.v.); >300 m g k g (dog, p.0.)

CN: [ I R-(1 R*,3S*,5R*,7R*,8E,12R*, 14E,16E,18E,20E,22R*,24S*,25R*,26S*)]-22-[(3-amino-3,6-dideoxy-~-

D-mannopyranosyl)oxy]-1 ,3,26-trihydroxy- l2-methyl-lO-oxo-6,11,28-trioxatricyclo[22.3.1.0'~7]octacosa-

8,14,16,18,20-pentaene-25-carboxylic acid

Notomycin

From fermentation solutions of Streptomyces natalensis

Reference (s):

GB 844 289 (Konigl Niederl Gist- & Spiritusfabr.; appl 1957; NL-prior 1956)

GB 846 933 (American Cyanamid; appl 1957; USA-prior 1956)

Fomtulation(s): cream 2 gllOO g; drg 100 mg; ointment 10 mglg; tabl 10 mg

Trade Name(s):

D: Deronga (Galderma)

Pima Biciron (S & K

Pharma)

Pimafucin (Galderma) F: Pimafucine (Beytout); wfm Pimafucort (Yamanouchi)- Pimafucine (Duphar); wfm

GB: Pimafucin (Brocades); wfm I: Natafucin (Yamanouchi J: Pimafucin (Toni)-comb

Nateglinide Use: hypoglycemic agent

(A 4 1 66; Ay 4 16; SDT-DJN 608)

RN: 105816-04-4 MF: C,,H,NO, MW: 317.43

(S)-(-)-perillic

ocid

/J,,,(CH~

CH3 trons-4-isapropylcyclo- hexanecarbonyl chloride (1)

107; oq NaOH, acetone

Noteglinide

I

curninic ocid

1 NOH 1 50°C

2 2 N NaOH, CH30H

3 H C , recrystallization

O-phcnylalanine

methyl ester

HOOC

~ l f tHI ~ ~ C

CH3

trons-4-isopmpyl- cyclohexanecarboxylic acid

0

H O - N > DCC, CHCI,

0

2 2 N NoOH CH,OH

Nateglinide

1 N-hydroxysuccinirnide

EP 196 222 (Ajinomoto; appl 26.3.1986; J-prior 27.3.1985)

Nazasetron N 1407

preparation of I:

JP 7 017 899 (Ajinomoto; appl 1.7.1993)

stable crystals:

US 5 463 11 6 (Ajinomoto; 3 1 lo 1999; J-prior 30.7.1991)

tablet formulation:

WO 9 822 105 (Ajinomoto; appl 14.1 1.1997; J-prior 15.1 1.1996)

Fornwlation(s): tabl 30 mg

Trade Name(s):

J: Starlix (Ajinomoto, 1999)

Nazasetron

(Y-25 130)

ATC: A04AA Use: anti-emetic, 5-HT3-antagonist

RN: 123040-69-7 MF: C17H20CIN,03 MW 349.82

CN: (~)-N-l-azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazine-8-

carboxamide

monohydrochloride

RN: 141922-90-9 MF: CI7H2,C1N3O3 HCl MW: 386.28

(-)-enantiomer

RN: 123040-95-9 MF: C17H20CIN303 MW: 349.82

(-)-enantiomer monohydrochloride

RN: 123040-96-0 MF: C,,Hz0CIN3O3 HCI MW: 386.28

(+)-enantiomer

RN: 123040-93-7 MF: C17H,ClN,03 MW: 349.82

(+)-enantiomer hydrochloride

RN: 123040-94-8 MF: C17H,C1N,03 HCI MW: 386.28

methyl 5-chloro-

salicylate

methyl 5-chloro-3- methyl 3-omino- nitrosolicylote 5-chlorosolicylote (1)

,o 0 1 K2C03, DMF

brornoocetyl

chloride

methyl 3-(2-bromo- ocetylomino)-5-chloro-

6-chloro-3.4-

dihydro-4-methyl-

3-0x0-2H-1.4-benz-

oxazine-8-

carboxylic ocid (U)

6-chloro-3.4- dihydro-4-methyl- 3-0x0-2H-1,4-benz- oxozine-8- corbonyl chloride @I)

Reference(s):

EP 3 13 393 (Yoshitomi; appl 21.10.1988; J-prior 22.10.1987,25.12.1987, 13.1.1988)

stable crystalline structure of (+)-enantiomer:

JP 07 070 120 (Yoshitomi; appl 5.7.1994; I-prior 5.7.1993)

medical use:

JP 08 027 001 (Yoshitomi; J-prior 13.7.1994)

JP 0 8 027 000 (Yoshitomi; J-prior 13.7.1994)

JP 0 8 026 999 (Yoshitomi; J-prior 12.7.1994)

WO 9 601 630 (Yoshilomi; appl 7.7.1995; J-prior 12.7.1994)

suppositoryformulation:

JP 06 305 969 (Yoshitomi; appl 27.4.1993; J-prior 27.4.1993)

light-stabilized injection solution:

WO 9 425 032 (Yoshitomi; appl 25.4.1995; J-prior 28.4.1994)

Formulation(s): amp for injection 10 mg/2 ml

Trade Name(s):

J: Serotone (Yoshitomi;

TobaccoIGreen Cross)

(ME-3255; R-65824; R-67555 as hydrochloride) Use: antihypertensive, fl,-adrenergic

blocker

RN: 1 18457- 14-0 MF: C22H25F2N04 MW: 405.44

CN: [2R*[R*[R*(S*)]]]-a,a'-~iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] hydrochloride

RN: 152520-56-4 MF: C22H25F2N04 HC1 MW: 441.90

Nedaplatin N 1409

0

0 COOH 3 H3C\r~~9CH3 , toluene

F 2 1,l'-corbonylbis- F

u

(1 H-imidozole) 6-fluoro-4-oxo- 3 bis(2-rnethylpropyl)- 6-fluoro-3.4-dihydro-

benzopyron-2- olurninum hydride 2H-benzopyran-2-

carboxylic ocid carboxaldehyde (I)

6-fluoro-3.4-dihydro- 2-oxiranyl-2H-1- benzopyran

Reference(s):

EP 145 067 (Janssen Pharm.; appl 22.1 1.1984; USA-prior 5.1 2.1983)

Formulation(s): tabl 5 mg (as hydrochloride)

Trade Name(s):

D: Nebilet (Berlin-Chemie) '

Nedaplatin

( S 254)

Use: antineoplastic platinum complex

RN: 95734-82-0 MF: C2H8N203Pt MW: 303.18

LD,,: 20 mgkg (R, i v.);

44.1 m g k g (M, i v.);

4 mgkg (dog, i v.)

CN: (~~-4-3)-~iammine[h~drox~acetato(2-)-O',0~]platinum

H3NL p H 3 AgNO, H3N\p:NH3 onion exchange resin H3N\ dNH3

CI/ \CI 02N-0 0 - N O 2 HO' \OH

cisplatin (q v.) diarnrnineplatinurn

glycolic

acid

Nedaplotin

Reference(s):

JP 59 222 497 (Shionogi & Co.; appl 1.6.1983)

US 4 575 550 (Shionogi & Co.; J-prior 11.3.1986; appl 14.4.1983; J-prior 23.10.1981; USA-prior 6.1.1982) Totani, T.; Aono, K.; Komura, M.; Adachi, Y.: Chern Lett (CMLTAG) 1986 (3), 429

Trade Narne(s):

J: Aqupla (S hionogi)

Use: antiallergic, antiasthmatic RN: 69049-73-6 MF: Cl,H17N07 MW: 371.35

CN: 9-ethyl-6,9-dihydro-4,6-dioxo-1O-propyl-4H-pyrano[3,2-g]quinoline-2,8.dicarboxylic acid

disodium salt

RN: 69049-74-7 MF: C,,H,,NNa,O, MW: 41 5.31

LD,,: 2000-4000 mgkg (R, dog, i.v.); >5000 mglkg (R, dog, p.o., s.c.)

4-(acelylethylomino)- ally1

2-hydroxyacetophenone bromide

4-(acety1ethylamino)- 2-allyloxyocetophenone (I)

O V O T H ~

CH3 polyphorphoric acid

iH3

C

o A o - c H 3

dimethyl acetylene- dimethyl [N-(4-acetyl- methyl 1 -ethyl-6-ocetyl-7-

dicarboxylote 3-hydraxy-2-propylpheny1)- hydroxy-4-0x0-8-propyl-