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Title:
SYNTHESIS OF CHIRAL SUBSTITUTED BENZENES AND RELATED AROMATIC COMPOUNDS CONTAINING 1,2 DIOLS PROTECTED AS DIACETAL GROUPS
Document Type and Number:
WIPO Patent Application WO/2012/114347
Kind Code:
A1
Abstract:
Disclosed herein is a compound of formula (A), its salts, enantiomers, and diastereomers thereof; wherein, Rl and R2 can be (C1-C6) alkyl groups, a phenyl group, a (C5-C7) cycloalkyl groups; X and Y individually selected from H, -N02, -NH2, -OH, -halo, -CHO, -COOH, - COOR, boronic acid-potassium bifluoride boronate salts, boronate esters, aryl, substituted aryl, alkyl or aryl carbamoyl, substituted alkyl or aryl carbamoyl; phosphines(R3R3P) and phosphine oxide of the formula R3R3P=0, where R3 represents an aryl group that can be substituted by one or more (C1-C5) alkyl group, a (C5-C7) cycloalkyl group, (Cl- C4) alkoxy group or di (C1-C4) alkyl amino groups, cyclic hetero aryl group preferably, a 5 membered ring or a halogen.(The R3 groups are normally identical and preferably phenyl groups); wherein both X and Y can be substituted in ortho, para or meta position of the phenyl ring w.r.t the diacetal/ ketal functional group in compound A. The invention also discloses process for preparation of the same.

Inventors:
RAMARAO, Chandrashekar (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
NANDIPATI, Ramadevi (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
NAVAKOTI, Rajasekhar (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
KOTTAMASU, Ramanjaneyulu (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
Application Number:
IN2011/000295
Publication Date:
August 30, 2012
Filing Date:
April 29, 2011
Export Citation:
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Assignee:
AVRA LABORATORIES PVT. LTD. (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
RAMARAO, Chandrashekar (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
NANDIPATI, Ramadevi (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
NAVAKOTI, Rajasekhar (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
KOTTAMASU, Ramanjaneyulu (Avra House, 7-102/54 Sai EnclaveHabshiguda,Hyderabad 7, Andhra Pradesh, 500 00, IN)
International Classes:
C07D493/00; C07D309/00; C07D319/06; C07D319/14
Foreign References:
US5801261A
US6939877B2
US20070185346A1
US4132737A
EP0812847B1
Other References:
HARRAK ET AL.: 'Synthesis and biological activity of new anti-inflammatory compounds containing the 1,4-benzodioxine and/or pyrrole system' BIOORGANIC AND MEDICINAL CHEMISTRY vol. 15, 2007, pages 4876 - 4890
SURESHAN ET AL.: 'Regioselective Protection and Deprotection of Inositol Hydroxyl Groups in' CHEMICAL REVIEWS vol. 103, 2003, pages 4477 - 4503
PAWLOWSKA ET AL.: 'Sensitive enantiomeric separation of aliphatic and aromatic amines using aromatic anhydrides as nonchiral derivatizing agents' JOURNAL OF CHROMATOGRAPHY vol. 666, 1994, pages 485 - 491
AGULAR ET AL.: 'Novel Reaction Leading to (1,2-Diphenylethyl)diphenylphosphine' JOURNAL OF ORGANIC CHEMISTRY vol. 27, 1962, pages 674 - 676
MATTESON ET AL.: 'Asymmetric Alkyldifluoroboranes and Their Use in Secondary Amine Synthesis' ORGANIC LETTERS vol. 4, 2002, pages 2153 - 2155
FREDRICKSON ET AL.: '(1R,4S,5R)-3-Fluoro-1,4,5-trihydroxy-2-cyc lohexene-1-carboxylic acid: the fluoro analogue of the enolate intermediate in the reaction catalyzed by type II dehydroquinases' ORGANIC BIOMOLECULAR CHEMISTRY vol. 2, 2004, pages 1592 - 1596
Attorney, Agent or Firm:
SREE, Aruna, P. (Gopakumar Nair Associates, 3rd Floor 'Shivmangal', Near Big Bazaar,Akurli Road, Kandivali ,Mumbai 1, Maharashtra, 400 10, IN)
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Claims:
We claim,

1. A compound of formula A, its salts, enantiomers, and diastereomers thereof;

A wherein, Rl and R2 can be (C1-C6) alkyl groups, a phenyl group, a (C5-C7) cycloalkyl groups;

X and Y individually selected from H, -N02, -NH2, -OH, -halo, -CHO, -COOH, -COOR, boronic acid-potassium bifluoride boronate salts, boronate esters, aryl, substituted aryl, alkyl or aryl carbamoyl, substituted alkyl or aryl carbamoyl; phosphines(R3R3P) and phosphine oxide of the formula R3R3P=0, where R3 represents an aryl group that can be substituted by one or more (C1-C5) alkyl group, a (C5-C7) cycloalkyl group, (CI -C4) alkoxy group or di (C1-C4) alkyl amino groups, cyclic hetero aryl group preferably, a 5 membered ring or a halogen.(The R3 groups are normally identical and preferably phenyl groups) ; wherein both X and Y can be substituted in ortho, para or meta position of the phenyl ring w.r.t the diacetal/ ketal functional group in compound A.

2. The compound according to claim 1, wherein, Rj & R2 are preferably methyl or ethyl groups.

3. The compound according to claim 1, wherein, R3 is preferably phenyl groups.

4. The compound according to claim 1, wherein the compound is selected from the group comprising of

a) 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxine;

b) 2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-nitrobenzo[b][l,4]dioxine;

c) 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-amine;

d) 2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyIbenzo[b][l,4]dioxin-7- ylcarbamoyl)benzoic acid;

e) 2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7- ylcarbamoyl)benzoic acid [R -(+)-l -methyl benzylamine salt];

f) 2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7- ylcarbamoyl)benzoic acid [S -(-)-l -methyl benzylamine salt]; g) (R)-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-amine; h) (S)-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-amine i) 6-Bromo-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxine; j) [2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][ 1 ,4]dioxin-7- yljdiphenylphosphine;

k) [2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l ,4]dioxin-7-yl]

diphenylphosphineoxide;

1) [2,3-dihydro-5-iodo-2,3-dimethoxy-2,3-dimethyIbenzo[b][l,4]dioxin-7-yl] diphenylphosphineoxide;

m) 2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine;

n) (-)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b] [ 1 ,4]dioxine (-)-Ο,Ο- dibenzoyltartaric acid salt;

o) (+)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine (+)-0,0- dibenzoyltartaric acid salt;

p) (-)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b] [ 1 ,4]dioxin-5yl)-2,3 -dimethoxy-2,3 - dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine;

q) (+)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- d imethyl-6-(diphenylphosph ineoxide)benzo[b] [ 1 ,4] dioxine ;

r) (-)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphino)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3-dimethyl-6- (diphenylphosphino)benzo[b][l,4]dioxine;

s) (+)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphino)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3-dimethyl-6- (diphenylphosphino)benzo[b][l,4]dioxine; t) 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-yl-6-boronic acid;

u) 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-yl-6-boronic acid [Potassium bifluoride salt];

v) 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-ol;

w) Ethyl-2,3-diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6- carboxylate;

x) 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6-carboxylic acid;

y) 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6-carboxylic acid

[(R)-(+)-a-methylbenzylamine salt] ;

z) 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][ 1 ,4]dioxine-6-carboxylic acid

[(S)-(-)-a-methylbenzylamine salt];

aa) 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6-carboxylic acid;

bb) Methyl-2,3-diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6- carboxylate;

cc) Methyl-2,3-diethoxy-2,3-dihydro-2,3-dimethyl-7-nitrobenzo[b][l,4]dioxine-6- carboxylate and

dd) Methyl-7-amino-2,3-diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine- 6-carboxylate.

5. The process for preparation of compounds of formula A according to claim

3,wherein said process comprising:

a) reacting benzene 1,2 diol catechol with a dione such as 2,3 butane dione in presence of methyl orthoformate or ethylorthoformate in presence of Lewis acid such as boron trifluoride diethyl etherate or a Bronsted acid such as camphor sulfonic acid at an ambient temperature to obtain 2,3-dihydro-2,3- dimethoxy-2,3-dimethyl-6-nitrobenzo[b][l,4]dioxine(a);

b) nitrating the 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxine to obtain 2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6- nitrobenzo[b][l,4]dioxine(b); c) reducing the nitro group of 2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6- nitrobenzo[b][l,4]dioxine to obtain 2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][ 1 ,4]dioxin-6-amine(c);

d) reacting the 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6- amine with phthalic anhydride to obtain 2-(2,3-dihydro-2,3-dimethoxy-2,3- dimethyIbenzo[b][l,4]dioxin-7-ylcarbamoyl)benzoic acid(d);

e) resolving 2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7- ylcarbamoyl)benzoic acid with chiral methyl benzyl amine in a suitable solvent followed by crystallization in solvents such as methanol, ethanol, isopropanol, butanol or acetone to obtain optically active 2-(2,3-dihydro-2,3- dimethoxy-2,3-dimethylbenzo[b] [ 1 ,4]dioxin-7-ylcarbamoyl)benzoic acid - 1 - methyl benzylamine salt [(e) or (f)] ;

f) hydrolysing the compound of optically active 2-(2,3-dihydro-2,3-dimethoxy- 2,3-dimethylbenzo[b][l,4]dioxin-7-ylcarbamoyl)benzoic acid -1 -methyl

' - benzylamine salt [(e) or (f)] using a base to obtain optically active 2,3- dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-amine[(g) or (h)] respectively;

g) diazotizing the optically active 2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][l,4]dioxin-6-amine[(g) and (h)] followed by treatment with cuprous bromide to obtain 6- bromo -2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][l,4]dioxine (i);

h) treating 6-bromo-2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][l,4]dioxine with an organo lithium species with a diphenyl chloro phosphine to obtain [2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][l,4]dioxin-7-yl]diphenyl phosphine(j);

i) oxidizing the [2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7- yl]di phenyl phosphine with a solution of hydrogen peroxide in methanol to obtain [2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l ,4]dioxin-7-yl] diphenyl phosphineoxide(k);

j) treating the [2,3-dihydro-2,3-dimethoxy-2,3-dimethyIbenzo[b][l,4]dioxin-7- yl] disubstituted phosphineoxide with organo lithium reagent such as lithium di-isopropyl amide at a temperature ranging between -78°C to -30°C followed by quenching the resulting lithiated species with molecular iodine to obtain [2,3-dihydro-5-iodo-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7-yl] diphenylphosphineoxide(l);

k) · Ullman coupling of the iodo compound obtained in the above step in DMF, in the presence of activated copper powder to obtain 2,3-dhihydro-5-(2,3- dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine (m);

1) resolving the compound obtained previous step with suitable chiral reagent in a suitable solvent at ambient temperature to form a diastereomeric salt, (-) 2,3- dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6- (diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine (-)-Ο,Ο- dibenzoyltartaric acid(n); m) resolving the compound obtained previous step with suitable chiral reagent in a suitable solvent at ambient temperature to form a diastereomeric salt, (+) 2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6- (diphenylphosphineoxide)benzo[b][l ,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b] [ 1 ,4]dioxine (+)-0,0- dibenzoyltartaric acid(o); n) treating the optically active salt of the step K with an aqueous alkaline solution in DCM to yield (-) 2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl- 6-(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine(p): o) treating the optically active salt of the step 1 with an aqueous alkaline solution in DCM to yield (+) 2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3- dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3- dimethoxy-2,3-dimethyl-6-(diphenylphosphineoxide)benzo[b][l,4]dioxine(q): p) reducing the compound in the step m in a high boiling hydrocarbon solvent such as xylene or other substituted benzenes with an alkyl amine such as tributylamine with trichlorosilane to yield (-) 2,3-dhihydro-5-(2,3-dihydro- 2,3-dimethoxy-2,3-dimethyl-6-(diphenylphosphino)benzo[b][l,4]dioxin-5yl)- 2,3-dimethoxy-2,3-dimethyl-6-(diphenylphosphino)benzo[b][l,4]dioxine(r): q) reducing the compound in the step o in a high boiling hydrocarbon solvent such as xylene or other substituted benzenes with an alkyl amine such as tributylamine with trichlorosilane to yield (+) 2,3-dhihydro-5-(2,3-dihydro- 2,3-dimethoxy-2,3-dimethyl-6-(diphenylphosphino)benzo[b][l,4]dioxin-5yl)- 2,3-dimethoxy-2,3-dimethyl-6-(diphenylphosphino)benzo[b][l,4]dioxine(s): r) reacting 6-halo-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxine with an organo lithium species such as n-butyllithium and triisopropyl borate at a temperature ranging between 75°C to 30°C followed by quenching with dilute HC1 solution to obtain 2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][l,4]dioxin-6-yl-6-boronic acid(t);

s) reacting 2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][ 1 ,4]dioxin-6-yl-6- boronic acid with potassium biflouride to obtain 2,3-dihydro-2,3-dimethoxy- 2,3-dimethylbenzo[b][l,4]dioxin-6-yl-6-boronic acid [Potassium bifluoride salt](u); and

t) reacting 6-halo-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxine with alkyl lithium such as n-butyllithium and treating the resulting lithiated species with a trialkyl borate such as triisopropyl borate or trimethyl borate followed by treatment with an oxidizing agent to yield 2,3-dihydro-2,3- dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-ol (v).

6. The process for preparation of compounds of formula A according to claim 3, further comprising the step of;

a) reacting 3,4-dihydroxybenzoic acid with 2,3-butane dione and a triethyl orthoformate in presence of Lewis acid/ Bronsted acid at an ambient temperature to obtain Ethyl-2,3-diethoxy-2,3-dihydro-2,3- dimethylbenzo[b][ 1 ,4]dioxine-6-carboxylate(w);

b) hydrolysing Ethyl-2,3-diethoxy-2,3-dihydro-2,3- dimethylbenzo[b][l,4]dioxine-6-carboxylate using a base to obtain 2,3- Diethoxy-2, 3 -dihydro-2, 3 -dimethy lbenzo [b] [ 1 ,4]dioxine-6-carboxylic acid(x) ; c) resolving the 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6- carboxylic acid with chiral methyl benzyl amine in a suitable solvent to obtain optically active 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l ,4]dioxine- 6-carboxylic acid -methylbenzylamine salt (R)or (S)(y or z );

d) treating the optically active 2,3-Diethoxy-2,3-dihydro-2,3- dimethylbenzo[b][l,4]dioxine-6-carboxylic acid -methylbenzylamine salt with mineral acid to obtain optically active 2,3-Diethoxy-2,3-dihydro-2,3- dimethy lbenzo [b] [ 1 ,4]dioxine-6-carboxy 1 ic acid(aa) ;

e) methyiating the optically active 2,3-Diethoxy-2,3-dihydro-2,3- dimethylbenzo[b][l,4]dioxine-6-carboxylic acid to obtain Methyl-2,3- diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6-carboxylate(bb); f) nitrating the Methyl-2,3-diethoxy-2,3-dihydro-2,3- dimethylbenzo[b][l,4]dioxine-6-carboxylate to obtain Methyl-2,3-diethoxy- 2,3-dihydro-2,3-dimethyl-7-nitrobenzo[b][ 1 ,4]dioxine-6-carboxylate(cc); and g) reducing the Methyl-2,3-diethoxy-2,3-dihydro-2,3-dimethyl-7- nitrobenzo[b][l,4]dioxine-6-carboxylate involving a metal catalyst along with source of hydrogen to obtain Methyl-7-amino-2,3-diethoxy-2,3-dihydro-2,3- dimethylbenzo[b][l,4]dioxine-6-carboxylate(dd).

Description:
"SYNTHESIS OF CHIRAL SUBSTITUTED BENZENES AND RELATED AROMATIC COMPOUNDS CONTAINING 1,2 DIOLS PROTECTED AS

DIACETAL GROUPS"

Technical field:

The present invention relates to substituted racemic and optically active benzenes containing 1,2 diols protected as diacetal groups of formula A. These compounds have a chiral framework in the form of a substituted diacetal functionality attached directly to the aromatic backbone allowing the structure to have chirality and extending the use of these novel asymmetric aryl compounds in applications concerning asymmetric catalysis and also as biologically active building blocks and pharmaceutical drugs and products.

Background of the invention:

1,2 diacetals especially 2,3 butane diacetals (referred herein as BDA) have been known in the literature and used for protection of 1,2 diols only on saturated systems and also for stereo-controlled transformations by virtue of their ability towards retention and transmission of chirality (Chemical Reviews, 2001, 101 , pages 53-80). This application has been limited to the protection of 1,2 diols attached to saturated sp3 carbon atoms. No attempt has been made until now to extend this application for 1,2 dihydroxy substituted benzenes.

Therefore, the object of the present invention is to provide chiral substituted benzenes and related aromatic compounds containing 1 ,2 diols protected as diacetal groups and synthesis thereof.

Another object of the present invention is to provide unique substituted benzenes that are electron rich and possessing chirality by virtue of the asymmetric diacetal/ketal functionality.

Summary of the invention:

In accordance with the above object, the present invention provides a method for protection of 1,2 diols attached to unsaturated sp2 carbon atoms and aromatic species such as catechol or substituted 1,2 dihydroxy aromatic compounds with 2,3 butane dione or any similar alkyl dione to result in a protected diacetal and the subsequent resolution of such chiral compounds and further functional group transformations. The invention is concerned with the development of a process for the protection of catechol or substituted 1,2 dihydroxy benzenes or related aromatic compounds and the subsequent transformation to both racemic and optically active butane diacetal protected products.

Detailed description of the invention:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

The present invention provides substituted racemic and optically active benzenes of formula A, its salts, enantiomers, and diastereomers thereof,

wherein, Rl and R2 can be (C1-C6) alkyl groups, a phenyl group, a (C5-C7) cycloalkyl groups; X and Y individually selected from H, -N02, -NH2, -OH, -halo, -CHO, -COOH, -COOR, boronic acid-potassium bifluoride boronate salts, boronate esters, aryl, substituted aryl, alkyl or aryl carbamoyl, substituted alkyl or aryl carbamoyl; phosphines(R3R3P) and phosphine oxide of the formula R3R3P=0, where R3 (see scheme 1) represents an aryl group that can be substituted by one or more (C1-C5) alkyl group, a (C5-C7) cycloalkyl group, (C1-C4) alkoxy group or di (C1-C4) alkyl amino groups, cyclic hetero aryl group preferably, a 5 membered ring or a halogen.fThe R3 groups are normally identical and preferably phenyl groups); wherein, both X and Y can be substituted in ortho, para or meta position of the phenyl ring w.r.t the diacetal/ ketal functional group in Fig A.

Thus, the invention encompasses substituted anilines, phenols, aryl halides, benzoic acids, benzaldehydes, substituted benzenes and other related products which possess a diacetal/ketal functionality of formula (A). The compound of formula (A) can be useful as a ligand or be converted to variety of structures that can perform as ligands independently or by forming a metal complex to catalyze asymmetric reactions.

The compound of formula (A) can be used to further prepare chiral bases or acids that can be used as catalysts, resolving agents and chiral auxiliaries.

The compound of formula (A) can also be used as a unique building block that allows for the preparation of biologically and pharmaceutically active products and drugs.

The present invention further describes synthesis of novel optically active and racemic substituted benzenes and related substructures to prepare such compounds.

According to the present invention, the synthesis of compounds of formula A in racemic and optically active forms are illustrated in scheme 1

The compound of formula 1 is prepared by the reaction of a 2,3 alkyl or cycloalkyl dione, preferably 2,3 butane dione with an alkyl orthoformate, preferably trimethy orthoformate or triethyl orthoformate using a Lewis acid such as boron trifluoride diethyl ^therate. Other Lewis acids may also be used. The reaction is performed at a temperature ranging between 10°C to 40°C. This reaction can also be done using Bronsted acids such as camphor sulfonic acid (CSA) in place of boron trifluoride diethyl etherate.

The compound of formula 2 is prepared by the nitration of compound of formula 1.

The compound of formula 3 is prepared by the reduction of 2 using a metal catalyst and any source of hydrogen or other reducing agents.

The compound of formula 4 is synthesized by treatment of 3 with phthalic anhydride in a solvent at ambient temperature.

The compound of formula 5 is a salt obtained by reacting 4 with any chiral amine, preferably a chiral methyl benzyl amine in a suitable solvent at ambient temperature. The resulting salt is further purified by crystallization using suitable solvents such as methanol, ethanol, isopropanol, butanol or acetone to obtain an optically active diastereomeric salt. The stereochemistry of the optically active butane diacetal moiety was confirmed by X-ray data of the diastereomeric salt formed from the chiral methyl benzyl amine. The salt formed with (R)-(+) methyl benzyl amine [also known as (R)-(+)- 1-Phenylethylamine] gave the R„R isomer with an optical rotation of (-) 71.12°, compound 5(a). (See Fig. 1)

Fig. 1: Compound 5(a) - R,R isomer formed due to the reaction of compound 4 with (R)- (+) methyl benzyl amine.

Resolution of the diastereomeric salt prepared by treating the compound of formula 4 with (S)-(-) methyl benzyl amine [also known as (S)-(-)-l-Phenylethylamine] gave the S,S isomer with an optical rotation of (+) 72.76°, compound 5(b).

The compound of formula 6(a) is obtained by base hydrolysis of the salt 5(a) using metal hydroxide, preferably sodium hydroxide at a temperature ranging from 20°C to 100°C. The resulting (-) isomer of butane diacetal substituted aniline can be further purified by recrystallization from an alcoholic solvent.

The compound of formula 6(b) is obtained by base hydrolysis of the salt 5(b) using metal hydroxide, preferably sodium hydroxide at a temperature ranging from 20°C to 100°C. The resulting (+) isomer of butane diacetal substituted aniline can be further purified by recrystallization from an alcoholic solvent.

The compound of formula 7 is prepared by the diazotization of 6 using conditions well known to those in the art.

The compound of formula 8 is made from the aryl halide 7 by reaction with an organo lithium species such as n-butyl lithium with a di-substituted chloro phosphine (R3R3PCI, scheme 1) where the R 3 groups are defined for compound 8. The reaction is done at a temperature ranging between -78°C to -30°C. R3 represents an aryl group that can be substituted by one or more (C1-C5) alkyl group, a (C5-C7) cycioalkyl group, (C1-C4) alkoxy group or di (C1-C4) alkyl amino groups, cyclic hetero aryl group preferably, a five membered ring or a halogen. The R3 groups are normally identical and preferably phenyl groups.

The compound of formula 9 is prepared by the oxidation of phosphine 8 using methods known in the prior art and preferably with a solution of hydrogen peroxide in methanol.

The compound of formula 10 is obtained by iodination of the phosphine oxide 9 which is achieved by initial treatment with an organo lithium reagent such as lithium di-isopropyl amide at a temperature ranging between -78°C to -30°C followed by quenching the resulting lithiated species with molecular iodine. The compound of formula 11 is obtained by the Ullman coupling of the iodo compound 10 in DMF, in the presence of activated copper powder.

The compound of formula 12 is an optically active diastereomeric salt obtained by reacting compound 11 with suitable chiral reagent commonly used in the art for resolution, for example (-)-0,0-dibenzoyltartaric acid, in a suitable solvent at ambient temperature to form a diastereomeric salt. The other (+) isomer was prepared using the same procedure but with the other isomer that is (+)-0,0-dibenzoyltartaric acid. The compound of formula 13 is obtained by treating the optically active salt 12 with an aqueous alkaline solution in DCM to yield the (-) isomer with an ertatiomeric excess (ee) = 99.39% and optical rotation of (-) 74.05°.

The compound of formula 14 is obtained by treating the compound 13, in a high boiling hydrocarbon solvent such as xylene or other substituted benzenes with an alkyl amine such as tributylamine with trichlorosilane. Several procedures are known in the art to reduce aryl substituted phosphine oxides that can be utilized to obtain a similar result.

The compound of formula 16 is prepared by reaction of the aryl halide 7 with an organo lithium species such as n-butyllithium and a trialkyl borate such as triisopropyl borate or trimethyl borate at a temperature ranging between -75°C to 30°C followed by quenching with dilute HC1 solution and extracting into ethyl acetate to obtain compound 15. The compound 15 which is unstable is then treated with a salt, like potassium bifluoride, at about 0°C to form the salt 16.

The compound of formula 17 is prepared by reacting aryl halide 7 with alkyl lithium such as n-butyllithium and treating the resulting lithiated species with a trialkyl borate such as triisopropyl borate or trimethyl borate. The resulting boronic acid is immediately treated with an oxidizing agent such as hydrogen peroxide at a temperature range between -75°C to 30°C to yield to the required alcohol 17.

The compound of formula 18 as shown in scheme 2, can be prepared by the reaction of 3,4-dihydroxybenzoic acid with 2,3-butane dione and a trialkyl orthoformate such as trimethyl or triethyl orthoformate using any Lewis acid such as boron trifluoride diethyl etherate at an ambient temperature for 3 to 5 days. This reaction can also be done using a Bronsted acid such as camphor sulfonic acid (CSA).

The compound of formula 19 is prepared by base hydrolysis of compound 18 using conditions known in the art.

The compound of formula 20 is a racemic salt which can be obtained by reacting 19 with a suitable chiral amine, preferably a chiral methyl benzyl amine in a suitable solvent at ambient temperature.

The compound of formula 21 is an optically pure diastereomeric salt obtained from the process of resolution from the racemate salt 20. The salt formed with (R)-(+) methyl benzyl amine [also known as (R)-(+)-l-Phenylethylamine] gave the R,R isomer with an optical rotation of (-) 55.91° .

Resolution of the diastereomeric salt prepared by treating the compound of formula 20 with (S)-(-) methyl benzyl amine [also known as (S)-(-)-l-Phenylethylamine] gave the S,S isomer with an optical rotation of (+) 58.3°.

The compound of formula 22 is prepared by reacting compound 21 with a mineral acid. The compound of formula 23 is prepared by treating compound 22 with suitable conditions for methylation know in the art. One such method involves the use of a mild base with an alkylating agent such as dimethyl sulphate.

The compound of formula 24 is prepared by nitration of compound 23 using conditions known in the art.

The compound of formula 25 is prepared by the reduction of nitro compound 24 using several methods that may involve a metal catalyst along with any source of hydrogen or other reducing agents known in the art. Scheme-

* (R)-(+) of 1-phenylethanamine results in [R,R] compound 5. Similarly, (S)-(-) results in [S,S] compound 5

Scheme-2

Racemic salt

Fuming HN0 3

Acetic acid

The formula A of the present invention encompasses compounds 1 -25 as depicted in schemes 1 and 2 are novel and hence forms part of the scope of the invention.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

5

10

Examples:

Preparation of compound 1:

2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxine: Procedure:

200g of Catechol was dissolved in 1000ml of methanol and 1742.4g of trimethyl orthoformate, 334.22 g of 2,3-butanedione were added at room temperature. 61.02g of BF 3 .Et 2 0 was added drop wise at 10°C - 15°C. On completion, the reaction mixture was allowed to warm up to room temperature and stirred for another 5 hours. Methanol was removed under reduced pressure and the resulting brown colour crude residue was taken in 1500ml of water and extracted with (1000ml χ 3) of ethyl acetate. The organic layer was washed with 1500ml of water, dried over Na 2 S0 4 and concentrated. The obtained crude product was purified by column chromatography with silica using 2% ethyl acetate/hexane (Yield=78.6%).

Melting range: 54.8°C - 57.8°C

1H NMR (300 MHz) CDC1 3 : d = 1.61 (s, 3H, CHs), 3.30 (s, 3H, OCHjJ, 6.9 (m, 2H, aromatic)

,3 C NMR (300 MHz) CDCI 3 : d= 17.27, 48.79, 98.21, 1 16.93, 121.66, 140.88. Preparation of compound 2

2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-nitrobenzo[b][l,4]d ioxine: Procedure:

320 g of Compound 1 was dissolved in 1920 ml of acetic acid and a mixture of 144 g of fuming nitric acid dissolved in 432 ml of acetic acid was added drop wise at 15°C - 20°C over a period of 2 hours. The reaction mixture was stirred at room temperature for 12 hours and subsequently poured into 5000 ml of ice water. The colourless solid that separated out was filtered and washed with 2000 ml of water, dried under vacuum and crystallized in isopropyl alcohol (Yield=83.5%).

Mass: m/z EIMS 270 (M + +1): 269.25.

Melting range: 140.8°C - 147°C 1H NMR (300 MHz) CDC1 3 : d =1.6 (s, 3H, CHj), 3.3 (s, 3H, OCH 3 ), 6.97 (d, J= 9.51 Hz, 1H, aromatic), 7.83 (m, 2H, aromatic).

13 C NMR (300 MHz) CDC1 3 : d =17.10, 42.29 (d, J= 30 Hz), 99.02 (d, J=153 Hz), 113.32, 117.13, 117.99, 140.91, 142.34, 147.12.

Preparation of compound 3

2,3-dihydro-2,3-dimethoxy-2,3-dimethyIbenzo[b]fl,4]dioxin-6- amine: Procedure:

120 g of Compound 2 was subjected to catalytic hydrogenation using 6 g of 20% Pd(OH) 2 in 700 ml of methanol at 60 psi for 2 hours. The solution was filtered through celite and the filtrate was concentrated. The resulting solid product was crystallized in ethanol (Yield=84%).

Mass: m/z EIMS 240 (M + +l): 239.27

[a] 20 D = (+) 4.53 (C = 1% in CHCI3).

Melting range: 104.8°C - 112.4°C

1H NMR (300 MHz) CDC1 3 : d = 1.54 (s, 3H, CH 3 ), 3.26 (d, J= 9.45 Hz, 3H OCH3), 3.40 (broad s, 2H, NH^), 6.23 (d,d J= 5.82, 2.58 Hz 1H, aromatic), 6.30 (s, 1H, aromatic), 6.69 (d J= 8.4 Hz, 1H, aromatic)

13 C NMR (300 MHz) CDCI 3 : d =17.40, 48.83 (d, J= 51 Hz), 97.97, 98.38, 104.25, 109.05, 1 17.36, 133.49, 141.08 (d, J= 60 Hz).

Preparation of compound 4

2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b] [l,4]dioxin-7- ylcarbamoyl)benzoic acid:

Procedure:

37.2 g of Phthalic anhydride was dissolved in 240 ml of dimethylformamide and 60 g of compound 3 was added at room temperature over a period of 30 min. The reaction mixture was stirred for 2 hours at room temperature and then around 200 ml of dimethylformamide was distilled at 60°C at 10 mm. The obtained residue was poured into 2000 ml of ice water and stirred at room temperature for 2 hours. A colourless solid separated out which was filtered and dried under vacuum. 90 g of the product (compound 4) was obtained and was used for next step without any further purification.

Mass: m/z EIMS 386 (M + -1): 387.38

Melting range: 160.1°C - 163.1°C l H NMR (300 MHz) DMSO-d 6 : d = 1.50 (s, 3H, CH 3 ), 3.21 (d, J= 11.19 Hz, 3H OCH3), 6.80 (d, J= 8.67, IH, aromatic), 7.1 1 (d,d J= 2.19, 8.4 Hz IH, aromatic), 7.34 (s, IH, aromatic), 7.49 - 7.66 (m, 4H, aromatic), 7.84 (d, J= 7.44 Hz, IH aromatic), 10.15 (s, 1 H, CONH2), 13.0 (broad s, IH, COOH)

13 C NMR (DMSO-CJ6, 300 MHz): d = 17.03, 48.47 (d, J= 51 Hz), 97.09 (d, J= 66 Hz), 108.37, 113.16, 116.25, 127.68, 129.21 (d, J=69 Hz), 129.96, 131.56, 133.70, 136.54, 138.89, 140.26, 166.94, 167.74.

Preparation of compound 5(a)

2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b] [l,4]dioxin-7- ylcarbamoyl)benzoic acid [R -(+)-l-methyI benzylamine salt]: [Fig. 1]

Procedure:

150 g of Compound 4 was suspended in 2330 ml of isopropyl alcohol and 59 g of R-(+)- 1 -methyl benzylamine was added to this mixture. The reaction mixture appeared as a light orange coloured solution which was stirred at room temperature for 12 hours. The resulting colourless solid was filtered and dried under vacuum to give 190 g of the diastereo-isomeric salt.

This salt was taken into 380 ml of methanol and heated at 65°C - 70°C for 15 minutes, filtered under hot conditions and dried under vacuum. This process was repeated twice (Yield=22.85%).

Melting range: Decompose at 172.3°C Mass: m/z EI S 388 (M* +1): 491.56; mass confirmed by the peak minus the R -(+)-l- methyl benzylamine.

[a] 20 D = (-) 71.12° (C = 1% in MeOH).

1H NMR (300 MHz) DMSO-d 6 : d = 1.41 (d, J= 6.72 Hz, 3H, PhCHCHsNHz),

1.49 (s, 3H, CHs), 3.18 (d, J= 6.96 Hz, 3H OCH 3 }, 4.30 (m, 1H aromatic), 6.79 (d J= 8.7 Hz, 1H, aromatic), 7.08 (d, J= 2.01, 1H, aromatic), 7.29-7.46 (m, 6H, aromatic), 7.66- 7.71 (m, 2H, aromatic), 7.90 (broad s, 2H, PhCHCH 3 NH 2 ),12.4 (broad s,lH, COOH).

13 C NMR (300 MHz) DMSO-d 6 : d = 17.45, 48.88 (d, J= 63 Hz), 98.01, 98.43, 104.30, 109.09, 117.41, 133.54, 141.12 (d, J= 60 Hz), 49.88, 126.56, 127.83 (d, J= 45 Hz), 128.24 (d, J= 60 Hz), 134.20, 135.11, 136.18, 139.18, 140.23, 140.53, 166.88, 171.55.

Preparation of compound 5(b)

2-(2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin -7- ylcarbamoyl)benzoic acid [S -(-)-l -methyl benzylamine salt]:

Procedure:

152 g of Compound 4 was suspended in 2361 ml of isopropyl alcohol and 59.8 g of S-(-)- 1 -methyl benzylamine was added to this mixture. The reaction mixture appeared as a light orange coloured solution which was stirred at room temperature for 12 hours. The resulting colourless solid was filtered and dried under vacuum to give 192.5 g of the diastereo-isomeric salt.

This salt was taken into 385 ml of methanol and heated at 65°C - 70°C for 15 minutes, filtered under hot conditions and dried under vacuum. This process was repeated twice (Yield=22.85%).

Melting range: Decompose at 174°C

Mass: m/z EIMS 388 (M* +1): 491.56; mass confirmed by the peak minus the S-(-)-l- methyl benzylamine.

[a] 20 D = (+) 72.76° (C = 1% in MeOH). 1H NMR (300 MHz) DMSO-d 6 : d = 1.41 (d, J= 6.72 Hz, 3H, PhCHCH 3 NH 2 ), 1.49 (s, 3H, CH 3 ), 3.18 (d, J= 6.96 Hz, 3H OCH 3 }, 4.30 (m, 1H aromatic), 6.79 (d J= 8.7 Hz, 1H, aromatic), 7.08 (d, J= 2.01, 1H, aromatic), 7.29-7.46 (m, 6H, aromatic), 7.66-7.71 (m, 2H, aromatic), 7.90 (broad s, 2H, PhCHCH 3 NH2),12.4 (broad s,lH, COOH).

I3 C NMR (300 MHz) DMSO-d 6 : d = 17.45, 48.88 (d, J= 63 Hz), 98.01, 98.43, 104.30, 109.09, 1 17.41, 133.54, 141.12 (d, J= 60 Hz), 49.88, 126.56, 127.83 (d, J= 45 Hz), 128.24 (d, J= 60 Hz), 134.20, 135.11, 136.18, 139.18, 140.23, 140.53, 166.88, 171.55.

Preparation of compound 6(a)

(R)-2,3-dihydro-2,3-dimethoxy-2,3-dimethyIbenzo[b][l,4]dioxi n-6-amine: Procedure:

65 g of Compound 5(a) was subjected to base hydrolysis using 1300 ml of 5N sodium hydroxide solution at 100°C for 18 hours. The reaction mixture was cooled to room temperature and diluted with 1000 ml of ice water. Extracted with (1000 ml x 3) of ethyl acetate and washed with water, brine and dried over Na 2 S0 4 . The solvent was removed under reduced pressure and the resulting pale yellow oil was taken into hexane and stirred at 10°C. An off-white solid separated out from the solution which was filtered and crystallized in ethanol.

Mass: m/z EIMS 240 (M + +1): 239.27.

Melting range: 105.2°C - 110.5°C

[a] 20 D = (-) 233.61 (C = 1% in CHC1 3 ).

Chiral HPLC purity: 99.38%

Preparation of compound 6(b)

(S)-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxi n-6-amine: Procedure:

65 g of Compound 5(b) was subjected to base hydrolysis using 1300 ml of 5N sodium hydroxide solution at 100°C for 18 hours. The reaction mixture was cooled to room temperature and diluted with 1000 ml of ice water. Extracted with (1000 ml * 3) of ethyl acetate and washed with water, brine and dried over Na 2 S0 4. The solvent was removed under reduced pressure and the resulting pale yellow oil was taken into hexane and stirred at 10°C. An off-white solid separated out from the solution which was filtered and crystallized in ethanol.

Melting range: 106.1°C - 109.5°C 2 0 D = (+) 236.07 (C = 1 % in CHC1 3 ).

Chiral HPLC purity: 99%

1H NMR (300 MHz) CDC1 3 : d = 1.54 (s, 3H, Cfc ), 3.26 (d, J= 9.45 Hz, 3H OCH3), 3.02 (broad s, 2H, NH2), 6.23 (d,d J= 5.82, 2.58 Hz IH, aromatic), 6.30 (s, IH, aromatic), 6.69 (d J= 8.4 Hz, IH, aromatic).

13 C NMR (300 MHz) CDC1 3 : d = 17.45, 48.88 (d, J= 54 Hz), 98.01, 98.43, 104.30, 109.09, 117.41, 133.54, 141.12 (d, J= 60 Hz).

Preparation of compound 7

6-Bromo-2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]d ioxine:

Procedure:

10 g of Compound 6 was dissolved in 100 ml of (1 :1) acetic acid-acetonitrile mixture and 6.92 g of sodium nitrite was dissolved in 20 ml of water and added drop wise at 0°C - 5°C and stirred for 20 minutes. This diazonium salt was added portion wise at 55°C - 60°C to a suspension of 19.2 g of cuprous bromide in 40 ml of acetic acid. Then the reaction mixture was stirred for 60 minutes at 60°C and was poured in 300 ml of ice water and filtered through a celite bed. The filtrate obtained was extracted with (240 ml χ 3) dichloromethane given (200 ml χ 3) water washes, dried over Na 2 SC>4 and concentrated. The crude product obtained was purified by column chromatograph with silica gel using 5% ethyl acetate-hexane (Yield=59.5%).

[a] 20 D = (-) 178.58° (C = 1% in CHCI3), when 6(a) compound was used.

Chiral HPLC purity: 94.2%

[a] 20 D = (+) 180.46° (C = 1% in CHCI3), when 6(b) compound was used. Chiral HPLC purity: 94.74% 1H MR (300 MHz) CDC1 3 : d = 1.54 (s, 3H, CH 3 ), 3.26 (d, J= 9.45 Hz, 3H OCH 3 ), 6.76 (d, J= 8.52 Hz, 1H, aromatic), 6.97 (dd, lH, aromatic), 7.05 (s, 1H, aromatic)

13 C NMR (300 MHz) CDCI 3 : d =17.23, 49.05 (d, J= 27 Hz), 98.47 (d, J= 39 Hz), 113.20, 118.41, 120.11, 124.61, 140.27, 141.88.

Preparation of compound 8

[2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7 - yljdiphenylphosphine:

Procedure:

29.5 g of Compound (-)7 was dissolved in 300 ml of dry THF and 42.5 ml of n-BuLi (2.5 M solution in hexane) and was added drop wise at -75°C over period of 60 min and stirred for another 60 min at -75°C. Then 23.32 g of chlorodiphenylphosphine dissolved in 25 ml of dry THF was added drop wise to the reaction mixture over a period of 45 min at -75°C. The reaction mixture was stirred further for 180 minutes and was allowed warm up to 0°C. 150 ml of saturated NH4CI solution was added drop wise and the organic layer was separated. The aqueous layer was extracted with (100 ml * 3) ethyl acetate and the combined organic layers were dried over Na 2 S0 4 and concentrated. The resulting compound was used in the next step without any further purification. The same procedure was used with (+)7 compound also.

Preparation of compound 9

[2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-7 -yl]

diphenylphosph in eoxid e:

Procedure:

50 g of compound 8 was dissolved in 300 ml of methanol and 9.9 g of 40% hydrogen peroxide was added drop wise at 15°C - 20°C for 30 minutes. The reaction mixture was stirred at room temperature for 10 hours and the excess of H 2 0 2 was quenched with 150 ml of 15% NaHS0 3 solution at 0°C - 15°C. The methanol was removed under reduced pressure and the resulting mass was taken into 150 ml of water. The reaction mixture was extracted with (250 ml χ 3) ethyl acetate and the combined organic layers were washed with water and brine, dried over Na 2 S0 4 and concentrated. The resulting viscous yellow coloured compound was taken into 120 ml of diethyl ether and stirred at 10°C. A colourless solid separated out which was filtered and dried under vacuum. (Yield=65.8%, Chiral HPLC purity: 97.39%).

[a] 20 D = (-) 128.74 (C = 1%, CHC1 3 ), when (-)7 compound was used.

[a] 20 D = (+) 129.0 (C = 1%, CHC1 3 ), when (+)7 compound was used. Mass: m/z EIMS 425 (Iv +1): 424.23 Melting range: 188.1°C - 191.7°C

1H NMR (300 MHz) CDC1 3 : d = 1.56 (d, J= 9.9 Hz 6H, CH3J, 3.25 (d, J= 16.86 Hz, 3H OCH 3 ), 6.97 (dd J= 11.61, 3.06, 1H, aromatic), 7.15 - 7.21 (m, 2H, aromatic), 7.44-7.63 (m, 6H, aromatic) 7.66-7.70 (m, 4H, aromatic).

I3 C NMR (300 MHz) CDC1 3 : d =17.26 (d, J= 9 Hz), 49.28 (d, J= 18 Hz), 98.64 (d, J= 96 Hz), 1 17.47 (d, J= 57 Hz), 121.17 (d, J= 48 Hz), 124.63, 126.07,

(t, J= 33, 42 Hz), 128.31 (d J= 48 Hz), 131.78, 131.99 (d, J= 42 Hz), 133.38, 140.83 (d, J= 66 Hz), 144.42 (d J= 12 Hz).

Preparation of compound 10

[2,3-dihydro-5-iodo-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]d ioxin-7-yl]

diphenylphosphineoxide:

Procedure:

7.63 g of (2.0 M, LDA) Freshly distilled diisopropyl amine was dissolved in 8 ml of dry THF and 27.3 ml of n-BuLi (2.5 M solution in hexane) was added drop wise at 0°C and stirred at -10°C - 0°C for 30-45 min.

20 g of Compound 9 was dissolved in 200 ml dry THF and added drop wise to 2.0 M LDA solution at -70°C. After stirring at -70°C for 3.5 hrs, the reaction mixture was cannulated at -70°C over 20 min. In a 500 ml 3N RB (equipped with a thermometer and nitrogen out let), 23.96 g of iodine and 48 ml of dry THF were stirred for 60 min at - 70°C. The reaction mixture was then slowly allowed to warm up to 20°C and 50 mi of water was added drop wise. This reaction mixture was taken in 800 ml of ethyl acetate, washed with 500 ml of 20% aqueous solution of sodium disulfite, 500 ml of water and 500 ml of brine, dried over Na 2 S0 4 and concentrated. The obtained crude was taken in hexane and stirred at 10°C and the thrown out solid was filtered and dried under vacuum (Yield=84.9%)

For analytic data 10 g of Compound 10 was purified by diethyl ether. HPLC purity: 81.48% (HPLC purity 12.7% of compound 9) Mass: m/z EIMS 551 (M + +1): 550.32 Melting range: 182.TC - 187°C

Ή NMR (300 MHz) CDCI 3 : d = 1.60 (d, J= 11.94 Hz 6H, CH 3 ), 3.26 (d, J= 12.84 Hz, 3H OCH3), 6.64 - 6.68 (m, 1H, aromatic), 6.79 - 6.82 (d, J= 9 Hz, 1H, aromatic), 7.45- 7.63 (m, 6H, aromatic) 7.66-7.70 (m, 4H, aromatic).

13 C NMR (300 MHz) CDC1 3 : d =17.08 (d, J= 12 Hz), 49.30 (d, J= 21 Hz), 99.32, 99.99, 116.31 (d, J= 57 Hz), 128.37 (dd, J= 12 39 Hz) 131.54, 132.07, 141.69, 143.90, 143.93.

Preparation of compound 11:

2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dime thoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxine:

Procedure:

5 g of Compound 10 (81.48 % purity) was dissolved in 20 ml dry DMF under nitrogen and 2.31 g of activated copper powder was added. The reaction mixture was stirred for 15hrs at 150°C, cooled to RT (30°C), filtered through celite bed and washed with 10 ml DMF. The solvent was distilled off under reduced pressure and the resulting oily residue was dissolved in 60 ml ethyl acetate. Water and brine washes were given to this mixture, dried over Na 2 S0 4 , concentrated and used in the next step. Preparation of compound 12:

(-)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyI-6- (diphenylphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dimetho xy-2,3-dimethyl-6- (diphenylphosphineoxide)benzo[b][l,4]dioxine.

(-)-0,0-dibenzoyItartaric acid salt: (Resolution of compound 11).

Procedure:

33 g of crude racemic compound 11 (10.5 g of 31.8 % purity) was dissolved in 200 ml CHC1 3 under nitrogen. A solution of 5.4 g of (-)-0,0-dibenzoyltartaric acid in 254 ml ethyl acetate was added drop wise to the reaction mixture at 20°C and stirred for 12hrs at RT to form a white suspension. The white suspension was cooled to 0°C, stirred for another hour at 0°C and filtered. The resulting solid was washed with 30 ml of ethyl acetate and dried under vacuum for 2hrs to give -12 g white solid. This was taken in 120 ml of DCM and stirred for 5hrs at 20°C. The obtained suspension was filtered and dried under vacuum for lhr and the filtrate was stored for recovery of the other isomer. The resulting white solid, 10 g, was once again taken in 100 ml of DCM and stirred for 5hrs at 20°C. The suspension was filtered and dried under vacuum for lhr to result compound 12. (Yield: 58%, Chiral HPLC Purity: 99.60%; ee: 99.2%). The other (+) isomer was prepared using the same procedure but with (+)-0,0-dibenzoyltartaric acid.

Melting range: Decomposes at 237.8°C.

Mass: m/z EIMS 847 (M + +1), calculated for C 4g H 4 80ioP 2 . Ci 8 Hi 4 0 8 : 1204.91 mass was showing without (-)-0,0-dibenzoyltartaric acid.

[a] 20 D = (-) 42.66 (C = 1% in MeOH)

*H NMR (DMSO-d 6 , 300 MHz): d = 0.63 (s, 3H, CH 3 ), 1.31 (s, 3H, CH 3 ), 3.00 (s, 3H, OCH3J, 3.12 (s, 3H, OCH 3 J, 5.84 (s, 1H C-OH ), 6.63 - 6.66 (m, 1H, aromatic), 6.84 - 6.87 (m, 1H, aromatic), 7.34 -7.36 (m, 2H, aromatic), 7.43-7.75 (m, 11H, aromatic), 8.00 (s, 2H, aromatic) 14.5 (broad s 2H, COOH ).

13 C NMR (DMSO-d 6 , 300 MHz): d = 15.96, 16.37, 48.67, 49.64, 71.43, 98.12, 98.96, 1 15.00 (d, J= 63 Hz ), 125.96 (d, J= 54 Hz), 127.77 (d, J= 45 Hz), 128.47, 129.02, 129.38, 131.79 (d, J= 39 Hz), 132.94, 134.09 (d, J= 60 Hz), 137.02, 138.39, 139.63 (d, J= 60 Hz), 142.30, 164.65, 167.12. IR Data (KBr): 1058.9 (¾C-Q), 1112.1 (CH^-C-O), 1170.1 (P=0), 1240 ( PhO=C-0). 1725.4 (COOH), 1755.9 ( PhC≡0), 3433.7 ( COOH).

Preparation of compound 13:

(-)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenyIphosphineoxide)benzo[b][l,4]dioxin-5yl)-2,3-dime thoxy-2,3-dimethyl-6-

(diphenylphosphineoxide)benzo[b][l,4]dioxine:

Procedure:

7 g of Compound 12 was taken in 85 ml DCM and treated with 1 N aqueous KOH. After stirring for 30 min, the clear organic layer was separated, washed with 50 ml water, dried over Na 2 S0 4 and concentrated to give compound 13. (Yield: 83.3%, ee = 99.39 %)

Melting range: 149.3°C - 173.8°C

Mass: m/z EIMS 847 (M + +1), calculated for C 4 8H 48 O I0 P 2 : 846

[a] 20 D = (-) 74.05° (C = 1% in CHC1 3 )

1H NMR (CDC , 300 MHz): d = 0.78 (s, 3H, CH3), 1.38 (s, 3H, CH3 ), 3.11 (s, 3H, OCH 3 J, 3.22 (s, 3H, OCH 3 J, 6.72 - 6.84 (m, IH, aromatic), 6.85 -6.88 (m, IH, aromatic), 7.25 -7.47 (m, 6H, aromatic), 7.61-7.71 (m, 4H, aromatic).

13 C NMR (CDCb, 300 MHz): d = 16.01, (d, J= 102 Hz ), 49.22, 50.06, 98.54, 99.67, 115.55 (d, J= 66 Hz ), 122.95, 124.40, 126.70 (d, J= 54 Hz), 127.65 - 128.06 (q, J= 45, 30, 48 Hz ), 130.75, 132.40 - 132.61 (q, J= 24, 12, 27 Hz ), 133.92, 135.28, 136.08, 137.47, 140.12, 142.86.

IR Data (KBr): 1039.1 (¾C-0), 1114.2 (CH 3 -OO), 1199.5 (P=0) Preparation of compound 14:

(-)2,3-dhihydro-5-(2,3-dihydro-2,3-dimethoxy-2,3-dimethyl-6-

(diphenylphosphino)benzo[b][l,4]dioxin-5yl)-2,3-dimethoxy -2,3-dimethyI-6-

(diphenylphosphino)benzo[b][l,4]dioxine: Procedure:

2.5 g of Compound 13 was dissolved in 25 ml dry xylene under nitrogen and 5.5 g of tributylamine was added. The resulting solution was cooled to 10°C and 4 g of trichlorosilane was added drop wise at 10°C. The reaction mixture was heated at 130°C for 5hrs and was then cooled to 0°C. 50 ml of degassed 4 N NaOH solution was added drop wise, very slowly at 0°C and stirred for 30 min. The 200 ml of degassed DCM was separated and the organic layer was washed with 2 x 100 ml degassed water, 2 x 100 ml degassed brine. This was dried over Na 2 S0 4 and concerted to give 14 g, oily crude compound, containing more quantity of xylene, tributylamine, compound 14 and mono phosphine oxide reduced compound. Xylene was distilled off using high vacuum pump and the obtained white semi solid was taken in 25 ml degassed ethanol, heated to 80°C due to which the total suspension goes into the solvent. It was cooled to -40°C. The thrown out white solid was filtered at -40°C and dried under vacuum for 2hrs to give compound 14. (Yield: 20%, Chiral purity: 99.28 %)

Melting range: 239°C

Mass: m/z EIMS 815 (M + +1), calculated for C 48 H 48 0gP : 814. [a] 20 D = (-) 104.92 (C = 1% in CHC1 3 )

'H NMR (CDCI3, 300 MHz): d = 0.87 (s, 3H, CH3J, 1.42 (s, 3H, CH 3 ), 3.16 (s, 3H, OCH j J, 3.22 (s, 3H, OCH 3 J, 6.70 - 6.72 (d, J= 8 Hz, 1H, aromatic), 6.89 (d, J= 8.28 Hz, 1H, aromatic), 6.91 -7.02 (m, 2H, aromatic), 7.14 (m, 2H, aromatic) 7.24 -7.26 (m, 6H, aromatic)

TR Data (KBr): 1046 (H 3 C-0), 1 112 (CH.-C-O). Preparation of compound 16:

2,3-dihydro-2,3-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6- yl-6-boronic acid Potassium bifluoride salt]:

Procedure:

3 g of Compound (-)7 (9.9 mmol) was dissolved in 30 ml of dry THF and 5.16 ml of n- BuLi (2.3 M solution in hexane, 1 1.8 mmol) was added over 20 min at -75°C. After stirring for 60 min at -75°C, 5.5 g of freshly distilled triisopropyl borate (29.2 mmol) was added for 20 min at -60°C. Then the reaction mixture was stirred for 2 hrs and allowed to slowly warm up to room temperature. Stirring was continued for 12 hrs and the reaction mixture was quenched with 20 ml 2N HC1 solution while stirring continued for more 30 min. The organic layer extracted with (2 x 20 ml) of ethyl acetate was separated from the water layer, combined and washed with water followed by brine. The organic layer dried over Na 2 S04 was concentrated under vacuum and low temperature. 2.6 g of the obtained crude compound, Compound 15, was dissolved in 12 ml of methanol and 1.5 ml of water. It was then cooled to 0°C and 2.27 g of potassium bifluoride (29mmol) was added portion wise. After stirring for 24 hrs at 0°C, methanol was distilled off and the obtained solid was washed with (2x30 ml) of ethyl acetate at 10°C for removing all the impurities. This was taken into 70 ml of acetone, stirred for 1 hr at 10°C and undissolved particles were filtered. The filtrate was distilled off under vacuum to get 1.6 g of Compound 16 (Yield: 64%). The same procedure was used with (+) 7 compound also.

Melting Range: Decomposes at 192.1 °C

[a] 20 D = (-) 92.7° (C = 1% in CHC1 3 ), when (-)7 compound was used.

Melting Range: Decomposes at 194°C

[a] 20 D = (+) 90° (C = 1% in CHC1 3 ), when (+)7 compound was used.

H'NMR (CDCI3, 300 MH 2 ): d: 1.47(s, 3H, CH 3 ), 3.15 (s, 3H, OCH 3 ), 6.6 (s, 1H, aromatic), 6.7 (s, 1H, aromatic), 6.8 (s, 1H aromatic).

13C NMR (CDCb, 300 MHz): d =17.3, 48.28, 97.5, 114.5, 119.24, 124.51, 138.32, 139.21.

Preparation of compound 17:

2,3-dihydro-2^-dimethoxy-2,3-dimethylbenzo[b][l,4]dioxin-6-o l:

Procedure:

Compound (-)7 (5 g, 16.5 mmol) was dissolved in 50 ml of dry THF and n-BuLi (10.7 ml, 2.3M solution in hexane 24.6 mmol) was added over period of 25 min at -75°C. After stirring this reaction mixture for 60 min at -75°C, freshly distilled triisopropyl borate (4.65 g, 24.6 mmol) was dissolved in 5 ml of dry THF and was added drop wise for 20 min at -60°C. Stirring was continued for further 2hrs at -60°C and then 48 % H 2 0 2 (4.66 ml, 65.8 mmol) was added drop wise for 20 min at -40°C. After complete addition, stirring was continued for another 30 min at -40°C and then the temperature was slowly brought to R.T. Stirring was continued for further 10 hrs. Excess of H 2 0 2 was quenched with 20% sodium bi sulphite solution. The reaction mixture was extracted with (25 ml χ 2) ethyl acetate and the combined organic layers were dried over sodium sulphate, concentrated under vacuum and obtained crude compound was purified using column chromatography to give white colour solid of 2,3-dihydro-2,3-dimethoxy-2,3- dimethylbenzo[b][l,4]dioxin-6-ol (2.18 g; yield: 55.8%). The same procedure was used with (+)7 compound also.

Mass: m/z EIMS 239 (M + -1), Calculated for C ]2 Hi 7 N0 4 : 240.25 Melting range: 131.9 - 139.7°C

[a] 20 D = (-) 218.98° (C = 1% in CHC1 3 ), when (-)7 compound was used. Chiral HPLC purity: 99.34%

[a] 20 D = (+) 215.70 (C = 1% in CHC1 3 ), when (+)7 compound was used. Chiral HPLC purity: 99.22%

1H NMR (CDC , 300 MHz): d = 1.54 (s, 3H, ¾, 3.26 (d, J= 9.45 Hz, 3H OCH3J, 4.53 (broad s, 1H, OH), 6.34 (d,d 1H, aromatic), 6..43 (s, 1H, aromatic), 6.77 (d J= 8.61 Hz, 1H, aromatic).

13C NMR (CDCb, 300 MHz): d =17.4, 48.8, 98.12, 98.4, 104.3, 108.7, 1 17.3, 134.6, 141.27, 150.51.

Preparation of compound 18:

Ethyl-2,3-diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]diox ine-6-carboxylate: Procedure:

50 g of 3,4-dihydroxybenzoic acid was taken in 250 ml ethanol at room temperature (30°C) and 58.9 g of 2,3-butediane, 174 g of triethyl orthoformate were added to this reaction mixture. Then 13.8 g of boron trifluoride etherate was added drop wise for about 20 min. at room temperature (30°C) due to which the reaction mixture turned red in colour. Stirring was continued at room temperature (30°C) for 5 days. After 5 days, the reaction mixture was neutralized up to pH~7 with the addition of TEA. Solvents were removed under reduced pressure and the crude compound was purified by column chromatography to give an off-white coloured solid of Compound 18 (20 g; Yield: 19%). *H NMR (300 MHz) CDCI 3 : d = 0.99 - 1.03 (q, 6H, OCH 2 CH 3 ); 1.62 (s, 6H, CH 3 ); 3.56 - 3.66 (m, 4H, OClfcCHa); 4.29 - 4.36 (q, 2H, OCHjCHs); 1.34 - 1.43 (t, 3H, OCH 2 CH 3 ); 6.89 - 6.92 (d, 1H, aromatic, 6 Hz); 7.60 (s, 1H, aromatic); 7.61 - 7.63 (d, 1H, aromatic, 6Hz).

Preparation of compound 19:

2^-Diethoxy-2,3-dihydro-2,3-dimethyIbenzo[b][l,4]dioxine-6-c arboxylic acid: Procedure:

100 ml of Methanol was added to 20 g of Compound 18. To this mixture NaOH solution (15.5 g in 100 ml water) was added drop wise and allowed to stir at room temperature for 14 hrs. After completion of the reaction, methanol was distilled completely from reaction: mixture and acidified with 2N HC1 to attain a pH of ~7. The compound was extracted with (2 x 250 ml) of ethyl acetate and the organic layers were combined, dried over Na 2 S0 4 and concentrated the organic layer under reduced pressure to get the required product, Compound 19 as a white solid (17 g; Yield: 90%).

*H NMR (300 MHz) CDC1 3 : d = 0.99 - 1.05 (q, 6H, OCH 2 CH 3 , J = 6 Hz); 1.63 (s, 6H, CH 3 ); 3.57 - 3.56 (m, 4H, OCHzCH^; 6.92 - 6.95 (d, 1H, aromatic, 6Hz); 7.66 (s, 1H, aromatic); 7.67 - 7.69 (d, 1H, 6Hz, aromatic).

Preparation of compound 20:

2,3-Diethoxy-2,3-dihydro-2,3-dimethyIbenzo[b][l,4]dioxine-6- carboxyIic acid [(R)- (+)-a-methyIbenzylamine salt]

Procedure:

70 g Compound 19 was dissolved in 700 ml of IPA and 32 g of (R)-(+)-a- methylbenzylamine was added at room temperature and stirred at room temperature (30°C) for 24 hrs. After completion of reaction, IPA was distilled off; 500 ml of Hexane was added to the obtained crude compound and stirred for 15 min. Solid was filtered and dried to give 80 g of Compound 20 (Yield: 81 %). Preparation of compound 21:

Preparation of optically active diastereomer of compound 20:

Recrystallization: 2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxine-6- car boxy lie acid [(R)-(+)-a-methylbenzylamine salt]

Procedure:

400 ml of IPA was added to 100 g of Compound 20 and heated to 100°C till the compound dissolved completely. Then the compound was allowed to cool to room temperature and left undisturbed for 4 hrs for the complete solid to throw out. The obtained solid was filtered, dried and the above process was repeated twice. Finally, about 35 g of the obtained solid was taken into 140 ml of (Methanol/IPA in 1:3), heated to 100°C till the compound dissolved and left undisturbed for 3-4 hrs at room temperature. The thrown out solid was filtered and dried to give 25 g of Compound 21(Yield: 25%).

2 0 D = (-) 55.91 0 (C = 1 % in MeOH).

Similarly 2,3-Diethoxy-2,3-dih dro-2,3-dimethylbenzo[b][l,4]dioxine-6-carboxylic acid [(S)-(-)-a-methylbenzylamine salt] is prepared and recrystallized.

[a] 20 D = (+) 58.3° (C = 1 % in MeOH).

Preparation of compound 22:

(R)-2,3-Diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dioxin e-6 carboxylic acid. Procedure:

19 g of Compound 21 was dissolved in 190 ml of DCM and 95 ml of IN HCl was added and stirred for 10 min. After completion of the reaction, the DCM layer was separated, washed with (2x200 ml) of water, (1x100 ml) of brine, dried over Na 2 S0 4 and concentrated under reduced pressure to give 13 g of Compound 22 (Yield: 97%).

Chiral HPLC purity: 99 %

[«] 20 D = (-) 92.78° (C = 1 % in MeOH).

¾ NMR (300 MHz) CDCI 3 : d = 0.99 - 1.05 (q, 6H, OCH 2 CH3, J = 6 Hz); 1.63 (s, 6H, CH 3 ); 3.57 - 3.56 (m, 4H, Oq&CH-j); 6.92 - 6.95 (d, 1H, aromatic, 6Hz); 7.66 (s, 1H, aromatic); 7.67 - 7.69 (d, 1H, 6Hz, aromatic). Preparation of compound 23:

Methyl-2,3-diethoxy-2,3-dihydro-2,3-dimethylbenzo[b][l,4]dio xine-6-carboxylate: Procedure:

13 g of Compound 22 was dissolved in 130 ml of acetone; 18 g of K 2 C0 3 was added to it and stirred for 10 min. Then 8.3 g of dimethyl sulphate was added to the reaction mixture and stirred for 1 hr. After completion of the reaction, acetone was distilled under reduced pressure and crude compound was poured into 200 ml of water. The compound was then extracted with (2 x 50 ml) of ethyl acetate and the combined organic layers were washed with (2 x 100 ml) of water, dried over Na 2 S0 4 and concentrated under reduced pressure to give 13 g (Yield: 95%) of Compound 23.

1H NMR (300 MHz) CDC1 3 : d 1.62 (s, 6H, CH 3 ); 3.55 - 3.67 (m, 4H, OCH2CH 3 ); 3.87 (s, 3H, OCH 3 ); 6.89 - 6.92 (d, 1H, aromatic, 6 Hz); 7.59 (s, 1H, aromatic); 7.60 - 7.62 (d, 2H, aromatic, 6Hz).

Preparation of compound 24:

Methyl-2,3-diethoxy-2,3-dihydro-2,3-dimethyI-7-nitrobenzo[b] [l,4]dioxine-6- carbox late:

Procedure:

13 g of Compound 23 was dissolved in 65 ml of acetic acid and 10.5 g of fuming nitric acid was added drop wise at 60°C over a period of 10 minutes. The reaction mixture was stirred at 60°C for 4 hours and subsequently poured into 200 m! of ice water. The compound was extracted with (2 x 100 ml) of DCM and the combined organic layer was washed with (2 x 150 ml) water, 150 ml brine, dried over Na 2 S0 4 and concentrated under reduced pressure to give 13 g of crude Compound 24 (Yield: 87%).

1H NMR (300 MHz) CDCI3: d = 1.02 - 1.06 (t, 6H, OCH2CH3, J = 6 Hz); 1.63 (s, 6H, CH 3 ); 3.51 - 3.70 (m, 4H, OCH2CH 3 ); 3.89 (s, 3H, OCH 3 ); 7.17 (s, 1H, aromatic); 7.51 (s, 1H, aromatic). Preparation of compound 25:

(R)Methyl-7-amino-2,3-diethoxy-2,3-dihydro-2,3-dimethylbenzo [b][l,4]dioxine-6- carboxylate:

Procedure:

13 g of Compound 24 was subjected to catalytic hydrogenation using 1.3 g of 10% Pd(OH) 2 in 150 ml of methanol at 60 psi for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite bed and the bed was washed with 200 ml of DCM and the filtrate was concentrated under reduced pressure. This crude compound was purified by column chromatography to give 7.3 g of Compound 25. (Yield: 62 %).

1H MR (300 MHz) CDC1 3 : d = 0.962 - 1.08 (tt, 6H, OCH^Hs); 1.58 (s, 6H, CH 3 ); 3.52 - 3.66 (m, 4H, OCH2CH3); 3.82 (s, 3H, OCH 3 ); 5.41 (s, 2H, NH 2 ); 6.18 (s, 1H, aromatic); 7.40 (s, 1H, aromatic).

[a] D = (-) 31.32° (C = 1% in MeOH).