CN103601666B - The preparation method of octahydro pentamethylene [C] pyrroles - Google Patents

Abstract

The invention provides a kind of preparation method of octahydro pentamethylene [C] pyrroles (I); The method, by under Lewis acid promotion, obtains octahydro pentamethylene [C] pyrroles (I) by boron reductive agent reduction ring valeryl group with imine moiety (II) single stage method.

Description

The preparation method of octahydrocyclopentane [C] pyrrole

technical field

The invention belongs to the field of chemical pharmacy, and in particular relates to a preparation method of octahydrocyclopenta[c]pyrrole (octahydrocyclopenta[c]pyrrole, CAS No. 5661-03-0), a key synthetic intermediate of medicine.

Background technique

Hepatitis C virus is a single-stranded linear positive-sense RNA virus. Because it can cause various chronic liver diseases, HCV is one of the main killers of human deaths due to diseases so far. In 2011, the U.S. Food and Drug Administration (FDA) approved two small-molecule drugs, Telaprevir and Boceprevir, to be marketed in the United States. The launch of these two protease inhibitors has changed the treatment effect of hepatitis C in the past ten years; this is a relatively big breakthrough in the field of hepatitis C treatment.

Octahydrocyclopentane[C]pyrrole (or its salt) is a very useful pharmaceutical intermediate in drug synthesis. It is not only a key intermediate for the synthesis of telaprevir, but also a synthetic intermediate for the diabetes drug gliclazide. Therefore, for its large-scale industrial production, it has very important market value. Octahydrocyclopentane [C] pyrrole is the following structural formula (I):

The preparation method of octahydrocyclopentane [C] pyrrole has been reported in the literature for a long time: R.Griot first proposed a direct synthetic method in Helv.Chim.Acta., 1959,67-72 magazine in 1959; Griot The target compound octahydrocyclopentane[C]pyrrole (I) was obtained by reducing cyclopentanimide (II) in tetrahydrofuran solution with LiAlH ₄ in 51% yield.

WO2009/55467 reported another synthetic method: N-benzyl cyclopentanimide was first reduced by LiAlH ₄ and then hydrogenated with 10% palladium on carbon (Pd/C) to obtain it in two steps with a total yield of 55%. The target compound octahydrocyclopentane[C]pyrrole (I). The method flow is as follows:

In the industrial research and development of the pharmaceutical intermediates of octahydrocyclopentane [C] pyrrole, the inventor found that the yield of the final product obtained by the above two methods on the one hand is not high, lower than 55%; Lithium aluminum hydride (LiAlH ₄ ), and LiAlH ₄ is a chemical reagent that is very sensitive to water. In laboratory applications, because the amount of use is small, the risk can be tolerated; however, in industrial production, due to the large amount of use , its danger is very high, during the reduction reaction process and after treatment of excess reducing agent LiAlH ₄ will violently exothermic, in the case of local heat inhomogeneity, it is very easy to cause safety accidents such as explosion. Generally speaking, chemical reagents that are very sensitive to water such as LiAlH ₄ should be avoided in chemical industrial production.

So far, no industrial production method of octahydrocyclopentane[C]pyrrole has been reported, and it is urgent to find a safe and effective industrial quantitative production method with high yield.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of octahydrocyclopentane [C] pyrrole (I) that is suitable for industrialized production.

In order to achieve the above object, after in-depth research, the present invention has designed a new method different from the prior art for preparing octahydrocyclopentane [C] pyrrole, that is, by cyclopentanimide (II) in a suitable reducing agent and a suitable The target compound octahydrocyclopentane[C]pyrrole (I) was obtained by direct reduction under the action of a promoter in a "one-step method".

Specifically, the preparation method of octahydrocyclopentane [C] pyrrole (I) provided by the present invention comprises the reaction substrate cyclopentanimide (II) under the action of a boron reducing agent and a Lewis acid promoter, in In a suitable solvent, react at a suitable temperature to obtain the target compound octahydrocyclopentane[C]pyrrole (I).

In one embodiment, the suitable reducing agent is selected from sodium borohydride or potassium borohydride; preferably sodium borohydride.

In one embodiment, the Lewis acid accelerator is selected from zinc chloride, calcium chloride, ferric chloride, ferrous chloride, magnesium chloride, etc.; more preferably, the Lewis acid accelerator is zinc chloride.

In one embodiment, the appropriate solvent is an inert solvent; the inert solvent is selected from tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, xylene, benzene, ethylene glycol dimethyl ether, ethylene glycol Monomethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, chloroform as a single solvent or a mixed solvent of two or more of them. Preferably, the solvent is tetrahydrofuran or toluene, or a mixed solvent of the two.

In one embodiment, the reaction uses a single solvent, and the reaction temperature is the reflux temperature of the solvent used.

In one embodiment, a mixed solvent is used for the reaction, and the reaction temperature is any temperature between the boiling points of the solvents used or the azeotropic temperature of the mixed solvent.

In one embodiment, the molar ratio of the reducing agent to the reaction substrate (II) is 1:1 to 10:1; preferably 1.1:1 to 5:1.

In one embodiment, the molar ratio of the accelerator to the reaction substrate (II) is 0.5:1 to 10:1; preferably 1.1:1 to 5:1.

Compared with the currently disclosed technology, the new preparation method of the present invention prepares octahydrocyclopentane [C] pyrrole (I) in one step by reducing the cyclopentanimide compound (II). The advantage is that, on the one hand, it adopts The reducing agent is cheap, mild in reaction, and safe in operation. On the other hand, the reactivity of the reducing agent is improved by an appropriate Lewis acid, and the product yield is high and the purity is also high (>97%). Therefore, the reagents used in the new method are safe, the reaction conditions are mild, and the product yield is high; it can well meet industrial production.

The following examples are only to further illustrate the present invention, and are not intended to limit the present invention to the specific examples. Those skilled in the art will realize that the invention covers all possible alternatives, modifications and equivalents within the scope of the claims.

Example

Raw materials and reagents:

Cyclopentanimide (II) (self-made, formed by dehydration and condensation of 1,2-cyclopentadicarboxylic acid and urine according to existing literature);

Sodium borohydride, potassium borohydride, zinc chloride, ferric chloride and other solvents and reagents used were provided by Sinopharm Chemical Reagent Co., Ltd.

Example 1

Under nitrogen atmosphere, tetrahydrofuran (500mL), toluene (1.5L), sodium borohydride (68.40g, 2.5eq.) and zinc chloride (125.0g, 1.3eq.). The resulting suspension was heated to reflux. The tetrahydrofuran was distilled off slowly, and the temperature was controlled at 90±5°C until a black solid was formed. A solution of cyclopentanimide (100 g, 0.72 mol) in tetrahydrofuran (500 mL) was added dropwise and refluxed at this temperature overnight. Cool, neutralize with dilute hydrochloric acid to pH=2-3, separate the organic phase, extract the aqueous phase with ethyl acetate (1L x3) three times, and separate the organic phase. The acidic aqueous layer was neutralized to pH=8-9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (1L x3). The combined organic phases were dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Octahydrocyclopentane[C]pyrrole (72.8 g, 90.9%) was obtained as a white solid with an HPLC purity of 97%.

Example 2

Under nitrogen atmosphere, tetrahydrofuran (50mL), toluene (150mL), sodium borohydride (6.84g, 2.5eq.) and zinc chloride (12.5g, 1.3 eq.). The resulting suspension was heated to reflux. The tetrahydrofuran was distilled off slowly, and the temperature was controlled at 90±5°C until a black solid was formed. A solution of cyclopentanimide (10 g, 72 mmol) in tetrahydrofuran (50 mL) was added dropwise and refluxed at this temperature overnight. Cool, neutralize with dilute hydrochloric acid to pH=2-3, separate the organic phase, extract the aqueous phase with ethyl acetate (100mL x 3) three times, and separate the organic phase. The acidic aqueous layer was neutralized to pH=8-9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (100mL x3). The combined organic phases were dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Octahydrocyclopentane[C]pyrrole (7.35 g, 91.8%) was obtained as a white solid with an HPLC purity of 97%.

Example 3

Under nitrogen atmosphere, tetrahydrofuran (50mL), toluene (150mL), potassium borohydride (9.76g, 2.5eq.) and zinc chloride (14.4g, 1.5 eq.). The resulting suspension was heated to reflux. The tetrahydrofuran was distilled off slowly, and the temperature was controlled at 90±5°C until a black solid was formed. A solution of cyclopentanimide (10 g, 72 mmol) in tetrahydrofuran (50 mL) was added dropwise and refluxed at this temperature overnight. Cool, neutralize with dilute hydrochloric acid to pH=2-3, separate the organic phase, extract the aqueous phase with ethyl acetate (100mL x 3) three times, and separate the organic phase. The acidic aqueous layer was neutralized to pH=8-9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (100mL x3). The combined organic phases were dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Octahydrocyclopentane[C]pyrrole (7.33 g, 91.6%) was obtained as a white solid with an HPLC purity of 97%.

Example 4

Under nitrogen atmosphere, acetonitrile (25mL), xylene (75mL), sodium borohydride (4.93g, 3.0eq.) and ferric chloride (11.5g, 2.0eq.). The resulting suspension was heated to 90±5. The tetrahydrofuran was distilled off slowly, and the temperature was controlled at 90±5°C until a black solid was formed. A solution of cyclopentimide (5 g, 36 mmol) in tetrahydrofuran (50 mL) was added dropwise and left at this temperature overnight. Cool, neutralize with dilute hydrochloric acid to pH=2-3, separate the organic phase, extract the aqueous phase with ethyl acetate (100mL x 3) three times, and separate the organic phase. The acidic aqueous layer was neutralized to pH=8-9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (100mL x3). The combined organic phases were dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Octahydrocyclopentane[C]pyrrole (3.26 g, 81.4%) was obtained as a white solid with 95% purity by HPLC.

Example 5

Under nitrogen atmosphere, tetrahydrofuran (25mL), xylene (75mL), potassium borohydride (11.22g, 5.0eq.) and zinc chloride (19.32g, 4.0eq.). The resulting suspension was heated to 90±5°C. The tetrahydrofuran was distilled off slowly, and the temperature was controlled at 90±5°C until a black solid was formed. A solution of cyclopentimide (5 g, 36 mmol) in tetrahydrofuran (50 mL) was added dropwise and left at this temperature overnight. Cool, neutralize with dilute hydrochloric acid to pH=2-3, separate the organic phase, extract the aqueous phase with ethyl acetate (50mL x3) three times, and separate the organic phase. The acidic aqueous layer was neutralized to pH=8-9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (50mL x3). The combined organic phases were dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Octahydrocyclopentane[C]pyrrole (3.65 g, 91.2%) was obtained as a white solid with an HPLC purity of 96%.

Claims (6)

1. the preparation technology of octahydro pentamethylene [C] pyrroles I, it is characterized in that, by reaction substrate ring valeryl imines II under boron reductive agent, lewis promoters effect, react in appropriate solvent, under proper temperature, obtain target compound octahydro pentamethylene [C] pyrroles I; Chemical reaction is shown in following formula:

Described boron reductive agent is sodium borohydride or POTASSIUM BOROHYDRIDE, and described lewis promoters is zinc chloride,

Described appropriate solvent is selected from two or more the mixed solvent in tetrahydrofuran (THF), toluene, dimethylbenzene,

Described proper temperature is arbitrary temp between the boiling point of each solvent used or the azeotropic temperature of this mixed solvent.

2. preparation technology as claimed in claim 1, it is characterized in that, described appropriate solvent is selected from the mixed solvent of tetrahydrofuran (THF) and toluene.

3. preparation technology as claimed in claim 1, it is characterized in that, the mol ratio of described reductive agent and reaction substrate ring valeryl imines II is 1:1 to 10:1.

4. preparation technology as claimed in claim 3, it is characterized in that, the mol ratio of described reductive agent and reaction substrate ring valeryl imines II is 1.1:1 to 5:1.

5. preparation technology as claimed in claim 1, it is characterized in that, the mol ratio of described promotor and reaction substrate ring valeryl imines II is 0.5:1 to 10:1.

6. preparation technology as claimed in claim 5, it is characterized in that, the mol ratio of described promotor and reaction substrate ring valeryl imines II is 1:1 to 5:1.