MXPA00003820A - Process for the recycle of a waste product of diltiazem synthesis - Google Patents
Process for the recycle of a waste product of diltiazem synthesisInfo
- Publication number
- MXPA00003820A MXPA00003820A MXPA/A/2000/003820A MXPA00003820A MXPA00003820A MX PA00003820 A MXPA00003820 A MX PA00003820A MX PA00003820 A MXPA00003820 A MX PA00003820A MX PA00003820 A MXPA00003820 A MX PA00003820A
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- Mexico
- Prior art keywords
- formula
- process according
- compound
- iii
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- HSUGRBWQSSZJOP-RTWAWAEBSA-N Diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 title claims abstract description 18
- 229960004166 diltiazem Drugs 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 13
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- 230000002194 synthesizing Effects 0.000 title abstract description 13
- 239000002699 waste material Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 239000000203 mixture Substances 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 26
- 239000002253 acid Substances 0.000 claims description 17
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 13
- 230000000875 corresponding Effects 0.000 claims description 7
- 238000007363 ring formation reaction Methods 0.000 claims description 7
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000003125 aqueous solvent Substances 0.000 claims description 4
- 125000000204 (C2-C4) acyl group Chemical group 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 230000001476 alcoholic Effects 0.000 claims description 3
- MIOPJNTWMNEORI-UHFFFAOYSA-N Camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 1
- -1 2- aminophenylthio Chemical group 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000004064 recycling Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 4
- XWCIXXXLOAAWPU-IHWYPQMZSA-N [(Z)-prop-1-enyl]phosphonic acid Chemical compound C\C=C/P(O)(O)=O XWCIXXXLOAAWPU-IHWYPQMZSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- LHBHZALHFIQJGJ-LSDHHAIUSA-N (2R,3R)-3-hydroxy-2-(4-methoxyphenyl)-3,5-dihydro-2H-1,5-benzothiazepin-4-one Chemical compound C1=CC(OC)=CC=C1[C@@H]1[C@H](O)C(=O)NC2=CC=CC=C2S1 LHBHZALHFIQJGJ-LSDHHAIUSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 150000003460 sulfonic acids Chemical class 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-Phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- LGFTULJJDDFVFE-UHFFFAOYSA-N 2-(4-methoxyphenyl)-5H-1,5-benzothiazepine-3,4-dione Chemical compound C1=CC(OC)=CC=C1C1C(=O)C(=O)NC2=CC=CC=C2S1 LGFTULJJDDFVFE-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N 5-(7-(4-(4,5-DIHYDRO-2-OXAZOLYL)PHENOXY)HEPTYL)-3-METHYL ISOXAZOLE Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229940040461 Lipase Drugs 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229940017219 METHYL PROPIONATE Drugs 0.000 description 1
- YRWWWPMLATUJOI-UHFFFAOYSA-N [2-(4-methoxyphenyl)-4-oxo-5H-1,5-benzothiazepin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1C1=C(OC(C)=O)C(=O)NC2=CC=CC=C2S1 YRWWWPMLATUJOI-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 102000004882 lipase Human genes 0.000 description 1
- 108090001060 lipase Proteins 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KKVTYAVXTDIPAP-UHFFFAOYSA-M sodium;methanesulfonate Chemical compound [Na+].CS([O-])(=O)=O KKVTYAVXTDIPAP-UHFFFAOYSA-M 0.000 description 1
- 230000002269 spontaneous Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
Abstract
A process which allows the re-use of compounds of formula (III-(2R, 3R)) in diltiazem synthesis through a process of conversion to a mixture of enantiomers III-(2R,3R) and III-(2S,3S) is described.
Description
PROCESS FOR THE RECYCLING OF A RESIDUAL PRODUCT OF THE SYNTHESIS OF DILTIAZEM
The present invention relates to a method for the recycling of a residual product from the synthesis of diltiazem and, more particularly, relates to a method for the preparation of esters of threo-2-hydroxy-3- (2- aminophenylthio) -3- (4-methoxyphenyl) propionic intermediates useful for the synthesis of diltiazem, starting from (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (-methoxyphenyl) propionic acid or derivatives of the same. Diltiazem, (+) - (2S, 3S) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 ( 5H) -one (The Merck Index, XII ed., No. 3247, page 541), is a known drug with calcium antagonist activity described in British Patent 1236467 (Tanabe Seiyaku Co. Ltd.). Various methods for. the preparation of diltiazem, such as, for example, those described in British Patent 1236467 cited above, in European Patent Application 0 059 335 and in Japanese Patent no. 71/8982, all in the name of Tanabe Seiyaku Co. Ltd., are described in the literature.
Most of these methods substantially provide the following synthesis scheme.
Scheme 1
N * 'Diltiazem where R is a hydrogen atom or a lower alkyl and the asterisk marks the stereogenic carbon atoms. These methods use the compound of formula III-threo in racemic form, as an intermediate. However, diltiazem shows stereocenters with S configuration and then, after the scheme reported above, a separation step of the (2S, 3S) enantiomer of the ona (2R, 3R) is necessary. The separation of the two enantiomers can be carried out on the intermediate (III) in the form of an ester (R = alkyl), as well as in the acid form (R = H). For example, the separation of the enantiomers
(2S, 3S) and (2R, 3R) at the level of ester III can be carried out using an optically active acid as a resolving agent (US Patent 5,144,025 - Zambon
Group S.p.A.) or by spontaneous resolution (Patent
United States 5,097,059 - Zambón Group S.p.A.). In the case of separation at the level of acid III, the methods described in the literature provide, inter alia, resolution with optically active bases such as a-phenylethylamine (patent application).
European 0 098 892 - Tanabe Seiyaku Co. Ltd.) or L-lysine
(British patent application 2130578 - Istituto Luso Fármaco d 'Italia S.p.A.) or acylation in the presence of a lipase (European patent application 0 617 130 - Orion-Yhtyma Oy Fermion). It is evident that the resolution methods have the disadvantage of giving the (2S, 3S) isomer with a maximum theoretical yield of 50% over the racemate and also giving the corresponding (2R, 3R) isomer at the same time. The isomers with configuration (2R, 3R), unsuitable for the synthesis of diltiazem, are then a residual product in the industrial synthesis. As a consequence, a process for the recycling of such compounds to recover them for the synthesis of diltiazem would be useful. As far as we know, the only method described in the literature to recycle an intermediary with configuration (2R, 3R) is the process called in the
U.S. Patent 5,102,999 (Zambón Group S.p.A.), which provides the racemization of the IV-cis intermediate (2R, 3R). We have now found a process for the conversion of the intermediates III- (2R, 3R) to a mixture of enantiomers III- (2R, 3R) and III- (2S, 3S) which allows to reuse the enantiomers with configuration (2R, 3R ) of the intermediates of formula III for the synthesis of diltiazem. Therefore, the object of the present invention is a. process for the conversion of threo- (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenylthio) -3- (4-methoxyphenyl) propionic acid derivatives of the formula "formula
wherein R1 is a linear or branched C? -C3 alkyl or a hydrogen atom; in a mixture of enantiomers III- (2R-3R) and III- (2S, 3S). characterized by the steps of: (a) cyclization of compound III- (2R, 3R) to give the corresponding compound of formula
(b) the conversion of the compound of formula wherein R2 is a hydrogen atom or a C2-C4 acyl group. (c) the reduction to give the compound of formula
(d) the opening reaction by treatment with a strong acid or a strong base in an alcoholic or aqueous solvent. The mixture of the two enantiomers III- (2R, 3R) and
III- (2S, 3S) obtained with the process object of the present invention, can be solved according to the methods already reported to separate the (2S, 3S) enantiomers useful for the synthesis of diltiazem.
In the present context, if not otherwise specified, the term enantiomer mixture means a substantially racemic mixture (ratio of
2R, 3R: 2S, 3S of about 1: 1) or a mixture where the 2S, 3S enantiomer prevails. Analogously, if the absolute configuration of the compounds of formula III or IV is not indicated, it means that the compounds are in a substantially racemic mixture (ratio of 2R, 3R: 2S, 3S of about 1: 1) or a mixture where the 2S, 3S enantiomer prevails. The term "straight or branched C1-C3 alkyl" means methyl, ethyl, propyl, isopropyl and the term "C2-C4 acyl group" means acetyl, propionyl, butyryl, isobutyryl. The intermediates of formula III- (2R, 3R) used as initial products in the process object of the present invention are known compounds and are obtained as residual products in the process of optical separation for the synthesis of diltiazem. In general, the compounds of formula III are in the form of acid (R1 = H) or in the form of methyl (RX = CH3) or ethyl (R1 = CH2-CH3) ester. Preferably, in the process object of the present invention, the compounds of formula III are methyl esters.
Cyclization of compound III- (2R, 3R) to give the compound of formula IV- (2R, 3R) can be carried out according to the known methods for cyclization of the corresponding (2S, 3S) enantiomer. For example, the cyclization of the esters of formula III- (2R, 3R) can be carried out by treating with phosphonic acids (US Pat. No. 5,223,612 - Zambon Group SpA) or by treating with sulfonic acids (European patent application 0 447 135 - Tanabe Seiyaku Co. Ltd.). Similarly, the cyclisation of the acid of formula III- (2R, 3R) can be carried out by treating with sulphonic acids (European patent application 0 395 323 Tanabe Seiyaku Co. Ltd.) or with bases (European patent application 0 450 705 - Stamicarbon BV). In the process object of the present invention, the cyclization reaction is preferably carried out starting from the methyl ester of formula III- (2R, 3R) by treating with cis-propenyl phosphonic acid. The subsequent conversion reaction to the derivative V can be carried out according to known methods as well. For example, the methods described in J. Org. Chem., 1996. 8586-8590 or in the aforementioned U.S. Patent 5,102,999. Preferably, in the process object of the present invention, the acetyl derivative of formula V (R2 = COCH3) is prepared, then hydrolyzed to give the compound Va, which will be in equilibrium with the tautomer (Vb) as it is reported here later.
Va Vb The following reduction reaction allows obtaining the IV-cis compound. Optionally, the hydrolysis and reduction reactions can be carried out in a vessel, ie in a single reaction environment, without isolating the compound Va or (Vb). The preparation of the acetyl derivative V is preferably carried out by treating with acetic anhydride in dimethyl sulfoxide, in the presence of catalytic amounts of pyridine. Optional hydrolysis can be carried out by treating with bases such as sodium hydroxide or sodium mesylate. The reduction of the compound of formula V can be carried out with known methods, for example, by treating with hydrams according to that reported in the aforementioned US Patent 5,102,999. The resulting IV-cis compound can then be converted to the corresponding compound of formula III-threo by treating with strong acid or with a strong base in an alcoholic or aqueous solvent. The amount of acid or base is at least equimolar, preferably in excess, with respect to the IV-cis compound. In general, the reaction is carried out using an excess of acid or base equal to 10% -30% by mole with respect to compound IV. The strong acids used in the process of the invention are inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids or organic acids such as sulfonic acids, preferably methanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid. Preferably, sodium hydroxide is used as the strong base. Methanesulfonic acid is preferably used in the process object of the present invention. The reaction is carried out in an alcohol solvent, such as, for example, methane or ethanol, preferably in methanol or water optionally in admixture with a suitable cosolvent, such as dimethylsulfoxide. Depending on the alcohol used as a solvent, the corresponding ester of formula III-threo is obtained, which can then be used again in the preparation of diltiazem according to the synthetic route illustrated in scheme 1 above. When an aqueous solvent is used, the acid (R1 = H) of formula III-threo is obtained and used according to the synthetic route illustrated in scheme 1 as well. The initial reaction of the compound of formula
IV-cis represents the most outstanding characteristic of the process object of the present invention. In fact, as far as we know, this reaction has never been described in the literature. On the contrary, cyclizations of the compound III-threo to give the compound IV-cis using acids or bases have been widely described in the literature. In addition, it is evident that the possibility of racemizing the residual products with configuration
(2R, 3R) of the process for the preparation of diltiazem at the level of one of the first synthetic intermediates represents a relevant advantage from a practical and economic point of view.
A particularly preferred embodiment of the process object of the present invention is the following. The methyl ester of formula III- (2R, 3R), obtained by resolution of the corresponding racemic mixture, is cyclized with cis-propenyl-phosphonic acid and then oxidized by treatment with acetic anhydride / dimethylsulfoxide / pyridine to obtain the acetyl derivative of formula V. After hydrolysis and basic reduction with sodium borohydride, the racemic compound IV-cis is obtained and treated with an excess of methanesulfonic acid in methanol until the racemic methyl ester III-threo is obtained. The resolution of the racemic methyl ester? Ll-threo allows obtaining the compound III- (2S, 3S) which is used for the synthesis of diltiazem and the enantiomer III- (2R, 3R), which may undergo an additional recycling phase according to the object of the process of the present invention. To better illustrate the present invention, the following examples are now given.
Example 1 A mixture of methyl (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxy) -propionate (5 g, "15 mmol) and cis-propenyl phosphonic acid (0.183 g;
1. 5 mmoles) 'in xylene (35 ml), heated under reflux and stirred for 5.5 hours. After distilling a mixture of xylene / methanol (at about 3%), the reaction mixture was cooled to 15 ° C. The resulting precipitate was filtered under vacuum, washed with xylene (2x5 ml) and then dried in an oven at 65 ° C to obtain (2R, 3R) -2, 3-dihydro-3-hydroxy-2- (4- methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (42 g, 89.6% yield).
Example 2 A catalytic amount of pyridine (19.5 g, 0.25 mole) was added to a solution of (2R, 3R) -2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepine- 4 (5H) -one (500 g, 1.6 moles) in dimethylsulfoxide (1100 g, 14.1 moles) and acetic anhydride (425 g, 4.17 moles). After maintaining the solution under stirring at room temperature for 24 hours, water (1000 rcl) was added slowly and the mixture was kept under stirring for 30 minutes. The crystalline precipitate was filtered, washed with methanol and dried to obtain 3-acetoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (481.6 g, yield 84.7%).
Example 3 A suspension of 3-acetoxy-2- (methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one (17.1 g, 0.05 mmol) in methanol (51 ml) was cooled in ice and then added a solution of NaOH (5 g, 0.125 mmol) in water (63 ml). The solution was then kept under stirring for 2 hours at room temperature. t After neutralizing with 2N HCl (50 ml) and extraction with ethyl acetate, the organic phase was washed twice, dried and concentrated to obtain a viscous oil. The oil was treated with ethyl ether to obtain 2- (4-methoxyphenyl) -1,5-benzothiazepin-3,4 (4H, H) -dione (12.98 g, 86.7% yield) as a crystalline solid.
Example 4 Sodium borohydride (0.567 g, 15 mmol) was added to a solution of 2- (4-methoxyphenyl) -1,5-benzothiazepin-3,4 (2H, 5H) -dione (4.25 g, 14.2 mmol) in methanol (65 ml) was kept under stirring at 15 ° C. 1 hour later, the reaction mixture was poured into a buffer solution (100 ml) at pH 7 and the methanol was removed by distillation under vacuum.
The resulting mixture was extracted with methylene chloride (2x30 ml). After evaporation of the solvent under reduced pressure, cis-2,3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one was obtained (4.15 g; 97%) as a racemic mixture.
Example 5 In a 500 ml flask, equipped with thermometer and condenser, cis-2, 3-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one was suspended ( 50 g, 165.9 mmol) in methanol (200 ml) and methanesulfonic acid (19.2, 200 mmol) was added to the mixture. The reaction mixture was brought to reflux and the progress of the reaction was followed by TLC (Thin Layer Chromatography) (eluent ethyl acetate: hexane = 6: 4). After heating for 7 hours, the content of the initial product was about 1%. The reaction mixture was then cooled to room temperature before adding, with a dropping funnel, an 8% sodium bicarbonate solution (208 g, final pH = 7.0). The resulting precipitate was filtered and washed three times with water (3x50 ml). The resulting solid was then dried at 50 ° C under vacuum to a constweight to obtain methyl threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) -propionate (54 g, 94.2 molar yield). %, CLAP title 96.5%).
Example 6 30% sodium methylate in methanol was added
(0.1 ml, 0.5 mmol) and, 15 minutes later, sodium borohydride (54 mg, 1.42 mmol) to a suspension of 3-acetoxy-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) - Ona (1 g, 2.9 mmol) in methanol (5 ml). After maintaining the mixture under stirring at room temperature for 5 hours, methanesulfonic acid (0.6 ml, 9.3 mmol) was added and the mixture was stirred under reflux for 5 hours. After cooling to room temperature, 8% sodium bicarbonate (9 ml) was added. After adding toluene, the resulting solid was filtered, washed with water (3x1 ml) and dried at 50 ° C under vacuum to obtain threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) Methyl propionate (0.92 g, 90% molar yield, CLAP 95% title).
Example 7 30% sodium methylate in methanol (0.5 ml, 2.5 mmol) was added and, 15 minutes later, sodium borohydride (0.28 g, 7.35 mmol) to a suspension of 3-acetoxy-2- (4-methoxyphenyl). -1,5-benzothiazepin-4 (5H) -one (5 g, 14.7 mmol) in methanol (25 ml). After maintaining the mixture under stirring at room temperature for 5 hours, a 6.5 M solution of hydrochloric acid in methanol (2.7 ml;
17. 6 mmoles) and the mixture was heated under reflux for
hours . After cooling to room temperature, 8% sodium bicarbonate (16 ml) was added. The resulting precipitate was filtered, washed with water (3x5 ml) and dried at 50 ° C under vacuum to obtain methyl threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) -propionate ( 5 g, 85% molar yield, XH-NMR 75% title). It is noted that in relation to this date, the best method known to the applicto carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (9)
1. A process for the conversion of threo- (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenylthio) -3- (4-methoxyphenyl) propionic acid derivatives and their derivatives of the formula where R1 is a linear or branched C? -C3 alkyl or a hydrogen atom; in a mixture of enantiomers III- (2R-3R) and III- (2S, 3S), characterized by the following steps: (a) cyclization of compound III- (2R, 3R) to give the corresponding compound of formula (b) ) the conversion of the compound of formula where R is a hydrogen atom or a C2-C4 acyl group. (c) the reduction to give the compound of formula rv-c / s (d) the opening reaction by treatment with a strong acid or with a strong base in an alcoholic or aqueous solvent.
2. The process according to claim 1, characterized in that it serves for the conversion of threo- (2R, 3R) -2-hydroxy-3- (2-aminophenylthio) -3- (-methoxyphenyl) propionic acid methyl ester.
3. The process according to claim 1, characterized in that the compound of formula V wherein R2 is acetyl is used.
4. The process according to claim 1, characterized in that the opening reaction is carried out by treating with a strong acid.
5. The process according to claim 4, characterized in that the strong acid is hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic or camphorsulfonic acid.
6. The process according to claim 5, characterized in that the strong acid is methanesulfonic acid.
7. The process according to claim 4, characterized in that an alcohol solvent is used.
8. The process according to claim 7, characterized in that the solvent is methanol.
9. Diltiazem, (+) - (2S, 3S) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepin-4 ( 5H) -one, characterized in that it is obtained by using an intermediate of formula III prepared with the process according to claim 1.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MIMI97A002374 | 1997-10-22 |
Publications (1)
Publication Number | Publication Date |
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MXPA00003820A true MXPA00003820A (en) | 2001-06-26 |
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