Claims:WE CLAIM:

1. A process for the preparation of highly pure 3-n-Butylphthalide of formula I, comprising the steps of:

a) 2-formyl benzoic acid is reacted with n-butylmagnesium chloride in presence of THF / Aq. NH4Cl / conc. HCl and EtOAc to obtain crude 3-n-Butylphthalide.

b) The crude 3-n-Butylphthalide is purified with alkali hydroxides / aromatic hydrocarbon solvents under high vacuum distillation to obtain highly pure 3-n-Butylphthalide (I).

2. The process as claimed in claim 1, wherein the aromatic hydrocarbon solvents are selected from Benzene, Toluene and xylene.

3. The process as claimed in claim 1, wherein the alkali hydroxides are selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, Rubidium hydroxide and Caesium hydroxide.

4. The process as claimed in claim 1, the purity of 3-n-Butylphthalide is >99%.
, Description:PROCESS FOR THE PREPARATION OF PURE 3-N-BUTYLPHTHALIDE

FIELD OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of pure 3-n-Butylphthalide.

BACKGROUND OF THE INVENTION

3-Butylphthalide (3-Butyl-3H-isobenzofuran-1-one) chemical name 3-n-butyl-(3H) Isobenzofuran, which was isolated from celery seeds by Yang Junshan and others for the first time in 1978. Butylphthalide obtained by chemical synthesis is a colorless or light yellow oily substance with celery aroma. It is the first class of new drugs with independent intellectual property rights in the field of cerebrovascular therapy in China. Studies have shown that butylphthalide has strong pharmacological effects such as anti-cerebral ischemia, improving microcirculation and blood flow in the ischemic brain area, increasing the number of capillaries in the ischemic area, inhibiting thrombosis and nerve cell apoptosis. Butylphthalide, an oily liquid with strong flavour of celery, is represented by the following chemical formula:

(I)

Studies in animal models suggest that butylphthalide may be useful for the treatment of hypertension and may have neuroprotective effects. In 2002, NBP was approved in China for the treatment of cerebral ischemia. NBP undergoes extensive metabolism in humans. The major metabolites in human plasma were 3-OH-NBP, 10-OH-NBP, 10-CO-NBP, 11-COOH-NBP. The AUC of metabolites was much larger than that of NBP. Minor side effects were observed in preclinical and clinical studies. The minor bioactivation pathway of NBP was proved to be mediated via sulfation of 3-OH-NBP.

There are many synthetic routes for butylphthalide reported in patents and literatures, but basically all crude butylphthalide is synthesized, and then the product is purified by column chromatography, vacuum distillation or adjusting acid and alkali to open and close the ring many times. It is complicated and takes a long time. The resulting product needs to be decolorized many times to reach the quality standard, which is not conducive to industrial production.

CN107216298 discloses a process for the preparation of 3-n-Butylphthalide, butenylphthalide undergoes hydrogenation in presence of Raney. Ni / EtOH, and then undergo steps such as alkali addition to form a salt, dichloromethane extraction, acid adjustment filtration, and ring closure. To obtain 3-n-butylphthalide with higher yield and purity, the starting material used in this method, butenephthalide, is not easy to purchase on the market, and still needs to be synthesized by itself, and requires high temperature and catalytic hydrogenation reaction. The operation is more hazardous and is not easy for industrial production.

The above process is schematically shown as below:

CN105130934 obtains the potassium salt of hydroxypentylbenzoic acid through the ring-opening reaction of crude butylphthalide and alkali, which is then recrystallized and purified, and then cyclized to form butylphthalide, and then passed 1-2 times Vacuum distillation under vacuum conditions yields qualified products. The operation is cumbersome and complicated, and is not easy for industrial production.

The above process is schematically shown as below:

CN105884726 discloses a process for the preparation of 3-n-Butylphthalide, o- is reacted with n-butylmagnesium chloride in presence of THF / NH4Cl / conc. HCl and EtOAc to obtain 3-n-Butylphthalide, which is followed by purified with LiOH / MeOH / H2O / citric acid / conc. HCl and EtOAc to get Pure 3-n-Butylphthalide. but due to the method The crude product of butylphthalide is low in purity, so it is necessary to repeat the above adjustment of acid-base process and decolorization of activated carbon many times to obtain high-purity butylphthalide, resulting in a longer process cycle, lower yield and higher cost.

As per the process claimed / disclosed in CN 105884726 used base and acid treatment with Lithium hydroxide and citric acid repeatedly (2 to 4 times), then finally treating with ethyl acetate and hydrochloric acid for further cyclization to get the 3-n-Butylphathalide with lower concentration of Phthalide impurity.

CN105859670 discloses crude butylphthalide is collected by distillation under reduced pressure (130-140°C. 1-2mbar), and this fraction is added with alkali to ring-open to generate 1-hydroxypentyl-2-benzene Formate, distill off the solvent under reduced pressure, add dichloromethane to purify 1-hydroxypentyl-2-benzoate, and then combine 1-hydroxypentyl-2-benzoate in acid solution to obtain purity Higher butylphthalide. The method still uses the rectification method under high temperature and high vacuum, the process is not easy to control, and the ability to remove impurities is weak, and it is not easy to continuously obtain products of consistent quality.

CN 109081822 discloses a process for the preparation of 2-formyl benzoic acid is reacted with n-butylmagnesium chloride in presence of THF / Aq. NH4Cl / conc. HCl and EtOAc to get 3-n-Butylphthalide, which is followed by purified with NaHCO3 / H2O / NaCl / under reduced pressure to get pure 3-n-Butylphthalide.

As per the process claimed / disclosed process in CN 109081822 was used sodium bicarbonate solution to remove the impurities in Aqueous phase but the Phtahlide impurity which was not washed out by applying this process and also during high vacuum distillation it is remained at the level of 3.0% to 5% in the collected fractions.

In summary, the methods for preparing butylphthalide have different defects, which are not conducive to later industrial production. Therefore, it is still very important to develop a process suitable for industrial production. With o-carboxybenzaldehyde as the starting material, the price is cheap, the market supply is sufficient, and the quality is controllable. The industrial preparation of Grignard reagent is very mature and easy to operate. After the reaction between the two is completed, it is not in a hurry to adjust the acid to form a ring to synthesize the crude product.

By considering the above demerits, we have improved the purity of 3-n-butylphathalide by treatment of biphasic solution of Aq sodium hydroxide and toluene to the cyclised crude compound which containing more than 5.0% phthalide impurity, without further acidification with con HCl.

After the basic treatment in toluene to the crude 3-n-Butylphathlide. The Phthalide impurity observed at the level of ~0.01%, thereafter subjected for high vacuum distillation to afford high purity of n-Butylphathalide (>99%)

None of the above prior-art processes teaches nor suggests the use of NaOH / toluene under high vacuum distillation for the purification of 3-n-Butylphthalide (I) with high purity.

SUMMARY OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous purification process for the preparation of 3-n-Butylphthalide (I) with high purity.

In one aspect of the present invention, provides a process for the preparation of highly pure 3-n-Butylphthalide of formula I, comprising the steps of:

2-formyl benzoic acid is reacted with n-butylmagnesium chloride in presence of THF / Aq. NH4Cl / conc. HCl and EtOAc to obtain crude 3-n-Butylphthalide.

The crude 3-n-Butylphthalide is purified with alkali hydroxides / aromatic hydrocarbon solvents under high vacuum distillation to obtain highly pure 3-n-Butylphthalide (I).

Another aspect of the present invention provides an improved process for the purity of 3-n-butylphathalide by treatment of biphasic solution of Aq. sodium hydroxide and toluene to the cyclised crude compound which containing more than 5.0% phthalide impurity, without further acidification with con HCl. After the basic treatment in toluene to the crude 3-n-Butylphathlide. The Phthalide impurity observed at the level of ~0.01%, thereafter subjected for high vacuum distillation to afford high purity of n-Butylphathalide (>99%)

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved, commercially viable and industrially advantageous purification process for the preparation of 3-n-Butylphthalide (I) with high purity.

In one embodiment of the present invention, provides a process for the preparation of highly pure 3-n-Butylphthalide of formula I, comprising the steps of:

2-formyl benzoic acid is reacted with n-butylmagnesium chloride in presence of THF / Aq. NH4Cl / conc. HCl and EtOAc to obtain crude 3-n-Butylphthalide.

The crude 3-n-Butylphthalide is purified with alkali hydroxides / aromatic hydrocarbon solvents under high vacuum distillation to obtain highly pure 3-n-Butylphthalide (I).
According to the embodiment of the present invention provides an process for the preparation of highly pure 3-n-Butylphthalide of formula I, which comprises solution of Phthalaldehydic acid in THF was cooled at 20°C under nitrogen atmosphere then added n-Butyl magnesium chloride solution at 20-35°C, further reaction stirred at the same temperature for 2 h, cooled the mixture at 15-20°C, followed by addition of Ammonium chloride solution and Aq. Hydrochloric acid.

The obtained residue was dissolved in toluene and added Aq. sodium hydroxide solution stirred the mixture for 20-30 min under reduced pressure below 50°C to obtain the crude oil, which was subjected for high vacuum distillation at 115-145°C to obtain highly pure compound of 3-n-Butylphthalide.

In an embodiment of the present invention provides, wherein the aromatic hydrocarbon solvents are selected from Benzene, Toluene and xylene;
, wherein the alkali hydroxides are selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, Rubidium hydroxide and Caesium hydroxide.

Another embodiment of the of the present invention provides an improved process for the purity of 3-n-butylphathalide by treatment of biphasic solution of Aq sodium hydroxide and toluene to the cyclised crude compound which containing more than 5.0% phthalide impurity, without further acidification with con HCl. After the basic treatment in toluene to the crude 3-n-Butylphathlide. The Phthalide impurity observed at the level of ~0.01%, thereafter subjected for high vacuum distillation to afford high purity of n-Butylphathalide (>99%).

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example-1:
Process for the preparation of pure 3-n-Butylphthalide:

A solution of Phthalaldehydic acid (100.0 g, 1.0 m. eq) in THF (700 ml) was cooled at 20°C under nitrogen atmosphere then slowly added 1.0 M n-Butyl magnesium bromide solution in THF (2000 ml, 3.0 m. eq) at 20-35°C, further reaction (the addition is exothermic)stirred at the same temperature for 2 h, then monitored the reaction progress by Qualitative TLC, after completion of reaction, cooled the mixture at 15-20°C and quenched the mixture by slow addition of Saturated Ammonium chloride solution (1000 mL) then warm the mixture at 25-30°C followed by addition Aq. Hydrochloric acid (287 ml Con HCl in 300 ml purified water) and stirred the biphasic mixture vigorously for 45 min, separated organic layer and Aq. Layer was back extracted with ethyl acetate ( 300 ml). The organic layer was combined and distilled under reduced pressure at below 45°C, to afford a residue, which was dissolved in toluene (700 ml), added Aq. sodium hydroxide solution (26.8 g of NaOH in 1000 ml Water) and stirred the mixture for 20-30 min, to separate the layers. The obtain toluene layer was evaporated under reduced pressure below 50°C to get the crude oil, (~97% NBP and ~0.01% Phthalide impurity by HPLC purity) which was subjected for high vacuum distillation at 115-145°C, collected first impure fraction ~6.0 g and second pure fraction (85.0 g, 67%).

1H NMR (400 MHz, CDCl3): d 7.89-7.90 (d, 1H, 7.6Hz), 7.65-7.69 (t, 1H), 7.50-7.54 (t, 1H), 7.45--43 (d. 1H, 7.6Hz), 5.46-5.49 (m, 1H), 2.01-2.09 (m, 1H), 1.78-1.81 (m, 1H), 1.32-1.53 (m, 4H), 0.89-0.95 (t, 3H), Mass : 191.19 (M+1).

13CNMR (100 MHz, CDCl3): d. 170.60, 150.06, 133.87, 128.94, 126.09, 125.60, 121.67, 81.37, 34.37, 26.81, 22.35, 13.78.

IR: 1764±5 –cm (-C=O Stretching vibration)

Example-2:

Process for the preparation of pure 3-n-Butylphthalide:

A solution of Phthalaldehydic acid (100.0 g, 1.0 m. eq) in THF (700 ml) was cooled at 20°C under nitrogen atmosphere then slowly added 2.0 M n-Butyl magnesium chloride solution in THF (1000 ml, 3.0 m. eq) at 20-35°C, the addition is exothermic further reaction stirred at the same temperature for 2 h, then monitored the reaction progress by Qualitative TLC, after completion of reaction, cooled the mixture at 15-20°C and quenched the mixture by slow addition of Sat. Ammonium chloride solution (1000 mL) then warm the mixture at 25-30°C followed by addition Aq. Hydrochloric acid (287 ml Con HCl in 300 ml purified water) and stirred the biphasic mixture vigorously for 45 min, separated organic layer and Aq. Layer was back extracted with ethyl acetate ( 300 ml), combine organic layer was distilled under reduced pressure below 45°C, residue obtained was dissolved in ethyl acetate (400 ml) and added Aq. Hydrochloric acid (35.96 ml Con HCl in 150 ml of purified water) and mixture was stirred at 25-30°C for 45 min, then separated Ethyl acetate layer and Aq. Layer was back extracted with ethyl acetate (100 ml), combined ethyl acetate extract was distilled under reduced pressure below 45°C to afford the residue (~92% NBP and >5% Phthalide impurity by HPLC purity), which was dissolved in toluene (700 ml) and added Aq. sodium hydroxide solution (26.8 g of NaOH in 1000 ml Water), stirred the mixture for 20-30 min thereafter, separated toluene layer and Aq. Layer was back extracted with toluene (200 ml) and evaporated combined layer under reduced pressure below 50°C to get the crude oil (~97% NBP and ~0.01% Phthalide impurity by HPLC purity), which was subjected for high vacuum distillation at 115-145°C, collected first impure fraction ~5.0 g and second pure fraction (92.0 g, 72.5%).

1H NMR (400 MHz, CDCl3): d 7.89-7.90 (d, 1H, 7.6Hz), 7.65-7.69 (t, 1H), 7.50-7.54 (t, 1H), 7.45--43 (d. 1H, 7.6Hz), 5.46-5.49 (m, 1H), 2.01-2.09 (m, 1H), 1.78-1.81 (m, 1H), 1.32-1.53 (m, 4H), 0.89-0.95 (t, 3H), Mass : 191.19 (M+1).

13CNMR (100 MHz, CDCl3): d. 170.60, 150.06, 133.87, 128.94, 126.09, 125.60, 121.67, 81.37, 34.37, 26.81, 22.35, 13.78.

IR: 1764±5 –cm (-C=O Stretching vibration)