Preparation of mibefradil via a naphthalenylacetic acid

A method of preparing 2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate comprises contacting (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid or an activated derivative of (6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid with 3-(1H-benzimidazol-2-yl)propyl!methylamine to form N-3-(1H-benzimidazol-2-yl) propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 ,4-tetrahydronaphthalen-2- yl)-N-methylacetamide, reducing this to 2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro pyl-1, 2,3,4-tetrahydronaphthalen-2-ol, and treating the 2-2-{3-(1H-benzimidazol-2-yl) propyl!-methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthal en-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid. The invention is particularly applicable to the preparation of mibefradil, (1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}-ethyl!-6-fluoro -1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its dihydrochloride salt. N-3-(1H-benzimidazol-2yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide is new.

CROSS-REFERENCE TO RELATED APPLICATIONS 
This application claims the benefit under 35 USC 119(e) of provisional 
application No. 60/046,795, filed Apr. 30, 1997, which is incorporated 
herein by reference in its entirety. 
The subject matter of this application is related to the subject matter of 
application Ser. No. 09/060,151 (Attorney Docket No. 22138-1004), entitled 
"PREATION OF MIBEFRADIL VIA AN ACETAMIDE ANION", and of application 
Ser. No. 09/060,401 (Attorney Docket No. 22138-1006), entitled 
"PREATION OF MIBEFRADIL VIA AN ACETONITRILE ANION", both filed 
simultaneously with this application. Application Ser. No. 09/060,151 
claims the benefit under 35 USC 119(e) of provisional application No. 
60/045,151, filed Apr. 30, 1997, and application Ser. No. 09/060,401 
claims the benefit under 35 USC 119(e) of provisional application No. 
60/045,150, filed Apr. 30, 1997 These applications and other documents 
referred to elsewhere in the specification of this application are 
incorporated herein by reference in their entirety. 
BACKGROUND OF THE INVENTION 
This invention relates to the preparation of mibefradil and its 
dihydrochloride salt. 
U.S. Pat. No. 4,808,605 (to Hoffmann-La Roche) discloses various calcium 
antagonists including mibefradil, 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 
1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, the 
dihydrochloride salt of which is the antihypertensive POSICOR.RTM.. The 
synthesis of mibefradil, as described in that patent, involves the 
reaction of 
(1S,2S)-6-fluoro-1-isopropyl-2-2-(4-toluenesulfonyloxy)ethyl!-1, 
2,3,4-tetrahydronaphthalene-2-ol with 
3-(1H-benzimidazol-2-yl)propyl!methylamine in the presence of Hunig base 
(ethyldiisopropylamine) to form 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)-propyl!methylamino}ethyl!-6-fluoro 
-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, which is then acylated with 
methoxyacetyl chloride to form mibefradil. 
The (1S,2S)-6-fluoro-1-isopropyl-2-2-(4-toluenesulfonyloxy) 
ethyl!-1,2,3,4-tetrahydro-naphthalene-2-ol, as described in U.S. Pat. No. 
4,680,310 (also to Hoffmann-La Roche), is prepared by reacting 
(S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl 
bromoacetate in the presence of activated magnesium to form tert-butyl 
(1S, 2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl 
)acetate, which is reduced with lithium aluminum hydride to form 
(1S,2S)-6-fluoro-2-(2-hydroxyethyl)-1-isopropyl-1,2,3,4-tetrahydro-naphtha 
len-2-ol, and then reacted with 4-toluenesulfonyl chloride in pyridine to 
form the (1S,2S)-6-fluoro-1-isopropyl-2-2-(4-toluenesulfonyloxy) 
ethyl!-1,2,3,4-tetrahydronaphthalene-2-ol. 
It would be of value to have a method for the preparation of mibefradil and 
mibefradil dihydrochloride that affords the desired compound easily and in 
reproducible high yield and purity, and is readily adaptable to large 
scale commercial production. 
BRIEF SUMMARY OF THE INVENTION 
In a first aspect, this invention provides N-3-(1H-benzimidazol-2-yl) 
propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-y 
l)-N-methylacetamide, and in particular its (1S,2S)-enantiomer. 
In a second aspect, this invention provides a method of preparing 
N-3-(1H-benzimidazol-2-yl) 
propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-y 
l)-N-methylacetamide, and in particular its (1S,2S)-enantiomer, comprising 
contacting 
(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic 
acid or an activated derivative of 
(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acetic 
acid, and in particular its (1S,2S)-enantiomer, with 
3-(1H-benzimidazol-2-yl)propyl!methylamine. 
In a third aspect, this invention provides a method of preparing 
2-2-{(3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopr 
opyl-1, 2,3,4-tetrahydronaphthalen-2-ol, and in particular its 
(1S,2S)-enantiomer, comprising reducing 
N-3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3 
,4-tetrahydro-naphthalen-2-yl)-N-methylacetamide, and in particular its 
(1S,2S)-enantiomer, especially with a metal hydride. 
In a fourth aspect, this invention provides a method of preparing 
2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro 
pyl-1, 2,3,4-tetrahydronaphthalen-2-yl methoxyacetate and its acid addition 
salts, and in particular its (1S,2S)-enantiomer, comprising preparing 
2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}-ethyl!-6-fluoro-1-isopr 
opyl-1,2,3,4-tetrahydronaphthalen-2-ol, and in particular its 
(1S,2S)-enantiomer, as described above, and contacting the product with 
methoxyacetic acid or an activated derivative of methoxyacetic acid, 
optionally followed by formation of an acid addition salt, especially the 
dihydrochloride salt. 
In particular, this invention relates to the preparation of mibefradil, 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 
1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, and its 
dihydrochloride salt.

DETAILED DESCRIPTION OF THE INVENTION 
While the invention will be generally described with reference to the 
preparation of mibefradil, it will be apparent to one of ordinary skill in 
the art that the coupling of 
(R)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one with tert-butyl 
acetate, hydrolysis, and subsequent reaction with 
3-(1H-benzimidazol-2-yl)propyl!methylamine, will result in the 
preparation of 
(1R,2R)-N-3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isoprop 
yl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, which may be used 
to prepare the (1R,2R)-enantiomer of U.S. Pat. No. 5,120,759 in the same 
manner as the (1S,2S)-isomer is used here to prepare mibefradil. 
Accordingly, unless the context requires otherwise, reference to any 
compound is to be considered as a reference to individual enantiomers of 
the compound, and to racemic or non-racemic mixtures thereof 
The process of this invention may be represented schematically as follows: 
##STR1## 
Definitions 
An "activated derivative" of 
(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl) acetic 
acid is a derivative that renders the acid more active in the reaction 
with 3-(1H-benzimidazol-2-yl)propyl!methylamine to form 
(1S,2S)-N-3-(1H-benzimidazol-2-yl) 
propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-y 
l)-N-methylacetamide. Typical such derivatives include the corresponding 
acyl halides and anhydrides, and a preferred activated derivative is the 
mixed anhydride of(6-fluoro-2-hydroxy-1-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetic acid with trimethylacetic acid. 
An "activated derivative" of methoxyacetic acid is a derivative that 
renders the acid more active in the esterification of 
2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1-isopro 
pyl-1,2,3,4-tetrahydronaphthalen-2-ol. Typical such derivatives include the 
methoxyacetyl halides and methoxyacetyl anhydride, and a preferred 
activated derivative is methoxyacetyl chloride. 
An "aprotic polar solvent" includes organic solvents that may be either 
water-immiscible, such as halogenated hydrocarbons, e.g. methylene 
chloride, or water-miscible, such as ethers, e.g. tetrahydrofuran and 
bis(2-methoxyethyl ether), dimethylformamide, N-methylpyrrolidone, 
dimethylsulfoxide, etc. The solvent may also contain minor proportions of 
aprotic non-polar solvents such as hydrocarbons, e.g. cyclohexane, 
toluene, etc., provided that the solvent properties are largely determined 
by the polar solvent. 
Starting Materials 
Compounds 1. 6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one and its 
(S)-isomer are known, for example, from U.S. Pat. No. 4,680,310, where 
their preparation from 2-(4-fluorophenyl)-3-methylbutyric acid and its 
(S)-isomer are disclosed. 
(R)-6-Fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one is known, for 
example, from U.S. Pat. No. 5,120,759, where its preparation from 
(R)-2-(4-fluorophenyl)-3-methylbutyric acid is disclosed. 
Compounds 2. tert-Butyl 
(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) acetate 
and its (1S,2S)-isomer are known, for example, from U.S. Pat. No. 
4,680,310. tert-Butyl 
(1R,2R)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetate is known, for example, from U.S. Pat. No. 5,120,759. An alternative 
synthesis of the tert-butyl ester is shown in the Example. 
Compounds 3. 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetic acid is known from H.R. Wiltshire et al., Xenobiotica, 22(7), 
837-857 (1992), as a biliary metabolite of mibefradil in the rat, but no 
synthesis is given. 
Compound 4. 3-(1H-Benzimidazol-2-yl)propyl!methylamine is known, for 
example, from U.S. Pat. No. 4,808,605, where its preparation from 
4-1-benzyloxy-N-methylformamido!-butyric acid is disclosed. 
All other reagents and solvents are readily commercially available, for 
example from Aldrich Chemical Company or equivalent suppliers. 
The Process 
In the first step, 
(S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one, compound 1, is 
converted to tert-butyl 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetate, compound 2, by reaction with the anion of tert-butyl acetate. 
Typically, tert-butyl acetate is treated with a strong base such as 
lithium diisopropylamide in an aprotic polar solvent. The tetralone (1) is 
added to the resulting solution at a reduced temperature, such as at 
-20.degree. C., and the resulting ester (2) is isolated by neutralization 
of the reaction mixture, extraction into a water-immiscible organic 
solvent, and evaporation of the solvent. 
In the second step, the ester (2) is hydrolyzed with acid to give 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetic acid, compound 3. The hydrolysis 
may be carried out under conventional conditions for ester hydrolysis, 
such as with the use of trifluoroacetic acid, but a preferred hydrolysis 
method uses formic acid as both the solvent and hydrolysis catalyst at 
room temperature. The acid (3) can be isolated simply by dilution of the 
formic acid solution with water and cooling, thereby precipitating the 
acid (3). 
Alternative routes to the acid (3) include the base-catalyzed hydrolysis of 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetonitrile, which may be prepared from the tetralone (1) by reaction with 
the anion of acetonitrile; and the base-catalyzed hydrolysis of 
(1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetamide, which may also be prepared from 
the tetralone (1) by reaction with the anion of N,N-dimethylacetamide. 
These routes are shown in the Preparation. 
In the third step, the acid (3) is reacted with 
3-(1H-benzimidazol-2-yl)propyl!-methylamine, compound 4, to form 
(1S,2S)-N-3-(1H-benzimidazol-2-yl) 
propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-y 
l)-N-methylacetamide, compound 5. Typically, the acid (3) is activated by 
reaction with a trimethylacetyl halide in the presence of an organic base 
in an organic solvent such as toluene to form the mixed anhydride, which 
is used as-is in the solution in which it is formed. The mixed anhydride 
solution is contacted with a solution of the amine (4), forming 
(1S,2S)-N-3-(1H-benzimidazol-2-yl) 
propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-y 
l)-N-methylacetamide, compound 5. A typical recovery procedure for the 
amide-alcohol (5) involves quenching the reaction mixture with water and 
extraction of the amide-alcohol (5) into a water-immiscible organic 
solvent, such as the toluene used as the reaction solvent. The 
amide-alcohol (5) may be purified by crystallization from an organic 
solvent such as toluene. The amide-alcohol (5) is new. 
In the fourth step, the amide-alcohol (5) is reduced to 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl) propyl!methylamino } 
ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol, compound 6. 
The reduction is performed with a reducing agent having a high degree of 
specificity for the reduction of the amide carbonyl group to a methylene 
group without affecting other portions of the molecule; and suitable 
reducing agents include the metal hydrides, in particular sodium 
bis(2-methoxyethoxy)aluminum hydride. Typically, the amide-alcohol (5), in 
solution in an organic solvent such as toluene, is treated with an excess 
of the reducing agent (approximately 2.25-3 equivalents when the reducing 
agent is sodium bis(2-methoxyethoxy)- aluminum hydride), also in solution, 
by addition of the amide-alcohol (5) to the reducing agent, though the 
reverse addition is also satisfactory. The crude amide-alcohol (5) 
solution from the previous step may be used without purification in this 
step. A typical temperature for the addition is between -5.degree. C. and 
10.degree. C.; and the reaction is allowed to continue to completion, 
typically for approximately 20-24 hours at room temperature or 2-3 hours 
at 40-45.degree. C. Following completion of the reaction, the reaction 
mixture is treated in a conventional manner to recover the alcohol (6). A 
typical recovery procedure for the resulting alcohol (6) involves 
quenching the reaction mixture with aqueous base and extraction of the 
alcohol (6) into a water-immiscible organic solvent, such as the toluene 
used as the reaction solvent. 
The alcohol (6) may be isolated if desired by conventional methods, such as 
by drying the solution containing it with a drying agent such as anhydrous 
sodium sulfate and evaporation of the solvent. However, it will preferably 
be isolated as an acid addition salt, such as the dioxalate salt. 
Preparation and isolation of the dioxalate salt may be performed by 
conventional methods for the formation of acid addition salts. A presently 
preferred method, using acetic acid as the solvent, is shown in the 
Example: the use of acetic acid as solvent is valuable in that it gives 
the dioxalate salt of the alcohol (6) in especially pure form. 
In the fifth step, the alcohol (6) is esterified with methoxyacetic acid or 
an activated derivative of methoxyacetic acid to form mibefradil, 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)-propyl!methylamino}ethyl!-6-fluoro 
-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, compound I, 
which is typically isolated as an acid addition salt, especially the 
dihydrochloride salt. This esterification reaction is known from U.S. Pat. 
No. 4,808,605, where it is performed with methoxyacetyl chloride in 
chloroform in the presence of ethyldilsopropylamine; and it will be 
evident to one of ordinary skill in the art that methoxyacetic acid or 
other activated derivatives of methoxyacetic acid and other reaction 
conditions such as are typical in esterification of alcohols may be used. 
A presently preferred esterification, also using methoxyacetyl chloride, 
but with toluene as solvent and potassium carbonate sesquihydrate as base, 
is shown in the Example. 
Mibefradil (I) may be isolated as the free base if desired, but will 
preferably be isolated as an acid addition salt, more preferably as the 
dihydrochloride salt. The preparation and isolation of mibefradil 
dihydrochloride may be performed by conventional methods, such as by 
contacting a solution of mibefradil with a solution of hydrogen chloride 
in a lower alkanol, followed by crystallization of the salt, as shown in 
the Example. 
The invention is illustrated by the following Preparation and Example. 
Preparation: 
(1S,2S)-(6-Fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetic acid. 
Preparation of tert-butyl 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetate. 
Diisopropylamine, 12.5 mL (9.65 g, 95 mmol) was added by syringe to 20 mL 
dry tetrahydrofuran at about -20.degree. C. Butyllithium, 38.0 mL of a 2.5 
molar solution in hexane 5 (95 mmol), was added dropwise at the same 
temperature over 40 minutes. After stirring for five minutes, 80 mL dry 
toluene was added, also at the same temperature, and the solution stirred 
for a further 1.5 hours. tert-Butyl acetate, 17.6 mL (15.17 g, 131 mmol), 
was added dropwise at the same temperature over sixteen minutes, the 
solution stirred for a further 35 minutes, and a solution of 11.22 g (54 
mmol) (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 10 mL 
dry toluene was added dropwise over nineteen minutes. The resulting 
suspension was warmed to 0.degree. C. over 45 minutes, then stirred at 
that temperature for a further 45 minutes. The solution was poured over a 
mixture of 60 g ice, 68 mL water, and 28 mL 12 molar hydrochloric acid, 
ensuring that the temperature did not exceed 10.degree. C. After stirring 
for fifteen minutes, the phases were separated, and the aqueous layer 
(which had a pH of 0) was extracted with 50 mL toluene. The combined 
organic phases were washed with 50 mL saturated aqueous sodium 
bicarbonate, dried over anhydrous magnesium sulfate, filtered, and 
concentrated under vacuum to give 16.45 g tert-butyl 
(lS,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetate as a pale yellow liquid. 
Preparation of 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetic acid from its tert-butyl ester. 
A mixture of 3.02 g crude tert-butyl 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetate and 8 mL 96% formic acid was 
stirred at 25.degree. C. for four hours. The solution was diluted with 6 
mL water; then heated to 75.degree. C and filtered. The filtrate was 
slowly cooled to 25.degree. C. with stirring. The resulting suspension was 
cooled to 0.degree. C., stirred for one hour, and suction filtered. The 
precipitate was washed with 15 mL water, air dried at 25.degree. C. for 
one hour, then oven dried at 50.degree. C. for 22 hours to give 1.59 g 
(1S,2S)-(6-fluoro-2-hydroxy-l-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetic acid as a colorless solid, m.p. 
102-103.5.degree. C., .alpha.!.sub.D.sup.27 = 78.80.degree. (CHCl.sub.3). 
Preparation of 
(1S,2S)-(6-fluoro-2-hydroxy-1isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)a 
cetic acid via (1S, 
2S)-(6-fluoro-2-hydroxy-l-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)acet 
onitrile. 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)a 
cetonitrile and its preparation are disclosed and claimed in Application 
No. 09/060,401. 
A 2.5 molar solution of butyllithium in hexane, 10.8 mL, was added dropwise 
over 20 minutes through an addition funnel to a solution of 1.4 mL 
acetonitrile in 10 mL tetrahydrofuran at -78.degree. C. The addition 
funnel was rinsed with an additional 7 mL tetrahydrofuran; and the 
solution was stirred at -78.degree. C. for 20 minutes. A solution of 4.99 
g (S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 10 mL 
tetrahydrofuran was added dropwise through the addition funnel to the 
solution at -78.degree. C. over 20 min. The addition funnel was rinsed 
with an additional 2 mL tetrahydrofuran. The light brown solution was 
allowed to warm to -10.degree. C. over approximately two hours; and was 
then quenched with 75 mL 5% aqueous hydrochloric acid. The resulting 
mixture was transferred to a 500 mL separatory funnel; and the reaction 
vessel was rinsed with 75 mL isopropyl acetate, which was added to the 
separatory funnel. The aqueous and organic layers were separated, and the 
aqueous layer was extracted twice with 75 mL isopropyl acetate. The 
combined organic layers, containing 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetonitrile, were concentrated to 
approximately 10-15 mL. 
From a similar preparation in which the nitrile was extracted into diethyl 
ether instead of isopropyl acetate, the ether solution was dried over 
anhydrous magnesium sulfate, and the ether removed on a rotary evaporator 
to give a brown oil, which dried to a beige solid under vacuum drying. A 
2.0 g portion of the crude nitrile was recrystallized from hexane to give 
1.52 g of pure 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetonitrile as a white solid. 
(1S,2S)-(6-Fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl)a 
cetonitrile, 250 mg, was mixed with 1 mL 25% aqueous potassium hydroxide, 2 
mL methanol, and 0.3 mL 30% aqueous hydrogen peroxide, and the mixture was 
stirred at 60-65.degree. C. overnight. The methanol was removed on a 
rotary evaporator, 3 mL water added, and the solution extracted twice with 
5 mL portions of diethyl ether. The ether extracts were dried with 
magnesium sulfate, and stripped to give 80 mg of the acid (3) as a light 
yellow oil. The aqueous phase was acidified with concentrated hydrochloric 
acid, and extracted three times with 5 mL portions of diethyl ether. The 
ether extracts were dried and stripped to give 170 mg of the acid (3) as a 
light brown oil which solidified on standing. 
Preparation of 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl) 
acetic acid via 
(1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronap 
hthalen--2-yl) acetamide. 
Lithium diisopropylamide, 1.3 mL of 0.84 molar solution in tetrahydrofuran, 
was added to a solution of 0.11 mL N,N-dimethylacetamide in 1 mL 
tetrahydrofuran at -78.degree. C. The mixture was stirred for fifteen 
minutes, then allowed to warm to -55.degree. C. A solution of 220 mg 
(S)-6-fluoro-1-isopropyl-3,4-dihydro-1H-naphthalen-2-one in 1 mL 
tetrahydrofuran was added at that temperature, then allowed to warm to 
0-5.degree. C. with stirring, and stirred for 2.5 hours. The reaction 
mixture was quenched with 3 mL saturated aqueous ammonium chloride, and 
extracted three times with 3 mL portions of diethyl ether. The ether 
extracts were combined, dried with magnesium sulfate, and stripped to give 
290 mg (1S,2S)-N,N-dimethyl-(6-fluoro-2-hydroxy-1-isopropyl-1, 
2,3,4-tetrahydronaphthalen-2-yl)acetamide as a pale yellow oil. 
The crude amide was mixed with 1 mL methanol and 1 mL 50% aqueous potassium 
hydroxide, and heated to 60-70.degree. C. for two days, by which time most 
starting material had been consumed. The solution was cooled, and 2 mL 
water and 2 mL diethyl ether added. The mixture was extracted three times 
with 3 mL portions of diethyl ether. The ether extracts were dried with 
magnesium sulfate, and stripped to give 40 mg of the acid (3) as a light 
yellow oil. The aqueous phase was acidified with concentrated hydrochloric 
acid, and extracted three times with 4 mL portions of diethyl ether. The 
ether extracts were dried and stripped to give 210 mg of the acid (3) as a 
brown oil. 
Example: 
Mibefradil and mibefradil dihydrochloride. 
Preparation of 
(1S,2S)-N-3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isoprop 
yl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide. 
Triethylamine, 20.6 mL (14.93 g, 148 mmol) was added dropwise at -5.degree. 
C. to 0.degree. C. to a solution of 39.30 g (149 mmol) of 
(1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl 
) acetic acid in 400 mL toluene. The solution was stirred at that 
temperature for 10 minutes. Trimethylacetyl chloride, 18.2 mL (17.79 g, 
148 mmol) and 10 mL toluene were added; and the suspension was stirred at 
that temperature for ten minutes, warmed to 25.degree. C. over 35 minutes, 
stirred at that temperature for 25 minutes, then cooled again to 0.degree. 
C. 3-(1H-Benzimidazol-2-yl)propyl!methylamine, 27.93 g (148 mmol), and 10 
mL dry toluene were added, and the mixture was stirred at -5.degree. C. to 
0.degree. C. for ten minutes, then at 25.degree. C. for four hours. 
Water, 200 mL, was added, and the layers were separated. The organic layer 
was washed with 200 mL water, dried over anhydrous magnesium sulfate, 
filtered, and concentrated on a rotary evaporator at 45.degree. C. to 
afford 169 g of a toluene solution of 
(1S,2S)-N-3-(1H-benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isoprop 
yl-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide. This solution was 
washed three times with 100 mL 2.5 molar aqueous sodium hydroxide, once 
with 50 mL brine, and once with 100 mL water. Water or toluene were added 
as needed to break emulsions during these washes. The organic layer was 
dried over anhydrous magnesium sulfate, filtered, and then distilled to 
reduce the volume and remove residual water. The solution was slowly 
cooled, with stirring, and a seed crystal was added. After stirring at 
25.degree. C. for several hours, the precipitate was suction filtered, 
washed with 75 mL toluene, then dried in vacuo to give 52.93 g 
(1S,2S)-N-3-(1H-benzimidazol-2-yl) 
propyl!-2-(6-fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-y 
l)-N-methyl-acetamide as a colorless solid, m.p. 137.5-138.5.degree. C., 
.alpha.!.sub.D.sup.26 = 16.40.degree. (CHCl.sub.3). 
Preparation of 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 
1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol. 
(1S,2S)-N-3-(1H-Benzimidazol-2-yl)propyl!-2-(6-fluoro-2-hydroxy-1-isopropy 
l-1, 2,3,4-tetrahydronaphthalen-2-yl)-N-methylacetamide, 20.22 g (45.7 
mmol), dissolved in 200 mL toluene at 40.degree. C., was added by cannula 
over 40 minutes at 0-5.degree. C. to a suspension of sodium 
bis(2-methoxyethoxy)aluminum hydride in toluene, 40 mL (41.44 g 
suspension, 26.94 g sodium bis(2-methoxyethoxy)aluminum hydride, 133 
mmol), and a further 20 mL toluene used to complete the transfer. After 
completion of the addition, the mixture was stirred at 0.degree. C. for 15 
minutes, then at 35-40.degree. C. for three hours. 
The mixture was cooled to 25.degree. C. then added carefully to 70 g sodium 
hydroxide in 140 g ice at less than 10.degree. C. Toluene, 25 mL, was used 
to complete the transfer. The resulting suspension was warmed to 
25.degree. C. over 30 minutes, and the phases were separated. The aqueous 
phase was. extracted with 25 mL toluene; and the combined toluene phase 
was washed twice with 50 mL 10% aqueous sodium hydroxide, once with 50 mL 
water, then once with 50 niL saturated brine. The toluene phase was dried 
over magnesium sulfate, filtered, and concentrated in vacuo to give 20.61 
g (1S,2S)-2-2-{3-(lH-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluor 
o-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol as a colorless foam. 
Preparation of (1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino 
}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol dioxalate. 
Acetic acid, 120 mL, was added to a concentrated toluene solution (15-20 
mL) containing approximately 10 g 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro- 
1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol. An azeotropic mixture of 
acetic acid and toluene was distilled at ambient pressure until the volume 
was reduced to about 50 mL. Oxalic acid dihydrate, 5.44 g, was added to 
the solution, and the solution was stirred at approximately 100.degree. C. 
for fifteen minutes. The solution was then allowed to cool slowly to 
45.degree. C., held at that temperature for two hours, allowed to cool 
further to 30.degree. C, and held at that temperature for another one 
hour. A precipitate of (1S,2S)-2-2-{3-(lH-benzimidazol-2-yl) 
propyl!-methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthal 
en-2-ol dioxalate formed during this cooling. The mixture was filtered at 
30.degree. C., and the warm filtrate was used to rinse residual 
precipitate onto the filter. The filter cake was washed three times with 
10 mL acetic acid at room temperature and dried in a vacuum oven at 
55-60.degree. C. under nitrogen flow for eighteen hours to give 9.32 g 
(1S,2S)-2-2-{3-(1H-benimidazol-2-yl)propyl!methylamino}ethyl!-6-fluoro-1 
-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol dioxalate as a white solid, 
containing one molecule of acetic acid of crystallization per molecule of 
the dioxalate acid addition salt. 
Preparation of mibefradil and mibefradil dihydrochloride. 
To a 1 L flask was added 41.0 g (actual) 
(1S,2S)-2-2-{3-(1H-benzimidazol-2-yl) 
propyl!-methylamino}ethyl!-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthal 
en-2-ol dioxalate, 240 mL water, and 240 mL toluene, with stirring. 
Potassium hydroxide pellets, 22.4 g, were added, and the mixture heated to 
45-50.degree. C. for one hour, with continued stirring. The resulting 
two-phase mixture was separated using a separatory funnel while still 
warm. The organic phase was washed with 65 mL water and then vacuum 
filtered through CELATOM .RTM.(diatomaceous earth filter agent). 
To the organic phase was added 39.4 g (4.0 equivalents) potassium carbonate 
sesquihydrate; then a solution of 21.0 g (17.7 mL, 3.25 equivalents) 
methoxyacetyl chloride in 33 mL toluene was added over two hours at 
25-30.degree. C., and the resulting mixture stirred for an additional 30 
minutes at that temperature. Water, 200 mL, was added at room temperature 
to quench the reaction; and the phases separated using a separatory 
funnel. The organic phase, containing mibefradil as the free base, was 
washed with 66 mL water. The washed organic phase was vacuum filtered 
through a pad of CELATOM.RTM.; and most of the toluene removed by 
distillation at 50.degree. C. and 4 mmHg, leaving a solution of mibefradil 
in approximately 10 mL toluene. Ethanol, 17.8 mL, was added, and the 
mixture allowed to cool to room temperature. 
To the stirred mixture was added a solution of 4.4 g of hydrogen chloride 
in 44.6 mL (35.0 g) ethanol at 20.degree. C., and then a further 10.2 mL 
(8.0 g) ethanol. The resulting mixture was heated to 50.degree. C.; and 
1.0 mL water was added, followed by a solution of 3.4 mL water in 332 mL 
methyl tert-butyl ether over one hour. The mixture was stirred for ten 
minutes at 50.degree. C., seeded with mibefradil dihydrochloride crystals, 
then stirred at 50.degree. C. for three hours. A solution of 0.6 mL water 
in 65 mL methyl tert-butyl ether was added over one hour, and the mixture 
aged for a further 1.5 hours at 50.degree. C. The mixture was then cooled 
to 15.degree. C. over two hours and aged at 15.degree. C. for a further 
hour, and the resulting slurry of mibefradil dihydrochloride was filtered 
on a Buchner funnel and rinsed with 95 mL dry methyl tert-butyl ether. The 
product was dried in a vacuum oven at 50.degree. C. to yield mibefradil 
dihydrochloride as the monohydrate in 95% yield. 
While this invention has been described in conjunction with specific 
embodiments and examples, it will be evident to one of ordinary skill in 
the art, having regard to this disclosure, that equivalents of the 
specifically disclosed materials and techniques will also be applicable to 
this invention; and such equivalents are intended to be included within 
the following claims.