Claims:We Claim:
1. A process for the preparation of compound of formula-I(a), comprising the steps of:

Formula-I(a)
(i) reducing ethyl ester functionality of compound of formula-I(b) using suitable reducing agent in an organic solvent.

Formula-I(b)
to afford compound of compound of formula-I(a),
(ii) purifying compound of formula-I(a) from a suitable solvent or solvent mixture.
2. The process as claimed in claim-1, in step (i) wherein the reducing agent is lithium aluminum hydride.

3. The process as claimed in claim-1, in step (i) wherein, Lithum aluminum hydride used is selected from powder, granules, pellets or a solution in an ether solvent such as THF, 2-Methyl tetrahydrofuran, diethyl ether or 1,4-dioxane.

4. The process as claimed in claim 1, in step (i), wherein the organic solvent used in the reaction is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether or 1,4-dioxane.
5. The process as claimed in claim 1, in step (i), wherein, the temperature at which reduction of compound of formula-I(b) is ranging from -78 to 30°C preferably -25 to 5°C.

6. The process as claimed in claim 1, in step (i), wherein, the molar equivalent of lithium aluminum hydride used against compound of formula-I(b) is selected from 0.5 to 5.0 mole equivalents preferably 1.0 to 3.0 mole equivalents and most preferably 1.5 to 2.0 mole equivalents.

7. The process as claimed in claim 1, in step (i), wherein the reaction mixture is quenched using ethyl acetate, acetone, acetic acid, water, aq. THF, aq. methanol, aq. sodium sulfate, aq. ammonium chloride, aq. HCl.

8. The process as claimed in claim 1, in step (ii), wherein the HPLC purity of the purified product is >95%.

9. The process as claimed in claim-1, in step (ii) wherein, after isolation of crude compound of formula-I(a), the crude product is optionally purified from column chromatography, flash chromatography.

10. The process as claimed in claim-1, in step (ii) wherein, the solvents used for chromatographic purification is selected from ethyl acetate, hexane, heptane, methylene chloride or its mixture thereof.
, Description:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of one of the Trabectedin key intermediates of formula-I(a), which is used in process of Trabectedin of formula-I. The chemical name of Trabectedin intermediate of formula-I(a) is 1,5-Imino-3-benzazocine-11-carboxylic acid, 4-cyano-2-[[[(1,1-dimethylethyl)dimethylsilyl]oxy]methyl]-1,2,3,4,5,6-hexahydro-3-[(1R)-2-hydroxy-1-[6-(methoxymethoxy)-7-methyl-1,3-benzodioxol-4-yl]ethyl]-9-methoxy-8-methyl-10-(2-propen-1-yloxy)-2-propen-1-yl ester, (1R,2R,4R,5S)-. Trabectedin intermediate of formula-I(a) is a pale yellow to white glassy solid / thick syrupy liquid.

Formula-I(a)
Formula-I
BACKGROUND OF THE INVENTION
Trabectedin (Ecteinascidin 743 or ET-743) has a complex tris(tetrahydroisoquinolinephenol) structure of the following formula.

Formula-I
It was approved under the brand name YONDELIS® and indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma.
Trabectedin modified process is disclosed in EP1792904 (2005) further the same process is published in J. Am. Chem. Soc., 2006, 128, 87-89. According to this patent, Trabectedin intermediate of formula-I(a) is prepared from corresponding ester of formula-I(b) (as shown below) by reduction using lithium borohydride in tetrahydrofuran-methanol mixture.

Formula-I(b)
The process disclosed in EP1792904 suffers from the following disadvantages outlined below:
a) Reported process is scale dependant.
b) On reported scale reaction proceeds well. On higher scale reaction is very slow and will not proceed beyond 25% due to poor conversion.
c) Due to poor conversion, it requires repeated recovery of unreacted compound of formula-I(b) and recycle to get compound of formula-I(a).
d) Cost of reagent is very high when compared to other reducing agents.
e) Recovery and recycling of compound of formula-I(b) requires energy and time consuming.
f) Prolonged reaction times lead to formation of many undesired impurities which are very difficult to eliminate from the purification process.
g) Huge quantity of organic solvent mixture (Ethylacetate-heptane) and silica gel are required for flash chromatography purification.
h) On a commercial scale such type of process is tedious and uneconomical.
In spite of having literature method for the preparation of compound of formula-I(a), there is still a need to have simple, cost effective and commercially viable process for the preparation of compound of formula-I(a) on large scale operations since, the above disadvantages are the limiting factors for commercial production of compound of formula-I(a) as this is one of the rate determining step in the multistep synthesis of Trabectedin of formula (I).
Accordingly, the process should be circumventing the following disadvantages like:
a) Avoiding expensive lithium borohydride reagent in the reduction process.
b) Identifying suitable alternate reagent which can obviate the demerits associated with lithium borohydride reagent.
c) Avoiding recovery and recycling of compound of formula-I(b) thereby saving energy consumption and time.
d) Avoiding prolonged reaction times thereby controlling the formation of many undesired impurities which are very difficult to eliminate from the purification process.
e) Avoiding huge quantity of organic solvent mixture (Ethylacetate-heptane) and silica gel required for flash chromatography purification.

OBJECTIVE OF THE INVENTION
Keeping in view of the above disadvantages associated with the process disclosed in the literature for the preparation of compound of formula-I(a), the inventors of the present invention have developed a simple, economical and commercially viable process for commercial production of compound of formula- I(a) by circumventing the above mentioned disadvantages.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of compound of formula-I(a) as shown in scheme-1, which comprises simple, economical and commercially viable process which surpasses the above mentioned disadvantages.
Accordingly, another main objective of the present invention is to provide an improved process for the preparation of compound of formula-I(a), which comprises reduction of compound of formula-I(b) with suitable reducing agent other than lithium borohydride.
Accordingly, another main objective of the present invention is to provide an improved process for the preparation of compound of formula-I(a), where recovery and recycling of compound-I(b) is avoided thereby reducing the energy and time consumption.
Accordingly, another main objective of the present invention is to provide an improved process for the preparation of compound of formula-I(a), where reaction times of reduction process from compound of formula-I(b) to compound of formula-I(a) are significantly minimized thereby controlling many undesired impurities which are very difficult to eliminate during purification.
Accordingly, another main objective of the present invention is to provide an improved process for the preparation of compound of formula-I(a), wherein consumption of organic solvent mixture and silica gel minimized.

Scheme-1

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of compound of formula-I(a), comprising the steps of:

Formula-I(a)
(i) reducing ethyl ester of compound of formula-I(b) using suitable reducing agent in an organic solvent.

Formula-I(b)
to afford compound of formula-I(a),
(ii) purifying compound of formula-I(a) from a suitable solvent or solvent mixture.
DETAILED DESCRIPTION OF THE INVENTION:
The main embodiment of the present invention provides an improved process for the preparation of compound of formula-I(a), comprising the steps of:
(i) reducing ethyl ester functionality of compound of formula-I(b) using suitable reducing agent in an organic solvent,
(ii) purifying compound of formula-I(a) from a suitable solvent or solvent mixture to afford pure compound of formula-I(a).
In step (i) of the present invention, the compound of formula-I(a) is prepared by reducing compound of formula-I(b) with reducing agent like lithium aluminum hydride.
In step (i) of the present invention, Lithum aluminum hydride used is selected from powder, granules, pellets or a solution in an ether solvent such as THF, 2-Methyl tetrahydrofuran, diethyl ether or 1,4-dioxane.
In step (i) of the present invention, the compound of formula-I(a) is prepared by reducing compound of formula-I(b) with lithium aluminum hydride in an organic solvent selected from tetrahydrofuran, 2-methyl tetrahydrofuran, diethylether, 1,4-dioxane preferably tetrahydrofuran.
In step (i) of the present invention, the temperature at which reduction of compound of formula-I(b) is ranging from -78 to 30°C preferably -25 to 5°C.
In step (i) of the present invention, the time of reduction is ranging from 15 min to 2h preferably 15 min to 30 min.
In step (i) of the present invention, the volume of solvent used in the reduction process is ranging from 3 volumes to 30 volumes preferably 10 volumes with respect to compound of formula-I(b).
In step (i) of the present invention, the molar equivalent of lithium aluminum hydride used against compound of formula-I(b) is selected from 0.5 to 5.0 mole equivalents preferably 1.0 to 3.0 mole equivalents and most preferably 1.5 to 2.0 mole equivalents.
In step (i) of the present invention, after completion of reaction, the reaction mixture is quenched using ethyl acetate, acetone, acetic acid, water, aqueous tetrahydrofuran, aqueous methanol, aqueous sodium sulfate, aqueous ammonium chloride (or) aqueous hydrochloric acid.
In step (ii) of the present invention, after isolation of crude of compound of formula-I(a), the crude product is optionally purified from column chromatography, flash chromatography.
In step (ii) of the present invention, the solvents used for chromatographic purification is selected from ethyl acetate, hexane, heptane, methylene chloride or its mixture thereof.
In step (ii) of the present invention, after chromatographic purification, the pure fractions are collected and isolated the product by solvent distillation under vacuum.

Advantages:
(i) The process of the present invention does not require expensive lithium borohydride.
(ii) The process of the present invention successfully circumvents the demerits of the literature process.
(iii) No prolonged times are required for reduction of compound of formula-I(b) to compound of formula-I(a).
(iv) All the reagents used in the present process are commercially available.
(v) No recovery and recycling of compound of formula-I(b) is required thereby reducing the energy and time consumption.
(vi) The purity of the isolated product is >98% which is sufficient to convert it to Trabectedin.
(vii) The solvent or solvent mixture required for purification by chromatographic method is greatly reduced thereby reducing the environmental pollution.
(viii) The isolated yield after purification is above 80%.
(ix) The process of the present invention is commercially viable and industrially applicable.

The Present invention is further illustrated in detail with reference to following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the invention in any way.

EXAMPLES:
EXAMPLE-1: Preparation of compound of formula-I(a):
Compound-I(b) (5g; 1.0 m.eq.) was dissolved in tetrahydrofuran (50 mL) and cooled to -20 to -10°C. To this cooled solution, a solution of lithium aluminum hydride (18.6 mL; 1M solution; 3.0 m.eq.) was added at -20 to -10°C in about 10 min. The progress of the reaction mass was monitored by TLC. After completion of reaction, the reaction mass was quenched by adding aqueous ammonium chloride and the product was extracted with ethyl acetate. The organic layer was concentrated under vacuum to afford oily crude. The resulting crude was purified by column chromatography.
Yield: 3.6g (76% by theory); HPLC purity: 99.15%

EXAMPLE-2: Preparation of compound of formula-I(a):
Compound-I(b) (50.0g; 1.0 m.eq.) was dissolved in tetrahydrofuran (500 mL) and cooled to -25 to -20°C. To this cooled solution, a diluted solution of lithium aluminum hydride (77 mL; 2M solution; 2.5 m.eq.) in tetrahydrofuran (77 mL) was added at -25 to -5°C in about 20 min. The progress of the reaction mass was monitored by TLC. After completion of reaction, the reaction mass was quenched by adding ethyl acetate followed by aqueous acetic acid and filtered. The organic layer was washed with aqueous sodium chloride and concentrated under vacuum. The resulting crude was purified by column chromatography.
Yield: 35.4g (74.6% by theory); HPLC purity: 98.45%
EXAMPLE-3: Preparation of compound of formula-I(a):
Compound-I(b) (100.0g; 1.0 m.eq.) was dissolved in tetrahydrofuran (1L) and cooled to -25 to -20°C. To this cooled solution, a diluted solution of lithium aluminum hydride (154 mL; 2M solution; 2.5 m.eq.) in tetrahydrofuran (154 mL) was added at -25 to -5°C in about 20 min. The progress of the reaction mass was monitored by TLC. After completion of reaction, the reaction mass was quenched by adding ethyl acetate followed by aqueous acetic acid and filtered. The organic layer was washed with aqueous sodium chloride and concentrated under vacuum. The resulting crude was purified by column chromatography.
Yield: 67.5g (77.3% by theory); HPLC purity: 98.31%
EXAMPLE-4: Preparation of compound of formula-I(a):
Compound-I(b) (500.0g; 1.0 m.eq.) was dissolved in tetrahydrofuran (5L) and cooled to -25 to -20°C. To this cooled solution, a diluted solution of lithium aluminum hydride (770 mL; 2M solution; 2.5 m.eq.) in tetrahydrofuran (770 mL) was added at -25 to -5°C in about 20 min. The progress of the reaction mass was monitored by TLC. After completion of reaction, the reaction mass was quenched by adding ethyl acetate followed by aqueous acetic acid and filtered. The organic layer was washed with aqueous sodium chloride and concentrated under vacuum. The resulting crude was purified by column chromatography.
Yield: 368g (77.6% by theory); HPLC purity: 98.1%
EXAMPLE-5: Preparation of compound of formula-I(a):
Compound-I(b) (500.0g; 1.0 m.eq.) was dissolved in tetrahydrofuran (5L) and cooled to -25 to -20°C. To this cooled solution, a diluted solution of lithium aluminum hydride (616 mL; 2M solution; 2.0 m.eq.) in tetrahydrofuran (616 mL) was added at -25 to -5°C in about 20 min. The progress of the reaction mass was monitored by TLC. After completion of reaction, the reaction mass was quenched by adding ethyl acetate followed by aqueous acetic acid and filtered. The organic layer was washed with aqueous sodium chloride and concentrated under vacuum. The resulting crude was purified by column chromatography.
Yield: 345g (72.7% by theory); HPLC purity: 97.9%
EXAMPLE-6: Preparation of compound of formula-I(a):
Compound-I(b) (500.0g; 1.0 m.eq.) was dissolved in tetrahydrofuran (5L) and cooled to -25 to -20°C. To this cooled solution, a diluted solution of lithium aluminum hydride (555 mL; 2M solution; 1.8 m.eq.) in tetrahydrofuran (555 mL) was added at -25 to -5°C in about 20 min. The progress of the reaction mass was monitored by TLC. After completion of reaction, the reaction mass was quenched by adding ethyl acetate followed by aqueous acetic acid and filtered. The organic layer was washed with aqueous sodium chloride and concentrated under vacuum. The resulting crude was purified by column chromatography.
Yield: 419g (88% by theory); HPLC purity: 97%