OXINDOLEDIOXANS, SYNTHESIS THEREOF, AND INTERMEDIATES
THERETO
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to United States provisional patent application
serial number 60/808,394, filed May 25, 2006, the entirety of which is hereby incorporated
herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for synthesizing compounds useful as
dopamine autoreceptor agonists and partial agonists at the postsynaptic dopamine D2
receptor, derivatives thereof, and to intermediates thereto.
BACKGROUND OF THE INVENTION
[0003] The clinical treatment of schizophrenia has long been defined by the dopamine
hypothesis of schizophrenia, which holds that schizophrenia is a result of hyperactivity of dopaminergic neurotransmission, particularly in limbic brain structures such as nucleus
accumbens (the mesolimbic dopamine system). Indeed, the positive symptoms of
schizophrenia (hallucinations, delusions, thought disorder) are successfully treated with
neuroleptics, which block dopamine receptors. However, such treatment is accompanied by
the production of movement disorders or dyskinesias (extrapyramidal side effects), due to the
blockade of nigrostriatal dopamine receptors. In addition, neuroleptics do not treat the
negative symptoms of schizophrenia (social withdrawal, anhedonia, poverty of speech) which
are related to a relative hypoactivity of neurotransmission in the mesocortical dopamine
system and which respond to treatment by dopamine agonists.
[0004] Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have
been, successful (Corsini et al., Adv. Biochem. Psychopharmacol. 16, 645-648, 1977;
Tamminga et al., Psychiatry 398-402, 1986). A method for determining intrinsic activity at
the dopamine D2 receptor was recently published [Lahti et ai., Mol. Pharm. 42, 432-438,
(1993)]. As reported, intrinsic activity is predicted using the ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist" (HighAg) state of the receptor,

i.e. LowAg/HighAg. These ratios correlate with agonist, partial agonist, and antagonist
activities for a given compound, which activities characterize a compound's ability to elicit an
antipsychotic effect.
[0005) Dopamine autoreceptor agonists produce a functional antagonism of dopaminergic
neurotransmission by the reduction of neuronal firing and the inhibition of dopamine
synthesis and release. Since dopamine autoreceptor agonists are partial agonists at
postsynaptic dopamine receptors, they provide a residual level of stimulation sufficient to.
prevent the production of dyskinesias. Indeed, partial agonists are capable of functioning as
either agonists or antagonists depending on the level of dopaminergic stimulation in a given
tissue or brain region, and would therefore be expected to have efficacy versus both positive
and negative symptoms of schizophrenia. Thus, novel dopamine partial agonists are of great
interest for the treatment of schizophrenia and related disorders.
SUMMARY OF THE INVENTION
[0006] As described herein, the present invention provides methods for preparing
compounds having activity as dopamine autoreceptor agonists and partial agonists at the
postsynaptic dopamine D2 receptor. These compounds are useful for treating dopaminergic
disorders, such as schizophrenia, schizoaffective disorder, Parkinson's disease, Tourette's
syndrome, hyperprolactinemia, and drug addiction. Such compounds include those of
formula 1:

or a pharmaceutically acceptable salt thereof, wherein:
Ra is -(CH2)„phenyl; and
n is 1 or 2.
[0007] The present invention also provides synthetic intermediates useful for preparing
such compounds.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0008] The methods and intermediates of the present invention are useful for preparing
compounds as described in, e.g. United States patent number 5,756,532, in the name of Stack,
et al, the entirety of which is incorporated herein by reference. The present synthesis is
advantageous for preparing such compounds on a large scale using readily available reagents.
In certain embodiments, the present compounds are generally prepared according to Scheme I
set forth below:

[0009] In Scheme I above, each of R1, R2, LG1, and LG2 is as defined below and in classes
and subclasses as described herein.
[0010] At step S-1, the 4-nitro catechol G is treated with an epoxide of formula F, where
LG1 is a suitable leaving group, to form a compound of formula E. Suitable leaving groups
are well known in the art, e.g., see, "Advanced Organic Chemistry," Jerry March, 5* Ed., pp.
445-448, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to,
halogen, sulfonyloxy, optionally substituted ; alkylsulfonyloxy, optionally substituted
alkenylsulfonyloxy, optionally substituted arylsulfonyloxy. Examples of suitable leaving

groups include chloro, iodo, bromo, fluoro, methanesulfonyloxy (mesyloxy), tosyloxy,
triflyloxy, nitrophenylsulfonyloxy (nosyloxy), and bromophenylsulfonyloxy (brosyloxy). In
certain embodiments, LG1 is halogen. In other embodiments, LG1 is an optionally substituted
alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, or optionally substituted
arylsulfonyloxy group. In certain embodiments, LG1 is halogen. In other embodiments, LG1
is chloro.
[0011) The use of Makosza's vicarious nucleophilic substitution of hydrogen reaction in
step S-2 is performed by treating a compound of formula E with the appropriately substituted
acetonitrile compound to form a compound of formula D, As defined herein, the R1 group is
a suitable leaving group. In certain embodiments, R1 is -OPhenyl, wherein the phenyl ring is
substituted by one or more electron withdrawing groups.' In other embodiments, R1 is OPhenyl, wherein the phenyl ring is substituted by chloro. According to another aspect, R1 is
chloro. The reaction at step S-2 is performed in the presence of a suitable base. In certain
embodiments, the suitable base is a strong base. Such bases include metal alkoxides and
metal hydrides. In certain embodiments, the base is potassium tert-butoxide. In certain
embodiments, at least one equivalent of base is used at step S-2. In other embodiments, from
about 2 to about 5 equivalents of base are used. In still other embodiments, from about 2.3 to
about 4 equivalents of base are used.
[0012] At step S-3, the hydroxyl group of compound D is converted to a suitable leaving
group, LG2. The conversion of hydroxyl groups to leaving groups is well known to one of
ordinary skill in the art an includes those methods described in March. Such LG2 groups
include, but are not limited to, halogen, alkpxy, sulphonyloxy, optionally substituted
alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, and optionally substituted
arylsulfonyloxy moieties. For the above mentioned "optionally substituted" moieties, the
moieties may, for example, be optionally substituted with C1-4 aliphatic, fluoro-substituted
C1-4 aliphatic, halogen, or nitro. Examples of suitable leaving groups include chloro, iodo,
bromo, methanesulfonyloxy (mesyloxy), tosyloxy, triflyloxy, nitro-phenylsulfonyloxy
(nosyloxy), and bromo-phenylsulfonyloxy (brosyloxy). According to one aspect of the
present invention, LG2 in compounds of formula D is toluenesulfonyloxy (tosyloxy).
According to another aspect of the invention, a compound of formula E is allowed to react
withtoluenesulfonyl chloride (tosyl chloride) to afford a compound of formula D in which
LG is toluenesulfonyloxy (tosyloxy).

[0013] In certain embodiments step S-3 is performed in ethereal solvents, ester solvents,
halogenated hydrocarbon solvents, or nitrile solvents. In certain embodiments this reaction is
performed in tetrahydrofuran (THF), dichloromethane, acetonitrile, or isopropyl acetate. In
other embodiments the reaction is run in THF. According to one aspect of the present
invention, the reaction is run in the presence of suitable base. Exemplary bases include
tertiary amines such as triethylamine (TEA), pyridine, and DBPEA. In certain embodiments,
the reaction is run at a temperature that is between about -20 °C and about 40 CC. In other
embodiments, the reaction is conducted at a temperature of about 0 °C.
[0014] At step S-4, the LG2 group of formula D is displaced by benzylamine to form
compound B. In certain embodiments, this displacement step is performed using from about
1 to about 5 equivalents of benzylamine. In other embodiments, this step is performed using,
from about 1 to about 3.5 equivalents of benzylamine. According to another aspect, S-4 is
performed in a suitable medium.
[0015] A suitable medium is a solvent or a solvent mixture that, in combination with the
combined compounds, may facilitate the progress of the reaction therebetween. The. suitable
solvent may solubilize one or more of the reaction components, or, alternatively, the suitable
solvent may facilitate the agitation of a suspension of one or more of the reaction-
components. Examples of suitable solvents useful in the present invention include but are not
limited to a protic solvent, a halogenated hydrocarbon, an ether, an ester, an aromatic
hydrocarbon, a polar or a non-polar aprotic solvent, or any mixtures thereof. These and other
such suitable solvents are well known in the art, e.g., see, "Advanced Organic Chemistry",
Jerry March, 5* edition, John Wiley and Sons, N.Y. Such suitable solvents include polar
aprotic solvents. In certain embodiments, step S-4 is performed in DMSO.
[0016] In certain embodiments, the displacement reaction at step S-4 is optionally
performed in the presence of a suitable base. One of ordinary skill would recognize that the
displacement of a leaving group by an amino moiety is achieved either with or without the
presence of a suitable base. Such suitable bases are well known in the art and include organic
and inorganic bases.
[0017] The conversion of the cyano group of formula B to the -CO2R2 group of formula A
is achieved by hydrolysis at step S-S. In certain embodiments, step S-S is performed in an
alcoholic solvent such that a compound of formula A is formed wherein R forms the
corresponding ester. According to one aspect of the present invention, the hydrolysis at step
S-5 is performed by treating a compound of formula B with gaseous HC1 in an alcohol. In

certain embodiments, the hydrolysis at step S-5 is performed by treating a compound of
formula B with gaseous HO in a lower alkyl alcohol. Such lower alkyl alcohols include
methanol, ethanol, propanol, and isopropanol.
[0018] At step S-6, the nitro group of formula A is reduced to form the amine. The
resulting compound cyclizes in situ to form a compound of formula I. One of ordinary skill
in the art will recognize that there are many methods for reducing a nitro group to the
corresponding amine. In certain embodiments, the reduction/cyclization step is performed by
hydrogenation in the presence of a suitable catalyst. In other embodiments, the suitable
catalyst is a platinum catalyst, Fe/HCI, or Sn/HCl. In still other embodiments, the suitable
catalyst is platinum oxide.
[0019] At step S-7, the compound of formula I is optionally treated with fumaric acid to
form the compound of formula I-a.
[0020] In certain embodiments, the present invention provides a method for preparing a
compound of formula D:

comprising the steps of:
(a) providing a compound of formula E:

and
(b) treating said compound of formula E with a compound of the formula ""V^ ,
wherein R1 is a suitable leaving group, in the presence of a suitable base.

[0021] As defined generally above, R1 is a suitable leaving group. Leaving groups are
well known in the art and include those described in detail in March. Exemplary leaving
groups include halogen, alkoxy, and phenoxy groups wherein the phenyl ring is optionally
substituted with one or more halogen, nitro, and ester groups. In certain embodiments, Rl is a
phenoxy group substituted with halogen.
[0022] As described above, step (b) is performed in the presence of a suitable base. In
certain embodiments, the suitable base is a strong base. Exemplary strong bases include
metal alkoxides and metal hydrides. In certain embodiments, step (b) is performed in the
presence of a metal alkoxide. In other embodiments, step (b) is performed in the presence of
potassium tert-butoxide.
[0023] In other embodiments, the present invention provides a method for preparing a
compound of formula C:

wherein LG2 is a suitable leaving group,
comprising the steps of:
(a) providing a compound of formula D:

and
(b) converting the free hydroxy 1 moiety of said compound of formula D into a suitable
leaving group to afford a compound of formula C.
[0024] In step (b), the hydroxyl group of compound D is activated such that it becomes
leaving group LG2 that is subject to nucleophilic displacement. A suitable "leaving group"
that is "subject to nucleophilic displacement" is a chemical group that is readily displaced by

a desired incoming nucleophilic chemical entity. According to one aspect of the present
invention, a compound of formula D is allowed to react with toluenesulfonyl chloride (tosyl
chloride) to afford a compound of formula C in which LG2 is toluenesulfonyloxy (tosyloxy).
[0025] In certain embodiments this reaction is performed in a suitable medium. In certain
embodiments, the suitable medium is a polar aprotic solvent or halogenated hydrocarbon
solvent such as tetrahydrofuran (THF), dichloromethane, acetonitrile, or isopropyl acetate. In
other embodiments the suitable medium is dichloromethane.
[0026] According to one aspect of the present invention, the reaction is run in the presence
of a suitable base. In certain embodiments, the suitable base is triethylamine (TEA). In other
embodiments, the conversion of a compound D to a compound C is achieved in the presence
of a catalytic amount of 4-(dimethylamino)pyridine.
[0027] Another aspect of the present invention provides a method for preparing a
compound of formula B:

comprising the steps of:
(a) providing a compound of formula C:

wherein LG2 is a suitable leaving group;
and
(b) treating said compound of formula C with benzylamine.
[0028] In certain embodiments, the displacement step (b) is performed using from about 1
to about 5 equivalents of benzylamine. In other embodiments, this step is performed using

from about 1 to about 3.5 equivalents of benzylamine. According to another aspect, step (b)
is performed in a suitable medium.
[0029] A suitable medium is a solvent or a solvent mixture that, in combination with the
combined compounds, may facilitate the progress of the reaction therebetween. The suitable
solvent may solubilize one or more of the reaction components, or, alternatively, the suitable
solvent may facilitate the agitation of a suspension of one or more of the reaction
components. Examples of suitable solvents useful in the present invention are a protic
solvent, a halogenated hydrocarbon, an ether, an ester, an aromatic hydrocarbon, a polar or a
non-polar aprotic solvent, or any mixtures thereof. Such mixtures include, for example,
mixtures of protic and non-protic solvents such as benzene/methanol/water; benzene/watef •
DME/water, and the like. In other embodiments, such suitable solvents include polar aprotic
solvents. In certain embodiments, step (b) is performed in DMSO.
[0030] These and other such suitable solvents are well known in the art, e.g., see,
"Advanced Organic Chemistry", Jerry March, 5th edition, John Wiley and Sons, N.Y.
[0031] In certain embodiments, the displacement reaction at step (b) is optionally
performed in the presence of a suitable base. One of ordinary skill would recognize that the
displacement of a leaving group by an amino moiety is achieved either with or without the
presence of a suitable base. Such suitable bases are well known in the art and include organic
and inorganic bases.
[0032] In certain embodiments, the present invention provides a method for preparing a
compound of formula A:

wherein R2 is a carboxylate protecting group,
comprising the steps of:
(a) providing a compound B:


and
(b) hydfolyzing the nitrile moiety of said compound B to form a compound of formula A.
[0033J As defined above, R2 is a suitable carboxylate protecting group. Protected
carboxylic acids are well known in the art and include those described in detail in Greene
(1999). Suitable protected carboxylic acids further include, but are not limited to, optionally
substituted CMS aliphatic esters, optionally substituted aryl esters, silyl esters, activated esters,
amides, hydrazides, and the like. Examples of such ester groups include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, benzyl, and phenyl ester, wherein each group is optionally
substituted- Additional suitable protected carboxylic acids include oxazolines and ortho
esters. In certain embodiments, R2 is an optionally substituted CM> aliphatic ester or an
optionally substituted aryl ester. In other embodiments, R2 is a CMS aliphatic ester. Such Cj_
6 aliphatic esters include methyl, ethyl, propyl, and isopropyl.
[0034] The conversion of the cyano group of formula B to the -CO2R2 group of formula A
is achieved by hydrolysis at step (b). In certain embodiments, step (b)is performed in an
alcoholic solvent such that a compound, of formula A is formed wherein R2 forms the
corresponding ester. According to one aspect of the present invention, the hydrolysis at step
(b) is performed by treating a compound of formula B with gaseous HC1 in an alcohol. In
certain embodiments, the hydrolysis at step (b) is performed by treating a compound of
formula B with gaseous HC1 in a lower alkyl. alcohol. Such lower alkyl alcohols include
methanol, ethanol, propanol, and isopropanol.
[0035] In one aspect, the present invention provides methods for preparing chiral
compounds of formula I-a according to the steps depicted in Scheme I, above. It will be
appreciated that although Scheme 1 depicts a method for preparing a racemic compound of
formula I-a, a desired enantiomer is similarly prepared using the appropriate chiral glycidyl
ether of formula F. A general method for preparing a chiral compound of formula I-a is
depicted in Scheme II, below.


EXAMPLES
[0037] Melting points were obtained on a Buchi B-545 melting point apparatus and are
uncorrected. *H NMR spectra were obtained on a Bruke'r DPX 301 at 300 MHz and l3C

NMR spectra were obtained on a Bruker DPX 301 75 MHz. The chemical shifts are reported
in ppm relative to TMS (internal standard).

(7-nitro-2^-dihydrobenzo[b]{l,4]dioxin-2-yl)methanol: 4-Nitrocatechol (30g, 0.19 mol),
iithium carbonate (36 g, 0.49 mol), and epichlorohydrin (38 mL, 0.49 mol) in DMF (180mL)
were heated to 70-85°C for 47 hours. Water was added and the mixture extracted with EtOAc
(3x). Concentration of the combined EtOAc extracts and crystallization from MeOH gave the
title compound, first crop, 5.98 g, 14.7% yield, mp 131.8-135°C and second crop, 1.64 g, 4%
yield, mp mi-Be^C, (lit. mp 131-134°C). -'H NMR (d6-DMSO) 5 7:78 (1H, dd, J=8.9,
2.7 Hz); 7.72 (IH, d, J=2.7 Hz); 7.11 (1H, d, J=8.9 Hz); 5.16 (1H, br s); 4.48 (1H, dd, J=l 1.4,
2.1 Hz); 4.32-4.23 (1H, m); 4.17 (1H, dd, J=11.4, 7.4 Hz); 3.66 (2H, br s).

2-(3-(hydroxyraethyl)-6-nitro-2r3-dihydrobenzo[b)[l,4]dioxin-5-yl)acetonitrile: A
solution of racemic (7-nitro-2,3-dihydrobenzo[b][l,4]dioxin-2-yl)methanol (1.00 g, 4.73
mmol) and 4-chlorophenoxyacetonitrile (827 mg, 4.94 mmol) in DMF (12 raL) was added
dropwise to a solution of potassium tert-butoxide (2.12 g, 18.9 mmol) in DMF (20 mL) at -5-
0°C. After the addition was complete (7 minutes), the reaction mixture was stirred for 1 hour
at -5-0°C. The reaction mixture was acidified with I N HC1 before drowning into water (200
mL). The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers

were washed with IN NaOH (3 x 50 mL) to remove most of the 4-chIorophenoi. After
removal of solvent, the residue was purified by flash chromatography on silica gel, gradient
elution using 2:3, 1:1, 3:2, 100:0 ethyl acetate/hexane, to give 139 mg, 14% recovered
starting material and 804 mg, 68% yield of the title compound as a solid, 'H NMR (CDCIJ)
8 7.77 (1H, d, J=9.12 Hz); 7.01 (1H, d, J=9.12 Hz); 4.50-4.40 (2H, m); 4.30-3.91 (5H, m);
2.25-2.21 (1H, m). I3C NMR (CDC13) 5 148.07, 141.71, 141.55, 119.44, 117.07, 116.96,
115.71,74.36,65.31,61.18,14.89.

(8-(Cyanomethyl)-7-nitro-2,3-dihydrobenzo[b][l,4]dioxin-2-yl) methyl4-methylbenzene
sulfonate: A solution of the 2-(3-(hydroxymethyl)-6-nitro-2,3-dihydrobenzo[b][l,4]dioxin-5-
yl)acetonitrile formed at Example 2, (721.5 mg, 2.88 mmol), in CH*Cl2(30v mL) was treated
with tosyl chloride (604.7 mg, 3.17 mmol), triethylamine (602 uL, 4.32 mmol), and catalytic
DMAP. After 4 hours, starting material was still present by TLC (100% CHiCh) and more
tosyl chloride (60 mg) was added. After 18 hours the solution was washed with 10% aq HC1
then IN NaOH. Concentration and trituration with CH2CI2 gave 746 mg, 64% yield of the
title compound as a solid. 'H NMR (d6-DMSO) 6 7.82 (2H, d, J=8.3l Hz); 7.75 (1H, d,
J=9.09 Hz); 7.48 (2H, d, J=8.13 Hz); 7.12 (1H, d, J=9.12 Hz); 4.74-466 (1H, m); 4.49-4.42
(2H, m); 4.30-4.15 (2H, m); 3.94 (2H, ab q, Jab=16.83 Hz); 2^41 (3H, s).


2-(3-((BenzyIamino)methyl)-6-nitro-2,3-dihydr6benzo[b][l,4]dioxin-5-yl)acetonitrile: A
solution of the tosylate compound formed at Example 3 (700 mg, 1.73 mmpl) in DMSO (6
mL) was treated with benzyl amine (416 uL, 3.81 mmol). The solution immediately turned
purple upon addition of benzyl amine. The mixture was heated to 85°C for 23 hours and more
benzyl amine (200 uL) was added. After another 18 hours at 85°C, the solution was cooled to
room temperature, diluted wiA CH2CI2, washed with 5% aq. NaHCOj (3x), and concentrated.
Flash chromatography (eluting with CH2C12 then 40% EtOAc/CH2Cl2) gave 29.9 mg
recovered starting material, 440 mg, 75% yield of the title compound. 'H NMR (CDCIJ)
5 7.75 (1H, d, J=9.15 Hz); 7.45-7.18 (5H5 m): 6.97 (1H, d, J=9.12 Hz); 4.43-4.34 (2H, m);
4.21 -4.01 (3H, m); 3.68 (2H, s); 3.05-2.93 (2H, m); 1.85 (1H, br s).

Methyl 2-(3-((benzylamino)methyl)-6-nitro-23-dihydrobenzo[b][l,4]dioxin-5-yl)acetate:
Hydrogen chloride was bubbled through a solution of the nitrile from Example 4 (374 mg,
1.10 mmol) in MeOH (5 mL) at 0°C for 1 hour. The flask was sealed and left in a freezer
overnight. The mixture was concentrated, diluted with EtOAc, and washed with dilute aq.
NaOH. The aqueous layer was extracted once with EtOAc and the combined organic layers
concentrated to give 344 mg, 84% yield of the title compound as a dark oil. *H NMR (CDCIj)
5 7.67 (1H, d, J=9.09 Hz); 7.34-7.23 (5H, m); 6.92 (1H, d, J=9.09 Hz); 4.40-4.30 (2H, m);
4.17-4.11 (1H, m); 3.93-3.80 (4H, m); 3.67 (3H, s); 2.98-2.89 (2H,
m).


2-((Benzylamino)methyl)-2r3-dihydro-7H-[l,4]dioxiDo[2>3-e]indol-8(9H>one: The methyl
ester from Example 5 (43 mg) was dissolved in 1:1 ethyl acetate/ethanol (10 mL) and filtered •
through a syringe filter to remove insoluble material. Platinum oxide (35, weight percent)
was added and the mixture placed under SO psi of hydrogen gas on a Parr shaker overnight,
TLC analysis with 95:5 CHzCh/MeOH showed consumption of starting material with a more
polar product having been formed. The mixture was filtered through a 0.5 um syringe filter,
washing with 1:1 EtOAc/EtOH, and the filtrate concentrated under reduced pressure to a pale
red-brown glass. The crude material was redissolved in- ethanol (20 mL) and 20 f-iL of
concentrated HC1 were added. The solution was warmed to 70 °C and allowed to stir
overnight. TLC of the reaction mixture (96:4 CH2Cl2/MeOH) showed the formation of a new
product with no remaining starting material. The reaction mixture was cooled to ambient
temperature and concentrated under reduced pressure to a light orange film. This was
chromatographed over silica gel eluting with 96:4 CH2CJ2/MeOH. The title product was
isolated in 22% yield.

CLAIMS
We claim:
1. A method for preparing a compound of formula D:

comprising the steps of:
(a) providing a compound of formula E:

and
(b) treating said compound of formula E with a compound of the formula
wherein R1 is a suitable leaving group, in the presence of a suitable base.
'
2. The method according to claim 1, wherein R1 is halogen or a phenoxy group
wherein the phenyl ring is optionally substituted one or more halogen, nitro, or ester groups.
3. The method according to claim 2, wherein R1 is a phenyoxy group substituted
with halogen.
4. The method according to any one of claims 1 to 3, wherein the suitable base at
step (b) is a strong base.

5. The method according to claim 4, wherein the strong base is a metal alkoxide
or a metal hydride.
6. The method according to claim 5, wherein the strong base is potassium tert-
butoxide.
7. The method according to any one of claims 1 to 6, further comprising the step
of converting the free hydroxyl moiety of said compound of formula D into a suitable leaving
group to afford a compound of formula C:

wherein LG2 is a suitable leaving group.
8. The method according to claim 7, wherein LG2 is tosyl.
9. The method according to claim 8, wherein the step of converting the free
hydroxyl moiety of said compound of formula D into a suitable leaving group is performed in
the presence of a suitable base.
10. The method according to claim 9, wherein the suitable base is triethylamine.
11. The method according to any one of claims 7 to 10, further comprising the
step of treating the compound of formula C with benzylamine to form a compound B:


12. The method according to claim 11, wherein the compound of formula C is
treated with about 1 to about 5 equivalents of benzylamine.
13. The method according to claim 11 or claim 12, further comprising the step of
hydrolyzing the nitrile group of compound B to form a compound of formula A:

wherein R2 is a carboxylate protecting group.
14. The method according to claim 13, wherein R2 is an optionally substituted C1-_
6 aliphatic ester or an optionally substituted aryl ester.
15. The method according to claim 14, wherein R is methyl, ethyl, propyl, or
isoproyl.
16. The method according to any one of claims 13 to 15, further comprising the
step of reducing the nitro group of the compound of formula A to form compound I:

17. The method according to claim 16, wherein the reduction is performed by
hydrogenation in the presence of a suitable catalyst.

18. The method according to claim 17, wherein the suitable catalyst is a platinum
catalyst, Fe/HCl or Sn/HCl.
19. The method according to claim 18, wherein the suitable catalyst is platinum
oxide.
20. The method according to any one of claims 16 to 19, further comprising the
step of treating the compound I with fumaric acid to form compound I-a:

ABSTRACT

A METHOD FOR PREPARING A COMPOUND OF FORMULA D
The present invention discloses a method for preparing a compound of formula D
having activity as dopamine autoreceptor agonist and partial agonists at the postsynaptic dopamine
D2 receptor. This compound is useful for treating dopaminergic disorders, such as schizophrenia,
schizoaffective disorder, Parkinson's disease, Tourette's syndrome, hyperprolactinemia and drug

addiction.