阅读说明：本技术 一种拉罗替尼中间体的制备方法以及中间体化合物 (Preparation method of larotinib intermediate and intermediate compound ) 是由 钟桂发 于 2020-08-10 设计创作，主要内容包括：本发明公开了一种如V所示拉罗替尼中间体的制备方法以及中间体化合物,该方法包括以2,5-二氟溴苯与N-叔丁氧羰基-L-焦谷氨酸酯为起始原料,进行偶联,脱保护基关环,还原,脱羧得到式V所示的化合物。本发明的制备方法新颖,成本低,原料廉价易得,产率高,适于大规模工业化生产。<Image he="302" wi="700" file="DSA0000216300810000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of a larotinib intermediate shown as V and an intermediate compound, and the method comprises the steps of taking 2, 5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamic acid ester as starting raw materials, coupling, deprotection, ring closing, reduction and decarboxylation to obtain the compound shown as the formula V. The preparation method is novel, low in cost, cheap and easily available in raw materials, high in yield and suitable for large-scale industrial production.)

1. A preparation method of a larotinib intermediate shown as a formula V is characterized by comprising the following steps: in an organic solvent, carrying out decarboxylation reaction on the compound shown in the formula IV under the action of a catalyst;

2. the method of claim 1, wherein: the preparation method comprises the following steps: adding a catalyst and a compound shown in a formula IV into an organic solvent to perform decarboxylation reaction; wherein the material molar ratio of the catalyst to the compound shown in the formula IV is 0.05-0.3: 1; the catalyst is 2-cyclohexene-1-ketone, acetophenone, 4-methylacetophenone, 4-methyl-2-pentanone or levo carvone; the organic solvent is xylene, mesitylene, cyclohexanol or polyethylene glycol; the reaction temperature is 100-200 ℃; the reaction time is measured until the reaction is completed.

3. The method of claim 1, wherein: the preparation method of the compound IV comprises the following steps:

(1) r is ethyl, reducing the compound shown in the formula II in an organic solvent under the action of a catalyst and hydrogen or a reducing agent to obtain a compound shown in the formula III, and hydrolyzing to remove R;

(2) r is benzyl, and the compound shown in the formula II is reduced and debenzylated in an organic solvent under the action of a catalyst and hydrogen.

4. The method of claim 3, wherein: the preparation method comprises the following steps:

(1) r is ethyl, adding a catalyst and a compound II into an organic solvent, reacting under the action of hydrogen or a reducing agent to obtain a compound III, and removing R from the compound III under the action of alkali to obtain a compound IV; wherein, the catalyst is represented by the formula IThe mass ratio of the materials of the compound shown as I is 0.01-0.3: 1; the catalyst is palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide, Raney nickel or rhodium carbon; the reducing agent is sodium borohydride, potassium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; the alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate or cesium carbonate; the pressure of the hydrogen is 1-20 atmospheric pressures; the organic solvent is C₁～C₅An alkyl alcohol solvent of (1); the reaction temperature is 25-100 ℃; the reaction time is used for detecting the completion of the reaction;

(2) r is benzyl, and a catalyst and a compound II are added into an organic solvent to react under the action of hydrogen to prepare a compound IV; wherein the mass ratio of the catalyst to the compound shown in the formula II is 0.01-0.3: 1; the catalyst is palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide, Raney nickel or rhodium carbon; the pressure of the hydrogen is 1-20 atmospheric pressures; the organic solvent is C₁～C₅An alkyl alcohol solvent of (1); the reaction temperature is 25-100 ℃; the reaction time is measured until the reaction is completed.

5. The method of claim 3, wherein: the compound II is prepared by the following method: in an organic solvent, carrying out the reaction shown in the specification of the compound I under the action of acid;

6. the method of claim 5, wherein: the compound II is prepared by the following method: in an organic solvent, carrying out tert-butyloxycarbonyl removal reaction and ring closure reaction on a compound I under the action of acid; wherein the acid is trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride ethyl acetate solution, hydrogen chlorideDioxane solution or hydrogen bromide acetic acid solution; the organic solvent is dichloromethane, 1, 2-dichloroethane, ethyl acetate, dioxane or C₁～C₅An alkyl alcohol solvent of (1); the reaction temperature is-20-50 ℃; the reaction time is measured until the reaction is completed.

7. The method of claim 5, wherein: the compound I is prepared by the following method: under the action of an organic metal reagent, 2, 5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamic acid ester are subjected to the following reaction in an organic solvent;

8. the method of claim 7, wherein: the compound I is prepared by the following method: under the action of an organic metal reagent, performing coupling reaction on 2, 5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamate in an organic solvent to obtain the compound I; wherein the organic metal reagent is isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride lithium chloride, ethyl magnesium bromide, ethyl magnesium chloride, methyl magnesium chloride, phenyl magnesium bromide, n-butyl lithium or tert-butyl lithium; the organic solvent is C₁～C₅Ether solvents of (4); the reaction temperature is-78-25 ℃; the reaction time is measured until the reaction is completed.

9. Intermediate compounds I a, I b, II a, II b and III for preparing larotinib, the structural formulae of which are respectively shown below:

Technical Field

The invention particularly relates to a preparation method of a larotinib intermediate and an intermediate compound.

Background

Larotinib (larotretinib) is an orally available, selective, ATP-competitive, potent inhibitor of the tropomyosin receptor kinase TRK, obtained in 2018 and 11 months and approved by the food and drug administration FDA for marketing for the treatment of adult or pediatric solid tumors bearing an NTRK fusion gene. This means that not only is the use of erlotinib available for the treatment of tumors at a particular location, but it is also useful for the treatment of a class of tumors that carry a genetic signature or a biomarker, including 17 cancers such as colon, lung, pancreas, thyroid, saliva, and gastrointestinal cancer. It has become the first anticancer drug to obtain FDA approval with major breakthrough therapy.

(R) -2- (2, 5-difluorophenyl) pyrrolidine is a key intermediate of the larotinib, and currently, the synthesis of the larotinib generally adopts a certain process route to firstly prepare (R) -2- (2, 5-difluorophenyl) pyrrolidine for subsequent synthesis, and finally the larotinib is prepared.

Currently, the preparation of (R) -2- (2, 5-difluorophenyl) pyrrolidine mainly comprises the following three synthetic routes:

firstly, the synthetic route of WO2010048314 is as follows:

the (R) -2- (2, 5-difluorophenyl) pyrrolidine is synthesized by taking 2, 5-difluorobromobenzene as a starting material and (-) -Sparteine as a chiral induction reagent. The route uses expensive (-) -Sparteine, has high cost, complex operation and harsh reaction conditions (requiring no water and oxygen and low temperature of-78 ℃), and is not suitable for industrial production.

Secondly, the synthetic route of US20160168156 is as follows:

according to the method, 2, 5-difluorobromobenzene is used as a starting material, an (S) -2-tert-butyl sulfonamide chiral induction reagent is used for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine through multiple steps, expensive (S) -2-tert-butyl sulfonamide is needed in the preparation process, dangerous lithium triethylborohydride and low-temperature reaction at-78 ℃ are needed, the reaction condition is severe, the cost is high, and the method is not suitable for industrial production.

Thirdly, the synthetic route of WO2017201241 is as follows:

in the method, 2, 5-difluorobenzaldehyde and (R) -2-tert-butyl sulfonamide are condensed into imine, then the imine and (1, 3-dioxolane-2-ethyl) magnesium bromide are subjected to addition reaction, and cyclization and reduction are carried out to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine.

Disclosure of Invention

The invention aims to overcome the defects of expensive reagent, higher cost, lower yield and the like in the existing preparation method of the intermediate of the erlotinib, and provides a preparation method of the intermediate of the erlotinib and an intermediate compound. The preparation method has the advantages of low cost, cheap and easily obtained raw materials, high yield and suitability for industrial production.

Therefore, the invention relates to a preparation method of a larotinib intermediate shown as a formula V, which is characterized by comprising the following steps: in an organic solvent, carrying out decarboxylation reaction on the compound shown in the formula IV under the action of a catalyst;

wherein, the decarboxylation reaction method and conditions of the compound IV can be the conventional method and conditions of the reaction in the field, and the following methods and conditions are particularly preferred in the invention: adding a catalyst and a compound shown in a formula IV into an organic solvent for reaction; wherein the material molar ratio of the preferable catalyst to the compound shown in the formula IV is 0.05-0.3: 1; the preferred catalyst is 2-cyclohexen-1-one, acetophenone, 4-methylacetophenone, 4-methyl-2-pentanone or levocarvone; the preferable organic solvent is xylene, mesitylene, cyclohexanol or polyethylene glycol; the preferable reaction temperature is 100-200 ℃; the preferred reaction time is determined until the reaction is complete.

In the invention, the preparation method of the compound IV is characterized by comprising the following steps:

(1) wherein R is ethyl, and the reduction reaction of the compound IIThe methods and conditions of (a) are all conventional in the art for such reactions, and the following are particularly preferred in the present invention: adding a catalyst and a compound II into an organic solvent, reacting under the action of hydrogen or a reducing agent to prepare a compound III, and removing R from the compound III under the action of alkali to obtain a compound IV; wherein the mass ratio of the better catalyst to the compound shown in the formula II is 0.01-0.3: 1; the preferred catalyst is palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide, raney nickel or rhodium carbon; the preferable reducing agent is sodium borohydride, potassium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride; the preferred base is sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, potassium carbonate or cesium carbonate; the pressure of the preferred hydrogen is 1-20 atmospheric pressures; the preferred organic solvent is C₁～C₅An alkyl alcohol solvent of (1); the preferable reaction temperature is 25-100 ℃; the preferred reaction time is to detect reaction completion;

(2) wherein R is benzyl, the methods and conditions for the reduction of said compound II are conventional in the art and are particularly preferred in the present invention: adding a catalyst and a compound II into an organic solvent, and reacting under the action of hydrogen to obtain a compound IV; wherein the mass ratio of the better catalyst to the compound shown in the formula II is 0.01-0.3: 1; the preferred catalyst is palladium carbon, palladium hydroxide, platinum carbon, platinum dioxide, raney nickel or rhodium carbon; the pressure of the preferred hydrogen is 1-20 atmospheric pressures; the preferred organic solvent is C₁～C₅An alkyl alcohol solvent of (1); the preferable reaction temperature is 25-100 ℃; the preferred reaction time is determined until the reaction is complete.

In the invention, the compound II is prepared by the following method: in an organic solvent, carrying out the reaction shown in the specification of the compound I under the action of acid;

wherein, the method and the condition for carrying out the tert-butyloxycarbonyl removal reaction and the ring closing reaction of the compound I can be the conventional method and condition of the reaction in the field, and the following method and condition are particularly preferred in the invention: in an organic solvent, carrying out tert-butyloxycarbonyl removal reaction and ring closure reaction on a compound I under the action of acid; wherein, the preferred acid is trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, a hydrogen chloride methanol solution, a hydrogen chloride ethanol solution, a hydrogen chloride ethyl acetate solution, a hydrogen chloride dioxane solution or a hydrogen bromide acetic acid solution; the preferred organic solvent is dichloromethane, 1, 2-dichloroethane, ethyl acetate, dioxane or C₁～C₅An alkyl alcohol solvent of (1); the preferable reaction temperature is-20 to 50 ℃; the preferred reaction time is determined until the reaction is complete.

In the invention, the compound I is prepared by the following method: under the action of an organic metal reagent, 2, 5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamic acid ester are subjected to the following reaction in an organic solvent;

wherein, the method and the conditions of the coupling reaction of the 2, 5-difluorobromobenzene and the N-tert-butoxycarbonyl-L-pyroglutamate can be the conventional method and the conditions of the reaction in the field, and the following method and the conditions are particularly preferred in the invention: under the action of an organic metal reagent, performing coupling reaction on 2, 5-difluorobromobenzene and N-tert-butoxycarbonyl-L-pyroglutamate in an organic solvent to obtain the compound I; wherein said preferred organometallic reagent is isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium chloride lithium chloride, ethyl magnesium bromide, ethyl magnesium chloride, methyl magnesium chloride, phenyl magnesium bromide, n-butyl lithium or t-butyl lithium; the preferred organic solvent is C₁～C₅Ether solvents of (4); the preferable reaction temperature is-78-25 ℃; the preferredThe time of the reaction was measured until the reaction was completed.

After the above reactions are completed, the post-treatment processes are all conventional operations, and the pure target compound can be obtained.

In the preparation method of the intermediate of the erlotinib, the route is preferably as follows:

the invention further relates to intermediate compounds Ia, Ib, IIa, IIb and III for preparing the erlotinib, wherein the structural formulas are respectively shown as follows:

the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available unless otherwise specified.

The preparation method has the advantages of cheap and easily-obtained raw materials, high yield and novel route, obtains a plurality of brand-new intermediates in the synthesis process, has stable properties of the intermediates, and is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following embodiments, the room temperature is 20 to 35 ℃.