MXPA99010434A - A new process for the preparation of a pharmacologically active substance - Google Patents
A new process for the preparation of a pharmacologically active substanceInfo
- Publication number
- MXPA99010434A MXPA99010434A MXPA/A/1999/010434A MX9910434A MXPA99010434A MX PA99010434 A MXPA99010434 A MX PA99010434A MX 9910434 A MX9910434 A MX 9910434A MX PA99010434 A MXPA99010434 A MX PA99010434A
- Authority
- MX
- Mexico
- Prior art keywords
- general formula
- solution
- compounds
- thienyl
- racemic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000000126 substance Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 56
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 8
- 230000003287 optical Effects 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 230000002785 anti-thrombosis Effects 0.000 abstract description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 abstract 1
- 150000003869 acetamides Chemical class 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 45
- 239000000047 product Substances 0.000 description 39
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000002844 melting Methods 0.000 description 25
- -1 for example Substances 0.000 description 20
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000002329 infrared spectrum Methods 0.000 description 14
- 238000009114 investigational therapy Methods 0.000 description 14
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 13
- 238000000921 elemental analysis Methods 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012071 phase Substances 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- WTLWYLDVLAIHPU-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetamide Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)N)NCCC1=CC=CS1 WTLWYLDVLAIHPU-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- JXMUSLFGOYRHHE-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetonitrile Chemical compound ClC1=CC=CC=C1C(C#N)NCCC1=CC=CS1 JXMUSLFGOYRHHE-UHFFFAOYSA-N 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 229940011051 isopropyl acetate Drugs 0.000 description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N (+)-tartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 235000019253 formic acid Nutrition 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 239000001358 L(+)-tartaric acid Substances 0.000 description 4
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000005712 crystallization Effects 0.000 description 4
- 238000010908 decantation Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002194 synthesizing Effects 0.000 description 4
- ALLFNKNHKLXYSI-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetamide;hydron;chloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C(C(=O)N)NCCC1=CC=CS1 ALLFNKNHKLXYSI-UHFFFAOYSA-N 0.000 description 3
- HLTBXUWKIUQAJX-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetonitrile;hydrochloride Chemical compound Cl.ClC1=CC=CC=C1C(C#N)NCCC1=CC=CS1 HLTBXUWKIUQAJX-UHFFFAOYSA-N 0.000 description 3
- HVLUYXIJZLDNIS-UHFFFAOYSA-N 2-thiophen-2-ylethanamine Chemical compound NCCC1=CC=CS1 HVLUYXIJZLDNIS-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- MIOPJNTWMNEORI-UHFFFAOYSA-M camphorsulfonate anion Chemical compound C1CC2(CS([O-])(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-M 0.000 description 3
- 239000002178 crystalline material Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 2
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 2
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
- 229960003009 Clopidogrel Drugs 0.000 description 2
- GKTWGGQPFAXNFI-HNNXBMFYSA-N Clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 description 2
- MNWBNISUBARLIT-UHFFFAOYSA-N Sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 2
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4R)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 229950008597 drug INN Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000002050 international nonproprietary name Substances 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- PAOGEKGFTGONII-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetate Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)OC)NCCC1=CC=CS1 PAOGEKGFTGONII-UHFFFAOYSA-N 0.000 description 2
- ZXANKCFSGFEBQW-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetate;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C(C(=O)OC)NCCC1=CC=CS1 ZXANKCFSGFEBQW-UHFFFAOYSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- GAQWDBUWBUOFLS-UHFFFAOYSA-N (7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid;hydrate Chemical compound O.C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C GAQWDBUWBUOFLS-UHFFFAOYSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- XHAPROULWZYBGA-UHFFFAOYSA-N 2-bromo-2-(2-chlorophenyl)acetic acid Chemical compound OC(=O)C(Br)C1=CC=CC=C1Cl XHAPROULWZYBGA-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- ZZLKPFGLOQUCNC-UHFFFAOYSA-N 2-thiophen-2-ylethanamine;hydrochloride Chemical compound Cl.NCCC1=CC=CS1 ZZLKPFGLOQUCNC-UHFFFAOYSA-N 0.000 description 1
- 102100001249 ALB Human genes 0.000 description 1
- 101710027066 ALB Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- NDXRNFGHRDRBGC-UHFFFAOYSA-M C1N(CC(=O)[O-])CCC2=C1C=CS2 Chemical class C1N(CC(=O)[O-])CCC2=C1C=CS2 NDXRNFGHRDRBGC-UHFFFAOYSA-M 0.000 description 1
- LFHDINMNPBZSNH-UHFFFAOYSA-N C1N(OC(=O)C)CCC2=C1C=CS2 Chemical compound C1N(OC(=O)C)CCC2=C1C=CS2 LFHDINMNPBZSNH-UHFFFAOYSA-N 0.000 description 1
- PPLIMQIIFDCVGY-UHFFFAOYSA-N Cl.CN(CCc1cccs1)OC(=O)Cc1ccccc1Cl Chemical compound Cl.CN(CCc1cccs1)OC(=O)Cc1ccccc1Cl PPLIMQIIFDCVGY-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 208000010110 Spontaneous Platelet Aggregation Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- PZAGQUOSOTUKEC-UHFFFAOYSA-N acetic acid;sulfuric acid Chemical compound CC(O)=O.OS(O)(=O)=O PZAGQUOSOTUKEC-UHFFFAOYSA-N 0.000 description 1
- 229940050528 albumin Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000003522 irritant Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Abstract
A process for the preparation of methyl-[2(2-thienyl)-ethylamino]-(2-halogenophenyl)-acetates of general formula (VI) starting from the acetamides of general formula (VII). There are valuable pharmaceutically active ingredients of antithrombotic effect among the compounds of general formula (VI).
Description
NEW PROCESS FOR THE PREPARATION OF A PHARMACOLOGICALLY ACTIVE SUBSTANCE
DESCRIPTION OF THE INVENTION The invention relates to a new process for the preparation of compounds with the general formula (VI)
rm
- in which X represents a halogen atom. It is known that methyl (2-halogenophenyl) - (6,7-dihydro-4H-thieno [3,2-c] pyridin-5-ylacetates and their salts can be conveniently used in treatments, especially because of their inhibitory effects of platelet aggregation and antithrombotic A particularly favorable representative of these compounds, which responds to the general formula (VI)
rm - in which X represents a chlorine atom - is the acid sulfate acetate of (+) - [(S) - (2-chlorophenyl) - (6,7-dihydro-4H-thieno [3, 2-c] dextrorotatory pyridin-5-yl, which corresponds to the international non-proprietary name (INN) of clopidogrel (European patent application, publication No. 099802) .The large-scale preparation of compounds with the general formula (VI)
rm
- in which X represents a halogen atom - was previously only possible through halohalophenylacetic acid derivatives, extremely lacrimosos and irritants of mucosal membranes and difficult to manipulate technologically, being inconvenient from the point of view of health and environment (European patent applications, publications Nos. 099802, 0420706, 0466569). In addition, the yields of the methods are rather poor. Our aim was to eliminate the use of unpleasant intermediates (such as, for example, bromo- (2-chlorophenyl) acetic acid and its methyl ico ester) and to substantially increase the yield of the compounds with the general formula (VI)
in the synthesis. Since, in the synthesis according to the invention, each intermediate in the preparation of an optically active end product such as, for example, clopidogrel, is a chiral one, the possibility of the use - from the first step - of optically active compounds is opened as intermediaries. The economic benefit of the method is, among others, to avoid the preparation of an unwanted isomer. We have found that the preparation of compounds with the general formula (VI)
-OÍR, D **.
rvti *
by means of the route illustrated in scheme 1 it avoids the use of unpleasant intermediaries and that, additionally, the yield of the synthesis is much higher. The subject of the present invention is the third section of the reaction scheme 1. The optically active compound with the general formula (VI)
.Ka, ** t rm
is prepared both from optically active compounds with the general formula (VII)
as starting from the optically active intermediates obtained by solving the intermediates with the general formula (VIII),
or by solving the racemic compounds with the general formula (VI).
rm
According to our invention, a racemic or optically active compound is transformed with the general formula (VII)
- in which X represents a halogen atom - in the racemic or optically active compound with the general formula (VIII)
- in which X represents a halogen atom - and, if desired, the racemic compound with the formula (VIII)
The resulting compound is resolved into its optically active isomers and then, by means of a ring closure, by a method known per se, the compounds having the general formula (VIII)
they are transformed into the racemic or optically active compounds with the general formula (VT),
rm and, if desired, the racemic or optically active compounds with the general formula (VI)
they are resolved in their optical isomers and / or transformed into their salts and / or the racemic or optically active compound is released from its salts. Preferably, the compounds with the general formula (VII)
they are reacted with methanol in the presence of methyl acid sulfate. The reaction can also be carried out under pressure, preferably at 5-20 bar. The most advantageous temperature range is between 50 ° C 150 ° C. Methyl acid sulfate was prepared in the reaction vessel, refluxing methanol and sulfuric acid.
The ring closure of the compounds with the general formula (VIII)
it is carried out by a method known per se. The resolution of racemic intermediaries with the general formula (VIII)
known or that of the racemic compounds with the general formula (VI)
rvt i- is carried out by a resolution method known per se, obtaining optically active compounds with the general formula (VI).
»* C-" MI1 'rm
The preparation of the starting compounds applied in our invention is shown in the examples. The starting materials shown in scheme 1 can be acquired, the synthesis of the compound with the formula (II)
(iri
it is described, for example, in the French patent application, publication No. 2608607. Further details of the invention are illustrated in the following examples, without thereby limiting the scope of the invention to the examples.
Example 1 [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile 104 g (1 mol) of sodium bisulfite are dissolved in a mixture of 900 ml of water and 250 ml of ethanol, and the solution is added to the solution. 140.6 g (1 mol) of o-chloro-benzaldehyde. After a few minutes, the aldehyde bisulfite adduct is precipitated in the form of white crystals, while the temperature increases to 40 ° C. After stirring for 1 hour, 127.2 g (1 mol) of 2- (2-thienyl) ethylamine are added to the reaction mixture, and the stirring is maintained for 2 hours at 50 ° C. During this time, the crystalline aldehyde bisulfite is transformed into an oily material. The mixture is cooled to room temperature and a solution of 49 g (1 mole) of sodium cyanide in 100 ml of water is added. During the addition, the temperature of the reaction mixture increases to 40 ° C. The mixture is then stirred at 60 ° C, until the reaction is complete (1 hour). The oily organic phase is then extracted with 400 ml of 1,2-dichloroethane, washed to the absence of cyanide with 2 x 200 ml of water and the traces of 2- (2-thienyl) ethylamine are removed by a treatment with 100 ml. of 3% solution of hydrochloric acid. The dichloroethane phase is dried over anhydrous sodium sulfate and evaporated under vacuum. The residual oil, which crystallizes quickly, is the product. Weight: 260g (94%); melting point: 40-41 ° C. The product was identified by elemental analysis, an IR spectrum and a 1H-NMR investigation.
Example 2 [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile 9.8 g (0.2 mole) of sodium cyanide are dissolved in 70 ml of water, and to the solution are added, first, 32, 8 g (0.2 mol) of 2- (2-thienyl) ethylamine hydrochloride and then, in a period of a few minutes, a solution of 28.2 g (0.2 mol) of o-chlorobenzaldehyde in 30 ml of ethanol . During the addition, the temperature of the mixture increases to 45 ° C. The mixture is then stirred at 60 ° C for 2 hours, cooled to room temperature and diluted with 50 ml of water. The resulting oily product is extracted with 100 ml of 1,2-dichloroethane, the organic phase is washed to the absence of cyanide with 2x50 ml of water, the traces of 2- (2-thienyl) ethylamine are removed by a treatment with 20 ml. of 3% solution of hydrochloric acid. The residual oil, which crystallizes quickly, is the product. Weight: 52g (94%); melting point: 40-41 ° C. The product was identified as described in example 1. The quality of the product is identical to that of the product prepared according to example 1.
Example 3 [2- (2-thienyl) ethylamino] (2-chlorophenethyl) acetonitrile hydrochloride 276.7 g (1 mol) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile are dissolved, prepared in accordance with Example 1 or 2, in 600 ml of ethanol, and to the solution is added 100 ml of 10% aqueous hydrochloric acid solution. In the course of a few minutes white crystals precipitate, which are collected, washed with 60 ml of a 1: 1 mixture of 10% hydrochloric acid and ethanol, then with acetone and dried. Weight: 305g (97.4%); melting point: 153-154 ° C. The product was identified by elemental analysis, an IR spectrum and an investigation - "- H-NMR Example 4 [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile bromohydrate
13.8 g (0.05 mol) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile, prepared according to example 1 or 2, are dissolved in 30 ml of ethanol, and the solution is add 40 ml of 20% aqueous solution of hydrobromic acid. The product, which precipitates in the course of a few minutes, is collected, washed with ethyl acetate and dried. Weight: 14 g (78.2%); melting point: 144-145 ° C. The product was identified by elemental analysis, an IR spectrum and an investigation -NMR.
Example 5 [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide hydrochloride In 1200 ml of methyl acetate, 204 g (5.6 mol) of gaseous hydrogen chloride are introduced at 15-25 ° C, 221.4g (0.8 moles) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile is added to the solution with the formula (I),
prepared as described in example 1, and 48 ml (1.2 moles) of methanol, stirring for 6 hours at 20-25 ° C. In the course of the reaction, the starting hydrochloride of the starting "nitrile" is first precipitated and then, gradually, the resulting "acid amide" hydrochloride, in the form of white crystals. The crystals are collected by filtration, washed with methyl acetate and dried. Weight: 249g (94%); melting point: 231-232 ° C. The product was identified by elemental analysis, an IR spectrum and an investigation-1H-NMR.
Example 6 [2- (2-Thienyl) ethylamino] (2-chlorophenethyl) acetamide hydrochloride
In 700 ml of ethyl acetate at 0-10 ° C, 109.8 g (3 moles) of gaseous hydrogen chloride are introduced, and to the solution is added 83 g (0.3 mole) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile with the formula (I)
il!
prepared as described in example 1 or 2, and 15 ml (0.37 mol) of methanol, and the mixture is slowly heated, within 20 minutes, to 45-50 ° C. The reaction mixture is then stirred for 4 hours at 45-50 ° C, the crystalline product is collected by filtration, washed with ethyl acetate and dried. Weight: 90.4 g (91%); melting point: 231-232 ° C. The quality of the product is identical to that of the product of example 5.
Example 7 [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide 24.8 g (0.075 mol) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide hydrochloride prepared in according to Example 5 or 6, with 170 ml of water, and then, with gentle cooling, 30 ml of a 10% solution of sodium hydroxide and 170 ml of 1,2-dichloroethane are added. The phases are separated, the aqueous phase is extracted with 2 x 20 ml of 1,2-dichloroethane and the combined organic phases are evaporated under vacuum. Residue: 22g of an oil that crystallizes quickly. The crude product is recrystallized from 80 ml of isopropyl acetate, to give 19.5 g of the crystalline base with the formula (VII).
Yield: 88.2%, melting point: 90-92 ° C. The product was identified by an analysis
elemental, an IR spectrum and a 1H-NMR investigation.
Example 8 [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide bromohydrate 14.7 g (0.05 mole) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide are dissolved, prepared as described in example 7, in 150 ml of acetone. To the solution is added 4 ml of a 60% aqueous solution of hydrobromic acid, the precipitated white crystals are filtered, washed with acetone and dried. The product was identified by elemental analysis, an IR spectrum and an XH- investigation. NMR.
Example 9 Methyl [2- (2-thienyl) ethylamino] 2-chlorophenylacetate hydrochloride 21.5 ml (0.4 mol) of 100% sulfuric acid in 100 ml of methanol are dissolved under cooling, the The solution is refluxed for 1 hour, then cooled to room temperature, 33.1 g (0.1 mol) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide hydrochloride, prepared as described, are added thereto. in Example 5, and the resulting mixture is heated under reflux conditions for 10 hours. The methanol is then distilled under vacuum, and 150 ml of 1,2-dichloroethane and 150 ml of water are added to the residue, stirred well, and the two phases are separated. The aqueous phase is washed with 2 x 30 ml of 1,2-chloroethane, the combined organic phases are washed with 80 ml of 5% sodium hydroxide solution, then with 100 ml of water, dried over anhydrous sodium sulfate. and evaporate under vacuum.
Weight of the residue: 28.5 g. The oily product, which forms the basis with the formula (VIII),
it is dissolved in 50 ml of isopropyl ether, 7.3 ml (0.087 mol) of concentrated hydrochloric acid solution are added and the mixture is stirred for 1 hour at room temperature. The precipitated product is filtered, washed with 2 x 10 ml of isopropyl acetate and dried. Weight: 28.4 g (82%); melting point: 177 - 178 ° C (literature: 175 ° C). The product was identified by elemental analysis, an IR spectrum, ^ -H-NMR and MS investigations, and a melting point determination.
EXAMPLE 10 [2- (2-thienyl) ethylamino] -2-chlorophenyl-methyl acetate hydrochloride 8.5 ml (0.15 mol) of 96% sulfuric acid in 150 ml of methanol are dissolved under cooling, and The solution is heated to reflux for an hour. After cooling to room temperature, 20g (0.0678 mole) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide, which corresponds to the general formula (VII), is added to the solution.
and is prepared as described in example 7, the mixture is placed in a closed apparatus (autoclave) and stirred therein for 5 hours at 130 ° C, while the internal pressure increases to 13 bar. The reaction mixture is then cooled to room temperature (remaining pressure: 1-2 bar), the methanol is distilled off under vacuum, 100 ml of isopropyl acetate and 100 ml of water are added to the residue and the pH value of the mixture is adjusted. mix to 7.5 by adding, dropwise and under cooling and stirring, 60 ml of 10% solution of sodium hydroxide, keeping the mixture at room temperature. The phases are separated, the organic phase is stirred with 60 ml of a 3% aqueous solution of maleic acid at 40-50 ° C for 10 minutes, then separating the two phases. After reextracting the aqueous solution of maleic acid with 30 ml of isopropyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated to half their volume. The product precipitates as an oil that crystallizes within a few minutes, by the addition of 5 ml of concentrated hydrochloric acid solution. It is cooled to 0 - (+) 5 ° C and, after two hours, the crystals are collected by filtration, washed with a small amount of isopropyl acetate and dried. Weight: 19.4 g (82.5%); melting point: 177-178 ° C. The quality of the product is identical to that of the material obtained in example 9.
EXAMPLE 11 Methyl [2- (2-thienyl) ethylamino] 2-chlorophenylacetate bromohydrate The procedure described in Example 9 is followed, methyl [2- (2-thienyl) ethylamino] 2-chlorophenylacetate is dissolved in 50 ml. of isopropyl acetate, 8 ml of a 62% aqueous solution of hydrobromic acid are added to the solution and the mixture is stirred at room temperature for 1 hour. The product crystallizes during this period of time. The crystals are harvested, washed with 2x10 ml of isopropyl acetate and dried. Weight: 32.5g (83%); melting point: 164-165 ° C. The product was identified by elemental analysis, an IR spectrum and a 1H-NMR investigation.
Example 12 (2-Chlorophenyl) hydroxy (6,7-dihydro-4H-thieno- [3,2-c] pyridin-5-yl) methyl hydrate hydrate A 28.4 g (0.082 mole) of hydrochloride [ Methyl 2- (2-thienyl) ethylamino] 2-chlorophenylacetate, prepared according to example 9 or 10, is added 50 ml of 1,2-dichloroethane and the solution of 7.5 g (0.09 mol) of sodium bicarbonate in 10O ml of water. The mixture is stirred well, the phases are separated, the aqueous phase is washed with 2 x 30 ml of 1,2-dichloroethane, the combined organic phases are dried over anhydrous sodium sulfate and the solvent is removed under vacuum. The 25g of remaining material (acetate base) are dissolved in 90 ml of formic acid, 4g (0.13 mole) of paraformaldehyde are added to the solution and the mixture is stirred at 50 ° C for 20 minutes. The majority of the formic acid is then distilled under vacuum, the residue is dissolved in a mixture of 100 ml of water and 100 ml of water., 2-dichloroethane, the phases are separated, the aqueous phase is extracted again with 30 ml of dichloroethane, the combined organic phases are stirred well with 100 ml of 5% sodium bicarbonate solution, the phases are separated, the organic phase over anhydrous sodium sulfate and evaporated under vacuum. The residue is dissolved in 45 ml of acetone and 6.5 ml (0.077 mole) of concentrated hydrochloric acid at 5-10 ° C are added to the solution with cooling. The product crystallizes slowly. The mixture is stirred for 1 hour at 0-10 ° C, then the crystals are filtered, washed with 2 x 10 ml of acetone and dried. Weight: 26, Ig (theoretical: 30, 8g); yield: 86.6%; melting point: 138-140 ° C (literature: 130-140 ° C). The product was identified by elemental analysis, an IR spectrum, a 1H-NMR investigation and a melting point determination.
EXAMPLE 13 Levorotatory [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile hydrochloride. LOg (0.036 mole) of racemic [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile in 15 ml. acetone, to the solution are added lOg (0.043 mole) of (IR) - (-) - camphor-10-sulphonic acid and 0.5 ml (0.013 mole) of formic acid, the mixture is heated to 50-55 ° C and, after 1-2 minutes, cool to room temperature. In this way, the salt formed between the dextrorotatory enantiomer of the starting material and the (IR) - (-) -camphor-10-sulphonic acid is precipitated in a weakly optically contaminated form. The crystals are separated by filtration. To the mother liquor is added 7 ml of methyl acetate containing 10% hydrochloric acid, or a calculated amount of gaseous hydrogen chloride is introduced, the crystalline precipitate is filtered, washed with acetone and dried. Weight: 2.5g; [] 22 D = - 43 ° (c = 1, methanol). Yield: 43%, calculated on the content of left-handed enantiomer of the starting material. After a methanol crystallization: [a] 22D = -48 °
(c = 1, methanol); melting point: 151-152 ° C (decomposition); optical purity: > 98% (determined by an HPLC investigation).
The product was identified by elemental analysis, an IR spectrum and a 1H-NMR investigation.
EXAMPLE 14 Dextrorotatory [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetonitrile hydrochloride The procedure described in the previous example is followed, but (ÍS) - (+) - camphor-10-sulphonic is used as acid resolution. Product: weight: 2.5- g; [a] 22D = + 43 ° (c = 1, methanol). Yield: 43%, calculated on the dextrorotatory enantiomer content of the starting material. After a crystallization of ethanol: [] 22D = -48 ° (c = 1, methanol); melting point: 151-152 ° C
(decomposition); optical purity: > 98% (determined by an HPLC investigation). The product was identified by elemental analysis, an IR spectrum and an investigation 1H-N R.
EXAMPLE 15 Dextrorotative [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide 11.8 g (0.037 mol) of [2- (2-thienyl) ethylamino] (2-chloro-phenyl) acetonitrile hydrochloride are suspended. left-handed in 100 ml of methyl acetate and introduced, at room temperature,
9, 6 g of gaseous hydrogen chloride. Next they are added
3.6 g (0.113 mol) of methanol and the mixture is stirred at room temperature until the reaction has completed 6 hours. The precipitated crystalline material is filtered, which turns out to be the hydrochloride salt of the product, is suspended in water, neutralized, with stirring, with sodium bicarbonate. The crude white crystalline product is filtered, dried and recrystallized from ethanol. Weight: 5g; [a] 22D = + 63 ° (c = 1, methanol); melting point:
122-124 ° C; performance: 46%; Optical purity: 97%. The product was identified by elemental analysis, an IR spectrum and a 1H-NMR investigation.
Example 16 Dextrorotatory [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide. 38g (0.129 mole) of racemic [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide are dissolved at 50 ° C. ml of isopropanol containing 0-0.4%, conveniently, 0.2% of water, and to this solution is added a solution at 50 ° C of 10.6g
(0.071 moles) of L (+) - tartaric acid in 230 ml of isopropanol containing 0-0.4%, conveniently, 0.2% of water. The mixture is stirred at 50 ° C for 30 minutes. A thick white precipitate forms. 3.4 ml (0.09 mol) of formic acid are added to the mixture and stirring is continued at 50 ° C for 1 hour. The reaction mixture is then cooled to room temperature, stirred for another hour and the solid phase is filtered. The precipitated material is the salt formed between the levorotatory enantiomer of the starting material and the L (+) - tartaric acid, in a weakly optically contaminated form. Weight: 30g; melting point: 167-169 ° C, after a crystallization of ethanol. The mother liquor is evaporated under vacuum. The residue (29g) is taken up in 200 ml of water and 200 ml of 1,2-dichloroethane and neutralized with stirring with 16g (0.19 mole) of sodium bicarbonate. The phases are separated, the aqueous phase is washed with 2 x 30 ml of 1,2-dichloroethane, the combined organic phases are extracted with 50 ml of water, dried over anhydrous sodium sulfate and evaporated under vacuum. Weight: 18g. The crude product of 70 ml of ethanol is crystallized, washed with a small amount of ethanol and dried. Weight: 12, 6g; melting point: 122-124 ° C; [a] 2D = + 69 ° (c = 1, methanol); yield: 66.3%, calculated on the dextrorotatory enantiomer content of the starting material; optical pu: 99-100%, usually greater than 98% (determined by HPLC). The product was identified by elemental analysis, an IR spectrum and an XH-NMR investigation. 4 g of the racemic starting material can be recovered by concentration of the filtrate.
EXAMPLE 17 Dextrorotatory [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide. 76 g (0.257 mol) of racemic [2- (2-thienyl) ethylamino] (2-chlorophenyl) acetamide are dissolved at 50 ° C. 1200 ml of isopropanol containing 0.2% water and 21.2 g (0.141 mole) of L (+) tartaric acid and 8.3 g (0.18 mole) of formic acid are added to this solution. The mixture is stirred at 50 ° C for
1 hour while the thick white precipitate forms. The reaction mixture is then cooled to room temperature over a period of 1 hour, stirred another two hours and the solid phase is filtered. The precipitated material is the salt formed between the levorotatory enantiomer of the starting material and the L (+) tartaric acid is in an optically light contaminated form. Weight: 57 g. P. f. : 167-169 ° C after the crystallization of ethanol. After filtration of the solid material 5.2 g (0.141 mol), the hydrochloric acid gas is introduced into the filter to precipitate the product hydrochloride. The precipitated white crystalline material is filtered and dried. Weight: 41.7 g. The slightly contaminated salt obtained optically is extracted in 100 ml of ethanol and 5.3 g (0.13 mole) of sodium hydroxide dissolved in 70 ml of ethanol is added therein gradually to liberate the free base. The formed product containing some sodium chloride is filtered and washed with distilled water. After drying, its weight is 27.7 g, 73% of the dextrorotatory enatiomer content of the initial material P.f .: 122-124 ° C, [] 22D == + 69 ° (c = 1, methanol). 9 g of the racemic starting material are recovered if the ethanolic filtrate is evaporated and the remainder is extracted in water.
EXAMPLE 18 Dextrorotative methyl [2- (2-thienyl) ethylamino] -2-chlorophenylacetate hydrochloride. 11.5 ml (0.215 mol) of 100% sulfuric acid are dissolved, in cooling, in 40 ml of methanol, and the solution is heated at reflux for 1/2 hour, then cooled to room temperature and added to the solution. the solution 12.4 g (0.042 mole) of [2- (2-thienyl) ethylamino] (2-chlorophenyl) -acetamide dextrorotatory and the mixture is heated under reflux for 6-7 hours, until the reaction is complete. The methanol is distilled under vacuum, 75 ml of 1,2-dichloroethane and 75 ml of water are added to the residue, the mixture is stirred well and the phases are separated. The aqueous phase is extracted with 2 x 20 ml of 1,2-dichloroethane, and the combined organic phases are extracted with 50 ml of a 5% solution of sodium hydroxide, then with 50 ml of water and dried over sodium sulfate. anhydrous sodium The dried material is filtered and, with cooling, 1.5 g (0.041 mole) of gaseous hydrogen chloride is introduced into the solution. The precipitated white crystalline product is filtered, washed with 1,2-dichloroethane and dried. Weight: 12.1 g; melting point: 185-186 ° C (decomposition); [a] 22 D == + 107 ° (c = 1, methanol); performance: 83%; Optical purity: generally 99-100%. The product was identified by elemental analysis, an IR spectrum and a 1H-NMR investigation.
EXAMPLE 19 Dextrorotatory methyl (2-thienylethylamino) -2-chlorophenylacetate, through resolution of the racemate. a) 175 g of the hydrochloride salt of the compound with the general formula (VIII) are dissolved
- in which X represents a chlorine atom - in the mixture of 0.75 1 dichloromethane and 0.25 1 of water, and to the solution is added, gradually, 45 g of sodium bicarbonate. After mixing, the organic phase is separated by decantation. The amino ester is obtained following the usual procedure, it is then dissolved in 850 ml of acetone, and 87 g of acid are added to the solution.
(+) -alphafor-10-sulphonic. The mixture is kept at room temperature for 12 hours and the resulting precipitate is separated.
Thus, 146.5 g of camphor sulfonate are obtained; [a] 22D = + 51.7 °
(c = 1, methanol). The camphor sulfonate is suspended in 700 ml of acetone, while heating under reflux conditions, and to achieve complete dissolution, 300 ml of methyl ethyl ketone are added. The mixture is allowed to cool to room temperature. The resulting precipitate is separated and treated at room temperature with 500 ml of acetone and 300 ml of methyl ethyl ketone. This is how 95 g of (+) - camphor sulfonate are obtained from the expected product, melting point: 95 ° C, [a] 22 D = + 82 ° (c = 1, methanol). b) 33.5 g of the hydrochloride salt of the compound are mixed with the general formula (VIII)
- wherein X represents a chlorine atom - and 14.6 g of (+) - tartaric acid in 500 ml of isopropanol, is heated to 50 ° C and maintained at room temperature. The resulting precipitate is separated and crystallized four times from isopropanol. In this way the (+) - tartrate of the desired dextrorotatory product is obtained, melting point: 105 ° C, specific rotation of the amine: [a] 20 D = + 99, 76 ° (c = 1, methanol)
EXAMPLE 20 Levorotatory Methyl (2-thienylethylamino) -2-chlorophenylacetate, by resolution of the racemate 100 g of the hydrochloride salt of the compound are mixed with the general formula (VIII)
- in which X represents a chlorine atom - and 30 g of sodium bicarbonate in 500 ml of dichloromethane and 200 ml of water. After stirring, the organic phase is separated by decantation and the solvent is distilled under vacuum. The residue is dissolved in 800 ml of acetone, and 53.3 g of (-) - camphor-10-sulfonic acid are added to this solution. The mixture is kept at room temperature for 12 hours. The resulting precipitate is separated and suspended in 300 ml of acetone. The insoluble solid precipitate is crystallized from a mixture of 600 ml of acetone and 160 ml of methyl ethyl ketone, to obtain 52.5 g of the (-) - albumin sulfonate of the desired product, melting point: 95 ° C, [a] 22 D = + 82 ° (c = 1, methanol)
Example 21 (+) - (S) - (2-chlorophenyl) hydrochloride (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) methyl acetate 6 g (0.017 moles) are suspended. ) of methyl [2- (2-thienyl) ethylamino] -2-chlorophenylacetate hydrochloride in 6.7 ml of a 38% aqueous solution of formalin and heated, with stirring, to 60 ° C. The starting material is dissolved at 60 ° C, the resulting solution is stirred at said temperature for 30 minutes, until the reaction is complete. The reaction mixture is then diluted with 100 ml of 1,2-dichloroethane and 150 ml of water and, after stirring well, the phases are separated. The aqueous phase is extracted with 2 x 30 ml of 1,2-dichloroethane, the combined organic phase is extracted with 100 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The 6 g of residual material are dissolved in 30 ml of 30 ml of diethyl ether and, while the reaction mixture is cooled, 0.6 g of dry hydrogen chloride gas are introduced into the solution at room temperature. The precipitated white crystalline material is filtered, washed with ether and dried. Weight: 5.5 g; melting point: 130-132 ° C; [] 22 D = + 60 ° (c = 1, methanol); yield: 90.1%; Optical purity: 99% (investigated by HPLC).
Example 22 a) (-) - methyl (+) - (2-chlorophenyl) (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) acetate) -phosphonate is dissolved 32 g ( 0.0994 mol) of (2-chlorophenyl) (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) methyl acetate in 150 ml of acetone, and the solution is added to the solution. , 95g (0.0397 moles) of 10-camphor sulfonic acid monohydrate. The homogenous reaction mixture is maintained at room temperature. After 48 hours, a few crystals appear. The mixture is concentrated by evaporation to 50 ml and maintained at room temperature for 24 hours. The resulting crystals are filtered, washed with acetone and dried. The crystals obtained in this way are again dissolved in a very small amount of (50 ml) of hot acetone and, after allowing to cool, the crystals are filtered, washed with acetone and dried. The title compound is thus obtained. Yield: 88%; melting point: 165 ° C; [] 20D = + 24 ° (c = 1, 68 g / 100 ml, methanol). b) (+) - (2-chlorophenyl) (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) methyl acetate To the suspension made with 200g of (-) - alkylphosphonate from (+) - (2-chlorophenyl) (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) methyl acetate and 800 ml of dichloromethane are added 800 ml of a bicarbonate solution of sodium. After stirring, the organic phase is separated by decantation, dried over sodium sulfate and the solvent is removed under vacuum. The (+) - (2-chlorophenyl) is obtained (6, Methyl 7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) acetate as a solution in 800 ml of dichloromethane. After stirring, the organic phase is separated by decantation, dried over sodium sulfate and the solvent is removed under vacuum. The (+) - (2-chlorophenyl) (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) methyl acetate is obtained in the form of a colorless oil. c) methyl (+) - (2-chlorophenyl) acid (6,7-dihydro-4H-thieno [3,2- c] pyridin-5-yl) acetate. The residue obtained in the previous example is dissolved in 500 ml of ice-cold acetone, and to this solution are added, dropwise, 20.7 ml of concentrated sulfuric acid (93.64%); density: 1.83). The resulting precipitate is filtered off, washed with 1000 ml of acetone and dried in an oven under vacuum at 50 ° C. In this way, 139 g of the title salt are obtained in the form of white crystals. Melting point: 184 ° C; [] 20 D = + 55.1 ° (c = 1.891 g / 100 ml, methanol).
Claims (4)
1. A process for the preparation of racemic or optically active compounds with the general formula (VI) - in which X represents a halogen atom - or its salts, characterized by converting a new racemic or optically active compound with the general formula (VII) " - in which X represents a halogen atom - in the racemic or optically active compound with the general formula (VIII) - wherein X represents a halogen atom - and, if desired, the resulting racemic compounds with the general formula (VIII) they are resolved into their optically active isomers and then, by means of a ring closure, by a method known per se, the compounds with the general formula (VIII) they are transformed into the racemic or optically active compounds with the general formula (VI), and, if desired, the racemic or optically active compounds with the general formula (VI) rm they are resolved in their optical isomers and / or transformed into their salts and / or the racemic or optically active compound is released from its salts.
2. The process defined in claim 1, characterized in that the compounds with the general formula (VII) - in which X represents what is defined in claim 1 - are transformed with methanol, in the presence of methyl acid sulfate, in the compounds with the general formula (VIII).
3. The process defined in claim 1, characterized in that the process is carried out at temperatures between 50 and 150 ° C.
4. The process defined in claim 1, characterized in that the compounds with the general formula (VII) - in which X represents a chlorine atom - are transformed into the compounds with the general formula (VIII) - in which X represents a chlorine atom.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUP9700885 | 1997-05-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99010434A true MXPA99010434A (en) | 2000-08-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0981529B1 (en) | A new process for the preparation of a pharmacologically active substance | |
EP0981524B1 (en) | New intermediates and process for the preparation thereof | |
JP4279903B2 (en) | Novel intermediates and methods for their preparation | |
JP4598276B2 (en) | Racemization method | |
MXPA99010434A (en) | A new process for the preparation of a pharmacologically active substance | |
JP4256478B6 (en) | Novel process for the preparation of pharmacologically active substances | |
MXPA99010431A (en) | New intermediates and process for the preparation thereof | |
MXPA99010433A (en) | New intermediates and process for the preparation thereof | |
MXPA01004644A (en) | Process for racemization |