ES2237312B1 - CHEMIOENZYMA SYNTHESIS OF ENANTIOPURE DERIVATIVES OF 3-AMINOINDAN-1-OL AND INDANO-1,3-DIAMINE - Google Patents

CHEMIOENZYMA SYNTHESIS OF ENANTIOPURE DERIVATIVES OF 3-AMINOINDAN-1-OL AND INDANO-1,3-DIAMINE

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ES2237312B1
ES2237312B1 ES200302536A ES200302536A ES2237312B1 ES 2237312 B1 ES2237312 B1 ES 2237312B1 ES 200302536 A ES200302536 A ES 200302536A ES 200302536 A ES200302536 A ES 200302536A ES 2237312 B1 ES2237312 B1 ES 2237312B1
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Vicente Gotor Santamaria
Ignacio Alonso Rodriguez
Monica Lopez Garcia
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Universidad de Oviedo
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Abstract

Síntesis quimioenzimática de derivados enantiopuros de 3-aminoindan-1-ol e indano-1,3-diamina. Dicho procedimiento consiste en la acilación enantioselectiva catalizada por hidrolasas, principalmente lipasas en medios orgánicos, de los grupos hidroxilo de los aminoalcoholes citados. El mejor biocatalizador es la lipasa de Candida antarctica y el agente de acilación más eficaz es el acetato de vinilo. Así, pueden obtenerse los aminoindanoles enantiopuros de configuración (1S,3S) y (1S,3R) y los correspondientes productos acetilados de configuración (1R,3R) y (1R,3S). A partir de los aminoindanoles enantiopuros obtenidos mediante esta metodología se han preparado, de forma eficaz y en un solo paso, las correspondientes diaminas análogas, productos de gran interés por su potente actividad neuroprotectora. También se describe la desprotección selectiva de los grupos amino de las diaminas enantiopuras obtenidas.Chemoenzymatic synthesis of enantiopide derivatives of 3-aminoindan-1-ol and indane-1,3-diamine. Said process consists of the enantioselective acylation catalyzed by hydrolases, mainly lipases in organic media, of the hydroxyl groups of the aforementioned amino alcohols. The best biocatalyst is Candida antarctica lipase and the most effective acylating agent is vinyl acetate. Thus, the configuration enantiopide aminoindanes (1S, 3S) and (1S, 3R) and the corresponding acetylated configuration products (1R, 3R) and (1R, 3S) can be obtained. The corresponding analog diamines, products of great interest for their potent neuroprotective activity, have been prepared efficiently and in a single step from the enantiopide aminoindanols obtained by this methodology. The selective deprotection of the amino groups of the enantiopure diamines obtained is also described.

Description

Síntesis quimioenzimática de derivados enantiopuros de 3-aminoindan-1-ol e indano-1,3-diamina.Chemoenzymatic synthesis of derivatives enantiopuros of 3-aminoindan-1-ol e indane-1,3-diamine.

Campo de la invenciónField of the Invention

Los aminoindanoles enantiopuros son compuestos de gran interés en química orgánica debido a sus aplicaciones como auxiliares quirales, agentes de resolución e intermedios sintéticos de productos de alto valor añadido (fármacos, pesticidas,...). Así, por ejemplo, el (1S,3R)-3-aminoindan-1-ol se encuentra presente en la estructura de inhibidores de la proteasa del HIV-1 (J. Med. Chem. 1998, 41, 836).The enantiopuro aminoindanoles are compounds of great interest in organic chemistry due to their applications as chiral auxiliaries, resolution agents and synthetic intermediates of high value-added products (drugs, pesticides, ...). Thus, for example, (1 S , 3 R ) -3-aminoindan-1-ol is present in the structure of HIV-1 protease inhibitors ( J. Med. Chem . 1998 , 41 , 836).

Por otra parte, las diaminas ópticamente puras son compuestos muy útiles como ligandos de metales de transición en síntesis asimétrica y como precursores en la preparación de poliaminas y azamacrociclos, productos de aplicación en química terapéutica y supramolecular. Recientemente se ha descrito la potente actividad neuroprotectora de nuevas poliaminas derivadas del 1-aminoindano (J. PharmacoL Exp. Ther. 1999, 291, 39) entre las que se encuentran el cis y trans-1,3-diaminoindano de forma racémica.On the other hand, optically pure diamines are very useful compounds as transition metal ligands in asymmetric synthesis and as precursors in the preparation of polyamines and azamacrocycles, products of application in therapeutic and supramolecular chemistry. Recently the potent neuroprotective activity of new polyamines derived from 1-aminoindane has been described ( J. PharmacoL Exp. Ther . 1999 , 291 , 39) among which are cis and trans -1,3-diaminoindane in a racemic manner.

En la presente invención se describe la resolución biocatalítica de los 1,3-aminoindanoles (\pm)-cis-4 y (\pm)-trans-4 (Figura 2), así como la preparación de las diaminas enantiopuras análogas. Del mismo modo, se trata la desprotección selectiva de los grupos amino de las diaminas sintetizadas.The present invention describes the biocatalytic resolution of 1,3-aminoindanols (±) - cis -4 and (±) - trans -4 (Figure 2), as well as the preparation of the analog enantiopuras diamines. Similarly, the selective deprotection of the amino groups of the synthesized diamines is treated.

Antecedentes de la invenciónBackground of the invention

La preparación de cis- y trans-3-aminoindan-1-ol, (\pm)-cis-3 y (\pm)-trans-3, se ha llevado a cabo por reducción moderadamente selectiva de derivados de la 3-aminoindan-1-ona (Figura 1). Estos resultados están descritos en el trabajo Chem. Lett. 2002, 3, 266 y en la patente US 6479702 B1. Así, pueden obtenerse los productos (\pm)-trans-3 y (\pm)-cis-3, partiendo de la aminocetona 2, con un rendimiento del 47% y el 31% respectivamente.The preparation of cis - and trans -3-aminoindan-1-ol, (±) - cis -3 and (±) - trans -3, has been carried out by moderately selective reduction of 3-aminoindan derivatives -1-one (Figure 1). These results are described in the Chem. Lett . 2002 , 3 , 266 and in US Patent 6479702 B1. Thus, the products (±) - trans -3 and (±) - cis -3 can be obtained, starting from amino ketone 2, with a yield of 47% and 31% respectively.

Por otra parte, estas referencias son las únicas que tratan la resolución de los productos (\pm)-trans-3 y (\pm)-cis-3.On the other hand, these references are the only ones that deal with the resolution of the products (±) - trans -3 and (±) - cis -3.

Las formas enantiopuras (+)-trans-3 y (-)-trans-3 pueden obtenerse por cristalización de sus sales diastereoméricas con ácidos quirales. En concreto, se utiliza como agente de resolución el ácido (-) y (+)-dibenzoil-L-tartárico, dependiendo del enantiómero que se pretenda preparar. Los inconvenientes de este método son su laboriosidad y bajo rendimiento (38% para (+)-3 y 30% para (-)-3), ya que para obtener los compuestos enantiopuros son necesarios tres ciclos de recristalización.The enantiopuras (+) - trans -3 and (-) - trans -3 forms can be obtained by crystallization of their diastereomeric salts with chiral acids. In particular, the (-) and (+) - dibenzoyl-L-tartaric acid is used as the resolution agent, depending on the enantiomer to be prepared. The disadvantages of this method are its industriousness and low yield (38% for (+) - 3 and 30% for (-) - 3), since three recrystallization cycles are necessary to obtain the enantiopide compounds.

Respecto al aminoindanol (\pm)-cis-3, no se ha podido llevar a cabo su resolución diasteromérica. Las formas enantioenriquecidas de (+)-cis-3 y (-)-cis-3 se obtuvieron por separación en HPLC con relleno quiral. Sin embargo, los rendimientos de los productos son muy bajos y no se consiguen de forma enantiopura (rto. 28%, ee 97.3% y rto. 18%, ee 95%).Regarding aminoindanol (±) - cis -3, its diasteromeric resolution could not be carried out. The enanti-enriched forms of (+) - cis -3 and (-) - cis -3 were obtained by separation in HPLC with chiral filling. However, the yields of the products are very low and are not achieved enantiopura (rto. 28%, ee 97.3% and rto. 18%, ee 95%).

La síntesis de cis y trans-1,3-diaminoindano sólo se encuentra recogida en la patente WO 9702027.The synthesis of cis and trans -1,3-diaminoindane is only found in WO 9702027.

Su resolución no se ha llevado a cabo con anterioridad a la presente patente, por lo que estas diaminas sólo se encuentran caracterizadas en su forma racémica. Teniendo en cuenta que los componentes de una mezcla racémica pueden producir efectos biológicos muy distintos y que estas diaminas son interesantes por su actividad neuroprotectora, la resolución de estos compuestos podría ser muy relevante.Its resolution has not been carried out with prior to this patent, so these diamines only They are characterized in their racemic form. Having in realize that the components of a racemic mixture can produce very different biological effects and that these diamines are interesting for its neuroprotective activity, the resolution of These compounds could be very relevant.

Descripción general de la invenciónGeneral Description of the Invention

En la presente invención se describen por primera vez los compuestos racémicos (\pm)-trans-4, (\pm)-cis-4, y los productos enantiopuros (1S,3S)-4, (1S,3R)-4, (1R,3R)-5, (1R,3S)-5, (1R,3S)-6, (1R,3R)-6, (1S,3S)-6, (1S,3R)-7, (1R,3R)-7, (1R,3S)-8 y (1R,3R)-8.The present invention describes for the first time the racemic compounds (±) - trans -4, (±) - cis -4, and the enantiopuro products (1 S , 3 S ) -4, (1 S , 3 R ) -4, (1 R , 3 R ) -5, (1 R , 3 S ) -5, (1 R , 3 S ) -6, (1 R , 3 R ) -6, (1 S , 3 S ) -6, (1 S , 3 R ) -7, (1 R , 3 R ) -7, (1 R , 3 S ) -8 and (1 R , 3 R ) -8.

Es objeto de la presente invención un procedimiento de preparación y posterior separación de los aminoindanoles racémicos (\pm)-cis-4 y (\pm)-trans-4 a partir de la aminocetona 2.The object of the present invention is a process for the preparation and subsequent separation of racemic aminoindanols (±) - cis -4 and (±) - trans -4 from amino ketone 2.

También es objeto de la presente invención un procedimiento de resolución enzimática del aminoindanol racémico (\pm)-trans-4, que permite obtener los compuestos (1S,3S)-4 y (1R,3R)-5 de forma enantioméricamente pura. Del mismo modo, siguiendo un procedimiento análogo con el diastereoisómero (\pm)-cis-4 se pueden obtener los compuestos enantiopuros (1S,3R)-4 y (1R,3S)-5. Dicho procedimiento consiste en la acilación enantioselectiva -catalizada por una enzima- de los grupos hidroxilo de los compuestos (\pm)-trans-4 y (\pm)-cis-4 para dar lugar a los productos (1R,3R)-5 y (1R,3S)-5 respectivamente.The subject of the present invention is also a method of enzymatic resolution of racemic aminoindanol (±) - trans -4, which allows the compounds (1 S , 3 S ) -4 and (1 R , 3 R ) -5 to be obtained so enantiomerically pure. In the same way, following an analogous procedure with the diastereoisomer (±) - cis -4 the enantiopuro compounds (1 S , 3 R ) -4 and (1 R , 3 S ) -5 can be obtained. Said process consists of the enantioselective acylation -catalyzed by an enzyme- of the hydroxyl groups of the compounds (±) - trans -4 and (±) - cis -4 to give rise to the products (1 R , 3 R ) -5 and (1 R , 3 S ) -5 respectively.

También es objeto de la presente invención un procedimiento que permite la asignación de la configuración absoluta del aminoindanol enantiopuro (1S,3R)-4.The object of the present invention is also a process that allows the assignment of the absolute configuration of aminoindanol enantiopuro (1 S , 3 R ) -4.

También es objeto de la presente invención un procedimiento de preparación de las diaminas ópticamente puras (1R,3S)-6, (1R,3R)-6, (1S,3S)-6 a partir de los compuestos enantioméricamente puros (1S,3S)-4, (1S,3R)-4, (1R,3S)-4, que consiste en una reacción de Mitsunobu con ftalimida.Also object of the present invention is a process for preparing optically pure diamines (1 R , 3 S ) -6, (1 R , 3 R ) -6, (1 S , 3 S ) -6 from the compounds enantiomerically pure (1 S , 3 S ) -4, (1 S , 3 R ) -4, (1 R , 3 S ) -4, which consists of a Mitsunobu reaction with phthalimide.

También es objeto de la presente invención un procedimiento de preparación de los compuestos enantiopuros (1S,3R)-7, (1R,3R)-7 a partir de los compuestos enantiopuros (1R,3S)-6, (1R,3R)-6, que consiste en su tratamiento con hidrazina en MeOH.The subject of the present invention is also a process for preparing the enantiopuro compounds (1 S , 3 R ) -7, (1 R , 3 R ) -7 from the enantiopuro compounds (1 R , 3 S ) -6, (1 R , 3 R ) -6, which consists of its treatment with hydrazine in MeOH.

También es objeto de la presente invención un procedimiento de preparación de los compuestos enantiopuros (1R,3S)-8, (1R,3R)-8 a partir de los compuestos enantiopuros (1R,3S)-6, (1R,3R)-6, que consiste en su tratamiento con ácido fórmico en MeOH utilizando Pd-black como catalizador.The subject of the present invention is also a process for preparing the enantiopuro compounds (1 R , 3 S ) -8, (1 R , 3 R ) -8 from the enantiopuro compounds (1 R , 3 S ) -6, (1 R , 3 R ) -6, which consists of its treatment with formic acid in MeOH using Pd-black as a catalyst.

Descripción detallada de la invenciónDetailed description of the invention

En la Figura 3 se muestra un esquema sintético de los aminoindanoles racémicos (\pm)-cis-4 y (\pm)-trans-4 a partir de la aminocetona acetilada 2 (descrita en la patente US 6479702 B1). En primer lugar, se lleva a cabo la hidrólisis en medio ácido del grupo amino acetilado seguida de la reducción del grupo carbonilo. Finalmente, se aislan los productos (\pm)-cis-4 y (\pm)-trans-4 en su forma de carbamatos de bencilo y en una relación 1:3, respectivamente. La separación de los diastereoisómeros se realiza mediante cromatografía líquida de alta eficacia.A synthetic scheme of racemic aminoindanols (±) - cis -4 and (±) - trans -4 from acetylated amino ketone 2 (described in US 6479702 B1) is shown in Figure 3. First, hydrolysis is carried out in an acid medium of the acetylated amino group followed by the reduction of the carbonyl group. Finally, the products (±) - cis -4 and (±) - trans -4 are isolated in their form of benzyl carbamates and in a 1: 3 ratio, respectively. The separation of diastereoisomers is performed by high performance liquid chromatography.

El procedimiento de resolución enzimática consiste en hacer reaccionar los aminoindanoles racémicos con un agente acilante en presencia de un enzima. Por acción del biocatalizador, uno de los enantiómeros del sustrato es acilado selectivamente, mientras que el otro enantiómero permanece sin acilar. Debe tenerse en cuenta que la elección del enzima puede determinar el enantiómero acilado.The enzymatic resolution procedure consists in reacting racemic aminoindanes with a acylating agent in the presence of an enzyme. By action of biocatalyst, one of the enantiomers of the substrate is acylated selectively, while the other enantiomer remains without acilar It should be borne in mind that the choice of enzyme can determine the acylated enantiomer.

En la resolución del compuesto (\pm)-trans-4 (Figura 4), la enzima cataliza preferentemente la acilación del enantiómero (1R,3R)-4, dando lugar al producto (1R,3R)-5, mientras que el isómero (1S,3S)-4 permanece mayoritariamente sin acilar. Los mejores agentes de acilación son acetato de vinilo y de isopropenilo.In the resolution of the compound (±) - trans -4 (Figure 4), the enzyme preferably catalyzes the acylation of the enantiomer (1 R , 3 R ) -4, giving rise to the product (1 R , 3 R ) -5, while the isomer (1 S , 3 S ) -4 remains mostly unhardened. The best acylating agents are vinyl acetate and isopropenyl.

Del mismo modo, en la resolución del compuesto (\pm)-cis-4 (Figura 5), la enzima cataliza preferentemente la acilación del enantiómero (1R,3S)-4, dando lugar al producto (1R,3S)-5, mientras que el isómero (1S,3R)-4 permanece mayoritariamente sin acilar.Similarly, in the resolution of the compound (±) - cis -4 (Figure 5), the enzyme preferably catalyzes the acylation of the enantiomer (1 R , 3 S ) -4, giving rise to the product (1 R , 3 S ) -5, while the isomer (1 S , 3 R ) -4 remains mostly unhardened.

Por tanto, en ambos procesos de resolución, la acilación del aminoindanol con configuración R (en el centro que contiene al grupo hidroxilo) está más favorecida que la de su enantiómero.Therefore, in both resolution processes, the acylation of the aminoindanol with R configuration (in the center containing the hydroxyl group) is more favored than that of its enantiomer.

A medida que aumenta la conversión del proceso biocatalítico el enantiómero preferido se va consumiendo, mientras que el otro permanece prácticamente intacto. El valor concreto de conversión a la que hay que detener la reacción dependerá de la enantioselectividad de cada caso particular y de los requerimientos de pureza óptica de los productos. Cuando la reacción es suficientemente enantioselectiva, la conversión de la reacción debe ser cercana al 50% para obtener el máximo rendimiento de producto acilado y de sustrato remanente ópticamente enriquecidos. No obstante, cuando la enantioselectividad es moderada, otros valores de conversión pueden ser preferibles para asegurar un valor del exceso enantiomérico lo bastante alto de alguno de los componentes de la mezcla de reacción. Por ejemplo, es sabido que a medida que aumenta la conversión, en unas condiciones de reacción dadas, el exceso enantiomérico del sustrato remanente va aumentando y el exceso enantiomérico del producto va disminuyendo. Los. valores de los excesos enantioméricos se determinan de acuerdo con el trabajo descrito en la bibliografía por Sih y col. (J. Am. Chem. Soc. 1982, 104, 7294). Una vez que se alcanza el valor deseado de conversión se detiene la reacción -mediante filtración de la enzima, por ejemplo- y los compuestos resultantes se separan. Esta separación se puede hacer por cualquier método que resulte conveniente, por ejemplo por precipitación o cromatografía.As the conversion of the biocatalytic process increases, the preferred enantiomer is consumed, while the other remains virtually intact. The specific conversion value at which the reaction must be stopped will depend on the enantioselectivity of each particular case and the optical purity requirements of the products. When the reaction is sufficiently enantioselective, the conversion of the reaction should be close to 50% to obtain the maximum yield of acylated product and optically enriched remaining substrate. However, when the enantioselectivity is moderate, other conversion values may be preferable to ensure a high enough enantiomeric excess value of any of the components of the reaction mixture. For example, it is known that as the conversion increases, under given reaction conditions, the enantiomeric excess of the remaining substrate increases and the enantiomeric excess of the product decreases. The. Enantiomeric excess values are determined according to the work described in the literature by Sih et al. ( J. Am. Chem. Soc . 1982 , 104 , 7294). Once the desired conversion value is reached, the reaction is stopped - by filtration of the enzyme, for example - and the resulting compounds are separated. This separation can be done by any convenient method, for example by precipitation or chromatography.

El proceso se lleva a cabo disolviendo el sustrato en un disolvente adecuado, y añadiendo la enzima y el agente acilante.The process is carried out by dissolving the substrate in a suitable solvent, and adding the enzyme and the acylating agent

Como medio de reacción puede emplearse un disolvente orgánico. Un disolvente adecuado puede ser un éter. Sin embargo, otros disolventes como tolueno, hidrocarburos o alcoholes pueden ser también de utilidad.A reaction medium can be used as a organic solvent A suitable solvent may be an ether. Without However, other solvents such as toluene, hydrocarbons or alcohols They can also be useful.

Como agente acilante se emplea un éster activado. El mejor resultado se obtiene cuando se usa acetato de vinilo.An activated ester is used as acylating agent. The best result is obtained when using vinyl acetate.

Las enzimas adecuadas para catalizar este proceso son las hidrolasas, tanto de origen animal como microbiano, en forma pura o semipurificada, libres o inmovilizadas. Especial objeto de la presente invención es el uso de la lipasa de Candida antarctica (CALB). Esta lipasa se presenta en diferentes formas de inmovilización sobre soportes hidrófobos y mecánicamente resistentes o sobre resinas acrilícas, como puede ser una resina epoxiacrílica activada con grupos deca-octilo.Suitable enzymes to catalyze this process are hydrolases, both of animal and microbial origin, in pure or semi-purified form, free or immobilized. Special object of the present invention is the use of Candida antarctica lipase (CALB). This lipase comes in different forms of immobilization on hydrophobic and mechanically resistant supports or on acrylic resins, such as an epoxyacrylic resin activated with deca-octyl groups.

La reacción puede llevarse a cabo entre 5 y 60ºC.The reaction can be carried out between 5 and 60 ° C

La configuración absoluta de los compuestos resultantes de la resolución enzimática se determinó de la siguiente forma:The absolute configuration of the compounds resulting from the enzymatic resolution was determined from the following form:

- La desprotección del grupo amino del compuesto (1S,3S)-4, mediante tratamiento con una disolución metanólica al 10% en ácido fórmico en presencia de "Pd-black", permite asignar su configuración absoluta por comparación con los datos publicados en el trabajo Chem. Lett. 2002, 3, 266.- The deprotection of the amino group of the compound (1 S , 3 S ) -4, by treatment with a 10% methanolic solution in formic acid in the presence of "Pd-black", allows to assign its absolute configuration by comparison with the published data at work Chem. Lett . 2002 , 3 , 266.

- El proceso seguido en el caso del compuesto (1S,3R)-4 se describe en la Figura 6. En primer lugar, se lleva a cabo una oxidación con PCC del aminoindanol (1S,3R)-4, seguida de una reducción con NaBH_{4} en MeOH. La mezcla cis:trans obtenida puede ser separada por HPLC. A continuación, se asigna la configuración absoluta del diastereoisómero trans por comparación con el signo de rotación óptica de (1S,3S)-4, lo que permite conocer indirectamente la configuración de (1S,3R)-4.- The process followed in the case of compound (1 S , 3 R ) -4 is described in Figure 6. First, a PCC oxidation of aminoindanol (1 S , 3 R ) -4 is carried out, followed of a reduction with NaBH4 in MeOH. The cis : trans mixture obtained can be separated by HPLC. Next, the absolute configuration of the trans diastereoisomer is assigned by comparison with the optical rotation sign of (1 S , 3 S ) -4, which allows indirectly knowing the configuration of (1 S , 3 R ) -4.

También es objeto de la presente invención un procedimiento de preparación de las diaminas ópticamente puras (1R,3S)-6, (1R,3R)-6, (1S,3S)-6 a partir de los compuestos enantioméricamente puros (1S,3S)-4, (1S,3R)-4, (1R,3S)-4.Also object of the present invention is a process for preparing optically pure diamines (1 R , 3 S ) -6, (1 R , 3 R ) -6, (1 S , 3 S ) -6 from the compounds enantiomerically pure (1 S , 3 S ) -4, (1 S , 3 R ) -4, (1 R , 3 S ) -4.

De acuerdo con el proceso biocatalítico descrito anteriormente, se pueden obtener de forma enantiopura los aminoindanoles (1S,3S)-4, (1S,3R)-4 y sus correspondientes enantiómeros acetilados (1R,3R)-5 y(1R,3S)-5. Estos últimos pueden ser hidrolizados con NaOH 1N en MeOH para obtener los correspondientes aminoindanoles libres. Así, se pueden obtener los cuatro isómeros del 1,3-aminoindanol de forma enantiopura, productos de alto interés como precursores de las diaminas análogas. De esta forma, se preparó el isómero (1R,3S)-4 a partir de (1R,3S)-5 (ver Figura 9). El isómero (1R,3R)-4 no ha sido preparado ya que sería, al igual que (1S,3S)-4, precursor de la diamina cis y como ésta es una forma meso a no ser por la distinta sustitución de los grupos amino, si se consigue una desprotección selectiva de los mismos no es necesaria la síntesis de los dos enantiómeros de esta diamina.In accordance with the biocatalytic process described above, aminoindanoles (1 S , 3 S ) -4, (1 S , 3 R ) -4 and their corresponding acetylated enantiomers (1 R , 3 R ) -5 can be obtained enantiopurately and (1 R , 3 S ) -5. The latter can be hydrolyzed with 1N NaOH in MeOH to obtain the corresponding free aminoindanols. Thus, the four isomers of 1,3-aminoindanol can be obtained enantiopura, products of high interest as precursors of analogous diamines. In this way, the isomer (1 R , 3 S ) -4 was prepared from (1 R , 3 S ) -5 (see Figure 9). The isomer (1 R , 3 R ) -4 has not been prepared since it would be, like (1 S , 3 S ) -4, a precursor to cis diamine and as this is a meso form unless for the different substitution of the amino groups, if a selective deprotection of the same is achieved, the synthesis of the two enantiomers of this diamine is not necessary.

Una vez obtenidos los tres aminoindanoles enantiopuros (1S,3S)-4, (1S,3R)-4, (1R,3S)-4 puede accederse a las correspondientes diaminas (1R,3S)-6, (1R,3R)-6, (1S,3S)-6 en un solo paso de reacción, mediante una reacción de Mitsunobu (Figuras 7, 8 y 9). El procedimiento de reacción consta de la adición sucesiva de Ph_{3}P, ftalimida y DEAD sobre una disolución de los compuestos (1S,3S)-4, (1S,3R)-4, (1R,3S)-4 en THF.Once the three enantiopide aminoindane (1 S , 3 S ) -4, (1 S , 3 R ) -4, (1 R , 3 S ) -4 can be accessed the corresponding diamines (1 R , 3 S ) - 6, (1 R , 3 R ) -6, (1 S , 3 S ) -6 in a single reaction step, by a Mitsunobu reaction (Figures 7, 8 and 9). The reaction procedure consists of the successive addition of Ph 3 P, phthalimide and DEAD on a solution of the compounds (1 S , 3 S ) -4, (1 S , 3 R ) -4, (1 R , 3 S ) -4 in THF.

El tratamiento de las diaminas enantiopuras (1R,3S)-6 y (1R,3R)-6 con una disolución metanólica de hidrazina conduce a los productos enantiopuros (1S,3R)-7 y (1R,3R)-7, respectivamente (Figuras 7 y 8). De este modo, se consigue la desprotección selectiva del grupo ftalimido, permaneciendo el grupo amino protegido como carbamato de bencilo intacto.Treatment of the enantiopuras diamines (1 R , 3 S ) -6 and (1 R , 3 R ) -6 with a methanolic solution of hydrazine leads to the enantiopuro products (1 S , 3 R ) -7 and (1 R , 3 R ) -7, respectively (Figures 7 and 8). In this way, selective deprotection of the phthalimido group is achieved, the protected amino group remaining as benzyl carbamate intact.

Por otra parte, el tratamiento de las diaminas enantiopuras (1R,3S)-6 y (1R,3R)-6 con una disolución metanólica al 10% en ácido fórmico, en presencia de "Pd-black", conduce a los productos enantiopuros (1R,3S)-8 y (1R,3R)-8, respectivamente (Figuras 7 y 8). Así, se consigue la desprotección selectiva del grupo amino protegido como carbamato de bencilo, permaneciendo el grupo ftalimido intacto.On the other hand, the treatment of enantiopure diamines (1 R , 3 S ) -6 and (1 R , 3 R ) -6 with a 10% methanolic solution in formic acid, in the presence of "Pd-black", leads to the enantiopuro products (1 R , 3 S ) -8 and (1 R , 3 R ) -8, respectively (Figures 7 and 8). Thus, selective deprotection of the protected amino group as benzyl carbamate is achieved, the phthalimido group remaining intact.

Para una mejor comprensión del procedimiento objeto de la presente invención, se exponen los siguientes ejemplos, que deben entenderse sin carácter limitativo del alcance de la invención.For a better understanding of the procedure object of the present invention, the following are set forth examples, which should be understood without limitation of scope of the invention.

Ejemplos Examples Ejemplo 1Example 1 Síntesis de los aminoindanoles racémicos (\pm)-cis-4 y (\pm)-trans-4Synthesis of racemic aminoindanols (±) - cis -4 and (±) - trans -4

A 2 mmol de 3-(acetamido)indan-1-ona (2) se le añaden 4 ml de HCl 3N y la mezcla se agita a 80ºC durante una noche. Posteriormente, se lava con CH_{2}Cl_{2} y la fase acuosa resultante se concentra a sequedad. Los restos de ácido acético se eliminan del producto mediante lavados sucesivos con heptano. Al residuo así obtenido se le añaden 6 ml de MeOH y 2.7 mmol de NaBH_{4}, lentamente y a 0ºC. A continuación, la mezcla se agita vigorosamente a temperatura ambiente durante 3 horas. El crudo resultante se concentra a sequedad y se redisuelve en 4 ml de agua. A 0ºC se adicionan 2.3 mmol de Na_{2}CO_{3} y 2.3 mmol de cloroformiato de bencilo, gota a gota y con agitación vigorosa. Después de una noche de reacción a temperatura ambiente la mezcla se extrae con CH_{2}Cl_{2}. La fase orgánica se trata con Na_{2}SO_{4} anhidro, se filtra y se concentra a sequedad. El producto 3-(N-benciloxicarbonilamino)indan-1-ol (4) se obtiene, tras purificación por cromatografía, con un rendimiento global del 92% y como una mezcla diastereoisómeros (\pm)-cis-4 y (\pm)-trans-4 en relación 1:3, respectivamente.To 2 mmol of 3- (acetamido) indan-1-one (2) 4 ml of 3N HCl is added and the mixture is stirred at 80 ° C overnight. Subsequently, it is washed with CH 2 Cl 2 and the resulting aqueous phase is concentrated to dryness. The acetic acid residues are removed from the product by successive washing with heptane. To the residue thus obtained are added 6 ml of MeOH and 2.7 mmol of NaBH4, slowly and at 0 ° C. The mixture is then stirred vigorously at room temperature for 3 hours. The resulting crude is concentrated to dryness and redissolved in 4 ml of water. At 0 ° C, 2.3 mmol of Na2CO3 and 2.3 mmol of benzyl chloroformate are added dropwise and with vigorous stirring. After a night of reaction at room temperature the mixture is extracted with CH 2 Cl 2. The organic phase is treated with anhydrous Na2SO4, filtered and concentrated to dryness. The product 3- ( N -benzyloxycarbonylamino) indan-1-ol (4) is obtained, after purification by chromatography, with an overall yield of 92% and as a mixture of diastereoisomers (±) - cis -4 and (±) - trans -4 in 1: 3 ratio, respectively.

La separación de los diastereoisómeros se realiza mediante cromatografía líquida de alta eficacia.The separation of diastereoisomers is performed by high performance liquid chromatography.

Ejemplo 2Example 2 Resolución por acilación enzimática del aminoindanol racémico (\pm)-trans-4Resolution by enzymatic acylation of racemic aminoindanol (±) - trans -4

A un erlenmeyer que contiene 0.53 mmol de (\pm)-trans-3-(N-benciloxicarbonilamino)indan-1-ol (4) y CALB (169 mg) se le añade, bajo atmósfera de nitrógeno, 4.5 ml de ^{t}BuOMe y 5.3 mmol de acetato de vinilo. La mezcla resultante se agita a 30ºC. Cuando se alcanza la conversión deseada (dependiendo si se desea obtener de forma enantiopura sustrato o producto), el enzima se filtra y se lava con diclorometano. Los disolventes del filtrado se evaporan a presión reducida y se purifica el (1S,3S)-(-)-3-(N-benciloxicarbonilamino)indan-1-ol (4) remanente por cromatografía en gel de sílice. Rendimiento 98%. Sólido blanco, p.f. 147-149ºC. Conversión: 55%, ee >99%; [\alpha]_{D}^{20} -52.0 (c 1.02,
MeOH).To an erlenmeyer containing 0.53 mmol of (±) - trans -3- ( N -benzyloxycarbonylamino) indan-1-ol (4) and CALB (169 mg) is added, under a nitrogen atmosphere, 4.5 ml of t} BuOMe and 5.3 mmol of vinyl acetate. The resulting mixture is stirred at 30 ° C. When the desired conversion is achieved (depending on whether it is desired to obtain enantiopura substrate or product), the enzyme is filtered and washed with dichloromethane. The solvents in the filtrate are evaporated under reduced pressure and the remaining (1 S , 3 S ) - (-) - 3- ( N -benzyloxycarbonylamino) indan-1-ol (4) is purified by chromatography on silica gel. 98% yield. White solid, mp 147-149 ° C. Conversion: 55%, ee >99%; [α] D 20 -52.0 ( c 1.02,
MeOH).

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IR (cm^{-1}): 3511, 3339, 1671.IR (cm -1): 3511, 3339, 1671

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^{1}H-RMN (CD_{3}OD), \delta (ppm): (ver Figura 10) Porción AB de un sistema ABXY (\delta_{2a} 2.18, \delta_{2b} 2.37, 2H, H_{2a} y H_{2b}, J_{2a-2b} 13.7 Hz, J_{2a-1} 5.1 Hz, J_{2-3} 5.2 Hz, J_{2b-1} 2.2 Hz, J_{2b-3} 6.3 Hz), 5.12 (s, 2H, O-CH_{2}-Ph), 5.24 (dd, 1H, H_{1}, J_{1-2a} 5.1 Hz, J_{1-2b} 2.2 Hz), 5.36 (dd, 1H, H_{3}, J_{3-2a} 5.2 Hz, J_{3-2b} 6.3 Hz), 7.29-7.36 (m, 9H, 2Ph).1 H-NMR (CD 3 OD), δ (ppm): (see Figure 10) AB portion of an ABXY system (δ 2a18), δ 2b37, 2H, H_ {2a and H 2b, J 2a-2b 13.7 Hz, J 2a-1 5.1 Hz, J 2-3 5.2 Hz, J 2b-1 2.2 Hz, J 2b-3 6.3 Hz), 5.12 (s, 2H, OC H 2 -Ph), 5.24 (dd, 1H, H 1, J 1-2a 5.1 Hz, J 1-2b} 2.2 Hz), 5.36 (dd, 1H, H 3, J 3-2a 5.2 Hz, J 3-2b 6.3 Hz), 7.29-7.36 (m, 9H, 2Ph) .

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^{13}C-RMN (CDCl_{3}), \delta (ppm): 44.2 (CH_{2}), 54.4 (CH), 66.8 (CH_{2}), 73.8 (CH), 124.5 (CH), 124.7 (CH), 128.1 (CH), 128.5 (CH), 128.7 (CH), 129.2 (CH), 136.2 (C), 143.0 (C), 144.2 (C), 156.1 (NCOO).13 C-NMR (CDCl 3), δ (ppm): 44.2 (CH 2), 54.4 (CH), 66.8 (CH2), 73.8 (CH), 124.5 (CH), 124.7 (CH), 128.1 (CH), 128.5 (CH), 128.7 (CH), 129.2 (CH), 136.2 (C), 143.0 (C), 144.2 (C), 156.1 (NCOO).

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E.M.-ESI^{+}: 306 [M+Na]^{+}.E.M.-ESI +: 306 [M + Na] +.

El producto de, esta reacción enzimática es el éster (1R,3R)-(+)-1-acetoxi-3-(N-benciloxicarbonilamino)indano (5). Rendimiento 97%. Sólido blanco, p.f. 117-1191ºC. Conversión: 49%, ee >99%; [\alpha]_{D}^{20} + 127.3 (c 1.03, MeOH).The product of, this enzymatic reaction is the ester (1 R , 3 R ) - (+) - 1-acetoxy-3- ( N- benzyloxycarbonylamino) indane (5). 97% yield. White solid, mp 117-1191 ° C. Conversion: 49%, ee >99%; [α] D 20 + 127.3 ( c 1.03, MeOH).

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IR (cm^{-1}): 3311, 1735, 1684.IR (cm -1): 3311, 1735, 1684.

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^{H}-RMN (CD_{3}OD), \delta (ppm): 2.03 (s, 3H, CH_{3}), porción AB de un sistema ABXY (\delta_{2a} 2.23, \delta_{2b} 2.55, 2H, H_{2a} y H_{2b}, J_{2a-2b} 14.2 Hz, J_{2a-1} 6.3 Hz, J_{2a-3} 7.4 Hz, J_{2b-1} 1.7 Hz, J_{2b-3} 7.2 Hz), 5.15 (s, 2H, O-CH_{2}-Ph), 5.39 (dd, 1H, H_{3}, J_{3-2a} 7.4 Hz, J_{3-2b} 7.2 Hz), 6.21 (dd, 1H, H_{1}, J_{1-2a} 6.3 Hz, J_{1-2b} 1.7 Hz), 7.28-7.49 (m, 9H, 2Ph).H-RMN (CD 3 OD), δ (ppm): 2.03 (s, 3H, CH 3), AB portion of an ABXY system (δ 2) 2.23, δ 2b 2.55, 2H, H 2a and H 2b, J 2a-2b 14.2 Hz, J 2a-1 6.3 Hz, J 2a-3 7.4 Hz, J 2b- 1 1.7 Hz, J 2b-3 7.2 Hz), 5.15 (s, 2H, OC H 2 -Ph), 5.39 (dd, 1H, H 3, J 3-2a) 7.4 Hz, J 3-2b 7.2 Hz), 6.21 (dd, 1H, H 1, J 1-2a 6.3 Hz, J 1-2b 1.7 Hz), 7.28-7.49 ( m, 9H, 2Ph).

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^{13}C-RMN (CDCl_{3}), \delta (ppm): 21.1 (CH_{3}), 41.2 (CH_{2}), 54.4 (CH), 66.8 (CH_{2}), 75.6 (CH), 124.0 (CH), 126.1 (CH), 128.0 (CH), 128.1 (CH),128.4 (CH), 128.5 (CH), 129.7 (CH), 136.2 (C), 140.1 (C), 144.4 (C), 156.2 (NCOO), 170.9 (OCO).13 C-NMR (CDCl 3), δ (ppm): 21.1 (CH 3), 41.2 (CH 2), 54.4 (CH), 66.8 (CH2), 75.6 (CH), 124.0 (CH), 126.1 (CH), 128.0  (CH), 128.1 (CH), 128.4 (CH), 128.5 (CH), 129.7 (CH), 136.2 (C), 140.1 (C), 144.4 (C), 156.2 (NCOO), 170.9 (OCO).

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E.M.-ESI^{+}: 348 [M+Na]^{+}.E.M.-ESI +: 348 [M + Na] +.
Ejemplo 3Example 3 Resolución por acilación enzimática del aminoindanol racémico (\pm)-cis-4Resolution by enzymatic acylation of racemic aminoindanol (±) - cis -4

Se sigue un procedimiento análogo al comentado para el aminoindanol (\pm)-trans-4. De este modo se puede obtener el (1S,3R)-(+)-3-(N-benciloxicarbonilamino)indan-1-ol (4) con un rendimiento del 97%. Sólido blanco, p.f. 162-164ºC. Conversión: 50%, ee >99%; [\alpha]_{D}^{20} +58.5 (c 1.0, MeOH).A procedure analogous to that mentioned for aminoindanol (±) - trans -4 is followed. In this way the (1 S , 3 R ) - (+) - 3- ( N -benzyloxycarbonylamino) indan-1-ol (4) can be obtained with a yield of 97%. White solid, mp 162-164 ° C. Conversion: 50%, ee >99%; [α] D 20 +58.5 ( c 1.0, MeOH).

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IR (cm^{-1}): 3443, 3293, 1683.IR (cm -1): 3443, 3293, 1683

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^{1}H-RMN (CD_{3}OD), \delta (ppm): Porción AB de un sistema ABXY (\delta_{2a} 1.73, \delta_{2b} 2.93, 2H, H_{2a} y H_{2b}, J_{2a-2b} 13.4 Hz, J_{2a-1} 7.1 Hz, J_{2a-3} 6.2 Hz, J_{2b-1} 7.0 Hz, J_{2b-3} 6.6 Hz), 5.03 (dd, 1H, H_{1}, J_{1-2a} 7.1 Hz, J_{1-2b} 7.0 Hz), 5.11 (dd, 1H, H_{3}, J_{3-2a} 6.2 Hz, J_{3-2b} 6.6 Hz), 5.17 (s, 2H, O-CH_{2}-Ph), 7.27-7.43 (m, 9H, 2Ph).1 H-NMR (CD 3 OD), δ (ppm): AB portion of an ABXY system (δ 2a 1.73, δ 2b 2.93, 2H, H 2a and H_ {2b} J {2a-2b} 13.4 Hz, J _ {2a-1} 7.1 Hz, J _ {2a-3} 6.2 Hz, J _ {2b-1} 7.0 Hz, J _ {2b-3 6.6 Hz), 5.03 (dd, 1H, H 1, J 1-2a 7.1 Hz, J 1-2b 7.0 Hz), 5.11 (dd, 1H, H 3, J _ {3-2a 6.2 Hz, J 3-2b 6.6 Hz), 5.17 (s, 2H, OC H2 -Ph), 7.27-7.43 (m, 9H, 2Ph).

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^{13}C-RMN (CD_{3}OD), \delta (ppm): 44.9 (CH_{2}), 53.8 (CH), 67.6 (CH_{2}), 73.2 (CH), 124.7 (CH), 125.0 (CH), 128.8 (CH), 129.0 (CH),129.1 (CH), 129.3 (CH), 129.5 (CH), 138.4 (C), 143.8 (C), 145.9 (C), 158.8 (NCOO).13 C-NMR (CD 3 OD), δ (ppm): 44.9 (CH 2), 53.8 (CH), 67.6 (CH2), 73.2 (CH), 124.7 (CH), 125.0 (CH), 128.8 (CH), 129.0 (CH), 129.1 (CH), 129.3 (CH), 129.5 (CH), 138.4 (C), 143.8 (C), 145.9 (C), 158.8 (NCOO).

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E.M.-ESI^{+}: 306 [M+Na]^{+}.E.M.-ESI +: 306 [M + Na] +.

El producto de esta reacción enzimática es el éster (IR,3S)-(-)-1-acetoxi-3-(N-benciloxicarbonilamino)indano (5). Rendimiento 96%. Sólido blanco, p.f. 153-155ºC. Conversión: 50%, ee >99%; [\alpha]_{D}^{20} -9.3 (c 1.0, MeOH).The product of this enzymatic reaction is the ester (I R , 3 S ) - (-) - 1-acetoxy-3- ( N- benzyloxycarbonylamino) indane (5). 96% yield. White solid, mp 153-155 ° C. Conversion: 50%, ee >99%; [α] D 20 -9.3 ( c 1.0, MeOH).

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IR (cm^{-1}): 3296, 1734, 1685.IR (cm -1): 3296, 1734, 1685

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^{1}H-RMN (CD_{3}OD), \delta (ppm): Porción AB de un sistema ABXY (\delta_{2a} 1.88, \delta_{2b} 3.03, 2H, H_{2a} y H_{2b}, J_{2a-2b} 13.3 Hz, J_{2a-1} 7.2 Hz, J_{2a-3} 8.3 Hz, J_{2b-1} 7.8 Hz, J_{2b-3} 7.9 Hz), 2.11 (s, 3H, CH_{3}), 5.10 (dd, 1H, H_{3}, J_{3-2a} 8.3 Hz, J_{3-2b} 7.9 Hz), 5.16 (s, 2H, O-CH_{2}-Ph), 6.08 (dd, 1H, H_{1}, J_{1-2a} 7.2 Hz; J_{1-2b} 7.8 Hz), 7.31-7.43 (m, 9H, 2Ph).1 H-NMR (CD 3 OD), δ (ppm): AB portion of an ABXY system (δ 2a 1.88, δ 2b 3.03, 2H, H 2a and H_ {2b} J {2a-2b} 13.3 Hz, J _ {2a-1} 7.2 Hz, J _ {2a-3} 8.3 Hz, J _ {2b-1} 7.8 Hz, J _ {2b-3 7.9 Hz), 2.11 (s, 3H, CH 3), 5.10 (dd, 1H, H 3, J 3-2a 8.3 Hz, J 3-2b 7.9 Hz), 5.16 (s, 2H, OC H 2 -Ph), 6.08 (dd, 1H, H 1, J 1-2a 7.2 Hz; J 1-2b 7.8 Hz), 7.31-7.43 (m, 9H, 2Ph).

\bullet?
^{13}C-RMN (CDCl_{3}), \delta (ppm): 21.0 (CH_{3}), 40.6 (CH_{2}), 53.2 (CH), 66.7 (CH_{2}), 75.0 (CH), 124.4 (CH), 125.1 (CH), 128.0 (CH), 128.4 (CH), 128.6 (CH), 129.4 (CH), 136.2 (C), 140.3 (C), 143.0 (C), 155.8 (NCOO), 170.6 (OCO).13 C-NMR (CDCl 3), δ (ppm): 21.0 (CH 3), 40.6 (CH 2), 53.2 (CH), 66.7 (CH2), 75.0 (CH), 124.4 (CH), 125.1 (CH), 128.0 (CH), 128.4 (CH), 128.6 (CH), 129.4 (CH), 136.2 (C), 140.3 (C), 143.0 (C), 155.8 (NCOO), 170.6 (OCO).

\bullet?
E.M.-ESI^{+}: 348 [M+Na]^{+}.E.M.-ESI +: 348 [M + Na] +.
Ejemplo 4Example 4 Síntesis de (+)-cis-1-(N-benceno-1,2-dicarbonil)amino-3-(N-benciloxicarbonil)aminoindano, (1R,3S)-6Synthesis of (+) - cis -1- ( N -benzene-1,2-dicarbonyl) amino-3- ( N -benzyloxycarbonyl) aminoindane, (1 R , 3 S ) -6

A una disolución de 0.11 mmol de (1S,3S)-4 en THF seco (1.5 ml) se le añaden sucesivamente PPh_{3} (0.12 mmol), ftalimida (0.12 mmol) y DEAD (0.12 mmol) bajo atmósfera inerte. La reacción se agita a temperatura ambiente durante 24 horas. El disolvente se evapora a presión reducida y el producto resultante se purifica por cromatografía. Rendimiento 76%. Sólido blanco, p.f. 201-203ºC. ee > 99%; [\alpha]_{D}^{20} +106.7 (c 1.5, CHCl_{3}).To a solution of 0.11 mmol of (1 S , 3 S ) -4 in dry THF (1.5 ml) is added successively PPh3 (0.12 mmol), phthalimide (0.12 mmol) and DEAD (0.12 mmol) under an inert atmosphere . The reaction is stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure and the resulting product is purified by chromatography. Yield 76%. White solid, mp 201-203 ° C. ee >99%; [α] D 20 +106.7 (c 1.5, CHCl 3).

\bullet?
I.R (cm^{-1}): 3335, 1712, 1682.I.R (cm -1): 3335, 1712, 1682.

\bullet?
1H-RMN (CDCl_{3}), \delta (ppm): 2.26 (m, 1H, CHH), 3.21 (m, 1H, CHH), 5.20 (s, 2H, O-CH_{2}-Ph), 5.50 (m, 1H, H_{3}), 5.80 (m, 1H, H_{1}), 6.30 (d, 1H, NHCbz, J 9.7 Hz), 7.13-7.49 (m, 9H, 2Ph), 7.74-7.85 (m, 4H, 1 Ph).1 H-NMR (CDCl 3), δ (ppm): 2.26 (m, 1H, CH H ), 3.21 (m, 1H, CH H ), 5.20 (s, 2H, OC H 2 -Ph ), 5.50 (m, 1H, H 3), 5.80 (m, 1H, H 1), 6.30 (d, 1H, N H Cbz, J 9.7 Hz), 7.13-7.49 (m, 9H, 2Ph ), 7.74-7.85 (m, 4H, 1 Ph).

\bullet?
^{13}C-RMN (CDCl_{3}), \delta (ppm): 37.5 (CH_{2}), 51.5 (CH), 53.8 (CH), 66.4 (CH_{2}), 123.2 (CH), 123.4 (CH), 124.8 (CH), 127.8 (CH), 128.2 (CH), 128.5 (CH), 128.8 (CH), 131.5 (CH), 134.0 (CH), 136.5 (C), 139.6 (C), 143.4 (C), 156.1 (NCOO), 167.7 (CONCO).13 C-NMR (CDCl 3), δ (ppm): 37.5 (CH 2), 51.5 (CH), 53.8 (CH), 66.4 (CH2), 123.2 (CH), 123.4 (CH), 124.8 (CH), 127.8 (CH), 128.2 (CH), 128.5 (CH), 128.8 (CH), 131.5 (CH), 134.0 (CH), 136.5 (C), 139.6 (C), 143.4 (C), 156.1 (NCOO), 167.7 (CONCO).

\bullet?
E.M.-ESI^{+}: 413 [M+H]^{+}, 435 [M+Na]^{+}.E.M.-ESI +: 413 [M + H] +, 435 [M + Na] +.
Ejemplo 5Example 5 Síntesis de (+)-trans-1-(N-benceno-1,2-dicarbonil)amino-3-(N-benciloxicarbonil)aminoindano, (1R,3R)-6Synthesis of (+) - trans -1- ( N -benzene-1,2-dicarbonyl) amino-3- ( N -benzyloxycarbonyl) aminoindane, (1 R , 3 R ) -6

A una disolución de 0.14 mmol de (1S,3R)-4 en THF seco (1.9 ml) se le añaden sucesivamente PPh_{3} (0.15 mmol), ftalimida (0.15 mmol) y DEAD (0.15 mmol) bajo atmósfera inerte. La reacción se agita a temperatura ambiente durante 24 horas. El disolvente se evapora a presión reducida y el producto resultante se purifica por cromatografía. Rendimiento 68%. Sólido blanco, p.f. 202-204ºC. ee > 99%; [\alpha]_{D}^{20} +177.0 (c 0.90, CHCl_{3}):To a solution of 0.14 mmol of (1 S , 3 R ) -4 in dry THF (1.9 ml) are added successively PPh3 (0.15 mmol), phthalimide (0.15 mmol) and DEAD (0.15 mmol) under an inert atmosphere . The reaction is stirred at room temperature for 24 hours. The solvent is evaporated under reduced pressure and the resulting product is purified by chromatography. 68% yield. White solid, mp 202-204 ° C. ee >99%; [α] D 20 +177.0 ( c 0.90, CHCl 3):

\bullet?
I.R (cm^{-1}): 3335, 1708, 1675.I.R (cm -1): 3335, 1708, 1675

\bullet?
^{1}H-RMN (CDCl_{3}), \delta (ppm): 2.41 (m, 1H, CHH), 2.93 (m, 1H, CHH), 5.14 (d, 1H, NHCbz, J 8.0 Hz), 5.18 (s, 2H, O-CH_{2}-Ph), 5.80 (m, 1H, H_{3}), 6.00 (m, 1H, H_{1}), 7.17-7.46 (m, 9H, 2Ph), 7.72-7.84 (m, 4H, 1Ph).1 H-NMR (CDCl 3), δ (ppm): 2.41 (m, 1H, CH H ), 2.93 (m, 1H, C H H), 5.14 (d, 1H, N H Cbz , J 8.0 Hz), 5.18 (s, 2H, OC H 2 -Ph), 5.80 (m, 1H, H 3), 6.00 (m, 1H, H 1), 7.17-7.46 ( m, 9H, 2Ph), 7.72-7.84 (m, 4H, 1Ph).

\bullet?
^{13}C-RMN (CDCl_{3}), \delta (ppm): 38.4 (CH_{2}), 52.4 (CH), 55.7 (CH), 66.7 (CH_{2}), 123.2 (CH), 123.9 (CH), 124.6 (CH), 128.0 (CH), 128.4 (CH), 128.7 (CH), 128.9 (CH), 131.8 (CH), 133.9 (CH), 136.4 (C), 140.1 (C), 143.6 (C), 156.0 (NCOO), 167.6 (CONCO).13 C-NMR (CDCl 3), δ (ppm): 38.4 (CH 2), 52.4 (CH), 55.7 (CH), 66.7 (CH2), 123.2 (CH), 123.9 (CH), 124.6 (CH), 128.0 (CH), 128.4 (CH), 128.7 (CH), 128.9 (CH), 131.8 (CH), 133.9 (CH), 136.4 (C), 140.1 (C), 143.6 (C), 156.0 (NCOO), 167.6 (CONCO).

\bullet?
E.M.-ESI^{+}: 413 [M+H]^{+}, 435 [M+Na]^{+}.E.M.-ESI +: 413 [M + H] +, 435 [M + Na] +.
Ejemplo 6Example 6 Síntesis de (-)-trans-1-(N-benceno-1,2-dicarbonil)amino-3-(N-benciloxicarbonil)aminoindano, (1S,3S)-6Synthesis of (-) - trans -1- ( N -benzene-1,2-dicarbonyl) amino-3- ( N -benzyloxycarbonyl) aminoindane, (1 S , 3 S ) -6

A una disolución de 0.26 mmol de (1R,3S)-4 en 1 ml de MeOH se le añaden 0.27 ml de NaOH 1N. Tras 20 min de reacción a temperatura ambiente, se evapora el disolvente a presión reducida. El residuo resultante se lleva a pH ácido con HCl IN y se extrae con CH_{2}Cl_{2}. La fase orgánica se trata con Na_{2}SO_{4} anhidro, se filtra y se concentra a sequedad. Así, se obtiene el producto (1R,3S)-3 de forma cuantitativa y con la pureza suficiente como para ser utilizado directamente. Para la reacción de Mitsunobu se sigue un procedimiento análogo al descrito en el ejemplo 5. Rendimiento 64%. Sólido blanco, p.f. 201-203ºC. ee > 99%; [\alpha]_{D}^{20} -170.8 (c 0.85, CHCl_{3}).To a solution of 0.26 mmol of (1 R , 3 S ) -4 in 1 ml of MeOH is added 0.27 ml of 1N NaOH. After 20 min of reaction at room temperature, the solvent is evaporated under reduced pressure. The resulting residue is brought to an acidic pH with HCl IN and extracted with CH2Cl2. The organic phase is treated with anhydrous Na2SO4, filtered and concentrated to dryness. Thus, the product (1 R , 3 S ) -3 is obtained quantitatively and with sufficient purity to be used directly. For the Mitsunobu reaction, a procedure similar to that described in example 5 is followed. Yield 64%. White solid, mp 201-203 ° C. ee >99%; [α] D 20 -170.8 ( c 0.85, CHCl 3).

Ejemplo 7Example 7 (1S,3R)-(-)-cis-3-amino-1-(N-benciloxicarbonil)aminoindano, (1S,3R)-7(1 S , 3 R ) - (-) - cis -3-amino-1- ( N -benzyloxycarbonyl) aminoindane, (1 S , 3 R ) -7

La diamina (1R,3S)-6 (0.1 mmol) se disuelve en 2.2 ml de una disolución 2M de hidrazina en MeOH. La mezcla se agita a temperatura ambiente durante 2 horas y posteriormente se concentra a sequedad. El residuo obtenido se lava varias veces con cloroformo y se filtra. Tras evaporación a presión reducida del disolvente del filtrado obtenemos el producto (1S,3R)-7 con un rendimiento del 98%. Sólido blanco, p.f. 121-123ºC. ee > 99%; [\alpha]_{D}^{20} -45.9 (c 1.4, CHCl_{3}).The diamine (1 R , 3 S ) -6 (0.1 mmol) is dissolved in 2.2 ml of a 2M solution of hydrazine in MeOH. The mixture is stirred at room temperature for 2 hours and then concentrated to dryness. The obtained residue is washed several times with chloroform and filtered. After evaporation under reduced pressure of the solvent of the filtrate, we obtain the product (1 S , 3 R ) -7 with a yield of 98%. White solid, mp 121-123 ° C. ee >99%; [α] D 20 -45.9 ( c 1.4, CHCl 3).

\bullet?
I.R (cm^{-1}): 3301, 1684.I.R (cm -1): 3301, 1684.

\bullet?
^{1}H-RMN (CDCl_{3}), \delta (ppm): 1.49 (m, 1H, CHH), 2.06 (sa, 2H, NH_{2}), 2.97 (m, 1H, CHH), 4.28 (t, 1H, H1, J 7.4 Hz), 5.16 (m, 1H, H_{3}), 5.18 (s, 2H, O-CH_{2}-Ph), 5.41 (d, 1H, NHCbz, J 8.3 Hz), 7.29-7.41 (m, 9H, 2Ph).1 H-NMR (CDCl 3), δ (ppm): 1.49 (m, 1H, CH H ), 2.06 (sa, 2H, NH 2), 2.97 (m, 1H, C H H), 4.28 (t, 1H, H1, J 7.4 Hz), 5.16 (m, 1H, H3), 5.18 (s, 2H, OC H2 -Ph), 5.41 (d, 1H, N H Cbz, J 8.3 Hz), 7.29-7.41 (m, 9H, 2Ph). 

       \newpage\ newpage

\bullet?
^{13}C-RMN (CDCl_{3}), \delta (ppm): 45.9 (CH_{2}), 53.4 (CH), 54.0 (CH), 66.7 (CH_{2}), 123.3 (CH), 123.7 (CH), 127.8 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 136.4 (C), 142.5 (C), 146.1 (C), 16.1 (NCOO).13 C-NMR (CDCl 3), δ (ppm): 45.9 (CH 2), 53.4 (CH), 54.0 (CH), 66.7 (CH2), 123.3 (CH), 123.7 (CH), 127.8 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 136.4 (C), 142.5 (C), 146.1 (C), 16.1 (NCOO).

\bullet?
E.M.-ESI^{+}: 283 [M+H]^{+}, 305 [M+Na]^{+}.E.M.-ESI +: 283 [M + H] +, 305 [M + Na] +.
Ejemplo 8Example 8 (1R,3R)-(+)-trans-1-amino-3-(N-benciloxicarbonil)aminoindano, (1R,3R)-7(1 R , 3 R ) - (+) - trans -1-amino-3- ( N -benzyloxycarbonyl) aminoindane, (1 R , 3 R ) -7

Se sigue un procedimiento análogo al descrito en el ejemplo 7.A procedure similar to that described in Example 7

Rendimiento 74%. Aceite. ee > 99%; [\alpha]_{D}^{20} +14.1 (c 0.4, CHCl_{3}).Yield 74%. Oil. ee >99%; [α] D 20 +14.1 ( c 0.4, CHCl 3).

\bullet?
I.R (cm^{-1}): 3310, 1701.I.R (cm -1): 3310, 1701

\bullet?
^{1}H-RMN (CDCl_{3}), \delta (ppm): 1.85 (sa, 2H, NH_{2}), 2.18-2.38 (ma, 2H, CH_{2}), 4.53 (t, 1H, H_{1}, J 6.2 Hz), 4.94 (da, 1H, NHCbz), 5.16 (s, 2H, O-CH_{2}-Ph), 5.37 (ma, 1H, H_{3}), 7.28-7.38 (m, 9H, 2Ph).1 H-NMR (CDCl 3), δ (ppm): 1.85 (sa, 2H, NH 2), 2.18-2.38 (ma, 2H, CH 2), 4.53 (t, 1H, H 1, J 6.2 Hz), 4.94 (da, 1H, N H Cbz), 5.16 (s, 2H, OC H 2 -Ph), 5.37 (ma, 1H, H 3) , 7.28-7.38 (m, 9H, 2Ph).

\bullet?
^{13}C-RMN (CDCl_{3}), \delta (ppm): 45.0 (CH_{2}), 54.4 (CH), 54.8 (CH), 66.7 (CH_{2}), 123.9 (CH), 124.7 (CH), 128.1 (CH), 128.5 (CH), 128.7 (CH), 136.4 (C), 142.1 (C), 146.9 (C), 156.0 (NCOO).13 C-NMR (CDCl 3), δ (ppm): 45.0 (CH 2), 54.4 (CH), 54.8 (CH), 66.7 (CH2), 123.9 (CH), 124.7 (CH), 128.1 (CH), 128.5 (CH), 128.7 (CH), 136.4 (C), 142.1 (C), 146.9 (C), 156.0 (NCOO).

\bullet?
E.M.-ESI^{+}: 283 [M+H]^{+}, 305 [M+Na]^{+}.E.M.-ESI +: 283 [M + H] +, 305 [M + Na] +.
Ejemplo 9Example 9 (1R,3S)-(+)-cis-3-amino-1-ftalimidoindano, sal con ácido fórmico, (1R,3S)-8(1 R , 3 S ) - (+) - cis -3-amino-1-phthalimidoindane, salt with formic acid, (1 R , 3 S ) -8

La diamina (1R,3S)-6 (0.11mmol) se disuelve en 2.2 ml de una disolución metanólica al 10% en ácido fórmico (el metanol utilizado es desoxigenado previamente). Posteriormente, se añaden 14 mg de "Pd-black" y la mezcla se agita vigorosamente a temperatura ambiente durante 2 horas. La mezcla resultante se filtra sobre Celite® y se lava con MeOH. Tras evaporación a presión reducida del disolvente del filtrado obtenemos el producto (1R,3S)-8 de forma cuantitativa. Sólido blanco, p.f. 165-167ºC. ee > 99%; [\alpha]_{D}^{20} +145.4 (c 1.0, MeOH).Diamine (1 R , 3 S ) -6 (0.11mmol) is dissolved in 2.2 ml of a 10% methanolic solution in formic acid (the methanol used is previously deoxygenated). Subsequently, 14 mg of "Pd-black" is added and the mixture is vigorously stirred at room temperature for 2 hours. The resulting mixture is filtered over Celite® and washed with MeOH. After evaporation under reduced pressure of the solvent of the filtrate, we obtain the product (1 R , 3 S ) -8 quantitatively. White solid, mp 165-167 ° C. ee >99%; [α] D 20 +145.4 (c 1.0, MeOH).

\bullet?
I.R (cm^{-1}): 3446, 2966, 1716.I.R (cm -1): 3446, 2966, 1716

\bullet?
^{1}H-RMN (D_{2}O), \delta (ppm): 2.36 (m, 1H, CHH), 3.04 (m, 1H, CHH), 4.83 (m, 1H, H_{3}), 5.72 (m, 1H, H_{1}), 7.12-7.70 (m, 8H, 2Ph), 8.32 (sa, 1H, HCOO^{-}).1 H-NMR (D 2 O), δ (ppm): 2.36 (m, 1H, CH H ), 3.04 (m, 1H, C H H), 4.83 (m, 1H, H_ { 3}), 5.72 (m, 1H, H1), 7.12-7.70 (m, 8H, 2Ph), 8.32 (sa, 1H, HCOO -).

\bullet?
^{13}C-RMN (CD_{3}OD), \delta (ppm): 35.7 (CH_{2}), 52.8 (CH), 54.5 (CH), 124.5 (CH), 125.3 (CH), 125.9 (CH), 130.4 (CH), 131.4 (CH), 133.0 (CH), 135.8 (CH), 139.7 (C), 142.4 (C), 169.5 (CONCO).13 C-NMR (CD 3 OD), δ (ppm): 35.7 (CH 2), 52.8 (CH), 54.5 (CH), 124.5 (CH), 125.3 (CH), 125.9 (CH), 130.4 (CH), 131.4 (CH), 133.0 (CH), 135.8 (CH), 139.7 (C), 142.4 (C), 169.5 (CONCO).

\bullet?
E.M.-ESI^{+}: 262.1 [(M-HCOOH)-NH_{2}]^{+}, 279.1 [(M-HCOOH)+H]^{+}, 301.1 [(M-HCOOH)+Na]^{+}.E.M.-ESI +: 262.1 [(M-HCOOH) -NH 2] +, 279.1 [(M-HCOOH) + H] +, 301.1 [(M-HCOOH) + Na] +.
Ejemplo 10Example 10 (1R,3R)-(+)-trans-3-amino-1-ftalimidoindano, sal con ácido fórmico, (1R,3R)-8(1 R , 3 R ) - (+) - trans -3-amino-1-phthalimidoindane, salt with formic acid, (1 R , 3 R ) -8

Se sigue un procedimiento análogo al descrito en el ejemplo 8.A procedure similar to that described in Example 8

Rendimiento cuantitativo. Sólido blanco, p.f. 177-179ºC. ee > 99%; [\alpha]_{D}^{20} +167.7 (c 1.1, MeOH).Quantitative performance White solid, mp 177-179 ° C. ee >99%; [α] D 20 +167.7 ( c 1.1, MeOH).

\bullet?
I.R (cm^{-1}): 3446, 2968, 1716.I.R (cm -1): 3446, 2968, 1716

\bullet?
^{1}H-RMN (CD_{3}OD), \delta (ppm): 2.61 (ma, 1H, CHH), 2.99 (ma, 1H, CHH), 5.26 (ma, 1H, H_{3}), 6.11 (m, 1H, H_{1}), 7.26-7.87 (m, 8H, 2Ph), 8.56 (sa, 1H, HCOO^{-}).1 H-NMR (CD 3 OD), δ (ppm): 2.61 (ma, 1H, CH H ), 2.99 (ma, 1H, C H H), 5.26 (ma, 1H, H_ { 3}), 6.11 (m, 1H, H1), 7.26-7.87 (m, 8H, 2Ph), 8.56 (sa, 1H, HCOO -).

\bullet?
^{13}C-RMN (CD_{3}OD), \delta (ppm): 36.3 (CH_{2}), 53.6 (CH), 56.1 (CH), 124.2 (CH), 125.5 (CH), 125.8 (CH), 130.4 (CH), 131.3 (CH), 133.1 (CH), 135.6 (CH), 140.9 (C), 142.8 (C), 169.1 (CONCO).13 C-NMR (CD 3 OD), δ (ppm): 36.3 (CH 2), 53.6 (CH), 56.1 (CH), 124.2 (CH), 125.5 (CH), 125.8 (CH), 130.4 (CH), 131.3 (CH), 133.1 (CH), 135.6 (CH), 140.9 (C), 142.8 (C), 169.1 (CONCO).

\bullet?
E.M.-ESI^{+}: 262.1 [(M-HCOOH)-NH_{2}]^{+}, 279.1 [(M-HCOOH)+H]^{+}, 301.1 [(M-HCOOH)+Na]^{+}.E.M.-ESI +: 262.1 [(M-HCOOH) -NH 2] +, 279.1 [(M-HCOOH) + H] +, 301.1 [(M-HCOOH) + Na] +.

Claims (48)

1. Un (\pm)-trans-3-(N-benciloxicarbonilamino)indan-1-ol racémico de fórmula (\pm)-trans-4.1. A racemic (±) - trans -3- ( N -benzyloxycarbonylamino) indan-1-ol of formula (±) - trans -4. 1one 2. Un (\pm)-cis-3-(N-benciloxicarbonilamino)indan-1-ol racémico de fórmula (\pm)-cis-4.2. A racemic (±) - cis -3- ( N -benzyloxycarbonylamino) indan-1-ol of formula (±) - cis -4. 22 3. Un procedimiento para la síntesis de los aminoindanoles de fórmula (\pm)-trans-4 y (\pm)-cis-4 según las reivindicaciones 1 y 2, caracterizado por partir de la aminocetona de fórmula 2 y someterla a una hidrólisis, una reducción y una protección, sucesivamente.3. A process for the synthesis of the aminoindanols of formula (±) - trans -4 and (±) - cis -4 according to claims 1 and 2, characterized by starting from the amino ketone of formula 2 and subjecting it to hydrolysis , a reduction and a protection, successively. 4. Un procedimiento para la separación de los diastereoisómeros (\pm)-trans-4 y (\pm)-cis-4 según las reivindicaciones 1 y 2, caracterizado por el empleo de cromatografía líquida de alta resolución.4. A process for the separation of the diastereoisomers (±) - trans -4 and (±) - cis -4 according to claims 1 and 2, characterized by the use of high performance liquid chromatography. 5. Un (1S,3S)-(-)-3-(N-benciloxicarbonilamino)indan-1-ol de fórmula (1S,3S)-4.5. One (1 S , 3 S ) - (-) - 3- ( N -benzyloxycarbonylamino) indan-1-ol of formula (1 S , 3 S ) -4. 33 6. Un (1R,3R)-(+)-1-acetoxi-3-(N-benciloxicarbonilamino)indano de fórmula (1R,3R)-5.6. A (1 R , 3 R ) - (+) - 1-acetoxy-3- ( N -benzyloxycarbonylamino) indane of formula (1 R , 3 R ) -5. 44 7. Un (1S,3R)-(+)-3-(N-benciloxicarbonilamino)indan-1-ol de fórmula (1S,3R)-4.7. A (1 S , 3 R ) - (+) - 3- ( N -benzyloxycarbonylamino) indan-1-ol of formula (1 S , 3 R ) -4. 55 8. Un (1R,3S)-(-)-1-acetoxi-3-(N-benciloxicarbonilamino)indano de fórmula (1R,3S)-5.8. A (1 R , 3 S ) - (-) - 1-acetoxy-3- ( N -benzyloxycarbonylamino) indane of formula (1 R , 3 S ) -5. 66 
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9. Un procedimiento para la preparación de los compuestos de fórmula (1S,3S)-4 y (1R,3R)-5, según las reivindicaciones 5 y 6, caracterizado por9. A process for the preparation of the compounds of formula (1 S , 3 S ) -4 and (1 R , 3 R ) -5, according to claims 5 and 6, characterized by
\bullet?
acilar enantioselectivamente una mezcla de los isómeros (+) y (–) de un compuesto de fórmula (\pm)-trans-4 empleando un agente acilante y una enzima,enantioselectively acylating a mixture of the (+) and (-) isomers of a compound of formula (±) - trans -4 using an acylating agent and an enzyme,
\bullet?
detener la reacción a una conversión determinada, inferior al 100%, ystop the reaction to a determined conversion, less than 100%, and
\bullet?
separar el compuesto de fórmula (1R,3R)-5 así obtenido del compuesto (1S,3S)-4 remanente.separating the compound of formula (1 R , 3 R ) -5 thus obtained from the remaining compound (1 S , 3 S ) -4.
77 10. Un procedimiento para la preparación de los compuestos de fórmula (1S,3R)-4 y (1R,3S)-5, según las reivindicaciones 7 y 8, enantioméricamente enriquecidos, caracterizado por10. A process for the preparation of the compounds of formula (1 S , 3 R ) -4 and (1 R , 3 S ) -5, according to claims 7 and 8, enantiomerically enriched, characterized by
\bullet?
acilar enantioselectivamente una mezcla de los isómeros (+) y (–) de un compuesto de fórmula (\pm)-cis-4 empleando un agente acilante y una enzima,enantioselectively acylating a mixture of the (+) and (-) isomers of a compound of formula (±) - cis -4 using an acylating agent and an enzyme,
\bullet?
detener la reacción a una conversión determinada, inferior al 100%, ystop the reaction to a determined conversion, less than 100%, and
\bullet?
separar el compuesto de fórmula (1R,3S)-5 así obtenido del compuesto (1S,3R)-4 remanente.Separate the compound of formula (1 R , 3 S ) -5 thus obtained from the remaining compound (1 S , 3 R ) -4.
88 11. Procedimiento según reivindicación 9 caracterizado porque el agente acilante es acetato de vinilo o acetato de isopropenilo.11. Method according to claim 9 characterized in that the acylating agent is vinyl acetate or isopropenyl acetate. 12. Procedimiento, según reivindicación 10, caracterizado porque el agente acilante es acetato de vinilo.12. Method according to claim 10, characterized in that the acylating agent is vinyl acetate. 13. Procedimiento, según reivindicaciones 9 ó 10, caracterizado porque la reacción se lleva a cabo en un disolvente orgánico.13. Method according to claims 9 or 10, characterized in that the reaction is carried out in an organic solvent. 14. Procedimiento, según reivindicación 13, caracterizado porque dicho disolvente orgánico está incluido en el grupo de: dioxano, tetrahidrofurano, terc-butilmetiléter, di-iso-propiléter, dietiléter, tolueno, hexano, acetonitrilo, acetona, 2-propanol, 2-metilpropan-2-ol, cloroformo y diclorometano.14. Method according to claim 13, characterized in that said organic solvent is included in the group of: dioxane, tetrahydrofuran, tert -butylmethyl ether, di- iso- propyl ether, diethyl ether, toluene, hexane, acetonitrile, acetone, 2-propanol, 2- methylpropan-2-ol, chloroform and dichloromethane. 15. Procedimiento, según reivindicaciones 9 ó 10, caracterizado porque la reacción se lleva a cabo a temperaturas entre 5 y 60ºC.15. Method according to claims 9 or 10, characterized in that the reaction is carried out at temperatures between 5 and 60 ° C. 16. Procedimiento, según reivindicaciones 9 ó 10, caracterizado porque la reacción está catalizada por una enzima de la clase de las hidrolasas, que puede proceder de un microorganismo o de un organismo superior.16. A method according to claims 9 or 10, characterized in that the reaction is catalyzed by an enzyme of the hydrolase class, which can be derived from a microorganism or from a higher organism. 17. Procedimiento, según la reivindicación 16, caracterizado porque la enzima es una lipasa.17. Method according to claim 16, characterized in that the enzyme is a lipase. 18. Procedimiento, según la reivindicación 17, caracterizado porque la enzima es la fracción B de la lipasa de Candida antarctica.18. Method according to claim 17, characterized in that the enzyme is fraction B of the Candida antarctica lipase. 19. Procedimiento, según las reivindicaciones 9 ó 10, caracterizado porque la enzima está inmovilizada sobre un soporte.19. Method according to claims 9 or 10, characterized in that the enzyme is immobilized on a support. 20. Procedimiento, según la reivindicación 19, caracterizado porque la enzima está inmovilizada por adsorción interfacial sobre soportes muy hidrófobos y mecánicamente resistentes.20. Method according to claim 19, characterized in that the enzyme is immobilized by interfacial adsorption on very hydrophobic and mechanically resistant supports. 21. Procedimiento, según la reivindicación 19, caracterizado porque el soporte sobre el que se inmoviliza la lipasa es una resina epoxiacrílica activada con grupos deca-octilo.21. Method according to claim 19, characterized in that the support on which the lipase is immobilized is an epoxyacrylic resin activated with deca-octyl groups. 22. Procedimiento, según la reivindicación 9, caracterizado porque el exceso enantiomérico del compuesto
(1R,3R)-5 es mayor del 99%.22. Method according to claim 9, characterized in that the enantiomeric excess of the compound
(1 R , 3 R ) -5 is greater than 99%. 23. Procedimiento, según la reivindicación 9, caracterizado porque el exceso enantiomérico del compuesto
(1S,3S)-4 es mayor del 99%.23. Method according to claim 9, characterized in that the enantiomeric excess of the compound
(1 S , 3 S ) -4 is greater than 99%. 24. Procedimiento, según la reivindicación 9, caracterizado porque el compuesto (1S,3S)-4 recuperado de la reacción enzimática tiene configuración absoluta (1S,3S).24. Method according to claim 9, characterized in that the compound (1 S , 3 S ) -4 recovered from the enzymatic reaction has an absolute configuration (1 S , 3 S ). 25. Procedimiento, según la reivindicación 10, caracterizado porque el exceso enantiomérico de los compuestos (1S,3R)-4 y (1R,3S)-5 es mayor del 99%.25. Method according to claim 10, characterized in that the enantiomeric excess of the compounds (1 S , 3 R ) -4 and (1 R , 3 S ) -5 is greater than 99%. 26. Procedimiento, según la reivindicación 10, caracterizado porque el compuesto (1S,3R)-4 recuperado de la reacción enzimática tiene configuración absoluta (1S,3R).26. Method according to claim 10, characterized in that the compound (1 S , 3 R ) -4 recovered from the enzymatic reaction has an absolute configuration (1 S , 3 R ). 27. Procedimiento para la obtención de un aminoindánol (1R,3S)-4, enantioméricamente puro, caracterizado por la hidrólisis química del producto (1R,3S)-5, resultante de la acilación enzimática descrita en la reivindicación 10.27. Method for obtaining an enantiomerically pure aminoindolan (1 R , 3 S ) -4, characterized by the chemical hydrolysis of the product (1 R , 3 S ) -5, resulting from the enzymatic acylation described in claim 10. 99 28. Un (1R,3S)-(+)-cis-1-(N-benceno-1,2-dicarbonil) amino-3-(N-benciloxicarbonil)aminoindano enantioméricamente enriquecido de fórmula (1R,3S)-6.28. An enantiomerically enriched (( R- 3- S ) - (+) - cis -1- ( N- benzene-1,2-dicarbonyl) amino-3- ( N- benzyloxycarbonyl) aminoindane enriched formula (1 R , 3 S) ) -6. 1010 29. Un procedimiento para la preparación del compuesto de fórmula (1R,3S)-6, según la reivindicación 28, caracterizado por una reacción de Mitsunobu tomando como sustrato el compuesto (1S,3S)-4, resultante del proceso enzimático descrito en la reivindicación 9.29. A process for the preparation of the compound of formula (1 R , 3 S ) -6, according to claim 28, characterized by a Mitsunobu reaction taking as a substrate the compound (1 S , 3 S ) -4, resulting from the process Enzymatic described in claim 9. 30. Un procedimiento según las reivindicaciones 29 caracterizado porque el exceso enantiomérico de (1R,3S)-6 es mayor del 99%.30. A method according to claims 29 characterized in that the enantiomeric excess of (1 R , 3 S ) -6 is greater than 99%. 31. Un (1R,3R)-(+)-trans-1-(N-benceno-1,2-dicarbonil) amino-3-(N-benciloxicarbonil)aminoindano enantioméricamente enriquecido de fórmula (1R,3R)-6.31. An enantiomerically enriched (( R- 3- R ) - (+) - trans -1- ( N- benzene-1,2-dicarbonyl) amino-3- ( N- benzyloxycarbonyl) aminoindane enriched formula (1 R , 3 R) ) -6. 11eleven 32. Un procedimiento para la preparación del compuesto de fórmula (1R,3R)-6, según la reivindicación 31, caracterizado por una reacción de Mitsunobu tomando como sustrato el compuesto (1S,3R)-4, resultante del proceso enzimático descrito en la reivindicación 10.32. A process for the preparation of the compound of formula (1 R , 3 R ) -6, according to claim 31, characterized by a Mitsunobu reaction taking as a substrate the compound (1 S , 3 R ) -4, resulting from the process Enzymatic described in claim 10. 33. Un procedimiento, según la reivindicación 32, caracterizado porque el exceso enantiomérico de (1R,3R)-6 es mayor del 99%.33. A method according to claim 32, characterized in that the enantiomeric excess of (1 R , 3 R ) -6 is greater than 99%. 
         \newpage\ newpage
34. Un (1S,3S)-(-)-trans-1-(N-benceno-1,2-dicarbonil) amino-3-(N-benciloxicarbonil)aminoindano enantioméricamente enriquecido de fórmula (1S,3S)-6.34. One (1 S, 3 S) - (-) - trans -1- (N -benzene-1,2-dicarbonyl) amino-3- (N - benzyloxycarbonyl) aminoindan enantiomerically enriched of formula (1 S, 3 S ) -6. 1212 35. Un procedimiento para la preparación del compuesto de fórmula (1S,3S)-6, según la reivindicación 34, caracterizado por una reacción de Mitsunobu tomando como sustrato el compuesto (1R,3S)-4, resultante de la hidrólisis química descrita en la reivindicación 27.35. A process for the preparation of the compound of formula (1 S , 3 S ) -6, according to claim 34, characterized by a Mitsunobu reaction taking as a substrate the compound (1 R , 3 S ) -4, resulting from the Chemical hydrolysis described in claim 27. 36. Un procedimiento, según las reivindicación 35, caracterizado porque el exceso enantiomérico de (1S,3S)-6 es mayor del 99%.36. A method according to claim 35, characterized in that the enantiomeric excess of (1 S , 3 S ) -6 is greater than 99%. 37. Un (1R,3S)-(-)-cis-1-amino-3-(N-benciloxicarbonil) aminoindano enantioméricamente enriquecido de fórmula (1R,3S)-7.37. An enantiomerically enriched (-1 R , 3 S ) - (-) - cis -1-amino-3- ( N -benzyloxycarbonyl) aminoindane of formula (1 R , 3 S ) -7. 1313 38. Un procedimiento para la preparación del compuesto de fórmula (1S,3R)-7, según la reivindicación 37, caracterizado por el tratamiento con una disolución metanólica de hidrazina de la diamina (1R,3S)-6, resultante de la reacción de Mitsunobu descrita en la reivindicación 29.38. A process for the preparation of the compound of formula (1 S , 3 R ) -7, according to claim 37, characterized by treatment with a methanolic solution of diamine hydrazine (1 R , 3 S ) -6, resulting of the Mitsunobu reaction described in claim 29. 39. Un procedimiento, según la reivindicación 38, caracterizado porque el exceso enantiomérico de (1S,3R)-7 es mayor del 99%.39. A method according to claim 38, characterized in that the enantiomeric excess of (1 S , 3 R ) -7 is greater than 99%. 40. Un (1R,3R)-(+)-trans-1-amino-3-(N-benciloxicarbonil) aminoindano enantioméricamente enriquecido de fórmula (1R,3R)-7.40. An enantiomerically enriched (1 R , 3 R ) - (+) - trans -1-amino-3- ( N- benzyloxycarbonyl) aminoindane of formula (1 R , 3 R ) -7. 1414 41. Un procedimiento para la preparación del compuesto de fórmula (1R,3R)-7, según la reivindicación 40, caracterizado por el tratamiento con una disolución metanólica de hidrazina de la diamina (1R,3R)-6, resultante de la reacción de Mitsunobu descrita en la reivindicación 32.41. A process for the preparation of the compound of formula (1 R , 3 R ) -7, according to claim 40, characterized by the treatment with a methanolic solution of diamine hydrazine (1 R , 3 R ) -6, resulting of the Mitsunobu reaction described in claim 32. 42. Un procedimiento, según la reivindicación 41, caracterizado porque el exceso enantiomérico de (1R,3R)-7 es mayor del 99%.42. A method according to claim 41, characterized in that the enantiomeric excess of (1 R , 3 R ) -7 is greater than 99%. 43. Una sal con ácido fórmico de (1R,3S)-(+)-cis-3-amino-1- ftalimidoindano enantioméricamente enriquecido de fórmula (1R,3S)-8.43. A salt with formic acid of (1 R , 3 S ) - (+) - enantiomerically enriched cis -3-amino-1- phthalimidoindane of formula (1 R , 3 S ) -8. 15fifteen 44. Un procedimiento para la preparación del compuesto de fórmula (1R,3S)-8, según la reivindicación 43, caracterizado por su tratamiento con ácido fórmico en MeOH (utilizando Pd-black como catalizador) de la diamina (1R,3S)-6, resultante de la reacción de Mitsunobu descrita en la reivindicación 29.44. A process for the preparation of the compound of formula (1 R , 3 S ) -8, according to claim 43, characterized by its treatment with formic acid in MeOH (using Pd-black as catalyst) of the diamine (1 R , 3 S ) -6, resulting from the Mitsunobu reaction described in claim 29. 45. Un procedimiento, según la reivindicación 44, caracterizado porque el exceso enantiomérico de (1R,3S)-8 es mayor del 99%.45. A method according to claim 44, characterized in that the enantiomeric excess of (1 R , 3 S ) -8 is greater than 99%. 46. Una sal con ácido fórmico de (1R,3R)-(+)-trans-3-amino-1- ftalimidoindano enantioméricamente enriquecido de fórmula (1R,3R)-8.46. A salt with formic acid of (1 R , 3 R ) - (+) - enantiomerically enriched trans- 3-amino-1- phthalimidoindane of formula (1 R , 3 R ) -8. 1616 47. Un procedimiento para la preparación del compuesto de fórmula (1R,3R)-8, según la reivindicación 46, caracterizado por el tratamiento con ácido fórmico en MeOH (utilizando Pd-black como catalizador) de la diamina (1R,3R)-6, resultante de la reacción de Mitsunobu descrita en la reivindicación 32.47. A process for the preparation of the compound of formula (1 R , 3 R ) -8, according to claim 46, characterized by treatment with formic acid in MeOH (using Pd-black as catalyst) of the diamine (1 R , 3 R ) -6, resulting from the Mitsunobu reaction described in claim 32. 48. Un procedimiento, según la reivindicación 47, caracterizado porque el exceso enantiomérico de (1R,3R)-8 es mayor del 99%.48. A method according to claim 47, characterized in that the enantiomeric excess of (1 R , 3 R ) -8 is greater than 99%.
ES200302536A 2003-10-29 2003-10-29 CHEMIOENZYMA SYNTHESIS OF ENANTIOPURE DERIVATIVES OF 3-AMINOINDAN-1-OL AND INDANO-1,3-DIAMINE Expired - Fee Related ES2237312B1 (en)

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