阅读说明：本技术 一种(r)-2-(2,5-二氟苯基)吡咯烷的合成方法 (Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine ) 是由 开永平 文兆峰 鲁刚 柴宝红 范银彬 于 2020-12-10 设计创作，主要内容包括：本发明属于化学制药技术领域,涉及一种(R)-2-(2,5-二氟苯基)吡咯烷的合成方法。所述的合成方法包括如下步骤：(1)式1化合物与手性诱导试剂(R)-叔丁基亚磺酰胺经过脱水缩合反应得到式2化合物；(2)式2化合物与格式试剂加成反应得到式3化合物；(3)式3化合物与三氟乙酸和三乙基硅烷还原/合环反应得到式4化合物；(4)将式4化合物用(D)-苹果酸拆分,即可得式5的EE>98％的(R)-2-(2,5-二氟苯基)吡咯烷*D苹果酸盐化合物；(5)式5化合物再经过氢氧化钠溶液游离,即可得(R)-2-(2,5-二氟苯基)吡咯烷。利用本发明的(R)-2-(2,5-二氟苯基)吡咯烷的合成方法,能够成本低、光学纯度高、简化后续分离过程、原料易得、工艺条件温和、适于规模化生产的合成(R)-2-(2,5-二氟苯基)吡咯烷。(The invention belongs to the technical field of chemical pharmacy, and relates to a synthetic method of (R) -2- (2, 5-difluorophenyl) pyrrolidine. The synthesis method comprises the following steps: (1) the compound of the formula 1 and a chiral inducing reagent (R) -tert-butyl sulfenamide are subjected to dehydration condensation reaction to obtain a compound of a formula 2; (2) carrying out addition reaction on the compound shown in the formula 2 and a Grignard reagent to obtain a compound shown in a formula 3; (3) the compound in the formula 3 is subjected to reduction/cyclization reaction with trifluoroacetic acid and triethylsilane to obtain a compound in a formula 4; (4) resolving the compound of formula 4 with (D) -malic acid to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine D malate compound with EE > 98% of formula 5; (5) and dissociating the compound of the formula 5 by using a sodium hydroxide solution to obtain the (R) -2- (2, 5-difluorophenyl) pyrrolidine. The synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine has the advantages of low cost, high optical purity, simplified subsequent separation process, easily obtained raw materials, mild process conditions and suitability for large-scale production.)

1. A synthetic method of (R) -2- (2, 5-difluorophenyl) pyrrolidine is characterized by comprising the following steps:

(1) the compound of the formula 1 and a chiral inducing reagent (R) -tert-butyl sulfenamide are subjected to dehydration condensation reaction to obtain a compound of a formula 2;

(2) carrying out addition reaction on the compound shown in the formula 2 and a Grignard reagent to obtain a compound shown in a formula 3;

(3) the compound in the formula 3 is subjected to reduction/cyclization reaction with trifluoroacetic acid and triethylsilane to obtain a compound in a formula 4;

(4) resolving the compound of formula 4 with (D) -malic acid to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine D malate compound with EE > 98% of formula 5;

(5) the compound of the formula 5 is dissociated by sodium hydroxide solution to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine

2. The method of synthesis according to claim 1, characterized in that: in the step (1), the step (c),

using ethyl titanate as a dehydrating agent and tetrahydrofuran as a solvent, and performing dehydration condensation to obtain a compound shown in a formula 2;

or the compound of the formula 2 is obtained by dehydrating and condensing isopropyl titanate serving as a dehydrating agent and tetrahydrofuran serving as a solvent;

or anhydrous copper sulfate is used as a dehydrating agent, methylene dichloride is used as a solvent, and the compound shown in the formula 2 is obtained through dehydration condensation.

3. The method of synthesis according to claim 1, characterized in that: in the step (2), the Grignard reagent is prepared from 2- (2-bromoethyl) -1, 3-dioxane and metal magnesium powder in a tetrahydrofuran solution, or the Grignard reagent is prepared from 2- (2-bromoethyl) -1, 3-dioxane and metal magnesium powder in tetrahydrofuran, and the solvent for the addition reaction is one or more selected from tetrahydrofuran, diethyl ether and dichloromethane.

4. The method of synthesis according to claim 1, characterized in that: in the step (3), the volume ratio of trifluoroacetic acid to water is 90:10-99: 1.

5. The method of synthesis according to claim 1, characterized in that: in the step (3), the reaction temperature is 0-30 ℃, and the reaction time is 12-24 hours.

6. The method of synthesis according to claim 1, characterized in that: in the step (4), the temperature of the resolution reaction is 25-70 ℃.

Technical Field

The invention belongs to the technical field of chemical pharmacy, and relates to a synthetic method of (R) -2- (2, 5-difluorophenyl) pyrrolidine.

Background

23 months 9 and 2019, Baier company announces that the drug larotrecitinib for precisely treating the tumors under the flag obtains the marketing permission of European Union. Larotrectinib, as the first oral TRK inhibitor, is specially used for treating tumors with NTRK gene fusion, and is the first approved anti-cancer drug in European Union without tumor type differentiation.

The biggest difference from the traditional targeting drugs is that Larotrectinib is not specific to tumors at a certain anatomical position, but is developed as a broad-spectrum tumor drug and is used for all adult or child solid tumor patients carrying NTRK fusion genes.

TRK gene fusion refers to fusion of NTRK gene family members (NTRK1, NTRK2, NTRK3) with another unrelated gene due to chromosomal variation to generate conformationally activated aberrant TRK fusion proteins. The TRK fusion protein acts as a tumor driving factor and drives the diffusion and growth of TRK fusion tumor. NTRK gene fusion can occur anywhere in the body, and therefore, TRK fusion tumors may occur in a variety of adult and pediatric solid tumors. According to market related individuals, NTRK mutations occur in less than 1% of most solid tumor types, but are common in some rare cancers such as adult salivary cancer and infant fibrosarcoma. In the united states, 2000 to 3000 people are estimated to have NTRK-associated cancer annually. TRK fusion occurs early in tumorigenesis and persists during tumor growth and dissemination.

Larotrectinib is a potent, oral, selective inhibitor of Tropomyosin Receptor Kinases (TRKs) intended to directly target TRK (including TRKA, TRKB, and TRKC), closing off signaling pathways leading to TRK fusion tumor growth. At present, Larotrectinib is proved to have a lasting anti-tumor activity effect and good tolerance in TRK fusion cancers of wide ages and tumor types, and the treatment efficiency of the Larotrectinib can reach 75% for 17 tumors such as lung cancer, thyroid cancer, melanoma, GIST, colon cancer, soft tissue sarcoma, salivary gland tumor, infant fibrosarcoma and the like.

The structural formula of Larotrectinib is as follows:

the (R) -2- (2, 5-difluorophenyl) pyrrolidine with the following structure is the most important intermediate in the synthesis process and the most expensive intermediate.

In the prior art, the synthesis of (R) -2- (2, 5-difluorophenyl) pyrrolidine mainly comprises the following two methods:

the method comprises the following steps:

the synthesis method has the following problems: the process route is too long, the raw materials are expensive, the selectivity of chiral reduction is poor, the DE value is about 80 percent, diastereoisomers can be separated only by column chromatography, and the safety is not good when the metal compound sodium hydride is used in the cyclization reaction.

The method 2 comprises the following steps:

the synthesis method has the following problems: noble metals and coordination compounds are used in the chiral reduction process, so the chiral reduction process is expensive and difficult to recover; SEC-BuLi, a very active/hazardous organometallic compound, is used in the synthesis and therefore this step needs to be cryogenic (-78 ℃ C.) and therefore is less cost-effective and commercially viable.

Disclosure of Invention

The invention aims to provide a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, which has the advantages of low cost, high optical purity, simplified subsequent separation process, easily obtained raw materials, mild process conditions and suitability for large-scale production.

To achieve this object, in a basic embodiment, the present invention provides a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, comprising the steps of:

(1) the compound of the formula 1 and a chiral inducing reagent (R) -tert-butyl sulfenamide are subjected to dehydration condensation reaction to obtain a compound of a formula 2;

(2) carrying out addition reaction on the compound shown in the formula 2 and a Grignard reagent to obtain a compound shown in a formula 3;

(3) the compound in the formula 3 is subjected to reduction/cyclization reaction with trifluoroacetic acid and triethylsilane to obtain a compound in a formula 4;

(4) resolving the compound of formula 4 with (D) -malic acid to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine D malate compound with EE > 98% of formula 5;

(5) the compound of the formula 5 is dissociated by sodium hydroxide solution to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine

The relevant principle of the invention is as follows:

(1) synthesis of compounds of formula 2:

the compound of formula 1 and a chiral inducing reagent (R) -tert-butyl sulfinamide are subjected to dehydration condensation reaction to obtain a compound of formula 2.

1) Ethyl titanate is used as a dehydrating agent, tetrahydrofuran is used as a solvent, and the Schiff base type 2 compound is obtained through dehydration condensation.

Reaction conditions are as follows: dissolving 2, 5-difluorobenzaldehyde in 5 volumes of tetrahydrofuran, adding 2 equivalents of ethyl titanate, adding 1.5 equivalents of R-tert-butylsulfinamide, heating to 65 ℃, and reacting at normal pressure for 2 hours under the protection of nitrogen.

2) Isopropyl titanate is used as a dehydrating agent, tetrahydrofuran is used as a solvent, and the Schiff base 2 compound is obtained by dehydration condensation.

Reaction conditions are as follows: dissolving 2, 5-difluorobenzaldehyde in 5 volumes of tetrahydrofuran, adding 2 equivalents of isopropyl titanate, adding 1.5 equivalents of R-tert-butylsulfinamide, heating to 65 ℃, and reacting under normal pressure for 2 hours under the protection of nitrogen.

3) Anhydrous copper sulfate can be used as a dehydrating agent, methylene dichloride is used as a solvent, and the Schiff base 2 compound is obtained by dehydration condensation.

Reaction conditions are as follows: dissolving 2, 5-difluorobenzaldehyde and R-tert-butylsulfinamide in 1:1.2 equivalent in dichloromethane, adding 2.5 equivalent of anhydrous copper sulfate, heating to 30-40 ℃ for reaction, and completing the reaction for 3-4 hours.

(2) Synthesis of compounds of formula 3:

and (3) carrying out addition reaction on the compound of the formula 2 and a Grignard reagent to obtain a compound of a formula 3.

1) The Grignard reagent of 1M is prepared by reacting 2- (2-bromoethyl) -1, 3-dioxane and magnesium metal powder in tetrahydrofuran solution, or the Grignard reagent of 1M is prepared by reacting 2- (2-bromoethyl) -1, 3-dioxane and magnesium metal powder in tetrahydrofuran solution, and the solvent for addition reaction can be selected from tetrahydrofuran, diethyl ether, dichloromethane, preferably tetrahydrofuran.

2) The reaction ratio of the Schiff base and the format reagent is preferably 1:1.5 equivalent.

3) The addition reaction temperature is preferably-30 ℃, the reaction time is 3-5 hours, and the chiral selectivity is best.

(3) Synthesis of compounds of formula 4:

the compound of formula 3 has high chiral selectivity, DE value is more than 90%, and the compound of formula 4 is obtained by reduction/cyclization reaction with trifluoroacetic acid and triethylsilane.

1) The deliquifying inducing agent and acetal are preferably a system of trifluoroacetic acid and water, preferably in a volume ratio of 95: 5.

2) The reducing agent is preferably triethylsilane.

3) The reaction temperature is preferably 0-30 ℃ and the reaction time is 12-24 hours.

(4) Synthesis of compounds of formula 5:

the compound of formula 4 has very high chiral selectivity, EE is more than 90%, and the (R) -2- (2, 5-difluorophenyl) pyrrolidine D malate compound with EE more than 98% of formula 5 can be obtained by resolution with (D) -malic acid.

1) The chiral acid can be D-tartaric acid, D-malic acid, D-mandelic acid, preferably D-malic acid.

2) The alcohol solvent is preferably ethanol, and the volume of 5-10 is the best.

3) The reaction temperature is 25 to 70 ℃.

D-malic acid is adopted for resolution, ethanol is used as a solvent for resolution and crystallization, and the high chiral selectivity RD organic salt can be obtained.

(5) Synthesis of compounds of formula 6:

the compound of the formula 5 can obtain high selectivity with DE value of more than 98%, and the key intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine in the synthesis of high-quality larotretinib can be obtained by dissociating with sodium hydroxide solution, wherein the chemical purity is more than 98%, and the optical purity is more than 98%.

This step is attempted with methanol/sodium hydroxide, tetrahydrofuran/lithium hydroxide, dichloromethane/triethylamine, etc., preferably methanol/sodium hydroxide.

In a preferred embodiment, the present invention provides a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, wherein in step (1),

using ethyl titanate as a dehydrating agent and tetrahydrofuran as a solvent, and performing dehydration condensation to obtain a compound shown in a formula 2;

or the compound of the formula 2 is obtained by dehydrating and condensing isopropyl titanate serving as a dehydrating agent and tetrahydrofuran serving as a solvent;

or anhydrous copper sulfate is used as a dehydrating agent, methylene dichloride is used as a solvent, and the compound shown in the formula 2 is obtained through dehydration condensation.

In a preferred embodiment, the invention provides a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, wherein in step (2), the Grignard reagent is prepared by 2- (2-bromoethyl) -1, 3-dioxane and metal magnesium powder in tetrahydrofuran solution, or prepared by 2- (2-bromoethyl) -1, 3-dioxane and metal magnesium powder in tetrahydrofuran, and the solvent for addition reaction is one or more selected from tetrahydrofuran, diethyl ether and dichloromethane.

In a preferred embodiment, the present invention provides a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, wherein in step (3), the volume ratio of trifluoroacetic acid to water is 90:10 to 99: 1.

In a preferred embodiment, the present invention provides a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, wherein in step (3), the reaction temperature is 0-30 ℃ and the reaction time is 12-24 hours.

In a preferred embodiment, the present invention provides a method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, wherein in step (4), the temperature of the resolution reaction is 25-70 ℃.

The method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine has the advantages of low cost, high optical purity, simplified subsequent separation process, easily obtained raw materials, mild process conditions and suitability for large-scale production.

The invention aims to solve the problem of synthesis of a key intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine in synthesis of a novel anticancer drug Larotrectinib, and provides a high-selectivity asymmetric synthesis method, which comprises the steps of dehydrating and condensing aldehyde and a chiral induction reagent tert-butyl sulfenamide to generate Schiff base, carrying out addition reaction with a lattice reagent to obtain a high-selectivity target compound (the optical purity EE of a crude product is more than 90%), carrying out one-step reaction through temperature and condition ring closing and reduction, and carrying out one-step separation through D-malic acid to obtain the malate with high chemical purity and high optical purity. Compared with the existing reported process, the method is simpler, has shorter steps, avoids the use of noble metal catalysts and metal organic compounds, has better safety, and obtains the (R) -2- (2, 5-difluorophenyl) pyrrolidine with better chiral purity and easy resolution.

Drawings

FIG. 1 is a graph showing the results of High Performance Liquid Chromatography (HPLC) detection of (R) -2- (2, 5-difluorophenyl) pyrrolidine prepared in example 5.

FIG. 2 is a graph showing the results of Mass Spectrometry (MS) detection of (R) -2- (2, 5-difluorophenyl) pyrrolidine prepared in example 5.

FIG. 3 is a chart showing the results of nuclear magnetic hydrogen spectrum (H-NMR) measurement of (R) -2- (2, 5-difluorophenyl) pyrrolidine prepared in example 5, the upper chart shows the full view of the nuclear magnetic hydrogen spectrum measured with 400MHz deuterated chloroform as a solvent, and the lower chart shows an enlarged view of a part of the upper chart.

Fig. 4 is a graph showing the chiral purity EE detection result of (R) -2- (2, 5-difluorophenyl) pyrrolidine prepared in example 5, in which the upper graph is a racemate HPLC spectrum, the middle graph is a pure HPLC spectrum, and the lower graph is an enlarged view of the upper graph and the middle graph.

Detailed Description

The following examples further illustrate embodiments of the present invention.

Example 1: synthesis of Compound of formula 2

The reaction solution is washed and dried in a three-neck flask, 60 g of 2, 5-difluorobenzaldehyde, 76.6 g of R-tert-butylsulfinamide, 1.0 g of PPTS and 169 g of anhydrous copper sulfate are dissolved in 500 ml of dichloromethane, heated to 40 ℃ in an oil bath, stirred, refluxed for 3-5 hours, and monitored by TLC/HPLC for reaction completion. The product was filtered and concentrated under reduced pressure. Washing and layering after dissolving; washing with saturated salt water, and layering; the schiff base of the compound of formula 2 was obtained in 100.5 g (pale yellow oil) by drying over anhydrous sodium sulfate and concentrating under reduced pressure, the yield was 97%, and the next reaction was carried out without further purification.

Example 2: synthesis of Compounds of formula 3

Dissolving 100.5 g of Schiff base compound of formula 2 in 500 ml of tetrahydrofuran, reducing the temperature to-30 ℃ under the protection of nitrogen, slowly dropwise adding 1.5 equivalents of 1mol/L Grignard reagent, keeping the temperature at about-30 ℃, reacting at constant temperature for 2-3 hours after the dropwise adding is finished, and detecting the reaction by TLC/HPLC. The reaction was quenched with saturated aqueous ammonium chloride, separated into layers, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 141.0 g (pale yellow oil) (DE > 90%) of the crude compound with a yield > 95%.

Example 3: synthesis of Compound of formula 4

141.0 g of the compound of formula 3, stirring, and slowly adding a mixture of 3L trifluoroacetic acid and water (TFA: H)₂The volume ratio of O is 95:5), stirring for 1-2 hours, and controlling the temperature to be 25 ℃. Slowly adding 363 g of triethylsilane dropwise, controlling the temperature to be 30-40 ℃, controlling the temperature to be 30 ℃ after the dropwise adding is finished, stirring for 12-24 hours, and finishing the HPLC detection reaction. Concentration under reduced pressure gave 106 g of crude compound (tan liquid). The next reaction was carried out without further purification.

Example 4: synthesis of Compounds of formula 5

106 g of the compound of formula 4, 1.06 l of absolute ethanol, heating, adding 78.5 g of D-malic acid, heating and refluxing to be completely dissolved, stirring and cooling to room temperature, stirring for 2-3 hours, filtering to obtain (RR) -2, 5-difluorophenylpyrrolidine malate, stirring and washing with cold ethanol for 2-3 times, and drying to obtain 79.5 g (white-like crystal) malate compound with DE > 98%.

Example 5: synthesis of Compounds of formula 6

79.5 g of the malate compound of formula 5, 400 ml of methanol was added, 300 ml of a 1N aqueous solution of sodium hydroxide was slowly added dropwise thereto, and the mixture was stirred for 1 hour to measure the pH of the mixed solution to be 14. Concentrating under reduced pressure, adding 500 ml of methyl tert-butyl ether in turn, extracting for three times, combining organic phases, washing with saturated salt water for 1 time, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain 44.5 g of (R) -2- (2, 5-difluorophenyl) pyrrolidine as a light yellow oily substance with the yield of 96.95%. H-NMR (400MHz, CDC)l₃) Delta 7.241-7.286(m,1H)6.926-6.983(m,1H)6.832-6.891(m,1H)4.395-4.433(m,1H)3.145-3.188(m,1H)3.052-3.095(m,1H)2.249-2.281(m,1H)2.072(s,1H)1.845-1.915(m,2H)1.625-1.656(m, 1H); LCMS (M/z,184.1, M + 1); chemical purity HPLC ═ 99.09% (Agilent 1100, YMC ODS-AQ 3UM 120A 4.6X 50MM, 210nm, ACN/H₂O/buffer); chiral purity HPLC ═ 98.73% (Shimadzu LC 20A QA)&QC-HPLC-15,0.46cm I.D.. times.15 cm L.times.5 μm,220nm,10mM diammonium phosphate (pH 8.0)/acetonitrile). The detection results of the high performance liquid chromatography, the mass spectrum, the nuclear magnetic hydrogen spectrum and the chiral purity EE are respectively shown in the figures 1-4.

It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is intended to include such modifications and variations. The foregoing examples or embodiments are merely illustrative of the present invention, which may be embodied in other specific forms or in other specific forms without departing from the spirit or essential characteristics thereof. The described embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. The scope of the invention should be indicated by the appended claims, and any changes that are equivalent to the intent and scope of the claims should be construed to be included therein.