MXPA01006359A - A process of making 3-phenyl- 1-methylenedioxyphenyl -indane-2- carboxylic acid derivatives - Google Patents

Abstract

Invented is an improved process for preparing aromatic ring-fused cyclopentane derivatives. Preferred compounds prepared by this invention are indane carboxylates and cyclopentano[b]pyridine derivatives. The most preferred compounds prepared by this invention are (+)(1S, 2R, 3S)- 3-[2-(2-hydroxyeth-1-yloxy)- 4-methoxyphenyl]-1- (3,4-methylenedioxyphenyl)- 5-(prop-1-yloxy)indane- 2-carboxylic acid and pharmaceutically acceptable salts thereof and (+)(1S, 2R, 3S)-3- (2-carboxymethoxy- 4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)- 5-(prop-1-yloxy)indane- 2-carboxylic acid and pharmaceutically acceptable salts thereof. Also invented are novel intermediates useful in preparing these compounds.

Description

A PROCEDURE FOR PRODUCING PE DERIVATIVES 3-PHENYL-1-MEYLENDENIXXYPHENYLINDANE-2-CARBOXYLIC ACID FIELD OF THE INVENTION The present invention relates to an improved process for preparing molten cyclopentane derivatives in the aromatic ring. Preferably, the present invention relates to an improved process for preparing indane carboxylates and cyclopentane [α] pyridine. Advantageously, the present invention relates to an improved process for preparing (+) (1 S, 2R, 3S) -3- [2- (2-hydroxyeth-1-yloxy) -4-methoxyphenyl] -1- (3) acid (3). , 4-methylenedioxyphenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid and its pharmaceutically acceptable salts, and (+) (1S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) acid) -1 - < 3,4-methylene dioxyphenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid and its pharmaceutically acceptable salts. Such compounds are described in the international application number: PCT / US94 / 04603, international publication number WO 94/25013, published on November 10, 1994 and in US patent No. 5,389,620, as useful as endothelin receptor antagonists. The invention also comprises novel intermediates useful in the preparation of these compounds.

BACKGROUND OF THE INVENTION The processes for the preparation of indane carboxylates, specifically (+) (1S, 2R, 3S) -3- [2- (2-hydroxyeth-1-yloxy) -4-methoxyphenyl-1- (3,4-methylene) -dioxy-phenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid and (+) (1 S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1 - ( 3,4-methylene-dioxyphenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid, have been previously described. In particular, a multi-step process for preparing (+) (1S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1- (3) 4-methylenedioxyphenyl) -5- (prop-1) acid -alloxy) indane-2-carboxylic, in an overall yield of 6% (not including the racemic separation step), from methyl 3- (prop-1-yloxy) benzoylacetate, and a process for preparing acid (+) (1S, 2R, 3S) -3- [2- (2-Hydroxy-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl) -5- (prop-1-yloxy) Indane-2-carboxylic acid, in an overall yield of 2% (not including the racemic separation step), from methyl 3- (prop-1-yloxy) benzoylacetate, are reported in International Publication Number WO 94/25013 , published on November 10, 1994. The synthesis of these molecules is complicated by the presence of three chiral centers in each compound. Methods for the preparation of cyclopentane [α] pyridine derivatives have previously been described. In particular, multi-step processes are reported for preparing cyclopentane [α] pyridine derivatives, in low overall yields, in U.S. Patent 5,389,620.

Thus, there is a need in the art for an inexpensive method for preparing indane carboxylates and cyclopentane [α] pyridine derivatives, specifically (+) (1 S, 2R, 3S) -3- [2- (2-hydroxyethyl-1) acid -yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxy-phenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid and its pharmaceutically acceptable salts, and (+) (1S, 2R) acid , 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1 - (3,4-methylenedioxyphenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid, and pharmaceutically acceptable salts thereof. The numerous advantages of the method and of the intermediates of the present invention will be apparent when the following description is summarized.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to an improved process for preparing cyclopentane derivatives, with an aromatic molten ring. This invention also relates to novel intermediates useful in the preparation of aromatic molten ring cyclopentane derivatives. This invention relates to an improved process for preparing indane carboxylates. This invention also relates to novel intermediates useful in the preparation of indane carboxylates.

This invention relates to an improved process for preparing cyclopentane [α] pyridine derivatives. This invention also relates to novel intermediates useful in the preparation of cyclopentane [α] pyridine derivatives. The invention relates to an improved process for preparing (+) (1S) acid, 2R, 3S) -3- [2- (2-hydroxyethyl-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxy-phenyl) -5- (prop-1-yloxy) indane- 2-carboxylic acid and its pharmaceutically acceptable salts, preferably the ethylenediamine salt 2: 1. The invention relates to novel intermediates useful in the preparation of (+) (1S, 2R, 3S) -3- acid. { 2- (2-hydroxyeth-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxy-phenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid. The invention relates to an improved process for preparing (+) (1 S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1- (3,4-methylenedioxyphenyl) -5- ( 1-yloxy) indane-2-carboxylic acid, and pharmaceutically acceptable salts thereof, preferably the disodium salt. The invention relates to novel intermediates useful in the preparation of (+) (1S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1- (3,4-methylenedioxyphenyl) -5- (prop -1-yloxy) indane-2-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise defined the term "molten aromatic ring cyclopentane derivatives" means the racemic compounds of the formula (1): where A, B, C and D are carbon atoms, or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R 'is: wherein R3 and R4 are independently H, OH, alkoxy of 1 to 8 carbon atoms, F, CF3 or alkyl of 1 to 6 carbon atoms and R5 is -OCH2CO2H or -OCH2CH2OH; R2 is wherein R3 and R4 are as indicated above and Z is H, OH or alkoxy of 1 to 5 carbon atoms; or a pharmaceutically acceptable salt thereof. Preferred racemic compounds among those of formula (1) are the compounds of formula (17): wherein A, B, C, D, R1, R2 and Z are as described for formula (1); or a pharmaceutically acceptable salt thereof. By the term "indane carboxylates", as used herein, is meant the racemic compounds of the formula (2): wherein R1, R2 and Z are as described in formula (1); or a pharmaceutically acceptable salt thereof. Among the racemic compounds of the formula (2), those compounds of the formula (18) are preferred: wherein R1, R2 and Z are as described for formula (1); or a pharmaceutically acceptable salt thereof. By the term "cyclopentane [α] pyridine derivatives", as used herein, is meant the racemic compounds of the formula (3): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and R1, R2 and Z are as described for formula (1); or a pharmaceutically acceptable salt thereof. Among the racemic compounds of the formula (3), the compounds of the formula (19) are preferred: wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom; and R1, R2 and Z are as described for formula (1); or a pharmaceutically acceptable salt thereof.

In the compounds of the formula (3), in the compounds of the formula (19) and in the compounds of the formula (1), when one of A, B, C or D is a nitrogen atom, preferably A is nitrogen. The pharmaceutically acceptable salts of the compounds of formulas (1), (2), (3), (17), (18) and (19) are formed when appropriate by methods well known to those skilled in the art. The pharmaceutically acceptable salts of (+) (1S, 2R, 3S) -3- [2- (2-hydroxyeth-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl) -5- ( prop-1-yloxy) indane-2-carboxylic acid and (+) (1S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1 - (3,4-methylenedioxyphenyl) -5- ( prop-1-yloxy) indane-2-carboxylic acid are formed by appropriate methods well known to those skilled in the art. By the term "Pr" as used herein, n-propyl is meant. By the term "Ph", as used herein, is meant phenyl. As used in the specification and claims, unless defined otherwise, the term Xc means a chiral auxiliary. By the term "chiral auxiliary" as used herein, a non-racemic functional group is meant to impart a diastereoselective reaction in a remote prochiral center of a molecule. The chiral auxiliaries which are used herein are used by reaction with a compound of the formula HXc wherein Xc is as described above. Examples of HXc, when used herein, include 8-phenylmentol (as described in D. Comins and co-authors, J. Org. Chem., Volume 58, 4656 (1993)), borane-2-10-sultans N-substituted (were described in W.Oppolzer J. Am. Chem. Soc, 112, 2767 (1990 ==, preferably 4-substituted or 4,5-substituted 2-oxazolidinones, derived from amino acid derivatives such as phenylglycinol or valinol (as described in D. Evans and co-authors, J. Am. Chem. Soc, 109, 6881 (1987) and in D. Evans and co-authors, T. Lett. 28, 1123 (1990)) and, very preferable , 4-substituted or 4,5-substituted 2-imidazolidinones derived from compounds such as ephedrine (as described in SE Drewes and co-authors, Chem. Ber., 126, 2663 (1993).) The most preferred "Xc" for Use herein is the predominantly optically pure substituent of the formula: (ac) Thus, the most preferred form of chiral auxiliary for use herein is a compound of formula (q) (u).

Additionally, the racemic compounds of formulas (1), (2), and (3) are prepared as described herein by substituting the chiral substituent Xc, as used herein, for an achiral group, such as a alkoxy or amine group. The term "activation reaction" for use herein refers to numerous reactions and numerous reaction conditions known to those skilled in the art to effect the introduction of a Br, I, -OSO2CF3 or a substituent -OS02F. The term (+) (1S, 2R, 3S) -3- [2- (2-hydroxyeth-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl) -5- (prop-1) acid -iloxy) indane-2-carboxylic acid, as used herein, uses the common chemical terminology, and refers to the compound (r) The term ethylene diamine salt of (+) - (1S, 2R, 3S) -3- [2- (2-hydroxyeth-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl) -5- (prop-1-yloxy) indane-2-carboxylic acid (2: 1), as used herein, uses the common chemical terminology and refers to the compound (s): (s) The term (+) (1S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1- (3,4-methylenedioxyphenyl) -5- (prop-1-yloxy) indane- 2-carboxylic acid, as used herein, uses the common chemical terminology and refers to compound (j): The term disodium salt of (+) - (1S, 2R, 3S) -3- (2-carboxymethoxy-4-methoxyphenyl) -1- (3,4-methylenedioxyphenyl) -5- (prop-1-yloxy) indane -2-carboxylic, as used herein, uses the common chemical terminology and refers to the compound (k): The indane carboxylates of the formula (18), of the present invention, are prepared by methods indicated in the schemes below and in the examples, from the compounds of the formula (a): wherein R is H, OH, alkoxy of 1 to 5 carbon atoms (preferably n-PrO) or a protected oxy group, such as benzyloxy. The compounds of the formula (a) are known or can be prepared from readily available starting materials by those skilled in the art.

By the term "protected oxy group" and "protected OH" as used herein, is meant any blocking group conventional in the art, as described in "Protective Groups in Organic Synthesis" by Theodora W. Greene, Wiley-lnterscience, 1981, New York, USA, provided that said protected oxy groups or protected OH groups do not include portions that render the process of the present invention inoperative. A preferred protected oxy group for use herein is benzyloxy. A preferred protected OH group for use herein is benzyloxy. In addition, when necessary or desired, R can be converted to a substituent of Z. Reactions to convert R to Z are made in synthetic pathway products described or claimed herein or, where appropriate or preferable, in certain intermediaries in these synthesis trajectories. For example, the hydroxyl groups can be converted to alkoxy groups of 1 to 5 carbon atoms, by alkylation. The protected oxy groups can be deprotected and can be further reacted to form a Z substituent. The present invention provides an improved process for the production of indane carboxylates of the formula (18), as indicated in schemes 1 and 2 that come next: SCHEME 1 hydrochloric acid (a) (c) reaction of < x acylation (and) Scheme 1 indicates the formation of indane carboxylates wherein R 5 is -OCH 2 CO 2 H, preferably the disodium salt, compound (k). As used in scheme 1, R3 and R4 are as described in formula (1), R is as described in formula (a) and R7 is Br, I, -OSO2CF3 or -OSO2F. The compounds of the formula (c) are prepared in one or more steps by treating a compound of the formula (a) in an activation reaction, preferably with bromine in methylene chloride, to introduce the substituent R7. The compounds of the formula (d) are prepared by reacting a compound of the formula (c) with an acid chloride, such as thionyl chloride, and using this product as an acylating agent in a reaction, such as a Grignard reaction. with a compound of the formula (t), as defined below, or a Friedel-Crafts reaction, as described in example 1, step (iii). The compounds of the formula (e) are prepared by reacting a compound of the formula (d) with a chiral auxiliary in the presence of palladium acetate (II) / triphenylphosphine catalyst. The treatment of a compound of the formula (e) with a 3,4- (methylenedioxy) phenylmagnesium bromide, appropriately substituted (which can be easily prepared from starting materials obtainable commercially) and a copper complex, such as a complex of copper (l) -dimethyl sulfide (which can be obtained commercially easily from Aldrich Chemical Co. of Milwaukee, Wisconsin, USA), in tetrahydrofuran, followed by crystallization, gives compounds of the formula (f) which are the predominantly pure diastereomer. The treatment of a compound of the formula (f) with sodium methoxide / methanol gives compounds of the formula (g). The compounds of the formula (h) are prepared by treating a compound of the formula (g) in methanol with anhydrous acid. The compounds of the formula (i) are prepared by hydrogenating a compound of the formula (h) on palladium on carbon. The treatment of a compound of the formula (i) with methyl bromoacetate and potassium carbonate in acetone / methanol, followed by saponification / epimerization carried out with lithium hydroxide monohydrate and working with acid, yield the corresponding diacid of the formula (6) ) (preferably compound (j) as used herein). The compounds of the formula (6) are treated with sodium hydroxide to give compounds of the formula (4) (preferably the compound (k) as used herein). Additionally, treatment of a compound of the formula (i) with ethylene carbonate (potassium carbonate in toluene at 90-115 ° C, followed by saponification / epimerization with lithium hydroxide and working with acid is a preferred method for preparing a It is readily apparent to those skilled in the art that the OCH2Ph substituent in the above scheme is functioning as a protected OH and that another protected OH group could be used in place of, 1, or that, under In appropriate circumstances, the unprotected OH could be used.

SCHEME 2 (m) Scheme 2 indicates the formation of indane carboxylates wherein R 5 is -OCH 2 CH 2 OH, preferably the ethylenediamine salt (2: 1), compound (s). As used in scheme 2, R3 and R4 are as described in formula (1), R is as described in formula (a) and R7 is Br, I, -OSO2CF3 or -OSO2F. The acid chloride of the compounds of the formula (c) of scheme 1, is reacted in an acylation reaction, preferably in a Grignard reaction, with a compound of the formula (v), prepared as described below, to give compounds of the formula (1 ). The compounds of the formula (m) are prepared by reacting a compound of the formula (I) with a chiral auxiliary in the presence of palladium acetate (II) / triphenylphosphine catalyst. The treatment of a compound of the formula (m) with an appropriately substituted 3,4- (methylenedioxy) phenylmagnesium bromide (which can be easily prepared from starting materials obtainable commercially), and a copper complex, preferably a copper (I) salt, such as CuCI, CuBr, CuCN or, most preferably, a copper (l) -dimethyl sulfide complex (available commercially from Aldrich Chemical Co. of Milwaukee, Wisconsin, USA) in tetrahydrofuran, gives a compound of the formula (n) as the predominantly pure diastereomer. Treatment of a compound of the formula (n) with sodium methoxide / methanol gives compounds of the formula (o). Compounds of the formula (p) are prepared by treating a compound of the formula (o) in methanol with anhydrous acid. Compounds of the formula (q) are prepared by hydrogenating compounds of the formula (p) on palladium on carbon. Treatment of compounds of the formula (q) with lithium hydroxide monohydrate, followed by work with acid, gives the acid of the formula (7) (preferably the compound (r) as used herein). The compounds of the formula (7) are treated with ethylenediamine to give the compound of the formula (8) (preferably the compound (s), as used herein). It is readily apparent to those skilled in the art that the -OCH2Ph substituent in the above scheme is functioning as protected OH, and that another protected OH group could be used in place of it or that, under appropriate circumstances, OH could be used. protected. The racemic compounds of the formulas (1), (2) and (3) are prepared according to the methods indicated in the schemes (1) and (2) and in the examples, substituting a compound of the formula (9): where A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom and R is H, OH, alkoxy of 1 to 5 carbon atoms ( preferably n-PrO) or a protected oxy group, such as benzyloxy; by the compound of the formula (a) and substituting the chiral substituent Xc of the chiral auxiliary with an achiral group such as an alkoxy group or an amine group. The compounds of the formula (9) are known or can be prepared from starting materials readily obtainable by those skilled in the art. Thus, an achiral group replaces the substituent Xc of the chiral auxiliary in Schemes 1 and 2 to prepare the compounds of the formula (2) and the intermediates useful in the preparation of the compounds of the formula (2).

The compounds of the formula (9) are used in schemes 1 and 2, substituting the chiral auxiliary Xc substituent chiral auxiliary, for an achiral group to prepare the compounds of the formula (1) and the intermediates useful for preparing the compounds of the Formula 1). The compounds of the formula (9), wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, are used in schemes 1 and 2, substituting the chiral auxiliary Xc substituent chiral auxiliary with an achiral group, for preparing the compounds of the formula (3) and the intermediates useful in the preparation of the compounds of the formula (3). The cyclopentane [α] pyridine derivatives of the formula (19) of the present invention are prepared according to the methods indicated in schemes 1 and 2 and in the examples, from compounds of the formula (9) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred compounds among the compounds of the formula (9), when a nitrogen is present, are those in which A is nitrogen. The aromatic ring-cyclopentane derivatives of the formula (17) of the present invention are prepared according to the methods indicated in schemes 1 and 2 and in the examples starting from compounds of the formula (9) wherein A, B, C and D are carbon atoms or three of A, B, C and D are carbon atoms and one is a nitrogen atom. Preferred among the compounds of the formula (9), when a nitrogen is present, those in which A is nitrogen. It is prepared in the synthesis of the indane carboxylates of the formula (18), preferably the compound (k) and the compound (s), the novel intermediates of the formula (c): (c) wherein R is as described in formula (a) and R7 is Br, I, -OSO2CF3 or -OSO2F. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k) and the compound (s), the novel intermediates of the formula: wherein R is as described in formula (a) and R7 is Br, I, -OSO2CF3 or -OSO2F. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k), the novel intermediates of the formula (d): () wherein R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or a protected OH and R7 is Br, I, - Also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k), the novel intermediates of the formula (e): (and) wherein R3 and R4 are as described in formula (1), Xc is as described above, R is as described in formula (a), R6 is OH or a protected OH. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k), the novel intermediates of the formula (f): ( wherein R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or a protected OH. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k), the novel intermediates of the formula (g): (g) wherein R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or a protected OH. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k), the novel intermediates of the formula (h): (h) wherein R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or a protected OH. It is prepared by synthesizing the indane carboxylates of the formula (2), preferably the compound (k), the novel racemic intermediates of the formula (27): (27) wherein R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or a protected OH. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (k) and the compound (s), the novel intermediates of the formula (i): (i) wherein R3 and R4 are as described in formula (1) and R is as described in formula (a). It is prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (s), the novel intermediates of the formula (I): wherein R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or a protected OH and R7 is Br, I, - Also by synthesizing indane carboxylates of the formula (18), preferably the compound (s) is prepared the novel intermediates of the formula (m): (m) wherein R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or a protected OH. Also when synthesizing the indane carboxylates of the formula (18), preferably the compound (s) is prepared the novel intermediates of the formula (n): (n) wherein R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or a protected OH. Also when synthesizing the indane carboxylates of the formula (18), preferably the compound (s) is prepared the novel intermediates of the formula (o): (OR) wherein R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or a protected OH. Also when synthesizing the indane carboxylates of the formula (18), preferably the compound (s) is prepared the novel intermediates of the formula (p): (P) wherein R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or a protected OH. Also when synthesizing the indane carboxylates of the formula (2), preferably the compound (s), the novel racemic intermediates of the formula (28) are prepared: (28) wherein R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or a protected OH. It is also prepared by synthesizing the indane carboxylates of the formula (18), preferably the compound (s), the novel intermediates of the formula (q): (q) wherein R3 and R4 are as described in formula (1) and R is as described in formula (a). The novel intermediates of the formula (10) are also prepared by synthesizing the molten aromatic ring cyclopentane derivatives of the formula (1): wherein A, B, C and D are carbon atoms, or three of A, B, C and D are carbon atoms and one is a nitrogen atom, and R is as described in formula (a).

It is prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the intermediates of the formula (10) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, and R is as described in formula (a). The novel intermediates of the formula (11) are prepared by synthesizing the molten aromatic ring cyclopentane derivatives of the formula (1): where A, B, C and D are carbon atoms, or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in formula (a) and R7 is Br, I, -OS02CF3 or -OS02F. It is prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the intermediates of the formula (11) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in formula (a) and R7 is Br, I, -OS02CF3 or -OSO2F. It is also prepared by synthesizing the molten aromatic ring cyclopentane derivatives of the formula (1), the novel intermediates of the formula: where A, B, C and D are carbon atoms, or three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in formula (a) and R7 is Br, I, -OS02CF3 or -OS02F. It is prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the intermediates of the preceding compound, wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in formula (a) and R7 is Br, I, -OSO2CF3 or -OSO2F. It is also prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the intermediates of the formula (12): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R is as described in formula (a), R6 is OH or a protected OH and R7 is Br, I, - OSO2CF3 or -OS02F.

It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (13): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in formula (1), R is as described in the formula (a) and R6 is OH or a protected OH. It is also prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (14): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in formula (1), R is as described in the formula (a) and R6 is OH or a protected OH. It is also prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (15): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is comma described in formula (a) and R6 is OH or a protected OH. The novel intermediates of the formula (16) are also prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or a protected OH. Also, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel racemic intermediates of the formula (29) are prepared: wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 It is OH or a protected OH. It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (20): (20) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1) and R is as described in the formula ( to). It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (21): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is as described in formula (a), R6 is OH or OH protected and R7 is Br, I, -OSO2CF3 or -OS02F. It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (22): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in formula (1), R is as described in the formula (a) and R6 is OH or OH protected. It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (23): (23) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, Xc is as described above, R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or OH protected. The novel intermediates of the formula (24) are also prepared by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or OH protected. It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (25): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is as described in formula (a) and R6 is OH or OH protected. It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel racemic intermediates of the formula (30): (30) wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1), R is as described in the formula ( a) and R6 is OH or OH protected. It is also prepared, by synthesizing the cyclopentane [α] pyridine derivatives of the formula (19), the novel intermediates of the formula (26): wherein three of A, B, C and D are carbon atoms and one is a nitrogen atom, R3 and R4 are as described in formula (1) and R is as described in formula (a). The novel intermediates of the predominantly optically pure compound are prepared by synthesizing the compounds of the invention: (ab).

It is prepared by synthesizing the compounds of this invention, the novel intermediates of the predominantly optically pure compound: All starting materials and reagents used herein are known and readily obtainable, or can be readily prepared from known and readily obtainable reagents. For example, compound (t) is prepared according to the following steps (as used below, R3 and R4 are as described in formula (1)): (a) a suitably substituted 2-bromo-5-methoxyphenol, prepared by methods such as those described by de Paulis and coauthors, J. Med. Chem., 28, 1236 (1985), is treated with benzyl bromide and carbonate of potassium to form the compound. (b) the product of step (a) is treated with magnesium in tetrahydrofuran to form the compound: For example, compound (v) is prepared according to the following steps: (c) an appropriately substituted 2-bromo-5-methoxyphenol from step (a) above, is treated with ethylene carbonate and potassium carbonate in toluene to form the compound: (d) the compound of step (c) is treated with potassium carbonate and benzyl chloride in N, N-dimethylformamide to form the compound: (ae) (e) the product of step (d) is treated with magnesium in tetrahydrofuran to form the compound: (v) For example, the most preferred compound (u) is prepared according to the following steps: (e) (1 R, 2S) - (-) ephedrine hydrochloride, obtainable commercially, is reacted with urea and heat, to form the compound: (f) the product of step (e) is treated with acroyl chloride in the presence of a base to form the compound (u). Preferably, the product of step (e) is reacted in the presence of 3-chloropropionyl chloride and a base to form the optically pure compound (u) predominantly: (or) Without further complication, it is believed that whoever is skilled in the art can, using the preceding description, use the present invention to its fullest extent. Therefore, the following examples should be considered merely as illustrative and not as a limitation of the scope of the present invention, in any way.

EXAMPLES EXAMPLE 1 CORRESPONDING TO THE SCHEME 1 DISODIUM SALT OF THE ACID i +) (1S.2R.3S) -3- (2-CARBOXIMETOXI-4-METOXYPHENYL- (3,4-METHYLENDIOXYPHENIL.-5 PROP-1 -ILOXI .INDANO- 2- CARBOXILIC (with compound of formula (a)) A three-neck, 12-liter flask was charged with 500 g (3.62 moles) of 3-hydroxybenzoic acid, 4 liters of acetonitrile and 435 g (10.88 moles) of sodium hydroxide in 1.1 liters of water. The resulting mixture was heated at 60 ° C, for 40 minutes. Over a period of 60 minutes, 2.5 equivalents of n-dipropyl sulfate was added through an addition funnel, while maintaining the reaction temperature at 65-70 ° C. After 6 hours a second portion of sodium hydroxide was added in 1.0 liters of H20, for 30 minutes, within the range of 65-70 ° C. After another 1.0 liters at 65-70 ° C, the acetonitrile was allowed to evaporate to half its original volume. 1.0 L of water was added and the pH was adjusted to 3.0, using 850 mL of concentrated HCl. 7 liters of ethyl acetate was added and the mixture was allowed to stir for 30 minutes at room temperature. At this time, the reaction mixture was transferred to a 22 liter separatory funnel and 1 liter of water was added to dissolve the inorganic particles. The organic layer was separated and the organic layer was washed with 2 x 4 liters of water and 1 x 4 liters of brine. The solvent was removed until only 600 to 700 ml remained. 700 ml of hexanes was added and the solution was cooled to 0-5 ° C for 3 hours. The solid that precipitated was filtered and yielded 274 g (1.52 mol). A second crop of 254 g (1.41 mol) was obtained for a total yield of the compound illustrated above 81%, m.p. 69-71 ° C. (with compound of formula (c)) A three-neck, 22-liter flask was charged with 1037 kg (5.70 moles) of the compound from step (i), 14.2 liters of methylene chloride and 579 g of sodium acetate. Bromo was added slowly to this stirred solution, keeping the temperature below 34 ° C. 1.15 equivalents of bromine was added until a dark reddish brown bromine color persisted. The reaction appeared to be complete when monitored by HPLC, showing that the starting material was less than 1.5%. 1.0 liter of water and 60 g of sodium bisulfite were added. The solvent was removed until the reaction mixture was about 3.0 liters. 4 liters of ethyl acetate was added and the volume of the reaction was reduced to 2.5-3 liters. Ethyl acetate was added and the pH was adjusted to about 2 using 300 ml of 50% concentrated HCl (volume / volume). 2 liters of water was added and the organic layer was separated. The aqueous layer was washed with 1 x 4 liters of water and 1 x 3 liters of brine. The solution was reduced to 2 liters, after which a white suspension was obtained. 800 ml of hexanes was added and the flask was cooled to 0-5 ° C for 3 hours, with stirring. The solid was collected by filtration to yield 1171.8 g, 4.5 moles, of the compound illustrated above. A second crop of 189.8 g, 0.73 mol was obtained, for a total of 5.23 mol, 91% yield; p.f. 100-102 ° C. of formula (d)) (iii) A 3-neck, 3-neck flask was charged with 1 kg (3.86 moles) of the compound from step (ii) and 114.7 g, 700 ml, 9.62 moles, 2.49 equivalents, of chloride of thionyl, adding everything all at once. The mixing is endothermic and the reaction temperature drops to 12 ° C. The suspension is heated at 20-30 ° C for 5 hours and 3/4 or until the HPLC indicates the disappearance of the starting material. The reaction mixture is cooled to room temperature and 1 liter of toluene is added. The reaction mixture is concentrated by vacuum distillation to about 700 ml, and another 500 ml of toluene is added. Vacuum distillation was continued until 250 ml of toluene was collected. A three-necked flask, 12 liters, was charged with the above solution (assumed to be 3.86 moles) and 553 g, 3.86 moles, of 1,3-dimethoxybenzene. The subsequent solution was cooled to 10 ° C and placed under a nitrogen atmosphere. Boron trichloride (1 m solution in xylene, 4.2 liters, 4.2 moles, 1088 equivalents) was added at a rate such that the temperature did not exceed 16 ° C. The addition is carried out for 4 hours, the reaction being 91% complete after the addition is complete. The reaction mixture is stirred for another hour, cooled to 10 ° C with an ice bath and carefully quenched with 3 liters of water, keeping the temperature below 15 ° C. The reaction suspension is then heated to 50 ° C to dissolve all solids, transferred to a separatory funnel and the organic phase is washed, washed with 2 x 2 liters of water, 1 liter of 50% brine. Concentrate the organic solubles in vacuo and combine with hexane to produce a crude solid which is recrystallized from 2,800 ml of EtOH, of grade 190. It produces 1202.8 g of the 4-methoxy-2-hydroxy precursor of the title compound (85%, purity by HPLC, 97.0% per area). In a 3-liter, three-necked flask, 1.5 liters of acetonitrile, 277.4 g, 0.76 moles, of the above 4-methoxy-2-hydroxy precursor and 214.4 g, 1.55 moles, of K2C03 were added. 132.6 g, 0.76 mol of benzyl bromide was added at room temperature under nitrogen. The reaction was heated to reflux (80-81 ° C) for 2-4 hours and followed by HPLC until the starting material disappeared. The reaction mixture was then cooled to 50 ° C and filled to remove the inorganics. The solvent was removed in vacuo to yield the compound illustrated above, as a white solid; 347.0 g, 0.762 moles; p.f. 46-51 ° C, 100% yield. (with compound of formula (e)) In a 12-liter, three-necked flask, 600 g (1,316 moles) of the compound from step (iii), 312 g of the compound (u) (the preparation of the compound (u) as used in this example, was added. described in the specification, on page 33 and in example 4), 7.4 g of palladium acetate (0.033 moles), 20.2 g of tri-o-tolylphosphine (0.066 moles), 3.3 liters of DMF and 107.9 (1.316) moles) of sodium acetate. The reaction mixture was degassed with nitrogen, then heated to 135-140 ° C. The reaction was monitored by HPLC until the disappearance of the starting material. The reaction mixture was cooled to 115 ° C, when 2 liters of water and 2 liters of toluene were carefully added. The solution was allowed to stir for 7 hours under nitrogen. The reaction solution was heated to 40-45 ° C, 3.3 liters of water and 3.3 liters of toluene were added at 50 ° C, then transferred hot to a 12 liter separatory funnel. The separated organic layer was separated and the aqueous layer was washed with 2 x 3.3 liters of water. The organic layer was concentrated to produce a wet solid. This material was dissolved in 3.2 liters of 19% ethanol. This solution was cooled to 0-5 ° C. The precipitated solids were collected by filtration to yield 586 g (0.95 mol, 72%) of the compound illustrated above. (with compound of formula (f)) (v) A 250 ml three-necked flask was charged, with 319 g, 0.19 moles, of a cuprous bromide / dimethyl sulfoxide complex in 5 ml of THF / dimethyl sulfide (ratio 3/1 in volume / volume). The suspension was cooled to -35 ° C and 0.04 moles of Grignard was added at that temperature. The dark brown suspension was allowed to warm to -5 ° C and stirred for 2 to 3 minutes, then cooled again to -35 ° C. After a total stirring time of 35 minutes, the compound from step (iv) (10.0 g, 0.016 mol) was dissolved in 33 ml of THF and added for 30 minutes. The reaction was stirred at -35 ° C for 2 hours and then at -10 ° C for 1 hour. 100 ml of saturated aqueous ammonium acetate solution was added at 0 ° C and the suspension was stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with 3 x 100 ml of tert-butylmethyl ether. The combined organic layer was washed with 25% ammonium hydroxide solution until the blue color no longer persisted. The solvent was removed in vacuo and 50 ml of toluene was added, which was also removed under vacuum. The residual oil was dissolved in 50 ml of IPA and 150 ml of hexanes was added. The solution was allowed to stir for 18 hours, and in that time a suspension was obtained. Another 150 ml of hexanes was added and the flask was cooled to 0 ° C and stirred for 30 minutes, then filtered. The solid product was dried under vacuum to give the compound illustrated above, predominantly as a single diastereomer; p.f. 164-166 ° C; 9.72 g (0.013 moles, 81% yield). (with compound of formula (h)) A 2.0 liter flask, three necks, with a round bottom, was charged with 1.5 liters of toluene and 80.0 g (0.108 mol) of the compound from step (v). The solution was heated to reflux until about 700 ml of solution remained. The solution was then allowed to cool to room temperature under nitrogen. 3.0 equivalent of sodium methoxide was added slowly, as a 25% solution, for 10 minutes. The solution was allowed to stir until less than 1.0% of the starting material remained, by HPLC. The reaction mixture was cooled to -20 ° C, then diluted with 200 ml of methanol. To this solution was added 4.5 equivalents of acetyl chloride (net), dropwise, for 15 minutes, maintaining the reaction temperature at -10 ° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1 hour. Then it was diluted with 200 ml of TBME and 500 ml of water with vigorous stirring. The organic layer was removed (pH = 1) and washed with 20% ethanol (3 x 600 ml) to remove the chiral auxiliary and the compound illustrated above was produced, predominantly as a single enantiomer. (with compound of formula (i)) 150 ml of the solution was diluted in ethyl acetate of the compound from step (vi) (30 g, 0.053 mol), with 100 ml of methanol. To this solution was added 4.0 g of palladium hydroxide on carbon, followed by 0.5 ml of concentrated HCl, at pH 2-3. The reduction vessel was pressurized to 5.27 kg / cm 2 and held for about 1.5 hours or until the HPLC indicated the disappearance of the starting material. The reaction was filtered and concentrated to yield 18 g (70% yield) of the compound illustrated above, predominantly as a single enantiomer. compound of formula (k)) A 5 liter, three neck round bottom flask equipped with air driven agitator and nitrogen inlet / outlet was charged with 212.0 g (98.4% w / w, 437.8 mmole) of the step compound (vii). ), 2120 ml of acetone and 212 ml of methanol. The resulting suspension / solution was degassed for about 10 minutes, under a house vacuum. After relieving the vacuum and flooding the flask with nitrogen, 302.5 g (2.19 moles) of potassium carbonate was added in individual portions, followed by 87.1 g (546.6 mmol) of methyl bromoacetate. The resulting suspension was stirred at room temperature under a nitrogen atmosphere while monitoring the progress of the reaction by HPLC. The reaction was considered to be complete when all of the starting material had been converted to the title compound. The suspension was filtered through 300 g of aluminum oxide, rinsing with 1250 ml of acetone. The resulting filtrate was concentrated under reduced pressure, to an approximate volume of 500 ml. The concentrate was diluted with 2000 ml of tert-butyl methyl ether (TBME), then washed with two 1000 ml portions of 5% aqueous citric acid, followed by 1000 ml of saturated aqueous brine, to yield 1720 g of (+) (1S, 2S, 3S) -5-propoxy-1- (3,4-methylenedioxy) -phenyl-3- (2-carboxymethoxy] methoxy-4-methoxyphenyl) indane-2-carboxylic acid methyl ester (the cis diester intermediate rented from the compound illustrated above), as a solution in TBME. The analysis indicated 15.6% weight / weight and 98.5% PAR by HPLC. An analytical sample could be obtained by crystallization of a concentrate from a mixture of hexanes and TBME. 1 H NMR (CDCl 3 67.36 (d, 1H), 7.07 (d, 1H), 6.73-6.88 (m, 5H), 6.49 (c, 1H), 6.37 (d, 1H), 5.94 (s, 2H), 5.17 (d, 1H), 4.68-4.74 (m, 3H), 4.02 (t, 1H), 3.90 (t, 2H), 3.81 (d, 3H), 3.75 (s, 3H), 2.97 (s, 3H), 1.75-1.87 (m, 2H), 1.0 (t, 3H) ppm The saponification / epimerization of (+) (1S, 2S, 3S) -5-propoxy-1- (3,4-methylenedioxy) was carried out methyl-phenyl-3- (2-carboxymethoxy] methoxy-4-methoxyphenyl) indane-2-carboxylate to (+) (1S, 2R, 3S) -5-propoxy-1- (3,4-methylenedioxy-phenyl) acid ) -3- (2-carbomethoxy] methoxy-4-methoxyphenyl) indane-2-carboxylic acid, by concentration of the TBME solution, dilution with 2-propanol and water and subsequent treatment with an excess of 50% aqueous solution of sodium hydroxide (25 equivalents). When the saponification / epimerization was considered complete, the mixture was acidified with 6N aqueous HCl. Subsequent extraction work produced the di acid intermediate of the title compound as a solution in TBME. Treatment of the di acid with sodium hydroxide afforded the compound illustrated above, predominantly as a single enantiomer.

EXAMPLE 2 CORRESPONDING TO THE SCHEME 2 ETHYLENDIAMINE SALT OF THE ACID (+ U1S.2R.3S) -3-f2- (2-HYDROXLET-1-ILOXI) -4-METOXYPHENYL1-1- (3,4-METHYLENDIOXYPHENYL) -5- ( PROP-1- ILOXI.INDANO-2-CARBOXILICO (i) The title compound was prepared, according to the example 1, steps (i) to (vii), substituting 1, 3-dimethoxybenzene from step (iii) for 1-bromo-4-methoxy-2- (2-benzyloxy) ethoxybenzene, and using a Grignard reaction instead of the conditions of Fiedel-Crafts of step (iii) to prepare the monoester of the compound (q), as described in scheme 2. The saponification / epimerization of the monoester Co lithium hydroxide in THF produced the free acid, compound (r) ), as described on page 7. The compound (r) was treated with ethylenediamine to produce the title compound.

EXAMPLE 3 CORRESPONDING TO THE SCHEME 1 ETHYLENDIAMINE SALT (2: 1) OF THE ACID + K1S.2R.3S.-3-f2- (2-HYDROXYET-1-ILOXI) -4-METOXYPHENYLM- (3,4-METHYDE-DIOXYPHENYL) -5 - (PROP-1-ILOXI.INPANO-2-CARBOXILICO (i) A 500 ml flask was charged with 150 ml of toluene, followed by 29. 4 g, 98%, 327 mmoles, of ethylene carbonate and 15.9 g, 97.4%, 32.6 mmoles, of (1 S, 2S, 3S) -1- (3,4-methylenedioxyphenyl) -3- (4-methoxy) 2-hydroxyphenyl) -5-propoxy-indane-2-carboxylic acid methyl ester (a compound of the formula (i) prepared as in step (vii) of example 1). 23.1 g, 98%, 163.8 mmoles) of potassium carbonate was added with moderate stirring at room temperature. The contents of the flask were heated to approximately 112 ° C under nitrogen atmosphere and with moderate agitation. After about 3 hours at or around 112 ° C, the reaction was cooled to 25-30 ° C over a period of 20 minutes and 120 ml of deionized water was added. The mixture was stirred, then the aqueous layer was separated. The organic phase was concentrated to a gum, under reduced pressure, then diluted with 50 ml of methanol and 80 ml of tetrahydrofuran. A solution of 4.5 g, 477.8 mmol, of lithium hydroxide monohydrate dissolved in 50 ml of water was then added. The reaction mixture was heated to reflux (internal temperature 62-65 ° C) for about 15 minutes and refluxed while monitoring the progress of the reaction by HPLC. The reaction was considered complete when no intermediates could be detected by HPLC analysis. After about 60 minutes at reflux, the reaction was considered complete and the contents of the flask were cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. Then 150 ml of toluene, 150 ml of water, followed by 15 g of citric acid, was added to the resulting solution, and the mixture was stirred for approximately 15 minutes. The lower aqueous layer was drained and the organic layer was washed with 100 ml of aqueous brine solution. The organic layer of the flask was drained, then concentrated in vacuo to give 16.2 g of the free acid of the title compound, as a foam. HPLC analysis on weight / weight indicated 90.5% purity for a corrected yield of 88.8%.

An analytical sample could be obtained by recrystallization from 2-propanol, m.p. 125-127 ° C. (ii) A toluene solution of 868.8 g of acid was concentrated (+) (1 S, 2R, 3S) -3- [2- (2-Hydroxy-1-yloxy) -4-methoxyphenyl] -1- (3,4-methylenedioxyphenyl) -5-prop-1-yloxy) indane-2-carboxylic acid, about 11.2% w / w, 192.5 mmoles, under reduced pressure, up to an approximate volume of 200 ml. Distillation was discontinued and 500 ml of 2-propanol was added to the concentrate. The organic solution was concentrated again under reduced pressure to an approximate volume of 200 ml. Distillation was discontinued and 500 ml of 2-propanol was added to the concentrate. The resulting solution was left stirring in 2-propanol at room temperature for about 15 minutes to obtain a homogeneous mixture, then diluted with another 1000 ml of 2-propanol. The resulting solution was heated to about 60 ° C for a period of 15-20 minutes, under moderate purge with nitrogen. The heating was discontinued and 11.6 g of ethylenediamine (99.5%, 192.5 mmol) was added. The mixture was cooled to 30-35 ° C over a period of 4 hours. When the solution was cooled to 57 ° C, precipitation of the title compound occurred. The resulting suspension was stirred at room temperature for about 12 hours, then cooled to 0 ° C for 3 more hours, before isolating the title compound, by filtration. The product was washed with 3 portions of 300 ml of 2-propanol, followed by 600 ml of hexanes, and cooled to 0-5 ° C. The product was dried in a vacuum oven for approximately 16 hours at 20-25 ° C. , to give 91.6 g (87%) of the title compound. Analysis calculated for C30H34NO8; C, 67.15; H, 6.39; N, 2.61. Found: C, 67.2; H, 6.48; N, 2.67.

EXAMPLE 4- AUXILIAR QUIRAL L-ephedrine hydrochloride It was loaded into a round bottom flask, three necks, 12 liters, 5 liters of toluene and 1625 hg, 8.06 moles, of ephedrine hydrochloride. The flask was heated at 110 ° C with mechanical stirring while continuously purging the solution with nitrogen. The toluene was distilled using a distillation condenser and the solution was heated at 164-170 ° C for 3 hours. HPLC showed the disappearance of most of the product so the reaction mixture was allowed to cool to 120 ° C, and then 4 liters of water was added. The mixture was stirred and allowed to cool to room temperature and then filtered. The white solid product was dissolved in 2 liters of acetonitrile and concentrated until almost dry, when most of the solid product of the solution crystallized. The flask was stored in a refrigerator overnight at 0 ° C. The solid was filtered and washed with 1 liter of acetonitrile / 15% water, under vacuum, at 60 ° C for 24 hours. The above-illustrated, predominantly optically pure compound was obtained as a white solid, 664.8 g (43.4% yield); p.f. 177.179 ° C. .i) A three-neck, 5-liter flask was charged with 300 g (1.54 moles) of the compound from step (i), 200 ml of 3-chloropropionyl chloride and 3 liters of acetonitrile. The solution was heated at 75 ° C for 8 hours, then allowed to cool to room temperature. 435 g, 3.15 moles, 2 equivalents of potassium carbonate were added and the suspension was reheated to 75 ° C for 7 hours. The reaction mixture was then cooled to room temperature and filtered. The solvent was removed in vacuo and 680 ml of n-propanol was added and the solvent was cooled to 0 ° C and held there for 1 hour. The predominantly optically pure compound illustrated above was isolated by filtration, washed with 150 ml of hexanes and dried; 326 g (85% yield); p.f. 149.5-151.0 ° C. Although the preferred embodiments of the invention are illustrated by the foregoing, it is understood that the invention is not limited to the precise instructions described herein and that it reserves the right to all modifications that fall within the scope of the claims that follow.

Claims (16)

. NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (11): where A, B, C and D are carbon atoms, or three of A, B, C and D are carbon atoms and one is a nitrogen atom; R is H, OH, alkyl of 1 to 5 carbon atoms or a protected oxy group and R7 is Br, I, -OSO2CF3 or-OS02F.

2. A compound of the formula: wherein A, B, C, D, R, and R7, are as defined in claim 1.

3. -A compound of the formula (12): (12) wherein A, B, C, D, R, and R7, are as defined in claim 1, R3 and R4 are independently H, OH, C? _3 alkoxy, F, CF3 or C "| and R6 is OH or OH protected.

4. A compound of the formula (13): (13) wherein A, B, C, D, R, R3, R4, and R6 are as defined in claims 1 and 3, Xc is an achiral group.

5. A compound of the formula: where A, B, C, D, R, R3. R4 and R6 are as defined in claims 1 and 3.

6. A compound of the formula (21): (21) wherein A, B, C, D, R, R3, R4, and R6 are as defined in claims 1 and 3.

7. A compound of the formula (22): wherein A, B, C, D, R, R3, R4, R6 and Xc are as defined in claims 1,3 and 4.

8. The compound of claim 1, further characterized by having the formula wherein R is as defined in claim 1 and R7 is Br, I, OSO2CF3 or -OSO2F.

9. - The compound of claim 2, further characterized by having the formula wherein R is as defined in claim 1 and R7 is Br, I, -OS02CF3 or -OS02F.

10. The compound of claim 3, further characterized by having the formula wherein R is as defined in claim 1 and R7 is Br, I, OS02CF3 or -OS02F.

11. - The compound of claim 4, further characterized by having the formula wherein R is as defined in claim 1 and Xc is (ac)

12. - The compound according to claim 6, further characterized by having the structure: wherein R is as defined in claim 1, and R7 is Br, I, -OSO2CF3 or -OSO2F.

13. The compound according to claim 7, further characterized in that it has the formula: wherein R is as defined in claim 1 and Xc is (ac)

14. -A composite of the structure: predominantly as the only illustrated enantiomer.

15. A process for preparing a compound of the structure: characterized in that it comprises reacting a compound of the structure with 3-chloropropionyl chloride and a base.

16. A process for preparing a compound of the structure: wherein A, B, C, D, R, R3, and R4, are as defined in claims 1 and 3, predominantly as the only enantiomer illustrated, characterized in that it comprises reacting a compound of the formula (±) wherein A, B, C, D, R, R3, and R4, are as defined in claims 1 and 3, with ethylene carbonate and a base, preferably potassium carbonate, at 90-115 ° C, followed by the treatment of lithium hydroxide monohydrate to form free acid, and then the addition of ethylenediamine.