CN102070624B - Method for synthesizing tiagabine hydrochloride and method for preparing anhydrous tiagabine hydrochloride - Google Patents
Method for synthesizing tiagabine hydrochloride and method for preparing anhydrous tiagabine hydrochloride Download PDFInfo
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- CN102070624B CN102070624B CN 201110026938 CN201110026938A CN102070624B CN 102070624 B CN102070624 B CN 102070624B CN 201110026938 CN201110026938 CN 201110026938 CN 201110026938 A CN201110026938 A CN 201110026938A CN 102070624 B CN102070624 B CN 102070624B
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- tiagabine hydrochloride
- compound
- tiagabine
- synthesizing
- anhydrous
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- YUKARLAABCGMCN-PKLMIRHRSA-N tiagabine hydrochloride Chemical compound Cl.C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C YUKARLAABCGMCN-PKLMIRHRSA-N 0.000 title claims abstract description 30
- 229960002410 tiagabine hydrochloride Drugs 0.000 title claims abstract description 30
- 238000000034 method Methods 0.000 title abstract description 11
- 230000002194 synthesizing effect Effects 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- 238000000746 purification Methods 0.000 claims description 10
- 238000010189 synthetic method Methods 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 229940125904 compound 1 Drugs 0.000 claims description 6
- 239000012047 saturated solution Substances 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 150000002430 hydrocarbons Chemical class 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 12
- 239000003960 organic solvent Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- 229960001918 tiagabine Drugs 0.000 description 8
- PBJUNZJWGZTSKL-MRXNPFEDSA-N tiagabine Chemical compound C1=CSC(C(=CCCN2C[C@@H](CCC2)C(O)=O)C2=C(C=CS2)C)=C1C PBJUNZJWGZTSKL-MRXNPFEDSA-N 0.000 description 8
- QENGPZGAWFQWCZ-UHFFFAOYSA-N 3-Methylthiophene Chemical compound CC=1C=CSC=1 QENGPZGAWFQWCZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000001961 anticonvulsive agent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- -1 3-bromo-1-propyl Chemical group 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NSGCWILIYQUGIO-GOSISDBHSA-N ethyl (3r)-1-[4,4-bis(3-methylthiophen-2-yl)but-3-enyl]piperidine-3-carboxylate Chemical compound C1[C@H](C(=O)OCC)CCCN1CCC=C(C1=C(C=CS1)C)C1=C(C)C=CS1 NSGCWILIYQUGIO-GOSISDBHSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- YYJBWYBULYUKMR-UHFFFAOYSA-N 2-bromo-3-methylthiophene Chemical compound CC=1C=CSC=1Br YYJBWYBULYUKMR-UHFFFAOYSA-N 0.000 description 1
- IXGJBVPAZJNNRN-UHFFFAOYSA-N CC1=C(SC=C1)C1OCCC1 Chemical compound CC1=C(SC=C1)C1OCCC1 IXGJBVPAZJNNRN-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 101000939467 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 28 Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102100029821 Ubiquitin carboxyl-terminal hydrolase 28 Human genes 0.000 description 1
- OVSYYYAKOISBKJ-UHFFFAOYSA-M [Br-].CC=1C=CSC=1[Mg+] Chemical compound [Br-].CC=1C=CSC=1[Mg+] OVSYYYAKOISBKJ-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- LKXYJYDRLBPHRS-UHFFFAOYSA-N bromocyclopropane Chemical compound BrC1CC1 LKXYJYDRLBPHRS-UHFFFAOYSA-N 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- XIWBSOUNZWSFKU-SSDOTTSWSA-N ethyl (3r)-piperidine-3-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCNC1 XIWBSOUNZWSFKU-SSDOTTSWSA-N 0.000 description 1
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N ethyl butyrate Chemical compound CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- XIWBSOUNZWSFKU-UHFFFAOYSA-N ethyl piperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCNC1 XIWBSOUNZWSFKU-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- SGDMQXAOPGGMAH-UHFFFAOYSA-N phenol;thiophene Chemical compound C=1C=CSC=1.OC1=CC=CC=C1 SGDMQXAOPGGMAH-UHFFFAOYSA-N 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a method for synthesizing tiagabine hydrochloride, which has the following synthesizing route. The invention also provides a method for preparing anhydrous tiagabine hydrochloride of medicinal preparation level in a single or mixed organic solvent. An important dithiophene N-alkylated intermediate is prepared by the compact synthesizing method; and the synthesizing route does not need expensive special reagents, is convenient to operate, has mild reaction conditions, and is suitable for expanded preparation. In addition, when the anhydrous tiagabine hydrochloride is prepared by adopting the single or mixed organic solvent, the residual organic solvent is tried to remove so that the anhydrous tiagabine hydrochloride meets the requirement of a medicament preparation.
Description
Technical field
The present invention relates to a kind of synthetic method of Tiagabine Hydrochloride and prepare the method for its anhydrous formulation level.
Background technology
(
R)-(-)-N-[4,4-two (3-methyl-2-thienyl)-1-butyl-3-alkene] piperidines-3-formate hydrochlorate, its common name is Tiagabine Hydrochloride (Tiagabine Hydrochloride).USP 5,010, and 090 has reported the earliest the synthetic of Tiagabine Hydrochloride and absorbed protein inhibitor as GABA.At first gone on the market in Denmark and France by Novo Nordisk company in 1996, now many countries listing in the whole world.As the Newer antiepileptic of a novel binding mode, this medicine is an important breakthrough of Antiepileptic Drugs.For approximately 30% existing medicine epileptic seizures rambunctious, it has significant curative effect.Compare with other antiepileptic drug, its side effect is gentle and have no drug resistance, and clinical study shows, this medicine be more suitable for long-term taking (1. P. K. Datta and P. M. Crawford,
Seizure 2000, 9:51-57; 2. Paul Mckee,
Seizure,
2004, 13:478-480).
Patent USP 5,010, and 090 provides the synthesis route of Tiagabine Hydrochloride as follows, and N-alkylating agent intermediate is provided
62 kinds of different synthetic methods of [4-bromo-1.1-two (3-methyl-2-thienyl)-1-butylene] (are seen route
AWith
B).
In synthetic route
AIn, intermediate
6Synthesis step more loaded down with trivial details, need the Er Bugeshi reaction, 3 methyl thiophene formaldehyde source difficulty and Cyclopropyl Bromide price are too high; In synthetic route
BIn: intermediate
6Synthetic, shortcoming is n-Butyl Lithium source difficulty, is difficult for large suitability for industrialized production, and needs utmost point low-temp reaction condition.Also there are some problems in all the other steps in addition: low such as the hydrocarbonylation yield, only have 50%.
After this patent CN 1288145C has proposed following synthetic technology route:
The same year, patent CN 1314684C also proposed following synthetic technology route:
The synthetic route of above 2 Chinese patents
CWith
DIn, with technological line
AWith
BDifference also is the synthetic method that is N-alkylating agent [4-bromo-1.1-two (3-methyl-2-thienyl)-1-butylene].The N-alkylating agent
14With
16Synthetic, at first need to be by triphenyl phosphorus and 1,3-dibromopropane, or prepare triphenylphosphine salt by the protection thing of 3-bromo-1-propyl alcohol dihydropyrane (THP), step is all comparatively loaded down with trivial details, and cost is too high; Also there are the problems such as condensation and hydrocarbonylation yield are too low.
Tiagabine Hydrochloride is under the condition of the acid of humidity or alkalescence humidity, or all easily decomposition under the illumination condition, and it is easily oxidized; In polar organic solvent, larger such as solubleness in the micromolecular alcohol, and in polarity less organic solvent such as ether, methylene dichloride and ethyl acetate, its solubleness is less.
Patent (CN 1225094A, USP 5,958,951) if in mention in organic solvent preparation and separate Tiagabine Hydrochloride, can contain unnecessary recrystallisation solvent in the Tiagabine Hydrochloride.This is because organic solvent and crystallization form clathrate compound (chalthrathes), i.e. solvation (solventation) thing that crystallization and organic solvent form.And these recrystallisation solvents are unwanted, and after Tiagabine Hydrochloride was made preparation, these solvents may produce murder by poisoning to human body, also might cause the interaction between each composition in the pharmaceutical preparation, thereby affect the stability of formulation.Therefore patent CN1225094A is given in the acidic aqueous solution, high yield prepares the scheme of Tiagabine Hydrochloride crystallization, centrifugal and filtration is obtained the crystallization of water content, obtains stable anhydrous hydrochloric acid tiagabine through 40 ° of following vacuum-dryings of C.
But the powder that comes from the sour water is superfine crystal, and difficulty in filtration is larger, and water content is high, and drying is comparatively difficult when being lower than 40 ° of C, therefore the water content maximum of United States pharmacopoeia specifications Tiagabine Hydrochloride bulk drug can allow 5%.But moisture Tiagabine Hydrochloride is unstable, easily decomposes during storage, color burn.In addition, can effectively not reduce the method for foreign matter content in the Tiagabine Hydrochloride in the prior art.
Summary of the invention
The object of the present invention is to provide the synthetic method of the Tiagabine Hydrochloride that a kind of preparation technology is simple, cost is low and the preparation method of anhydrous hydrochloric acid tiagabine.
The precursor of Tiagabine Hydrochloride provided by the invention, structural formula is as follows:
The synthetic method of Tiagabine Hydrochloride provided by the invention is expressed as follows with reaction formula:
X, X '=Cl, Br or I; X, X ' are identical or not identical group.
R and R ' are the hydrocarbon of 1-8 carbon, and R is identical or not identical group with R '.
The synthetic method of Tiagabine Hydrochloride of the present invention, its concrete steps are as follows:
(1) the control temperature is lower than under 10 ° of C, with the compound of 1 weight part
2, join the compound that contains 1～2 weight part
3Tetrahydrofuran solution in, reflux is after 2～4 hours, separation and purification obtains compound
1
(2) at compound
1Middle adding H saturated solution, wherein compound 1 is 1:5～15 with the mol ratio of H X ', in reaction is after 2-10 hour under the 50-100 ° of C condition, separation and purification obtains compound again
4Preferred HX ' saturated solution is the 48%HBr saturated solution, and compound 1 is preferably 1:9.2 with the mol ratio of H X ', and preferred temperature of reaction is 80 ° of C, and the reaction times is preferably 6 hours.
(2) compound
4, compound
5, in the presence of Anhydrous potassium carbonate, take acetone as solvent, potassiumiodide is made catalyzer, at room temperature stirs more than 72 hours, and separation and purification obtains compound 6; Compound wherein
4, compound
5,The molar ratio of Anhydrous potassium carbonate is 1:1:2～4, and preferred molar ratio is 1:1:2.5, and the molar weight of catalyzer is 0.03～0.06 times of compound 4, is preferably 0.05 times.
(3) compound
6In the presence of highly basic, logical N
2Gas, the stirring at room hydrolysis is more than 4 hours in alcoholic solution, and separation and purification obtains compound 7; Wherein compound 6 is 1:1～3 with the mol ratio of highly basic, and preferred mol ratio is 1:2, and described highly basic is potassium hydroxide, sodium hydroxide or lithium hydroxide; Described alcoholic solution is the alcohol of small molecules 1-4 carbon, and commonly used is 95% ethanol.
The key of the synthetic method of Tiagabine Hydrochloride of the present invention (being the hydrocarbon of 2 carbon as example take R and R ') is grignard reagent and the addition of 4-halo butyric ester by 2-bromo-3 methyl thiophene, obtain 2,2-two (3 methyl thiophene base) tetrahydrofuran (THF), again through the haloid acid open loop, obtain the important intermediate 4-bromo-1.1-two (3-methyl-2-thienyl) of synthetic tiagabine-1-butylene.The present invention also provides the method for useful in preparing drug formulations level anhydrous hydrochloric acid tiagabine in single or mixed organic solvents.
Utilize compound obtained above
7Carry out recrystallization, then vacuum-drying obtains the anhydrous hydrochloric acid tiagabine.
The solvent of recrystallization adopts the alcohol of 1-4 carbon, perhaps uses mixed solvent, and this mixed solvent is mixing of the less solvent of alcohol and the another kind of polarity of 1-4 carbon, and the solvent that described polarity is less is the ether of 4-10 carbon or the ester of 3-6 carbon.The volume ratio of the solvent that alcohol and polarity are less is 1:2～1:9, and preferred volume ratio is 1:3.Described vacuum drying temperature is 60-120 ° of C, and preferred temperature is 90～110 ° of C.
Prepared two important thiophene phenol N-hydrocarbonylation intermediates with succinct synthetic method among the present invention, this synthetic route need not expensive special reagent, and is easy to operate, and reaction conditions is gentle, is suitable for enlarging preparation.Adopt in addition single or mixed organic solvents prepares the anhydrous hydrochloric acid tiagabine, and manage to remove residual organic solvent, make it reach the requirement of pharmaceutical preparation.
Embodiment
Embodiment 1
Compound 12, the preparation of 2-two (3-methyl-2-thienyl) tetrahydrofuran (THF)
In anhydrous tetrahydro furan (10.5 ml), by magnesium chips (237 mg, 8.42 * 10
-3Mol) with 2-bromine 3 methyl thiophene (1.64 g, 9.27 * 10
-3Mol) make the tetrahydrofuran solution of (3-methyl-2-thienyl) magnesium bromide, be cooled to 0 ° of C with frozen water, add 4-bromo-butyric acid ethyl ester (0.897 g, 4.60 * 10
-3Mol), be controlled at 10 ° and finish below the C, then temperature rising reflux 3 h.After reaction mixture is cooled to 0 ° of C, be controlled at the following saturated NH of adding of 10 ° of C
4In the Cl solution (20.0 ml).Tell organic phase, water extracts with ethyl acetate (6 ml * 2).Merge organic phase, with anhydrous Na
2SO
4Dry. organic phase gets compound through rotary evaporation
1: faint yellow solid with a small amount of dissolve with ethanol, adds the sherwood oil precipitation compounds; Be white crystals (1.11g, productive rate 91.1%); Mp:68-72 ° of C; MS ESI
+265 [M+1]
+;
1H NMR (CDCl
3): d 2.10 (s, 3H), 2.12 (s, 3H), (2.00-2.18 m, 2H), 2.56-2.70 (m, 2H), (4.02-4.11 m, 2H), 6.82 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), (6.91 d, J=5.2 Hz, 1H), (7.09 d, J=5.2 Hz, 1H).
Embodiment 2
Compound 4 4-bromo-1.1-two (3-methyl-2-thienyl)-1-butylene
With compound
1(1.21 g, 4.58 * 10
-3Mol) with 47.0% HBr (7.26 g, 42.1 * 10
-3Mol) mixture is in 80 ° of C stirring heating 6 h.After being cooled to room temperature, extract with ethyl acetate 10ml 2, merge organic phase, successively again with water, 1% K
2CO
3The aqueous solution and be washed to neutrality.Organic phase is with anhydrous Na
2SO
4Drying, behind the activated carbon decolorizing, rotary evaporation gets purple oily matter, gets compound through column chromatography purification (silica gel 300 ~ 400 orders, sherwood oil) again
4: yellow oil (1.31 g, productive rate 87.5%); MS ESI
+: 327 [M+1]
+; IR (KBr):
=3103,2962,1443,1267,712 cm
-1; MS ESI
+: 328 [M+1]
+ 1H NMR (CDCl
3) d 2.05 (s, 3H), 2.07 (s, 3H), 2.72 (q,
J=7.2 Hz, 2H), 3.45 (t,
J=7.0 Hz, 2H), 6.08 (t,
J=7.2 Hz, 1H), 6.80 (d,
J=5.2 Hz, 1H), 6.87 (d,
J=5.2 Hz, 1H), 7.08 (d,
J=5.2 Hz, 1H), 7.24 (d,
J=5.2 Hz, 1H).
Embodiment 3
Compound 6(
R)-(-)-N-[4,4-two (3 methyl thiophene-2-yl)-3-butenyl]-preparation of ethyl nipecotate [tiagabine ethyl ester]
Under the room temperature
R-ethyl nipecotate (2.27 g, 14.4 * 10
-3Mol),
7(4.90 g, 14.4 * 10
-3Mol), anhydrous K
2CO
3(2.98 g, 21.6 * 10
-3Mol), KI (120 mg, 7.2 * 10
-4Mol) and the mixture of acetone (30 ml) stirred 72 hours, remove by filter inorganic salt, the filtrate rotary evaporation, residue through column chromatography purification (silica gel 200-300 order, sherwood oil: acetone) compound
6: yellow oil (4.28 g, productive rate 74.3%); [a]
D 25=-24.9 ° (
c=1.00, EtOH); IR (KBr):
=3104,2942,1732,1446,712cm
-1; MS (ESI
+): 404.2 [M+1]
+;
1H-NMR (500MHz, CDCl
3) d:1.24 (t,
J=7.1 Hz, 3H), 1.41 (ddd,
J=3.5/12.7/16.2 Hz, 1H), 1.50 ~ 1.60 (m, 1H), 1.62 ~ 1.75 (m, 1H), 1.87 ~ 1.99 (m, 2H), 2.00 (s, 3H), 2.04 (s, 3H), 2.10 ~ 2.17 (m, 1H), 2.26 (q
J=5.5 Hz, 2H), 2.45 ~ 2.57 (m, 3H), 2.68 ~ 2.76 (m, 1H), 2.90 ~ 2.98 (m, 1H), 4.11 (q,
J=7.1 Hz, 2H), 6.04 (t,
J=7.3 Hz, 1H), 6.75 (d,
J=5.1 Hz, 1H), 6.83 (d,
J=5.1 Hz, 1H), 7.04 (d,
J=5.1 Hz, 1H), 7.20 (d,
J=5.1 Hz, 1H).
Embodiment 4
Compound 7(
R)-(-)-N-[4,4-two (3-methyl-2-thienyl)-1-butyl-3-alkene] piperidines-3-formate hydrochlorate
Synthesizing of [Tiagabine Hydrochloride]
The preparation of Tiagabine Hydrochloride crude product
Compound
6[tiagabine ethyl ester] 3.83 g (103 * 10
-3Mol) be dissolved in pure 18.0 ml after, add 12 N NaOH, 1.72 ml (206 * 10
-3Mol), logical N
2Gas, stir about 4 hours (TLC detects, sherwood oil: acetone=20: 1, the disappearance of raw material point) under the room temperature.The decompression rotary evaporation, bath temperature＜60 C, the ice water circulation water coolant steams except ethanol, gets approximately 5.0 ml of orange starchiness thing.Add CH
2Cl
235.0 ml jolting, under the frozen water cooling, be no more than 20 C, splash into approximately 10.0 ml of 6 M HCl, carefully be acidified to pH 2-3, separate out faint yellow solid, leave standstill 5-10 minute suction filtration, filter cake compresses to be drained, and with a small amount of washed with dichloromethane 2 ~ 3 times, room temperature (water circulating pump) vacuum-drying gets compound first
7: Tiagabine Hydrochloride crude product, yellowish white solid 3.59g(productive rate 92.0%).
Embodiment 5
The process for purification 1 of anhydrous hydrochloric acid tiagabine:
The 10.0 g Tiagabine Hydrochloride crude products and 95% ethanol, 20 ml that add embodiment 4 in the glass reaction still are mixed in the 70 degree heating in water bath, be heated to entirely molten, white crystals is separated out in placement, put into again refrigerator 12 hours, centrifuge dripping, wash with a small amount of ether, with product in room temperature vacuum-drying 12 hours, thermogravimetric analysis (TGA) test shows that crystallization contains 9.13% volatile matter, we infer that it is dissolvent residual, and (USP 5,958 such as patent CN 1225094A, 951) reason of explanation in, this is that crystal solvent causes.In vacuum drier with product in 100-110 ° of C, after 15-20 minute, it is 0.35% that thermogravimetric analysis (TGA) detects dissolvent residual, gets product 8.40 g (productive rate 84.0%).
Mp:192.3 ~ 195.1 ° C; Chemical purity: 99.40%,
R t(method is seen in the USP28 version inspection to relative substance to=9.73 min; An impurity peaks: 0.46%,
R t=11.38 min); [a]
D 25=-10.5 ° (
c=1.00, H
2O); IR (KBr):
=2926,2549,1736,1458,721cm
-1; MS (ESI
-): 376.2 [M-Cl]
+;
1H-NMR (500MHz, DMSO-d
6) d:1.38 ~ 1.52 (m, 1H), 1.75 ~ 1.95 (m, 2H), 1.98 (s, 3H), 2.03 (s, 3H), 2.55 (q,
J=5.7 Hz, 2H), 2.74 ~ 2.98 (m, 3H), 3.10 ~ 3.55 (m, 5H), 6.00 (t,
J=7.2 Hz, 1H), 6.85 (d,
J=5.1 Hz, 1H), 6.96 (d,
J=5.1 Hz, 1H), 7.32 (d,
J=5.1 Hz, 1H), 7.51 (d,
J=5.1 Hz, 1H), 11.0 (s, 1H), 12.8 (s, 1H).
Embodiment 6
The process for purification 2 of anhydrous hydrochloric acid tiagabine
Adding 10.0 g samples and 95% ethanol, 20 ml in the glass reaction still is mixed in the 70 degree heating in water bath, be heated to entirely molten, white crystals is separated out in placement, after being cooled to room temperature, add ether 60ml, put into again refrigerator after shaking up 12 hours, centrifuge dripping is washed with a small amount of ether, with product in room temperature vacuum-drying 12 hours, thermogravimetric analysis (TGA) test shows that crystallization contains 8.91% volatile matter, we infer that it is dissolvent residual, and (USP 5,958 such as patent CN 1225094A, 951) reason of explanation in, this is that crystal solvent causes.In vacuum drier with product in 100-110 ° of C, after 15-20 minute, it is 0.30% that thermogravimetric analysis (TGA) detects dissolvent residual, gets product 9.10g (productive rate 91.0%).
Claims (1)
1. the synthetic method of a Tiagabine Hydrochloride intermediate 4 is expressed as follows with reaction formula:
，
X=Cl, Br or I; X '=Br,
R is the hydrocarbon of 1-8 carbon;
Its concrete steps are as follows:
(1) the control temperature is lower than under 10 ° of C, with the compound of 1 weight part
2, join the compound that contains 1～2 weight part
3Tetrahydrofuran solution in, reflux is after 2～4 hours, separation and purification obtains compound
1
(2) at compound
1Middle adding H X ' saturated solution, wherein compound 1 is 1:5～15 with the mol ratio of H X ', in reaction is after 2-10 hour under the 50-100 ° of C condition, separation and purification obtains compound again
4Described HX ' saturated solution is the 48%HBr saturated solution.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5010090A (en) * | 1985-06-26 | 1991-04-23 | Novo Nordisk A/S. | N-(butenyl substituted) azaheterocyclic carboxylic acids |
-
2011
- 2011-01-25 CN CN 201110026938 patent/CN102070624B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5010090A (en) * | 1985-06-26 | 1991-04-23 | Novo Nordisk A/S. | N-(butenyl substituted) azaheterocyclic carboxylic acids |
Non-Patent Citations (3)
| Title |
|---|
| John M.Herbert et.al.Ring-chain tautomerism in 2,2-bis(2-thienyl)-tetrahydrofurans: preparation of [butene-2H5]-tiagabine.《J.Label Compd.Radiopharm》.2010,第53卷第598-600页. |
| Ring-chain tautomerism in 2,2-bis(2-thienyl)-tetrahydrofurans: preparation of [butene-2H5]-tiagabine;John M.Herbert et.al;《J.Label Compd.Radiopharm》;20100730;第53卷;第598-600页 * |
| Ursula Sonnewald.Substituted Geminal Dithienyltetrahydrofurans via an Intramolecular Williamson Reaction.《Acta Chem.Scand.》.1988,第B42卷第567-568页. * |
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