WO2017071569A1 - 1, 2, 5-噻二唑烷-1, 1-二氧化物的盐型、晶型及其制备方法和中间体 - Google Patents
1, 2, 5-噻二唑烷-1, 1-二氧化物的盐型、晶型及其制备方法和中间体 Download PDFInfo
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- WO2017071569A1 WO2017071569A1 PCT/CN2016/103297 CN2016103297W WO2017071569A1 WO 2017071569 A1 WO2017071569 A1 WO 2017071569A1 CN 2016103297 W CN2016103297 W CN 2016103297W WO 2017071569 A1 WO2017071569 A1 WO 2017071569A1
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- SDPGYQZOLJZRKW-UHFFFAOYSA-N CC(C)(C)OC(N(CCN1c2cc(N)ncc2)S1(=O)=O)=O Chemical compound CC(C)(C)OC(N(CCN1c2cc(N)ncc2)S1(=O)=O)=O SDPGYQZOLJZRKW-UHFFFAOYSA-N 0.000 description 1
- 0 CCCC(C)CC(*C(C)(C(*)C(CCCC(*)CCCC(CCCC(CCC(CC1)N)O)C1(C)N(C)CC1*C1)(N=O)O)N=O)N=O Chemical compound CCCC(C)CC(*C(C)(C(*)C(CCCC(*)CCCC(CCCC(CCC(CC1)N)O)C1(C)N(C)CC1*C1)(N=O)O)N=O)N=O 0.000 description 1
- LGLWQZQYCRSSPV-UHFFFAOYSA-N CC[n]1nnc(-c(cc2)cnc2OCCC(C)(C)CCN(CCN2c3cc(N)ncc3)S2(=O)=O)n1 Chemical compound CC[n]1nnc(-c(cc2)cnc2OCCC(C)(C)CCN(CCN2c3cc(N)ncc3)S2(=O)=O)n1 LGLWQZQYCRSSPV-UHFFFAOYSA-N 0.000 description 1
- GJWREVJVOCKEII-UHFFFAOYSA-N Nc1nccc(N(CCN2)S2(=O)=O)c1 Chemical compound Nc1nccc(N(CCN2)S2(=O)=O)c1 GJWREVJVOCKEII-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/433—Thidiazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/02—Formation or introduction of functional groups containing oxygen of hydroxy or O-metal groups
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- C07B43/04—Formation or introduction of functional groups containing nitrogen of amino groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/86—Hydrazides; Thio or imino analogues thereof
- C07D213/87—Hydrazides; Thio or imino analogues thereof in position 3
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a salt form, a crystal form of the compound 1, a preparation method thereof and an intermediate.
- Enterovirus 71 belongs to the family of small RNA viruses and is one of the most common sources of hand, foot and mouth disease. It can also cause a variety of neurological-related diseases such as herpes pharyngitis, aseptic meningitis, encephalitis, and polio-like paralytic diseases, which can be accompanied by severe central nervous system complications or neuroinflammation. Pulmonary Edema.
- Hand, foot and mouth disease has the characteristics of high epidemic intensity, strong contagiousness and complicated transmission route. So far, there is no specific anti-enteric virus type 71 drug.
- the present invention provides a method for preparing Compound 1,
- the molar ratio of compound 3-2 to NaNO 2 is selected from 1:1 to 2;
- the reaction solvent for preparing compound 3-3 from compound 3-2 is selected from the group consisting of methanol/water, ethanol/water, isopropanol/water or acetic acid/water;
- the volume ratio of water to methanol, ethanol, isopropanol or acetic acid is selected from 1:1 to 3;
- the weight ratio of compound 3-2 to H 2 O is selected from 1:1 to 3.
- the above preparation method comprises the following steps:
- the reaction solvent for preparing compound 3-2 from compound 3-1 is selected from the group consisting of methanol/dioxane, ethanol/dioxane, isopropanol/dioxane;
- the volume ratio of dioxane to methanol, ethanol or isopropanol is selected from 0.5 to 1:0.5 to 1;
- the molar ratio of compound 3-1 to base is selected from 1:1 to 2;
- Base A is selected from the group consisting of sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium t-butoxide, sodium t-butoxide, aluminum isopropoxide, sodium hydride, potassium hydride, calcium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide. , barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
- the molar ratio of compound 3-1 to hydrazine hydrate is selected from 1:2 to 15.
- the molar ratio of the above compound 3-1 to the base is selected from the group consisting of 1:1.5.
- the molar ratio of the above compound 3-1 to hydrazine hydrate is selected from 1:6 to 9.
- the above preparation method comprises the following steps:
- molar ratio of 2-amino-4-bromopyridine to compound 2-4 is selected from 1:1 to 2;
- the molar ratio of the ligand to the compound 2-4 is selected from 0.1 to 0.5:1;
- the ligand is selected from the group consisting of TRANS-N, N'-dimethylcyclohexyl-1,2-diamine N,N'-dimethylethylenediamine or Xphos;
- Catalyst is selected from CuI, Pd 2 (dba) 3 ;
- the molar ratio of base B to compound 2-4 is selected from 2 to 4:1;
- the base B is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, sodium hydrogencarbonate and/or potassium hydrogencarbonate;
- the reaction solvent for preparing compound 2-5 from compound 2-4 is selected from the group consisting of DMF, dioxane or dimethyl sulfoxide;
- the weight ratio of the reaction solvent to the compound 2-4 is selected from 10 to 20:1.
- the molar ratio of the above 2-amino-4-bromopyridine to the compound 2-4 is selected from the group consisting of 1:1.5.
- the molar ratio of the above ligand to compound 2-4 is selected from 0.2:1.
- the molar ratio of base B to compound 2-4 is selected from 3:1.
- the weight ratio of the above reaction solvent to compound 2-4 is selected from the group consisting of 15:1.
- the above preparation method comprises the following steps:
- the molar ratio of the above compound 1-2 to red aluminum is selected from 1:2 to 3.
- the invention further includes the following steps:
- the invention further includes the following steps:
- the invention further includes the following steps:
- the invention further includes the following steps:
- the invention further includes the following steps:
- the invention further includes the following steps:
- the invention also provides a compound of the formula: as an intermediate for the preparation of compound 1:
- the present invention also provides Form A of Compound 1, the XRPD pattern of which is shown in Figure 1.
- the present invention also provides a compound 2 of the formula:
- the present invention provides Form B of Compound 2, the XRPD pattern of which is shown in Figure 4.
- the invention provides a preparation method of the B crystal form, which comprises dissolving the compound 1 of any form in a mixed solvent of DMF and acetone, and adding a DMF solution of hydrogen chloride under stirring, and slowly adding the acetic acid after the dropwise addition. Ester crystallization;
- weight ratio of compound 1 to DMF is selected from 1:5 to 10;
- the volume ratio of DMF to acetone is selected from 4 to 6:1;
- the volume ratio of DMF to ethyl acetate is selected from 1:1 to 4.
- the volume ratio of DMF to acetone is selected from 5:1.
- the volume ratio of DMF to ethyl acetate is selected from the group consisting of 1:2 to 3.
- Another object of the present invention is to provide a use of the crystalline form A of Compound 1 and the crystalline form B of Compound 2 for the preparation of a medicament for the treatment of a disease associated with enterovirus 71.
- intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
- Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
- DCM dichloromethane
- PE petroleum ether
- EA ethyl acetate
- DMF N,N-dimethylformamide
- DMSO dimethyl sulfoxide
- EtOAc ethyl acetate
- EtOH stands for ethanol
- MeOH stands for methanol
- HCl (g) stands for hydrogen chloride gas
- HOAc acetic acid
- TFA trifluoroacetic acid
- DIPEA diisopropylethylamine
- t-BuOK stands for potassium t-butoxide
- PPh 3 stands for three Phenylphosphine
- Pd 2 (dba) 3 represents tris(dibenzylideneacetone)dipalladium
- Pd(PPh 3 ) 4 represents tetrakistriphenylphosphine palladium
- Pd(dppf)Cl 2 represents 1,1'-double ( diphenyl)
- the present invention has high industrial application value and economic value in the preparation of the compound of the formula (I) and its intermediate.
- XRPD X-ray powder diffractometer
- Tube voltage 40kV
- tube current 40mA
- DSC Differential Scanning Calorimeter
- Test conditions The sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing at 25 ° C, 250 ° C or 300 ° C, and the heating rate was 10 ° C / min.
- TGA Thermal Gravimetric Analyzer
- Test conditions Samples (2 to 5 mg) were placed in a TGA platinum pot for testing at room temperature - 300 ° C and a heating rate of 10 ° C / min.
- Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A.
- Figure 2 is a DSC pattern of Form A.
- Figure 3 is a TGA pattern of Form A.
- Figure 4 is an XRPD spectrum of Cu-K ⁇ radiation of Form B.
- Figure 5 is a DSC pattern of Form B.
- Figure 6 is a TGA pattern of Form B.
- DMSO (20 L) was added to the kettle, and 2-3 (2 kg, 7.8 mol) was added to the kettle to maintain the temperature in the kettle at about 19 °C.
- K 2 CO 3 1.6kg, 11.6mol
- the reaction solution was discharged, and after standing to stand for separation, the lower solid was washed three times with DMSO (1 L x 3). The DMSO phase was combined with the supernatant and processed in two batches.
- ⁇ RTI ID 0.0>( ⁇ /RTI> ⁇ /RTI> ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; ⁇ /RTI> ⁇ RTIgt; m, 2H), 6.64-6.61 (m, 1H), 6.43 (s, 1H), 3.95-3.92 (m, 2H), 3.60-3.56 (m, 2H).
- the resulting solid was treated again as above.
- the solids were combined to give a crude product of 4.2 kg (except inorganic salts).
- the above 4.2 kg solid was suspended in acetone (30 L) and heated to reflux. Most of the solids dissolved and cooled to 40 °C.
- the diatomaceous earth (500 g) was filtered, and the filtrate was dried to give a crude product (3.5 g). (except water).
- the above operation was repeated once (acetone 25 L), the suspension was filtered, and the filtrate was dried to give a crude product (3 kg).
- the above 3 kg of the solid was suspended in (12 L) methyl tert-butyl ether and stirred at 60 ° C for 2 hours.
- CPE cytopathic effect
- RD cells were digested from the adherent state, diluted to a density of 80,000 cells/ml in a medium, and inoculated into 100 microwells to microwells of a 96-well plate.
- a dry powder of the test compound was prepared as a 10 mM DMSO solution. The compound was then diluted 3 times and diluted at 8 concentration points. The reference compound will be diluted in the same manner.
- Second step The DMSO dilution of the compound was further diluted with cell culture medium. 10 ul of DMSO solution per well was added to 240 ul of medium.
- the compound dilution was added to the 96-well plate inoculated with cells at a volume of 50 ul per well, double wells, and the final concentration of DMSO was 1%.
- Virus dilution The EV71 virus solution was diluted 10,000 times at a concentration of 100 TCID 50 /50 ul. The virus dilution was added to a 96-well plate at a volume of 50 ul per well. Another 96-well plate was prepared by replacing the virus with a medium, and the cells were also inoculated, and a compound was added for detecting the toxic effect of the compound on the cells.
- the 96-well plate was incubated for 3 days at 37 ° C under 5% CO 2 .
- the cell activity assay reagent CCK8 was added to the wells at 20 ul/well. The absorbance at a wavelength of 450 nm and 630 nm was read using a microplate reader.
- Analytical data The data were analyzed using Prism 5.0 to calculate the anti-viral activity EC50 value and cytotoxic CC50 value of the compound.
- Test sample EV71 Compound 1 ⁇ 10nM
- Compound 1 has a significant inhibitory effect on EV71 virus at the cellular level.
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
NO. | 2-Theta | d(A) | I% | NO. | 2-Theta | d(A) | I% |
1 | 6.151 | 14.3575 | 100.0 | 11 | 19.718 | 4.4986 | 14.4 |
2 | 9.206 | 9.5988 | 34.0 | 12 | 20.132 | 4.4071 | 50.1 |
3 | 12.205 | 7.2457 | 31.1 | 13 | 20.809 | 4.2652 | 10.1 |
4 | 13.840 | 6.3931 | 46.2 | 14 | 21.964 | 4.0434 | 11.3 |
5 | 14.452 | 6.1240 | 69.8 | 15 | 22.476 | 3.9525 | 5.4 |
6 | 16.586 | 5.3404 | 9.4 | 16 | 23.208 | 3.8294 | 16.5 |
7 | 16.916 | 5.2370 | 30.4 | 17 | 26.422 | 3.3705 | 30.4 |
8 | 18.118 | 4.8921 | 79.6 | 18 | 27.605 | 3.2287 | 5.8 |
9 | 18.690 | 4.7436 | 92.4 | 19 | 29.714 | 3.0041 | 10.3 |
10 | 19.027 | 4.6605 | 63.0 | 20 | 31.132 | 2.8704 | 5.9 |
NO. | 2-Theta | d(A) | I% | NO. | 2-Theta | d(A) | I% |
1 | 5.637 | 15.6641 | 84.0 | 18 | 22.000 | 4.0369 | 4.8 |
2 | 8.397 | 10.5209 | 100.0 | 19 | 22.284 | 3.9861 | 6.3 |
3 | 11.160 | 7.9216 | 18.0 | 20 | 23.071 | 3.8519 | 30.6 |
4 | 13.937 | 6.3491 | 43.2 | 21 | 23.820 | 3.7325 | 21.7 |
5 | 14.253 | 6.2088 | 37.6 | 22 | 25.234 | 3.5263 | 6.4 |
6 | 14.513 | 6.0982 | 86.5 | 23 | 26.545 | 3.3551 | 3.7 |
7 | 14.846 | 5.9622 | 68.1 | 24 | 27.233 | 3.2719 | 62.9 |
8 | 16.701 | 5.3041 | 58.4 | 25 | 28.595 | 3.1191 | 5.6 |
9 | 17.272 | 5.1299 | 16.3 | 26 | 29.105 | 3.0656 | 8.4 |
10 | 17.549 | 5.0496 | 97.7 | 27 | 29.899 | 2.9859 | 3.7 |
11 | 18.099 | 4.8972 | 45.8 | 28 | 30.604 | 2.9188 | 6.9 |
12 | 18.444 | 4.8065 | 7.0 | 29 | 31.413 | 2.8454 | 9.2 |
13 | 18.987 | 4.6702 | 61.0 | 30 | 32.416 | 2.7597 | 3.5 |
14 | 19.443 | 4.5617 | 69.6 | 31 | 34.094 | 2.6276 | 10.2 |
15 | 20.094 | 4.4152 | 59.5 | 32 | 34.806 | 2.5754 | 5.7 |
16 | 20.469 | 4.3353 | 32.3 | 33 | 36.520 | 2.4583 | 8.0 |
17 | 20.959 | 4.2349 | 28.6 | 34 | 37.860 | 2.3744 | 5.0 |
No. | 溶剂 | 溶解度(mg/mL) |
1 | 甲醇 | <1.98 |
2 | 乙醇 | <2.09 |
3 | 丙酮 | 5.58-7.43 |
4 | 乙酸乙酯 | <2.13 |
5 | 2-甲基四氢呋喃 | <2.18 |
6 | 1,4-二氧六环 | 11.8-13.2 |
7 | 甲醇-水(3∶1) | <2.07 |
8 | 乙醇-水(3∶1) | <2.32 |
9 | 丙酮-水(3∶1) | <2.24 |
供试样品 | EV71 |
化合物1 | ≤10nM |
Claims (10)
- 根据权利要求1或2的制备方法,其包括如下步骤:其中,2-氨基-4-溴吡啶与化合物2-4的摩尔比选自1∶1~2,优选自1∶1.5;配体与化合物2-4的摩尔比选自0.1~0.5∶1,优选自0.2∶1;配体选自TRANS-N,N′-二甲基环己基-1,2-二胺、N,N′-二甲基乙二胺或Xphos;催化剂选自CuI或Pd2(dba)3;碱B与化合物2-4的摩尔比选自2~4∶1,优选自3∶1;碱B选自氢氧化锂、氢氧化钠、氢氧化钾、氢氧化铯、碳酸钠、碳酸钾、碳酸铯、碳酸氢钠和/或碳酸氢钾;由化合物2-4制备化合物2-5的反应溶剂选自DMF、二氧六环或/二甲亚砜;反应溶剂与化合物2-4的重量比选自10~20∶1,优选自15∶1。
- 化合物1的A晶型,其XRPD图谱如图1所示。
- 化合物2的B晶型,其XRPD图谱如图4所示。
- 根据权利要求9所述B晶型的制备方法,包括将任意一种形式的化合物1溶于DMF与丙酮的混合溶剂中,在搅拌条件下滴加氯化氢的DMF溶液,滴加完毕后,缓慢加入乙酸乙酯析晶制得;其中,化合物1与DMF的重量比选自1∶5~10;DMF与丙酮的体积比选自4~6∶1,优选自5∶1;DMF与乙酸乙酯的体积比选自1∶1~4,优选自1∶2~3。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/573,061 US10227339B2 (en) | 2015-10-26 | 2016-10-25 | Salt form and crystal form of 1,2,5-thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate |
DK16859004.0T DK3257851T3 (da) | 2015-10-26 | 2016-10-25 | Salt- og krystalform af 1,2,5 thiadiazolidin-1,1-dioxid, fremstillingsmetode og intermediat |
SG11201708692WA SG11201708692WA (en) | 2015-10-26 | 2016-10-25 | Salt form, crystal form and intermediate of 1,2,5-thiadiazolidine-1,1-dioxide and preparation method thereof |
EP16859004.0A EP3257851B1 (en) | 2015-10-26 | 2016-10-25 | Salt form and crystal form of 1,2,5 thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate |
CN201680011737.0A CN107406439B (zh) | 2015-10-26 | 2016-10-25 | 1,2,5-噻二唑烷-1,1-二氧化物的盐型、晶型及其制备方法和中间体 |
KR1020177029200A KR102048391B1 (ko) | 2015-10-26 | 2016-10-25 | 1,2,5-티아디아졸리딘-1,1-이산화물의 염형, 결정형 및 그 제조 방법과 중간체 |
JP2017566189A JP6427695B2 (ja) | 2015-10-26 | 2016-10-25 | 1,2,5−チアジアゾリジン−1,1−ジオキシドの塩形態、結晶形態及びその調製方法と中間体 |
ES16859004T ES2835061T3 (es) | 2015-10-26 | 2016-10-25 | Forma de sal y forma cristalina de 1,2,5-tiadiazolidina 1,1-dióxido, método de preparación de las mismas e intermedios |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1173131A (zh) * | 1994-12-02 | 1998-02-11 | 圣诺菲药品有限公司 | 2-(2,3,5,6-四氟-4-吡啶基)-1,2,5-噻二唑烷-3-酮1,1-二氧化物和其组合物及其使用方法 |
US20070049623A1 (en) * | 2001-08-21 | 2007-03-01 | National Health Research Institutes, A Taiwan Corporation | Imidazolidinone compounds |
CN100999441A (zh) * | 2006-01-13 | 2007-07-18 | 北京金源化学集团有限公司 | 红铝还原烷基丙二酸二酯为烷基-1,3-丙二醇 |
WO2008142550A2 (en) * | 2007-05-24 | 2008-11-27 | Pfizer Limited | Spirocyclic derivatives |
CN103351352A (zh) * | 2013-07-15 | 2013-10-16 | 南通市华峰化工有限责任公司 | 一种5-苯基四氮唑新合成方法 |
CN105085512A (zh) * | 2014-04-28 | 2015-11-25 | 南京明德新药研发股份有限公司 | 抗肠病毒71噻二唑烷衍生物 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2658906A1 (de) * | 1976-12-24 | 1978-07-06 | Bayer Ag | Beta-lactam-antibiotika, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
ZA846525B (en) * | 1983-08-29 | 1985-04-24 | Sterling Drug Inc | (substituted)phenyl-aliphatic-isoxazoles useful as antiviral agents and preparation thereof |
US6706739B2 (en) * | 2001-08-21 | 2004-03-16 | National Health Research Institute | Imidazolidinone compounds |
TWI361808B (en) * | 2008-01-08 | 2012-04-11 | Nat Health Research Institutes | Imidazolidinone and imidazolidinethione derivatives |
CN104744433B (zh) * | 2013-12-30 | 2016-09-21 | 中国科学院生物物理研究所 | Ald及其作为ev71病毒和cav16病毒抑制剂的用途 |
GB201402169D0 (en) * | 2014-02-07 | 2014-03-26 | Isis Innovation | Viral inhibitors |
EP3138840B1 (en) * | 2014-04-28 | 2020-09-23 | Jiangsu Kanion Pharmaceutical Co., Ltd. | Thiadiazolidine derivative as anti-enterovirus 71 |
WO2015165340A1 (zh) * | 2014-04-28 | 2015-11-05 | 南京明德新药研发股份有限公司 | 抗肠病毒71噻二唑烷衍生物 |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1173131A (zh) * | 1994-12-02 | 1998-02-11 | 圣诺菲药品有限公司 | 2-(2,3,5,6-四氟-4-吡啶基)-1,2,5-噻二唑烷-3-酮1,1-二氧化物和其组合物及其使用方法 |
US20070049623A1 (en) * | 2001-08-21 | 2007-03-01 | National Health Research Institutes, A Taiwan Corporation | Imidazolidinone compounds |
CN100999441A (zh) * | 2006-01-13 | 2007-07-18 | 北京金源化学集团有限公司 | 红铝还原烷基丙二酸二酯为烷基-1,3-丙二醇 |
WO2008142550A2 (en) * | 2007-05-24 | 2008-11-27 | Pfizer Limited | Spirocyclic derivatives |
CN103351352A (zh) * | 2013-07-15 | 2013-10-16 | 南通市华峰化工有限责任公司 | 一种5-苯基四氮唑新合成方法 |
CN105085512A (zh) * | 2014-04-28 | 2015-11-25 | 南京明德新药研发股份有限公司 | 抗肠病毒71噻二唑烷衍生物 |
Non-Patent Citations (2)
Title |
---|
DATABASE REGISTRY TC Scientific Inc.; 18 July 2011 (2011-07-18), XP055427119, retrieved from STN Database accession no. 1312919-49-5 * |
PRAJAPTI, SANTOSH KUMAR ET AL.: "An Efficient Synthesis of 5-substituted 1H-tetrazoles via B(C6F5) 3-catalyzed [3+2] cycloaddition of Nitriles and Sodium Azide", TETRAHEDRON LETTERS, vol. 55, no. 24, 31 December 2014 (2014-12-31), pages 3507 - 3510, XP055379991 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022012152A1 (zh) * | 2020-07-17 | 2022-01-20 | 江苏康缘药业股份有限公司 | 一种药物组合物及制备方法 |
EP4159200A4 (en) * | 2020-07-17 | 2024-07-17 | Jiangsu Kanion Pharmaceutical Co Ltd | PHARMACEUTICAL COMPOSITION AND MANUFACTURING METHOD |
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US10227339B2 (en) | 2019-03-12 |
SG11201708692WA (en) | 2017-11-29 |
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EP3257851A4 (en) | 2018-09-19 |
CN107406439B (zh) | 2020-06-16 |
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US20180141940A1 (en) | 2018-05-24 |
ES2835061T3 (es) | 2021-06-21 |
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