EP1196402A1 - Verfahren zur herstellung von 4-cyano-2-aminomethylthiazol - Google Patents
Verfahren zur herstellung von 4-cyano-2-aminomethylthiazolInfo
- Publication number
- EP1196402A1 EP1196402A1 EP00954468A EP00954468A EP1196402A1 EP 1196402 A1 EP1196402 A1 EP 1196402A1 EP 00954468 A EP00954468 A EP 00954468A EP 00954468 A EP00954468 A EP 00954468A EP 1196402 A1 EP1196402 A1 EP 1196402A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- alkyl
- branched
- cyano
- thiazole
- 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- Withdrawn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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the present invention relates to a new process for the preparation of 2-aminomethyl-4-cyanothiazole.
- the key step in the synthesis sequence is the construction of the thiazole ring.
- the thiazole ring is obtained by reacting a thioamide with a bromobenzotriene acid derivative (1) G. Videnov, D. Kaiser, C. Kempter, G. Jung, Angew. Chem. Int. Ed. Engl. 1996, 35, 1503; (2) Y. Naka ura, C. Shin, K. Umemura, J. Yoshimura, Chem. Lett. 1992, 1005;
- the thioamides used for this are obtained, for example, by reacting an amide with Lawesson's reagent (1), (2), (3) or by reacting an aminonitrile with H S (7) K.P. Moder, F.R. Busch, D.C. Richter, Org. Prep. Proced. Int. 1992, 24.66; G. Li, P.M. Warner, D.J. Jebaratnam, J. Org. Chem. 1961, 61, 778; T. P. Holler, F.Q. Ruan, A. Split Stone, P.B. Hopkins, J. Org. Chem. 1989, 54, 4570; T. P. Culbertson, J.M. Dornagala, P. Peterson, S.
- 2-Aminomethyl-4-cyano-thiazole would be interesting as an intermediate for the production of serine protease-inhibiting, low-molecular substances (e.g. thrombin inhibitors), if it were technically easily accessible.
- thrombin inhibitors are e.g. mentioned in WO 9806741.
- the L-aminomethyl-4-cyanothiazole can be used for the production of further thrombin inhibitors and their prodrugs, e.g. N- (Ethoxycarbonylmethylene) - (D) -cyclohexylalanyl-3,4-dehydroprolyl- [2- (4-hydroxyamidino) thiazole] methylamide hydrochloride.
- An object of the invention is to provide a process for the preparation of 2-aminomethyl-4-cyanothiazole, as a result of which this synthesis building block is available in a cost-effective manner for further syntheses.
- R 1 is branched or unbranched C ⁇ -C ⁇ rj-alkyl or
- R 2 is branched or unbranched C 1 -C 1 -alkyl or C 1 -C 4 alkoxy or C ⁇ -C-dialkyl-a ino.
- Preferred substituents are -OCH 3 OCHCH 3 , N (CH 3 ) 2 , N (C 2 H 5 ) 2 , CH 3 , C 2 H 5 , C 3 H 7 .
- the thiazole ring is obtained by reacting an aminonitrile with L-cysteine to give the thiazolidine followed by its oxidative aromatization.
- thiazolidine or thiazolane starting from a cysteine derivative is rarely mentioned in the literature. Examples are known in which a cysteine ester is reacted with amino aldehydes to give the thiazolane (3), (4), which is then converted into the thiazole via the intermediate stage of the thiazolidine.
- ⁇ -amino aldehydes are not very stable. In addition, they are not commercially available and must therefore be produced from the corresponding amino acids using multi-stage processes.
- thiazolidine syntheses are known which are obtained by reacting the cysteine derivative with imido esters (3), (4), (10), (13) K. Inami, T. Shiba, Bull. Chem. Soc. Jpn. 1985, 58, 352.
- imido esters are not commercially available and must be synthesized, for example, from an aminonitrile using a multistage process. According to the invention, the synthesis of the thiazolidine was successful starting from an aminonitrile with quantitative conversion.
- the reaction of the cysteine ester hydrochlorides, especially methyl and ethyl esters, with the protected aminoacetonitrile is carried out in an inert solvent, for example in cyclic or open-chain ethers such as THF, dioxane, DME, in acetonitrile, DMF, or chlorinated hydrocarbons such as CH 2 C1, CHC1 3 or in toluene, or in an alcoholic medium (Ci-Cg alcohol, preferably isopropanol, ethanol or methanol) in the presence of a base such as NEt 3 , morpholine, pyridine, lutidine, DMAP, DBU, DBN (preferably triethylamine) carried out.
- an inert solvent for example in cyclic or open-chain ethers such as THF, dioxane, DME, in acetonitrile, DMF, or chlorinated hydrocarbons such as CH 2 C1, CHC1 3 or in tolu
- the thiazolidine can then be oxidized with quantitative conversion to the corresponding thiazole.
- the oxidation also takes place in inert solvents, such as chlorinated hydrocarbons, toluene or cyclic and open-chain ethers.
- Organic amines such as NEt 3 , morpholine, pyridine, DMAP (dirnethylaminopyridine) and lutidine serve as the base.
- the raw products can be used directly in the next step without extensive cleaning.
- the next step in the synthesis sequence according to the invention is the aminolysis of the ester to the amide.
- Aminolysis can be carried out both in an aqueous medium and in an alcoholic ammonia solution.
- Alcoholic NH 3 solutions eg in MeOH, EtOH, iPrOH
- aqueous NH 3 solutions eg 25%
- the method according to the invention is characterized by simple implementation, without complex cleaning.
- the reaction steps take place in the essential steps with quantitative or almost quantitative yields.
- the operating costs are low and there is no need to use toxic substances (especially gases).
- the aminolysis of the thiazolecarboxylic acid ester with aqueous ammonia to give the t iazolecarboxamide was equally surprising.
- An excess of at least 5 molar equivalents of NH 3, in particular values of at least 10 mole equivalents of NH 3 is preferable.
- Alcohol can also be used as a solubilizer. In the alcohol series, however, the yields with methanol were higher than with iso-propanol. If alcohols are used, small amounts of NH 3 can be used.
- the thiazolecarboxylic acid ester can be obtained in crystalline form.
- hydrolysis of the ester with e.g. Sodium hydroxide solution and subsequent pH-controlled addition of acid can also be used in this way to produce the corresponding BOC-protected thiazolecarboxylic acid easily and with good yields.
- the present invention relates to a process for the preparation of 2-aminomethyl-4-cyano-thiazole and its salts of the formulas Ia and Ib,
- the intermediate compounds IV and V can advantageously be converted into the respective secondary product by this process, without further work-up.
- the 4-cyano-thiazole salt VIII which in general
- Formula la is included, can be reacted with bases under pH-controlled conditions to the salt-free form of formula Ib.
- the invention further relates to processes for the preparation of 2-aminomethyl-4-cyano-thiazole and its salts of the formulas Ia and Ib
- R 1 is branched or linear C ⁇ - ⁇ rj alkyl or
- n 0, 1 or 2 and R 2 is branched or unbranched C 1 -C 4 alkyl or C 1 -C 4 alkoxy or C 1 -C 4 dialkylamino, in an inert solvent in the presence of a base -0 ° C to 80 ° C is stirred until the reaction is essentially complete.
- the cysteine ester is preferably in the form of the hydrochloride.
- R 1 has the meaning given above, until the reaction is essentially complete in an alcohol R 2 OH, in which R 2 is branched or linear C ⁇ - 8- alkyl, HO-CH 2 -CH 2 -, HO-CH 2 -CH 2 -CH 2 - or C ⁇ - 4 -Alkyi-0-CH 2 -CH 2 - means at 0 ° C to 40 ° C with 1 to
- the invention further relates to a process for the preparation of the compound of formula V.
- R 1 is branched or linear C ⁇ - ⁇ rj alkyl or
- n 0, 1 or 2 and R 2 is branched or unbranched C 1 -C 1 -alkyl or C 1 -C 4 alkoxy or C 1 -C 4 -dialkylamino, in an inert solvent in the presence of a base, at - 0 ° C to 80 ° C until the reaction is essentially complete.
- the invention further relates to compounds of the formulas Ia and Ib,
- the mixture was heated to 20 ° C, and 240 ml of methylene chloride and then 310 ml of water.
- the organic phase was separated, the aqueous phase washed with 200 ml of methylene chloride and the organic phases combined.
- the collected organic phases were mixed with 200 ml of water and the pH with conc. Hydrochloric acid adjusted to pH 3.
- the organic phase was separated again and then washed with 200 ml of water.
- the solvent of the organic phase was distilled off and the residue was taken up in 860 ml of isopropanol. 140 ml (about 2 molar equivalents) of isopropanolic hydrochloric acid were added and the mixture was heated to 40 to 45 ° C.
- the reaction was monitored by TLC. After the reaction was complete, the solution was warmed to room temperature and 180 ml of water were added. The pH of the mixture 0 was conc. Hydrochloric acid adjusted to pH 3. The organic phase was separated and the aqueous phase extracted again with 120 ml of methylene chloride. The combined organic phases were washed with a further 170 ml of water at pH 3 and then washed with 170 ml of water, dried over magnesium sulfate and the solvent was distilled off in vacuo. 117 g (90% yield) of the title compound were obtained as a colorless solid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19934066A DE19934066A1 (de) | 1999-07-23 | 1999-07-23 | Verfahren zur Herstellung von 4-Cyano-2-aminomethylthiazol |
DE19934066 | 1999-07-23 | ||
PCT/EP2000/006563 WO2001007426A1 (de) | 1999-07-23 | 2000-07-11 | Verfahren zur herstellung von 4-cyano-2-aminomethylthiazol |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1196402A1 true EP1196402A1 (de) | 2002-04-17 |
Family
ID=7915457
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00954468A Withdrawn EP1196402A1 (de) | 1999-07-23 | 2000-07-11 | Verfahren zur herstellung von 4-cyano-2-aminomethylthiazol |
Country Status (21)
Country | Link |
---|---|
US (1) | US6639081B1 (es) |
EP (1) | EP1196402A1 (es) |
JP (1) | JP4027093B2 (es) |
KR (1) | KR20020028214A (es) |
CN (1) | CN1364164A (es) |
AU (1) | AU6691600A (es) |
BG (1) | BG106332A (es) |
BR (1) | BR0012710A (es) |
CA (1) | CA2380169C (es) |
DE (1) | DE19934066A1 (es) |
HK (1) | HK1047931A1 (es) |
HU (1) | HUP0201977A2 (es) |
IL (2) | IL147804A0 (es) |
MX (1) | MXPA02000773A (es) |
NO (1) | NO20020328L (es) |
NZ (1) | NZ516807A (es) |
PL (1) | PL355111A1 (es) |
SK (1) | SK1062002A3 (es) |
TR (1) | TR200200181T2 (es) |
WO (1) | WO2001007426A1 (es) |
ZA (1) | ZA200200459B (es) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19933861A1 (de) * | 1999-07-23 | 2001-01-25 | Basf Ag | Verfahren zur Herstellung von 2-Aminomethyl-4-cyano-thiazol |
US20050027128A1 (en) * | 2003-07-30 | 2005-02-03 | Robbins Timothy A. | Substituted thiazoles |
WO2012007426A1 (en) | 2010-07-13 | 2012-01-19 | Basf Se | Azoline substituted isoxazoline benzamide compounds for combating animal pests |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20000047461A (ko) * | 1998-12-29 | 2000-07-25 | 성재갑 | 트롬빈 억제제 |
DE19933861A1 (de) * | 1999-07-23 | 2001-01-25 | Basf Ag | Verfahren zur Herstellung von 2-Aminomethyl-4-cyano-thiazol |
-
1999
- 1999-07-23 DE DE19934066A patent/DE19934066A1/de not_active Withdrawn
-
2000
- 2000-07-11 BR BR0012710-8A patent/BR0012710A/pt not_active IP Right Cessation
- 2000-07-11 TR TR2002/00181T patent/TR200200181T2/xx unknown
- 2000-07-11 EP EP00954468A patent/EP1196402A1/de not_active Withdrawn
- 2000-07-11 KR KR1020027000960A patent/KR20020028214A/ko not_active Application Discontinuation
- 2000-07-11 AU AU66916/00A patent/AU6691600A/en not_active Abandoned
- 2000-07-11 PL PL00355111A patent/PL355111A1/xx not_active Application Discontinuation
- 2000-07-11 MX MXPA02000773A patent/MXPA02000773A/es unknown
- 2000-07-11 JP JP2001512511A patent/JP4027093B2/ja not_active Expired - Fee Related
- 2000-07-11 IL IL14780400A patent/IL147804A0/xx unknown
- 2000-07-11 CA CA002380169A patent/CA2380169C/en not_active Expired - Fee Related
- 2000-07-11 WO PCT/EP2000/006563 patent/WO2001007426A1/de active IP Right Grant
- 2000-07-11 NZ NZ51680700A patent/NZ516807A/xx unknown
- 2000-07-11 US US10/031,703 patent/US6639081B1/en not_active Expired - Lifetime
- 2000-07-11 SK SK106-2002A patent/SK1062002A3/sk not_active Application Discontinuation
- 2000-07-11 CN CN00810619A patent/CN1364164A/zh active Pending
- 2000-07-11 HU HU0201977A patent/HUP0201977A2/hu unknown
-
2002
- 2002-01-18 ZA ZA200200459A patent/ZA200200459B/en unknown
- 2002-01-21 BG BG106332A patent/BG106332A/bg unknown
- 2002-01-22 NO NO20020328A patent/NO20020328L/no unknown
- 2002-01-23 IL IL147804A patent/IL147804A/en not_active IP Right Cessation
-
2003
- 2003-01-02 HK HK03100002.3A patent/HK1047931A1/zh unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0107426A1 * |
Also Published As
Publication number | Publication date |
---|---|
US6639081B1 (en) | 2003-10-28 |
MXPA02000773A (es) | 2002-07-22 |
CA2380169C (en) | 2007-01-09 |
AU6691600A (en) | 2001-02-13 |
HUP0201977A2 (en) | 2002-09-28 |
WO2001007426A1 (de) | 2001-02-01 |
NO20020328D0 (no) | 2002-01-22 |
PL355111A1 (en) | 2004-04-05 |
SK1062002A3 (en) | 2002-07-02 |
TR200200181T2 (tr) | 2002-08-21 |
NZ516807A (en) | 2004-12-24 |
BG106332A (bg) | 2002-08-30 |
JP2003532624A (ja) | 2003-11-05 |
IL147804A0 (en) | 2002-08-14 |
CA2380169A1 (en) | 2001-02-01 |
BR0012710A (pt) | 2002-04-09 |
DE19934066A1 (de) | 2001-01-25 |
ZA200200459B (en) | 2004-05-26 |
JP4027093B2 (ja) | 2007-12-26 |
IL147804A (en) | 2008-11-03 |
NO20020328L (no) | 2002-01-31 |
CN1364164A (zh) | 2002-08-14 |
KR20020028214A (ko) | 2002-04-16 |
HK1047931A1 (zh) | 2003-03-14 |
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Legal Events
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Free format text: AL;LT;LV;MK;RO PAYMENT 20020131;SI PAYMENT 20020131 |
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RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: ABBOTT GMBH & CO. KG |
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17Q | First examination report despatched |
Effective date: 20080506 |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
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18D | Application deemed to be withdrawn |
Effective date: 20081118 |