CN103420952A - Method for synthesizing 3-fluoro-3-phenyloxetane - Google Patents

Abstract

The invention relates to a method for synthesizing 3-fluoro-3-phenyloxetane. According to the method, 3-oxetanon is used as a starting raw material, a key intermediate is obtained after formatting reaction, wherein the yield is greater than 80%, and then the 3-fluoro-3-phenyloxetane is obtained through fluoridation, wherein the total yield is greater than 50%. According to the method, various negative factors in amplified production of the 3-fluoro-3-phenyloxetane can be overcome. The method has the advantages of being low in raw material price, short in route, free of use of dangerous reagents, high in yield and the like, and the product can be generated on a large scale, and is low in price and convenient to popularize.

Description

The method of the fluoro-3-phenyl of a kind of synthetic 3-trimethylene oxide

Technical field

The present invention relates to biomedicine field, especially relate to a kind of synthetic method of pharmaceutical intermediate.

Background technology

The fluoro-3-phenyl of 3-trimethylene oxide is important biological medicine intermediate, can be widely used in the middle of various medicines synthetic.Its molecular weight is little, and the structure uniqueness can derive multiple derived product, just has been widely used.At present, the synthetic method that there is no this compound of bibliographical information.

Summary of the invention

Technical problem solved by the invention is to provide a kind of method of the fluoro-3-phenyl of synthetic 3-trimethylene oxide newly; it can overcome the fluoro-3-phenyl of 3-trimethylene oxide in all unfavorable factors of amplifying on producing; and have that raw material is cheap, route is short, the use without hazardous agents, yield high; make this product can carry out the mass-producing generation; and cheap, be convenient to promote.

This patent solves the technical scheme that its technical problem adopts: take the 3-oxetanone as starting raw material, after the format reaction, obtain key intermediate, yield is greater than 80%, then goes up fluorine and obtains the fluoro-3-phenyl of 3-trimethylene oxide, and total recovery is greater than 50%.Route is as follows:

Concrete steps can be:

(1) format reaction:

Under-78 ℃, n-Butyl Lithium is added drop-wise in the acetonitrile solution of Benzyl Chloride, dropwise, temperature control stirring 30 minutes, under-78 ℃, drip into the acetonitrile solution of 3-oxetanone, and after dropwising, TLC follows the tracks of reaction until finish; The aqueous solution that drips ammonium chloride under-78 ℃ carrys out the cancellation reaction, and after cancellation, that reaction solution is concentrated dry, the ethyl acetate extraction, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 2;

(2) fluoridation:

Compound 2 is dissolved in methylene dichloride, slowly drips the diethylin sulfur trifluoride under-70 ℃, temperature control is at-70 ℃, and after reacting 2 hours, the TLC detection reaction is complete; Under 0 ℃, reaction solution is slowly poured in the aqueous solution of sodium bicarbonate, after being adjusted to alkalescence, is extracted with ethyl acetate, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 3.

The beneficial effect of this patent is, started the synthetic method of the fluoro-3-phenyl of 3-trimethylene oxide, and in reaction, avoided hazardous chemical use, reduced reaction cost, improved reaction yield, simple to operate, easily purifying, can amplify production.This patent adopts conventional operation process, the comparatively cheap raw material of the 3-oxetanone of usining is as initial reactant, through simple format, fluoridation, obtain the finished product, and in reaction, avoided hazardous chemical use, reduced reaction cost, improved reaction yield, simple to operate, easy purifying, can amplify production, make the amplification of this compound easily realize.

Method of the present invention be take the 3-oxetanone as starting raw material, and starting material cheaply are easy to get, and has reduced the cost of suitability for industrialized production, has solved the shortcoming of amplifying the production cost costliness.Through format and fluoridation, synthetic route is short, high without use, the yield of hazardous agents, makes this product can carry out the mass-producing generation, and cheap, is convenient to promote.

Embodiment

For further illustrating the present invention, illustrate with the following Examples:

Embodiment 1: laboratory is synthetic

1. format reaction

Under-78 ℃, n-Butyl Lithium (33mL) is added drop-wise in the acetonitrile solution (75mL) of Benzyl Chloride (20g), dropwise, temperature control stirring 30 minutes, under-78 ℃, the acetonitrile solution of 3-oxetanone (5g) (75mL) is dripped, and after dropwising, TLC follows the tracks of reaction until finish.The aqueous solution that drips ammonium chloride under-78 ℃ carrys out the cancellation reaction, and after cancellation, that reaction solution is concentrated dry, the ethyl acetate extraction, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 2(10g), yield is 80%.

2. fluoridation

By compound 2(5g) be dissolved in methylene dichloride (75mL), slowly drip diethylin sulfur trifluoride (6.45g) under-70 ℃, temperature control is at-70 ℃, and after reacting 2 hours, the TLC detection reaction is complete.Under 0 ℃, reaction solution is slowly poured in the aqueous solution of sodium bicarbonate, after being adjusted to alkalescence, is extracted with ethyl acetate, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 3(3.3g), yield is 65%.

Embodiment 2: lab scale

1. format reaction

Under-78 ℃, n-Butyl Lithium (330mL) is added drop-wise in the acetonitrile solution (750mL) of Benzyl Chloride (200g), dropwise, temperature control stirring 30 minutes, under-78 ℃, the acetonitrile solution of 3-oxetanone (50g) (750mL) is dripped, and after dropwising, TLC follows the tracks of reaction until finish.The aqueous solution that drips ammonium chloride under-78 ℃ carrys out the cancellation reaction, and after cancellation, that reaction solution is concentrated dry, the ethyl acetate extraction, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 2(100g), yield is 80%.

2. fluoridation

By compound 2(50g) be dissolved in methylene dichloride (750mL), slowly drip diethylin sulfur trifluoride (64.5g) under-70 ℃, temperature control is at-70 ℃, and after reacting 2 hours, the TLC detection reaction is complete.Under 0 ℃, reaction solution is slowly poured in the aqueous solution of sodium bicarbonate, after being adjusted to alkalescence, is extracted with ethyl acetate, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 3(33g), yield is 65%.

Embodiment 3: pilot scale

1. format reaction

Under-78 ℃, n-Butyl Lithium (3.3L) is added drop-wise in the acetonitrile solution (7.5L) of Benzyl Chloride (2kg), dropwise, temperature control stirring 30 minutes, under-78 ℃, the acetonitrile of 3-oxetanone (500g) solution (7.5L) of muttering is dripped, and after dropwising, TLC follows the tracks of reaction until finish.The aqueous solution that drips ammonium chloride under-78 ℃ carrys out the cancellation reaction, and after cancellation, that reaction solution is concentrated dry, the ethyl acetate extraction, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 2(1kg), yield is 80%.

2. fluoridation

By compound 2(500g) be dissolved in methylene dichloride (7.5L), slowly drip diethylin sulfur trifluoride (645g) under-70 ℃, temperature control is at-70 ℃, and after reacting 2 hours, the TLC detection reaction is complete.Under 0 ℃, reaction solution is slowly poured in the aqueous solution of sodium bicarbonate, after being adjusted to alkalescence, is extracted with ethyl acetate, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 3(330g), yield is 65%.

As can be seen from the above embodiments, synthetic method of the present invention can directly be amplified, for industrial production.This patent adopts conventional operation process, the comparatively cheap raw material of the 3-oxetanone of usining is as initial reactant, through simple format, fluoridation, obtain the finished product, and in reaction, avoided hazardous chemical use, reduced reaction cost, improved reaction yield, simple to operate, easy purifying, can amplify production, make the amplification of this compound easily realize.And purifying is simple and convenient, reduced the cost of suitability for industrialized production, solved the shortcoming of amplifying the production cost costliness.

Above-described embodiment is described the preferred embodiment of the present invention; not scope of the present invention is limited; design under the prerequisite of spirit not breaking away from the present invention; various distortion and improvement that the common engineering technical personnel in this area make technical scheme of the present invention, all should fall in the definite protection domain of claims of the present invention.

Claims (3)

1. the method for the fluoro-3-phenyl of a synthetic 3-trimethylene oxide, it is characterized in that: take the 3-oxetanone as starting raw material, after the format reaction, obtain key intermediate, yield is greater than 80%, then go up fluorine and obtain the fluoro-3-phenyl of 3-trimethylene oxide, total recovery is greater than 50%.

2. method according to claim 1, it is characterized in that: the process of described reaction is:

3. method according to claim 2, it is characterized in that: concrete steps are:

(1) format reaction:

Under-78 ℃, n-Butyl Lithium is added drop-wise in the acetonitrile solution of Benzyl Chloride, dropwise, temperature control stirring 30 minutes, under-78 ℃, drip into the acetonitrile solution of 3-oxetanone, and after dropwising, TLC follows the tracks of reaction until finish; The aqueous solution that drips ammonium chloride under-78 ℃ carrys out the cancellation reaction, and after cancellation, that reaction solution is concentrated dry, the ethyl acetate extraction, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 2;

(2) fluoridation:

Compound 2 is dissolved in methylene dichloride, slowly drips the diethylin sulfur trifluoride under-70 ℃, temperature control is at-70 ℃, and after reacting 2 hours, the TLC detection reaction is complete; Under 0 ℃, reaction solution is slowly poured in the aqueous solution of sodium bicarbonate, after being adjusted to alkalescence, is extracted with ethyl acetate, merge organic phase, and by salt solution washing, dried over sodium sulfate, concentrated after, column chromatography obtains product 3.