CN1350526A - A process for the preparation of thiazolidine derivatives - Google Patents
A process for the preparation of thiazolidine derivatives Download PDFInfo
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- CN1350526A CN1350526A CN00807522A CN00807522A CN1350526A CN 1350526 A CN1350526 A CN 1350526A CN 00807522 A CN00807522 A CN 00807522A CN 00807522 A CN00807522 A CN 00807522A CN 1350526 A CN1350526 A CN 1350526A
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000003548 thiazolidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical group 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- 125000001118 alkylidene group Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 239000005977 Ethylene Substances 0.000 claims 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- -1 thiazolidine compound Chemical class 0.000 abstract description 2
- 125000002947 alkylene group Chemical group 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000013078 crystal Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- ZWWCURLKEXEFQT-UHFFFAOYSA-N dinitrogen pentoxide Inorganic materials [O-][N+](=O)O[N+]([O-])=O ZWWCURLKEXEFQT-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KNCDZHRNIUVHHW-UHFFFAOYSA-N iron(3+);nitrate Chemical compound [Fe+3].[O-][N+]([O-])=O KNCDZHRNIUVHHW-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical class C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- LITYQKYYGUGQLY-UHFFFAOYSA-N iron nitric acid Chemical compound [Fe].O[N+]([O-])=O LITYQKYYGUGQLY-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
- C07D277/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
Abstract
The invention relates to a process for the preparation of a thiazolidine compound of formula (I): wherein D ring is (i); wherein R is hydrogen; C1-4 alkyl, halogen or cyano; or (ii) and A is C2-6 alkylene. According to the present method, a compound of formula (I) is obtained in higher yield than the previous method.
Description
Technical field
The present invention relates to a kind of method for preparing tetrahydrothiazole derivates, more particularly, the present invention relates to the preparation method of formula (I) compound (symbol definition wherein is as follows), this compound
Medicine as non-insulin-dependent diabetes mellitus (NIDDM).
Background technology
In the WO97/47612 specification sheets, described comprise formula (I) but the tetrahydrothiazole derivates of compound is described to the lowering blood glucose level and thereby is used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM).In this specification sheets, many methods of preparation tetrahydrothiazole derivates have been described.Some preparation method of formula wherein (I) compound is incorporated in following reaction scheme 1 and 2.
In reaction formula 1, the D ring is
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano group.) or
A is that C2-6 alkylidene group and X are halogen.In reaction scheme 2, R
1For all the other symbol definitions of alkyl as above.
Graphic 1
Graphic 2
Yet, low with the yield of formula (I) compound that obtains of methods of reaction scheme 1 and 2 statements, so they are not suitable for industrial a large amount of synthetic.Such as, book according to the above description, as the example of reaction scheme 1, formula (I-1) compound
By formula (II-1) compound
Make, yield is about 23%.
As the example of reaction scheme 2, formula (I-2) compound
By formula (II-2) compound
Make, yield is about 23%.
Therefore, wish to have and a kind ofly improve chemical yield and can be applicable to industrial a large amount of synthetic method.
The present invention is open
Present inventor's active research is with head it off, thereby the present inventor finds that can improve yield greatly in the presence of the alkali-metal ammonia of adding finishes the present invention.
The present invention relates to the preparation method of formula (I) compound
(wherein the D ring is
(wherein R is hydrogen, C1-4 alkyl, halogen or cyano group.) or
With A be the C2-6 alkylidene group.), this method comprises makes formula (II) compound
(wherein X is a halogen, and other symbol definition as above.) and the formula V compound
In the presence of basic metal, adopt liquefied ammonia reaction back to generate.
Reaction by formula (II) compound and formula V compound formula (I) compound, such as, in the presence of liquefied ammonia, adopt basic metal (lithium, sodium etc., preferred lithium) and catalyzer (anhydrous nitric acid iron (III) etc.), have or when solvent-free (tetrahydrofuran (THF), ether, dioxane etc.), under-78 ℃ to-60 ℃ temperature, preferably (this is reflected at " synthesizing " under-70 ℃ to-60 ℃ temperature, in 310 (1971) explanation is arranged), undertaken by making the reaction of formula (II) compound and formula V compound.
Formula (II) compound that is used as raw material in above-mentioned reaction is known, and as prepares according to above-mentioned reaction scheme 1.
In this manual, the C1-4 alkyl is methyl, ethyl, propyl group, butyl and their isomer.
In this manual, the C2-6 alkylidene group is ethylene, propylene, tetramethylene, pentamethylene, hexamethylene and their isomer.
In this manual, halogen is fluorine, chlorine, bromine and iodine.
In formula prepared in accordance with the present invention (I) compound, the D ring is preferably
Or
In formula prepared in accordance with the present invention (I) compound, A is preferably the C2-3 alkylidene group.As formula (I) compound, preferred
Or
Industrial application
The present invention has provided the excellent process of formula (I) compound that is prepared as target compound.Method of the present invention thinks that about 2 to 3 times of yield of previously known method obtain formula (I) compound (that is, the yield by our French (I) compound is about 60-90%; And the yield of previous method is about 20-30%).
Therefore, method of the present invention is more excellent more and be suitable for industrial extensive synthetic than previous method.
Implement best mode of the present invention
The following example is intended to explanation rather than places restrictions on the present invention.Solvent in the bracket is represented the expansion solvent that uses in the chromatographic separation or the volume ratio of eluting solvent and solvent for use.
Solvent in the bracket of NMR represents to measure used solvent.
The preparation of reference example 11-(2-bromine oxethyl)-4-cyanobenzene
Under refluxad, dropwise added 4-cyanophenol (357g) solution in the acetonitrile (0.7L) with 9 hours time in salt of wormwood (622g) suspension in ethylene dibromide (2.5L).This mixture of restir 2.5 hours.With this mixture cool to room temperature and elimination precipitation.Concentrated filtrate under step-down.In resistates, add ethyl acetate-hexanes mixtures (1.5L, ethyl acetate: hexane=1: 2), and at room temperature all night stir this mixture.Remove precipitation.Under pressure-lowering condition, make an appointment with the solvent of the mother liquor of half volume to be evaporated.Leach crystal.The crystal that generates is the dry target compound (386g, 63% yield) that obtains white crystal under reduced pressure.TLC:Rf0.55 (hexane: ethyl acetate=1: 1); NMR (CDCl
3): δ 7.60 (d, J=7.5Hz, 2H), 7.00 (d, J=7.5Hz, 2H), 4.35 (t, J=5Hz, 2H), 3.65 (t, J=5Hz, 2H)
Embodiment 15-[2-(4-cyano-benzene oxygen) ethyl]-thiazolidine-2, the preparation of 4-diketone
Under-70 ℃ to-60 ℃ temperature, in liquefied ammonia (2.5L), add metallic lithium (5.8g).In mixture, add anhydrous nitric acid iron (III) (150mg).In this mixture, add metallic lithium (23.3g) and mixture is stirred to mazarine and disappear.In this mixture, add anhydrous nitric acid iron (trivalent) (150mg) again, and it was stirred 20 minutes.Add 1,3-thiazoles alkane-2 with 15 minutes times in this mixture, 4-diketone (234g) stirs this mixture 30 minutes again.Add in this reaction mixture with 5 fens clock times and to be dissolved in compound (348g) solution in the tetrahydrofuran (THF) (420ml), preparation in reference example 1.Under-60 ℃ to-50 ℃ temperature, stirred this reaction mixture one hour.In this mixture, add ammonium chloride (269g) and this mixture placed under the room temperature and spend the night.In this resistates, add entry (2L) and ethyl acetate-ether mixture (1.5L; Ether=1: 1) and separate the waterbearing stratum ethyl acetate:.Under with ice-cooled condition, it is 2-3 that adding concentrated hydrochloric acid (2.5L) is acidified to pH with the waterbearing stratum.Collect the crystal that generates, and water and ethanol continuous washing, drying under reduced pressure generates the crude product crystal.Under refluxad the crude product crystal is dissolved in ethanol.Activated carbon is added in the mixture.Under uniform temp, stir this mixture and heating and filtering.Filtrate was at room temperature stirred 5 hours.Leach the crystal and the drying under reduced pressure of generation, obtain compound of the present invention (303g, yield is 75%), it has following physical data.TLC:Rf0.46 (hexane: ethyl acetate=1: 1); NMR (DMSO-d
6): δ 12.20-11.90 (br.s, 1H), 7.75 (d, J=7.5Hz, 2H), 7.10 (d, J=7.5Hz, 2H), 4.70 (dd, J=5.0,2.5Hz, 1H), 4.25 (t, J=5.0Hz, 2H), 2.60-2.30 (m, 2H); IR (KBr): 3181,2229,1746,1697,1606,1509,1305,1257,1180,1154,1029,829,669,549cm
-1.
The preparation of reference example 22-(2-bromine oxethyl) naphthalene
Replace 4-cyano group phenol with 2-Naphthol, by obtaining target compound in the same quadrat method described in the reference example 1, its physical data is as follows.TLC:Rf0.50 (normal hexane: ethyl acetate=9: 1); NMR (CDCl
3): δ 7.80-7.65 (m, 3H), 7.50-7.05 (m, 4H), 4.40 (t, 2H, J=7Hz), 3.70 (t, 2H, J=7Hz).
Embodiment 25-[2-(naphthalene-2-base oxygen base) ethyl] thiazoline-2, the preparation of 4-diketone
Under-70 ℃ to-60 ℃ temperature, in liquefied ammonia (1.5L), add continuously metallic lithium (1.32g), anhydrous nitric acid iron (III) (35mg) and metallic lithium (5.28g), and mixture is stirred to the mazarine disappearance.In this mixture, add anhydrous nitric acid iron (III) (35mg) again, and it was stirred 20 minutes.Add 1,3-thiazoles alkane-2 in this mixture, 4-diketone (52.7g) stirs this mixture 30 minutes again.In this reaction mixture, add and be dissolved in compound (75.4g) in the anhydrous tetrahydro furan (250ml), preparation in reference example 2.Under room temperature, stirred this mixture 2.5 hours.This mixture is cooled to-70 ℃, spends the night to wherein adding ammonium chloride (50.6g) and this mixture being placed under the room temperature again.With this mixture concentrating under reduced pressure.In this resistates, add normal hexane-ethyl acetate mixture (500ml; 1) and 5N aqueous sodium hydroxide solution (300ml) normal hexane: ethyl acetate :=1:.Under with ice-cooled condition, add concentrated hydrochloric acid with the waterbearing stratum acidifying.And with this mixture of ethyl acetate extraction.With the salt acid elution of organic layer, and use anhydrous magnesium sulfate drying, again concentrating under reduced pressure with 2N.Resistates is through silica gel column chromatography purification (methylene dichloride: ethyl acetate=10: 1).With the resistates recrystallize, obtain compound of the present invention (56g, 65%) with ethanol (400ml), it has following physical data.TLC:Rf0.33 (methylene dichloride: ethyl acetate=10: 1); NMR (CDCl
3+ DMSO-d
6): δ 10.50 (br.s, 1H), 7.75 (m, 3H), 7.44 (m, 1H), 7.35 (m, 1H), 7.12 (m, 2H), 4.51 (m, 1H); 4.32 (m, 1H), 4.20 (m, 1H), 2.75 (m, 1H), 2.40 (m, 1H); IR (KBr): 3171,3058,1747,1688,1626,1600,1259,1216,1184,1030,839,752,656cm
-1
Claims (6)
1. method for preparing (I) compound
(wherein the D ring is
(wherein R is hydrogen, Cl-4 alkyl, halogen or cyano group) or
And A is the C2-6 alkylidene group), it is characterized in that, make formula (II) compound
(wherein X is that halogen and other symbol as above define) and formula V compound
React in the presence of alkali-metal in liquefied ammonia.
2. the preparation method of claim 1 is characterized in that using lithium as basic metal.
3. the method for the preparation formula of claim 1 (I) compound, D ring wherein is
And A is an ethylidene.
4. the method for the preparation formula of claim 1 (I) compound, D ring wherein is
And A is an ethylene.
5. the preparation method of claim 1, this method is used to prepare 5-[2-(4-cyano-benzene oxygen) ethyl]-thiazolidine-2, the 4-diketone.
6. the preparation method of claim 1, this method are used to prepare 5-[2-(naphthalene-2-base oxygen base) ethyl] thiazoline-2, the 4-diketone.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP73519/99 | 1999-03-18 | ||
| JP7351999 | 1999-03-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1350526A true CN1350526A (en) | 2002-05-22 |
Family
ID=13520586
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00807522A Pending CN1350526A (en) | 1999-03-18 | 2000-03-16 | A process for the preparation of thiazolidine derivatives |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP1165529A1 (en) |
| KR (1) | KR20010112328A (en) |
| CN (1) | CN1350526A (en) |
| AU (1) | AU3192400A (en) |
| BR (1) | BR0009079A (en) |
| CA (1) | CA2368146A1 (en) |
| HU (1) | HUP0200585A3 (en) |
| NO (1) | NO20014451L (en) |
| NZ (1) | NZ514177A (en) |
| TR (1) | TR200102689T2 (en) |
| WO (1) | WO2000055146A1 (en) |
| ZA (1) | ZA200107603B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2012212393B2 (en) | 2011-02-02 | 2015-06-11 | Bionomics Limited | Positive allosteric modulators of the alpha 7 nicotinic acetylcholine receptor and uses thereof. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8919417D0 (en) * | 1989-08-25 | 1989-10-11 | Beecham Group Plc | Novel compounds |
| FR2749583B1 (en) * | 1996-06-07 | 1998-08-21 | Lipha | NOVEL SUBSTITUTED THIAZOLIDINE -2,4- DIONE DERIVATIVES, PROCESSES FOR OBTAINING SAME AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
-
2000
- 2000-03-16 EP EP00909666A patent/EP1165529A1/en not_active Withdrawn
- 2000-03-16 TR TR2001/02689T patent/TR200102689T2/en unknown
- 2000-03-16 KR KR1020017011662A patent/KR20010112328A/en not_active Application Discontinuation
- 2000-03-16 AU AU31924/00A patent/AU3192400A/en not_active Abandoned
- 2000-03-16 WO PCT/JP2000/001595 patent/WO2000055146A1/en not_active Application Discontinuation
- 2000-03-16 NZ NZ514177A patent/NZ514177A/en unknown
- 2000-03-16 CN CN00807522A patent/CN1350526A/en active Pending
- 2000-03-16 BR BR0009079-4A patent/BR0009079A/en not_active IP Right Cessation
- 2000-03-16 CA CA002368146A patent/CA2368146A1/en not_active Abandoned
- 2000-03-16 HU HU0200585A patent/HUP0200585A3/en unknown
-
2001
- 2001-09-13 NO NO20014451A patent/NO20014451L/en not_active Application Discontinuation
- 2001-09-14 ZA ZA200107603A patent/ZA200107603B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| TR200102689T2 (en) | 2002-01-21 |
| NO20014451D0 (en) | 2001-09-13 |
| NZ514177A (en) | 2003-04-29 |
| NO20014451L (en) | 2001-11-12 |
| KR20010112328A (en) | 2001-12-20 |
| HUP0200585A3 (en) | 2004-07-28 |
| CA2368146A1 (en) | 2000-09-21 |
| HUP0200585A2 (en) | 2002-06-29 |
| ZA200107603B (en) | 2003-02-26 |
| EP1165529A1 (en) | 2002-01-02 |
| AU3192400A (en) | 2000-10-04 |
| WO2000055146A1 (en) | 2000-09-21 |
| BR0009079A (en) | 2002-01-02 |
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