CN118184571A - Synthesis method of trelagliptin succinate impurity compound - Google Patents
Synthesis method of trelagliptin succinate impurity compound Download PDFInfo
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- CN118184571A CN118184571A CN202410266995.XA CN202410266995A CN118184571A CN 118184571 A CN118184571 A CN 118184571A CN 202410266995 A CN202410266995 A CN 202410266995A CN 118184571 A CN118184571 A CN 118184571A
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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 24
- 229950010728 trelagliptin Drugs 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 title claims abstract description 19
- 239000012535 impurity Substances 0.000 title claims abstract description 18
- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000011230 binding agent Substances 0.000 claims abstract description 14
- 239000000543 intermediate Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 239000012065 filter cake Substances 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 238000000967 suction filtration Methods 0.000 claims abstract description 9
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 239000000047 product Substances 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 239000007788 liquid Substances 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- CHCAGFNTASDQFX-UHFFFAOYSA-N 2-(bromomethyl)-4-fluorobenzonitrile Chemical compound FC1=CC=C(C#N)C(CBr)=C1 CHCAGFNTASDQFX-UHFFFAOYSA-N 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 abstract description 14
- 239000001384 succinic acid Substances 0.000 abstract description 7
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- -1 2-cyano-5-fluorobenzyl Chemical group 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- ITYKBOIQLYMDTI-UHFFFAOYSA-N piperidin-3-amine;hydrochloride Chemical compound Cl.NC1CCCNC1 ITYKBOIQLYMDTI-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Classifications
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a synthesis method of a succinic acid trelagliptin impurity compound, which comprises the specific operation processes of mixing raw materials of 2-cyano-5-fluorobenzyl, 3-hydroxy piperidine, an acid binding agent A and an organic solvent A, stirring and heating for reaction, and obtaining an intermediate I through aftertreatment; mixing the intermediate I, PTSC, an acid binding agent B and an organic solvent B, stirring and heating for reaction, and then carrying out post-treatment to obtain an intermediate II; mixing the intermediate II, an ammonia reagent and an organic solvent C, stirring and heating for reaction, then adding HCl through post-treatment, carrying out suction filtration, collecting a filter cake and drying to obtain a product 2- (3-aminopiperidine-1-methyl) -4-fluoro-benzonitrile hydrochloride TL214. According to the invention, the standard reference substance can be provided for quality control of the succinic acid trelagliptin by synthesizing the succinic acid trelagliptin impurity compound, 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 synthesis method of a trelagliptin succinate impurity compound.
Background
Trelagliptin succinate (Trelagliptinsuccinate) is an inhibitor of dipeptidyl peptidase IV (DDP-4). 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, the reaction has the possibility of generating a plurality of related compounds, namely one of the compounds 2- (3-aminopiperidine-1-methyl) -4-fluoro-benzonitrile, and the structural formula is as follows:
for convenience of storage, the material was synthesized to the hydrochloride form, having the following structural formula:
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide a method for synthesizing a trelagliptin succinate impurity compound.
The specific technical scheme is as follows:
A synthesis method of a trelagliptin succinate impurity compound comprises the following steps:
1) Mixing raw materials of 2-cyano-5-fluorobenzyl bromide, 3-hydroxypiperidine, an acid binding agent A and an organic solvent A, stirring and heating to 60-80 ℃, reacting for 5-7h, and performing post-treatment to obtain an intermediate I;
2) Mixing the intermediate I, PTSC, an acid binding agent B and an organic solvent B, stirring and heating to 10-40 ℃, reacting for 5-7 hours, and then performing post-treatment to obtain an intermediate II;
3) Mixing an intermediate II, an ammonia reagent and an organic solvent C, stirring and heating to 60-80 ℃, reacting for 16 hours, then adding HCl through post-treatment, carrying out suction filtration, collecting a filter cake and drying to obtain a product 2- (3-aminopiperidine-1-methyl) -4-fluoro-benzonitrile hydrochloride TL214;
the synthetic route is as follows:
Further, the acid binding agent A in the step 1) is one or more of triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride and lithium hydroxide; the organic solvent A is one or more of ethanol, methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, DMSO and DMF.
Further, the molar ratio of the 2-cyano-5-fluorobenzyl bromide, the 3-hydroxypiperidine and the acid-binding agent A in the step 1) is 1:1.0-1.2:1.5-4.0.
Further, the post-treatment process in step 1) is as follows: after the reaction is finished, maintaining the temperature at 65-75 ℃ for suction filtration, then cooling to 40-50 ℃, adding water, continuously cooling to 10-20 ℃, performing suction filtration, collecting a filter cake, and performing vacuum drying to obtain an intermediate I.
Further, the acid binding agent B in the step 2) is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride and lithium hydroxide, and the organic solvent B is one or more of toluene, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, DMSO and DMF.
Further, the molar ratio of the intermediate I, PTSC and the acid binding agent B in the step 2) is 1:1.0-1.2:1.5-4.0.
Further, after the reaction is finished, the post-treatment process in the step 2) is to keep the temperature of 20-40 ℃ for standing and layering, wash the organic layer twice, control the temperature of 55-65 ℃ for decompression concentration until no obvious liquid drops flow out, carry out column chromatography purification on the concentrated residual liquid, and purify the residual liquid by methanol: dichloromethane=1:0.5-30 as eluent, collecting eluent containing target compound, evaporating solvent and drying to obtain intermediate II.
Further, the organic solvent C in the step 3) is one or more of toluene, acetonitrile, acetone, tetrahydrofuran, DMSO and DMF, and the ammonia reagent is one of ammonia water, ammonia gas and liquid ammonia.
Further, the molar ratio of the intermediate II, the ammonia reagent and the HCl in the step 3) is 1:4-20:4-20.
Further, the post-treatment process of the step 3) is that after the reaction is finished, the temperature is reduced to 10-25 ℃, 10% sodium hydroxide is added for washing twice, water is used for washing 1 time, the organic layer is decompressed and concentrated at the temperature of 65-75 ℃ until no obvious outflow occurs, absolute ethyl alcohol is added for dissolution, HCl gas is used for stirring for 2 hours at the temperature of 20-30 ℃, suction filtration is carried out, filter cakes are leached twice by ethanol, and TL214 is obtained by vacuum drying.
The invention has the beneficial effects that:
The invention provides a trelagliptin succinate impurity compound: a method for synthesizing 2- (3-aminopiperidine-1-methyl) -4-fluoro-benzonitrile, and structural confirmation thereof was performed to confirm the structure of the compound. The synthesis of the impurity compound of the trelagliptin succinate can provide a standard reference substance for quality control of the trelagliptin succinate, and monitor the impurity generation condition in the production process, so that the quality standard of the trelagliptin succinate is improved, and the method has important guiding significance for safe administration of the trelagliptin succinate. In the prior art, 3-aminopiperidine hydrochloride is used as a raw material for synthesizing the impurity, the reaction is extremely easy to produce isomerism, and the impurity is often purified through a plurality of working procedures, so that the yield is low, and meanwhile, the price of the 3-aminopiperidine hydrochloride is higher, and the number of manufacturers is less. The process can obtain high-purity non-isomerism impurity TL214, and the raw materials used are low in price and easy to obtain.
Drawings
FIG. 1 is an infrared spectrum of the trelagliptin succinate impurity compound TL214 of the invention;
FIG. 2 is a nuclear magnetic resonance spectrum of the trelagliptin succinate impurity compound TL214 of the invention;
fig. 3 is a high resolution mass spectrum of the trelagliptin succinate impurity compound TL214 of the present invention.
Detailed Description
The invention will be further described with reference to the drawings and examples of the specification, but the scope of the invention is not limited thereto.
Example 1
Preparation of intermediate I
21.4G (0.1 mol) of 2-cyano-5-fluorobenzyl bromide, 10.1g (0.11 mol) of 3-hydroxypiperidine, 70ml of acetonitrile, 120ml of ethanol and 21.2g (0.21 mol) of triethylamine are added into a four-necked glass flask, stirred and heated, reacted for 5 hours at 75-80 ℃, TLC monitored the end point of the reaction, suction filtered at 65-75 ℃ and then cooled to 40 ℃,200 ml of water is added, the temperature is continuously reduced to 10 ℃, the mixture is stirred for 2 hours, suction filtered, and a filter cake is collected and dried in vacuum to obtain an intermediate I: 21.1g of off-white solid in 90% yield.
1HNMR:(300MHz,DMSO):7.61(H-1),7.35(H-2),7.15(H-3),5.37(H-10),3.62(H-4),3.60(H-6),2.62-2.37(2H-5),2.44-2.48(2H-9),1.52-1.77(2H-7),1.43-1.53(2H-8).
Example 2
Preparation of intermediate II
20G (0.085 mol) of intermediate I, 16.7g (0.087 mol) of p-toluenesulfonyl chloride PTSC and 200ml of toluene are stirred and controlled at 18 ℃, sodium hydroxide solution (11.9 g (prepared by 0.21mol of potassium hydroxide and 98ml of water) is dripped, the reaction is completed for 1 hour, the temperature is kept at 18 ℃ for 5 hours, TLC monitors the end point of the reaction, after the reaction is completed, the reaction is controlled to be kept stand at 25 ℃ for layering, an organic layer is washed twice by water, each 100ml of the organic layer is subjected to rotary evaporation, the temperature is controlled to be 55-65 ℃ until no obvious liquid drops flow out, the concentrated residual liquid is subjected to column chromatography purification, eluent containing target compounds is collected by methanol: dichloromethane=1:15, the solvent is distilled off and dried, and thus the intermediate II is obtained as light yellow oil with the yield of 63.7%.
1HNMR:(300MHz,DMSO):7.75(H-10,H-13)7.61(H-1),7.45(H-11,H-12)7.35(H-2),7.15(H-3),3.62(H-4),3.60(H-6),2.62-2.37(2H-5),2.44-2.48(2H-9),2.43(3H-14),1.52-1.77(2H-7),1.43-1.53(2H-8)
Example 3
Preparation of TL214
20G (0.05 mol) of intermediate II, 250ml of toluene and 20ml of THF are stirred, 15g (0.88 mol) of ammonia gas is introduced for 3 hours, then the temperature is raised to 82 ℃, the reaction is monitored by TLC, after the reaction is finished, the temperature is reduced to 10 ℃, 10% of sodium hydroxide is added for 100ml to wash twice, 100ml of water is washed for 1 time, the organic layer is distilled off in a rotary way, the temperature is controlled to 65 ℃ until no obvious outflow exists, 350ml of absolute ethyl alcohol is added for dissolution, 18g (0.49 mol) of HCl gas is introduced at the temperature of 20 ℃, the stirring is carried out for 2 hours, the suction filtration is carried out, the filter cake is leached twice by ethanol, and the filter cake is dried for 6 hours at 45 ℃ in a vacuum oven, thus obtaining TL214:8.0g of white solid, yield 68.4%.
1HNMR:(400MHz,DMSO-d6):12.37(1H),8.78(2H),8.20-8.18(1H),8.12-8.08(1H),7.61-7.56(1H),4.62-4.51(2H),3.69(1H),3.58-3.55(1H),3.40(1H),3.08(2H),2.09-1.94(3H),1.66-1.63(1H), Shown in fig. 2.
As can be seen from the infrared spectrum of the sample in FIG. 1, the structure of the catalyst contains structural units such as primary amine, amine salt, 1,2, 4-trisubstituted benzene ring, methylene, cyano, ar-F and the like, and is consistent with the structure of TL 214.
As shown in fig. 3, MS (ES) [ m+h ], calculated C 13H16FN3 ·hcl 234.1401; actual measurement value: 234.1403.
MS (ES) [ M+Na ], calculated 256.1220; actual measurement value: 256.1217.
The foregoing describes in detail specific embodiments of the present invention, 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. The synthesis method of the trelagliptin succinate impurity compound is characterized by comprising the following steps of:
1) Mixing raw materials of 2-cyano-5-fluorobenzyl bromide, 3-hydroxypiperidine, an acid binding agent A and an organic solvent A, stirring and heating to 60-80 ℃, reacting for 5-7h, and performing post-treatment to obtain an intermediate I;
2) Mixing the intermediate I, PTSC, an acid binding agent B and an organic solvent B, stirring and heating to 10-40 ℃, reacting for 5-7 hours, and then performing post-treatment to obtain an intermediate II;
3) Mixing an intermediate II, an ammonia reagent and an organic solvent C, stirring and heating to 60-80 ℃, reacting for 16 hours, then adding HCl through post-treatment, carrying out suction filtration, collecting a filter cake and drying to obtain a product 2- (3-aminopiperidine-1-methyl) -4-fluoro-benzonitrile hydrochloride TL214;
the synthetic route is as follows:
2. The synthesis method according to claim 1, wherein the acid binding agent A in the step 1) is one or more of triethylamine, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride and lithium hydroxide; the organic solvent A is one or more of ethanol, methanol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, DMSO and DMF.
3. The synthesis method according to claim 1, wherein the molar ratio of 2-cyano-5-fluorobenzyl bromide, 3-hydroxypiperidine and acid-binding agent A in step 1) is 1:1.0-1.2:1.5-4.0.
4. The synthesis method according to claim 1, wherein the post-treatment process in step 1) is: after the reaction is finished, maintaining the temperature at 65-75 ℃ for suction filtration, then cooling to 40-50 ℃, adding water, continuously cooling to 10-20 ℃, performing suction filtration, collecting a filter cake, and performing vacuum drying to obtain an intermediate I.
5. The synthesis method according to claim 1, wherein the acid-binding agent B in the step 2) is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride and lithium hydroxide, and the organic solvent B is one or more of toluene, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, DMSO and DMF.
6. The synthesis method according to claim 1, wherein the molar ratio of the intermediates I, PTSC and the acid-binding agent B in the step 2) is 1:1.0-1.2:1.5-4.0.
7. The synthesis method according to claim 1, wherein the post-treatment process in step 2) is that after the reaction is finished, the mixture is kept at 20-40 ℃ for standing and layering, the organic layer is washed twice with water, the temperature is controlled at 55-65 ℃ and reduced pressure is concentrated until no obvious liquid drops flow out, the concentrated residual liquid is subjected to column chromatography purification, and methanol is used for: dichloromethane=1:0.5-30 as eluent, collecting eluent containing target compound, evaporating solvent and drying to obtain intermediate II.
8. The synthesis method according to claim 1, wherein the organic solvent C in the step 3) is one or more of toluene, acetonitrile, acetone, tetrahydrofuran, DMSO and DMF, and the ammonia reagent is one of ammonia water, ammonia gas and liquid ammonia.
9. The synthesis according to claim 1, wherein the molar ratio of intermediate II, ammonia reagent and HCl in step 3) is 1:4 to 20:4 to 20.
10. The method of synthesis according to claim 1, wherein the post-treatment process of step 3) is to cool to 10-25 ℃ after the reaction is completed, add 10% sodium hydroxide to wash twice, wash with water 1 time, decompress and concentrate the organic layer at 65-75 ℃ until no obvious flow out, add absolute ethanol to dissolve, pass HCl gas at 20-30 ℃ and stir for 2 hours, suction filter, filter cake is rinsed twice with ethanol, and vacuum dry to obtain TL214.
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| CN202410266995.XA CN118184571A (en) | 2024-03-08 | 2024-03-08 | Synthesis method of trelagliptin succinate impurity compound |
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| CN202410266995.XA CN118184571A (en) | 2024-03-08 | 2024-03-08 | Synthesis method of trelagliptin succinate impurity compound |
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