United States Patent [19] [11] Patent Number: 4,585,877

Demerson et al. [45] Date of Patent: Apr. 29, 1986

[54] PROCESS FOR PREPARING [56] References Cited

1,8-DIETHYL-l,3,4,9-TETRAHY- S PATENT D NT
DROPYRANO(3,4-B)-INDOLE-l-ACETIC U‘ ' OCUME S
ACID’ ETQDQLAC 3,939,178 2/ 1976 Demerson et a1. . . . . . . . . .. 548/432
4,012,417 3/1977 Demerson et a1. .... .. 548/432
4,021,451 5/ 1977 Dobson et a1. . ................... .. 548/432
[75] Inventors: Christopher A. Demerson, LI AT
Plainsboro; Leslie G. Humber, North OTHER PUB c IoNS
Brunswick, both of NJ’ Demerson et al., J. Med. Chem, 19, 391 (1976).
I. I. Grandberg and T. P. Moskvina, Khim. Geterotsikl.
Soedin., 1366 (1972), English translation.
[73] Assignee: American. Home Products Prima1y Examzner—-Dona1d
' G. Daus
Corpomnon’ New York’ NY‘ Assistant Examiner-Mary E. Ceperley
Attorney, Agent, or Firm-Walter Patton; John W.
[21] Appl. No.: 730,963 Routh
[57] ABSTRACT
[22] Filed: May 6’ 1985 A process for preparing 1,8-diethy1-l,3,4,9-tetrahy
dro[3,4-b]-indole-I-acetic acid (etodolac) is disclosed.
Etodolac is a useful antiin?ammatory and analgesic
[51] Int. Cl.4 ............... .. C07D 491/052; C07D 209/12 agent
[52] US. Cl. ................................... .. 548/432; 548/508
[58] Field of Search .............................. .. 548/432, 508 4 Claims, N0 Drawings
 4,585,877
1 2
PROCESS FOR PREPARING -continued
PROCESS FOR THE PREPARATION OF ETODOLAC
1,8-DIETHYL-1,3,4,9-TETRAHYDROPYRANO(3,4
B)-INDOLE-1-ACETIC ACID, ETODOLAC
BACKGROUND OF THE INVENTION
This invention relates to the process for the prepara Example 3
tion of l,8-diethyl-l,3,4,9-tetrahydropyrano[3,4-b]in
dole-l-acetic acid, also designated etodolac, disclosed
as a potent antiin?ammatory and analgesic compound OCH3
in Demerson et al., U.S. Pat. No. 3,939,178.
Preparations for pyrano[3,4-b]indoles have been pre CZHSJ\/ CO2CH3
viously described in Demerson et al., U.S. Pat. Nos. OH Example 4 E
3,939,178 and 4,012,417 and in Demerson et al., J. Med. N
Chem, 19, 391 (1976). | H2504 R.T.
Demerson et al., U.S. Pat. Nos. 3,939,178 and H Example 1
4,012,417 disclose reaction of substituted tryptophols 7-ethyltryptophol HC(OcH3)3
with keto ester to produce pyrano[3,4-b]indoles (see
col. 9, lines 5 to 35). Etodolac is produced according to 20
Example 477 of U.S. Pat. No. 4,012,417 by the reaction
of 7-ethyltryptophol and the keto ester, ethyl propiony O
N
lacetate, followed by alkaline hydrolysis. The 7-ethyl l CO0CI-l3
tryptophol is produced by the reaction of Z-ethyl H
phenylhydrazine with 4-hydroxybutyraldehyde. 25 + KOH
Demerson et al., J. Med. Chem., 19, 391 (1976) also Example 4
discloses the preparation of pyrano[3,4-b]indoles by the
reaction of substituted tryptophols with keto esters. The O 0
ll ll
7-ethyltryptophol, necessary for the production of
etodolac, is prepared by the reduction of ethyl 7-ethyl 30 Noon; N 0
3-indolylglyoxylate with LiAlH4 (page 394, right col 1 coon
umn). The glyoxylate is produced by the reaction of H
7-ethylindole with oxalyl chloride. The 7-ethylindole is etodolac
produced from 2-ethylaniline in a thee step process.
Demerson et al., also discloses the preparation of 7 35 The following Examples will further illustrate this
cyclopropyltryptophol by the reaction of 2-cyclo invention.
propylphenylhydrazine hydrochloride with 2,3-dihy EXAMPLE 1
drofuran using the method described by I. I. Grandberg
and T. P. Moskvina, Khim. Geterotsikl, Soedin., 1366 3-Methoxy-2-pentenoic Acid Methyl Ester
(1972). To a mixture of methyl propionylacetate (104 g. 0.8
SUMMARY OF THE INVENTION mole) and trimethyl orthoformate 98% (95.3 g, 0.88
mole) was added dropwise 1 m1 of concentrated H2SO4
According to the process of the present invention, at room temperature and it was allowed to stir over
etodolac is produced by the reaction of 7-ethyltrypto night. After neutralization with excess anhydrous
phol with 3-methyoxy-2-pentenoic acid methyl ester at K2CO3, the solution was ?ltered and distilled to yield
room temperature followed by alkaline hydrolysis. The the title ester, b.p. 55° C. (0.55 mm).
7-ethyltryptophol is produced directly by the reaction
of Z-ethylphenylhydrazine hydrochloride with 2,3 EXAMPLE 2
dihydrofuran. The 3-methoxy-2-pentenoic acid methyl 50
Z-Ethylphenylhydrazine Hydrochloride
ester is produced by the reaction of methyl propiony A vigorously stirred solution of 487 ml concentrated
lacetate with trimethyl orthoformate in the presence of hydrochloric acid and 218 ml of water at 0° C. was
sulfuric acid. With the exception of an optional short treated dropwise with 1.93 moles (234 g) of Z-ethylani
heating period in the reaction of 2-ethylphenylhydra line. To the resulting thick suspension was added a
zine with 2,3-dihydrofuran, and the hydrolysis of the solution of sodium nitrite (143 g, 2.07 moles) in 218 ml
etodolac ester to etodolac in the ?nal step, all the steps of water over 1.5 hours while maintaining the internal
are carried out at or below room temperature. The
temperature between 8° C. and 14° C. Next, a solution
process of the present invention is illustrated by the of SnCl2.2H2O (4.37 moles, 985 g) in 1.3121 of 1:1 con
following scheme. centrated hydrochloric acidzwater was added over 5
60 hours while the internal temperature was kept between
PROCESS FOR THE PREPARATION OF ETODOLAC 5° C. and 10° C. After 15 hours, the solid was collected
on a ?lter paper and boiled in 1.2 l of water with decol
(a) NaNO; orizing carbon. The solution was ?ltered through Cel
HCl(aq) ite, treated with 400 ml of concentrated hydrochloric
(b) SnClZ 65 acid and put in an ice bath for 0.5 hours. The tan plates
Example 2 5
were ?ltered and dried in vacuo over phosphorous
pentoxide for 24 hours affording title compound, m.p.
l8l°-l83° C.
 4,585,877
3 4
NMR (D20): 1.039 (t,J=7.6l, 3H, CH3), 2.45 Typical results obtained with these tests are:
(q,J=7.6l, 2H, CH1) 4.630 (HOD, reference),
7.0l8-7.194 (m, 4H, aromatics). Preventive Adjuvant-Edema
EXAMPLE 3 compound EDSO "lg/kg, P-O
etodolac 4
7-Ethyltryptophol aspirin 184
Drug Effects Phenyquinone-Induced Writir_1g in Mice
2,3-Dihydropyran (2.2 g, 0.0314 mol) was added
compound antinociceptive
dropwise over 0.25 hours to a stirred mixture of 2-ethyl ED50 mg/kg, p.o.
phenylhydrazine hydrochloride (5.0 g, 0.03 mol), diox etodolac 154
ane (40 ml) and water (1.8 ml) at room temperature. aspirin 54
After the addition was complete the mixture was heated
at 95° C. for 4 hours, cooled, diluted with diethyl ether Further tests for demonstrating the utility of etodolac
and decanted. The ethereal phase was dried (MgSO4), are found in US. Pat. No. 3,939,178. The formulation
?ltered, and concentrated to give 4.3 g of oil. Flash and dose of etodolac to be used in the treatment of
chromatography using 40% ethyl acetate in hexane as inflammation and pain are also set forth in US. Pat. No.
an eluant gave the title compound. 3,939,178.
We claim:
NMR (CDCl3): # of protons type chemical shift (6) 1. A process for preparing the compound 1,8-diethyl
l,3,4,9-tetrahydropyrano[3,4-b]indole-l-acetic acid of
3 CH3 1.3 (t, J = 7)
1 0H 1.8 (bs, OH)
the formula
2 CEgCl-lg, 2.85 (q, I = 7)
2 iCl-l; 3.0 (t, J = 6.5)
2 CH20 3.9 (t,J = 6.5)
4 aromatic 7.3 (m)
1 NH 8.1 (bs) 25
0

COOH
EXAMPLE 4
l, S-Diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole- l 30 comprising reacting the compound 7-ethyltryptophol of
acetic Acid. Etodolac formula
A mixture consisting of 7-ethyltryptophol (3.8 g, 0.02
mol), 3-methoxy-2-pentenoic'acid, methyl ester (7 ml),
dichloromethane (100 ml) and boron tri?uoride etherate
(0.2 ml) was stirred at room temperature for 2.5 hours. 35
The solution was washed twice with 5% aqueous so
dium bicarbonate, water, dried (MgSO4), ?ltered, and
concentrated to give 9.7 g of an oil that solidi?ed on
standing. This was dissolved in methanol (30 ml), and a
solution of potassium hydroxide (6.5 g, 0.12 mol) in 40 with 3-methoxy-2-pentenoic acid, methyl ester of for
water (5 ml) added. The solution was re?uxed for 3 mula
hours, cooled, concentrated and diluted with 20 ml
water. The aqueous solution was washed twice with ocn;
diethyl ether, acidi?ed with 6N HCl and extracted
twice with chloroform. The combined chloroform ex 45
tracts were washed with water, dried (MgSO4) ?ltered,
and concentrated to give the title compound as an oil and hydrolyzing the ester with base.
that solidi?ed on standing. Recrystallization was from 2. The process according to claim 1 wherein the
benzene-petroleum ether, m.p. l46°~l47° C. reaction of 7-ethyltryptophol with 3-methoxy-2-pen
The useful antiin?ammatory and analgesic activities 50 tenoic acid, methyl ester is carried out in the presence of
of etodolac may be demonstrated by standard pharma boron tri?uoride etherate.
cological tests. The antiin?ammatory activity may be 3. The process according to claim 2 wherein a mix
demonstrated by the Preventive Adjuvant Edema test ture consisting of 7-ethyltryptophol, 3-methoxy-2-pen
described in J. Wax, et al., J. Pharmacol. Exp. Ther., tenoic acid, methyl ester and boron tri?uoride etherate
192, 166-171 (1975). The analgesic activity may be 55 are stirred in dichloromethane solvent.
demonstrated by the Effects on Phenylquinone-Induced 4. The process according to claim 3 wherein stirring
writhing in Mice test described in E. Siegmund et al., is carried out at room temperature for about 2.5 hours.
Proc. Soc. Exp. Biol. Med., 95, 729—731 (1957). i i‘ * i i

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