U.S. patent application number 09/783649 was filed with the patent office on 2001-11-22 for novel process to prepare 2-aminoindan derivatives.
Invention is credited to Cleek, Kerry Anne, Haadsma-Svensson, Susanne R., Hewitt, Bradley D., Lin, Chiu-Hong, Romero, Arthur Glenn, Runge, Thomas Andrew, Svensson, Kjell Anders Ivan.
Application Number | 20010044471 09/783649 |
Document ID | / |
Family ID | 22675272 |
Filed Date | 2001-11-22 |
United States Patent
Application |
20010044471 |
Kind Code |
A1 |
Romero, Arthur Glenn ; et
al. |
November 22, 2001 |
Novel process to prepare 2-aminoindan derivatives
Abstract
The present invention relates to (2S)-enantiomers of
2-aminoindan derivatives of formula I: 1 and a novel process for
the preparation of them.
Inventors: |
Romero, Arthur Glenn;
(Kalamazoo, MI) ; Runge, Thomas Andrew; (Scotts,
MI) ; Hewitt, Bradley D.; (Kalamazoo, MI) ;
Svensson, Kjell Anders Ivan; (Portage, MI) ; Lin,
Chiu-Hong; (Portage, MI) ; Cleek, Kerry Anne;
(Kalamazoo, MI) ; Haadsma-Svensson, Susanne R.;
(Portage, MI) |
Correspondence
Address: |
Pharmacia & Upjohn Company
Global Intellectual Property
301 Henrietta Street
Kalamazoo
MI
49001
US
|
Family ID: |
22675272 |
Appl. No.: |
09/783649 |
Filed: |
February 14, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60184020 |
Feb 22, 2000 |
|
|
|
Current U.S.
Class: |
514/619 ;
564/157 |
Current CPC
Class: |
A61P 37/04 20180101;
C07C 217/74 20130101; A61P 3/04 20180101; C07C 2602/08 20170501;
A61P 25/20 20180101; A61P 25/06 20180101; A61P 25/00 20180101; A61P
25/24 20180101; A61P 1/00 20180101; A61P 25/16 20180101; A61P 25/28
20180101; A61P 25/22 20180101; C07B 2200/07 20130101; C07C 237/48
20130101; A61P 25/18 20180101; A61P 25/14 20180101; A61P 9/00
20180101 |
Class at
Publication: |
514/619 ;
564/157 |
International
Class: |
A61K 031/166; C07C
233/64 |
Claims
We claim:
1. A compound of formula I 16or a pharmaceutically acceptable salt
thereof wherein each R is independently C.sub.1-8 alkyl.
2. A compound of formula 1 as shown in claim I which is
(2S)-(+)-2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamide
or a pharmaceutically acceptable salt thereof.
3. A process for preparing a compound of formula I 17wherein each R
is independently C.sub.1-8 alkyl which comprises steps of a)
hydrogenation of compound of I-1 to compound I-2 as a racemic
mixture 18 in the presence of an appropriate catalyst and an
appropriate solvent; b) resolution of compound I-2 to compound I-2b
19 chiral acid by treating compound I-2 with a chiral acid in an
appropriate solvent; c) alkylation of I-2b in the presence of a
base and an appropriate solvent system to provide compound I-3;
20d) converting compound I-3 to compound I-4; 21e) bromination of
compound I-4 to compound I-5; 22with a brominating reagent in the
presence of an acid and an appropriate solvent system; and f)
carboxamidation I-5 in the presence of transition metal and an
associated ligand in an appropriate solvent with an appropriate
base, or alternatively treating 1-5 with an alkyllithium followed
by trimethylsilylisocyanate, to provide a compound of formula
I.
4. A process of claim 3 wherein said chiral acid is tartaric acid,
di-benzoyltartaric acid, di-para-toluoyltartaric acid,
camphorsulfonic acid, or mandelic acid.
5. A process of claim 3 wherein the chiral acid is
(1R)-(-)-I0-camphorsulf- onic acid, or (R)-(-)-mandelic acid.
6. A process of claim 3 wherein said appropriate solvent system in
step b) is a mixture of methanol and tetrahydrofuran.
7. A process of claim 3 wherein said brominating reagent in step d)
is pyridinium tribromide.
8. A process of claim 3 wherein said transition metal in step e) is
palladium, palladium on carbon or palladium acetate and said
associated ligand is triphenylphosphine, tri-orthotolulyphosphine,
or 1,3-bis(diphenylphosphino)propane.
9. An intermediate of I-2b or its chiral salt for the preparation
of a compound of formula I as shown in claim 1 23 chiral acid
wherein R is C.sub.1-8 alkyl.
10. An intermediate of claim 9 which is (1S,
2S)-trans-(-)-2-amino-6-ethox- y-2,3-dihydro-1H-inden-1-o or its
chiral salt.
11. An intermediate of claim 9 which is (1S,
2S)-trans-(-)-2-amino-6-ethox- y-2,3-dihydro-1H-inden-1-ol
(R)-(-)-mandelate.
12. An intermediate selected from a group consisting of I-3, I-4,
or I-5 for the preparation of a compound of formula I as shown in
claim 1 24wherein each R is independently C.sub.1-8 alkyl.
13. An intermediate of claim 12 which is (1S,
2S)-trans-2-(dipropylamino)-- 6-ethoxy-2,3-dihydro-1H-inden-1-ol or
a pharmaceutically acceptable salt thereof.
14. An intermediate of claim 12 which is
(2S)-5-ethoxy-2,3-dihydro-N,N-dip- ropyl-1H-inden-2-amine or a
pharmaceutically acceptable salt thereof.
15. An intermediate of claim 12 which is
(R)-5-bromo-6-ethoxy-2,3,-dihydro- -N,N,-dipropyl -1H-inden-2-amine
or a pharmaceutically acceptable salt thereof.
16. A method for treating or preventing a central nervous system
disorder associated with dopamine D3 receptor activity comprising
administering to a mammal in need thereof an effective amount of
formula I as shown in claim 1.
17. The method of claim 16 wherein said disorder is anxiety,
obesity, depression, schizophrenia, a stress related disease, panic
disorder, sleep disorders, a phobia, mania, obsessive compulsive
disorder, post-traumatic-stress syndrome, immune system depression,
a stress induced problem with the gastrointestinal or
cardiovascular system, or sexual dysfunction.
18. The method of claim 16 wherein said disorder is attention
deficit hyperactivity disorder, migraine, substance abuse,
cognitive deficits, memory impairment, alzheimer's disease,
movement disorders, disease, motor complications, extrapyramidal
side effects related to the use of neuroleptics, or "Tics"
including Tourette's syndrome.
19. The method of claim 18 wherein said substance abuse is drug
abuse or smoking abuse; wherein movement disorder is choreatic
movements in huntington's; wherein motor complications are
dystonias and dyskinesias in Parkinson's disease.
Description
CROSS REFERENCE RELATED TO APPLICATION
[0001] This application claims the benefit of the following
provisional application: U.S. Ser. No: 60/184,020, filed Feb. 22,
2000, under 35 USC 119(e)(i).
FIELD OF THE INVENTION
[0002] The present invention relates to (2S)-enantiomers of
2-aminoindan derivatives and a novel process for the preparation of
them.
BACKGROUND OF THE INVENTION
[0003] Schizophrenia is a common and devastating mental disorder
which is currently an unmet medical need. It is characterized by
so-called positive (hallucinations, delusions) and negative
(blunted affect, poverty of speech, social & emotional
withdrawal) symptoms, as well as cognitive deficits (working memory
impairment). About 1% of the world population is affected, men and
women equally, with typical onset between ages 15 and 25.
Antagonists of the neurotransmitter dopamine are known to block
psychosis. The present invention provides compounds of formula I
(wherein each R is independently C.sub.1-C.sub.8 alkyl), a highly
selective D.sub.3 receptor antagonist, for the treatment of
Schizophrenia and other CNS diseases. 2
[0004] Racemic forms of formula I and their preparations have been
disclosed in PCT publication WO 97/45403. The present invention has
discovered that the (2S)-enantiomer of formula I is the form that
possesses the superior desirable bioactivity. The present invention
also provides a process for the synthesis, in a large scale, of
said (2S)-enantiomer in a highly enantiomerically enriched form,
which solved an extremely challenging problem of a long period of
time.
INFORMATION DISCLOSURE
[0005] PCT International Publication No. W097/45403 discloses aryl
substituted cyclic amines as selective dopamine D3 ligands.
[0006] U.S. Pat. No. 5,708,018 discloses 2-aminoindans as selective
dopamine D3 ligands.
SUMMARY OF THE INVENTION
[0007] The present invention provides compounds of formula I: 3
[0008] or a pharmaceutically acceptable salt thereof wherein each R
is independently C.sub.1-8 alkyl.
[0009] More preferably, a compound of formula I of the present
invention is
(2S)-(+)-2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-carboxamid-
e or a pharmaceutically acceptable salt thereof.
[0010] In another aspect, the present invention also provides:
[0011] a process for the preparation of (2S)-enantiomers of
formulas I in a highly enantiomerically enriched form;
[0012] novel intermediates in a highly enantiomerically enriched
form useful for preparing compounds of formula I;
[0013] a pharmaceutical composition comprising a compound of
formula I, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier (the composition preferably
comprises a therapeutically effective amount of the compound or
salt),
[0014] a method for treating a disease or condition in a mammal
wherein a D.sub.3 receptor is implicated and modulation of a
D.sub.3 receptor function is desired comprising administering a
therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof to the mammal;
[0015] a method for treating or preventing anxiety, obesity,
depression, schizophrenia, a stress related disease (e.g. general
anxiety disorder), panic disorder, sleep disorders, a phobia,
mania, obsessive compulsive disorder, post-traumatic-stress
syndrome, immune system depression, a stress induced problem with
the gastrointestinal or cardiovascular system, or sexual
dysfunction in a mammal comprising administering a therapeutically
effective amount of a compound of formula I, or a pharmaceutically
acceptable salt thereof to the mammal;
[0016] a method for treating or preventing ADHD (attention deficit
hyperactivity disorder), migraine, substance abuse (including
smoking cessation), cognitive deficits, memory impairment,
alzheimer's disease, movement disorders including choreatic
movements in huntington's disease or motor complications such as
dystonias and dyskinesias in Parkinson's disease, extrapyramidal
side effects related to the use of neuroleptics, and "Tics"
including Tourette's syndrome in a mammal comprising administering
a therapeutically effective amount of a compound of formula I, or a
pharmaceutically acceptable salt thereof to the mammal.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The following definitions are used, unless otherwise
described.
[0018] The term alkyl refer to both straight and branched groups,
but reference to an individual radical such as "propyl" embraces
only the straight chain radical, a branched chain isomer such as
"isopropyl" being specifically referred to.
[0019] The carbon atom content of various hydrocarbon-containing
moieties is indicated by a prefix designating the minimum and
maximum number of carbon atoms in the moiety, i.e., the prefix
C.sub.ij indicates a moiety of the integer "i" to the integer "j"
carbon atoms, inclusive. Thus, for example, C.sub.1-.sub.8 alkyl
refers to alkyl of one to eight carbon atoms, inclusive.
[0020] Mammal refers to human or animals.
[0021] Pharmaceutically acceptable salts refer to organic acid
addition salts such as tosylate, methanesulfonate, acetate,
citrate, malonate, tartarate, succinate, benzoate, ascorbate,
.alpha.-ketoglutarate, .alpha.-glycerophosphate, or suitable
inorganic salts including hydrochloride, hydrobromide, sulfate,
nitrate, bicarbonate, and carbonate salts, etc.
[0022] The term "chiral salt" refers to a salt containing a chiral
acid. The term "chiral acids" refers to the acids having one or
more chiral centers. Examples of chiral acids are tartaric acid,
di-benzoyltartaric acid, di-para-toluoyltartaric acid,
camphorsulfonic acid, and mandelic acid. The preferred chiral acid
is mandelic acid.
[0023] All temperatures are in degrees Centigrade.
[0024] [.alpha.].sub.D25 refers to the angle of rotation of plane
polarized light (specific optical rotation) at 25.degree. C. with
the sodium D line (589 A).
[0025] The compounds of formula I are active orally or
parenterally. Orally the formula I compounds can be given in solid
dosage forms such as tablets or capsules, or can be given in liquid
dosage forms such as elixirs, syrups or suspensions as is known to
those skilled in the art. It is preferred that the formula I
compounds be given in solid dosage form and that it be a
tablet.
[0026] Typically, the compounds of formula I can be given in the
amount of about 0.5 mg to about 250 mg/person, one to three times a
day. Preferably, about 5 to about 50 mg/day in divided doses.
[0027] The exact dosage and frequency of administration depends on
the particular compound of formula I used, the particular condition
being treated, the severity of the condition being treated, the
age, weight, general physical condition of the particular patient,
other medication the individual may be taking as is well known to
those skilled in the art and can be more accurately determined by
measuring the blood level or concentration of the active compound
in the patient's blood and/or the patient's response to the
particular condition being treated.
[0028] Thus, the subject compounds, along with a
pharmaceutically-acceptab- le carrier, diluent or buffer, can be
administrated in a therapeutic or pharmacological amount effective
to alleviate the central nervous system disorder with respect to
the physiological condition diagnosed. The compounds can be
administered intravenously, intramuscularly, topically,
transdermally such as by skin patches, buccally or orally to man or
other vertebrates.
[0029] The compositions of the present invention can be presented
for administration to humans and other vertebrates in unit dosage
forms, such as tablets, capsules, pills, powders, granules, sterile
parenteral solutions or suspensions, oral solutions or suspensions,
oil in water and water in oil emulsions containing suitable
quantities of the compound, suppositories and in fluid suspensions
or solutions.
[0030] For oral administration, either solid or fluid unit dosage
forms can be prepared. For preparing solid compositions such as
tablets, the compound can be mixed with conventional ingredients
such as talc, magnesium stearate, dicalcium phosphate, magnesium
aluminum silicate, calcium sulfate, starch, lactose, acacia,
methylcellulose, and functionally similar pharmaceutical diluent or
carrier materials. Capsules are prepared by mixing the compound
with an inert pharmaceutical diluent and filling the mixture into a
hard gelatin capsule of appropriate size. Soft gelatin capsules are
prepared by machine encapsulation of a slurry of the compound with
an acceptable vegetable oil, light liquid petrolatum or other inert
oil.
[0031] Fluid unit dosage forms for oral administration such as
syrups, elixirs, and suspensions can be prepared. The forms can be
dissolved in an aqueous vehicle together with sugar, aromatic
flavoring agents and preservatives to form a syrup. Suspensions can
be prepared with an aqueous vehicle with the aid of a suspending
agent such as acacia, tragacanth, methylcellulose and the like.
[0032] For parenteral administration, fluid unit dosage forms can
be prepared utilizing the compound and a sterile vehicle. In
preparing solutions, the compound can be dissolved in water for
injection and filter sterilized before filling into a suitable vial
or ampoule and sealing. Adjuvants such as a local anesthetic,
preservative and buffering agents can be dissolved in the vehicle.
The composition can be frozen after filling into a vial and the
water removed under vacuum. The lyophilized powder can then be
sealed in the vial and reconstituted prior to use.
[0033] The present invention provides a process for preparing
compounds of formula I in a highly enantiomerically enriched form
as depicted in Scheme I. The starting material I-1 in Scheme I can
be prepared according to the procedures described in Chart A of
U.S. Pat. No. 5,708,018. 4
[0034] In step 1, compound I-1 is converted to compound I-2 as a
racemic mixture via catalytic hydrogenation in the presence of an
appropriate catalyst, such as palladium on carbon, W-2 Raney nickel
or platinum on sulfide carbon, in an appropriate solvent, such as
ethanol, THF, ethyl acetate or combinations thereof. The desired
enantiomer I-2b can be obtained by treating structure 1-2 with an
appropriate chiral acid in an appropriate solvent to form the
corresponding chiral salt complex, which subsequently crystallizes
from the solvent. Resolutions to separate an individual enantiomer
I-2a or I-2b from a racemic mixture often pose a significant
challenge in the quest to obtain enantiomerically pure compound. In
general, a wide variety of enantiomerically pure acids can provide
some measure of enantiomer enrichment. However, the choice of the
particular chiral acid and solvent system proves very important to
the efficiency of the resolution (enantiomeric purity and chemical
yield). The preferred chiral acids in the present invention for the
resolution include tartaric acid, di-benzoyltartaric acid,
di-para-toluoyltartaric acid, camphorsulfonic acid, and mandelic
acid. The most preferred chiral acid is mandelic acid. An
examination of resolving acids and solvent systems indicate that
(R)-(-)-mandelic acid and (1R)-(-)-10-camphorsulfon- ic acid
perform very well for the resolution of racemic 1-2 to induce the
crystallization of almost enantiomerically pure I-2b, with
(R)-(-)mandelic acid being preferred. Note that it is not necessary
to obtain enantiomer I-2b as 100% pure enantiomeric material at
this stage of the synthesis since subsequent crystallization
procedures in the following procedures will serve to provide a
slight upgrade to the final enantiomeric purity. It will be
apparent to those skilled in the art that other chiral acids
commonly used to perform resolution of amines may also be useful
for this resolution. Solvent systems in the present invention,
which are found to be useful to optimize the recovery of compound
I-2b, include alcohol solvents such as methanol, ethanol,
isopropanol, etc. as well as co-solvents of alcohol(s),
acetonitrile (ACN), or water in various proportions such as
tetrahydrofuran (THF), ether, methyl tertiary butyl ether (MTBE),
dimethoxyethane (DME), etc. The preferred solvent system in
combination with (R)-(-)-mandelic acid is a mixture of methanol and
tetrahydrofuran.
[0035] Next, alkylation of I-2b, in a form of free base or chiral
salt complex, with an alkylation agent in the presence of an
appropriate base and an appropriate polar solvent system at a
temperature in a range of about 20.degree. C. to 90.degree. C.
provides compound I-3. The appropriate base includes
K.sub.2CO.sub.3, Na.sub.3PO.sub.4, Na.sub.2B.sub.4O.sub.7, etc. The
preferred base is Na.sub.3PO.sub.4. The appropriate solvent
includes ACN, dimethylformamide (DMF), or THF. The preferred
solvent is ACN. The preferred temperature is in a range of from
about 60.degree. C. to about 75.degree. C. Compound 1-3 is then
converted to compound I-4 by acetylation followed by hydrogenolysis
in the presence of an appropriate catalyst, such as palladium on
carbon or platinum on sulfide carbon, and an appropriate
acetylation reagent such as acetic anhydride, or acetyl chloride
with catalytic dimethylaminopyridine, in an appropriate solvent,
such as acetic acid, an alcohol, water or combinations thereof, at
a temperature in a range of from about 20.degree. C. to reflux. The
preferred condition for this reaction is in acetic anhydride/acetic
acid at a temperature in a range of from about 55.degree. C. to
about 70.degree. C. Bromination of compound I-4 with a brominating
reagent in the presence of an acid and a polar solvent system at a
temperature in a range of from about -78.degree. C. to about room
temperature provides compound I-5. The instant bromination provides
an unexpected improvement in regioselectivity for bromination at
the desired position by using an appropriate brominating reagent. A
suitable brominating reagent may be Br.sub.2, dibromantin,
N-bromosuccinimide (NBS), pyridinium tribromide (pyrHBr.sub.3). The
preferred brominating reagent is pyridinium tribromide. The acid in
the reaction is preferably a strong acid such as HBr,
H.sub.2SO.sub.4, TiCl.sub.4, TFA, MeSO.sub.3H, Cl.sub.3CCO.sub.2H,
Cl.sub.2CCO.sub.2H, or citric acid. The more preferred acid is TFA.
The suitable polar solvent may be ACN, DMF, EtOAc, an alcohol such
as methanol, CH.sub.2Cl.sub.2, MTBE, THF, etc. The preferred
solvent is CH.sub.2Cl.sub.2. The preferred temperature is in a
range from about -15.degree. C. to room temperature. Finally,
carboxamidation I-5 in the presence of transition metal such as
palladium, palladium on carbon or palladium acetate and associated
ligands such as mono or bidentate phosphines in an appropriate
solvent with an appropriate base at a temperature in a range from
about 70.degree. C. to about 140.degree. C. provides the desired
compound I-6. Preferred ligands include triphenylphosphine,
tri-orthotolulyphosphine, or 1,3-bis(diphenylphosphino)propane.
Preferred temperature is in a range from about 95.degree. C. to
about 105.degree. C. The appropriate solvents include
dimethylformamide, dioxane, toluene, dimethoxyethane,
dimetylacetamide, etc. The preferred solvent is dimethylformamide.
The appropriate base include potassium carbonate, tertiary amine
bases, Na.sub.3PO.sub.4, LiHMDS, Li-amides, alkoxides, etc. The
preferred base is potassium carbonate.
[0036] Without further elaboration, it is believe that one skilled
in the art can, using the preceding description, practice the
present invention to its fullest extent. The following detailed
example describe how to prepare the various compounds and/or
perform the various processes of the invention and are to be
construed as merely illustrative, and not limitations of the
preceding disclosure in any way whatsoever. Those skilled in the
art will promptly recognize appropriate variations from the
procedures both as to reactants and as to reaction conditions and
techniques.
EXAMPLE
Preparation of
(2S)-(+)-2-(Dipropylamino)-6-ethoxy-2,3-dihydro-1H-indene-5-
-carboxamide
[0037] 5
[0038] Step 1: Preparation of 4-ethoxycinamic acid 6
[0039] 4-Ethoxybenzaldehyde (1) is condensed with malonic acid in
the presence of base (Knovenagel reaction) to obtain the cinnamic
acid derivative 2. This is accomplished by dissolving 1 in pyridine
with 0.15 eq. of piperidine and heating the resulting solution to
50-135.degree. C. (preferably 105-125.degree. C.) after which a
solution of malonic acid (2 eq.) dissolved in pyridine is added in
a slow stream. Approximately 40% of the pyridine is slowly
distilled off and the heating continued at 125.degree. C. until TLC
indicated that all of 1 has been consumed. Cool to 40.degree. C.
and add excess concentrated hydrochloric acid, keeping the
temperature at around 40.degree. C. Cool to below room temperature
and filter the solid product (2), washing with water and then
drying.
[0040] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.43 (t, J=7.0 Hz,
3 H), 4.07 (q, J=7.0 Hz, 2 H) 6.31 (d, J=16.0 Hz, 1 H), 6.90 (d,
J=8.8 Hz, 2 H), 7.49 (d, J=8.7 Hz, 2 H), 7.74 (d, J=15.9 Hz, 1
H).
[0041] Step 2: Preparation of 4-ethoxycinnamic acid 7
[0042] 4-Ethoxycinnamic acid (2) is hydrogenated at 40 p.s.i. with
catalytic 5% palladium on carbon in tetrahydrofuran solvent to
obtain 3-(4-ethoxyphenyl)propionic acid (3). A sample is
recrystallized from ethyl acetate/hexane to obtain an analytically
pure sample (m.p. 101-103.degree. C.).
[0043] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.40 (t, J=7.0 Hz,
3 H), 2.65 (t, J=7.7 Hz, 2 H 2.90 (t, J=7.7Hz, 2 H), 4.01 (q,
J=7.0Hz, 2 H), 6.83 (d, J=8.6Hz, 2 H), 7.12 (d, J=8.6 Hz,2H).
[0044] Step 3: Preparation of 6-ethoxy-1-indanone 8
[0045] To carboxylic acid 3 is added thionyl chloride (2 eq.) and
catalytic dimethylformamide. The solution is stirred until analysis
indicated that all of the carboxylic acid had been converted to the
acid chloride. Remove volatile reagents under vacuum. The acid
chloride is dissolved in dichloromethane and added to a slurry of
aluminum chloride (1.1 eq.) in dichloromethane over 15-60 minutes.
The resulting mixture is heated to reflux for 30 minutes (until
analysis indicated that all of the starting material had been
consumed) and then cooled to 0-15.degree. C. Water is added slowly
to quench the reaction and then the mixture is extracted. The
organic layer is washed with saturated aqueous sodium bicarbonate
and the organic solution is stripped of dichloromethane solvent
under vacuum to afford a residue that is redissolved in methyl
t-butyl ether and then dried with magnesium sulfate. The solution
is filtered and the solvent removed under vacuum to afford solid 4.
The solid could be recrystallized from octane to afford an
analytical sample (m.p. 57-58.degree. C.).
[0046] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.41 (t, J=7.0 Hz,
3 H), 2.66-2.71 (m, 2 H), 3.04 (t, J=5.7Hz, 2H), 4.04 (q, J=7.0Hz,
2 H), 7.13-7.18 (m, 2 H), 7.32-7.35 (m, 1 H).
[0047] Step 4: Preparation of
6-ethoxy-1H-indene-1,2(3H)-dione-2-oxime 9
[0048] A solution of 6-ethoxy-1-indanone and isoamylnitrite (1.5
eq.) in ethyl acetate are cooled to approximately 0.degree. C. and
concentrated hydrochloric acid (1.1 acid equivalents) is added at a
rate to keep the temperature below 40.degree. C. After the addition
is completed the slurry is stirred at 5-10.degree. C. until
analysis indicated that all of the starting material is consumed.
The product is filtered and rinsed with cold ethyl acetate. The
oxime product (5) can be easily purified by refluxing as a slurry
in anhydrous ethanol, cooling filtering, and then washing the solid
with more ethanol and then drying (m.p. 220.degree. C.
decomp.).
[0049] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.1.32 (t, J=7.0
Hz, 3 H), 3.65 (s, 2 H), 4.06 (q, J=7.0 Hz, 2 H), 7.14 (d, J=2.5
Hz, 1 H), 7.27 (dd, J=2.6, 8.4 Hz, 1 H), 7.49 (d, J=8.4 Hz, 1 H),
12.57 (s, 1 H).
[0050] Step 5: Preparation of
(.+-.)-trans-2-amino-6-ethoxy-2,3-dihydro-1H- -inden-1-ol 10
[0051] 6-Ethoxy-1H-indene-1,2(3H)-dione 2-oxime is slurried in
absolute ethanol, and approximately 0.5 eq. 2N sodium hydroxide is
added. Palladium on carbon is added, and the mixture is
hydrogenated in a Parr shaker with an initial hydrogen pressure of
40 psi for several hours (depending upon the scale of the reaction
and the catalyst loading). After analysis indicated that all of the
starting material is consumed, the catalyst is filtered from the
solution and then the solvent is removed under vacuum, and the
residue is diluted with water and extracted with ethyl acetate
several times. The ethyl acetate extracts are combined and
concentrated under vacuum. Hexane is added and the resulting slurry
is cooled to 0-15.degree. C. and the solid product (6) is rinsed
with cold ethyl acetate/hexane (1:1). The product is dried under
vacuum.
[0052] An analytical sample is obtained by combined an aliquot of
the product (6) with p-toluene sulfonic acid, and the resulting
salt is crystallized from methanol/diethylether to afford a
material of m.p. 172-173.degree. C.
[0053] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.394 (t, J=7.0 Hz,
3 H), 2.51 (dd, J=8.3, 14.9 Hz, 1 H), 3.13 (dd, J=7.3, 15.1 Hz, 1
H), 3.43 (q, J=7.2Hz, 1 H), 4.02 (q, J=7.0Hz, 2 H), 4.73 (d, J=6.7
Hz, 1 H), 6.78 (dd, J=2.2, 8.2 Hz, 1 H), 6.90 (d, J=2.2 Hz, 1 H),
7.06 (d, J=8.2Hz, 1H).
[0054] Step 6: Preparation of (1S,
2S)-trans-(-)-2-amino-6-ethoxy-2,3-dihy- dro-1H-inden-1-ol
(R)-(-)-mandelate 11
[0055] (.+-.)-trans-2-Amino-6-ethoxy-2,3-dihydro-1H-inden-1-ol in a
mixture of methanol and tetrahydrofuran is added to a warm solution
of a slight molar excess of (R)-(-)-mandelic acid in
tetrahydrofuran, so that the result is a solution at about
60.degree. C. in about 3-4 ml/g methanol and about 40-50 ml/g
tetrahydrofuran. The desired mandelate salt (7) crystallizes from
solution and is isolated by filtration and drying. ( m.p.
170-195.degree. C. ). When treated with (R)-(-)-10-camphorsulfonic
acid in methanol, the desired enantiomer (7) crystallizes from
solution as the sulfonic acid salt complex ( m.p. 238-239.degree.
C. ). [.alpha.].sup.25D=-8.degree. (c=0.94, methanol).
[0056] Step 7: Preparation of (1S,
2S)-trans-2-(dipropylamino)-6-ethoxy-2,- 3-dihydro-1H-inden-1-ol
12
[0057] Aminoalcohol mandelate salt (7) is added to acetonitrile
solvent with excess tribasic sodium phosphate and n-bromopropane
and stirred until analysis indicates that starting material is
completely converted to the dipropyl-substituted material (8). The
preferred procedure is to heat the slurry at 60-70.degree. C. for
two--three days. The reaction is cooled, filtered, and the solids
rinsed with methyl t-butyl ether. The solution is concentrated
under vacuum and then more methyl t-butyl ether is added and the
solution extracted with aqueous sodium hydroxide. The organic layer
is washed with excess dilute aqueous hydrochloric acid and the
aqueous hydrochloric acid extracts are combined and back-washed
with methyl t-butyl ether and then made basic with concentrated
aqueous sodium hydroxide. This aqueous solution is then washed with
methyl t-butyl ether. The ether is removed under vacuum to obtain
the dipropyl compound (8) as a solid. It is apparent to those
skilled in the art that other similar alkylating reagents can be
utilized in place of n-bromopropane, such as n-propyliodide, etc.
Also, other bases can be utilized in place of the phosphate base,
such as sodium carbonate, organic tertiary amine bases such as
diisopropylethylamine, etc. The preferred procedure is to use
n-bromopropane and tribasic sodium phosphate. Additionally, it is
apparent to those skilled in the art that reductive amination
procedures can also be used to perform this chemical
transformation, including using propanal in the presence of a
hydride transfer reducing reagent such as sodium
triacetoxyborohydride, sodium cyanoborohydride, etc. Alternatively,
the amine can be repetitively acylated to form the propionamide of
the amine and then reduced to the amine with lithium aluminum
hydride, diisobutylhydride, a borane reagent, etc. two times to
introduce the required propyl groups. The preferred method to
obtain 8 is to heat 7 with n-bromopropane in the presence of
tribasic sodium phosphate. An analytical sample can be crystallized
from ethyl acetate/hexane (m.p. 74-75.degree. C.).
[0058] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0.90 (t, J=7.4 Hz,
6 H), 1.40 (t, J=7.0 Hz, 3 H) 1.52 (sextet, J=7.3 Hz, 4 H), 2.38
(br.s, 1 H), 2.47-2.64 (m, 4 H), 2.72 (dd, J=9.1, 15.1 Hz, 1 H),
2.89 (dd, J=7.8, 15.1 Hz, 1 H), 3.41 (dd, J=7.7, 16.6 Hz, 1 H),
4.02 (q, J=7.0 Hz, 2 H), 5.07 (d, J=7.4 Hz, 1 H), 6.78 (dd, J=2.4,
8.2 Hz, 1 H), 6.92 (d, J=2.2 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H);
[.alpha.].sup.25D=34.degree. (c=1.01, methanol).
[0059] Step 8: Preparation of
(S)-5-ethoxy-2,3-dihydro-N,N-dipropyl-1H-ind- en-2-amine 13
[0060]
(1S)-Trans-2-(dipropylamino)-6-ethoxy-2,3-dihydro-1H-inden-1-ol 8
is placed into a hydrogenation reactor with a catalytic amount of
5% palladium on carbon and acetic acid added as solvent. Acetic
anhydride (excess over one equivalent--sufficient to completely
convert all of 8 to the unisolated acetate intermediate) is also
added and the mixture is hydrogenated at 40 p.s.i. while heating to
25.degree.-80.degree. C. (preferred temperature is
60.degree.-70.degree. C. When analysis indicated that 8 had been
completely converted into 9 the mixture is cooled and filtered. The
solvent is removed by heating under vacuum and the residue is
extracted with methyl t-butyl ether and aqueous sodium hydroxide
(added until the solution indicated a pH greater than 12). The
aqueous layer is back extracted with more methyl t-butyl ether and
the combined organic layers are washed with dilute aqueous sodium
hydroxide solution. The methyl t-butyl ether solution is then
extracted twice with 1 N aqueous hydrochloric acid, adding
sufficient acid to wash all of the amine product into the aqueous
layer). The aqueous acid layers are combined and washed with methyl
t-butyl ether after which the aqueous layer is adjusted to a pH
greater than 12 and then extracted with two portions of
dichloromethane. The dichloromethane is washed with water and the
solvent removed by heating under vacuum to afford 9. An analytical
sample can be prepared as the p-toluenesulfonic acid salt from
methanol/diethylether to afford crystals (m.p. 136-138.degree.
C.).
[0061] .sup.1H NMR (free base, 300 MHz, CDCl.sub.3) .delta.0.88 (t,
J=7.3 Hz, 6 H), 1.39 (t, J=7.0 Hz, 2 H), 1.49 (sextet, J=7.5 Hz, 4
H), 2.46-2.51 (m, 4 H), 2.75-3.01 (m, 4 H), 3.64 (quintet, J=8.2
Hz, 1 H), 3.99 (q, J=7.0 Hz, 2 H), 6.68 (d, J=8.2 Hz, 1 H), 6.73
(s, 1 H), 7.05 (d, J=8.1 Hz, 1 H);
[.alpha.].sup.25D=11.degree.(c=0.82, methanol).
[0062] Step 9: Preparation of
(R)-5-bromo-6-ethoxy-2,3-dihydro-N,N-dipropy- l-1H-inden-2-amine
14
[0063] Pyridinium perbromide 1-1.5 equivalents (preferably 1.3-1.4
equivalents) is added to dichloromethane solvent and cooled between
-60.degree. C. and 25.degree. C. (-15.degree. C. to 25.degree. C.
is the preferred temperature range). A-15.degree. C. solution of
(S)-6-ethoxy-2,3-dihydro-N,N-dipropyl-1H-inden-2-amine (9) and
trifluoroacetic acid (1-5 equivalents with 3 equivalents being
preferred) dissolved in dichloromethane is added. After stirring
for several hours the reaction is warmed to 0.degree. C. When
analysis indicated that all of 9 had been consumed, the reaction is
quenched with a reducing agent such as aqueous sodium bisulfite.
Aqueous sodium hydroxide is then added to make the pH greater than
12 and most of the dichloromethane and pyridine are removed by
heating under vacuum. The residue is extracted several times with
methyl t-butyl ether, the organic layers are combined, stirred with
magnesium sulfate to dry, filtered, and the solvent removed by
heating under vacuum to afford 10 in crude form. If necessary, this
is crystallized from methanol/methyl t-butyl ether as the
hydrochloride salt to afford purified 10 as its hydrochloride salt
(m.p. of an analytical sample 202-204.degree. C.).
[0064] It will be apparent to one skilled in the art that other
methods of brominating 9 exist, such as direct treatment with
bromine, N-bromosuccinimide, dibromohydantoin, etc. Other acid
catalysts can also be utilized, such as acetic acid and other low
molecular weight carboxylic acids, mineral acids, organic sulfonic
acids, etc. Trifluoroacetic acid is the preferred acid
catalyst.
[0065] .sup.1H NMR (free base, 300 MHz, CDCl.sub.3) .delta.0.86 (t,
J=7.4 Hz, 6 H), 1.41-1.55 (m, 7 H), 2.43-2.49 (m, 4 H), 2.76-2.99
(m, 4 H), 3.57 (quintet, J=8.2 Hz, 1 H), 4.05 (q, J=7.0 Hz, 2 H),
6.73 (s, 1 H), 7.31 (s, 1 H); [.alpha.].sup.25D=5.degree.(c=1.01,
methanol).
[0066] Step 10: Preparation of
(S)-(+)-(dipropylamino)-6-ethoxy-2,3-dihydr-
o-1H-indene-5-carboxamide 15
[0067] Compound 10 (as its hydrochloride salt) is combined with
dimethylformamide with a catalytic amount of palladium acetate
(0.008-0.08 equiv., with 0.01-0.04 equiv. being preferred) and
1,3-bis(diphenylphosphino)propane (approximately twice the number
of molar equivalents as the palladium catalyst), potassium
carbonate, and hexamethyldisilylazane. The reaction is heated to
70.degree.-120.degree. C. (100.degree. C. being preferred) under an
atmosphere of carbon monoxide until analysis indicated that all of
10 had been consumed. The reaction is cooled, diluted with methyl
t-butyl ether (MTBE) and water, and filtered to remove solids. The
two-phase mixture is made basic and product is extracted into MTBE.
The extracts are washed with dilute base, then water. The solution
is placed under vacuum and heated to remove volatile reagents and
solvents. The residue is slurried with aqueous hydrochloric acid
and filtered. The filtrate is extracted with MTBE. The aqueous
phase is made basic with aqueous sodium hydroxide, and the product
is extracted into methyl t-butyl ether. The extracts are washed
again with water and then dried by distillation. The resulting MTBE
solution is treated with magnesium silicate adsorbent, which is
removed by filtration. The methyl t-butyl ether filtrate is
concentrated and heptane added at approximately 50.degree. C.
followed by gradual cooling to induce the crystallization of 11
which is filtered and dried. It is readily apparent to one skilled
in the art that a variety of palladium catalysts (PdCl.sub.2,
Pd.sub.n(dba).sub.m, etc.) and associated ligands
(triphenylphosphine, tri-ortho-tolulyphosphine, etc) can be
utilized in varying catalytic quantities.
[0068] Additionally, 10 in its free base form can be dissolved in
an etheral solvent such as tetrahydrofuran and cooled to
-20.degree. to -78.degree. C. (preferably -25.degree. to
-50.degree. C.) and a solution of an alkyllithium such as
t-butyllithium added. Trimethylsilylisocyanate (see Parker, K. A.;
Gibbons, E. G. "A Direct Synthesis of Primary Amides from Grignard
Reagents", Tetrahed. Lett. 1975, 981-984) is then added and the
solution is allowed to slowly warm to 10.degree. C. and then
quenched by the addition of water. Methyl t-butyl ether is added
and the mixture is extracted. The organic layer is dried with
magnesium sulfate and the solvent removed to afford 11 which is
purified as the hydrochloride salt by treating with a methanol
solution of hydrochloric acid, concentrating under vacuum, and
recrystallizing the solid from ethyl acetate. The crystals are
converted to the freebase by treatment with aqueous sodium
hydroxide, extraction into ethyl acetate, drying with magnesium
sulfate, and removal of the solvent under vacuum (m.p.
100-101.degree. C.).
[0069] .sup.1H NMR (CDCl.sub.3) .delta.7.99 (s, 1 H), 7.87 (bs, 1
H), 6.78 (s, 1 H), 6.12 (bs, 1 H), 4.17-4.11 (q, J=7.0 Hz, 2 H),
3.72-3.61 (m, 1 H), 3.06-2.78 (m, 4 H), 2.48-2.43 (m, 4 H),
1.54-1.41 (m, 7 H), 0.87 (t, J=7.3 Hz, 6 H;
[.alpha.].sup.25D=+4.94.degree.(c=0.842, MeOH).
* * * * *