CN116143748A - Preparation method of trelagliptin succinate related substances - Google Patents
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- IWYJYHUNXVAVAA-OAHLLOKOSA-N trelagliptin Chemical compound C=1C(F)=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 title claims abstract description 38
- 229950010728 trelagliptin Drugs 0.000 title claims abstract description 38
- 239000000126 substance Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- SGLXGFAZAARYJY-UHFFFAOYSA-N 6-Chloro-3-methyluracil Chemical compound CN1C(=O)C=C(Cl)NC1=O SGLXGFAZAARYJY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- CHCAGFNTASDQFX-UHFFFAOYSA-N 2-(bromomethyl)-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(CBr)=C1 CHCAGFNTASDQFX-UHFFFAOYSA-N 0.000 claims abstract description 6
- WUOQXNWMYLFAHT-UHFFFAOYSA-N tert-butyl n-piperidin-3-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCCNC1 WUOQXNWMYLFAHT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 238000004321 preservation Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 150000001298 alcohols Chemical class 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 12
- 239000003480 eluent Substances 0.000 claims description 12
- 238000004440 column chromatography Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 150000002825 nitriles Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- 239000008346 aqueous phase Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 abstract description 26
- 239000001384 succinic acid Substances 0.000 abstract description 13
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 4
- 239000013558 reference substance Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- -1 (1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) amino Chemical group 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 4
- 150000008282 halocarbons Chemical class 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- WUOQXNWMYLFAHT-MRVPVSSYSA-N tert-butyl n-[(3r)-piperidin-3-yl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCNC1 WUOQXNWMYLFAHT-MRVPVSSYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- 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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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of a related substance of trelagliptin succinate, which comprises the following steps: mixing 6-chloro-3-methyl uracil, 3-boc-aminopiperidine, an acid binding agent and an organic solvent, heating to 78-83 ℃ for reaction to obtain an intermediate 1; dissolving the intermediate 1 in an organic solvent, adding an deboc reagent, and deboc at 20-35 ℃ to obtain an intermediate 2; adding the intermediate 2 and 2-cyano-5-fluorobenzyl bromide into an organic solvent, stirring and heating to 78-83 ℃, adding an acid binding agent, and carrying out heat preservation reaction to obtain a product ZAZ; according to the invention, the quality control of the succinic acid trelagliptin can be provided with a standard reference substance by synthesizing the succinic acid trelagliptin related substance ZAZ, and the impurity generation condition of the succinic acid trelagliptin in the production process is monitored, so that the quality standard of the succinic acid trelagliptin is improved, and the method has important guiding significance for safe administration of succinic acid trelagliptin;
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of a related substance of trelagliptin succinate.
Background
Trelagliptin succinate (Trelagliptin succinate) is an inhibitor of dipeptidyl peptidase IV (DPP-4). The new drug application of the new drug trelagliptin succinate for diabetes has been filed by the wuta corporation in japan at 3 and 7 of 2014 for the treatment of type 2 diabetes. The preparation route is as follows:
finally, salt formation is carried out on the trelagliptin succinate and succinic acid in an organic solvent to obtain the trelagliptin succinate, wherein the structural formula is as follows:
from the synthetic route, there are many possibilities of related compounds in this reaction, namely, compound (S) -2- ((1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) amino) methyl) -4-fluorobenzonitrile is one of the following structural formulas:
the quality control of the medicine mainly controls the content of active ingredients and the content of related substances, particularly the content of the related substances needs to meet the medicinal requirements, and standard reference substances can be provided for the quality control of the succinic acid trelagliptin by synthesizing (S) -2- ((1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-yl) piperidine-3-yl) amino) methyl) -4-fluorobenzonitrile, the impurity generation condition of the trelagliptin succinate in the production process is monitored, so that the quality standard of the trelagliptin succinate is improved, and important guiding significance is provided for the safe administration of the trelagliptin succinate.
Disclosure of Invention
The invention aims to provide a preparation method of a succinic acid trelagliptin related substance, which is characterized in that the compound is obtained through a chemical synthesis method, and the result is confirmed to confirm the structure of the compound, so that the compound is used as an impurity reference substance in the detection of succinic acid trelagliptin related substance.
The technical scheme of the invention is as follows:
a method for preparing a trelagliptin succinate related substance ZAZ, which comprises the following steps:
(1) Mixing 6-chloro-3-methyl uracil, 3-boc-aminopiperidine, an acid binding agent and an organic solvent, heating to 78-83 ℃ for reaction, monitoring the reaction to be completed by TLC, and then carrying out aftertreatment to obtain an intermediate 1;
the molar ratio of the 6-chloro-3-methyl uracil to the 3-boc-aminopiperidine and the acid binding agent is 1:1.0 to 1.3:1.1 to 1.5;
the acid binding agent is one or more selected from triethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium carbonate;
the organic solvent is a mixed solvent of organic alcohols and organic nitriles, wherein the organic alcohols are selected from lower alcohols such as methanol, ethanol, propanol, isopropanol and the like, the organic nitriles are acetonitrile, and the volume ratio of the organic alcohols to the organic nitriles is 7-10: 1, a step of; preferably, the organic solvent is ethanol and acetonitrile with the volume ratio of 10:1;
the volume mass ratio of the organic solvent to the 6-chloro-3-methyl uracil is 10-20: 1, mL/g;
the post-treatment method comprises the following steps: after the reaction is completed, after the reaction liquid is cooled to room temperature, suction filtration is carried out, and column chromatography purification is carried out on filtrate after concentration, methanol is used for: dichloromethane = 1: 1-20 (v/v) as eluent, collecting eluent containing target compound, evaporating solvent and drying to obtain intermediate 1;
(2) Dissolving the intermediate 1 in an organic solvent, adding an deboc reagent, deboc at 20-35 ℃, monitoring the reaction to be completed by TLC, and then performing post-treatment to obtain an intermediate 2;
the molar ratio of the intermediate 1 to the deboc reagent is 1:5.0 to 10.0;
the debrominating agent is one or more of trifluoroacetic acid, industrial hydrochloric acid and hydrogen chloride alcohol solution; preferably trifluoroacetic acid;
the organic solvent is a mixed solvent of organic alcohols and halogenated hydrocarbons, wherein the organic alcohols are selected from lower alcohols such as methanol, ethanol, propanol, isopropanol and the like, the halogenated hydrocarbons are selected from short-chain halogenated hydrocarbons such as dichloromethane, dichloroethane, trichloromethane and the like, and the volume ratio of the organic alcohols to the halogenated hydrocarbons is 1: 15-20; preferably, the organic solvent is ethanol and dichloromethane with volume ratio of 1:15, a mixed solvent;
the volume mass ratio of the organic solvent to the intermediate 1 is 10-20: 1, mL/g;
the post-treatment method comprises the following steps: after the reaction is finished, the reaction solution is cooled to 0-10 ℃, the pH value is regulated to 9-10 by using 10% sodium carbonate solution, the layers are separated, the aqueous phase is extracted by using dichloromethane, the organic phases are combined, and the organic phases are concentrated and purified by column chromatography, wherein methanol is used for preparing the aqueous phase: dichloromethane = 1: 1-20 (v/v) as eluent, collecting eluent containing target compound, evaporating solvent and drying to obtain intermediate 2;
(3) Adding the intermediate 2 and 2-cyano-5-fluorobenzyl bromide into an organic solvent, stirring and heating to 78-83 ℃, adding an acid binding agent for heat preservation reaction, monitoring the reaction to be completed by TLC, and then performing post-treatment to obtain a product ZAZ;
the molar ratio of the intermediate 2 to the 2-cyano-5-fluorobenzyl bromide and the acid binding agent is 1:2 to 2.4:2 to 2.5;
the acid application agent is one or more selected from triethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate; preferably triethylamine;
the organic solvent is ethanol and acetonitrile with the volume ratio of 1: 15-20, preferably ethanol and acetonitrile in a volume ratio of 1:15, a mixed solvent;
the volume mass ratio of the organic solvent to the intermediate 2 is 10-20: 1, mL/g;
the post-treatment method comprises the following steps: after the reaction is completed, after the reaction solution is cooled to room temperature and concentrated, column chromatography purification is carried out, methanol is used for: dichloromethane = 1: 1-20 (v/v) as eluent, collecting eluent containing target compound, evaporating solvent and drying to obtain product ZAZ;
the reaction route is as follows:
6-chloro-3-methyluracil is commercially available, for example, from 99.5% of medical science, inc. of the east Xindao;
3-boc-aminopiperidine is commercially available, for example, from Emei mountain Honghua Co., ltd, 99.5%;
intermediate 1: (S) -6- (3-boc-aminopiperidin-1-yl) -3-methylpyrimidine-2, 4 (1 h,3 h) -dione;
intermediate 2: (S) -6- (3-aminopiperidin-1-yl) -3-methylpyrimidine-2, 4 (1 h,3 h) -dione;
ZAZ: (S) -2- ((1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) amino) methyl) -4-fluorobenzonitrile.
The invention has the beneficial effects that:
the invention provides a preparation method of (S) -2- ((1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) amino) methyl) -4-fluorobenzonitrile, which is obtained through a chemical synthesis method and subjected to structure confirmation to confirm the structure of the compound.
According to the invention, the (S) -2- ((1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidine-4-yl) piperidine-3-yl) amino) methyl) -4-fluorobenzonitrile is synthesized, so that a standard reference substance can be provided for quality control of the succinic acid trelagliptin, and the impurity generation condition of the succinic acid trelagliptin in the production process is monitored, so that the quality standard of the succinic acid trelagliptin is improved, and the method has important guiding significance for safe medication of succinic acid trelagliptin.
Drawings
Figure 1 an infrared spectrum of a trelagliptin succinate related substance ZAZ prepared according to the present invention.
FIG. 2 shows the hydrogen spectrum nuclear magnetism of the related substance ZAZ of the trelagliptin succinate prepared by the method.
Figure 3 high resolution mass spectrum of the trelagliptin succinate related substance ZAZ prepared by the present invention.
Detailed Description
The present invention is further described below by way of specific examples, but the scope of the present invention is not limited thereto.
EXAMPLE 1 preparation of (S) -6- (3-boc-aminopiperidin-1-yl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione
6-chloro-3-methyluracil (10 g,0.060 mol) and R-3-boc-aminopiperidine (13.8 g,0.069 mol) were added to a four-necked glass flask, 100ml of absolute ethanol and 10ml of acetonitrile were added, stirring and heating were carried out, the reaction was carried out at 78℃for 7 hours, TLC was monitored for the end point of the reaction, cooling and suction filtration were carried out, and purification by column chromatography was carried out to obtain 17g of a white solid, yield was 84.1%.
1 HNMR:(400MHz,DMSO-d 6 ):9.77(brs,H),5.51(s,H),5.27(d,H),5.00(s,2H),4.44-4.39(m,H),3.45-3.43(m,H),3.14(m,H),3.10(m,4H),2.75-2.69(m,H),2.09-2.06(m,H),1.86-1.77(m,2H),1.74-1.68(m,H),1.42(m,9H)。
EXAMPLE 2 preparation of (S) -6- (3-aminopiperidin-1-yl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione
(S) -6- (3-boc-aminopiperidin-1-yl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione (17 g,0.052 mol), trifluoroacetic acid (52 g,0.456 mol), dichloromethane 300ml and ethanol 20ml were added to a four-necked glass flask, reacted for 2 hours at 20-30 ℃, TLC was monitored for the end point of the reaction, cooled to 0-10 ℃, 10% soda ash solution was added to adjust pH to 9-10, the layers were separated, extracted with 100ml dichloromethane, and the dichloromethane was concentrated to obtain a solid which was purified by column chromatography to give 8.5g of a white solid with a yield of 72.1%.
1 HNMR:(400MHz,DMSO-d 6 ):9.77(brs,H),5.51(s,H),5.27(d,H),5.00(s,2H),4.44-4.39(m,H),3.45-3.43(m,H),3.14(m,H),3.10(m,4H),2.75-2.69(m,H),2.09-2.06(m,H),1.86-1.77(m,2H),1.74-1.68(m,H)。
EXAMPLE 3 preparation of (S) -2- ((1- (3- (2-cyano-5-fluorobenzyl) -1-methyl-2, 6-dioxo-1, 2,3, 6-tetrahydropyrimidin-4-yl) piperidin-3-yl) amino) methyl) -4-fluorobenzonitrile
(S) -6- (3-aminopiperidin-1-yl) -3-methylpyrimidine-2, 4 (1H, 3H) -dione (8 g,0.035 mol), 2-cyano-5-fluorobenzyl bromide (16.3 g,0.076 mol) were added to 150ml of acetonitrile and 10ml of ethanol, stirred and warmed to reflux, triethylamine (8.5 g,0.084 mol) was added dropwise, and the mixture was incubated for 3 hours, cooled and concentrated, followed by column chromatography to give 14.1g of a white solid with a yield of 81.2%.
1 HNMR:(400MHz,DMSO-d 6 ):9.77(brs,H),8.40(dd,H),7.99(dd,H),7.65(d,H),7.59-7.54(m,H),7.39-7.34(m,H),7.27(dd,H),5.51(s,H),5.27(d,H),5.14(d,H),5.00(s,2H),4.44-4.39(m,H),3.45-3.43(m,H),3.14(m,H),3.10(m,4H),2.75-2.69(m,H),2.09-2.06(m,H),1.86-1.77(m,2H),1.74-1.68(m,H)。MS(ES)[m+H]Calculated value C 26 H 24 F 2 N 6 O 2 491.19; high resolution mass spectrum measured value, m/z= 491.20
The foregoing describes the embodiments of the present invention in detail, but the description should not be construed as limiting the invention. Modifications and variations in the detailed description and scope of the application may be made by those skilled in the art in light of the teachings of the embodiments of the present invention, which fall within the purview of the appended claims and their equivalents.
Claims (10)
1. A method for preparing a trelagliptin succinate related substance ZAZ, which is characterized by comprising the following steps:
(1) Mixing 6-chloro-3-methyl uracil, 3-boc-aminopiperidine, an acid binding agent and an organic solvent, heating to 78-83 ℃ for reaction, monitoring the reaction to be completed by TLC, and then carrying out aftertreatment to obtain an intermediate 1;
the molar ratio of the 6-chloro-3-methyl uracil to the 3-boc-aminopiperidine and the acid binding agent is 1:1.0 to 1.3:1.1 to 1.5;
the organic solvent is a mixed solvent of organic alcohols and organic nitriles, wherein the organic alcohols are selected from methanol, ethanol, propanol and isopropanol, the organic nitriles are acetonitrile, and the volume ratio of the organic alcohols to the organic nitriles is 7-10: 1, a step of;
(2) Dissolving the intermediate 1 in an organic solvent, adding an deboc reagent, deboc at 20-35 ℃, monitoring the reaction to be completed by TLC, and then performing post-treatment to obtain an intermediate 2;
the molar ratio of the intermediate 1 to the deboc reagent is 1:5.0 to 10;
the organic solvent is a mixed solvent of organic alcohols and halogenated alkanes, wherein the organic alcohols are selected from methanol, ethanol, propanol and isopropanol, the halogenated alkanes are selected from dichloromethane, dichloroethane and trichloromethane, and the volume ratio of the organic alcohols to the halogenated alkanes is 1: 15-20;
(3) Adding the intermediate 2 and 2-cyano-5-fluorobenzyl bromide into an organic solvent, stirring and heating to 78-83 ℃, adding an acid binding agent for heat preservation reaction, monitoring the reaction to be completed by TLC, and then performing post-treatment to obtain a product ZAZ;
the molar ratio of the intermediate 2 to the 2-cyano-5-fluorobenzyl bromide and the acid binding agent is 1:2 to 2.4:2 to 2.5;
the organic solvent is ethanol and acetonitrile with the volume ratio of 1: 15-20% of mixed solvent;
the reaction route is as follows:
2. the method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (1), the acid-binding agent is one or more selected from triethylamine, sodium bicarbonate, soda ash and potassium carbonate.
3. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (1), the organic solvent is ethanol and acetonitrile in a volume ratio of 10: 1.
4. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (1), the post-treatment method comprises: after the reaction is completed, after the reaction liquid is cooled to room temperature, suction filtration is carried out, and column chromatography purification is carried out on filtrate after concentration, methanol is used for: dichloromethane = 1: 1-20 is eluent, eluent containing target compound is collected, solvent is distilled off and dried, and intermediate 1 is obtained.
5. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (2), the debrominating agent is one or more of trifluoroacetic acid, industrial hydrochloric acid and an alcohol solution of hydrogen chloride.
6. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (2), the organic solvent is ethanol and dichloromethane in a volume ratio of 1: 15.
7. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (2), the post-treatment method comprises: after the reaction is finished, the reaction solution is cooled to 0-10 ℃, the pH value is regulated to 9-10 by using 10% sodium carbonate solution, the layers are separated, the aqueous phase is extracted by using dichloromethane, the organic phases are combined, and the organic phases are concentrated and purified by column chromatography, wherein methanol is used for preparing the aqueous phase: dichloromethane = 1: 1-20 is eluent, eluent containing target compound is collected, solvent is distilled off and dried, and intermediate 2 is obtained.
8. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (3), the acid applying agent is one or more selected from triethylamine, sodium bicarbonate, soda ash and potassium carbonate.
9. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (3), the organic solvent is ethanol and acetonitrile in a volume ratio of 1: 15.
10. The method for preparing a trelagliptin succinate related substance ZAZ according to claim 1, wherein in the step (3), the post-treatment method comprises: after the reaction is completed, after the reaction solution is cooled to room temperature and concentrated, column chromatography purification is carried out, methanol is used for: dichloromethane = 1: 1-20 is eluent, eluent containing target compound is collected, solvent is distilled off and dried, and then the product ZAZ is obtained.
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