WO2012003598A1 - Intermediates for the synthesis of 1,2-bis(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and preparation method thereof - Google Patents
Intermediates for the synthesis of 1,2-bis(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and preparation method thereof Download PDFInfo
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- WO2012003598A1 WO2012003598A1 PCT/CN2010/001007 CN2010001007W WO2012003598A1 WO 2012003598 A1 WO2012003598 A1 WO 2012003598A1 CN 2010001007 W CN2010001007 W CN 2010001007W WO 2012003598 A1 WO2012003598 A1 WO 2012003598A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
Abstract
The present invention provides intermediates for the synthesis of 1,2-bis(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and preparation method thereof. The intermediates are protonated salts of 1,4-ditosylate-1,4,7-triazacyclononane or 1,4-dibenzenesulphonate-1,4,7-triazacyclononane. The preparation method of 1,4-diarylsulfonate-1,4,7-triazacyclononane (compound A) comprises reacting 1,4,7-triarylsulfonate-1,4,7-triazacyclononane (compound B) in an acidic medium comprising sulphuric acid, wherein the molar ratio of B to sulphuric acid is in the range from 1 : 0.5 to 1 : 10, or reacting 1,4,7-triarylsulfonate-1,4,7-triazacyclononane (compound B) in an acidic medium and working up the acidic medium when the conversion of B to A is at least 50 mol % yielding compound A.
Description
INTERMEDIATES FOR THE SYNTHESIS OF
1 ,2-BIS(4,7-DIMETHYL-1 ,4,7-TRIAZACYCLONON-1-YL)-ETHANE
AND PREPARATION METHOD THEREOF
FIELD OF INVENTION
The present invention concerns the synthesis of an
intermediate useful for the synthesis of 1 , 2-bis ( 1 , 4 , 7- triazacyclonon-l-yl ) -ethane (Me4-DTNE) .
BACKGROUND OF THE INVENTION
Manganese complexes containing the ligands Me3TACN (1,4,7- trimethyl-1 , 4 , 7-triazacyclononane) and Me-j-DTNE (1,2-bis- (4, 7-dimethyl-l, 4 , 7-triazacyclonon-l-yl) -ethane) are of interest for different bleaching of cellulosic and other substrates .
Different methods have been disclosed to synthesise 1,4- ditosyl-1, 4 , 7-triazacyclonone (Ts2TACN) from 1 , 4 , 7-tritosyl- 1 , 4 , 7-triazacyclonone (Ts3TACN) as described below.
Ts3TACN has been treated with a mixture of bromic acid and acetic acid for 20 h at 100°C and subsequently refluxed for 30 h to yield fully detosylated H3TACN as HBr salt, i.e.
H3TACN.HBr; subsequent reaction with 2 equivalents of tosyl chloride afforded Ts2TACN in 60 % yield as disclosed in Inorg. Chem. 1985, 24, 1230.
Ts3TACN has been treated with a mixture of bromic acid, acetic acid and phenol for 36 h at 90°C, to furnish
monotosylated TsTACN. Further reaction with 1 equivalent of tosyl chloride to afford Ts2TACN in a higher yield than using method 1 - 76% as disclosed in Inorg. Chem.,1990, 29, 4143.
Ts3TACN has been heated with a mixture of hydrobromic acid and acetic acid under reflux for 3 h to yield a mixture of TsTACN. HBr (68%) and Ts2TAC . HBr ( 30% ) as disclosed in
Synthetic Communication, 2001, 31(20), 3141.
Isolation of protonated 1 , 4-ditosyl-l , 4 , 7-triazacyclonone salt with bromide as counter ion has been described in
synthetic communication 31(20), 3141-3144, 2001; and
US2005/112066.
The reaction of 1 , 4-ditosyl-l , 4 , 7-triazacyclonone with 2 equivalents of ditosyl-ethyleneglycol in DMF to yield Ts4- DTNE is also disclosed in Inorg. Chem. 1985, 24, 1230; Inorg. Chem. 1996, 35, 1974-1979; Inorg. Chem. 1998, 37(5), 3705- 3713; Inorg. Chem. 2005, 44 (2), 401-409; and J. Chem. Soc, Dalton Trans. 1994, 457-464.
Ts4-DTNE has also been obtained using 0, 0' N, N' -tetratosyl- N, N ' -bis ( 2-hydroxyethyl ) ethylenediamine and ethylenediamine (Synthesis 2001, 2381-2383; Inorg. Chem. 2007, 46(1), 238- 250; Green Chem. 2007, 9, 996-1007).
Synthesis of 1, 2-bis (1, 4, -triazacyclonon-l-yl) -ethane (DTNE) from methine-1, 4 , 7-triazacyclononane and dibromoethane or diiodoethane has been disclosed in J. Chem. Soc, Chem Commun 1987, 886; J. Am. Chem. Soc . 1998, 120, 13104-13120; Inorg.
Chem. 1993, 32, 4300-4305; Inorg. Chem. 1997, 36, 3125-3132; Chem. Lett. 2000, 416-417; J.Chem.Soc, Dalton Trans. 2000, 3034-3040. Synthesis of Me4-DTNE from DTNE using formaldehyde and formic acid can be found in J. Am. Chem. Soc . 1998, 120, 13104-13120; Inorg. Chem. 1993, 32(20), 4300-4305; Chem. Lett. 2000, 416- 7. SUMMARY OF THE INVENTION
We have found that partial detosylation of 1 , 4 , 7-tritosyl- 1 , 4 , 7-triazacyclonane in a one pot process leads to the formation of 1 , 4-ditosyl-l , 4 , 7-triazacyclonane as its
protonated salt. This is an improvement over the two step process of complete detosylation of 1 , 4 , 7-tritosyl-l , 4 , 7- triazacyclonane followed by ditosylation of the 1,4,7- triazacyclonane adduct . Furthermore, less tosylchloride can be used to make 1, 4-ditosyl-l, 4, 7-triazacyclonane and less tosylate waste compared to the above route has been obtained.
In one aspect the present invention provides a method of producing a compound of formula (A) :
the method comprising the following step:
in an acidic medium comprising sulphuric acid, the molar ratio of B to sulphuric acid in the range from 1:0.1 to 1:10, preferably 1:0.5 to 1:10, more preferably 1:0.5 to 1:5, even more preferably from 1:1 to 1:4, wherein P is an
arylsulfonate protecting group and the compound of formula (A) is isolated as a protonated salt in amorphous or
crystalline form. In another aspect the present invention provides a method of producing a compound of formula (A) :
the method comprising the following step:
reacting a compoun of formula
in an acidic medium, wherein P is an arylsulfonate
protecting group, wherein the acidic medium is worked
when the conversion of B to A is at least 50 mol % yielding compound (A) .
As disclosed in the background of invention the 1,4-ditosyl- 1 , , 7-triazacyclonane may be used to form TS4-DTNE which can be detosylated and secondary amines of the product
methylated in a similar fashion described in US 5,284,944 for 1, , 7-tritosyl-l, , 7-triazacyclonone (Ts3TACN) . In a similar manner the same applies to the arylsulfonates as a class of protecting groups.
DETAILED DESCRIPTION OF THE INVENTION
The starting material 1 , 4 , 7-tri (arylsulfonate ) -1 , 4 , 7- triazacyclonane is reacted an acid to yield 1,4- di (arylsulfonate) -1,4, 7-triazacyclonane .
A preferred synthetic scheme for obtaining a 1,4-di
arylsulfonate-1 , 4 , 7-triazacyclonone (l,4-ditosyl-l,4,7- triazacyclonone ) is outlined below. propionic acid,
propionic anhydride
Ts3TACN Ts2TACN.TsOH
H2S04(96%), TsOH
The preferred temperature range for monodearylsulfonation of the triarylsulfonate is from 100 to 160 °C, with most preferred from 130 and 150 °C .
The preferred time for the method is from 1 h to 24 h, the most preferred time from 2 to 6 h.
Preferably the method is conducted as a one pot reaction.
The preferred acid for monodearylsulfonation of the tri arylsulfonate is sulphuric acid. Other acids, such as methanesulphonic acid and sulfonic acid resins may function to provide the monodetosylation . Preferably, the acidic medium does not contain any hydrogen halides and in this regard, the acidic medium preferably has less than 1 mol% hydrogen halides with respect to B.
Additionally auxiliary anhydrides are preferably present, such as acetic acid anhydride or propionic acid anhydride when excess water is present in the reaction mixture. The amount of acid anhydride required to facilitate the reaction depends upon the amount of water initially present in the reaction .
The acid anhydride serve to maintain the molar ratio of 1 , 4 , 7-tri (arylsulfonate) TACN : water at a level that aids the ideal molar ratio for the reaction, namely 1:1.
The optimum amount of acid anhydride to be added to the reaction mixture is dependent on the amount of 1,4,7- tri (arylsulfonate) TACN and the amount of water in the system (originating from the water present in 1,4,7- tri (arylsulfonate) TACN and sulphuric acid added). If the molar amount of water present in 1,4,7- tri (arylsulfonate) TACN and sulphuric acid is much larger than the molar amount of 1, 4 , 7-tri (arylsulfonate) TACN, the reaction may become less efficient, i.e. more
mono (arylsulfonate) TACN or H3TACN will be formed. It should
be noted that one mol of acid anhydride will react with one mol of water to form two moles of acid.
Therefore, the following relation exists (all on molar basis) :
H20 (Ts3TACN) + H20 (sulphuric acid) - acid anhydride = amount of water available to react with Ts3TACN.
Therefore, H20 (Ts3TACN) + H20 (sulphuric acid) - Ts3TACN = acid anhydride, which is equal to:
[H20 (Ts3TACN) + H20 (sulphuric acid) - Ts3TACN] : acid
anhydride = 1. Allowing variables in process conditions, this ratio should be varying between 0.1 and 10, more preferably between 0.3 and 5 and most preferably between 0.8 and 2.
It is preferred that a tosyl group is used as protecting group for the secondary amines of the 1 , , 7-triazacyclonane moiety. The tosyl group (abbreviated Ts or Tos) is CH3C6H4S02. This group is usually derived from the compound 4-toluene sulfonyl chloride, CH3C6H4S02C1 , which forms esters and amides of toluene sulphonic acid. The para orientation illustrated (p-toluenesulfonyl ) is most common, and by convention tosyl refers to the p-toluenesulfonyl group. Tosylate refers to the anion of p-toluenesulfonic acid (CH3C6H4SC>3~ ) . Whilst the tosyl group is the preferred protecting group other
arylsulfonyl groups (ArS02) will function to provide the advantages of the present invention. Preferably the
arylsulfonyl employed is a benzenesulfonate . Compared to the known procedures to make Ts2TACN, as outlined in the background of the invention, there will be one step
less needed to obtain this material in a high yield and purity. Furthermore, less tosylchloride (arylsulphonate) starting materials are needed to form 1, 4-di (arylsulfonate) - 1 , 4 , 7-triazacyclonane (3 instead of 5 molar equivalents) and as a consequence also less tosylate (arylsulphonate) waste will be generated.
In another aspect of the invention the 1,4- di (arylsulfonate) -1, , 7-triazacyclonane can be obtained and isolated as a protonated (HX) salt in which HX is selected from: toluenesulfonic acid; benzenesulfonic acid; sulfuric acid; acetic acid; formic acid; and, propionic acid, most preferably from toluenesulfonic acid, benzenesulfonic acid and sulphuric acid. One skilled in the art will appreciate that some acids will support more than one protonated 1,4- di (arylsulfonate) -1, 4 , 7-triazacyclonane, for example
sulphuric acid. Alternatively, sulphuric acid may support one protonated 1, 4-di (arylsulfonate) -1, 4 , 7-triazacyclonane, as the HS04 " counterion.
From the disclosure it will be evident that conditions and some reagents may be varied to provide the desired 1,4- di (arylsulfonate) -1, , 7-triazacyclonane . With this in mind, one skilled in the art can monitor the progress of the reaction, for example by thin layer chromatography, and determine the extent to which 1, 4-diarylsulfonate-l, , 7- triazacyclonone . When the conversion of B (1,4,7- triarylsulfonate-1, , 7-triazacyclonone) to A (1,4- diarylsulfonate-1, 4 , 7-triazacyclonone) is at least 50 mol % yielding compound (A) the reaction is worked-up, Preferably,
the reaction is worked up when the conversion of B to A is at least is at least 50 mol % yielding compound (A) .
The term worked-up is known in the art. In chemistry work-up refers to the series of manipulations required to isolate and purify the product (s) of a chemical reaction.
Typically, these manipulations include:
• quenching a reaction to deactivate any unreacted
reagents
• changing the pH to prevent further reaction
• cooling the reaction mixture or adding an antisolvent to induce precipitation, and collecting or removing the solids by filtration, decantation, or centrifuging
• removal of solvents by evaporation
• separating the reaction mixture into organic and
aqueous layers by liquid-liquid extraction
• purification by chromatography, distillation or
recrystalisation .
The following example illustrates the invention.
The amounts and ratios as given herein apply to the start of the method and will change during the reaction.
EXPERIMENTAL
1. Preparation of Ts2TACN TsOH (Ts2TACN =1 , 4-di (tosyl) - 1 , , 7-triazacyclononane ; TsOH = toluenesulfonic acid)
1, 4, 7-tritosyl-l, , 7-triazacyclononane (Ts3TACN) was been synthesised as disclosed in WO9400439. Ts3TACN (128.3 g, 96.6% containing 3.4% water, 209.5 mmol of Ts3TACN, 242 mmol H20) and propionic acid (113 mL) were placed in a 500mL three-necked-flask with thermometer and condenser. While
stirring magnetically and warming (bath 160-170 °C) most of the TS3TACN dissolved. Propionic anhydride (12 g, 92 mmol) and sulphuric acid (29.5 mL, 96%, 530 mmol, containing 120 mmol H2O) were then added. (Caution: at the beginning period of adding H2S04, exothermic reaction occurred violently) .
Stirring was continued (reaction mixture = 142-143 °C) until the TLC showed the conversion to be complete (about 3hrs) . After partial cooling, the warm (70 ~ 80°C) contents of the flask were poured into 1.5 L ice-water while stirring vigorously. The product was left at room temperature overnight, then filtered over a large frit (φΐθαιη ) and washed with water (6x300 mL) until pH=7, the obtained white solid was dried under vacuum at 60°C with P205 until the weight is constant (at least 2 days) . Yield of Ts2TACN . TsOH : 93 g (74%) with purity: 91.5%. The filtrate was neutralized with aqueous NaOH to pH14, white solid which proved to be Ts2TACN (Ts2TACN =1 , -bis (tosyl ) -1 , , 7-triazacyclononane ) appeared, filtered and washed with water, dried under vacuum to a constant weight. Another 4% product could be obtained with 90% purity. The total yield is about 78%.
1H NMR (400 MHz, CDC13):6 2.36 (s, [ArCH3 (TsOH), 3H] ) , 2.44 (s, (ArCH3 (N-Ts),6H), 3.41 (br.s, [N-CH2, 4H]),3.54 (br. S, [N-CH2, 4H] ) , 3.75 (br . s , [N-CH2 , 4H] ) , 7.20 (d, J = 7.4 Hz , [ArH, 2H] ) , 7.32 (d, J = 7.4 Hz , [ArH, 4H] ) , 7.66 (d, J = 7.4 Hz , [ArH, 4H] ) , 7.90 (d, J = 7.4 Hz , [ArH, 2H] ) .
ESI-MS(ES+): m/z 438 (Ts2TACN + H)+
Claims
1. A method of producing a compound of formula (A)
the method comprising the following step:
(a) reacting a comp (B) :
in an acidic medium comprising sulphuric acid, the molar ratio of B to sulphuric acid in the range from 1:0.5 to 1:10, wherein P is an arylsulfonate protecting group and the compound of formula (A) is isolated as a protonated salt in amorphous or crystalline form.
2. A method according to claim 1, wherein an acid anhydride is present in the acidic medium.
3. A method according to claim 1 or 2, wherein the counterion of the salt is selected from:
toluenesulfonic acid; benzenesulfonic acid; sulfuric acid; acetic acid; formic acid; and, propionic acid.
4. A method according to any preceding claim, wherein the method is conducted at a reaction temperature from 100 to 160 °C.
5. A method of pr ound of formula (A) :
the method comprising the following step
(a) reacting a comp (B) :
in an acidic medium, wherein P is an arylsulfonate protecting group, wherein the acidic medium is worked- up when the conversion of B to A is at least 50 mol % yielding compound (A) .
6. A method according to claim 5, wherein the acidic medium comprises sulphuric acid and an acid anhydride.
7. A method according to claim 5 or 6, wherein the method is conducted at a reaction temperature from 100 to 160 °C.
8. A protonated salt of formula (A), having a counter ion HX, the protonated salt in amorphous or crystalline form:
wherein P is a tosylate or benzene sulphonate and HX is selected from: toluenesulfonic acid; benzenesulfonic acid; sulfuric acid; acetic acid; formic acid; and, propionic acid.
9. A protonated salt as defined in claim 8, wherein
HX is selected from: toluenesulfonic acid;
benzenesulfonic acid; and, sulfuric acid.
10. A protonated salt as defined in claim 9, wherein the protonated salt is ( 1 , 4-ditosyl-l , 4 , 7- triazacyclonone) benzenesulfonate .
11. A protonated salt as defined in claim 9, wherein the protonated salt is (1, -ditosyl-l, 4 , 7- triazacyclonone) tosylate.
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
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PCT/CN2010/001007 WO2012003598A1 (en) | 2010-07-06 | 2010-07-06 | Intermediates for the synthesis of 1,2-bis(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and preparation method thereof |
BR112013000236-0A BR112013000236B1 (en) | 2010-07-06 | 2011-06-05 | method of producing a compound, and protonated salt |
PT171514573T PT3176155T (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate for the synthesis of same |
HUE17151457A HUE049652T2 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate for the synthesis of same |
EP11803066.7A EP2590952B1 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate thereof |
IN119MUN2013 IN2013MN00119A (en) | 2010-07-06 | 2011-07-05 | |
US13/808,565 US8907082B2 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate for the synthesis of same |
PL11803066T PL2590952T3 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate thereof |
CN201180042920.4A CN103180302B (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-three azacyclo-nonyl-1-yl)-ethane and intermediate thereof |
ES11803066.7T ES2621881T3 (en) | 2010-07-06 | 2011-07-05 | 1,2-Bis- (4,7-dimethyl-1,4,7-triazacyclonon-1-yl) -ethane and intermediate thereof |
EP17151457.3A EP3176155B1 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate for the synthesis of same |
CA3052591A CA3052591A1 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate thereof |
ES17151457T ES2764203T3 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis- (4,7-dimethyl-1,4,7-triazacyclonon-1-yl) -ethane and intermediate for its synthesis |
CA2804475A CA2804475C (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate thereof |
PCT/CN2011/001104 WO2012003712A1 (en) | 2010-07-06 | 2011-07-05 | 1,2-bis-(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and intermediate thereof |
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PCT/CN2010/001007 WO2012003598A1 (en) | 2010-07-06 | 2010-07-06 | Intermediates for the synthesis of 1,2-bis(4,7-dimethyl-1,4,7-triazacyclonon-1-yl)-ethane and preparation method thereof |
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WO2020008204A1 (en) | 2018-07-05 | 2020-01-09 | Catexel Limited | Oxidatively curable coating composition |
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US20050112066A1 (en) * | 2003-11-26 | 2005-05-26 | Concat Lp, A California Limited Partnership | Complexes of cyclic polyaza chelators with cations of alkaline earth metals for enhanced biological activity |
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US20050112066A1 (en) * | 2003-11-26 | 2005-05-26 | Concat Lp, A California Limited Partnership | Complexes of cyclic polyaza chelators with cations of alkaline earth metals for enhanced biological activity |
Non-Patent Citations (2)
Title |
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LAZAR, ISTVAN ET AL.: "Convenient Synthesis of Mono- and Ditosylated 1,4,7-triazacyclononane", SYNTHETIC COMMUNICATIONS, vol. 31, no. 20, 2001, pages 3141 - 3144 * |
WIEGHARDT, KARL ET AL.: "Coordination Chemistry of the Bimacrocyclic, Potentially Binucleating Ligand 1,2-Bis(1,4,7-triaza-1-cyclononyl)ethane (dtne).Electrochemistry of Its First Transition Series Metal(II,III) Complexes. Characterization of the New Hemerythrin Model Complex [Fe2(dtne)(mu-O)(mu-CH3CO2)2]Br2.H2O", INORGANIC CHEMISTRY, vol. 24, no. 8, 1985, pages 1230 - 1235 * |
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WO2020008204A1 (en) | 2018-07-05 | 2020-01-09 | Catexel Limited | Oxidatively curable coating composition |
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