EP1692120A1 - Procede de production de mercapto-aminoacides chiraux - Google Patents
Procede de production de mercapto-aminoacides chirauxInfo
- Publication number
- EP1692120A1 EP1692120A1 EP04797894A EP04797894A EP1692120A1 EP 1692120 A1 EP1692120 A1 EP 1692120A1 EP 04797894 A EP04797894 A EP 04797894A EP 04797894 A EP04797894 A EP 04797894A EP 1692120 A1 EP1692120 A1 EP 1692120A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- formula
- chiral
- alkyl
- aryl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
- C07C319/06—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols from sulfides, hydropolysulfides or polysulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- Chiral mercaptoamino acids such as alpha-methylcysteine or penicillamines
- intermediates for the production of pharmaceuticals such as iron chelators (S-alpha-methylcysteine), anti-rheumatic (R-alpha-methylcysteine) or as HIV protease inhibitors (L- Penicillamine) application.
- iron chelators S-alpha-methylcysteine
- R-alpha-methylcysteine anti-rheumatic
- L- Penicillamine HIV protease inhibitors Due to the strict regulations regarding cross-contamination with antibiotics, chemical synthesis routes are e.g. Penicillamine, which can also be obtained inexpensively from Pen-G, is in great demand.
- 2S, 4S ⁇ methyl-2-tert-butyl-1, 3-thiazolidine-3-formyl-4-methyl-4-carboxylate is based on (S) -cysteine methyl ester and pivaldehyde over 2S-methyl-2- tert-butyl-1, 3-thiazolidine-4-carboxylate, introduction of a formyl protective group to 2S, 4S-methyl-2-tert-butyl-1, 3-thiazolidine-3-formyl-4-carboxylate, reaction at -78 ° C with lithium diisopropylamide to the corresponding enolate and quenching the enolate with methyl iodide.
- racemic cysteine is, for example, from Angew. Chem. 93 (1981) No. 8, p.680f known that DL-cysteine hydrochloride H 2 O starting from chloroacetaldehyde, sodium hydrogen sulfide, ammonia and acetone via 2,2-dimethyl-3-thiazoline, followed by reaction with anhydrous hydrocyanic acid to give 2, 2 Dimethylthiazolidine-4-carbonitrile and the final addition of aqueous hydrochloric acid is obtained.
- the object of the present invention was to find a suitable process for the preparation of chiral mercaptoamino acids which provides the desired end compounds in a simple and inexpensive manner in high yield and with high optical purity.
- this task could include can be solved by selecting special ketones as starting materials.
- the present invention accordingly relates to a process for the preparation of chiral mercaptoamino acids of the formula
- R, R2 and R3 may be the same or different and are hydrogen, C ⁇ -Ce 2 - aryl, -C 6 alkyl-C6-C ⁇ 2 -aryl, C 6 -C 12 aryl-CrC 6 alkyl, Ci- Cis-alkyl or C 2 -C 8 alkenyl can mean, where R 2 and R 3 can form a saturated or unsaturated ring and the radicals can optionally be substituted one or more times by F, NO 2 or CN, which is characterized in that that a) an oxo compound of the formula
- Ri, R 2 and R 3 are as defined above and X is a leaving group from the group Cl, Br, iodine, triflate, acetate or the sulfonates, in the presence of Ammonia or ammonium hydroxide and a sulfide from the group consisting of ammonium bisulfide, alkaline earth bisulfides or alkali bisulfides, optionally with phase transfer catalysis or with the addition of a solubilizer with a ketone or aldehyde of the formula
- R 4 and R5 can be the same or different and can mean a CrC ⁇ 2 alkyl radical or a C 6 -C 2 o-aryl radical or one of the two radicals H or R and R5 together form a C 4 -C ring which optionally substituted one or more times by C 1 -C 6 -alkyl or C 6 -C 20 -aryl to the compound of the formula
- Ri, R 2 , R3, Rj and R5 are as defined above, is transferred and d) then by means of an amidase or a chiral splitting acid is converted into the corresponding chiral amide of the formula (VI *), whereupon the desired chiral mercaptoamino acid of the formula (I) is obtained by reaction with an acid, or e) first the reaction of the amide with an acid is carried out and then the conversion into the desired chiral mercaptoamino acid of the formula (I) takes place.
- Chiral mercaptoamino acids of the formula (I) are prepared by the process according to the invention.
- R 1, R 2 and R 3 can be the same or different and are hydrogen, C 6 -C 2 -aryl, CrCff-alkyl-C ⁇ -ciz-aryl, C 6 -C 12 -aryri-C ⁇ -C 6 alkyl, CC 18 alkyl or C 2 -C ⁇ s alkenyl mean.
- D-Ci ⁇ -alkyl is understood to mean straight, branched or cyclic alkyl radicals, such as methyl, ethyl, i-propyl, n-propyl, cyclopropyl, n-butyl, sec-butyl, tert.-butyl, n-pentyl, n-hexyl, cyclohexyl, 2-ethylhexyl, n-octyl, cyclooctyl, n-dodecyl, etc.
- C 2 -C 8 alkenyl radicals are straight, branched or cyclic alkenyl radicals which have one or more double bonds, such as ethylene, propenyl, 1-butenyl, isobutenyl, 2-pentenyl, 2-methyl-1-butenyl, propanedyl , Cyclopentenyl, cyclohexenyl, etc.
- Preferred are C 2 -C 2 alkenyl radicals, particularly preferably C 2 -C 6 alkenyl radicals.
- C 6 -C 2 aryl radicals examples are phenyl, naphthyl, indenyl, etc.
- aryl radicals are phenyl and naphthyl, the phenyl radical being particularly preferred.
- C 1 -C 6 -alky-C 6 -C 2 -aryl radicals are, for example, p-tolyl, o-xylyl, 4-ethylphenyl, 4-tert-butylphenyl, etc.
- C 1 -C 4 -alkyl-C 6 -aryl radicals are preferred, particularly preferably CC 2 alkyl phenyl radicals.
- Suitable C 6 -C 12 aryl-CrC 6 alkyl radicals are, for example, phenylpropyl, benzyl, phenylethyl, etc
- C 6 -Aryl-CrC-alkyl radicals are preferred, particularly preferably phenyl-dC 2 - alkyl radicals.
- R 2 and R 3 can also together form a saturated or unsaturated ring which then preferably contains 3 to 12 C atoms and particularly preferably 4 to 10 C atoms.
- radicals R 1, R 2 and R 3 can furthermore optionally be substituted one or more times by F, NO 2 or CN.
- Examples of compounds of the formula (I) which can be prepared according to the invention are alpha-methylcysteine, penicillamines, cysteine or beta-mercaptophenylalanine.
- an oxo compound of the formula (II) is reacted with a ketone or aldehyde of the formula (III).
- R 1, R 2 and R 3 are as defined above and X represents a leaving group such as chlorine, bromine, iodine, triflate, acetate or a sulfonate such as mesylate, tosylate or phenylsulfonate.
- X is preferably chlorine, bromine or iodine and particularly preferably chlorine.
- R * and R 5 independently of one another denote a C 1 -C 2 -alkyl radical, preferably a C 1 -C 6 -alkyl radical, or a C 6 -C 12 -aryl radical, preferably a phenyl radical, or one of the two radicals H.
- ⁇ and R 5 can also together form a C 4 -C 7 ring, preferably a C 5 -C 6 ring, one or more times by d-Ce alkyl, preferably by dC alkyl, or C 6 -C 20 aryl, preferably substituted by phenyl. Cyclic ketones are preferred.
- ketones of the formula (III) are cyclohexanone, cyclopentanone, 2-methylcyclohexanone, diphenyl ketone, acetone, diethyl ketone.
- the reaction takes place in the presence of ammonia or ammonium hydroxide and a sulfide.
- Ammonium hydrogen sulfide, alkaline earth metal sulfide or alkali metal hydrogen sulfide are suitable as sulfides.
- Sodium or potassium hydrogen sulfide are preferably used.
- the ammonia or the ammonium hydroxide can be introduced as such or as a solution.
- Aldehyde particularly preferably 2 to 3.5 mol of ketone or aldehyde added.
- the sulfide compound is used in an amount of 1 to 3 moles per mole of oxo compound, preferably from 1.1 to 2 moles per mole of oxo compound.
- the amount of ammonia or ammonium hydroxide added is 1 to 5 mol, preferably 1.5 to 3.5 mol, per mol of oxo compound.
- the reaction can, if the ketone or the aldehyde of the formula (III) serves as a solvent, be carried out without an additional solvent, or in the presence of a solvent from the group consisting of water, CrC alcohols or the aromatic or aliphatic hydrocarbons, which, if appropriate can be halogenated, or take place in mixtures thereof.
- the reaction is preferably carried out in a mixture of ketone / aldehyde of the formula (III) and water.
- the order of addition can in principle be chosen freely, but the ketone or the aldehyde and the sulfide compound are preferably introduced and then ammonia or ammonium hydroxide and the oxo compound are added.
- the reaction temperature is -10 ° C to + 30 ° C, preferably -5 ° C to + 15 ° C.
- reaction mixture is stirred at 0 to 70 ° C. for 5 to 300 minutes, preferably for 10 to 120 minutes and particularly preferably for 20 to 60 minutes.
- phase transfer catalysis can also be carried out with phase transfer catalysis or with the addition of a solubilizer.
- Suitable phase transfer catalysts are tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium come hydrogen sulfate, tetrabutylammonium nitrate, tetrabutylammonium chloride, benzyltributylammonium chloride, Tributylmethylammoniumbromid, Triethylmethylam- ammonium chloride, Aliquat 336 (3-methyltrioctylammonium chloride), Aliquat HTA-1, Ado gen 464 (methyltrialkyl (C8-C10) ammonium chloride) , Sodium tetraphenyl borate, ammonium tetraphenyl borate, etc in question.
- the catalyst is used in an amount of 1 to 15 mol%, preferably 3 to 8 mol%, based on the oxo compound of the form! (II) added.
- Suitable solubilizers are, for example, acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, pyridine, N-methylpyrrolidone, etc.
- the reaction temperature is again -10 ° C to + 30 ° C, preferably -5 ° C to + 15 ° C
- the thiazoline compound of the formula (IV) thus obtained is then isolated from the reaction mixture, for example by fractional distillation of the organic phase.
- the reaction of the thiazoline compound of the formula (IV) with HCN then takes place in step b).
- HCN can be used as such, in gaseous or liquid form or as a solution in water or organic solvents or as an intermediate prepared from NaCN and acid.
- the amount of HCN used is 1 to 5 mol, preferably 1.5 to 3.5 mol, per mol of thiazoline compound.
- the reaction is carried out in a solvent from the group consisting of water, CrC 4 alcohol, ester, ether or the aliphatic or aromatic hydrocarbons, which may or may not be halogenated, or in a mixture thereof.
- Step b) is preferably carried out in -CC alcohol, an aliphatic hydrocarbon or in a water / alcohol mixture.
- the reaction temperature is 0 to 40 ° C, preferably 5 to 30 ° C.
- step a) The ketone or aldehyde selected in step a) gives a nitrile compound of the formula (V) in step b), which crystallizes out of the reaction solution after HCN has been added.
- the crystallized nitrile of formula (V) is then optionally filtered off, washed and dried and, in step c), converted into the corresponding amide of formula (VI) by selective hydrolysis.
- Steps b) and c) can also be carried out as a "one pot" reaction, the nitrile not being isolated, but instead being hydrolyzed directly.
- the selective hydrolysis is carried out using a mineral acid such as HCl, H 2 SO 4 ,
- HCl is preferably used and particularly preferably concentrated HCl.
- the nitrile is suspended in the mineral acid and stirred for up to 15 hours at a temperature of 25 to 80 ° C, preferably from 35 to 60 ° C.
- the amide thus obtained is present as a salt, for example as the hydrochloride, and is converted into the corresponding chiral amide in step d) using an amidase or a chiral splitting acid.
- Suitable amidase are, for example, L-amidase made from Mycobacterium neoaurum ATCC 25795, Mycobacterium smeginatis ATCC 19420 or Mycoplana dimorpha ⁇ FO 13291.
- Suitable chiral splitting acids are, for example, the D and L forms of tartaric acid, dibenzoyl-tartaric acid, di-1,4-toluoyl-tartaric acid, mandelic acid, p-bromomandelic acid, p-chloromandelic acid, p-methylmandelic acid, 10-camphorsulfonic acid, 3 -Bromcampher-8-sulfonic acid, 3-bromocampher-10-sulfonic acid, malic acid, 2-pyrrolidone-5-carboxylic acid, 2,3,4,6-di-O-isopropylidene-2-keto-L-gulonic acid, 2- ( Phenylcarbamoyloxy) propionic acid, 2-phenoxypropionic acid, aspartic acid, N-benzoylasparginic acid, 2- (4-hydroxyphenoxy) propionic acid, (4-chlorophenyl) -2-isopropylacetic acid, 2- (2,4-d
- D- or L-tartaric acid or D- or L-di-1,4-toluoyl-tartaric acid are preferably used.
- the chiral amide is converted into the desired chiral mercaptoamino acid using an acid, such as HCl or acetic acid or a HCl / acetic acid mixture.
- HCl is preferably used and particularly preferably concentrated HCl.
- the reaction is preferably carried out under nitrogen inerting at the reflux temperature.
- step e it is also possible (step e) to react the amide first with the acid to give the corresponding (R, S) mercaptoamino acid, which is then reacted by one of the abovementioned led amidases or split acids into the corresponding chiral mercaptoamino acid is converted.
- the desired end compound is isolated, depending on the end compound, for example by extraction, crystallization, etc.
- the desired chiral mercaptoamino acids are obtained in a simple, inexpensive manner in high yields and with high optical purity by the process according to the invention.
- the hydrochloride was suspended in 25 ml of water and adjusted to pH 8.6 with 25% ammonium hydroxide solution. The precipitate was filtered off and washed several times with cold water. The product was then dried at 50 ° C. in vacuo.
- the pH was then adjusted to 8.5 with the addition of about 45 ml of 25% sodium hydroxide solution and the precipitate was filtered off.
- the product was washed with water and dried at 40 ° C in a vacuum.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT19682003 | 2003-12-09 | ||
PCT/EP2004/012919 WO2005061469A1 (fr) | 2003-12-09 | 2004-11-15 | Procede de production de mercapto-aminoacides chiraux |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1692120A1 true EP1692120A1 (fr) | 2006-08-23 |
Family
ID=34705515
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP04797894A Withdrawn EP1692120A1 (fr) | 2003-12-09 | 2004-11-15 | Procede de production de mercapto-aminoacides chiraux |
Country Status (3)
Country | Link |
---|---|
US (1) | US20070112216A1 (fr) |
EP (1) | EP1692120A1 (fr) |
WO (1) | WO2005061469A1 (fr) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005049557A1 (fr) * | 2003-11-18 | 2005-06-02 | Mitsubishi Gas Chemical Company, Inc. | Procede de production de 2-alkylcysteine et procede de production de ses derives |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998030538A1 (fr) * | 1997-01-14 | 1998-07-16 | Kaneka Corporation | Procede servant a preparer des derives de cysteine |
US7208631B2 (en) * | 2003-04-08 | 2007-04-24 | Mitsubishi Gas Chemical Company, Inc. | 2-alkylcysteinamide or salt thereof, process for producing these, and use of these |
-
2004
- 2004-11-15 WO PCT/EP2004/012919 patent/WO2005061469A1/fr active Application Filing
- 2004-11-15 EP EP04797894A patent/EP1692120A1/fr not_active Withdrawn
- 2004-11-15 US US10/581,790 patent/US20070112216A1/en not_active Abandoned
Non-Patent Citations (2)
Title |
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None * |
See also references of WO2005061469A1 * |
Also Published As
Publication number | Publication date |
---|---|
US20070112216A1 (en) | 2007-05-17 |
WO2005061469A1 (fr) | 2005-07-07 |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: KOTTHAUS, MARTINA Inventor name: KRICH, SYLVIA Inventor name: SIMETZBERGER, MICHAEL Inventor name: MAYRHOFER, HERBERT Inventor name: ROGL, CHRISTIAN |
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