CA2203435A1 - N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action - Google Patents
N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory actionInfo
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- CA2203435A1 CA2203435A1 CA002203435A CA2203435A CA2203435A1 CA 2203435 A1 CA2203435 A1 CA 2203435A1 CA 002203435 A CA002203435 A CA 002203435A CA 2203435 A CA2203435 A CA 2203435A CA 2203435 A1 CA2203435 A1 CA 2203435A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
- C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
- C07D291/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Novel N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ACE inhibitory action.
Novel compounds of formula (III), wherein R1 represents PhCH2-CH2- or CH3CH2-CH2- and R2 represents methyl or R3-NH-(CH2)3-CH2-, wherein R3 has the meaning of amino protective group, are disclosed. They are used as intermediates in the synthesis of ACE inhibitors, especially of enalapril and trandolapril.
Novel compounds of formula (III), wherein R1 represents PhCH2-CH2- or CH3CH2-CH2- and R2 represents methyl or R3-NH-(CH2)3-CH2-, wherein R3 has the meaning of amino protective group, are disclosed. They are used as intermediates in the synthesis of ACE inhibitors, especially of enalapril and trandolapril.
Description
~vel ~-~ult`o~v ~nhydrides, ~ proce~s t;)r the prep;lr.lti~n thereof ;lnd its u~e tor the prepar~tion of bio~lcti~e sub~t~nces h~vin~ A(~E inhihitoly 3ction T~'CIl/1iC'~ Fic lcl The present in~ention is trom the tield ot chemical svnthesi~ an~ relclte!i to no~el N-sultoxv Llnhv~lri~ies. to a process tor the preparcltion thereot as well as to the use thereot tor a ~imple an~t cheap prepLlrcltion ot hioacti~e suhstances havin~ ACE in-hibitorv ~Iction .
Tc~cll~lic~l Probl~m J
There was a need tor a simple and industrially suitable process t`or the synthesis ot active deri~ative that ~ould be apppropriate as starting material for the synthesis ot ACE inhibitors disclosed e.~n in Drugs ot the tuture 199~ 17(7), 551-55~. and others.
P~io~
For the preparation of ACE inhibitors two types ot processes are most trequentlvused. The tirst one i~ a reductive amination. which is di~ficult to be carried out on in-dustricll scale and is disclosed in US 4,374~29.
The second type u~es e.~. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-cllanyl-I~-carh(lxy-anhvdride (~iCA; see the t`ormula (II) below) as reactant. In EP 0215335 A~
J the re~lction ot N-[1-(S)-ethoxycarbonyl-3-phenvlpropyl~-L-alanine ot the tormula (I) -~H2~H2-CHNHCH--COOH
I
~ith plli)s~ene a~ olymel-!i thereot is tisclose~i an(l thel~e is ol-t~ t ~'-[l-(S)-etllo:;vcarhonvl-'-pll~nylr)ro~7yl]-L-LllLlnyl-~`-c~lrho~y-clnhy tri~le (NCA) ot the tOr-11l.11.1 ~11) CA 0220343~ 1997-04-22 ~H2~H2~g~H3 (NCA) Il which is reacted with salts and esters of L-proline to enalapril.
The preparation of active NCA is also described in EP 0114067, wherein a reaction of phosgene with amino acid (I) is disclosed. In EP 0061768 A1 the preparation of NCA (II) by a reaction of amino acid (I) and carbonyl diimidazole (CDI) is disclosed.
The preparation of NCA is also disclosed in ES 2004~04. The NCA (II) formed is then reacted with silylated L-proline (YU patent application 1355/~8) and with non-silylated L-proline (SI patent 9200213) to enalapril and enalapril maleate, resp., which is an interesting ACE inhibitor.
In all disclosed cases of activation of amino acid (I) there are used toxic phosgene, phosgene polymers (diphosgene, triphosgene) or phosgene derivatives such as CDI,which may be prepared by only a few phosgene producers. The use of CDI for ac-tivating amino acid (I) is expensive and it is also necessary to regenerate the waste imidazole, which may be converted again into CDI only by a phosgene producer.
Also in the synthesis of trandolapril disclosed in EP 00~341 and in US 4,490,3~6, for activating the compound (I) expensive carbonyl diimidazole CDI is used, which isconverted into the corresponding NCA (II).
r Tech~liccll Solution The first object of the invention are novel N-sulfoxy anhydrides ot the formula (III) (NSA) COOEt H
1.
Rl--CH--N~--R2 (III) ~ CA 02203435 1997-04-22 e r r r .3 ~
r r ~ r wherein Rl represents PhCH2-CH~- or CH3CH2CH2- and R2 represents methyl or R3-NH-(CH2)3-CH2-, R3 being an amino protecting group, preferably CF3CO-.
The second object of the invention is a process for the preparation of novel N-sulfoxy anhydrides of the formula (lII), characterized in that a compound of the formula tIV) COOEt Rl--CH--NH CIH R2 (N) COOH
wherein Rl in R2 have the above meanings, is reacted with an ~-(chlorosulfinyl)-heterocyclic compound of the general formula (V) a~l--R4 wherein R4 represents the rest of imidazole, of alkyl imidazole, of benzimidazole and of tetrazole.
Compounds of the general formulas (IV) and (V) are commercially available or maybe prepared according to processes known from the literature.
The preparation of the compound of the general formula (V), wherein R4 is an imidazole rest, i.e. chlorosulfinyl imidazole, is disclosed e.g. in Syl~J~tetic Communica-tiOrls~ 10 (10), 733-742, 1980~ Masaru O~ata and Hiroshi Matsumato. In the reaction in dry methylene chloride hetween SOCI, and imidazole in a 1:4 ratio there are ob-tained N.N'-thionyldiimid~lzole and imidazol~ hydrochlorid~, which is filtered off. An equimolar amount of thionylehloride is added to the filtrate with N,N'-thionyl-diimidazole and two molar equivalents of N-chlorosulfinyl imidazole of the formula (V) are obtained.
AMENDED S~EET
CA 0220343~ 1997-04-22 Thr pl-eparation of the co]npound ot the general formula (V), wherein R~ is a ~enzimid.lzole rest, i.e. N-ch]orc)sulfinyl benzimidazole, is disclosed in Sy~ c~ C0~11-1iC~l/i(l~l.s 1() (7), 559-567, 1'~0, Masaru Ogata and Hiroshi Matsumato.
The reaction between the compound ot the formula (IV) and the compo~lnd ot` the ~eneral tormula (V) is carried out in dry organic solvents (humidity < ().()4G~c), preferably in chlorinated organic solvents such as methylene chloride. or non-chlorinated organic solvents such as ethyl acetate, dimethyl carbonate, diethyl car-honate. acetonitrile etc.
The reaction between the compound of the formula (IV) and the compound of the formula (V) is carried out at a temperature between -15C and +25C.
The formed hydrochloride of a heterocyclic compound, e.g. imidazole HCI, methyl-imidazole HCl, benzimidazole HCI. tetrazole HCI etc., is filtered off or sucked off.
Organic bases may be regenerated and recycled.
The pure novel compound of the formula (III) (NSA) remains in the organic solvent.
The formation of the compound NSA is confirmed by a) quantitative isolation of a heterocyclic compound corresponding to the rest R4 in the form of hydrochloride, in two reaction steps;
b) iodometric titration of the amount of SO2 formed after the hydrolysis ot NSA;c) IR spectroscopy of the solution of a sample having characteristic absorption bands at 1~20 cm~l, 1750 cm~l in 1030 cm~~;
d) NMR spectra which do not contain signals for protons of the heterocyclic compound (V) used;
e) a further reaction of NSA with silylated amino acids under ~elease of SO2.
The third object ot the invention is a process for the preparation of corresponding ACE inhibitors, wherein NSA (III) is reacted with corresponding derivatives ot amino acids defined below. More particularly, the object of the invention is a process for the preparation of ACE inhibitors of the formula C00Et R2 R 1 ~ CH - N - CH - CO - R
in racelllate torm as well as in the form ot pure stereOisolllers, and pharmaceutically accept.lb]e sa]ts thereot such as hydroch]oride. maleinate. s~lltate~ wherein Rl and R, al e detined aS above and R has the following meanings H ~ H
H ~> l~s ,~S ~
C~
characterized in that the compound NSA of the formula III is reac~ed with a) mono- or disilylated amino acids or with mixtures of mono- and disilylated amino acids selected from the group consisting of H C~, N ~ COOH ~ H o~H
C~2-CCCH o ~ 'oooH
H H C~{, o~N~" ~ ~ N ~H
N J ~ ~ OooH
CH, H
H H
<~ aooH C~IIIC~OH ~7 H
H
I H
CH~S ~ COOH
c~3 C~, at a pH from 2 to 6, preferably 2 to 3, or b) with inorganic or organic salts of amino acids defined as under a) at a pH over 7, or c) with a free amino acid defined as under a), preferably with L-proline, and then the obtained compounds are converted in a conventional way into pharma-ceutically acceptable salts thereof such as hydrochloride, maleinate, sulfate.
As inorganic salts e.g. potassium or sodium salts are used.
As organic salts preferably salts ot` DBU (],~-diazabicyclo[5.4.0]undec-7-ene), DBN
(],5-diazclbicyclo[4.3.0]non-5-ene), TEA (triethylamine), tetramethylguanidine, im-idazole, methylimidazole etc. are used.
In the CclSe ot` amino acid N-[l-(S)-~thoxycarbonyl-3-phenylpropyl]-L-cllclnine (I) after activation with N-chlorosulfinyl imidazole NSA N-[ 1 -(S)-ethoxycarl~onyl-3-phenylr)ror)yl]-L-alanyl-N-sultoxyanhydride is ohtained. which is reacted with CA 0220343~ 1997-04-22 L-proline. silylated L-proline or with an organic or inorganic salt of L-proline to ~nalapl^il.
It the ~ame NSA (III) is reacted with a mixture. a silylat~d mixture or with an organic or inorganic salt of the mixture ot 2S,3aS 7aS- and 'R,3aR,7aR-octahydl-o-]H-indole-2-carboxylic acid, there is obtained a racemic mixture ot` SSS and RRR ACE
inhibitor having the chemical name 2S,3aS,7aS- or 2R,3aR,7aR-1-{2S-[(1R-ethoxy-carbonyl-3-phenylpropyl)amino]-1-oxopropyl}octa-hydro-lH-indole-2-c~rboxylic acid. If as octahydro-lH-indole-2-carboxylic acid a pure isomer is used such as ~S,3aS,7aS or 2S,3aR.7aS, SSS or SRS trandolapril is obtained (see J. Med. Chem.~7? 30, 992--99~)-For the preparation of enalapril the novel compound ot the formula (III) (Rl meansPhCH2-CH2-, R2 means methyl), which remains in the organic solvent such as methylene chloride after sucking off the hydrochloride of heterocyclic compound such as imidazole hydrochloride and is very reactive. is reacted with silylated L-proline (process variant a) or with inorganic or organic salt of L-proline as defined above (process variant b), to N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline (known as enalapril) with a high yield. During the reaction a gaseous SO2 isreleased, which also proves the existence of the novel compound NSA of formula (III). The reaction between NSA and silylated L-proline is carried out in the tem-perature range from -20C to +25C. This process is shown in Scheme 1.
In the process variant b) besides the desired ACE inhibitors also novel derivatives are formed, which in case of the preparation of trandolapril have the following for-mula VII
COOEt CH3 H ~ H
~H2 CH2~ CON~ (VII) ~OOEt It may h~ ic3entilied with spectroscopic methods. In the Ill.lSS spectrulll the t`ollo~ illg ~ii"ll.llS lll/Z lle pleSellt~ 2 (M+. I~ ) 4.1 (]()()C/f)~ 2~4 (7~9f). 17(~ ( ] ~)~ 1'4 (3 C/, ) (3 ¦ ( ~ 5 G~c ) .
In the NMR spectrulll oi the compound VII the ratio I etween phenyl protol1s Illd the ploton in position ' in octahydroindole moiety is 1():1 and thereby the sLIgg~!ited structLIl-e of the compound ol the formula (Vll) is confirmed.
The use ol the compound ot the formula (III) as a starting substance makes possi~tle al1 econolllical ettective and simple industrial process t`or the preparcltion ot el1.l1clpril~ trandolapril and other ACE inhibitors especially when the process variant a) is used.
The use ot NSA is very convenient since the conden~ation reaction proceeds well al-ready at lower temperatures in the range of trom -15C to +25C. Imidazole and other ambident compounds useful in the synthesis of NSA may be isolated quantitcl-tively and recycled. The process is ecologically pure since a major part of reactants may be regenerated and recycled.
Synthetised ACE inhibitors are recrystallized from acetonitrile or are purified by re-precipitation in ethyl acetate thus achieving high yields at purification (about 94~c).
Tc~cll~lic~l Probl~m J
There was a need tor a simple and industrially suitable process t`or the synthesis ot active deri~ative that ~ould be apppropriate as starting material for the synthesis ot ACE inhibitors disclosed e.~n in Drugs ot the tuture 199~ 17(7), 551-55~. and others.
P~io~
For the preparation of ACE inhibitors two types ot processes are most trequentlvused. The tirst one i~ a reductive amination. which is di~ficult to be carried out on in-dustricll scale and is disclosed in US 4,374~29.
The second type u~es e.~. N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-cllanyl-I~-carh(lxy-anhvdride (~iCA; see the t`ormula (II) below) as reactant. In EP 0215335 A~
J the re~lction ot N-[1-(S)-ethoxycarbonyl-3-phenvlpropyl~-L-alanine ot the tormula (I) -~H2~H2-CHNHCH--COOH
I
~ith plli)s~ene a~ olymel-!i thereot is tisclose~i an(l thel~e is ol-t~ t ~'-[l-(S)-etllo:;vcarhonvl-'-pll~nylr)ro~7yl]-L-LllLlnyl-~`-c~lrho~y-clnhy tri~le (NCA) ot the tOr-11l.11.1 ~11) CA 0220343~ 1997-04-22 ~H2~H2~g~H3 (NCA) Il which is reacted with salts and esters of L-proline to enalapril.
The preparation of active NCA is also described in EP 0114067, wherein a reaction of phosgene with amino acid (I) is disclosed. In EP 0061768 A1 the preparation of NCA (II) by a reaction of amino acid (I) and carbonyl diimidazole (CDI) is disclosed.
The preparation of NCA is also disclosed in ES 2004~04. The NCA (II) formed is then reacted with silylated L-proline (YU patent application 1355/~8) and with non-silylated L-proline (SI patent 9200213) to enalapril and enalapril maleate, resp., which is an interesting ACE inhibitor.
In all disclosed cases of activation of amino acid (I) there are used toxic phosgene, phosgene polymers (diphosgene, triphosgene) or phosgene derivatives such as CDI,which may be prepared by only a few phosgene producers. The use of CDI for ac-tivating amino acid (I) is expensive and it is also necessary to regenerate the waste imidazole, which may be converted again into CDI only by a phosgene producer.
Also in the synthesis of trandolapril disclosed in EP 00~341 and in US 4,490,3~6, for activating the compound (I) expensive carbonyl diimidazole CDI is used, which isconverted into the corresponding NCA (II).
r Tech~liccll Solution The first object of the invention are novel N-sulfoxy anhydrides ot the formula (III) (NSA) COOEt H
1.
Rl--CH--N~--R2 (III) ~ CA 02203435 1997-04-22 e r r r .3 ~
r r ~ r wherein Rl represents PhCH2-CH~- or CH3CH2CH2- and R2 represents methyl or R3-NH-(CH2)3-CH2-, R3 being an amino protecting group, preferably CF3CO-.
The second object of the invention is a process for the preparation of novel N-sulfoxy anhydrides of the formula (lII), characterized in that a compound of the formula tIV) COOEt Rl--CH--NH CIH R2 (N) COOH
wherein Rl in R2 have the above meanings, is reacted with an ~-(chlorosulfinyl)-heterocyclic compound of the general formula (V) a~l--R4 wherein R4 represents the rest of imidazole, of alkyl imidazole, of benzimidazole and of tetrazole.
Compounds of the general formulas (IV) and (V) are commercially available or maybe prepared according to processes known from the literature.
The preparation of the compound of the general formula (V), wherein R4 is an imidazole rest, i.e. chlorosulfinyl imidazole, is disclosed e.g. in Syl~J~tetic Communica-tiOrls~ 10 (10), 733-742, 1980~ Masaru O~ata and Hiroshi Matsumato. In the reaction in dry methylene chloride hetween SOCI, and imidazole in a 1:4 ratio there are ob-tained N.N'-thionyldiimid~lzole and imidazol~ hydrochlorid~, which is filtered off. An equimolar amount of thionylehloride is added to the filtrate with N,N'-thionyl-diimidazole and two molar equivalents of N-chlorosulfinyl imidazole of the formula (V) are obtained.
AMENDED S~EET
CA 0220343~ 1997-04-22 Thr pl-eparation of the co]npound ot the general formula (V), wherein R~ is a ~enzimid.lzole rest, i.e. N-ch]orc)sulfinyl benzimidazole, is disclosed in Sy~ c~ C0~11-1iC~l/i(l~l.s 1() (7), 559-567, 1'~0, Masaru Ogata and Hiroshi Matsumato.
The reaction between the compound ot the formula (IV) and the compo~lnd ot` the ~eneral tormula (V) is carried out in dry organic solvents (humidity < ().()4G~c), preferably in chlorinated organic solvents such as methylene chloride. or non-chlorinated organic solvents such as ethyl acetate, dimethyl carbonate, diethyl car-honate. acetonitrile etc.
The reaction between the compound of the formula (IV) and the compound of the formula (V) is carried out at a temperature between -15C and +25C.
The formed hydrochloride of a heterocyclic compound, e.g. imidazole HCI, methyl-imidazole HCl, benzimidazole HCI. tetrazole HCI etc., is filtered off or sucked off.
Organic bases may be regenerated and recycled.
The pure novel compound of the formula (III) (NSA) remains in the organic solvent.
The formation of the compound NSA is confirmed by a) quantitative isolation of a heterocyclic compound corresponding to the rest R4 in the form of hydrochloride, in two reaction steps;
b) iodometric titration of the amount of SO2 formed after the hydrolysis ot NSA;c) IR spectroscopy of the solution of a sample having characteristic absorption bands at 1~20 cm~l, 1750 cm~l in 1030 cm~~;
d) NMR spectra which do not contain signals for protons of the heterocyclic compound (V) used;
e) a further reaction of NSA with silylated amino acids under ~elease of SO2.
The third object ot the invention is a process for the preparation of corresponding ACE inhibitors, wherein NSA (III) is reacted with corresponding derivatives ot amino acids defined below. More particularly, the object of the invention is a process for the preparation of ACE inhibitors of the formula C00Et R2 R 1 ~ CH - N - CH - CO - R
in racelllate torm as well as in the form ot pure stereOisolllers, and pharmaceutically accept.lb]e sa]ts thereot such as hydroch]oride. maleinate. s~lltate~ wherein Rl and R, al e detined aS above and R has the following meanings H ~ H
H ~> l~s ,~S ~
C~
characterized in that the compound NSA of the formula III is reac~ed with a) mono- or disilylated amino acids or with mixtures of mono- and disilylated amino acids selected from the group consisting of H C~, N ~ COOH ~ H o~H
C~2-CCCH o ~ 'oooH
H H C~{, o~N~" ~ ~ N ~H
N J ~ ~ OooH
CH, H
H H
<~ aooH C~IIIC~OH ~7 H
H
I H
CH~S ~ COOH
c~3 C~, at a pH from 2 to 6, preferably 2 to 3, or b) with inorganic or organic salts of amino acids defined as under a) at a pH over 7, or c) with a free amino acid defined as under a), preferably with L-proline, and then the obtained compounds are converted in a conventional way into pharma-ceutically acceptable salts thereof such as hydrochloride, maleinate, sulfate.
As inorganic salts e.g. potassium or sodium salts are used.
As organic salts preferably salts ot` DBU (],~-diazabicyclo[5.4.0]undec-7-ene), DBN
(],5-diazclbicyclo[4.3.0]non-5-ene), TEA (triethylamine), tetramethylguanidine, im-idazole, methylimidazole etc. are used.
In the CclSe ot` amino acid N-[l-(S)-~thoxycarbonyl-3-phenylpropyl]-L-cllclnine (I) after activation with N-chlorosulfinyl imidazole NSA N-[ 1 -(S)-ethoxycarl~onyl-3-phenylr)ror)yl]-L-alanyl-N-sultoxyanhydride is ohtained. which is reacted with CA 0220343~ 1997-04-22 L-proline. silylated L-proline or with an organic or inorganic salt of L-proline to ~nalapl^il.
It the ~ame NSA (III) is reacted with a mixture. a silylat~d mixture or with an organic or inorganic salt of the mixture ot 2S,3aS 7aS- and 'R,3aR,7aR-octahydl-o-]H-indole-2-carboxylic acid, there is obtained a racemic mixture ot` SSS and RRR ACE
inhibitor having the chemical name 2S,3aS,7aS- or 2R,3aR,7aR-1-{2S-[(1R-ethoxy-carbonyl-3-phenylpropyl)amino]-1-oxopropyl}octa-hydro-lH-indole-2-c~rboxylic acid. If as octahydro-lH-indole-2-carboxylic acid a pure isomer is used such as ~S,3aS,7aS or 2S,3aR.7aS, SSS or SRS trandolapril is obtained (see J. Med. Chem.~7? 30, 992--99~)-For the preparation of enalapril the novel compound ot the formula (III) (Rl meansPhCH2-CH2-, R2 means methyl), which remains in the organic solvent such as methylene chloride after sucking off the hydrochloride of heterocyclic compound such as imidazole hydrochloride and is very reactive. is reacted with silylated L-proline (process variant a) or with inorganic or organic salt of L-proline as defined above (process variant b), to N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline (known as enalapril) with a high yield. During the reaction a gaseous SO2 isreleased, which also proves the existence of the novel compound NSA of formula (III). The reaction between NSA and silylated L-proline is carried out in the tem-perature range from -20C to +25C. This process is shown in Scheme 1.
In the process variant b) besides the desired ACE inhibitors also novel derivatives are formed, which in case of the preparation of trandolapril have the following for-mula VII
COOEt CH3 H ~ H
~H2 CH2~ CON~ (VII) ~OOEt It may h~ ic3entilied with spectroscopic methods. In the Ill.lSS spectrulll the t`ollo~ illg ~ii"ll.llS lll/Z lle pleSellt~ 2 (M+. I~ ) 4.1 (]()()C/f)~ 2~4 (7~9f). 17(~ ( ] ~)~ 1'4 (3 C/, ) (3 ¦ ( ~ 5 G~c ) .
In the NMR spectrulll oi the compound VII the ratio I etween phenyl protol1s Illd the ploton in position ' in octahydroindole moiety is 1():1 and thereby the sLIgg~!ited structLIl-e of the compound ol the formula (Vll) is confirmed.
The use ol the compound ot the formula (III) as a starting substance makes possi~tle al1 econolllical ettective and simple industrial process t`or the preparcltion ot el1.l1clpril~ trandolapril and other ACE inhibitors especially when the process variant a) is used.
The use ot NSA is very convenient since the conden~ation reaction proceeds well al-ready at lower temperatures in the range of trom -15C to +25C. Imidazole and other ambident compounds useful in the synthesis of NSA may be isolated quantitcl-tively and recycled. The process is ecologically pure since a major part of reactants may be regenerated and recycled.
Synthetised ACE inhibitors are recrystallized from acetonitrile or are purified by re-precipitation in ethyl acetate thus achieving high yields at purification (about 94~c).
2-CH2 ~ HNHCH - C O O H + a - s - N ~ ~N C H2a2 -C ~ -CH N ~ --CH3 + ~ HCI
O _ S ~ ~D (F~LTPUACIJA) o In silylated L-proli.ne H3CH2CO OC
- ~ ~CH2-CH2~HNHCH--COI~
(S2) CH3 COOH
0~ ~
o~ ~o III
silylated SRS H3CH2COCXC H~ ~COOH
ootahydro-1H-indo]e- ~ ~ I ~
(-SO2) <~CI12-CH2 :~H-- HICH--C_~"'H
SRS TRANDOLAPRIL
~ CA 0220343~ 1997-04-22 r r r ~ r ~ t ~ ~ r ~ r . r r ~ r, ~ r r The invention is illustrated by the following Examples.
Example I
Synthesis of N-[ 1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-sulfoxy anhydride (NSA, wherein Rl means PhCH2-CH2- and R2 means methyl) SOCI2 (0.18 ml; 0.0025 mole) was added to anhydrous methylene chloride (7 ml;
water content according to Karl Fischer < 0.04%) and the mixture was cooled to -10C and then imidazole (0.68 g; 0.01 mole) was added. During stirring for 60 minutes the temperature gradually increased to 15C. The precipitate of imidazole hydrochloride was filtered off, washed with dry CH2CI2 (5 ml) and a dry salt of im-idazole hydrochloride (0.58 g) was obtained. The mother liquor was again cooled to -10C and thionylchloride (0.18 ml; 0.0025 mole) was added. The solution was stirred for 60 minutes at a temperature between -10C and +15C. Then N-[1-(S)-ethoxy-carbonyl-3-phenylpropyl~-L-alanine (1.25 g; 0.0045 mole) and CH~CI2 (16 ml) was added. After stirring for 65 minutes (the temperature increased from -15C to +25C), the precipitate was filtered off, washed with methylene chloride (5 ml) and a dry salt of imidazole hydrochloride (0.51 g) was obtained. After both filtrations im-idazole hydrochloride could be re~enerated and recycled. The mother liquor con-tained the novel compound N-[l-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-sull~oxy- anhydride or NSA, which was analyzed. NSA is oily liquid, unstable in humidity and air, and has a molecular weight 325 determined by iodometric titration on the basis of the followin~ Scheme:
H3CH2COaC H
~_ Hz-CH2~!H~ H3 I2 ClOOEt CH3 ~ 2 ~CH2CH2-CH-NH-CH-COOH + ~2 2 H O + SO. + 1, 21- + SO, ~ + 4H+
Excessive 1, was determined hy titration with thios~llt:ate:
1~ + 2 S,O~ ~ ~1 + SJO"
A~CNOED SHEET
I R <~ o~ ti 1820n -1 O--SO
1750 cm -1 R
1030 cm -1 O
S
NSA thus prepared may be used as starting material for the synthesis of ACE in-hibitors.
Example 2 Synthesis ot' N-[ ] -(S)-ethoxycarbony]-3-phenylpropyl]-L-alanyl-L-proline maleinate ~) Prep~lrcltion ot'silylated L-proline Trilllethylchlorosilclne (5.7 ml; ().()45 mole) was ~dded to ~ mixture ot' L-r)roline (2.47 ~: ().()215 mole), ~Inhydrous methylene chlorid~ (~() ml) ~nd triethyl~nnin~ (2.5 ml:
().()](~7 mole) ~Ind the mixture W~IS stil-l-ed for 2 hours.
h) Thiol1ylclllol-ide (().73 ml; ().()I mole) W~IS ~Idd~(l to dl-y metllylen~ chloride mixtul~
(25 ml: H,O < < ().()4C~G) ~Ind the mixt-ll e W~IS cooled to -5C. Then imid~lzole (2.72 g:
().()4 Illol~) w~ . Tll~ ixt~lr~ w(l.~ tirr~ t'ol- (5 lnill-lt~ ~It ~I t~ l.lt CA 0220343~ 1997-04-22 .. r~ r~ ~-r~
r r ~ t ~ . trl -r r t ~ r r r between -5C and room temperature 20C. Then the separated imidazole hydro-chloride was filtered off and washed with methylene chloride (5 ml) (the yield of dry imidazole hydrochloride 2.09 g). Thionylchloride (0.73 ml; 0.01 mole) was added to the mother liquor and the mixture was stirred tor 60 minutes between -5C and +20C. The reaction mixture was again cooled to -15C and N-[1-(S)-ethoxy-carbonyl-3-phenylpropyl]-L-alanine (5 g; 0.0179 mole) in methylene chloride (65 ml) was added. The mixture was stirred for 65 minutes and during that time the tem-perature increased to 20-25C.
Silylated L-proline was added to the reaction mixture containing only NSA. Acylation was controlled by IR spectroscopy - it was found that -C=O- vibration at 1820 cm~l disappeared. The reaction was completed in a few hours depending upon reaction temperature. Then the slightly yellowish solution was evaporated on rotavapor and the solvent was removed and water (36 ml), NaCl (12 g) and ethyl acetate (18 ml)were added to the residue. The pH 2.66 was changed to pH 4.22 with 33% NaOH.
The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (10 ml). The combined ethyl acetate was dried with anhydrous sodium sulfate, sucked off and washed with ethyl acetate (2 x 10 ml) and then methyl acetate (14 ml) was poured thereto. Maleic acid (2.14 g; ().01844 mole) was added. The mix-ture was stirred for 20 minute~ at room temperature and then ~or 20 minutes at -25C. The precipitate ~ormed was filtered otf, washed with ethyl acetate and there was obtained enalapril maleate (7.~S g) (yield 88%), m.p. 14~-146C (in the literature 143-144.5C), [c~]~OD lC~o MeOH -44.16 (in the literature -42.2).
Example 3 Synthesis of SSS trandolapril Anhydrous methylene ~hloride (7 ml) and SOCI (0.18 ml; 0.0025 mole) were blended. The solution was cooled t() -5C and imidazole (0.68 g; 0.01 mole) was added (white suspension). The system WclS stirred for 1 hour and the temperaturewas allowed to increase from -5C to room temperature. Then it was filtered off and solid was wa~;hed with CH~Cl, (5 ml). The liquid was cooled to -5C and additional SOCI, (0.18 ml) was added while stirring the ~ystem t~r I hour and allowing the tem-perature to increase trom -5C to room temperclture. Then the system was cooled to -15C an(i l~l-[l-(S)-ethoxycarhonyl-3-phenylpropyl]-L-alanine (1.25 g; 0.0()45 mole) and anhydrous CH.CI, (16 ml) were added. The system was stirred for 65 minutes AMENDEO SHFCT
Ull~ the t~n~ rat~ as allow~(l to incr~cls~ trom - ] 'C to r oom t~mr~eratul-e. Thell t`ilt~r~d and the soli~ ~as wash~ with ~lnllydl-ous CH~CI (5 ml). An op.llescellt s-~lutioll A (the ~r~F~al-.ltioll ther~of is disclos~d h~lo~) of silylclt~ (2S.3aS.7aS)-o.~tall!~ll-o-]H-indole-'-~al-hoxylic aci~ was cldded to the tiltrclte an~ an op~llescellt c`]lo~ SOIUtiOn WclS o~ t.lined. This solution was stirre~ tor I to 6 hours at 100111 t~m-p~rcltur~ (2lC). Th~n the solution ot` H20 (l() ml) clnd NaCl (3 ~,) was cldded alld 35Yc HCI was added to achieve pH ().~. It was decant~d and the or~,anic phclse ~ IS
.ash~d with water (5 ml). A solution ot H2O (I() ml) and NaCl (3 g) was added to the Or~clnic phcls~ and 33'~c NaOH was added to achieve pH 4.33. Then it WclS d~cclnt~d alld th~ aqueous phas~ was washed with CH2CI2 (5 ml). Th~ organic phasc WclSdlied - ith anhydl-ous Na2SO ,. filtered and evaporated on rotavapor. Atter the eva~oration o~ CH,Cl2 methyl-tert.-butvlether (about 2n ml) was added and it was a~Tain ~\ ~porat~d on rotavapor. 2S,3aS,7aS-1{2S-[(1R-ethoxycarbonyl-3-phenylpropyl)-amino]-]-oxopropyl}octahydro-1-H-indole-2-carboxylic acid (trandolapril base: 1.94 ~T`) was obtained in a 1()(~% yield, m.p. 60C.
SSS trandolapril IR: 1755. 1660, 1450. 1220 cm~l l\-MR: 7.14-7.32 (m, 5H); 4.46 (t, lH); 3.95-4.22 (m, 6H); 2.25-2.4 (m, 3H); 2.()5 (t, lH); 1.4-1.85 (m. 5H): 1.31 (d, 3H); 1.23 (t, 3H); 0.9-1.35 (6H) ass spectrum: m/z 430 (M+, 2Yc); 429 (M+ - 1, 14Yc): 36~ (10); 357 (5); 339 (7);
30~ (32)~ 262 (34); 234 (45); 206 (22); 160 (21); 147 (~2): 1]7 (2~); 91 (59). 73 (]()o); 57 (47).
r ]ement~ nalysis iior C24H,,~N205:
Yc H %C %N
c~lc.: 7.~6 (~6.~5 ().5]
tOLIIl(~.] 3 ()().55 ().31 Prel-al-atioll ~-t th~ solution A
(2S.3~lS.7~lS)-octclhy~ro-lH-in~iol~-2-c~l^hoxylic ~ ; ().()()53 mOI~) W~IS
hl~ ie~ \~ith alllly~lrous CH~Cl (25 ml) tri~thyl~llllill~ (().73 ml; ().()()53 mole) an~
(C H~)~SiC`I (().(7 ml: ().()(153 mole). Tl-e s~/stelll was ~tirle~l t`or 1.~ to 2 h~ s nt rOO
t~ t~I]-~ (~1C).
Sylltllesi.~ ot SRS tr~ln-lol.ll~ril It w~lS l~roceeded in the same wcly as in Example 3 with tl~e ditterence that instead ot`
SSS o~tallydro-lH-illdole-2-cclrboxylic acid, the 2S.3aR.7aS isomer was use~. SRS
tran(301apl^il 2S,3aR.7~1S- I {2S-[( l R-ethoxycarhonyl-3-pheTlylpror1yl)alllino]- 1 -oxo-r~ropyl}octahydro-1-H-indole-t-cclrboxylic acid (1.72 g). m.p. ]4()-]43C~ W~IS ot~-tained.
Spectroscopic dat~:
IR: 1735; 167(); 1~5(); 1415: 128()cm~l 11aSS spectrum (FAB) m/z: 431 (M+ + 1, 52C~c); 3()7 (41); 289 (22): 234 (23): 154 (100); 137 (89); 12() (1~): 1()7 (27); 89 (25), 77 (21) EX~ 1PI~J S
Synthesis ot trandolapril sulfate Trandoklpril (().5 g: n.()n] 16 mole) obtained in Example 3 and methyl-tert.-t~utyl ether (]() ml) were hlended and a yellow solution was ohtained. To this ~olutiondul-ing I hour a sulfuri~ acid solution (().5 111]; ().()()()3G mole) (this solution was oh tained in ~u~h ~l way that ] 1111 ot ~3()% sulturi~ a~id was diluted to 25 111l with methyl-tel-t.-l utyl ether) was ~dded at 100111 temperatul-e (22C) and under good ~ith-l-ing. In 2() millutes another ().3 ml (().()()()21G mole) ot the above .~ulturi~ aci(i solution wel-e aclded at -15C to -2()-C. The systelll was tiltere(l ~It -2()C and the solid was W~lS11eCI
with ~ thyl-t~l-t.-hut)l ~th~l- (5 ~ t -2()C. A h~ig~ soli(3 (().41 ~)~ whi~h W~lli tl~lll-dOI~lr)l il .~ultate. was Ohtailled with the yield 74.5~,~ Ill.r). (~() to (3()C.
E~ /)lc () S! nthe~i~ ot trclndola;-l~il hy~:ll-ocllloride T~ iol.~ .()()l lf~ l~lol~) ohtclin~ in l~x~ t~ l-t~l-t.~ ty~th~l- ( l(i nll) were hlellded and a yellow ~olution wa~i ohtailled. Thi~i ~;olution .ooled at -ISCC to -2()-C and HCI ~a~ wa~ hubhled throu~h it. The titl~ prod-lct he--LIn to r~recir~itate. Since the ~u~pen~ion wa~ very thick anotller 3 ml ot metllyl-tel-t.-hutvl t'thel' Wcl~i added and HCI ~Ta~i Wa!i hubhled throu~?h it (HCI ~a~ wa~ huht led 5 to I() lninut~!i in total). The ~y?tem wa~; ~tirred at -15C to -2()C for anothel- I() min-lte~
alld then tiltered at thi~ temperature. The ~olid wa~ w a~hed with methyl-tert.-hutyl-ethel- (~ ml) at -2()C. A hei--e solid (().43 ~) which wa~ trandolapril hydrocllloride.
w a~ ohtained with the y ield æo~. m.p. 105 to 11()C.
E.~-u~71171c~ 7 S~nthe~i~ o~ trandolapril (proce~ variant b) A racemic mixture (().9 ~: ().()053 mole) of 2S?3aS 7aS and 2R,3aR 7aR octahvdro-1H-indo]e-2-carboxylic acid. anhydrou~ methylene chloride (22 ml) Ind tetralllethyl-ouanidine (TMG; 1.56 ml; ().()12~ mole) were b]ended. The mixture Wcl~iStirled IOr 2 hOUl~at 7()C.
To the mother liquor ohtained in Example I and cooled to -5C ~ome ~-N.N-dimethyl aminopyridine wa~ added a~ a eataly~t and the above ~olution wa~ added drop hy dl-op lor 15 minute~ at -5C to ()C. Then the ~y~tem wa~ ~tirred at -5C to ()~C tor '75 minUte~clnd cl~tel~clrd!?cl~`?OIUtiOn oi H O (]() m]) c~nd NaCl (3 -) wa~
added. 1 N HCI wa~ cldded to a~hieve I~H ~.21 and it Wcl~i de~cant~d. The ~ ueou~
r~ha~e wa~ wa~lled with methylene chloride (5 ml) and tinal]y the or~anic pha~e w a~
d]-ied witIl anhydro~ odium ~uItclte. tiltered and evar)olclted on rotavar)or. A yelIow ~olid r~a~te wa~ ohtained. MetllyI-tert.-h-ltyI ethel- ( 15 ml) wa~i add~d and it wa~ a~clin ev<lpol (Ited On rotclvclr~ol-. A mixt-ll e (2 ~) ot trclndoIcll~l-iI and oI the colllr)ound ot th~
torlllula Vll wa~ oht(lin~(l.
O _ S ~ ~D (F~LTPUACIJA) o In silylated L-proli.ne H3CH2CO OC
- ~ ~CH2-CH2~HNHCH--COI~
(S2) CH3 COOH
0~ ~
o~ ~o III
silylated SRS H3CH2COCXC H~ ~COOH
ootahydro-1H-indo]e- ~ ~ I ~
(-SO2) <~CI12-CH2 :~H-- HICH--C_~"'H
SRS TRANDOLAPRIL
~ CA 0220343~ 1997-04-22 r r r ~ r ~ t ~ ~ r ~ r . r r ~ r, ~ r r The invention is illustrated by the following Examples.
Example I
Synthesis of N-[ 1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-sulfoxy anhydride (NSA, wherein Rl means PhCH2-CH2- and R2 means methyl) SOCI2 (0.18 ml; 0.0025 mole) was added to anhydrous methylene chloride (7 ml;
water content according to Karl Fischer < 0.04%) and the mixture was cooled to -10C and then imidazole (0.68 g; 0.01 mole) was added. During stirring for 60 minutes the temperature gradually increased to 15C. The precipitate of imidazole hydrochloride was filtered off, washed with dry CH2CI2 (5 ml) and a dry salt of im-idazole hydrochloride (0.58 g) was obtained. The mother liquor was again cooled to -10C and thionylchloride (0.18 ml; 0.0025 mole) was added. The solution was stirred for 60 minutes at a temperature between -10C and +15C. Then N-[1-(S)-ethoxy-carbonyl-3-phenylpropyl~-L-alanine (1.25 g; 0.0045 mole) and CH~CI2 (16 ml) was added. After stirring for 65 minutes (the temperature increased from -15C to +25C), the precipitate was filtered off, washed with methylene chloride (5 ml) and a dry salt of imidazole hydrochloride (0.51 g) was obtained. After both filtrations im-idazole hydrochloride could be re~enerated and recycled. The mother liquor con-tained the novel compound N-[l-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-sull~oxy- anhydride or NSA, which was analyzed. NSA is oily liquid, unstable in humidity and air, and has a molecular weight 325 determined by iodometric titration on the basis of the followin~ Scheme:
H3CH2COaC H
~_ Hz-CH2~!H~ H3 I2 ClOOEt CH3 ~ 2 ~CH2CH2-CH-NH-CH-COOH + ~2 2 H O + SO. + 1, 21- + SO, ~ + 4H+
Excessive 1, was determined hy titration with thios~llt:ate:
1~ + 2 S,O~ ~ ~1 + SJO"
A~CNOED SHEET
I R <~ o~ ti 1820n -1 O--SO
1750 cm -1 R
1030 cm -1 O
S
NSA thus prepared may be used as starting material for the synthesis of ACE in-hibitors.
Example 2 Synthesis ot' N-[ ] -(S)-ethoxycarbony]-3-phenylpropyl]-L-alanyl-L-proline maleinate ~) Prep~lrcltion ot'silylated L-proline Trilllethylchlorosilclne (5.7 ml; ().()45 mole) was ~dded to ~ mixture ot' L-r)roline (2.47 ~: ().()215 mole), ~Inhydrous methylene chlorid~ (~() ml) ~nd triethyl~nnin~ (2.5 ml:
().()](~7 mole) ~Ind the mixture W~IS stil-l-ed for 2 hours.
h) Thiol1ylclllol-ide (().73 ml; ().()I mole) W~IS ~Idd~(l to dl-y metllylen~ chloride mixtul~
(25 ml: H,O < < ().()4C~G) ~Ind the mixt-ll e W~IS cooled to -5C. Then imid~lzole (2.72 g:
().()4 Illol~) w~ . Tll~ ixt~lr~ w(l.~ tirr~ t'ol- (5 lnill-lt~ ~It ~I t~ l.lt CA 0220343~ 1997-04-22 .. r~ r~ ~-r~
r r ~ t ~ . trl -r r t ~ r r r between -5C and room temperature 20C. Then the separated imidazole hydro-chloride was filtered off and washed with methylene chloride (5 ml) (the yield of dry imidazole hydrochloride 2.09 g). Thionylchloride (0.73 ml; 0.01 mole) was added to the mother liquor and the mixture was stirred tor 60 minutes between -5C and +20C. The reaction mixture was again cooled to -15C and N-[1-(S)-ethoxy-carbonyl-3-phenylpropyl]-L-alanine (5 g; 0.0179 mole) in methylene chloride (65 ml) was added. The mixture was stirred for 65 minutes and during that time the tem-perature increased to 20-25C.
Silylated L-proline was added to the reaction mixture containing only NSA. Acylation was controlled by IR spectroscopy - it was found that -C=O- vibration at 1820 cm~l disappeared. The reaction was completed in a few hours depending upon reaction temperature. Then the slightly yellowish solution was evaporated on rotavapor and the solvent was removed and water (36 ml), NaCl (12 g) and ethyl acetate (18 ml)were added to the residue. The pH 2.66 was changed to pH 4.22 with 33% NaOH.
The organic phase was separated and the aqueous phase was extracted twice with ethyl acetate (10 ml). The combined ethyl acetate was dried with anhydrous sodium sulfate, sucked off and washed with ethyl acetate (2 x 10 ml) and then methyl acetate (14 ml) was poured thereto. Maleic acid (2.14 g; ().01844 mole) was added. The mix-ture was stirred for 20 minute~ at room temperature and then ~or 20 minutes at -25C. The precipitate ~ormed was filtered otf, washed with ethyl acetate and there was obtained enalapril maleate (7.~S g) (yield 88%), m.p. 14~-146C (in the literature 143-144.5C), [c~]~OD lC~o MeOH -44.16 (in the literature -42.2).
Example 3 Synthesis of SSS trandolapril Anhydrous methylene ~hloride (7 ml) and SOCI (0.18 ml; 0.0025 mole) were blended. The solution was cooled t() -5C and imidazole (0.68 g; 0.01 mole) was added (white suspension). The system WclS stirred for 1 hour and the temperaturewas allowed to increase from -5C to room temperature. Then it was filtered off and solid was wa~;hed with CH~Cl, (5 ml). The liquid was cooled to -5C and additional SOCI, (0.18 ml) was added while stirring the ~ystem t~r I hour and allowing the tem-perature to increase trom -5C to room temperclture. Then the system was cooled to -15C an(i l~l-[l-(S)-ethoxycarhonyl-3-phenylpropyl]-L-alanine (1.25 g; 0.0()45 mole) and anhydrous CH.CI, (16 ml) were added. The system was stirred for 65 minutes AMENDEO SHFCT
Ull~ the t~n~ rat~ as allow~(l to incr~cls~ trom - ] 'C to r oom t~mr~eratul-e. Thell t`ilt~r~d and the soli~ ~as wash~ with ~lnllydl-ous CH~CI (5 ml). An op.llescellt s-~lutioll A (the ~r~F~al-.ltioll ther~of is disclos~d h~lo~) of silylclt~ (2S.3aS.7aS)-o.~tall!~ll-o-]H-indole-'-~al-hoxylic aci~ was cldded to the tiltrclte an~ an op~llescellt c`]lo~ SOIUtiOn WclS o~ t.lined. This solution was stirre~ tor I to 6 hours at 100111 t~m-p~rcltur~ (2lC). Th~n the solution ot` H20 (l() ml) clnd NaCl (3 ~,) was cldded alld 35Yc HCI was added to achieve pH ().~. It was decant~d and the or~,anic phclse ~ IS
.ash~d with water (5 ml). A solution ot H2O (I() ml) and NaCl (3 g) was added to the Or~clnic phcls~ and 33'~c NaOH was added to achieve pH 4.33. Then it WclS d~cclnt~d alld th~ aqueous phas~ was washed with CH2CI2 (5 ml). Th~ organic phasc WclSdlied - ith anhydl-ous Na2SO ,. filtered and evaporated on rotavapor. Atter the eva~oration o~ CH,Cl2 methyl-tert.-butvlether (about 2n ml) was added and it was a~Tain ~\ ~porat~d on rotavapor. 2S,3aS,7aS-1{2S-[(1R-ethoxycarbonyl-3-phenylpropyl)-amino]-]-oxopropyl}octahydro-1-H-indole-2-carboxylic acid (trandolapril base: 1.94 ~T`) was obtained in a 1()(~% yield, m.p. 60C.
SSS trandolapril IR: 1755. 1660, 1450. 1220 cm~l l\-MR: 7.14-7.32 (m, 5H); 4.46 (t, lH); 3.95-4.22 (m, 6H); 2.25-2.4 (m, 3H); 2.()5 (t, lH); 1.4-1.85 (m. 5H): 1.31 (d, 3H); 1.23 (t, 3H); 0.9-1.35 (6H) ass spectrum: m/z 430 (M+, 2Yc); 429 (M+ - 1, 14Yc): 36~ (10); 357 (5); 339 (7);
30~ (32)~ 262 (34); 234 (45); 206 (22); 160 (21); 147 (~2): 1]7 (2~); 91 (59). 73 (]()o); 57 (47).
r ]ement~ nalysis iior C24H,,~N205:
Yc H %C %N
c~lc.: 7.~6 (~6.~5 ().5]
tOLIIl(~.] 3 ()().55 ().31 Prel-al-atioll ~-t th~ solution A
(2S.3~lS.7~lS)-octclhy~ro-lH-in~iol~-2-c~l^hoxylic ~ ; ().()()53 mOI~) W~IS
hl~ ie~ \~ith alllly~lrous CH~Cl (25 ml) tri~thyl~llllill~ (().73 ml; ().()()53 mole) an~
(C H~)~SiC`I (().(7 ml: ().()(153 mole). Tl-e s~/stelll was ~tirle~l t`or 1.~ to 2 h~ s nt rOO
t~ t~I]-~ (~1C).
Sylltllesi.~ ot SRS tr~ln-lol.ll~ril It w~lS l~roceeded in the same wcly as in Example 3 with tl~e ditterence that instead ot`
SSS o~tallydro-lH-illdole-2-cclrboxylic acid, the 2S.3aR.7aS isomer was use~. SRS
tran(301apl^il 2S,3aR.7~1S- I {2S-[( l R-ethoxycarhonyl-3-pheTlylpror1yl)alllino]- 1 -oxo-r~ropyl}octahydro-1-H-indole-t-cclrboxylic acid (1.72 g). m.p. ]4()-]43C~ W~IS ot~-tained.
Spectroscopic dat~:
IR: 1735; 167(); 1~5(); 1415: 128()cm~l 11aSS spectrum (FAB) m/z: 431 (M+ + 1, 52C~c); 3()7 (41); 289 (22): 234 (23): 154 (100); 137 (89); 12() (1~): 1()7 (27); 89 (25), 77 (21) EX~ 1PI~J S
Synthesis ot trandolapril sulfate Trandoklpril (().5 g: n.()n] 16 mole) obtained in Example 3 and methyl-tert.-t~utyl ether (]() ml) were hlended and a yellow solution was ohtained. To this ~olutiondul-ing I hour a sulfuri~ acid solution (().5 111]; ().()()()3G mole) (this solution was oh tained in ~u~h ~l way that ] 1111 ot ~3()% sulturi~ a~id was diluted to 25 111l with methyl-tel-t.-l utyl ether) was ~dded at 100111 temperatul-e (22C) and under good ~ith-l-ing. In 2() millutes another ().3 ml (().()()()21G mole) ot the above .~ulturi~ aci(i solution wel-e aclded at -15C to -2()-C. The systelll was tiltere(l ~It -2()C and the solid was W~lS11eCI
with ~ thyl-t~l-t.-hut)l ~th~l- (5 ~ t -2()C. A h~ig~ soli(3 (().41 ~)~ whi~h W~lli tl~lll-dOI~lr)l il .~ultate. was Ohtailled with the yield 74.5~,~ Ill.r). (~() to (3()C.
E~ /)lc () S! nthe~i~ ot trclndola;-l~il hy~:ll-ocllloride T~ iol.~ .()()l lf~ l~lol~) ohtclin~ in l~x~ t~ l-t~l-t.~ ty~th~l- ( l(i nll) were hlellded and a yellow ~olution wa~i ohtailled. Thi~i ~;olution .ooled at -ISCC to -2()-C and HCI ~a~ wa~ hubhled throu~h it. The titl~ prod-lct he--LIn to r~recir~itate. Since the ~u~pen~ion wa~ very thick anotller 3 ml ot metllyl-tel-t.-hutvl t'thel' Wcl~i added and HCI ~Ta~i Wa!i hubhled throu~?h it (HCI ~a~ wa~ huht led 5 to I() lninut~!i in total). The ~y?tem wa~; ~tirred at -15C to -2()C for anothel- I() min-lte~
alld then tiltered at thi~ temperature. The ~olid wa~ w a~hed with methyl-tert.-hutyl-ethel- (~ ml) at -2()C. A hei--e solid (().43 ~) which wa~ trandolapril hydrocllloride.
w a~ ohtained with the y ield æo~. m.p. 105 to 11()C.
E.~-u~71171c~ 7 S~nthe~i~ o~ trandolapril (proce~ variant b) A racemic mixture (().9 ~: ().()053 mole) of 2S?3aS 7aS and 2R,3aR 7aR octahvdro-1H-indo]e-2-carboxylic acid. anhydrou~ methylene chloride (22 ml) Ind tetralllethyl-ouanidine (TMG; 1.56 ml; ().()12~ mole) were b]ended. The mixture Wcl~iStirled IOr 2 hOUl~at 7()C.
To the mother liquor ohtained in Example I and cooled to -5C ~ome ~-N.N-dimethyl aminopyridine wa~ added a~ a eataly~t and the above ~olution wa~ added drop hy dl-op lor 15 minute~ at -5C to ()C. Then the ~y~tem wa~ ~tirred at -5C to ()~C tor '75 minUte~clnd cl~tel~clrd!?cl~`?OIUtiOn oi H O (]() m]) c~nd NaCl (3 -) wa~
added. 1 N HCI wa~ cldded to a~hieve I~H ~.21 and it Wcl~i de~cant~d. The ~ ueou~
r~ha~e wa~ wa~lled with methylene chloride (5 ml) and tinal]y the or~anic pha~e w a~
d]-ied witIl anhydro~ odium ~uItclte. tiltered and evar)olclted on rotavar)or. A yelIow ~olid r~a~te wa~ ohtained. MetllyI-tert.-h-ltyI ethel- ( 15 ml) wa~i add~d and it wa~ a~clin ev<lpol (Ited On rotclvclr~ol-. A mixt-ll e (2 ~) ot trclndoIcll~l-iI and oI the colllr)ound ot th~
torlllula Vll wa~ oht(lin~(l.
Claims (5)
1. N-sulfoxy anhydrides of the formula (III) (NSA) (III) wherein R1 represents PhCH2-CH2- or CH3CH2CH2- and R2 represents methyl or R3-NH-(CH2)3-CH2-, R3 being an amino protecting group, preferably CF3CO-.
2. Process for preparing N-sulfoxy anhydrides of the formula (III) according to claim 1, characterized in that a compound of the formula (IV) (IV) wherein R1 in R2 have the above meanings, is reacted with a N-(chlorosulfinyl)-heterocyclic compound of the general formula (V) V
wherein R4 represents the rest of imidazole, of alkyl imidazole, of benzimidazole and of tetrazole, in dry organic solvents.
wherein R4 represents the rest of imidazole, of alkyl imidazole, of benzimidazole and of tetrazole, in dry organic solvents.
3. Process for preparing ACE inhibitors of the formula in the racemate form as well as in the form of pure stereoisomers, and pharmaceutically acceptable salts thereof such as hydrochloride, maleinate, sulfate, wherein R1 and R2 are defined as in Claim 1 and R has the following meanings characterized in that the compound NSA of the formula III is reacted with a) mono- or disilylated amino acids or with mixtures of mono- and disilylated amino acids selected from the group consisting of at a pH from 2 to 6, preferably 2 to 3, or b) with inorganic or organic salts of amino acids defined as under a) at a pH over 7, or c) with a free amino acid defined as under a), preferably with L-proline, and then the obtained compounds are converted in a conventional way into pharmaceutically acceptable salts thereof such as hydrochloride, maleinate, sulfate.
4. Process according to claim 3, characterized in that enalapril and trandolapril are prepared.
5. Process according to claim 3 or 4, characterized in that the synthesized ACE
inhibitor is purified by recrystallization from acetonitrile or by reprecipitation in ethyl acetate.
inhibitor is purified by recrystallization from acetonitrile or by reprecipitation in ethyl acetate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SIP-9500140 | 1995-04-24 | ||
| SI9500140A SI9500140A (en) | 1995-04-24 | 1995-04-24 | Novel n-sulfoxy anhydrides, process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2203435A1 true CA2203435A1 (en) | 1996-10-31 |
Family
ID=20431608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002203435A Abandoned CA2203435A1 (en) | 1995-04-24 | 1996-04-22 | N-sulfoxy anhydrides, a process for the preparation thereof and its use for the preparation of bioactive substances having ace inhibitory action |
Country Status (4)
| Country | Link |
|---|---|
| AU (1) | AU5294496A (en) |
| CA (1) | CA2203435A1 (en) |
| SI (1) | SI9500140A (en) |
| WO (1) | WO1996033984A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003209670A1 (en) * | 2003-02-27 | 2004-09-17 | Hetero Drugs Limited | Novel crystalline forms of trandolapril |
| DK1603558T3 (en) | 2003-02-28 | 2008-09-01 | Servier S A Lab | Process for the preparation of perindopril and its salts |
| ATE315043T1 (en) * | 2003-06-30 | 2006-02-15 | Servier Lab | METHOD FOR THE SYNTHESIS OF PERINDOPRIL AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS |
| SI21703A (en) | 2004-01-14 | 2005-08-31 | Lek Farmacevtska Druzba Dd | Inclusion complexes of perindopril, procedure of their preparation, pharmaceutical compositions containing these complexes and their application in treatment of hypertensia |
| SI21881A (en) | 2004-10-15 | 2006-04-30 | Diagen, Smartno Pri Ljubljani, D.O.O. | New crystal forms of perindopril erbumine hydrates, procedure of their preparation and pharmaceutical forms containing these compounds |
| US7291745B2 (en) | 2005-03-21 | 2007-11-06 | Glenmark Pharmaceuticals Limited | Process for the preparation of perindopril |
| US7973173B2 (en) | 2005-07-05 | 2011-07-05 | Cipla Limited | Process for the synthesis of an ACE inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4350704A (en) * | 1980-10-06 | 1982-09-21 | Warner-Lambert Company | Substituted acyl derivatives of octahydro-1H-indole-2-carboxylic acids |
| DE3260423D1 (en) * | 1981-02-17 | 1984-08-30 | Warner Lambert Co | Substituted acyl derivatives of octahydro-1h-isoindole-1-carboxylic acids and esters |
| JPS6248696A (en) * | 1985-08-27 | 1987-03-03 | Kanegafuchi Chem Ind Co Ltd | Production of n-(1(s)-ethoxycarbonyl-3-phenylpropyl)-l-alanyl-l-proline |
-
1995
- 1995-04-24 SI SI9500140A patent/SI9500140A/en not_active IP Right Cessation
-
1996
- 1996-04-22 WO PCT/SI1996/000009 patent/WO1996033984A1/en active Application Filing
- 1996-04-22 AU AU52944/96A patent/AU5294496A/en not_active Abandoned
- 1996-04-22 CA CA002203435A patent/CA2203435A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| SI9500140A (en) | 1996-10-31 |
| WO1996033984A1 (en) | 1996-10-31 |
| AU5294496A (en) | 1996-11-18 |
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