CA2479620A1 - Ethane-1,2-diamino-bis[2r)-2-bromo-3-phenylpropanoate], method for production and use thereof - Google Patents
Ethane-1,2-diamino-bis[2r)-2-bromo-3-phenylpropanoate], method for production and use thereof Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to ethane-1,2-diamino-bis[(2R)-2-bromo-3- phenylpropanoate], the production of ethane-1,2-diamino-bis[(2R)-2-bromo-3- phenylpropanoate] from (2R)-2-bromo-3-phenylpropionic acid and ethylendiamin e in 2-propanol and the use of ethane-1,2-diamino-bis[(2R)-2-bromo-3- phenylpropanoate] for the production of ACE/NEP inhibitors.
Description
WO 031078434 PCTlEP03102353 Description Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], processes for its preparation and its use Chira; compounds are employed as structural units for the synthesis of pharma-ceutical active compounds. For use, it is desirable that these compounds are stable on storage and moreover can be prepared and purified simply in order to ensure constant quality, to avoid frequent checks of the materials for keeping a record of the product quality, to avoid the necessity for cold-storage depots and/or refrigerated transport, to guarantee easy filling in production plants and/or to guarantee the simple cleaning of used containers.
Against this, viscous oils can often only be poured into another container or weighed exactly with difficulty. Moreover, the purification of oils or viscous liquids can in many cases only be carried out with considerable outlay in terms of apparatus. In addition, oils can exhibit nonoptimal behaviour on dissolving in solvents, for which reason the mixing of liquids having different densities and viscosities must be monitored with particular care.
(2R)-2-Bromo-3-phenylpropionic acid is a viscous oil which has several of the disadvantageous properties listed above. Use of (2R)-2-bromo-3-phenylpropionic acid on the industrial scale is therefore associated with difficulties and additional costs.
It is the object of the present invention to prepare (2R)-2-bromo-3-phenylpropionic acid in a form which does not have the abovementioned disadvantages and which can be employed in industrial syntheses.
The object is achieved according to the invention by the preparation of the salt (ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]) in pure form and with retention of the enantiomeric purity.
Surprisingly, it fias been found that a salt (ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]) can be isolated in good yield and excellent chemical and enantiomeric purity from (2R)-2-bromo-3-phenylpropionic acid and ethylenediamine in 2-propanol in the stoichiometry 2:1.
Against this, viscous oils can often only be poured into another container or weighed exactly with difficulty. Moreover, the purification of oils or viscous liquids can in many cases only be carried out with considerable outlay in terms of apparatus. In addition, oils can exhibit nonoptimal behaviour on dissolving in solvents, for which reason the mixing of liquids having different densities and viscosities must be monitored with particular care.
(2R)-2-Bromo-3-phenylpropionic acid is a viscous oil which has several of the disadvantageous properties listed above. Use of (2R)-2-bromo-3-phenylpropionic acid on the industrial scale is therefore associated with difficulties and additional costs.
It is the object of the present invention to prepare (2R)-2-bromo-3-phenylpropionic acid in a form which does not have the abovementioned disadvantages and which can be employed in industrial syntheses.
The object is achieved according to the invention by the preparation of the salt (ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]) in pure form and with retention of the enantiomeric purity.
Surprisingly, it fias been found that a salt (ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]) can be isolated in good yield and excellent chemical and enantiomeric purity from (2R)-2-bromo-3-phenylpropionic acid and ethylenediamine in 2-propanol in the stoichiometry 2:1.
The present application accordingly relates to ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate].
The invention further relates to a process for the preparation of ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenyipropanoate], which comprises a) mixing (2R}-2-bromo-3-phenylpropionic acid, ethylenediamine and 2-propanol, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] crystallizing, and b) isolating the crystallized ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate].
Preferably, the ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]
prepared in the process according to the invention has a higher purity than the starting material (2R)-2-bromo-3-phenylpropionic acid.
Preferably, the process according to the invention proceeds with retention of or an increase in the enantiomeric purity.
In step b), the crystallized ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] can be isolated by filtering it off or filtering it off with suction; optionally the product filtered off with suction or filtered off can then be washed using propanol and dried.
The starting material (2R)-2-bromo-3-phenylpropionic acid is obtainable, for example, from the company Zambon Group spa (I-20091 Bresso, Italy) or the company Kaneka (Osaka; Japan).
Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] can be used, for example, for the synthesis of ACE/NEP inhibitors, for example reacted to give a compound of the formula (I), \
H
'~. , H
O O N Z
CH
COORS
~ S-Rs (I) where R~ is H, -CH20-C(O)C(CH3)3, C,-C4-alkyl, or an aryl-Y- group, where Y is a single bond or C~-C4-alkyl, R3 is H, acetyl, -CH20-C(O)C(CH3)3 or benzoyl, and Z is (CHZ)~, -O-, S, NR6 or N-C(O)RD , where n is an integer 0 or 1, Rs is H, C~-C4-alkyl or an aryl-Y- group, and R~ is CF3, C~-C,o-alkyl or an aryl-Y- group, where, preferably, R~ is H, R3 is H or acetyl, and Z is (CH2)~, and n is 0, and where the CH-SR3 group can have the (R) or the (S) configuration, and preferably has the (S) configuration, and where the compound of the formula (I) is preferably described by a compound of the formula (la) H
w ,N.
O OH
O
(la) or of the formula (Ib) H
O
N N
H
SH O
O ~UH
(Ib), wherein either firstly (2R)-2-bromo-3-phenylpropionic acid is released from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] intermediately or in a separate step according to methods known per se with addition of an acid, and subsequently (2R)-2-bromo-3-phenylpropionic acid is reacted with a compound of the formula (II) H
'. ,H
H2N ~N~
Z
O
_ 10 COORS (II) and with a thioacetate to give a compound of the formula (I), and the thioacetate is optionally reacted to give the free thiol, or wherein (2R)-2-bromo-3-phenylpropionic acid is reacted as, for example, in European patent application EP 1056715 to give (S)-2-(acetylthio)-3-phenylpropionic acid and subsequently reacted as described, for example, in European Patent EP
481522 with a compound of the formula (II) to give a compound of the formula (I), and the thioacetate is optionally reacted to .give the free thiol.
"C,-C4-Alkyl" denotes a saturated straight-chain or branched hydrocarbon chain of 1-4 carbon atoms and comprises, for example, methyl, ethyl, propyl, isopropyl, n-but-yl, isobutyl, tert-butyl. The expression "C,-Coo-alkyl" denotes a saturated straight-chain or branched hydrocarbon radical having 1-10 carbop atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl.
"Aryl-Y-" denotes an aryl radical which is substituted by a group Y, where Y
can be a 5 direct bond or a C~-CQ-alkyl group. Aryl denotes a phenyl or naphthyl group which is unsubstituted or substituted by 1-3 substuents from the group consisting of methylenedioxy, hydroxyl, C,-C4-alkoxy, fluorine and chlorine. For example, the expression "aryl-Y-" denotes phenyl, naphthyl, phenylmethyl, benzyl, phenylethyl, p-methoxybenzyl, p-fluorobenzyl or p-chlorobenzyl. "Aryl-Y-" can also denote a diphenylmethyl group.
Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] can furthermore be used for the preparation of the compound omapatrilate ([4S-[4a(R*), 7a, 10a[i]]-octa-hydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]-thi-azepine-7-carboxylic acid) of the formula (III) O
CH
COZMe SH
(III), where firstly (2R)-2-bromo-3-phenylpropionic acid is released from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] intermediately or in a separate step according to methods known per se with addition of an acid, and subsequently (2R)-2-bromo-3-phenylpropionic acid is reacted to give (S)-2-(acetylthio)-3-phenyl-propionic acid and, according to J. Med. Chem., 1999 (42), 305-311, or J. Med.
Chem., 1997 (40) 1570-1577, in a further step (acetylthio)-3-phenylpropionic acid is reacted with a compound of the formula (IV) H'~, 'S H
H2N ~N
O
C02Me (IV) to give the compound of the formula (III).
The acid is an organic or inorganic acid, preferably an inorganic acid, for example a mineral acid such as H2S04 or HCI.
It has been found that when using 2-propanol as a solvent and ethylenediamine as amine the chemical purity of the product compared with the starting material increases from 92.5% to 98%; a good yield of 58% and a very good enantiomeric purity of 98.6% ee (starting from an enantiomeric purity of the starting material of 83.4% ee) can be achieved.
The present application accordingly relates to ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] of a chemical purity of greater than 92.5%, preferably greater than or equal to 98%.
The present application moreover relates to ethane-1,2-diaminium bis[(2R)-2-bromo 3-phenylpropanoate] of an enantiomeric purity of greater than 83.4% ee, preferably greater than or equal to 95% ee, particularly preferably greater than or equal to 98%
ee.
During the addition of basic agents such as, for example, amines, an elimination of hydrogen bromide from (2R)-2-bromo-3-phenylpropionic acid can occur, cinnamic acid resulting and the enantiomeric purity of the product being lowered. Such an elimination is not observed when using ethylenediamine as an amine in 2-propanol as a solvent. The product ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] is therefore obtained in excellent enantiomeric purity.
Moreover, it is to be taken into consideration in the choice of solvent and amine that the product salt crystallizes from the reaction mixture in order firstly to be easily isolable and where secondly the reaction equilibrium is shifted to the side of the p rod a ct.
The invention further relates to a process for the preparation of ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenyipropanoate], which comprises a) mixing (2R}-2-bromo-3-phenylpropionic acid, ethylenediamine and 2-propanol, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] crystallizing, and b) isolating the crystallized ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate].
Preferably, the ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]
prepared in the process according to the invention has a higher purity than the starting material (2R)-2-bromo-3-phenylpropionic acid.
Preferably, the process according to the invention proceeds with retention of or an increase in the enantiomeric purity.
In step b), the crystallized ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] can be isolated by filtering it off or filtering it off with suction; optionally the product filtered off with suction or filtered off can then be washed using propanol and dried.
The starting material (2R)-2-bromo-3-phenylpropionic acid is obtainable, for example, from the company Zambon Group spa (I-20091 Bresso, Italy) or the company Kaneka (Osaka; Japan).
Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] can be used, for example, for the synthesis of ACE/NEP inhibitors, for example reacted to give a compound of the formula (I), \
H
'~. , H
O O N Z
CH
COORS
~ S-Rs (I) where R~ is H, -CH20-C(O)C(CH3)3, C,-C4-alkyl, or an aryl-Y- group, where Y is a single bond or C~-C4-alkyl, R3 is H, acetyl, -CH20-C(O)C(CH3)3 or benzoyl, and Z is (CHZ)~, -O-, S, NR6 or N-C(O)RD , where n is an integer 0 or 1, Rs is H, C~-C4-alkyl or an aryl-Y- group, and R~ is CF3, C~-C,o-alkyl or an aryl-Y- group, where, preferably, R~ is H, R3 is H or acetyl, and Z is (CH2)~, and n is 0, and where the CH-SR3 group can have the (R) or the (S) configuration, and preferably has the (S) configuration, and where the compound of the formula (I) is preferably described by a compound of the formula (la) H
w ,N.
O OH
O
(la) or of the formula (Ib) H
O
N N
H
SH O
O ~UH
(Ib), wherein either firstly (2R)-2-bromo-3-phenylpropionic acid is released from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] intermediately or in a separate step according to methods known per se with addition of an acid, and subsequently (2R)-2-bromo-3-phenylpropionic acid is reacted with a compound of the formula (II) H
'. ,H
H2N ~N~
Z
O
_ 10 COORS (II) and with a thioacetate to give a compound of the formula (I), and the thioacetate is optionally reacted to give the free thiol, or wherein (2R)-2-bromo-3-phenylpropionic acid is reacted as, for example, in European patent application EP 1056715 to give (S)-2-(acetylthio)-3-phenylpropionic acid and subsequently reacted as described, for example, in European Patent EP
481522 with a compound of the formula (II) to give a compound of the formula (I), and the thioacetate is optionally reacted to .give the free thiol.
"C,-C4-Alkyl" denotes a saturated straight-chain or branched hydrocarbon chain of 1-4 carbon atoms and comprises, for example, methyl, ethyl, propyl, isopropyl, n-but-yl, isobutyl, tert-butyl. The expression "C,-Coo-alkyl" denotes a saturated straight-chain or branched hydrocarbon radical having 1-10 carbop atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl.
"Aryl-Y-" denotes an aryl radical which is substituted by a group Y, where Y
can be a 5 direct bond or a C~-CQ-alkyl group. Aryl denotes a phenyl or naphthyl group which is unsubstituted or substituted by 1-3 substuents from the group consisting of methylenedioxy, hydroxyl, C,-C4-alkoxy, fluorine and chlorine. For example, the expression "aryl-Y-" denotes phenyl, naphthyl, phenylmethyl, benzyl, phenylethyl, p-methoxybenzyl, p-fluorobenzyl or p-chlorobenzyl. "Aryl-Y-" can also denote a diphenylmethyl group.
Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] can furthermore be used for the preparation of the compound omapatrilate ([4S-[4a(R*), 7a, 10a[i]]-octa-hydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]-thi-azepine-7-carboxylic acid) of the formula (III) O
CH
COZMe SH
(III), where firstly (2R)-2-bromo-3-phenylpropionic acid is released from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] intermediately or in a separate step according to methods known per se with addition of an acid, and subsequently (2R)-2-bromo-3-phenylpropionic acid is reacted to give (S)-2-(acetylthio)-3-phenyl-propionic acid and, according to J. Med. Chem., 1999 (42), 305-311, or J. Med.
Chem., 1997 (40) 1570-1577, in a further step (acetylthio)-3-phenylpropionic acid is reacted with a compound of the formula (IV) H'~, 'S H
H2N ~N
O
C02Me (IV) to give the compound of the formula (III).
The acid is an organic or inorganic acid, preferably an inorganic acid, for example a mineral acid such as H2S04 or HCI.
It has been found that when using 2-propanol as a solvent and ethylenediamine as amine the chemical purity of the product compared with the starting material increases from 92.5% to 98%; a good yield of 58% and a very good enantiomeric purity of 98.6% ee (starting from an enantiomeric purity of the starting material of 83.4% ee) can be achieved.
The present application accordingly relates to ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] of a chemical purity of greater than 92.5%, preferably greater than or equal to 98%.
The present application moreover relates to ethane-1,2-diaminium bis[(2R)-2-bromo 3-phenylpropanoate] of an enantiomeric purity of greater than 83.4% ee, preferably greater than or equal to 95% ee, particularly preferably greater than or equal to 98%
ee.
During the addition of basic agents such as, for example, amines, an elimination of hydrogen bromide from (2R)-2-bromo-3-phenylpropionic acid can occur, cinnamic acid resulting and the enantiomeric purity of the product being lowered. Such an elimination is not observed when using ethylenediamine as an amine in 2-propanol as a solvent. The product ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] is therefore obtained in excellent enantiomeric purity.
Moreover, it is to be taken into consideration in the choice of solvent and amine that the product salt crystallizes from the reaction mixture in order firstly to be easily isolable and where secondly the reaction equilibrium is shifted to the side of the p rod a ct.
When using other solvents and/or amines, either the purity of the product compared to the starting material is not increased, or the reaction does not proceed, or the yield is low, or an elimination takes place as a secondary reaction.
The following examples are intended to illustrate the invention in greater detail without restricting it to these embodiments.
Example 1: Synthesis of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] in 2-propanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of 2-propanol and treated at room temperature with 0.87 g of ethylenediamine.
After a stirring time of about 150 minutes, the precipitated product was filtered off with suction and washed with 2-propanol. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was 98% according to HPLC, the content of the R enantiomer 98.6%, and the yield was 58%.
Example 2: Characterization of ethane-1,2-diaminium bis[(2Rr2-bromo-3-phenyl-propanoate]
The identity of ethane-1,2-diaminiurn bis[(2R)-2-bromo-3-phenylpropanoate] was determined by HPLC comparison with a sample of the starting material. The quality of the acid component of the salt was checked here; no cinnamic acid or other new, unknown substances were to be detected. The 1:2 stoichiometry was verified by means of a titration with 0.1 N NaOH in water as a solvent: 2 pH steps were to be observed, which both exhibit the same consumption of NaOH. The specific rotation of ethane-1,2-diarninium bis[(2R)-2-bromo-3-phenylpropanoate] was [a]2°o= +5.6°
(c=2 in DMF); the melting point was 147°C.
Tabelle 1: 1 H-NMR data of the compound ethane-1;2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] (chemical shifts) Position within 13C 8 (ppm) 1 H 8 (ppm) [phenyl-CH2-CHBr-COO-]
[+H3N-CH2-CH2-NH3+]
-COO- 176.24 --CHBr- 52.52 4.39 t -CH2- 41.03 3.30 dd 3.15 dd phenyl- 137.75 7.26 d 128.73 7.32 t 128.18 7.26 t 126.59 +H3N-CH2-CH2-NH3+ , 36.04 3.28 s Multiplicities:
s = singlet, d= doublet, t= triplet, dd= double doublet Example 3: Attempt at synthesis of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] in ethyl acetate 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of ethyl acetate and treated at room temperature with 0.87 g of ethylenediamine.
After a stirring time about 150 minutes, no precipitation of the product was observed.
An HPLC analysis of the solution showed that (2R)-2-bromo-3-phenylpropionic acid was present unchanged.
Example 4: Attempt at synthesis of cyclohexylamine [(2R)-2-bromo-3-phenyl-propanoate] in 2-propanol 2.38 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 15 ml of 2-propanol and treated at room temperature with 0.65 g of cyclohexylamine.
After a stirring time of about 150 minutes, the precipitated product was filtered off with suction, washed with 2-propanol and dried overnight at 45°C in vacuo. The purity of the isolated product was 92% according to HPLC. Among the impurities, cinnamic acid was also found. The yield was only 22%.
Example 5: Attempt at synthesis of triethylammonium [(2R)-2-bromo-3-phenyl-propanoate] in ethyl acetate 5 g of crude (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of ethyl acetate and treated at room temperature with 2.7 ml of triethylamine.
The following examples are intended to illustrate the invention in greater detail without restricting it to these embodiments.
Example 1: Synthesis of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate] in 2-propanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of 2-propanol and treated at room temperature with 0.87 g of ethylenediamine.
After a stirring time of about 150 minutes, the precipitated product was filtered off with suction and washed with 2-propanol. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was 98% according to HPLC, the content of the R enantiomer 98.6%, and the yield was 58%.
Example 2: Characterization of ethane-1,2-diaminium bis[(2Rr2-bromo-3-phenyl-propanoate]
The identity of ethane-1,2-diaminiurn bis[(2R)-2-bromo-3-phenylpropanoate] was determined by HPLC comparison with a sample of the starting material. The quality of the acid component of the salt was checked here; no cinnamic acid or other new, unknown substances were to be detected. The 1:2 stoichiometry was verified by means of a titration with 0.1 N NaOH in water as a solvent: 2 pH steps were to be observed, which both exhibit the same consumption of NaOH. The specific rotation of ethane-1,2-diarninium bis[(2R)-2-bromo-3-phenylpropanoate] was [a]2°o= +5.6°
(c=2 in DMF); the melting point was 147°C.
Tabelle 1: 1 H-NMR data of the compound ethane-1;2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] (chemical shifts) Position within 13C 8 (ppm) 1 H 8 (ppm) [phenyl-CH2-CHBr-COO-]
[+H3N-CH2-CH2-NH3+]
-COO- 176.24 --CHBr- 52.52 4.39 t -CH2- 41.03 3.30 dd 3.15 dd phenyl- 137.75 7.26 d 128.73 7.32 t 128.18 7.26 t 126.59 +H3N-CH2-CH2-NH3+ , 36.04 3.28 s Multiplicities:
s = singlet, d= doublet, t= triplet, dd= double doublet Example 3: Attempt at synthesis of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] in ethyl acetate 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of ethyl acetate and treated at room temperature with 0.87 g of ethylenediamine.
After a stirring time about 150 minutes, no precipitation of the product was observed.
An HPLC analysis of the solution showed that (2R)-2-bromo-3-phenylpropionic acid was present unchanged.
Example 4: Attempt at synthesis of cyclohexylamine [(2R)-2-bromo-3-phenyl-propanoate] in 2-propanol 2.38 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 15 ml of 2-propanol and treated at room temperature with 0.65 g of cyclohexylamine.
After a stirring time of about 150 minutes, the precipitated product was filtered off with suction, washed with 2-propanol and dried overnight at 45°C in vacuo. The purity of the isolated product was 92% according to HPLC. Among the impurities, cinnamic acid was also found. The yield was only 22%.
Example 5: Attempt at synthesis of triethylammonium [(2R)-2-bromo-3-phenyl-propanoate] in ethyl acetate 5 g of crude (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of ethyl acetate and treated at room temperature with 2.7 ml of triethylamine.
After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-bromo-3-phenyl-propionic acid had reacted completely to give cinnamic acid.
Example 6: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenylpropanoate]
in 2-propanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of 2-propanol and treated at room temperature with 4.25 g of dicyclohexylamine.
After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with 2-propanol. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was 94% according to HPLC, the yield was 44%.
Example 7: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenylpropanoate]
in ethyl acetate 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated at room temperature with 4.25 g of dicyclohexylamine in 20 ml of ethyl acetate. After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with ethyl acetate. The product was dried overnight at 45°C
in vacuo.
The purity of the isolated product was only 86% according to HPLC. Among the impurities, cinnamic acid was also found. The yield was 32%.
Example 8: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenylpropanoate]
in toluene 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated with 4.25 g of dicyclohexylamine in 20 ml of toluene at room temperature. After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with toluene. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was only 81 % according to HPLC. Among the impurities, cinnamic acid was also found. The yield was 31 %.
Example 9: Attempt at synthesis of triethylammonium [(2R)-2-bromo-3-phenyl-propanoate] in toluene 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated at room temperature with 2.7 ml of triethylamine in 20 ml of toluene. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC
analysis of the solution showed that the (2R)-2-bromo-3-phenylpropionic acid had 5 reacted completely to give cinnamic acid.
Example 10: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenyl-propanoate] in diisopropyl ether 10 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92,5%) were treated at room temperature with 4.25 g of dicyclohexylamine in 20 ml of diisopropyl ether.
After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with diisopropyl ether. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was only 85% according to HPLC.
Among the impurities, cinnamic acid was also found. The yield was 55%.
Example 11: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenyl-propanoate] in ethanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated in 20 ml of ethanol at room temperature with 4.25 g of dicyclohexylamine. After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with ethanol. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was 96% according to HPLC. Among the impurities, cinnamic acid was also found. The yield was only 12%.
Example 12: Attempt at synthesis of N,N,N',N'-tetramethylethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] in 2-propanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92,5%) were dissolved in 20 ml of 2-propanol and treated at room temperature with 1.39 g of tetramethylethylene-diamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that (2R)-2-bromo-3-phenylpropionic acid was present unchanged.
Example 13: Attempt at synthesis of N,N,N',N'-tetramethylethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] in toluene g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of toluene and treated at room temperature with 1.39 g of tetramethylethylene-diamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-5 bromo-3-phenylpropionic acid had reacted completely to give cinnamic acid.
Example 14: Preparation of (R)-2-bromo-3-phenylpropionic acid from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate]
95.0 g of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]
(0.0675mo1) were introduced into a 500 ml four-necked flask having an outlet valve, and treated with 105 ml of diisopropyl ether and 105 ml of water. The resulting white suspension was adjusted from pH 6.7 to pH 1.5 using 15 ml of 30% strength hydrochloric acid, the suspension dissolving. The reaction mixture was then stirred at pH 1.5 and room temperature (about 20°C) for 30 minutes, and the phases were separated.
The organic phase was extracted once with 35 ml of water; the aqueous phase was discarded. The solvent diisopropyl ether and traces of water were removed from the organic phase by distillation. The residue was treated with 90 ml of acetone and distilled again, acetone and traces of diisopropyl ether distilling off. The yield was quantitative with respect to (R)-2-bromo-3-phenylpropionic acid.
Example 6: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenylpropanoate]
in 2-propanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of 2-propanol and treated at room temperature with 4.25 g of dicyclohexylamine.
After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with 2-propanol. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was 94% according to HPLC, the yield was 44%.
Example 7: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenylpropanoate]
in ethyl acetate 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated at room temperature with 4.25 g of dicyclohexylamine in 20 ml of ethyl acetate. After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with ethyl acetate. The product was dried overnight at 45°C
in vacuo.
The purity of the isolated product was only 86% according to HPLC. Among the impurities, cinnamic acid was also found. The yield was 32%.
Example 8: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenylpropanoate]
in toluene 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated with 4.25 g of dicyclohexylamine in 20 ml of toluene at room temperature. After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with toluene. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was only 81 % according to HPLC. Among the impurities, cinnamic acid was also found. The yield was 31 %.
Example 9: Attempt at synthesis of triethylammonium [(2R)-2-bromo-3-phenyl-propanoate] in toluene 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated at room temperature with 2.7 ml of triethylamine in 20 ml of toluene. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC
analysis of the solution showed that the (2R)-2-bromo-3-phenylpropionic acid had 5 reacted completely to give cinnamic acid.
Example 10: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenyl-propanoate] in diisopropyl ether 10 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92,5%) were treated at room temperature with 4.25 g of dicyclohexylamine in 20 ml of diisopropyl ether.
After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with diisopropyl ether. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was only 85% according to HPLC.
Among the impurities, cinnamic acid was also found. The yield was 55%.
Example 11: Synthesis of dicyclohexylammonium [(2R)-2-bromo-3-phenyl-propanoate] in ethanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were treated in 20 ml of ethanol at room temperature with 4.25 g of dicyclohexylamine. After a stirring time of about 150 minutes, the precipitated salt was filtered off with suction and washed with ethanol. The product was dried overnight at 45°C in vacuo. The purity of the isolated product was 96% according to HPLC. Among the impurities, cinnamic acid was also found. The yield was only 12%.
Example 12: Attempt at synthesis of N,N,N',N'-tetramethylethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] in 2-propanol 5 g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92,5%) were dissolved in 20 ml of 2-propanol and treated at room temperature with 1.39 g of tetramethylethylene-diamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that (2R)-2-bromo-3-phenylpropionic acid was present unchanged.
Example 13: Attempt at synthesis of N,N,N',N'-tetramethylethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] in toluene g of (2R)-2-bromo-3-phenylpropionic acid (HPLC: 92.5%) were dissolved in 20 ml of toluene and treated at room temperature with 1.39 g of tetramethylethylene-diamine. After a stirring time of about 150 minutes, no precipitation of the product was to be observed. An HPLC analysis of the solution showed that the (2R)-2-5 bromo-3-phenylpropionic acid had reacted completely to give cinnamic acid.
Example 14: Preparation of (R)-2-bromo-3-phenylpropionic acid from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate]
95.0 g of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]
(0.0675mo1) were introduced into a 500 ml four-necked flask having an outlet valve, and treated with 105 ml of diisopropyl ether and 105 ml of water. The resulting white suspension was adjusted from pH 6.7 to pH 1.5 using 15 ml of 30% strength hydrochloric acid, the suspension dissolving. The reaction mixture was then stirred at pH 1.5 and room temperature (about 20°C) for 30 minutes, and the phases were separated.
The organic phase was extracted once with 35 ml of water; the aqueous phase was discarded. The solvent diisopropyl ether and traces of water were removed from the organic phase by distillation. The residue was treated with 90 ml of acetone and distilled again, acetone and traces of diisopropyl ether distilling off. The yield was quantitative with respect to (R)-2-bromo-3-phenylpropionic acid.
Claims (13)
1. Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate].
2. Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] as claimed in claim 1 in a purity of greater than or equal to 98%.
3. Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] as claimed in one of claims 1 or 2 in an enantiomeric purity of greater than 83.4% ee.
4. Ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] as claimed in claim 3 in an enantiomeric purity of greater than or equal to 95% ee, preferably greater than or equal to 98% ee.
5. A process for the preparation of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate], which comprises a) mixing (2R)-2-bromo-3-phenylpropionic acid, ethylenediamine and 2-propanol, ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate]
crystallizing, and b) isolating the crystallized ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate].
crystallizing, and b) isolating the crystallized ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenyl-propanoate].
6. The process as claimed in claim 5, the ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] product having a higher chemical purity than the starting material (2R)-2-bromo-3-phenylpropionic acid.
7. The process as claimed in claim 6, the chemical purity of the ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] product being greater than 92.5 %.
8. The process as claimed in one of claims 6 to 7, the chemical purity of the ethane 1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] product being at least 98 %.
9. The process as claimed in one of claims 5 to 8, the crystallized ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] being isolated in process step b) by filtering off or filtering off with suction, washing with 2-propanol and drying.
10.The use of ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] as claimed in one of claims 1 to 4 for the preparation of ACE/NEP inhibitors.
11. A process for the preparation of a compound of the formula (I) where R1 is H, -CH2O-C(O)C(CH3)3, C1-C4-alkyl or an aryl-Y- group, where Y is a single bond or C1-C4-alkyl, R3 is H, acetyl, -CH2O-C(O)C(CH3)3 or benzoyl, and Z is (CH2)n, -O-, S, NR6 or N-C(O)R7, where n is an integer 0 or 1, R6 is H, alkyl or an aryl-Y- group, and R7 is CF3, C1-C10-alkyl or an aryl-Y- group, which comprises either firstly releasing (2R)-2-bromo-3-phenylpropionic acid from ethane-1,2-di-aminium bis[(2R)-2-bromo-3-phenylpropanoate] intermediately or in a separate step with addition of an acid, then reacting (2R)-2-bromo-3-phenylpropionic acid with a compound of the formula (II) and reacting with a thioacetate to give a compound of the formula (I), and optionally reacting the thioacetate to give the free thiol, or which comprises reacting (2R)2-bromo-3-phenylpropionic acid to give (S)-2-(acetylthio)-3-phenylpropionic acid, then reacting with a compound of the formula (II) to give a compound of the formula (I), and optionally reacting the thioacetate to give the free thiol.
12. The process as claimed in claim 11, where the compound of the formula (I) is described by a compound of the formula (Ia) or of the formula (Ib)
13. A process for the preparation of the compound of the formula (III) which comprises firstly releasing (2R)-2-bromo-3-phenylpropionic acid from ethane-1,2-diaminium bis[(2R)-2-bromo-3-phenylpropanoate] intermediately or in a separate step with addition of an acid, then reacting (2R)-2-bromo-3-phenylpropionic acid to give (S)-2-(acetylthio)-3-phenylpropionic acid, and in a further step reacting (acetylthio)-3-phenylpropionic acid with a compound of the formula (IV) to give the compound of the formula (III).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10212198A DE10212198A1 (en) | 2002-03-19 | 2002-03-19 | Ethane-1-diaminium-bis (2R) -2-bromo-3-phenylpropanoate), process for its preparation and its use |
| DE10212198.2 | 2002-03-19 | ||
| PCT/EP2003/002353 WO2003078434A1 (en) | 2002-03-19 | 2003-03-07 | Ethane-1,2-diamino-bis[(2r)-2-bromo-3-phenylpropanoate], method for production and use thereof |
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|---|---|
| CA2479620A1 true CA2479620A1 (en) | 2003-09-25 |
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| CA002479620A Abandoned CA2479620A1 (en) | 2002-03-19 | 2003-03-07 | Ethane-1,2-diamino-bis[2r)-2-bromo-3-phenylpropanoate], method for production and use thereof |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP1487836B1 (en) |
| JP (1) | JP4532910B2 (en) |
| AT (1) | ATE338756T1 (en) |
| AU (1) | AU2003219027A1 (en) |
| BR (1) | BR0308485A (en) |
| CA (1) | CA2479620A1 (en) |
| DE (2) | DE10212198A1 (en) |
| IL (1) | IL164042A0 (en) |
| MX (1) | MXPA04008490A (en) |
| WO (1) | WO2003078434A1 (en) |
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| JP2678759B2 (en) * | 1988-02-23 | 1997-11-17 | 日本合成化学工業株式会社 | Method for producing ammonium salt of solid polymer compound |
| CA2053340C (en) * | 1990-10-18 | 2002-04-02 | Timothy P. Burkholder | Mercaptoacetylamide derivatives useful as inhibitors of enkephalinase and ace |
| JPH1014590A (en) * | 1996-06-28 | 1998-01-20 | Kanegafuchi Chem Ind Co Ltd | Production of optically active 2-substituted-3-phenylpropionic acid and its ester |
| IT1298267B1 (en) * | 1998-02-18 | 1999-12-20 | Zambon Spa | PROCEDURE FOR THE PREPARATION OF (S) -2-ACETYLTIO-3-PHENYL-PROPIONIC ACID AND ITS SALTS |
| NL1014354C2 (en) * | 2000-02-11 | 2001-08-14 | Dsm Nv | Process for the preparation of (S) -2-acethylthio-3-phenylpropanoic acid. |
| NL1014353C2 (en) * | 2000-02-11 | 2001-08-15 | Dsm Nv | Process for the preparation of (R) -2-bromo-3-phenylpropanoic acid. |
-
2002
- 2002-03-19 DE DE10212198A patent/DE10212198A1/en not_active Withdrawn
-
2003
- 2003-03-07 CA CA002479620A patent/CA2479620A1/en not_active Abandoned
- 2003-03-07 BR BR0308485-0A patent/BR0308485A/en not_active IP Right Cessation
- 2003-03-07 DE DE50304950T patent/DE50304950D1/en not_active Expired - Lifetime
- 2003-03-07 WO PCT/EP2003/002353 patent/WO2003078434A1/en active IP Right Grant
- 2003-03-07 EP EP03714788A patent/EP1487836B1/en not_active Expired - Lifetime
- 2003-03-07 JP JP2003576439A patent/JP4532910B2/en not_active Expired - Fee Related
- 2003-03-07 IL IL16404203A patent/IL164042A0/en unknown
- 2003-03-07 MX MXPA04008490A patent/MXPA04008490A/en unknown
- 2003-03-07 AT AT03714788T patent/ATE338756T1/en not_active IP Right Cessation
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| Publication number | Publication date |
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| MXPA04008490A (en) | 2004-12-06 |
| EP1487836A1 (en) | 2004-12-22 |
| AU2003219027A1 (en) | 2003-09-29 |
| DE10212198A1 (en) | 2003-10-02 |
| BR0308485A (en) | 2005-01-18 |
| WO2003078434A1 (en) | 2003-09-25 |
| JP4532910B2 (en) | 2010-08-25 |
| IL164042A0 (en) | 2005-12-18 |
| DE50304950D1 (en) | 2006-10-19 |
| ATE338756T1 (en) | 2006-09-15 |
| EP1487836B1 (en) | 2006-09-06 |
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