EP1748977A1 - Verfahren zur herstellung von 1-hydroxymethyl-1,3,5-triazapentan, trihydrochlorid - Google Patents
Verfahren zur herstellung von 1-hydroxymethyl-1,3,5-triazapentan, trihydrochloridInfo
- Publication number
- EP1748977A1 EP1748977A1 EP05734625A EP05734625A EP1748977A1 EP 1748977 A1 EP1748977 A1 EP 1748977A1 EP 05734625 A EP05734625 A EP 05734625A EP 05734625 A EP05734625 A EP 05734625A EP 1748977 A1 EP1748977 A1 EP 1748977A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- iva
- compound
- formula
- trihydrochloride
- ivb
- 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- Withdrawn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
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/18—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with hydroxy groups and at least two amino groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
Definitions
- the invention relates to the subject characterized in the claims, that is, a new process for the preparation of 1-hydroxymethyl-1, 3,5-triazapentane, trihydrochloride.
- MS-325 is 1-hydroxymethyl-1, 3,5-triazapentane, trihydrochloride.
- a disadvantage of this synthesis is the very expensive starting material O-benzyl-Boc-serine, which is obtained through a very lossy alkylation of the Boc-serine and is difficult to purify.
- the primary alcohol is prepared from the acid via a mixed anhydride formation by in situ reduction with sodium borohydride. Problems can be expected especially when scaling up such reactions to the 100 kg scale, since extended addition times and exotherms lead to the decomposition of the anhydride.
- the use of large amounts of trifluoroacetic acid, which is used in the spin-off of the BOC group is not optimal not only for reasons of cost but also from an environmental point of view.
- the synthesis also contains a chromatographic purification, which should be avoided as far as possible from the operational process perspective.
- the overall yield of the synthesis is: 57.9% of theory. Th.
- a major disadvantage of this synthesis is the use of the very expensive borane-THF complex (Aldrich 2003/2004: 20 liters of 1.0 M borane-tetrahydrofuran complex 2403.10 EURO!), which is used in a triple excess (! becomes.
- a strong dilution of approx. 16 times THF which hinders up-scaling, is noticeable in relation to the feed material.
- the handling of Diboran on an operational scale (1000-8000 I agitators) is problematic and safety-related in any case. Incidents with fatal consequences when handling large amounts of diborane solution have already been reported (Pfizer).
- the boric acid obtained during the workup has to be filtered off, which is very cumbersome from a process engineering point of view.
- the present process fulfills the requirements to a high degree.
- the cleavage takes place according to the methods of deprotection of amines known to the person skilled in the art and subsequent conversion into the hydrochlorides.
- the splitting off of the Z and Boc groups is described in T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons N.Y., 1981 and in P.J. Kocienski, Protecting Groups, Georg Thieme Verlag Stuttgart, 1994.
- the BOC group is split off by treatment with aqu. Hydrochloric acid (5% to concentrated HCl), at temperatures from 0 to 100 ° C, preferably 20 - 80 ° C.
- the trihydrochloride can be added by adding an alcohol, e.g. Ethanol, methanol, isopropanol, n-butanol, isobutanol or mixtures of these alcohols or mixtures of these alcohols with THF, methyl tert-butyl methyl ether or acetone are precipitated and isolated in crystalline form. In some cases it has proven advantageous to concentrate the aqueous hydrochloric acid solution before adding the organic solvent.
- the Z group is split off by treatment with aqu. Hydrochloric acid (10% to conc. HCl), at temperatures from 0 to 100 ° C, preferably 60 - 100 ° C or by catalytic hydrogenation on Pd / C in aqueous solution. Mixtures of water with ethanol, methanol or THF, optionally with the addition of aqu. Hydrochloric acid can be used for the hydrogenation. The hydrogenation is carried out at 10 - 60 ° C, preferably at room temperature, at pressures of 2 - 10 bar. After filtering off the catalyst, the product-containing filtrate is worked up.
- the trihydrochloride (I) can be added by adding an alcohol, such as.
- ethanol methanol, isopropanol, butanol, isobutanol or mixtures of these alcohols, preferably an ethanol / butanol mixture, or mixtures of these alcohols with THF, methyl tert-butyl methyl ether or acetone precipitated and isolated in crystalline form.
- THF methyl tert-butyl methyl ether
- acetone precipitated and isolated in crystalline form preferably an ethanol / butanol mixture, or mixtures of these alcohols with THF, methyl tert-butyl methyl ether or acetone precipitated and isolated in crystalline form.
- HBr instead of HCl can also be used to produce the hydrobromides or, using sulfuric acid, the sulfates or hydrosulfates, etc.
- the THP group is split off in such a way that the compounds of the formula purple and IIIb in an alcohol, such as, for example, ethanol, methanol, isopropanol, isobutanol or mixtures of these alcohols, or mixtures of these alcohols with water, THF, methyl tert-butyl methyl ether or acetone dissolves and a mineral acid, such as HCl, sulfuric acid, phosphoric acid, but preferably aqu. Hydrochloric acid (10% to conc.
- an alcohol such as, for example, ethanol, methanol, isopropanol, isobutanol or mixtures of these alcohols, or mixtures of these alcohols with water, THF, methyl tert-butyl methyl ether or acetone dissolves and a mineral acid, such as HCl, sulfuric acid, phosphoric acid, but preferably aqu.
- Hydrochloric acid (10% to conc.
- the dihydrochlorides (IIA and IIB) are dried in vacuo (T: 25-50 ° C./6-48 h) and then obtained as a colorless crystalline powder.
- X is a tosyloxy or a mesyloxy group obtained by reaction with 1, 2-diaminoethane.
- the reaction takes place at temperatures of 10 to 70 ° C, preferably 30-60 ° C.
- the reaction time is 3 to 12 hours, preferably 3-8 hours.
- Reaction can either be directly in pure diaminoethane, or with the addition of a
- Solvents such as THF, dioxane, 2-methyl-THF, pyridine or alcohols such as ethanol, methanol, isopropanol, butanol can be carried out. It can be 10 to
- diaminoethane 40 mol equivalents, preferably 12 to 25 mol equivalents, of diaminoethane, based on IVa or IVb, are used.
- the excess diaminoethane can optionally in
- Solvents such as THF, ethyl acetate, butanol, dichloromethane, 2-methyl
- THF are extracted.
- the alkylation of diamines is e.g. described in: Palmer, Brian D .; Lee, Ho
- the compound of the formula I from compounds of the formula lilac and IIIb by splitting off the THP and N-protecting group in a one-pot reaction. Both protective groups are split off by treatment with aqu. Hydrochloric acid (5% to conc. HCl), at temperatures from 0 to 100 ° C, preferably 20 - 95 ° C.
- the trihydrochloride can be added by adding an alcohol, e.g.
- Ethanol, methanol, isopropanol, n-butanol, isobutanol or mixtures of these alcohols or mixtures of these alcohols with THF, methyl tert-butyl methyl ether or acetone are precipitated and isolated in crystalline form.
- the alcohols Va and Vb are reacted with 1-1.5 equ. Methanesulfonic acid chloride or p-toluenesulfonic acid chloride in aprotic solvents such as THF, 2-methyl-THF, dichloromethane, toluene, preferably THF with the addition of an amine, such as e.g. Triethylamine, Hünig base or pyridine, preferably triethylamine, at temperatures from -20 ° C to + 20 ° C, preferably -5 to + 10 ° C.
- the reaction time is 1-12 hours, preferably 1-3 hours.
- the compound Va is also known from the literature: Wang, Yi-Fong; Lalonde, James J .; Momongan, Milagros; Bergbreiter, David E .; Wong, Chi-Huey; J. Amer; 110; 21; 1988; From 7200 to 7205.
- the analog BOC connection Vb is in: Sasaki, N.Andre; Hashimoto, Chiyomi; Potier, Pierre; Tetrahedron Lett .; 28; 48; , 1987; 6069-6072
- the two-pot processes are preferred for regulatory reasons, since they allow an additional cleaning option for the intermediates 11a and 11b.
- the Z method is preferably used.
- the synthesis also allows the corresponding antipodes or the racemate of target compound (I) to be produced.
- the Z intermediates are converted into the target compound in a one-pot variant.
- the Z protective group is cleaved by acidic hydrolysis with HCI
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE200410026102 DE102004026102B4 (de) | 2004-05-25 | 2004-05-25 | Verfahren zur Herstellung von 1-Hydroxymethyl-1,3,5-triazapentan, Trihydrochlorid |
PCT/EP2005/003365 WO2005115968A1 (de) | 2004-05-25 | 2005-03-24 | Verfahren zur herstellung von 1-hydroxymethyl-1,3,5-triazapentan, trihydrochlorid |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1748977A1 true EP1748977A1 (de) | 2007-02-07 |
Family
ID=34965249
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05734625A Withdrawn EP1748977A1 (de) | 2004-05-25 | 2005-03-24 | Verfahren zur herstellung von 1-hydroxymethyl-1,3,5-triazapentan, trihydrochlorid |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1748977A1 (de) |
JP (1) | JP2008500291A (de) |
DE (1) | DE102004026102B4 (de) |
WO (1) | WO2005115968A1 (de) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3728525A1 (de) * | 1987-08-24 | 1989-03-16 | Schering Ag | Mehrkernige substituierte komplexbildner, komplexe und komplexsalze, verfahren zu deren herstellung und diese enthaltende pharmazeutische mittel |
DE3806795A1 (de) * | 1988-02-29 | 1989-09-07 | Schering Ag | Polymer-gebundene komplexbildner, deren komplexe und konjugate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel |
TW319763B (de) * | 1995-02-01 | 1997-11-11 | Epix Medical Inc |
-
2004
- 2004-05-25 DE DE200410026102 patent/DE102004026102B4/de not_active Expired - Fee Related
-
2005
- 2005-03-24 JP JP2007513705A patent/JP2008500291A/ja not_active Withdrawn
- 2005-03-24 WO PCT/EP2005/003365 patent/WO2005115968A1/de active Application Filing
- 2005-03-24 EP EP05734625A patent/EP1748977A1/de not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO2005115968A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO2005115968A1 (de) | 2005-12-08 |
DE102004026102B4 (de) | 2006-08-24 |
JP2008500291A (ja) | 2008-01-10 |
DE102004026102A1 (de) | 2005-12-29 |
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Owner name: BAYER SCHERING PHARMA AG |
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RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: HUEBNER, JAN Inventor name: PETROV, ORLIN Inventor name: PLATZEK, JOHANNES |
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