Claims:We Claim:

1. A compound of formula I.

compound of formula I.

2. A process for the preparation of a compound of formula IA comprising the steps of:
a) reacting the compound of formula – II with a base to get the compound of formula-IA,
b) optionally purifying the compound of formula -IA.

Wherein R1 is – SO2Ph or SO2PhMe and R2 is an alcohol - protecting group.

3. A process for the preparation of a compound of formula I comprising the steps of:
a) reacting the compound of formula – II with a base to get the compound of formula-I,
b) optionally purifying the compound of formula -I.

4. A process as claimed in claims 2 and 3, wherein base used in step a) is selected from Sodium methoxide, sodium ethoxide, potassium tertiary butoxide and sodium tertiary butoxide.

5. A process as claimed in claims 2 and 3, wherein purification of compound of formula-I in step b) is carried out using preparative HPLC, flash chromatography.
, Description:Field of the invention:
The present invention relates to a process for the preparation of intermediates of Eribulin. The present invention involves less expensive reagents, solvents and the process conditions can be easily adopted for commercial scale.

Background of the Invention:
Eribulin, is a synthetic macrocyclic analog of halichondrin B, and is represented by structural formula as shown in below.

Eribulin

Eribulin is marketed as Eribulin Mesylate under the brand name HALAVEN® and it is indicated for the treatment of patients with metastatic breast cancer. U.S. patent No 6214865 discloses Eribulin.

PCT application WO 2005/118565 discloses process for the synthesis of Eribulin. compound of formula A is used as one of the intermediate.

Formula A
During development of the process, we observed some disadvantageous with the above compound of formula-A. The final two steps of the process involve two cryogenic conditions at -20 °C and -78 °C. which are not commercially viable. Hence, there remains a need to provide an alternative process for the preparation of Eribulin Intermediates.

Summary of the Invention:
According to a first aspect of the present invention, there is provided a process for the preparation of Eribulin Intermediates.

One aspect of the present invention provides a compound of formula I.

Yet another aspect of the present invention is to provide a process for the preparation of a compound of formula IA comprising the steps of:
a) reacting the compound of formula – II with a base to get the compound of formula-IA,
b) optionally purifying the compound of formula -IA.

Wherein R1 is – SO2Ph or SO2PhMe and R2 is an alcohol - protecting group.

Yet another aspect of the present invention is to provide a process for the preparation of a compound of formula I comprising the steps of:
a) reacting the compound of formula – II with a base to get the compound of formula-I,
b) optionally purifying the compound of formula -I.

Detailed description of the Invention:
The present invention is related to a process for the preparation intermediates of Eribulin.

One embodiment of the present invention provides a compound of formula I.

Yet another embodiment of the present invention is to provide a process for the preparation of a compound of formula I comprising the steps of:
a) reacting the compound of formula – II with a base to get the compound of formula-IA,
b) optionally purifying the compound of formula -IA.

Wherein R1 is – SO2Ph or SO2PhMe and R2 is an alcohol - protecting group.

Yet another embodiment of the present invention is to provide a process for the preparation of a compound of formula I comprising the steps of:
a) reacting the compound of formula – II with a base to get the compound of formula-I,
b) optionally purifying the compound of formula -I.

The invention according to above embodiments is shown in below scheme (Scheme-1).

Scheme-1

According to the present embodiment, wherein base used in step a) is selected from, Sodium methoxide, sodium ethoxide, potassium tertiary butoxide and sodium tertiary butoxide, preferably Sodium methoxide.

According to the present embodiment, wherein purification of compound of formula-I in step b) is carried out using preparative HPLC, flash chromatography.
According to the present invention alcohol protecting group is selected from mesylate, tosylate, acetyl, benzoyl, benzyl, β-methoxyethoxymethyl ether, methoxymethyl ether, dimethoxytrityl, p-methoxybenzyl ether, methylthiomethyl ether, allyl ether, t-butyl ether, pivaloyl, trityl, silyl ether (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBMDS), t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyloxymethyl (TOM) or triisopropylsilyl (TIPS) ether), tetrahydropyranyl (THP), methyl ether and ethoxyethyl ether (EE), or any suitable alcohol protecting group known in the art.

Advantages of the present invention:
1. Less expensive chemicals were used in the process.
2. Most of the reactions are taken insitu to subsequent stages without purification.
3. This sequence does not involve any cryogenic condition at low temperatures of -25 °C and -78°C.
4. The overall yield up to preparative purification stage from compound of formula-VI is 58%.
5. The above invention has one purification step less than the prior art process.
6. The above invention has one step less than the prior art process.

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-V

To a stirred solution of Compound-VI (18.0 g) in THF (54.0 mL), charged 54.0 mL of 5% K2HPO4 aqueous solution (prepared by dissolving 2.7 g of K2HPO4 in 54.0 mL of DM water and adjusted its PH from 9.3 to 7.4 by the gradual addition of 1 N HCl (4.0 mL)). Subsequently, 17.8 g of sodium periodate was added to the reaction mass at once and stirred the reaction mass for 4-5 h at room temperature while maintaining the PH of the reaction mass at above 4.0 throughout the maintenance of the reaction. After completion of the reaction, reaction mass is filtered over Buchner funnel, washed the filtered cake with ethyl acetate (450.0 mL). Separated the organic and aqueous layers, washed the organic layer with 10% sodium thiosulphate solution (450.0 mL), 5% sodium bicarbonate solution (450.0 mL), 10% sodium chloride solution (450 mL). Organic layer is dried over sodium sulphate (90.0 g) and solvent is evaporated under reduced pressure to afford 15.7 g of compound-V as a light yellow coloured viscous liquid.
Purity by HPLC: 96.92%.

Example-2: Preparation of compound of formula-III

To a stirred and pre-cooled (-30±5 °C) solution of compound-IV (15.26 g) in THF (75.0 mL), charged 9.0 mL of triethylamine and stirred for 5-10 min at the same temperature. Subsequently, 3.7 mL of methanesulfonyl chloride was introduced into the reaction mass dropwise at the same temperature. The resulting mass was stirred for 20-30 min at -30±5 °C, after completion of the reaction, reaction mass was diluted with 210.0 mL of 20% sodium chloride solution and 210.0 mL of n-heptane, stirred for 10 minutes. Separated the organic and aqueous layers, extracted the aqueous layer with 105.0 mL of n-heptane. Combined organic layers are dried over sodium sulphate (70.0 g) and the solvent is evaporated under reduced pressure at 28 °C to afford 17.8 g of compound-III as a light brown coloured oil.
Purity by HPLC; 87.92%

Example-3: Preparation of compound of formula-II

Compound-A (20.26 g) was transferred into an appropriately sized flask and dissolved it in 280.0 mL of tetrahydrofuran. 8.4 g of chromium (II) chloride was introduced into the flask and reaction mass was warmed up to attain a temperature of 33.5±1.5 °C. 9.5 mL of triethylamine was added drop wise to the reaction mass and the resultant intense green coloured mass was stirred at the same temperature for 3.0 h. To the Compound-A-Chromium complex thus obtained, 0.35 g of Nickel (II) chloride is charged at 0±5 °C. Separately, mixture of Compound-V (14.0 g) + compound-III (17.8 g) was dissolved in 112.0 mL of tetrahydrofuran, and added drop wise to the reaction mass at the same temperature and maintained for 15-20min min. Reaction mass was gradually allowed to attain a temperature of 23-26 °C and stirred it for 8 h at the same temperature after the completion of reaction, reaction mass is cooled to 0±5 °C and quenched by the addition of 13.5 mL of ethylenediamine. After stirring the quenched solution of reaction mass for 1 h at 0±5 °C, it is diluted with 650.0 mL of DM water, 840.0 mL of n-heptane and stirred for 20 min at room temperature. Separated the aqueous and organic layers, extracted the aqueous layer with 420.0 mL of n-heptane. Combined organic layers are washed with 840.0 mL of 20% sodium chloride solution, dried over sodium sulphate (70.0 g), evaporated the solvent under reduced pressure. Resulting residue is diluted with 560.0 mL of n-heptane, cooled to 0±5 °C, stirred for 1 h, filtered over Buchner funnel for the removal of compound-A. Residue obtained (31.0 g) after distillation is carried to the next reaction without any further purification.
Mass: m/Z: 1062.39 (M+NH4+).

Example-4: Preparation of compound of formula-I

To a stirred solution of compound-II (31.0 g) in THF (310.0 mL), charged 20.0 mL of 25% sodium methoxide at 25±5 °C. Reaction mass was stirred for 1-2 h at the same temperature. After completion of the reaction, reaction mass was cooled to 15±5 °C. Subsequently, reaction mass was diluted with 310.0 mL of DM water and 620.0 mL of n-heptane, stirred for 10 minutes. Separated the organic and aqueous layers, extracted the aqueous layer with 310.0 mL of n-heptane. Combined organic layers are washed with 640.0 mL of 5% ammonium chloride solution and 640.0 mL of 5% sodium chloride solution respectively. Dried the organic layer over sodium sulphate (155.0 g), evaporated the solvent under reduced pressure. The residue thus obtained (22.56 g) was purified by flash chromatography using 22-27% ethyl acetate and hexane as the eluent to afford 11.4 g of compound-I which was found to be an inseparable mixture of compound-I, compound-I-C-27 and Compound-I-C-34 isomers; hence it was subjected to preparative HPLC purification to get rid of aforementioned undesired isomers.
Crude Purity by HPLC: 66.21%
Purity by HPLC: 91.71%
1HNMR (400 MHz, CDCl3): dJ=zmd J=z-IsomermbsIsomersmIsomerdJ=zdJ=zmsomerm4.016-3.952 (m, 1H), 3.848-3.772 (m, 3H), 3.692-3.538 (m, 5H), 3.504-3.465 (dd, 1H, J=10.0, 5.2 Hz), 3.434 (s, 3H), 3.405-3.354 (m, 1H), 3.020-3.00 (m, 2H), 2.655-2.596 (ddd, 1H, J=15.6, 6.4, 1.6 Hz), 2.534-2.500 (m, 1H), 2.464 (s, 3H), 2.274-2.163 (m, 3H), 2.047-1.984 (m, 1H), 1.903-1.799 (m, 2H), 1.767-1.730 (m, 1H), 1.688-1.502 (m, 8H), 1.47-1.388 (m, 2H), 1.306-1.219 (m, 4H), 1.078-1.047 (m, 4H), 0.904-0.860 (m, 22H), 0.101 (s, 3H), 0.095 (s, 3H), 0.051 (s, 3H), 0.045 (s, 3H).

13C NMR(400 MHz, CDCl3): 151.12, 150.57, 144.98, 136.76, 130.08, 128.00, 130.08, 128.00, 104.87, 85.76, 80.72, 79.57, 78.28, 77.24, 76.82, 75.32, 71.38, 67.84, 62.80, 58.17, 57.51, 43.44, 42.66, 38.97, 37.51, 35.50, 33.09, 32.27, 31.67, 31.56, 31.25, 29.65, 25.98, 25.94, 22.63, 21.60, 18.37, 18.17, 17.89, -4.08, -4.73, -5.34.
Mass: m/Z: 865.33 (M+H), 887.31 (M+Na).

Example- 5: Purification of compound of formula -I
11.0 g of compound-I admixed with diastereomers (compound-I-C-34, compound-I-C-27) was purified by preparative HPLC to get 6.98 g of Pure compound-I which is free of diastereomers Pure fractions were eluted in MTBE:Hexane (4:6).
Final weight of pure compound I: 6.98 g (from 15.0 g of compound- V)
Yield: 50% from compound-V
Purity by HPLC: 98.71%.
C-34 Isomer by chiral HPLC: 0.29%
C-27 Isomer: 0.02%

Example- 6: Alternate Purification of compound of formula -I
105.3 g of compound-I crude was purified by flash chromatography using 35% MTBE-Hexane as eluent. Impure fractions from flash purification were reloaded on preparative HPLC to get a combined yield of 21.6 g of pure compound-I using 40% MTBE-Hexane as eluent.
Final weight of pure compound I: 21.6 g
Purity by HPLC: 97.53%.
C-34 Isomer by chiral HPLC: 0.51%.
C-27 Isomer: Not Detected.