DESC:TITLE OF THE INVENTION:
The present invention relates to a continues flow process for the preparation of intermediates useful in the synthesis of pharmaceutically active Halichondrin B analogues.

BACKGROUND OF THE INVENTION:
Halichondrin B is a large naturally occurring polyether macrolide originally isolated from the marine sponge Halichondria okadai with potent antiproliferative activities.

Halichondrin B

A total synthesis of Halichondrin B was published in 1992 (Aicher, T. D. et al. , J. Am. Chem. Soc. 114:3162-3164).

Eribulin, a synthetic macrocyclic ketone analogs of halichondrin B with potent antiproliferative activities is an anticancer drug marketed by Eisai Co, under the trade name Halaven and it is also known as E7389, B1939 and ER-086526.

It was first reported in U.S. Patent No. 6214865.

The methods disclosed in the art are performed in the batch process mode. The batch process is a single- or multi-stage process in which a certain quantity of inputs (starting materials, solvents, catalysts, energy, etc.) are fed into the chemical reaction unit (of the entire reaction) under conditions suitable for obtaining the desired reaction (temperature, pressure, required time, etc.). With the batch process, within the reactor and at any given period of time, various actions may be initiated in the wake of which a concentration of reactants and products varies so long as the reaction progresses. At the conclusion of the process the mixture is removed from the reactor and it then subjected to a suitable separation or purification steps (either physical or chemical) to reach the required degree of purity.

Accordingly, new methods for the synthesis of halichondrin B analogs and particularly, eribulin useful as anti-cancer agents, which will significantly contribute to the art, are desirable.

SUMMARY OF THE INVENTION:
The present invention relates to a new method for the preparation of intermediates useful in the synthesis of halichondrin B analogs more particularly eribulin or pharmaceutically acceptable salts thereof, said method comprises an integrated continuous flow process for reactions wherein a succession of connected (integrated) flow reactors are used to perform a series of reaction steps to yield the final product. The work-up is done in classical batch equipment. It is a mixed process with continuous reactions and batch workup.

This process permits large scale synthesis of useful reaction products in high yield.

The continuous flow process of the present invention has many advantage over the batch process as follows:-
1. Minimizes handling of intermediates, toxic and corrosive reagents and solvents.
2. Reduces solvent load, minimizes effluents and waste generation and hence more greener chemistry approach.
3. Dramatically reduced reaction times, less down streaming processing and increases process efficiency.
4. High through put, high yield and controlled particle size of active pharmaceutical ingredients.

In another aspect, the present invention provides halichondrin B analogs or pharmaceutically acceptable salts thereof, obtainable by the processes substantially as herein described with reference to the examples.

The halichondrin analogs and particularly, eribulin or pharmaceutically acceptable salts thereof, so prepared may be formulated with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition. Such excipients and compositions are well known to those skilled in the art.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.

OBJECTS OF THE INVENTION:
The object of the present invention is to provide a continuous flow process for preparation of intermediates useful in the synthesis of halichondrin B analogs or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a continuous flow process for preparing intermediate (3) by using intermediate (3 ester).

Yet anoher object of the present invention is to provide a continuous flow process for preparing intermediate (4B).

Yet another object of the present invention is to provide a continuous flow process for preparing intermediate (4) by using intermediate (4B).

Yet another object of the present invention is to provide a continuous flow process for preparing intermediate (5) by coupling of intermediate (3) with intermediate (4).

Yet another object of the present invention is to provide a continuous flow process for preparing intermediate (7) by using intermediate (6).

Yet another object of the present invention is to provide a continuous flow process for preparing intermediate (10) by using intermediate (9).

Yet another object of the present invention is to provide a continuous flow process for preparing Eribulin (1) or pharmaceutically acceptable salt thereof by using intermediate (10).

Yet another object of the present invention is to provide a continuous flow process for the synthesis of Eribulin (1) or pharmaceutically acceptable salt thereof which is simple, economical and suitable for industrial scale-up.
Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale-up.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: Flow synthesis of intermediate (3)

Figure 2: Flow synthesis of intermediate (4B)

Figure 3: Flow synthesis of intermediate (4)

Figure 4: Flow synthesis of intermediate (5)

Figure 5: Telescoped Flow synthesis of intermediate (5)

Figure 6: Flow synthesis of intermediate (7)

Figure 7: Flow synthesis of intermediate (10)

Figure 8: Telescoped Flow synthesis of Eribulin from intermediate (10)

DETAILED DESCRIPTION OF THE INVENTION:
The ability of continuous-flow systems to rapidly heat and cool reactions, micromix solutions, and improve reaction homogeneity affords opportunities to explore novel transformations while being environmentally conscious and creative. In addition, continuous-flow systems incorporate reaction scale-out at the inception of the science, allowing for effective on-demand compound generation in compact, reconfigurable
devices.

Flow chemistry, and the related microfluidic applications, exploit the inherent properties of micro and/ or meso-structured continuous flow reactors (µFRs) to enable the continuous production of chemicals within a strictly controlled environment. µFRs offer a wide range of advantages for processing chemicals: precise control over the local reaction conditions, fast mixing and heat transfer, inherent safety, and homogeneity of the production are amongst the most important. Extreme conditions of temperature and pressure are readily implemented in µFRs to boost chemical reactivity (also called process intensification). Additionally, µFRs enable a fast transfer between R&D and production using scale-out or numbering-up strategies.

Accordingly, inventors have developed continuous flow processes for the preparation of key intermediates which are useful in the synthesis of halichondrin B analogs and more particularly, eribulin or pharmaceutically acceptable salts thereof, which processes are economical, fast and which results in a high purity halichondrin B analogs.

The flow reactors are often modular being assembled from several integrated components such as heating and cooling zones, micro mixers, residence tubing coils, separators and diagnostic/ analysis units. This workflow not only allows facile automation and continuous operation of the processes but also enables to perform potentially hazardous and forbidden transformations in a safer and reliable mode.

One aspect of the invention consists of synthesis of Intermediate 5

The method comprises the following steps:

Step 1 : Synthesis of Intermediate 3 (aldehyde)

The reaction is achieved in one single flow in a continuous reactors as depicted in Figure 1.

In the Step 1, Intermediate 3 (ester) is reduced with DIBAL using toluene as solvent in a flow reactor to yield Intermediate 3 (aldehyde). In an embodiment 0.1M solution of Intermediate 3 (ester) in toluene at a flow rate of around 8ml/ min to 10 ml/min and 0.2M DIBAL in toluene at a flow rate of around 5ml/ min to 8 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 20 minutes, preferably about 5 seconds to 10 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between -50°C and -10°C, preferably between -40°C and -20°C and even more preferably between -40°C and -30°C. The intermediate 3 is isolated by normal work up.

The advantage of the process is :-
• Safe reaction with respect to the handling of moisture sensitive and pyrophoric reagent DIBAL at about -40°C to -30°C.
• Use of reduced molar quantity of DIBAL of 1.35 moles as compared to batch process of 1.5 moles.
• Reaction is done at elevated temperature of about -40°C and -30°C as against very low temperature of -70?C as reported in the batch process.
• By following prior art process the major by product (i.e. Int-3 alcohol impurity) is formed >5%, whereas flow process provides better control over by product.
• At an elevated reaction temperature of about -40°C to -30°C and 1.35 equiv of of DIBAL, flow reaction proceed with 89% of conversion.

Step 2 : Synthesis of Intermediate 4B

The reaction is achieved in one single flow in a continuous reactors as depicted in Figure 2.

In the Step 2, intermediate 4A is further introduced into micro channel reactor and cyclized using 0.2M KHMDS solution to yield Intermediate 4B. In an embodiment 0.05M solution of Intermediate 4A in toluene at a flow rate of around 4ml/ min to 8 ml/min and 0.2M KHMDS in toluene at a flow rate of around 4ml/ min to 8 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between -15°C and 5°C, preferably between -10°C and --0°C and even more preferably between -10°C and -5°C. The intermediate 4B is isolated by normal work up.

The advantage of the process is :-
• Safe reaction with respect to the handling of moisture sensitive and pyrophoric reagent KHMDS at about -10°C to -5°C as against low temperature of -20?C as reported in the batch process.
• No degradation of product due to excess of KHMDS solution
Step 3 : Synthesis of Intermediate 4

The reaction is achieved in one single flow in a continuous reactors as depicted in Figure 3.

In the Step 3, Intermediate 4B is deprotected with DIBAL using toluene as solvent in a flow reactor to yield Intermediate 4. In an embodiment 0.05M solution of Intermediate 4B in toluene at a flow rate of around 6ml/ min to 10 ml/min and 1 M DIBAL in toluene at a flow rate of around 0.2ml/ min to 5 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between --40°C and -10°C, preferably between -30°C and -15°C and even more preferably between -25°C and -20°C. The intermediate 4 is isolated by normal work up.

The advantage of the process is :-
• Safe reaction with respect to the handling of moisture sensitive and pyrophoric reagent DIBAL at about -25°C to -20°C.
• Use of reduced molar quantity of DIBAL of 3 equivalents as against 4 as reported in the batch process
• Reaction is done at elevated temperature of about -25°C and -20°C as against cryogenic temperature of -70?C as reported in the batch process.
• At an elevated reaction temperature of about -25°C to -20°C and 1:3 equiv of DIBAL, flow reaction proceed with 80% of conversion as against 55% . as reported in the batch process

Step 4 : Synthesis of Intermediate 5

The reaction is achieved in one single flow in a continuous reactors as depicted in Figure 4.

In the Step 4, Intermediate 4 is deprotonated using n-BuLi in one flow reactor and then introduced into next flow reactor and then reacted with Intermediate 3 to yield Intermediate 5. In an embodiment 0.1M solution of Intermediate 4 in THF at a flow rate of around 6ml/ min to 10 ml/min and 0.5 M solution of n-BuLi in Hexane at a flow rate of around 0.2ml/ min to 5 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between --15°C and 15°C, preferably between -10°C and 10°C.

The solution containing lithiated complex is then introduced into the next flow rector and coupled with intermediate 3. In an embodiment 0.1M solution of Intermediate 3 in Heptane at a flow rate of around 6ml/ min to 10 ml/min is streamed into the second flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between -15°C and 15°C, preferably between -10°C and 10°C. The intermediate 5 is isolated by normal work up.

The advantage of the process is :-
• Safe reaction with respect to the handling of moisture sensitive and pyrophoric reagent n-BuLi at about -10°C and 10°C.
• Use of reduced molar quantity of DIBAL of 2.25 equivalents as against 3 as reported in the batch process
• Reaction is done at elevated temperature of about -10°C and 10°C as against cryogenic temperature of -70?C as reported in the batch process.
• At an elevated reaction temperature of about -10°C and 10°C, flow reaction proceed with 100% of conversion as against 50% . as reported in the batch process

Alternatively Intermediate 5 may be produced by reaction telescoping Steps 1 to 4 in continuous flow as depicted in Figure 5, without isolation of intermediates produced during the flow.

In the context of the present invention, the term "without isolation" means that the product referred is not isolated as a solid, for example it is not isolated from the reaction mass and dried to form a solid. Thus, "without isolation" may mean that the product remains in solution and is then used directly in the next synthetic step.

In an embodiment, Intermediate 3 (ester) is reduced with DIBAL using toluene as solvent in a flow reactor to yield Intermediate 3 (aldehyde). In an embodiment 0.1M solution of Intermediate 3 (ester) in toluene at a flow rate of around 8ml/ min to 10 ml/min and 0.2M DIBAL in toluene at a flow rate of around 5ml/ min to 8 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 20 minutes, preferably about 5 seconds to 10 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between -50°C and -10°C, preferably between -40°C and -20°C and even more preferably between -40°C and -30°C.

In an embodiment, intermediate 4A is introduced into micro channel reactor and cyclized using 0.2M KHMDS solution to yield Intermediate 4B. In an embodiment 0.05M solution of Intermediate 4A in toluene at a flow rate of around 4ml/ min to 8 ml/min and 0.2M KHMDS in toluene at a flow rate of around 4ml/ min to 8 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between -15°C and 5°C, preferably between -10°C and --0°C and even more preferably between -10°C and -5°C.

The solution containing intermediate 4B is then streamed into next flow reactor and deprotected with DIBAL using toluene as solvent to yield Intermediate 4. In an embodiment 0.05M solution of Intermediate 4B in toluene at a flow rate of around 6ml/ min to 10 ml/min and 1 M DIBAL in toluene at a flow rate of around 0.2ml/ min to 5 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between --40°C and -10°C, preferably between -30°C and -15°C and even more preferably between -25°C and -20°C.

The solution containing Intermediate 4 is deprotonated using n-BuLi in one flow reactor and then introduced into next flow reactor and then reacted with a solution of Intermediate 3 to yield Intermediate 5. In an embodiment 0.1M solution of Intermediate 4 in THF at a flow rate of around 6ml/ min to 10 ml/min and 0.5 M solution of n-BuLi in Hexane at a flow rate of around 0.2ml/ min to 5 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between --10°C and 10°C, preferably between -5°C and 5°C.

The solution containing lithiated complex is then introduced into the next flow rector and coupled with a solution of intermediate 3. In an embodiment 0.1M solution of Intermediate 3 in Heptane at a flow rate of around 6ml/ min to 10 ml/min is streamed into the second flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between --10°C and 10°C, preferably between -5°C and 5°C. The intermediate 5 is isolated by normal work up.

The advantage of the reaction telescoping is :-
• Reaction telescoping consists in the implementation of multiple chemical steps within the same uninterrupted µFR network.
• On the industrial scale, reaction telescoping drastically improves the inherent
safety of the process as well as the purity profile of the processed material.
• It obviates time consuming purification operations and work towards goal of a fully continuous synthesis.

Second aspect of the invention consists of synthesis of Intermediate 7
Synthesis of Intermediate 7

The reaction is achieved in one single flow in a continuous reactors as depicted in Figure 6.

In this step , intermediate 6 is introduced into micro channel reactor and the arylsulfonyl moiety is reduced using a reducing agent, for example and without limitation, Sml2 to yield Intermediate 7. In an embodiment 0.05M solution of Intermediate 6 at a flow rate of around 2ml/ min to 8 ml/min and 0.1M Sml2 at a flow rate of around 4ml/ min to 8 ml/min are streamed into the flow reactor. The residence time of said mixture in the reactor is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature. The operation temperature in the reactor is typically anywhere between -50°C and -20°C, preferably between -40°C and -30°C. The intermediate 7 is isolated by normal work up.

The advantage of the process is:-
• Safe reaction with respect to the handling of moisture and oxygen sensitive pyrophoric reagent Sml2 at about -40°C to -30°C.
• Reaction is done at elevated temperature of about -40°C and -30°C as against cryogenic temperature of -70?C as reported in the batch process.
• At an elevated reaction temperature of about -40°C to -30°C, flow reaction proceed with 80% of conversion as against 60% . as reported in the batch process

Third aspect of the invention consists of synthesis of Intermediate 10

Synthesis of Intermediate 10

The reaction is achieved in one single flow in a continuous reactors as depicted in Figure 7.

In this step, intermediate 9 is desilylated using a fluoride source to give Intermediate 10. In an embodiment imidazole hydrochloride and a fluoride source preferably TBAF is introduced into micro channel reactor using THF as a solvent. A solution of Intermediate 9 in THF is introduced into micro channel reactor at a flow rate of around 2ml/ min to 8 ml/min . The residence time of said mixture in the reactor is typically anywhere between 10 hours and 40 hours, preferably about 15 hours to 20 hours depending on the temperature. The operation temperature in the reactor is typically anywhere between 20°C and 40°C, preferably between 25°C and 30°C. The intermediate 10 is isolated by normal work up.

The advantage of the process is:-
• Number of reaction hours reduced drastically from 7 days as reported in the batch process to about 20 hours
• At an elevated reaction temperature of about 25°C to 30°C, flow reaction proceed with isolated yield of 88% as against 70% as reported in the batch process

There are many configurations of such connected reactor system, that a person skilled in the art is aware of. Further, the use of direct in-line purification and analysis techniques can be implemented thus generating more streamlined and information enriched reaction sequence. Alternatively, all flow reactors could be connected with batch equipment to get the right purity before introducing the flow in the next following continuous reaction step.

Without departing from the scope of the invention , many parameters such as solvents and reagents, heat and mass transfer, mixing and residence times, direct in-line purification and analysis techniques can readily altered to obtain desired products with high yield and purity.

Intermediate 6, Intermediate 8 and Intermediate 9,

could be produce by using flow process of the present invention or can be formed by methods known in the art.

Intermediate 10 obtained by the process of the present invention is further converted into Eribulin or pharmaceutically acceptable salt thereof by processes known in the prior art.

A preferred pharmaceutically acceptable salts of eribulin, e.g., eribulin mesylate, can be formed by methods known in the art, e.g., in situ during the final isolation and purification of the compound or separately by reacting the free base group with a suitable organic acid.

EXAMPLES:
Example 1: Preparation of intermediate 3
In 2ml PFA tube reactor, 0.1M solution of Int-3 Ester in toluene at flow rate of 9.18 ml/min was allowed to reacts with 1.35 equivalent of 0.2M solution of Di-iso butyl aluminum hydride (DIBAL) in toluene at flow rate of 6.2 ml/min. The residence time in the reactor was 7.8 seconds at a temperature of -40°C. After achieving the steady state, reaction mass was quenched with Acetone & 1N HCl. Int-3 Aldehyde so formed was extracted in MTBE solvent, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 3.
Yield:- 2.5 g,
% Yield :- 89%

Example 2: Preparation of intermediate 4B
In a 2ml PFA tube reactor, 0.05M solution of Intermediate 4A in THF at flow rate of 4.44ml/min was allowed to reacts with 5 equivalent of 0.2M KHMDS in Toluene at flow rate of 5.55 ml/min. The residence time in the reactor was 12 seconds at -10°C. After achieving the steady state, reaction mixture was quenched with aqueous NH4Cl solution at 0°C. Int-4B so formed was extracted in MTBE solvent, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 4B.
Yield:- 7.5 g,
% Yield:- 83%
Example 3: Preparation of intermediate 4
In a 2ml PFA tube reactor, 0.05M solution on Intermediate 4B in toluene at flow rate of 7.62ml/min was allowed to reacts with 3 equivalent of 1M Di-iso butyl aluminum hydride (DIBAL) in toluene at flow rate of 0.38 ml/min respectively. The residence time in the reactor was 15 seconds at temperature of -20°C. After achieving the steady state, reaction mixture was quenched with aqueous sodium potassium tartrate solution at 0°C. The intermediate 4, so formed was extracted in MTBE solvent, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 4.
Yield:- 8.0 g,
% Yield:- 80%

Example 4: Preparation of intermediate 5
In a 2ml PFA tube reactor, 0.1M solution of Intermediate 4 in THF at flow rate of 8.74ml/min was allowed to react with 2.25 equivalent of 0.5M n-Butyl Lithium ( 0.5 M in hexane) at flow rate of 3.94 ml/min. The residence time in the reactor was 11.5 seconds at temperature of 0°C. Lithiated complex was further introduced into a 8 ml PFA tube reactor and allowed to react with 1.1 equivalent of 0.1M solution of Int-3 in Heptane. Intermediate 3 was fed at a rate of 9.63ml/min giving residence time of 54 sec at temperature 0°C. The reaction mixture, after steady state, was quenched with aqueous NH4Cl solution, extracted in MTBE, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 5.
Yield:- 12.5 g
% Yield:- 84%

Example 5: Preparation of intermediate 7
In a 2ml PFA tube reactor, 0.05M solution of Intermediate 6 (THF: MeOH) at a flow rate of 4.44ml/min was allowed to reacts with 2.5 equivalent of 0.1M Samarium iodide at a flow rate of 5.55ml/min. The residence time in the reactor was 12 seconds at temperature of -40°C. After achieving the steady state, the reaction mixture was quenched with aqueous solution of potassium bicarbonate & potassium sodium tartrate at 0°C. The reaction mixture was extracted in MTBE, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 7.
Yield:- 4.5 g
% Yield:- 90%

Example 6: Preparation of intermediate 10
2 g of Intermediate 9 was dissolved in THF (250 ml). In a separate flask Imidazole. HCl (890 mg, 5 Equiv) and 1 M TBAF in THF (24 ml, 16 Equiv) were dissolved. Intermediate 9 was added.
In a 2ml PFA tube reactor, at 30°C, the reaction solution was circulated at flow rate of 5 ml / for 20 h. The reaction mixture was extracted in THF-Toluene mixture, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 10.
Yield:- 1.0 g
% Yield:- 88%

Example 7: Preparation of intermediate 5 from intermediate 3
In 2ml PFA tube reactor, 0.1M solution of Int-3 Ester in toluene at flow rate of 9.18 ml/min was allowed to reacts with 1.35 equivalent of 0.2M solution of Di-iso butyl aluminum hydride (DIBAL) in toluene at flow rate of 6.2 ml/min. The residence time in the reactor was 7.8 seconds at a temperature of -40°C. After achieving the steady state, reaction mass was quenched with Acetone & 1N HCl. Int-3 Aldehyde so formed was extracted in heptane and introduced into the next flow reactor.

In a 2ml PFA tube reactor, 0.05M solution of Intermediate 4A in THF at flow rate of 4.44ml/min was allowed to reacts with 5 equivalent of 0.2M KHMDS in Toluene at flow rate of 5.55 ml/min. The residence time in the reactor was 12 seconds at -10°C. After achieving the steady state, reaction mixture was quenched with aqueous NH4Cl solution at 0°C . Int-4B so formed was extracted in toluene. The solution was introduced into the next flow reactor.

In a 2ml PFA tube reactor, 0.05M solution on Intermediate 4B in toluene at flow rate of 7.62ml/min was allowed to reacts with 3 equivalent of 1M Di-iso butyl aluminum hydride (DIBAL) in toluene at flow rate of 0.38 ml/min respectively. The residence time in the reactor was 15 seconds at temperature of -20°C. After achieving the steady state, reaction mixture was quenched with aqueous sodium potassium tartrate solution at 0°C. The Intermediate 4 so formed was dissolved in THF.

In a 2ml PFA tube reactor, 0.1M solution of Intermediate 4 in THF at flow rate of 8.74ml/min was allowed to react with 2.25 equivalent of 1.2 M n-Butyl Lithium (1.2 M in hexane) at flow rate of 1.63 ml/min. The residence time in the reactor was 11.5 seconds at temperature of 0°C. Lithiated complex was further introduced into a 8 ml PFA tube reactor and allowed to react with 1.1 equivalent of 0.1M solution of Int-3 in Heptane. Intermediate 3 was fed at a rate of 9.63ml/min giving residence time of 54 sec at temperature 0°C. The reaction mixture, after steady state, was quenched with aqueous NH4Cl solution, extracted in MTBE, evaporated under reduced pressure and purified by column chromatography to obtain intermediate 5.

Example 8: Preparation of Eribulin Mesylate from intermediate 10
In a 2ml PFA tube reactor, 0.1 M of Intermediate 10 was reacted with 5.5 equivalent of 0.5 M pyridinium p-toluenesulfonate. The residence time in the reactor was 15 minutes at temperature of 30°C. The solution was further treated with 15 equivalent of 0.1 M solution of 2,4,6 – collidine pyridine mixture. The residence time in the reactor was 15 seconds at temperature of 0°C. The solution was then streamed into next flow reactor and treated with 6 equivalent of 0.1 M p-toluenesulphonyl anhydride.. The residence time in the reactor was 30 seconds at temperature of 0°C. The reaction mixture was
quenched in water and further reacted with 0.1 M Ammonium hydroxide and IPA mixture, in a 2ml PFA tube reactor at 20-25°C. The reaction solution was circulated at flow rate of 5 ml /min for 6 h.

The residence time in the reactor was 6 h at temperature of 25°C which on further treatment with 1.0 equivalent of 0.1 M Methanesulfonic acid at a residence time of 30 sec at 30°C gives Eribulin Mesylate.
,CLAIMS:1. A process of preparing an Intermediate 3 (aldehyde), comprising:
Step 1: reducing Intermediate 3 (ester) with a solution of DIBAL in toluene to yield Intermediate 3 (aldehyde),

wherein said process is performed in one single flow in a continuous reactors as depicted in Figure 1.

2. The process as claimed in claim 1, wherein the residence time of said mixture in the reactor in Step 1, is typically anywhere between 5 seconds and 20 minutes, preferably about 5 seconds to 10 minutes depending on the temperature.

3. The process as claimed in claim 1 or 2, wherein the operation temperature in the reactor is typically anywhere between -50°C and -10°C, preferably between -40°C and -20°C and even more preferably between -40°C and -30°C.

4. The process as claimed in claim 1, wherein the Intermediate 3 (aldehyde) is further used in the synthesis of Intermediate 5.

5. A process of preparing an Intermediate 4B, comprising:
Step 2 : cyclizing intermediate 4A, using 0.2M KHMDS solution to yield Intermediate 4B,

wherein said process is performed in one single flow in a continuous reactors as depicted in Figure 2.

6. The process as claimed in claim 5, wherein the residence time of said mixture in the reactor in Step 2, is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature.

7. The process as claimed in claim 5 or 6, wherein the operation temperature in the reactor is typically anywhere between -15°C and 5°C, preferably between -10°C and --0°C and even more preferably between -10°C and -5°C.

8. The process as claimed in claim 5, wherein the Intermediate 4B is further used in the synthesis of Intermediate 4.

9. A process of preparing an Intermediate 4, comprising:
Step 3 : deprotecting Intermediate 4B, with DIBAL using toluene to yield Intermediate 4

wherein said process is performed in one single flow in a continuous reactors as
depicted in Figure 3.

10. The process as claimed in claim 9, wherein the residence time of said mixture in the reactor in Step 3, is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature.

11. The process as claimed in claim 9 or 10, wherein the operation temperature in the reactor is typically anywhere between 40°C and -10°C, preferably between -30°C and -15°C and even more preferably between -25°C and -20°C.

12. The process as claimed in claim 9, wherein the Intermediate 4 is further used in the synthesis of Intermediate 5.

13. A process of preparing an Intermediate 5, comprising:
Step 4 : a) deprotecting Intermediate 4 using n-BuLi and b) reacting the product of step a) with Intermediate 3 (aldehyde) of step 1 to yield Intermediate 5
wherein said process is performed in one single flow in a continuous reactors as
depicted in Figure 4.

14. The process as claimed in claim 13, wherein the residence time of said mixture in the reactor in Step 4(a), is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature.

15. The process as claimed in claim 13 or 14, wherein the operation temperature in the reactor is typically anywhere between -15°C and 15°C, preferably between -10°C and 10°C.

16. The process as claimed in claim 13, wherein the residence time of said mixture in the reactor in Step 4(b), is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature.

17. The process as claimed in claim 13 or 14, wherein the operation temperature in the reactor is typically anywhere between -15°C and 15°C, preferably between -10°C and 10°C.

18. A process of preparing an Intermediate 5, comprising:
Step 1: reducing Intermediate 3 (ester) with a solution of DIBAL in toluene to yield Intermediate 3 (aldehyde);
Step 2 : cyclizing intermediate 4A, using 0.2M KHMDS solution to yield Intermediate 4B;
Step 3 : deprotecting Intermediate 4B, with DIBAL using toluene as solvent in a flow reactor to yield Intermediate 4; and
Step 4 : a) deprotecting Intermediate 4 using n-BuLi and b) reacting the product of step a) with Intermediate 3 (aldehyde) of step 1 to yield Intermediate 5;
wherein the said process is performed in one single flow in a continuous reactors as depicted in Figure 5.

19. A process of preparing an Intermediate 7, comprising:
reducing intermediate 6, using a suitable reducing agent, for example and without limitation, Sml2 to yield Intermediate 7,
wherein said process is performed in one single flow in a continuous reactors as
depicted in Figure 6.

20. The process as claimed in claim 19, wherein the residence time of said mixture in the reactor, is typically anywhere between 5 seconds and 10 minutes, preferably about 10 seconds to 5 minutes depending on the temperature.

21. The process as claimed in claim 19 or 20, wherein the operation temperature in the reactor is typically anywhere between -50°C and -20°C, preferably between -40°C and -30°C.

22. A process of preparing an Intermediate 10, comprising:
desilylating intermediate 9 using a fluoride source to give Intermediate 10,
wherein said process is performed in one single flow in a continuous reactors as
depicted in Figure 7.

23. The process as claimed in claim 22, wherein the fluoride source preferably is TBAF.

24. The process as claimed in claim 22 and 23, wherein reaction is conduced in the presence of a solvent such as THF.

25. The process as claimed in any preceding claims 22 to 24, wherein the residence time of said mixture in the reactor , is typically anywhere between 10 hours and 40 hours, preferably about 15 hours to 20 hours depending on the temperature.

26. The process as claimed in any preceding claims 22 to 25, wherein the operation temperature in the reactor is typically anywhere between 20°C and 40°C, preferably between 25°C and 30°C.

27. The process as claimed in any preceding claims 22 to 26, wherein the reaction hours reduced from 7 days as reported in the batch process to about 20 hours.

28. The process as claimed in claim 22, wherein the Intermediate 10 is further used in the synthesis of Eribulin or pharmaceutically acceptable salt thereof.

29. A process of preparing eribulin, or a pharmaceutically acceptable salt thereof,
said process comprising the steps of:
(a) producing Intermediate 10 by the method of any one of claims 22-27; and
(b) reacting the Intermediate 10 under suitable conditions to produce eribulin,
or the pharmaceutically acceptable salt thereof

30. The process of claim 30, wherein in step (b), said process comprising steps of
i) reacting Intermediate 10, with pyridinium p-toluenesulfonate at a residence time 15 minutes at temperature of 30°C;
ii) treating the solution with 15 equivalent of 0.1 M solution of 2,4,6 – collidine pyridine mixture at a residence time of 15 seconds at temperature of 0°C;
iii) streaming the solution into next flow reactor and treating with 6 equivalent of 0.1 M p-toluenesulphonyl anhydride at a residence time of 30 seconds at temperature of 0°C;
iv) quenching the reaction mixture in water and further reacting with 0.1 M Ammonium hydroxide and IPA mixture in a 2ml PFA tube reactor at 25°C at a
residence time of 6 hr; and
v) treating the solution with 1.0 equivalent of 0.1 M Methanesulfonic acid at a residence time of 30 sec at 30°C to produce gives Eribulin Mesylate.

31. A process of preparing eribulin, or a pharmaceutically acceptable salt thereof,
said process comprising the steps of:
(a) producing Intermediate 5 by the method of any one of claims 13-17 or claim 18; and
(b) reacting the Intermediate 5 under suitable conditions to produce eribulin,
or the pharmaceutically acceptable salt thereof

32. The process of claim 31, wherein eribulin mesylate is formed in step (b).
33. A process of preparing eribulin, or a pharmaceutically acceptable salt thereof,
said process comprising the steps of:
(a) producing Intermediate 7 by the method of any one of claims 19-21 ; and
(b) reacting the Intermediate 7 under suitable conditions to produce eribulin,
or the pharmaceutically acceptable salt thereof

34. The process of claim 33, wherein eribulin mesylate is formed in step (b).