CN115947675B

CN115947675B - Rasagiline intermediate and preparation method and application thereof

Info

Publication number: CN115947675B
Application number: CN202211648550.5A
Authority: CN
Inventors: 吴桂宝; 王廷春; 左联; 高曙光; 廖大志; 刘宇哲
Original assignee: Boji Pharmaceutical Technology Co ltd
Current assignee: Boji Pharmaceutical Technology Co ltd
Filing date: 2022-12-21
Publication date: 2024-05-31
Anticipated expiration: 2042-12-21

Abstract

The invention discloses a rasagiline intermediate, a preparation method and application thereof, wherein the intermediate has a structure shown in a formula 3. 1-indenone is used as a synthesis raw material, and (S) -1-indenol with high purity is obtained through asymmetric reduction of chiral auxiliary and borane; reacting (S) -1-indenol with a compound shown in a formula 2, wherein amino protected by sulfonyl is used as a nucleophilic reagent for a photo-delay reaction, so that chiral amine is simpler to construct and operation is simple; the amino group is protected by nitro sulfonyl to avoid the generation of polysubstituted byproducts, thereby generating rasagiline intermediates with higher yield. The intermediate can be used for asymmetrically synthesizing rasagiline. The invention solves the problems of low yield, more side reactions and more impurities of the chiral resolution route. The route has high total yield and product purity and certain market competitiveness;

Description

Rasagiline intermediate and preparation method and application thereof

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a rasagiline intermediate, a preparation method and application thereof.

Background

Rasagiline (RASAGILINE), i.e. N-propargyl-1-aminoindene, having the structural formula:

The salt of rasagiline, such as rasagiline mesylate, is an irreversible monoamine oxidase inhibitor, can reduce the decomposition of dopamine by selectively inhibiting monoamine oxidase, can promote the extracellular level of dopamine in the brain striatum, and can relieve the symptoms of parkinsonism. The composition can be used as monotherapy (without L-dopamine) or as adjuvant therapy (in combination with L-dopamine) for treating idiopathic Parkinson disease.

The existing mode for synthesizing rasagiline mainly comprises the steps of introducing racemic 1-aminoindene or 1-hydroxy indene into propargyl through chiral resolution, and then separating through chiral resolving agent to obtain a target chiral product. The method has the defects of large loss, high cost and environmental protection; the amino has a plurality of reaction sites, has polysubstituted side reactions, and is difficult to control the product quality. Therefore, the improvement of the prior art conditions is urgent, and a method with simple operation steps and higher yield is found to be used for preparing rasagiline so as to meet the requirement of industrial production.

Disclosure of Invention

The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides the rasagiline intermediate, the preparation method and the application thereof, and the rasagiline intermediate can be used for preparing the rasagiline mesylate with high purity (more than or equal to 99.5%) and high yield, and the preparation process is simple and is suitable for industrial production.

In a first aspect of the present invention, there is provided a rasagiline intermediate having a structure represented by formula 3:

In a second aspect of the present invention, there is provided a process for preparing a compound of formula 3 as described above, comprising the steps of:

Reacting (S) -1-indenol with a compound of formula 2 in the presence of an activator and a first organic solvent to produce a compound of formula 3;

The invention adopts the compound of the formula 2 to react with (S) -1-indenol to obtain the compound of the formula 3. In the structure of the compound of the formula 2, the ortho-position nitro has an electron withdrawing effect, and the ortho-position nitro can form a hydrogen bond with the amino group of the sulfonamide, so that the nucleophilicity of the amino group is enhanced, and the yield and the purity of the compound of the formula 3 are improved.

According to some embodiments of the invention, the first organic solvent is tetrahydrofuran.

According to some embodiments of the invention, the molar ratio of the activator to (S) -1-indenol is from 2.0 to 3.0:1.

According to some embodiments of the invention, the molar ratio of the activator to the compound of formula 2 is from 1.0 to 3.0:1.

According to some embodiments of the invention, the molar ratio of (S) -1-indenol to the compound of formula 2 is 1:1.0 to 2.5.

According to some embodiments of the invention, the activator comprises triphenylphosphine and an azo condensing agent.

According to some embodiments of the invention, the azo condensing agent is at least one of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DTAD), dipropyl azodicarboxylate (DPAD), dimethyl azodicarboxylate (DMAD).

According to some embodiments of the invention, the molar ratio of triphenylphosphine to the azo condensing agent is between 0.5 and 1.5:1.

According to some embodiments of the present invention, triphenylphosphine, (S) -1-indenol is mixed with a compound of formula 2, and then an azo condensing agent is added to react.

According to some embodiments of the invention, the temperature of the reaction is 10 ℃ to 40 ℃ and the time of the reaction is 15 to 30 hours.

According to some embodiments of the invention, purifying the compound of formula 3 is also included.

Further, the purifying includes crystallization.

Further, the crystallization is performed by a solvent-based crystallization method, wherein the solvent is selected from n-heptane.

Further, the crystallization temperature is 20-30 ℃, and the crystallization time is 1-3 hours.

According to some embodiments of the invention, the crystallization is followed by solid-liquid separation in at least one of centrifugation, filtration, or sedimentation.

According to some embodiments of the invention, the method for preparing a compound of formula 3 further comprises the steps of:

reacting the 1-indenone with borane in the presence of a chiral auxiliary and a second organic solvent to form (S) -1-indenol.

According to some embodiments of the invention, the chiral auxiliary is at least one of (1R, 2 s) -1-amino-indenol, (R) -CBS; wherein the structure of (R) -CBS is

According to some embodiments of the invention, the borane is at least one of borane dimethyl sulfide, N-diethylaniline borane.

According to some preferred embodiments of the invention, the borane is N, N-diethylaniline borane.

According to the invention, the (1R, 2S) -1-amino-indenol or (R) -CBS is adopted as a chiral auxiliary agent, and N, N-diethylaniline borane is adopted as borane, and because N atoms in the chiral auxiliary agent have certain nucleophilicity, the N atoms are easily complexed with borane in a reaction system to enable B atoms to have Lewis acidity, the B atoms react with oxygen atoms on a ketone carbonyl to obtain an unstable intermediate, the unstable intermediate is easily cracked into chiral alcohol and the chiral auxiliary agent after undergoing a reduction reaction, then the chiral auxiliary agent enters into circulation again, the reaction is promoted, the chiral purity of the generated (S) -1-indenol is improved, and the ee value is more than 95%, so that the post-treatment step is greatly simplified.

According to some embodiments of the invention, the second organic solvent is at least one of tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, 1, 4-dioxane.

According to some embodiments of the invention, the molar ratio of the chiral auxiliary to 1-indenone is from 0.1 to 0.4:1.

According to some embodiments of the invention, the molar ratio of 1-indenone to the borane is 1:1.0 to 4.0.

According to some embodiments of the invention, the chiral auxiliary is mixed with the borane and then the 1-indenone is added to react.

Further, in order to maintain the uniformity of the reaction system, the mixing may be performed by stirring for a period of 0.5 to 1 hour.

According to some embodiments of the invention, the temperature of the reaction is between 0 ℃ and 25 ℃ and the time of the reaction is between 1 and 3 hours.

According to some embodiments of the invention, the purification of the (S) -1-indenol obtained is also included.

Further, the purifying includes crystallization.

Further, the crystallization adopts a solution crystallization method; the solvent of the solvent-out crystallization method is selected from n-heptane.

According to some embodiments of the invention, the crystallization is preceded by a quenching reaction and an acid wash. Wherein the quenching reaction is achieved by adding acetone; the acid washing adopts sulfuric acid solution with the mass concentration of 5% -15%, preferably 10%.

In a third aspect of the invention there is provided the use of a compound of formula 3 as hereinbefore described for the preparation of rasagiline mesylate.

In a fourth aspect of the present invention, there is provided a process for the preparation of rasagiline mesylate comprising the steps of:

Reacting a compound of formula 3 with a mercaptoacid compound in the presence of a base and a third organic solvent to obtain rasagiline; salifying rasagiline with methanesulfonic acid to obtain the product.

According to some embodiments of the invention, the base is lithium hydroxide and/or lithium bis trimethylsilylamide.

According to some embodiments of the invention, the mercaptoacid compound is mercaptoacetic acid and/or mercaptopropionic acid.

According to some embodiments of the invention, the third organic solvent is at least one of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.

According to some embodiments of the invention, the molar ratio of the compound of formula 3 to the base is 1:3.8 to 9.0.

According to some embodiments of the invention, the molar ratio of the compound of formula 3 to the mercaptoacid compound is 1:1 to 1.5.

According to some embodiments of the invention, the molar ratio of the base to the mercaptoacid compound is from 3.0 to 8.0:1.

According to some embodiments of the invention, the base is mixed with the compound of formula 3 prior to the addition of the mercaptoacid compound for reaction.

Further, the reaction temperature is 10-25 ℃, and the reaction time is 5-15 h.

According to some embodiments of the invention, purifying the rasagiline obtained is further included.

The purification comprises the following steps:

Adding water into the reaction system, adjusting the pH to 2-3, adding ethyl acetate for extraction, collecting water phase, adjusting the pH to 11-12, adding ethyl acetate for extraction, collecting organic phase, and concentrating to dryness.

According to some embodiments of the invention, the salt forming reaction is carried out at a temperature of 20-30 ℃ for a time of 2-4 hours.

According to some embodiments of the invention, the salifying reaction is carried out in a fourth organic solvent, which is ethyl acetate, isopropyl ether or a mixed solvent of isopropyl alcohol and isopropyl ether.

According to some embodiments of the invention, the salifying is followed by solid-liquid separation in at least one of centrifugation, filtration or sedimentation.

The beneficial effects are that:

The invention develops a brand new process route for asymmetrically synthesizing rasagiline, and the amino protected by sulfonyl is used as a nucleophilic reagent for the photo-delay reaction, so that chiral amine is constructed more simply, and the operation is simple; the amino group is protected by nitro sulfonyl, and the generation of polysubstituted byproducts is avoided. Solves the problems of low yield and more side reactions and impurities of chiral resolution routes. The route has higher total yield, high product purity and high chiral purity, and has market competitiveness.

Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.

Detailed Description

The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention.

When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values for the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range description features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to include any and all subranges subsumed therein.

Examples

EXAMPLE 1 Synthesis of Compound 1

Mixing 100g (0.76 mol) of 1-indanone with 800mL of anhydrous THF at room temperature of 25 ℃ to obtain a solution for later use; (1R, 2S) -1-amino-indanol (17 g,0.11mol,0.15 eq) was mixed with THF 1000mL, nitrogen was purged to reduce the temperature to 0 ℃, DEANB (185 g,1.14mol,1.5 eq) was added dropwise, stirring was continued for 30min at a constant temperature, 1-indanone in THF was added dropwise, stirring was continued for 1-3h at a constant temperature, acetone 800mL was added dropwise to quench the reaction, concentrated to dryness, 1000mL of ethyl propyl acetate was added, 600mL of 10% sulfuric acid solution was washed twice the organic phase, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the cake was dried under reduced pressure to give 181g (80%, purity: 98.6%, EE=96.2%) of the compound.

EXAMPLE 2 Synthesis of Compound 1

Mixing 100g (0.76 mol) of 1-indanone with 800mL of anhydrous MTBE at room temperature of 25 ℃ for later use; (1R, 2S) -1-amino-indanol (34 g,0.23mol,0.30 eq) was mixed with 1000mL of MTBE, nitrogen was purged to reduce the temperature to 0 ℃, DEANB (247 g,1.52mol,2.0 eq) was added dropwise, stirring was continued for 30min at the temperature, MTBE solution of 1-indanone was added dropwise, stirring was continued overnight at 25 ℃, 800mL of acetone was added dropwise to quench the reaction, 600mL of 10% sulfuric acid solution was used to wash the organic phase twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the cake was dried under reduced pressure to give 176.5g (75.6%, purity: 98.3%, EE=95.3%).

EXAMPLE 3 Synthesis of Compound 1

Mixing 100g (0.76 mol) of 1-indanone with 800mL of THF at room temperature of 25 ℃ for later use; (R) -CBS (63 g,0.23mol,0.30 eq) was mixed with 1000mL of THF, nitrogen was purged to reduce the temperature to 0 ℃, DEANB (247 g,1.52mol,2.0 eq) was added dropwise, stirring was continued for 30min, 1-indanone in THF was added dropwise, stirring was continued overnight at 25 ℃, acetone was added dropwise to quench the reaction, 10% sulfuric acid solution 600mL was used to wash the organic phase twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to give 183.2g (82% purity: 98.6%, EE=95.4%).

EXAMPLE 4 Synthesis of Compound 3

50G of Compound 1 (0.37 mol), 90g of Compound 2 (0.37 mol) and 127g of triphenylphosphine (0.48 mol) were taken, dissolved in 1500mL of THF, nitrogen-protected, and cooled to 0 ℃. 98g of diisopropyl azodicarboxylate (DIAD) (0.48 mol) was dissolved in 500mL of THF under nitrogen protection, and the system was dropped dropwise, followed by reaction at 25℃for 20 hours. After the reaction, 150mL of n-heptane was added, and the mixture was slurried at room temperature for 2 hours, filtered, and the cake was dried under vacuum at 45℃to a constant weight to give 107g (85%, purity: 98.8%) of compound 3.

¹H NMR(500MHz,Chloroform-d)δ8.25(d,J＝7.4Hz,1H),7.70(d,J＝10.4Hz,3H),7.33–7.22(m,3H),5.64(t,J＝7.7Hz,1H),4.23(dd,J＝18.7,2.0Hz,1H),3.63(dd,J＝18.7,2.4Hz,1H),3.08(ddd,J＝13.4,9.2,4.0Hz,1H),2.94–2.80(m,1H),2.55(dtd,J＝12.8,8.5,4.1Hz,1H),2.40(dq,J＝16.2,7.4Hz,1H).

EXAMPLE 5 Synthesis of Compound 3

50G of Compound 1 (0.37 mol), 180g of Compound 2 (0.75 mol), 127g of triphenylphosphine (0.48 mol), dissolved in 1500mL of THF, nitrogen-protected, and cooled to 0 ℃.85g of diethyl azodicarboxylate (DEAD) (0.42 mol) was dissolved in 500mL of THF, the system was dropwise added under nitrogen protection, and the temperature was raised to 35℃for 15 hours. After the reaction, 300mL of n-heptane was added and pulped at room temperature for 2 hours, and the mixture was filtered, and the filter cake was dried under vacuum at 45℃to a constant weight, to give 104.3g (82.9%, purity: 98%) of the compound. ¹ H NMR data were substantially the same as in scheme example 4.

EXAMPLE 6 Synthesis of Compound 3

50G of Compound 1 (0.37 mol), 90g of Compound 2 (0.37 mol), 127g of triphenylphosphine (0.48 mol), dissolved in 1500mL of THF, nitrogen-protected, and cooled to 0 ℃.98g of diisopropyl azodicarboxylate (DIAD) (0.48 mol) was dissolved in 500mL of THF under nitrogen protection, and the system was dropped, and the temperature was raised to 15℃for 24 hours. After the reaction, 150mL of n-heptane was added, and the mixture was slurried at room temperature for 2 hours, filtered, and the cake was dried under vacuum at 45℃to a constant weight to give 102.5g (81.5% purity: 98.3%) of a compound. ¹ The H NMR data were essentially the same as in example 4.

EXAMPLE 7 Synthesis of Compound 4

50G of Compound 3 (0.14 mol), 28g of lithium hydroxide (1.17 mol,8.4 eq) are dissolved in 500mL of DMF.17g of mercaptopropionic acid (0.16 mol,1.1 eq) was dissolved in 500mL of DMF and the system was added dropwise. After the addition, the mixture was reacted at 25℃for 5 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 with hydrochloric acid, washing twice with 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 with NaOH, extracting twice with 1000mL of ethyl acetate, merging the organic phases, washing once with 500mL of saturated aqueous NaCl solution, drying over 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining compound 4.6 g (92%, purity: 97.5%).

¹H NMR(500MHz,Chloroform-d)δ7.32–7.24(m,1H),7.20–7.07(m,3H),4.34(t,J＝6.1Hz,1H),3.54–3.38(m,2H),2.96(ddd,J＝14.8,8.2,5.8Hz,1H),2.75(ddd,J＝15.4,8.3,6.2Hz,1H),2.32(ddt,J＝12.8,8.3,6.3Hz,1H),2.17(t,J＝2.4Hz,1H),1.79(ddt,J＝13.3,8.3,5.7Hz,1H),1.63(s,1H),1.41–1.04(m,4H),0.85–0.73(m,1H).

EXAMPLE 8 Synthesis of Compound 4

50G of Compound 3 (0.14 mol), 14g of lithium hydroxide (0.58 mol,4.2 eq) are dissolved in 500mL of DMAc.14.7g of thioglycollic acid (0.16 mol,1.1 eq) was dissolved in 500mL of DMAc, and the system was dropped. After the addition, the mixture was reacted at 10℃for 11 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 by hydrochloric acid, washing twice by 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 by NaOH, extracting twice by 1000mL of ethyl acetate, merging the organic phases, washing once by 500mL of saturated NaCl aqueous solution, drying 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining 21.7g (84.4% purity 97.1%) of the compound. ¹ The H NMR data were essentially the same as in example 7.

EXAMPLE 9 Synthesis of Compound 4

50G of Compound 3 (0.14 mol), 88g of lithium bistrimethylsilylamino (0.53 mol,3.8 eq) are dissolved in 500mL of NMP.14.7g of thioglycollic acid (0.16 mol,1.1 eq) was dissolved in 500mL of NMP and the system was added dropwise. After the addition, the mixture was reacted at 10℃for 11 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 by hydrochloric acid, washing twice by 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 by NaOH, extracting twice by 1000mL of ethyl acetate, merging the organic phases, washing once by 500mL of saturated NaCl aqueous solution, drying 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining 4.7g (77.0% purity 95.8%) of the compound. ¹ The H NMR data were essentially the same as in example 7.

Example 10 Synthesis of RSG

20G of Compound 4 are dissolved in 100mL of isopropyl alcohol/isopropyl ether=1:2 solvent mixture under nitrogen. 12g of methanesulfonic acid, dissolved in 100mL of isopropyl alcohol/isopropyl ether=1:2 mixed solvent, nitrogen-protected, and the system was dropped. After the addition, the mixture was reacted at 25℃for 3 hours. After the reaction, the mixture was filtered, and the filter cake was dried under vacuum at 45℃to a constant weight to give 28.1g (90.1%, 99.8%) of rasagiline mesylate.

¹H NMR(500MHz,Chloroform-d)δ9.30(s,2H),7.62(d,J＝7.6Hz,1H),7.33–7.16(m,3H),4.90(p,J＝5.6Hz,1H),3.81(dq,J＝7.2,4.1Hz,2H),3.25(dt,J＝16.0,7.9Hz,1H),2.86(ddd,J＝16.3,7.9,4.8Hz,1H),2.53(d,J＝2.6Hz,1H),2.52(s,3H),2.47–2.36(m,2H).

EXAMPLE 11 Synthesis of RSG

20G of Compound 4 are dissolved in 500mL of ethyl acetate under nitrogen. 12g of methanesulfonic acid is added dropwise at 25 ℃, and the reaction is carried out for 3 hours after the addition of methanesulfonic acid. The mixture was filtered and the filter cake was dried under vacuum at 45℃to a constant weight to give 26.7g (85.5%, 99.5%) of rasagiline mesylate. ¹ HNMR data are substantially as in example 10.

EXAMPLE 12 Synthesis of RSG

20G of Compound 4 are dissolved in 100mL of isopropyl ether under nitrogen. 12g of methanesulfonic acid is added dropwise at 5 ℃, and the reaction is carried out for 3 hours after the addition of methanesulfonic acid. The mixture was filtered and the filter cake was dried under vacuum at 45℃to a constant weight to give rasagiline mesylate (19.3 g, 61.7%, 99.5%). ¹ The H NMR data were essentially the same as in example 10.

Comparative example 1

100G (0.76 mol) of 1-indanone is mixed with 800mL of dioxane at room temperature of 25 ℃ to dissolve for later use; (1R, 2S) -1-amino-indanol (17 g,0.11mol,0.15 eq) was mixed with 1000mL of dioxane, nitrogen was purged to reduce the temperature to 0 ℃, borane-tetrahydrofuran (98 g,1.14mol,1.5 eq) was added dropwise, stirring was continued for 30min, 1-indanone in THF was added dropwise, stirring was continued for 1-3h, 600mL of methanol was added dropwise to quench the reaction, concentrated to dryness, 1000mL of ethyl acetate was added 1000mL, 600mL of 10% hydrochloric acid solution was added to wash the organic phase twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The residue was added with about 200mL of n-heptane, crystallized at room temperature for 2 hours, filtered, and the filter cake was dried under reduced pressure to give 64.3g (63.5% purity: 98.2% EE=94.7%) of the compound 1.

Comparative example 2

50G of compound 1, 90g of compound 2b,127g of triphenylphosphine were dissolved in 1500mL of THF, nitrogen protection and cooled to 0 ℃.98g of diisopropyl azodicarboxylate (DIAD) was dissolved in 500mL of THF, nitrogen was used to protect the system, and the system was dropped, and the temperature was raised to 15℃for 24 hours. After the reaction, 150mL of n-heptane was added, and the mixture was slurried at room temperature for 2 hours, filtered, and the cake was dried under vacuum at 45℃to a constant weight to give 66.2g (52.6% purity: 96.8%) of Compound 3 b.

Comparative example 3

50G of Compound 3b (0.14 mol), 85.3g of DBU (0.56 mol,4.0 eq) were dissolved in 500mL of DMF,14.7g of thioglycolic acid (0.16 mol,1.1 eq) were dissolved in 500mL of DMF, and the system was dropped. After the addition, the mixture was reacted at 25℃for 6 hours. After the reaction, 1000mL of water was added and mixed, the pH was adjusted to 2-3 by hydrochloric acid, washing twice by 1000mL of ethyl acetate, merging the aqueous phases, adjusting the pH to 11-12 by NaOH, extracting twice by 1000mL of ethyl acetate, merging the organic phases, washing once by 500mL of saturated NaCl aqueous solution, drying 150g of anhydrous sodium sulfate for 0.5h, after the drying, filtering, concentrating the filtrate under reduced pressure until no fraction was obtained, and obtaining 11.5g (48% purity: 95.4%) of the compound.

Comparative example 4

20G of Compound 4 are dissolved in 100mnL isopropanol under nitrogen. 12g of methanesulfonic acid is added dropwise at 5 ℃, and the reaction is carried out for 3 hours after the addition of methanesulfonic acid. The mixture was filtered and the filter cake was dried under vacuum at 45℃to a constant weight to give 16.9g (54%, 99.2%) of rasagiline mesylate.

The above description has been given of the embodiments of the present invention, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.

Claims

1. A method for preparing rasagiline intermediate, which is characterized in that the rasagiline intermediate has a structure shown in a formula 3:

3；

the preparation method comprises the following steps:

Reacting 1-indenone with borane in the presence of a chiral auxiliary and a second organic solvent to form (S) -1-indenol; reacting (S) -1-indenol with a compound of formula 2 in the presence of an activator and a first organic solvent to produce a compound of formula 3;

2；

the chiral auxiliary is at least one of (1R, 2S) -1-amino-indenol and (R) -CBS;

The borane is N, N-diethyl aniline borane;

the activator is triphenylphosphine and an azo condensing agent;

Wherein the azo condensing agent is at least one of diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate, dipropyl azodicarboxylate and dimethyl azodicarboxylate.

2. The preparation method according to claim 1, wherein the molar ratio of the activator to (S) -1-indenol is 2.0 to 3.0:1.

3. The method of claim 1, wherein the molar ratio of the activator to the compound of formula 2 is 1.0 to 3.0:1.

4. The process according to claim 1, wherein the molar ratio of (S) -1-indenol to the compound of formula 2 is 1:1.0 to 2.5.

5. The preparation method according to claim 1, wherein the molar ratio of triphenylphosphine to the azo condensing agent is 0.5-1.5: 1.

6. The preparation method of claim 1, wherein the molar ratio of the chiral auxiliary to the 1-indenone is 0.1-0.4: 1.

7. The preparation method according to claim 1, wherein the molar ratio of 1-indenone to borane is 1:1.0 to 4.0.

8. The method according to any one of claims 1 to 7, wherein the first organic solvent is tetrahydrofuran;

And/or the second organic solvent is at least one of tetrahydrofuran, methyl tertiary butyl ether, methyl tetrahydrofuran and 1, 4-dioxane.

9. A preparation method of rasagiline mesylate, which is characterized in that a compound of formula 3 is reacted with a mercapto acid compound in the presence of alkali and a third organic solvent to obtain rasagiline; salifying rasagiline with methanesulfonic acid to obtain the rasagiline;

Wherein the compound of formula 3 is prepared by the preparation method of any one of claims 1 to 8.

10. The method of claim 9, wherein the base is lithium hydroxide and/or lithium bis trimethylsilylamide.

11. The process of claim 9, wherein the molar ratio of the compound of formula 3 to the base is 1:3.8 to 9.0.

12. The method of claim 9, wherein the molar ratio of the compound of formula 3 to the mercaptoacid compound is 1:1 to 1.5.

13. The preparation method according to claim 9, wherein the molar ratio of the base to the mercapto acid compound is 3.0 to 8.0:1.