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CN109824566A - The synthetic method of one kind (R) -2- (2,5- difluorophenyl) pyrrolidines - Google Patents

The synthetic method of one kind (R) -2- (2,5- difluorophenyl) pyrrolidines Download PDF

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CN109824566A
CN109824566A CN201910148303.0A CN201910148303A CN109824566A CN 109824566 A CN109824566 A CN 109824566A CN 201910148303 A CN201910148303 A CN 201910148303A CN 109824566 A CN109824566 A CN 109824566A
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reaction
difluorophenyl
pyrrolidine
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imine compound
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李新生
郭幸雪
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Zhejiang Normal University CJNU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pyrrole Compounds (AREA)

Abstract

The present invention discloses the synthetic method of one kind (R) -2- (2,5- difluorophenyl) pyrrolidines, comprising: group with imine moiety III carries out reduction reaction in the presence of reducing agent 3-sec-butyl lithium borohydride；Reduzate carries out annulation under alkaline condition；Cyclic product removes tert-butyl sulfoxide group in acid condition, and post-processing obtains final product.The present invention utilizes the reducing agent or Grignard Reagent of big steric hindrance, can not only reaction temperature be made to greatly improve, reaction condition is substantially improved than existing patented method, and substantially increases the content of required isomers.

Description

Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine
The invention is a divisional application of a patent application with the application number of 2017105904909 and the name of a synthetic method and an intermediate of "(R) -2- (2, 5-difluorophenyl) pyrrolidine".
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing chiral (R) -2- (2, 5-difluorophenyl) pyrrolidine by adopting induction of a chiral induction reagent and an intermediate.
Background
The compound has been widely noticed as a receptor target tropomyosin receptor kinase (Trk) inhibitor for years, a plurality of bioactive inhibitors have chiral pyrrolidine structure, and a plurality of novel compounds can effectively inhibit the Trk and show satisfactory results for treating pain, tumor or nerve diseases.
The Trk inhibitors disclosed in patent documents CN104114553, WO2013088256, WO2013088257 and WO2016077841 all contain a (R) -2- (2, 5-difluorophenyl) pyrrolidine structure, and the main structures thereof are as follows:
in the above structures, (R) -2- (2, 5-difluorophenyl) pyrrolidine is contained, and the (R) -2- (2, 5-difluorophenyl) pyrrolidine is an essential intermediate for synthesizing the inhibitor.
Among the methods for synthesizing chiral pyrrolidine, the method of chiral induction is one of the commonly used methods, and the reaction of the type often requires lower temperature (-78 ℃), and the result of chiral induction is deteriorated with the increase of temperature, which is a disadvantage of the method. Patent documents CN104114553, WO2013088256, WO2013088257, etc. disclose the following synthesis methods of (R) -2- (2, 5-difluorophenyl) pyrrolidine:
under the condition of-78 ℃, cooled lithium triethylborohydride is added for reduction, the content of useless isomers obtained after column chromatography treatment of a reaction liquid reaches up to 30 percent, the temperature required by the method is too low, general conditions are difficult to achieve, and the content of products with the final required configuration is less than 70 percent, which is only meaningful through column chromatography separation.
On the basis of this, patent document CN104672121 discloses the use of NaBH4The reduction method of the imine III comprises the steps of reducing at the temperature of 50 ℃ below zero, and finally separating by column chromatography to obtain the product. The temperature used in the method is improved, the yield of pyrrolidine with the required configuration is reported in the patent literature to be 56%, and the experimental result shows that under the condition, chiral groups hardly play a role in chiral induction, and the generated useless isomer is as high as 44%.
Patent documents WO2011006074 and WO2010033941 disclose methods for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine using sparteine base as a chiral inducing reagent:
the method uses sparteine alkali and sec-butyl lithium with more than equimolar quantity, after deprotonation is carried out at-78 ℃, anhydrous zinc chloride, tri-tert-butylphosphine and 2, 5-difluorobromobenzene are added, palladium acetate is used for catalytic coupling to obtain an intermediate, and then the intermediate is deprotected to obtain the (R) -2- (2, 5-difluorophenyl) pyrrolidine with the required configuration. The method can obtain the required configuration content of up to 93%, but the same method requires excessively low temperature, and the method also requires sec-butyl lithium which is excessively sensitive to air, and expensive palladium acetate and sparteine base, so that the method is difficult to industrialize due to excessively harsh reaction conditions and high cost.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine, the reaction condition is mild, the product yield and purity are high, and the preparation cost is low.
The invention also provides an intermediate for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine.
A method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine comprises the following steps:
(1) carrying out addition reaction on a Grignard reagent of halogenated propionaldehyde acetal and an imine compound I to obtain an addition product;
(2) the obtained addition product is subjected to cyclization reaction to obtain a chiral imine compound II;
(3) and (2) carrying out reduction reaction and post-treatment on the imine compound II to obtain the (R) -2- (2, 5-difluorophenyl) pyrrolidine:
the halogenated propionaldehyde acetal is a compound comprising the following fragment structure:
x ═ Cl or Br;
the structures of the imine compound I and the imine compound II are respectively as follows:
the structure of the addition product is as follows:
in step (1), the Grignard reagent can be prepared by conventional methods, for example, by reacting halogenated propionaldehyde acetal with magnesium ribbon in a solvent commonly used in Grignard reaction, preferably Tetrahydrofuran (THF).
Preferably, the halogenated propionaldehyde acetal is one or more of the following compounds:
as a further preference, the halogenated propionaldehyde in step (1) is preferably the acetal formed from 3-bromopropionaldehyde and ethylene glycol, i.e.:x is bromine.
In the step (1), adding a Grignard reagent into an imine compound I solution for addition reaction; in the process of adding the Grignard reagent, the temperature of the system is kept between minus 20 ℃ and minus 40 ℃, and under the general condition, the solution of the imine compound I can be cooled to a low temperature (for example, the temperature can be reduced to minus 20 ℃ to minus 40 ℃) in advance; the reaction temperature of the addition reaction is preferably from-20 ℃ to-40 ℃, and the temperature of the addition reaction is preferably not more than-30 ℃, for example, generally from-20 ℃ to-30 ℃; the reaction time of the addition reaction is generally 3-8 hours; the solvent of the imine compound I solution is dichloromethane or chloroform. After the addition reaction is finished, saturated ammonium chloride aqueous solution can be used for quenching reaction, and then the water phase is extracted by dichloromethane to obtain the addition product of the invention, and the post-treatment is simple.
In the step (1), the molar ratio of the Grignard reagent for halogenating propionaldehyde condensation to the imine compound I is (1-2.5): 1, and more preferably (1.5-2): 1.
The imine compound I can be prepared by the following method: dissolving 2, 5-difluorobenzaldehyde and R-tert-butyl sulfinamide in an organic solvent, adding tetraethyl titanate, heating and refluxing, and carrying out post-treatment to obtain the imine compound I.
Preferably, the reaction in the step (3) is directly carried out without post-treatment after the cyclization reaction in the step (2) is finished; the cyclization reaction in the step (2) is carried out under an acidic condition; the cyclization reaction is carried out at room temperature generally; and (3) adopting sodium borohydride and lithium borohydride as reduction reagents or adopting Pd/C for catalytic hydrogenation in the reduction reaction. Preferably, the reducing reagent is sodium borohydride, and the acidic environment after the cyclization reaction is completed is more favorable for enhancing the reducing activity of the sodium borohydride and improving the reaction efficiency. The step (2) and the step (3) adopt a one-pot method for continuous reaction, so that an intermediate post-treatment link is avoided, the waste of raw materials is reduced to the maximum extent, the final higher yield (more than 95%) is ensured, and the implementation of industrial expanded production is facilitated. When Pd/C catalytic hydrogenation is used, ethanol can be used as a reaction solvent.
Preferably, the acidic condition is 3M to 10M (M is mol/L) hydrochloric acid or trifluoroacetic acid containing 5 to 50% of water. Tetrahydrofuran may be used as the solvent.
After the reduction reaction is finished, extracting by using an extracting agent (such as dichloromethane), washing an organic phase with alkali, and removing an organic solvent to obtain a crude product of the (R) -2- (2, 5-difluorophenyl) pyrrolidine. After the crude product is salified, a recrystallization solvent is used for crystallization, high-purity (R) -2- (2, 5-difluorophenyl) pyrrolidine hydrochloride can be obtained, and finally, alkali neutralization is carried out, so that (R) -2- (2, 5-difluorophenyl) pyrrolidine with the isomer content of more than 98% can be finally obtained. The recrystallization solvent is selected from methanol, ethanol, isopropanol or a mixture thereof. In the following process, the related crude product of (R) -2- (2, 5-difluorophenyl) pyrrolidine can also be refined by the method, the whole refining process is simple, the loss is low, and the product purity is high.
The crystallization solvent of (R) -2- (2, 5-difluorophenyl) pyrrolidine hydrochloride is preferably isopropanol.
In the reduction reaction, the molar ratio of the reducing agent to the addition product is (1-2.5): 1, and more preferably (1.2-2): 1.
The invention also provides an intermediate compound for preparing (R) -2- (2, 5-difluorophenyl) pyrrolidine, which has the following structure:
wherein,the specific structure of (a) is determined by the specific structure of the halogenated propionaldehyde acetal, and preferably, the preferred structure is as follows:
r ═ methyl or ethyl.
The invention also provides another synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine, which comprises the following steps:
(1) carrying out reduction reaction on imine compound III in the presence of reducing agent lithium tri-sec-butylborohydride;
(2) the reduction product is subjected to cyclization reaction under alkaline condition;
(3) removing tert-butyl sulfoxide group from the cyclization product under an acidic condition, and performing post-treatment to obtain the (R) -2- (2, 5-difluorophenyl) pyrrolidine;
the imine compound III has the following structure:
the structure of the reduction product is as follows:
the cyclization product has the following structure:
the following is a description of a preferred embodiment of the second synthesis:
preferably, in the step (1), lithium tri-sec-butylborohydride is slowly added into the imine compound III solution; keeping the temperature of the system between 0 and 40 ℃ below zero in the process of adding lithium tri-sec-butyl borohydride; before adding lithium tri-sec-butylborohydride, the solution of the imine compound III can be selectively cooled to a low temperature (for example, to 0 ℃ to-40 ℃); the temperature of the reduction reaction is 0 ℃ to-40 ℃, and is preferably-30 ℃ to-40 ℃; the solvent of the imine compound III solution is tetrahydrofuran or diethyl ether.
Aiming at the synthesis method, the reduction reaction can adopt stage reaction at different low temperatures, for example, the reaction can be carried out for 2-4 hours at the temperature of-40 ℃ to-30 ℃, and then the temperature is increased to-10 ℃ to 0 ℃ for reaction for 1-3 hours.
In the step (1), the molar ratio of the imine compound III to lithium tri-sec-butylborohydride is 1 (1.5-3).
After the reduction reaction in the step (1) is completed, the cyclization reaction in the step (2) is directly carried out without post-treatment.
In the step (2), the temperature of the cyclization reaction is 0-30 ℃, and the reaction time is 1-3 hours. After the cyclization reaction is finished, a saturated ammonium chloride aqueous solution can be used for quenching the reaction, liquid separation is carried out, a water phase is extracted by dichloromethane, a solvent is removed after an organic phase is dried, and a product is obtained after the residue is subjected to column chromatography.
In the step (2), the alkali used in the alkaline condition is hexamethyldisilazane lithium amide, sodium hydroxide or potassium hydroxide.
In the step (3), the acidic condition refers to the condition of 3M-10M (M refers to mol/L) hydrochloric acid or trifluoroacetic acid with water content of 5-50%. Preferably, the acidic conditions are 6M hydrogen chloride in THF.
After the reaction in step (3), the obtained crude product of (R) -2- (2, 5-difluorophenyl) pyrrolidine hydrochloride is generally purified and refined by the method of combining acid-base extraction and recrystallization mentioned in the first synthesis method, and finally the isomer product with the purity of more than 98% is obtained.
The method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine provided by the invention utilizes a reducing agent or Grignard reagent with large steric hindrance, so that the reaction temperature is greatly increased, the reaction conditions are greatly improved compared with the prior method, and the content of the required isomer is greatly increased.
The advantages of the invention are mainly reflected in that: in the reaction step of chiral induction, the reaction temperature is improved by about 30 ℃ compared with that of the related patent, and the required isomer with the content of more than 95 percent can be obtained at the temperature, so that the content of the isomer is greatly improved, and qualified products can be obtained only by once crystallization in the following step; in the reduction reaction of the second synthesis method, the polarity difference between the reaction raw material and the product is large, and the product can be separated by fast column chromatography without bringing great trouble to the purification of the product. The reaction conditions of the invention can also be applied to mass preparation, and is relatively suitable for industrial production, thereby having higher practical value and social and economic benefits.
Detailed Description
The present invention will be further specifically described with reference to the following examples, but the present invention is not limited to these examples.
Example 1: synthesis of Compound 1
Adding 2.8g of magnesium strip, 2g of ethylene glycol 3-bromopropanal, THF10mL and one particle of iodine into a reaction bottle, heating to 65 ℃ to initiate reaction, stopping heating, cooling to room temperature, adding the rest 18g of ethylene glycol 3-bromopropanal dissolved in THF60mL at the room temperature, and stirring for 30min at the room temperature after the addition is finished for later use.
Example 2: synthesis of Compound 2
The method comprises the following steps: synthesis of Compound I:
7.1g of 2, 5-difluorobenzaldehyde and R-tert-butylsulfinamide are dissolved in 30mL of THF, 13g of tetraethyl titanate is added, heating and refluxing are carried out for 2h, after cooling, 20mL of water is added, extraction is carried out by using ethyl acetate, an extracting solution is dried, a solvent is removed after filtration, and 12g of a product is obtained by using petroleum ether ethyl acetate (10:1) column chromatography, wherein the yield is 98%.1H-NMR(400MHz，CDCl3)：δ1.26(s,9H),7.12-7.18(m,2H),7.64-7.68(m,1H),8.83(s,1H)。MS(ESI)246.53。
Step two: dissolving 16g of the imine compound I synthesized in the step one in 200mL of anhydrous dichloromethane, cooling to-40 ℃, slowly adding the mixed solution of the compound 1 prepared in the example 1, keeping the temperature not to exceed-35 ℃ in the adding process, and continuing to react for 5 hours at the temperature after the addition is finished. Adding saturated ammonium chloride aqueous solution to quench reaction, separating liquid, extracting water phase with dichloromethane, drying organic phase, removing organic solvent to obtain crude product of compound 2, purifying the crude product of compound 2 by column chromatography (eluent is petroleum ether ethyl acetate (3:1)) to obtain 18.4g of product, yield 81%, isomer is greater than 95%,1H-NMR(400MHz，CDCl3)：δ1.21(s,9H),1.26(m,1H),1.51-1.55(m,3H),3.31-3.33(m,1H),3.51-3.88(m,4H),4.84-4.86(m,1H),4.96-4.98(m,1H),6.94-7.15(m,3H)。MS(ESI)：348.65。
example 3: synthesis of Compound 3
217.4 g of compound was dissolved in THF50mL, 20mL of 6M HCl in THF was added, the mixture was stirred at room temperature for 1 hour, and NaBH was added in portions42.8g, after the addition, the mixture was stirred at room temperature for 1 hour. The reaction mixture is desolventized under reduced pressure, the residue is dissolved in 50mL of water, extracted with ethyl acetate, the organic phase is discarded and the aqueous phase is treated with K2CO3Basification, extraction again with ethyl acetate 3 × 30mL, acidification of the organic phase with 5M hydrochloric acid to acidity, removal of the solvent under reduced pressure, dissolution of the residue in 20mL of isopropanol, freeze crystallization of the isopropanol solution, filtration to give 8.1g, yield 73%, isomer > 98%, MS: 184.37 the hydrochloride salt was dissolved in 20mL water and 20mL ethyl acetate and washed with K2CO3Alkalizing to alkalinity, separating out the organic phase, extracting the aqueous phase with ethyl acetate 2X 20mL, drying the combined organic phases, and removing the solvent under reduced pressure to obtain 6.5g of the product with the yield of 96%.
Example 4: synthesis of Compound 5
Imine compound III (reference synthesis Erika leens, et al; chem. commun.,2010,46,3122 and CN104672121)8g is dissolved in anhydrous THF150mL, cooled to-40 ℃, 1M lithium tri-sec-butylborohydride 70ml THF solution is slowly added, after addition, the temperature is maintained at-40 ℃, the reaction is continued for 3h, naturally increased to 0 ℃ and then reacted for 2h, 1.3M lithium hexamethyldisilazide 30ml THF solution is added at 0 ℃, stirred for 2h, the reaction is quenched with saturated ammonium chloride water solution, separated, the aqueous phase is extracted with dichloromethane, the organic phase is dried and the solvent is removed, and column chromatography residue (eluent is petroleum ether ethyl acetate (1:1)) gives 4.5g of product with a yield of 63% and isomer of more than 96%.
Example 5: synthesis of Compound 3
Dissolving 52.9 g of the compound in THF20mL, adding 5mL of 6M hydrogen chloride dissolved in THF, stirring at room temperature for 1h, decompressing to remove the solvent, dissolving the residue in a small amount of isopropanol, freezing and crystallizing to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine hydrochloride with the isomer content of more than 98%, dissolving the (R) -2- (2, 5-difluorophenyl) pyrrolidine hydrochloride in water, neutralizing the solution with sodium hydroxide to the pH value of 11, and extracting the water phase with dichloromethane to obtain (R) -2- (2, 5-difluorophenyl) pyrrolidine with the isomer content of more than 98%, 1.7g and the yield of 94%.

Claims (4)

1. A method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine, which is characterized by comprising the following steps:
(1) carrying out reduction reaction on imine compound III in the presence of lithium tri-sec-butylborohydride;
(2) the reduction product is subjected to cyclization reaction under alkaline condition;
(3) removing tert-butyl sulfoxide group from the cyclization product under an acidic condition, and performing post-treatment to obtain the (R) -2- (2, 5-difluorophenyl) pyrrolidine;
the imine compound III has the following structure:
the structure of the reduction product is as follows:
the structure of the cyclization product is as follows:
2. the method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (1), lithium tri-sec-butylborohydride is slowly added to the solution of imine compound III; keeping the temperature of the system between 0 and 40 ℃ below zero in the process of adding lithium tri-sec-butyl borohydride; the temperature of the reduction reaction is 0 ℃ to-40 ℃; the solvent of the imine compound III solution is tetrahydrofuran or diethyl ether.
3. The method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein in step (2), the base used in the alkaline condition is lithium hexamethyldisilazide, sodium hydroxide or potassium hydroxide.
4. The method for synthesizing (R) -2- (2, 5-difluorophenyl) pyrrolidine according to claim 1, wherein the cyclization reaction in step (2) is performed directly without any post-treatment after the reduction reaction in step (1).
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