MXPA01004128A - Intermediate for the synthesis of amlodipine, preparation process and corresponding utilization - Google Patents
Intermediate for the synthesis of amlodipine, preparation process and corresponding utilizationInfo
- Publication number
- MXPA01004128A MXPA01004128A MXPA/A/2001/004128A MXPA01004128A MXPA01004128A MX PA01004128 A MXPA01004128 A MX PA01004128A MX PA01004128 A MXPA01004128 A MX PA01004128A MX PA01004128 A MXPA01004128 A MX PA01004128A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- ethoxy
- phthalimido
- amino
- crotonate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- HTIQEAQVCYTUBX-UHFFFAOYSA-N Amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 8
- 230000002194 synthesizing Effects 0.000 title claims abstract description 8
- 230000000875 corresponding Effects 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 claims abstract description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- 239000005695 Ammonium acetate Substances 0.000 claims abstract description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940043376 ammonium acetate Drugs 0.000 claims abstract description 6
- 235000019257 ammonium acetate Nutrition 0.000 claims abstract description 6
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- ZFDIRQKJPRINOQ-HWKANZROSA-N ethyl (E)-but-2-enoate Chemical compound CCOC(=O)\C=C\C ZFDIRQKJPRINOQ-HWKANZROSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000012429 reaction media Substances 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000005712 crystallization Effects 0.000 claims description 2
- OEBFVKDPQVFAPH-LUAWRHEFSA-N ethyl (Z)-3-amino-4-[2-(1,3-dioxoisoindol-2-yl)ethoxy]but-2-enoate Chemical compound C1=CC=C2C(=O)N(CCOCC(/N)=C/C(=O)OCC)C(=O)C2=C1 OEBFVKDPQVFAPH-LUAWRHEFSA-N 0.000 claims 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 abstract 2
- 125000005544 phthalimido group Chemical group 0.000 description 4
- PAWSVPVNIXFKOS-IHWYPQMZSA-M (Z)-2-aminobut-2-enoate Chemical compound C\C=C(/N)C([O-])=O PAWSVPVNIXFKOS-IHWYPQMZSA-M 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N Ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- AHHPZGUFLGCZCF-UHFFFAOYSA-N 3-O-ethyl 5-O-methyl 4-(2-chlorophenyl)-2-[2-(1,3-dioxoisoindol-2-yl)ethoxymethyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(COCCN2C(C3=CC=CC=C3C2=O)=O)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl AHHPZGUFLGCZCF-UHFFFAOYSA-N 0.000 description 2
- -1 4- (3-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl -1,4-dihydropyridine Chemical compound 0.000 description 2
- 102000014961 Protein Precursors Human genes 0.000 description 2
- 108010078762 Protein Precursors Proteins 0.000 description 2
- 241001558496 Talpa caeca Species 0.000 description 2
- 230000002253 anti-ischaemic Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000010192 crystallographic characterization Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- RIGKLAOKQFKWNN-UHFFFAOYSA-N ethyl 4-[2-(1,3-dioxoisoindol-2-yl)ethoxy]-3-oxobutanoate Chemical compound C1=CC=C2C(=O)N(CCOCC(=O)CC(=O)OCC)C(=O)C2=C1 RIGKLAOKQFKWNN-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- MNMKWCPLHQYQLU-UHFFFAOYSA-N methyl 2-[(2-chlorophenyl)methylidene]-3-oxobutanoate Chemical compound COC(=O)C(C(C)=O)=CC1=CC=CC=C1Cl MNMKWCPLHQYQLU-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- 150000004729 acetoacetic acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- XKORCTIIRYKLLG-ARJAWSKDSA-N methyl (Z)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(\C)N XKORCTIIRYKLLG-ARJAWSKDSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
Abstract
Intermediate product for the synthesis of amlodipine, process for its preparation and its utilization. The intermediate product is 3-amino-4-(2-phtalimide)ethoxy)crotonate of ethyl and has the formula (III). The preparation process comprises the reaction of acetoacetate having the formula (A) with ammonium acetate;it is used for the preparation of the compound having the formula (B) through the reaction of 3-amino-4-[2-(phtalimido)ethoxy]crotonate of ethyl with a derivative of benzylidene.
Description
INTERMEDIATE FOR THE SYNTHESIS OF AMLODIPINO, PROCEDURE FOR ITS OBTAINING AND ITS USE
DESCRIPTION The present invention relates to an intermediate for the synthesis of a lodipino, to a process for its preparation and to a use of the intermediate. The invention belongs to the field of heterocyclic chemistry and, as already indicated, refers to a chemical intermediate, the 3-amino-4- (2-phthalimido) ethoxy) ethyl crotonate, its preparation process, and its use for the synthesis of the compound 2- ((2-aminoethoxy) methyl) -4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine, generically called amlodipine, product with therapeutic activity used as anti-ischemic and antihypertensive agent. EP 0 089 167 discloses the use of 1,4-dihydropyridines of formula I, as immediate precursors of Amlodipine of formula II.
REF: 129000 R'R2 »protected ammo group (I) (II)
EP 0 060 674 discloses two processes for the preparation of 1,4-dihydropyridines which contain in the 2-position a substituent with an amino group and which possess anti-ischemic and anti-hypertensive utility. In both
cases, the yields they indicate are very low («15%) and the products have to be purified by chromatography, which makes their industrial application difficult. EP 0 089 167 describes the preparation of several 1,4-dihydropyridines of formula I, precursors of amlodipine, following the same procedures indicated in t EP 60674: (a) In the case where the aminoprotective groups are benzyl, azido or phthalimido, by reaction of 2-chlorobenzaldehyde (IV) with ethyl acetoacetate
(V) and methyl 3-aminocrotonate (VI) (I)
(b) Alternatively, in the case where the aminoprotective groups are benzyl and azido, by reaction of the benzylidene derivative (VII) with the aminocrotonate (VIII), the latter prepared "in situ" from the corresponding ethyl acetoacetate (V) and ammonium acetate.
R '»R2 = E3n R' = Bn. R2 = H NR'R * = N3
With both procedures the yields obtained are very low (30% and 11% respectively in the case of the azido protective group, NR1R2 = N3). On the other hand, the intermediate aminocrotonates (VIII) are not isolated or characterized since they are prepared "in situ" from the corresponding ethyl acetoacetate (V) prior to the reaction with the benzylidene derivative (VII). The isolation and characterization of these aminocrotonates (VIII) has not been described in the literature. The authors of the present invention have tried unsuccessfully to isolate the compound of formula VIII described in EP 0 089 167, where R1 = R2 = Bn. This patent describes these compounds as "in situ" preparations (page 8), without any experimental verification of their characteristics or chemical structure.
Because the acetoacetates (V) and the benzylidene derivative (VII) are oils, it was essential to have a solid intermediate that would allow to obtain compounds of formula (I) with high yield and purity. The present invention relates to a new compound, ethyl 3-amino-4- (2-phthalimido) ethoxy) crotonate, of formula III
The new compound of formula III has been able to be isolated in the solid state thus allowing its purification, identification and characterization. This compound has proved to be very useful as an intermediate for the synthesis of 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine (from Formula I, where NRXR2 = phthalimido) immediate precursor of amlodipine.
The preparation process of III consists in the reaction of ethyl 4- [2- (phthalimido) ethoxy] acetoacetate (V, NR -'- R2 = phthalimido) with ammonium acetate in a reaction medium, which is preferably an organic solvent (ethanol, isopropanol, toluene, xylene, etc.) yielding the desired product in solid state and with a good yield and a high degree of purity. When the reaction is conducted in toluene, a Dean-Stark device can be used to sepa the water formed. The reaction takes place at a tempere ranging from 10 ° C to the reflux tempere, preferably between 50 to 70 ° C. At the end of the reaction, the product is crystallized in an alcohol being isolated in solid form, leaving the dissolved impurities in the mother liquor. Preferably, ethanol or isopropanol is used as the crystallization solvent, to achieve a high degree of purity and yield.
An interesting use of the solid 3-amino-4- (2-phthalimido) ethoxy) crotonate (of formula III) is obtained by reacting it with methyl 2- (2-chloro-benzylidene) acetoacetate (of formula VII) in an organic solvent (methanol, ethanol, isopropanol, toluene, xylene), preferably ethanol, at a temperature comprised between 10 ° C and the reflux temperature, preferably between 60 and 80 ° C. The reaction is maintained between 12 and 24 hours, after which it is cooled with what crystallizes 4- (3-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl -1,4-dihydropyridine (1; NR1R2 = phthalimido) which is isolated with a high degree of purity and yield, superior to those described in the literature.
Next, some examples illustrating the invention are described.
EXAMPLE 1 3-amino-4- (2-phthalimido) ethoxy) ethyl crotonate (III) 32 g (100 m.moles) of ethyl 4- [2- (phthalimido) ethoxy] acetoacetate in 200 ml of toluene are made react with 8.1 g (105 m.moles) of ammonium acetate at 65 ° C for 4 hours by removing the water formed in the reaction by a Dean-Stark. The toluene is evaporated to dryness and the residue from the distillation is crystallized from isopropanol yielding 24.5 g (rdt 77%) of a beige solid corresponding to ethyl 3-amino-4- (2-phthalimido) ethoxy) crotonate. mp: 90-92 ° C, IR (KBr): 3460, 3343, 1769, 1674, 1618, 1571, 1430, 1398, 1364, 1354, 1158, 1125, 1031, 721 cm1 XH NMR (300 MHz, DMSO) d 7.8 (m, 4H, ar), 7.5 (s, 1H, NH2), 6.7 (s, lH, NH2), 4.4 (s, 1H, -CH =), 3.9 ( m, 4H, -COCH2-, = C-CH20-), 3.8 (t, 2H, -OCH2-), 3.6 (t, 2H, -CH2N), 1.1 (t, 3H, CH3) EXAMPLE 2 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-ethyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine. 24.0 g (75.4 mmol) of ethyl 3-amino-4- (2-phthalimido) ethoxy) crotonate and 18.9 g (79.2 mmol) of methyl 2- (2-chlorobenzylidene) -acetoacetate in 64 ml of ethanol are heated to reflux for 20 hours. The reaction mixture is diluted with 56 ml of ethanol and cooled to crystallize the product. 14.2 g (rdt.70%) of 4- (2-chloro-phenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- (2-phthalimidoethoxy) methyl-1,4-dihydropyridine are obtained. Mp: 150-151 ° C IR (KBr): 3370, 1712, 1489, 1422, 1392, 1287, 1201, 1122,1102, 1024 cm "1.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (5)
1. Intermediate for the synthesis of amlodipine, said intermediate being named 3-amino-4- (2-phthalimido) ethoxy) ethyl crotonate, of formula III (III)
2. Process for the preparation of an intermediate named 3-amino-4- (2-phthalimido) ethoxy) ethyl crotonate of formula III (III) characterized in that it comprises the reaction of the acetoacetate of formula with ammonium acetate, at a temperature ranging from 10 ° C to the reflux temperature, to prepare said intermediate, which is isolated in solid form by crystallization in the same reaction medium.
3. Method according to claim 2, characterized in that said reaction medium is an organic solvent.
4. Process according to claim 2, characterized in that said organic solvent is ethanol, isopropanol or toluene.
5. Method of using 3-amino-4- (2-phthalimido) ethoxy) crotonate of formula III (III) for the preparation of the compound of formula characterized by comprising the reaction of said ethyl 3-amino-4- (2-phthalimido) ethoxy) crotonate with a benzylidene derivative of formula VII (VII) at a temperature that varies from 10 ° C to the reflux temperature. SUMMARY OF THE INVENTION Intermediate for the synthesis of amlodipine, procedure for its obtaining and corresponding use. The intermediate is ethyl 3-amino-4- (2-phthalimido) ethoxy) crotonate and is of formula III (III) The process for obtaining it comprises the reaction of the acetoacetate of formula with ammonium acetate; and its use is for the preparation of the compound of formula being carried out by reaction of ethyl 3-amino-4- [2- (phthalimido) ethoxy] crotonate with a benzylidene derivative.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES9802240 | 1998-10-26 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01004128A true MXPA01004128A (en) | 2001-12-04 |
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