CN113121414B - Synthesis method of trelagliptin intermediate - Google Patents

Synthesis method of trelagliptin intermediate Download PDF

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CN113121414B
CN113121414B CN202010044091.4A CN202010044091A CN113121414B CN 113121414 B CN113121414 B CN 113121414B CN 202010044091 A CN202010044091 A CN 202010044091A CN 113121414 B CN113121414 B CN 113121414B
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methanol
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CN113121414A (en
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张贵民
杨德亮
黄文波
张奎昌
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a synthesis method of a trelagliptin intermediate (R) -3-aminopiperidine dihydrochloride, which comprises the following steps: 1) Reducing carbonyl of the compound of the formula I in an organic solvent A by a reducing agent to prepare a compound of the formula II; 2) Resolving the compound of the formula II in an organic solvent B by chiral reagents to obtain a compound of the formula III; 3) The compound of the formula III is subjected to palladium-carbon removal of benzyl to prepare (R) -3-aminopiperidine dihydrochloride in an organic solvent C, and the (R) -3-aminopiperidine dihydrochloride prepared by the invention has high yield and purity, high HPLC purity is higher than 98.16 percent, and optical purity is higher than 98.92 percent; the invention has low price of the initial raw materials, is beneficial to reducing the industrial cost, has short synthetic process route and mild reaction condition, and is easy to realize industrially.

Description

Synthesis method of trelagliptin intermediate
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a synthesis method of a tragliptin intermediate.
Background
Trelagliptin succinate (Trelagliptin succinate) is an inhibitor of dipeptidyl peptidase IV (DPP-4). The new medicine application of the new medicine troglitazone succinate for treating type 2 diabetes is submitted to the Ministry of health and welfare of japan by the wuta corporation in 2014, 3 and 7, and has the chemical structural formula as follows:
patent US2012197018A1 discloses a process for synthesizing trelagliptin, the synthetic process route of which is as follows:
among them, (R) -3-aminopiperidine dihydrochloride is an important intermediate for synthesizing trelagliptin, and many methods for synthesizing (R) -3-aminopiperidine dihydrochloride have been reported so far.
Patent WO2011160037 takes 3-acetaminopyridine as a raw material, and is resolved by hydrogenation reduction, amide hydrolysis and D- (+) dibenzoyltartaric acid (D-DBTA) in sequence, and then the (R) -3-aminopiperidine dihydrochloride is obtained by hydrochloride formation. In the route, the reduction reaction needs to be carried out under the pressure higher than 10bar, the pressure is higher, the requirement on reaction equipment is higher, and the large-scale production is not facilitated.
The patent CN103319399A takes 3-piperidine formamide as a raw material, 3-aminopiperidine is obtained by carrying out Huffman rearrangement reaction under the action of 1-fluoronaphthalene, oxidant and fluoroboric acid, then concentrated hydrochloric acid is acidified to prepare salt, then the free 3-aminopiperidine is alkalized, tartaric acid is used for resolution, and the product is acidified by the concentrated hydrochloric acid to obtain the target product. In the method, raw materials are relatively expensive, and the fluoroboric acid reagent has high requirements on reaction equipment.
Patent WO2007112368 and literature Bioorg.Med.chem.2006,14 (7), 2131-2150 report that the target product is finally obtained by taking D-ornithine salt as a raw material, sequentially esterifying with methanol, cyclizing, acidifying to form salt, then hydrogenation reducing and salifying. In this method, the chiral starting material is relatively expensive, and the esterification process is carried out under low temperature (-78 ℃) condition, and IRA-400 (OH) is used after the esterification of methanol - ) Ion exchange resin purification increases industrial costs.
Patent CN104211702a discloses that D-ornithine hydrochloride is used as a raw material, reacted with thionyl chloride at-80 ℃, purified by 717 (OH-) anion exchange resin, and reacted with lithium aluminum hydride at-80 ℃ to obtain a reddish brown oil. The raw materials used in the process are expensive, the ultralow temperature of-80 ℃ is difficult to realize industrially, the use of 717 (OH-) anion exchange resin with high price increases the industrial cost, and the obtained oily product contains a large amount of impurities and has lower purity.
Patent CN107445887a discloses that compound (3) is produced from compound (2) by imidization; the chiral compound (4) is prepared by asymmetric hydrogenation of the compound (3); finally, the chiral compound (4) is subjected to an acidic hydrolysis reaction to obtain a compound (1), and the asymmetric hydrogenation of the compound (3) is carried out by using a rhodium catalyst [ Rh ] 2 (pfb) 4 、Rh 2 (OAc) 4 、RhCl 3 、Rh 2 (OCOt-Bu) 4 Rhodium mandelate, rhodium trifluoroacetate and [ Rh (cod) 2 ]BF 4 ]Expensive, increases the industrial cost, and the synthetic route is as follows:
disclosure of Invention
Aiming at the problems of longer production period, expensive raw materials and high requirements on equipment existing in the process of preparing (R) -3-aminopiperidine dihydrochloride at present, the invention provides a novel method for synthesizing a tragliptin intermediate.
The technical scheme of the invention specifically comprises the following steps:
the synthesis method of the trelagliptin intermediate specifically comprises the following steps:
1) Reducing carbonyl of the compound of the formula I in an organic solvent A by a reducing agent to prepare a compound of the formula II;
2) Resolving the compound of the formula II in an organic solvent B by chiral reagents to obtain a compound of the formula III;
3) Removing benzyl groups from the compound of the formula III in an organic solvent C through palladium carbon to prepare a compound of a formula IV, namely (R) -3-aminopiperidine dihydrochloride;
the reaction route is as follows:
in the synthesis method, the reducing agent in the step 1 is selected from one of red aluminum and lithium aluminum hydride.
Preferably, step 1 specifically comprises the following steps: at the temperature of-10 to 0 ℃, adding a reducing agent into the organic solvent A suspending the compound of the formula I, stirring, and then heating for reaction.
Further preferably, the reducing agent is added dropwise or in a fed-batch manner.
In the synthesis method, the heating reaction temperature in the step 1 is 50-66 ℃.
Preferably, the molar ratio of reducing agent to compound of formula I is preferably from 4 to 6:1.
In the synthesis method, in the step 1, the organic solvent A is selected from one or two of anhydrous toluene and anhydrous tetrahydrofuran.
The following steps further detail the preparation of the compounds of formula II of the present invention:
under the protection of inert gas, suspending the compound of the formula I in an organic solvent A, cooling to-10-0 ℃, stirring, slowly dropwise adding an organic solution A dissolved with a reducing agent, heating to 50-66 ℃, and stirring for reaction for 4-7 hours. Cooling the reactant to 0-5 ℃, quenching the reaction by using saturated ammonium chloride solution, filtering, and concentrating the filtrate under reduced pressure to obtain the compound shown in the formula II.
Preferably, the inert gas is selected from nitrogen or argon.
Further preferably, the inert gas is nitrogen in one embodiment.
In the synthesis method, the chiral reagent in the step 2 is selected from one of D- (+) -camphorsulfonic acid and D-pyroglutamic acid.
Preferably, the molar ratio of compound of formula II to chiral resolving agent in step 2 is 1:1.95 to 2.50.
In the synthesis method, in the step 2, the organic solvent B is a combination of ethyl acetate and an alcohol solvent.
Preferably, the volume ratio of ethyl acetate to alcohol solvent is 1:2 to 9.
Preferably, the alcohol solvent is selected from one or a mixture of methanol and ethanol.
The following steps further detail the preparation of the compounds of formula III of the present invention:
dissolving chiral reagent in organic solvent B, heating to dissolve, adding compound of formula II, reflux reacting, cooling for crystallization, cooling, filtering, washing filter cake, and recrystallizing filter cake with ethanol/water. Dissolving the solid obtained by recrystallization in methanol/water, adjusting the pH with alkali, extracting, washing, drying, filtering and concentrating to obtain the compound of the formula III.
Preferably, the base is selected from NaOH, KOH, na 2 CO 3 And K 2 CO 3 One of them.
In one embodiment, the base is NaOH.
Preferably, the pH is 8.5 to 9.5.
In one embodiment, the pH is 9.0.
In the synthesis method, the reaction temperature in the step 3 is 40-50 ℃.
In the synthesis method, the organic solvent C in the step 3 is selected from one or two of methanol and ethanol.
In the synthetic method, in the step 3, the dosage of palladium-carbon is 3.0 to 5.0 percent of the mass of the compound in the formula III.
The following steps further detail the preparation of the compounds of formula IV of the present invention:
adding a compound shown in a formula III, palladium carbon, methanol and concentrated hydrochloric acid into a hydrogenation kettle, replacing the materials with nitrogen and hydrogen for three times in sequence, heating to 40-50 ℃ for reaction for 10-14 hours, cooling to room temperature, filtering, concentrating the filtrate under reduced pressure, adding isopropanol, distilling under reduced pressure, adding methanol, heating for dissolving, adding ethyl acetate, cooling for crystallization, filtering, washing a filter cake, and drying to obtain the compound shown in the formula I V.
Preferably, the temperature of the heated dissolution is 40-50 ℃.
Preferably, the temperature of the cooling crystallization is-10 to-5 ℃.
The compounds of formula I are commercially available or can be synthesized as described in reference to examples 1-3.
The compound of the formula I is obtained by reacting 3-bromopiperidine-2, 6-dione with benzylamine under the action of alkali.
Preferably, the solvent used for synthesizing the compound of formula I is selected from one or more of tetrahydrofuran, DMF and propylene glycol.
Preferably, the base used for the synthesis of the compound of formula I is selected from one of triethylamine, potassium carbonate and sodium carbonate.
Preferably, the reaction temperature for synthesizing the compound of formula I is 60-66 ℃.
It is further preferred that the molar ratio of 3-bromopiperidine-2, 6-dione to base in the reaction for the synthesis of the compound of formula I is 1:1.0 to 1.2.
Preferably, the molar ratio of 3-bromopiperidine-2, 6-dione to benzylamine is 1:1.05-1.20.
Compared with the prior art, the invention has the following remarkable progress:
(1) The price of the initial raw material is low and is lower than 1/35 of the price of the D-ornithine hydrochloride, which is beneficial to reducing the industrial cost;
(2) The synthetic route is short, and the method is easy to realize industrially;
(3) The product purity is high, the HPLC purity is higher than 98.16%, and the optical purity is higher than 98.92%;
(4) The process does not need to use expensive strong anion exchange resin, thereby remarkably reducing the industrial cost.
Detailed Description
The invention will be further described by the following examples, which should not be construed as limiting the scope of the invention. Variations that occur to those skilled in the art in light of the teachings of the present invention are intended to be within the scope of the claims of the present application.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
The trelagliptin intermediate is (R) -3-aminopiperidine dihydrochloride; the red aluminum is sodium dihydro-bis (2-methoxyethoxy) aluminate (consisting of 70% of sodium dihydro-bis (2-methoxyethoxy) aluminate and 30% of toluene, namely 70% of toluene solution, CAS: 22722-98-1); the DMF is N, N-dimethylformamide; the anhydrous tetrahydrofuran can be obtained by adding metallic sodium into commercial tetrahydrofuran solution, heating and refluxing, and distilling; the anhydrous toluene can be obtained by adding metallic sodium into a commercial toluene solution, heating and refluxing, and distilling.
Reference example 1 preparation of Compounds of formula I
Benzylamine (12.86 g,1.20 eq) and triethylamine (11.13 g,0.11 mol) were dissolved in 200mL tetrahydrofuran, heated to reflux, and then 3-bromopiperidine-2, 6-dione (19.20 g,0.10 mol) in tetrahydrofuran (200 mL) was added dropwise, and after the addition, the reflux reaction was continued for 2 hours. Filtering, collecting filtrate, concentrating under reduced pressure to obtain crude compound of formula I, purifying with silica gel column (chloroform/methanol=10:1) to obtain pure compound of formula I, yield 53.21%, HPLC purity: 98.65%.
Reference example 2 preparation of Compounds of formula I
Benzylamine (11.79 g,1.10 eq) and potassium carbonate (16.59 g,0.12 mol) were dissolved in 200mL propylene glycol, heated to 60-66℃and a solution of 3-bromopiperidine-2, 6-dione (19.20 g,0.10 mol) in propylene glycol (200 mL) was added dropwise, and the reaction was continued for 2 hours after the addition. Filtering, collecting filtrate, concentrating under reduced pressure to obtain crude compound of formula I, purifying with silica gel column (chloroform/methanol=10:1) to obtain pure compound of formula I, yield 52.56%, HPLC purity: 98.95%.
Reference example 3 preparation of Compounds of formula I
Benzylamine (11.25 g,1.05 eq) and sodium carbonate (10.60 g,0.10 mol) were dissolved in 200mL DMF, heated to 60-66℃and a solution of 3-bromopiperidine-2, 6-dione (19.20 g,0.10 mol) in DMF (200 mL) was added dropwise and the reaction was continued for 2.5 hours after the addition. Filtering, collecting filtrate, concentrating under reduced pressure to obtain crude compound of formula I, purifying with silica gel column (chloroform/methanol=10:1) to obtain pure compound of formula I, yield 52.34%, HPLC purity: 98.22%.
EXAMPLE 1 preparation of Compounds of formula II
Suspending a compound of formula I (10.91 g,0.05 mol) in anhydrous tetrahydrofuran (60 mL) under nitrogen protection, cooling to-10 to-5 ℃, and dropwise adding LiAlH into the solution 4 (7.59 g,0.20mol,4 eq) in 100mL of tetrahydrofuran, and after dropping, the reaction mixture was heated to reflux for 5 hours. The reaction was cooled to 0 ℃ and carefully quenched with saturated ammonium chloride solution, then filtered and the filtrate concentrated under reduced pressure to give the compound of formula II in 94.73% yield, HPLC purity: 97.63%.
EXAMPLE 2 preparation of Compounds of formula II
Under the protection of nitrogen, a compound (10.91 g,0.05 mol) of the formula I is dissolved in 150mL of anhydrous toluene, cooled to-5-0 ℃, red aluminum (70% toluene solution) (64.9 g,0.225mol,4.5 eq) is slowly added dropwise and dissolved in the anhydrous toluene, the dropping speed is controlled to keep the reaction temperature at-5-0 ℃, after the dropwise addition is finished, stirring is continued for 30min, and then the mixture is heated to 60-66 ℃ for reaction for 4 hours. Cooled to room temperature, 150mL of 5% HCl solution was added to the reaction system, the solvent was distilled off under reduced pressure, the solid was collected by filtration under reduced pressure, and the solid was washed with water. The resulting solid was suspended in methanol (80 mL) and heated to reflux for 30min, cooled to room temperature, 10% potassium carbonate solution (70 mL) was added, vigorously stirred at room temperature for 2 hours, the solid was collected by filtration, washed with water, dried in vacuo at 60 ℃ to give a compound of formula II as a solid in 96.25% yield, HPLC purity: 98.26%.
EXAMPLE 3 preparation of Compounds of formula II
Under the protection of nitrogen, a compound (10.91 g,0.05 mol) of the formula I is dissolved in 150mL of anhydrous toluene, cooled to-5-0 ℃, red aluminum (70% toluene solution, 86.5g,0.30mol,6.0eq, dissolved in the anhydrous toluene) is slowly added dropwise, the dropping speed is controlled to keep the reaction temperature at-10 to-5 ℃, after the dropwise addition is completed, stirring is continued for 30min, and then the mixture is heated to 60-66 ℃ for reaction for 4 hours. Cooled to room temperature, 150mL of 5% HCl solution was added to the reaction system, the solvent was distilled off under reduced pressure, the solid was collected by filtration under reduced pressure, and the solid was washed with water. The resulting solid was suspended in methanol (80 mL) and heated to reflux for 30min, cooled to room temperature, 10% potassium carbonate solution (70 mL) was added, vigorously stirred at room temperature for 2 hours, the solid was collected by filtration, washed with water, dried in vacuo at 60 ℃ to give a compound of formula II as a solid, yield 95.70%, HPLC purity: 97.85%.
EXAMPLE 4 preparation of Compounds of formula II
Suspending a compound of formula I (10.91 g,0.05 mol) in anhydrous tetrahydrofuran (60 mL) under the protection of argon, cooling to-20 to-15 ℃, and dropwise adding LiAlH into the solution 4 (3.80 g,0.10mol,2 eq) in 100mL of tetrahydrofuran, and after dropping, the reaction mixture was heated to reflux for 5 hours. The reaction was cooled to 0 ℃ and carefully quenched with saturated ammonium chloride solution, then filtered and the filtrate concentrated under reduced pressure to give the compound of formula II in 90.16% yield, HPLC purity: 94.58%.
EXAMPLE 5 preparation of Compounds of formula III
D-pyroglutamic acid (58.54 g,0.39 mol) was added to 500mL of a solvent (50 mL of ethyl acetate+450 mL of ethanol), heated to reflux, after which the compound of formula II (38.06 g,0.20 mol) was added, stirred to reflux for 2 hours, naturally cooled to room temperature, white solid was precipitated, then cooled at 0℃for 1 hour, filtered, washed with ethanol, and the filter cake was recrystallized from ethanol/water (volume ratio 1:1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water=2:8), pH was adjusted to 9 with 6M NaOH solution, and then extracted with dichloromethane (200 ml×3), the organic phase was washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness to obtain a white solid with a yield of 45.25% (relative to 50% of maximum yield), which was the compound of formula III, HPLC purity: 98.85%, optical purity: 99.95%.
EXAMPLE 6 preparation of Compounds of formula III
D-pyroglutamic acid (60.04 g,0.40 mol) was added to 500mL of a solvent (100 mL of ethyl acetate+400 mL of methanol), heated to reflux, after which the compound of formula II (38.06 g,0.20 mol) was added, stirred to reflux for 2 hours, naturally cooled to room temperature, white solid was precipitated, then cooled at 0℃for 1 hour, filtered, washed with ethanol, and the filter cake was recrystallized with ethanol/water (volume ratio 1:1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water=2:8), pH was adjusted to 8.5 with 6M KOH solution, and then extracted with dichloromethane (200 ml×3), the organic phase was washed with 200mL saturated brine and 200mL water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness to obtain a white solid, yield 46.72% (relative to 50% of the maximum yield), namely the compound of formula III, HPLC purity: 98.90%, optical purity: 99.97%.
EXAMPLE 7 preparation of Compounds of formula III
D- (+) -camphorsulfonic acid (115.64 g,0.50 mol) was added to 500mL of a solvent (150 mL of ethyl acetate+350 mL of ethanol), heated to reflux, after which the compound of formula II (38.06 g,0.20 mol) was added after dissolution, stirred to reflux for 2 hours, cooled naturally to room temperature, a white solid was precipitated, cooled again at 0℃for 1 hour, filtered, washed with ethanol, and the filter cake recrystallized from ethanol/water (volume ratio 1:1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water=2:8), and the mixture was treated with 6M Na 2 CO 3 The pH of the solution was adjusted to 9.5, extracted with dichloromethane (200 mL. Times.3), the organic phase was washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give a white solid in 45.41% yield (relative to 50% maximum yield), as compound of formula III, HPLC purity: 98.87%, optical purity: 99.93%.
EXAMPLE 8 preparation of Compounds of formula III
D-pyroglutamic acid (45.03 g,0.30 mol) was added to 500mL of ethanol, heated to reflux, and after the dissolution, the compound of formula II (38.06 g,0.20 mol) was added, stirred to reflux for 2 hours, naturally cooled to room temperature, white solid was precipitated, then cooled at 0℃for one hour, filtered, washed with ethanol, and the filter cake was recrystallized with ethanol/water (volume ratio 1:1).
The solid obtained by the above recrystallization was dissolved in 500mL of a mixed solution of methanol and water (methanol/water=2:8), and 6M of K was used 2 CO 3 The pH of the solution was adjusted to 10, extracted with dichloromethane (200 mL. Times.3), the organic phase was washed with 200mL of saturated brine and 200mL of water, respectively, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give a white solid in 43.11% yield (relative to 50% maximum yield), which was the compound of formula III, HPLC purity: 98.20%, optical purity: 99.76%.
EXAMPLE 9 preparation of Compounds of formula IV
In a 250mL dry hydrogenation kettle equipped with a thermometer and mechanically stirring, 19.00g of a compound of formula III, 0.60g (dry basis) of 10% palladium carbon, 180mL of methanol and 20.0mL of concentrated hydrochloric acid are sequentially added, the reaction kettle is filled after the addition, nitrogen is replaced for three times, then hydrogen is replaced for three times, the pressure is increased to 1.0MPa, the temperature is increased to 40-45 ℃ and the reaction is stirred for 12 hours, the reaction is stopped, the reaction is cooled to room temperature, the filtration is carried out, the filtrate is distilled under reduced pressure until no fraction exists, isopropanol (20 mL multiplied by 3) is added, the isopropanol is distilled under reduced pressure, then 25mL of methanol is added, the solution is heated and dissolved at 40-50 ℃, 55mL of ethyl acetate is slowly dripped into methanol, the solution is cooled to-10-5 ℃ after the addition, the crystallization is carried out, the filtration is carried out, the filter cake is washed by ethyl acetate, and the compound of formula I V is obtained after the drying, the yield is 92.73%, the HPLC purity is 99.75%, and the optical purity is obtained after the steps of: 99.92%.
EXAMPLE 10 preparation of Compounds of formula IV
In a 250mL dry hydrogenation kettle equipped with a thermometer and mechanically stirring, 19.00g of a compound of formula III, 0.95g (dry basis) of 10% palladium carbon, 180mL of ethanol and 20.0mL of concentrated hydrochloric acid are sequentially added, the reaction kettle is filled after the addition, nitrogen is replaced for three times, then hydrogen is replaced for three times, the pressure is increased to 1.0MPa, the temperature is increased to 45-50 ℃ and the reaction is stirred for 10 hours, the reaction is stopped, the reaction is cooled to room temperature, the filtration is carried out, the filtrate is distilled under reduced pressure until no fraction exists, isopropanol (20 mL multiplied by 3) is added, the isopropanol is distilled under reduced pressure, then 25mL of ethanol is added, the ethanol is heated and dissolved at 40-50 ℃, 55mL of ethyl acetate is slowly added into ethanol, the temperature is reduced to-10 to-5 ℃ after the addition, the crystallization is carried out, the filtration is carried out, the filter cake is washed by ethyl acetate, and the compound of formula I V is obtained after the drying, the yield is 93.83%, the HPLC purity is 99.64%, and the optical purity is obtained after the steps of: 99.90%.
EXAMPLE 11 preparation of Compounds of formula IV
In a 250mL dry hydrogenation kettle equipped with a thermometer and mechanically stirring, 19.00g of a compound of formula III, 0.76g (dry basis) of 10% palladium carbon, 180mL of a mixed solvent (80 mL of ethanol+100 mL of methanol) and 20.0mL of concentrated hydrochloric acid are sequentially added, the reaction kettle is filled after the addition, nitrogen is firstly used for three times, hydrogen is used for three times, the pressure is increased to 1.0MPa, the temperature is increased to 45-50 ℃ for stirring and reacting for 11 hours, the reaction is stopped, the reaction is cooled to room temperature, the filtration is carried out, after the filtrate is distilled under reduced pressure to no fraction, isopropanol (20 mL multiplied by 3) is added, the isopropanol is distilled under reduced pressure to remove the methanol, then 25mL of methanol is added for heating and dissolving at 40-50 ℃, 55mL of ethyl acetate is slowly dripped into the methanol, the temperature is reduced to-10 to-5 ℃ for crystallization, the filtration is carried out, a filter cake is washed by ethyl acetate, and the compound of formula I V is obtained after the drying, the yield 93.37%, the HPLC purity is 99.83%, and the optical purity is obtained after the reaction is dried: 99.91%.
EXAMPLE 12 preparation of Compounds of formula IV
In a 250mL dry hydrogenation kettle equipped with a thermometer and mechanically stirring, 19.00g of a compound of formula III, 1.25g (dry basis) of 10% palladium carbon, 180mL of isopropyl alcohol and 20.0mL of concentrated hydrochloric acid are sequentially added, the reaction kettle is filled after the addition, nitrogen is replaced for three times, hydrogen is replaced for three times, the pressure is increased to 1.0MPa, the temperature is increased to 60-65 ℃ and the reaction is stirred for 10 hours, the reaction is stopped, the reaction is cooled to room temperature, the filtration is carried out, the filtrate is distilled under reduced pressure until no fraction is obtained, 25mL of ethanol is added for heating and dissolving at 40-50 ℃, 55mL of ethyl acetate is slowly dripped into the ethanol, the temperature is reduced to-10 to-5 ℃ after the addition, the crystallization is carried out, the filtration is carried out, the ethyl acetate is used for washing filter cake, and the product of formula I V is obtained after the drying, the yield is 90.15%, the HPLC purity is 98.16%, and the optical purity is obtained: 98.92%.

Claims (7)

1. The synthesis method of the trelagliptin intermediate is characterized by comprising the following steps of:
1) Reducing carbonyl of the compound of the formula I in an organic solvent A by a reducing agent to prepare a compound of the formula II;
2) Resolving the compound of the formula II in an organic solvent B by chiral reagents to obtain a compound of the formula III;
3) Removing benzyl groups from the compound of the formula III in an organic solvent C through palladium carbon to prepare a compound of a formula IV of a Trelagliptin intermediate;
the reaction route is as follows:
；
in the step 1, the reducing agent is selected from one of red aluminum and lithium aluminum hydride;
the step 1 specifically comprises the following steps: adding a reducing agent into an organic solvent A suspending the compound of the formula I at the temperature of-10-0 ℃, stirring, and then heating for reaction;
the chiral reagent in the step 2 is selected from one of D- (+) -camphorsulfonic acid and D-pyroglutamic acid;
the reaction temperature in the step 3 is 40-50 ℃.
2. The method of claim 1, wherein the molar ratio of reducing agent to compound of formula I in step 1 is from 4 to 6:1.
3. The synthetic method according to claim 1, wherein the organic solvent a in step 1 is one or both selected from the group consisting of anhydrous toluene and anhydrous tetrahydrofuran.
4. The method of claim 1, wherein the molar ratio of the compound of formula II to chiral resolving agent in step 2 is 1:1.95 to 2.50.
5. The method according to claim 1, wherein the organic solvent B in step 2 is a combination of ethyl acetate and an alcohol solvent, and the alcohol solvent is methanol or ethanol.
6. The synthetic method according to claim 1, wherein the organic solvent C in step 3 is selected from one or both of methanol and ethanol.
7. The method according to claim 1, wherein in step 3, the palladium carbon is used in an amount of 3.0 to 5.0% by mass of the compound of formula III.
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