WO2008040947A2 - Soluble diazoalkane precursors - Google Patents

Soluble diazoalkane precursors Download PDF

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WO2008040947A2
WO2008040947A2 PCT/GB2007/003713 GB2007003713W WO2008040947A2 WO 2008040947 A2 WO2008040947 A2 WO 2008040947A2 GB 2007003713 W GB2007003713 W GB 2007003713W WO 2008040947 A2 WO2008040947 A2 WO 2008040947A2
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David Moody
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Almac Sciences Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/48—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom
    • C07C311/49—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups having nitrogen atoms of sulfonamide groups further bound to another hetero atom to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/04—N-nitroso compounds
    • C07C243/08—N-nitroso-carboxamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/66—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to halogen atoms or to nitro or nitroso groups
    • C07C275/68—N-nitroso ureas
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/30—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to nitro or nitroso groups

Definitions

  • Diazomethane is a highly reactive gas with a wide range of utility in chemical syntheses. It is of particular utility in the formation of carbon to carbon bonds in a variety of substrates such as acid chlorides and anhydrides. It is one of the most common methylating reagents for the preparation of methyl esters from the corresponding carboxylic acids. Additionally, diazomethane has found extensive application in the alkylation of phenols, enols, and heteroatoms such as nitrogen and sulfur.
  • Diazomethane has also been used in: cycloalkanone ring expansion, preparation of ⁇ -diazo ketones, and Pd-catalyzed cyclopropanation. Indeed, diazomethane is an extremely versatile reagent for the preparation of both carbon-carbon and carbon-heteroatom bonds and its use has been discussed extensively in for example: Hopps, H. B. et al. Aldrichimica Acta 1970, 3, 9; and Black, T. H. et al. Aldrichimica Acta 1983, 16, 3.
  • Diazomethane is a powerful carcinogen, allergen and is highly poisonous. However the principal impediment to its use is that it is highly explosive since its the toxic properties can be avoided by the use of appropriate apparatus. Most literature procedures recommend against the use of ground-glass joints and specifically designed glassware is recommended. Furthermore, the production and use of diazomethane is generally carried out in dilute solutions to minimise hazard. Generally, it is prepared in ethereal solutions.
  • a "large-scale" preparation is disclosed by Acevedo et al in U.S. Pat. No. 5,459,243, which discloses reactions that are performed on the 100 millimole scale and generate dilute solutions of diazomethane in dichloromethane.
  • a batch process for the production of gaseous diazomethane "A New Method for the Preparation of Diazomethane" is disclosed by De Boer, T. H. J., and Backer, H. J. See Recueil 73 229-234 (1954).
  • the process comprises introducing a solution of potassium hydroxide in a mixture of Carbitol — water to p-toly sulphonylmethylnitrosamide in anisole.
  • a gentle flow of nitrogen is passed through the apparatus and the liberated gaseous diazomethane is obtained in 48% yield.
  • the paper goes on to disclose that when the diazomethane was absorbed immediately in an excess of benzoic acid in ether, the yield was 63%.
  • US5459243 describes an apparatus for a large scale, controlled generation of diazomethane, diazoethane and diazopropane.
  • the apparatus includes a reaction vessel for the generation of diazomethane diazoethane or diazopropane through contact of a nitroso precursor compound with an aqueous base in the presence of an organic solvent compatible with diazo lower alkanes.
  • the apparatus further includes vessels for drying the organic solution of diazomethane diazoethane or diazopropane. A basic drying agent compatible with the diazomethane or diazoethane and the solvent in maintained in the drying vessels.
  • the apparatus further includes a vessel for storing the dry solution of diazomethane, diazoethane or diazopropane while maintaining it within an inert, gaseous environment.
  • diazomethane Due to its instability and toxicity, diazomethane is exteremely toxic and unstable and thus is always generated in situ.
  • diazomethane precursors have been developed over the past few decades and are commercially available; one example is Diazald which ic commercially available from Aldrich Chemical Company. The majority of diazomethane precursors contain an /V-methyl- ⁇ /-nitroso group, which generates diazomethane upon treatment with base. Of the precursors used, ⁇ /-methyl-/V'-nitro- ⁇ /- nitrosoguanidine (MNNG) and ⁇ /-methyl- ⁇ /-nitroso-p-toluenesulfonamide (Diazald ® ) have been the most popular. MNNG is toxic, a severe irritant, a carcinogen, and a potent mutagen. Additionally, the use of MNNG has historically been limited to small-scale production of diazomethane (ca. 1 mmol).
  • diazoalkane for example, diazomethane
  • the precursor should be more soluble and / or less toxic than existing precurors.
  • a water soluble diazoalkane precursor for example, water soluble diazoalkane
  • the compounds of the present invention described below are all capable of generating lower diazoalkanes.
  • the compounds can generate more than one mole of diazoalkane per mole of the precursor compound by incorporating more than one precursor group into the compounds of the present invention.
  • the resulting diazoalkanes will be based on C 1-I0 alkyl groups enabling diazomethane, diazoethane, diazopropane, etc to be prepared.
  • R 1 is C- I-10 alkyl
  • R 2 is a group selected from the group comprising
  • each W is an independently chosen water solubilising group
  • n is an integer from 1 to 3.
  • the compounds chosen as the diazomethane source according to the invention should have the advantage of being water soluble. They are capable of being decomposed to diazomethane or another diazoalkane (which is allowed to bubble out of the vessel to another vessel containing a solution of reactant) and are converted to by-products that are also water-soluble. These features represent major processing advantages of the compounds of the invention.
  • Compounds that are suitable include /V-nitroso sulfonamides, amides, ureas and guanidines.
  • Suitable compounds according to the invention may be represented in general terms as follows:
  • R alkyl
  • the water solubilising group W is a group that is capable of forming an anion in neutral or basic media or which bears a group that is capable of forming an anion in neutral or basic aqueous media.
  • the compounds of the present invention may have 1 , 2 or 3 solubilising groups.
  • Suitable water solubilising groups W are independently selected from the group comprising: OH, -COOR 3 , -COL ,-S(O) 2 OR 3 , -S(O) 2 L ,-S(O)OR 3 , -PO(OR 5 )(OR 6 ), - CONR 5 R 6 , and -S(O) 2 NR 5 R 6 , where R 3 , R 4 and R 5 independently represent hydrogen or C- I-10 alkyl; or the water solubilising groups are formed of an aromatic or heterocyclic group bearing from 1 to 3 independently chosen groups defined above, and L is halo.
  • Preferred water solubilising groups are independently selected from the group comprising: -COOR 3 , -COL ,-S(O) 2 OR 3 , and -S(O) 2 L, where R 3 , R 4 and R 5 independently represent hydrogen or C 1-10 alkyl.
  • Suitable groups include: phenolic groups; carboxylic acids, esters and salts; sulphonic acids, esters and salts; amides, and sulphonamides.
  • the solubilising group may be derived from a cyclic substituent on the aromatic ring which undergoes ring-opening in basic media to form one or more solubilising groups.
  • R 3 , R 4 and R 5 independently represent hydrogen or C 1-6 alkyl. In a further preferred embodiment, R 3 , R 4 and R 5 independently represent hydrogen or methyl.
  • L is chloro.
  • Suitable aromatic groups include: phenyl, tolyl, xylyl, naphthyl, fluorenyl, indenyl, anthracenyl and phenanthrenyl. Phenyl, tolyl and naphthyl are preferred.
  • Suitable heterocyclic groups include: pyridinyl, indolyl, isoindolyl, benzofuranyl, quinolinyl, isoquinolinyl and quinazolinyl.
  • the compound of formula (1) is a compound of formula (I),
  • R 1 is C 1- - I O alkyl
  • R z is selected from the group comprising: -OR , -L , -COOR , -COL ,-S(O) 2 OR , -S(O) 2 L, -NCOOR 3 and NS(O) 2 OR 3 where L is halo, and R 3 is selected from the group comprising: C 1-10 alkyl optionally substituted with from 1 to 3 independently selected halo atoms; hydrogen, and a Group IA metal; or
  • R is a group of Formula (II)
  • each R 4 independently represents a group capable of forming an anion in neutral or basic aqueous media, and n is 1 , 2 or 3;
  • X is C or SO.
  • L is chloro
  • X is SO
  • R 1 is C 1-6 alkyl.
  • R 1 is C 1-4 alkyl. More preferably, R 1 is methyl or ethyl
  • R 2 is a group of Formula (II).
  • R 2 is selected from the group comprising: -OR 3 , and -L.
  • each R 4 is independently selected from the group comprising: OH, -COOR 3 ; COL ;-S(O) 2 OR 3 ; -S(O) 2 L ; CONR 5 R 6 ; and S(O) 2 NR 5 R 5 where L is halo and each R 5 group is independently selected from the group comprising: H and C 1-10 alkyl; or
  • Y is CO or S(O) 2 ;
  • each R 4 is independently selected from the group comprising: OH, - COOR 3 ; COL ;-S(O) 2 OR 3 ; -S(O) 2 L ; CONR 5 R 6 ; and S(O) 2 NR 5 R 5 where each R 5 group is independently selected from the group comprising: H and C 1-I0 alkyl. More preferably, each R 4 is independently selected from the group comprising: -COOR 3 or S(O) 2 OR 3 .
  • R 3 , R 4 and R 5 independently represent hydrogen or Ci -6 alkyl. In a further preferred embodiment, R 3 , R 4 and R 5 independently represent hydrogen or methyl.
  • R 6 is -COOR 3 or -S(O) 2 OR 3 in which R 3 is as defined above in relation to Formula (I) or R 6 is a group of Formula (II) as defined above in relation to Formula (I); B is a bond or N; and Q is NH or O
  • R 6 is -COOR 3 Or -S(O) 2 OR 3 in which R 3 is as defined above in relation to Formula (I); or R 6 is a group of Formula (II) as defined above in relation to Formula (I).
  • Another important feature of the invention is the ability to generate more than one mole of diazoalkane per molecule of precursor. This is achieved by providing a precursor with two or three nitroso groups. This means that two or three moles, respectively, of diazoalkane are generated per mole of precursor.
  • the compounds of the invention may have 1 , 2 or 3 nitroso groups as required as diazoalkane precursor groups which are each capable of generating a diazoalkane.
  • a nitroso compound including 2 or 3 nitroso groups.
  • Each nitroso group serves as a diazoalkane precursor.
  • the compound may be aliphatic or aromatic. This compound does not necessarily have solubilising groups.
  • the compound may thus optionally contain from 1 to 3 solubilising groups of the type described previously in relation to compounds of Formulae (I) to (IV).
  • Each of the nitroso groups present may bear the same or different alkyl groups. Preferably they will be identical.
  • A is an aromatic or heteroaromatic nucleus containing from 6 to 20 atoms;
  • Q is O or NH;
  • W is a solubilising group as defined in relation to Formula (1); X is C or SO; and m is from 1 to 3, p is from 0 to 3.
  • the compound of formula (2) is a compound of Formula (Vl).
  • R ⁇ 1 is. as defined in relation to Formula (I); V is a solubilising group; m is 1 , 2 or 3 and p is 0, 1 , 2 or 3.
  • the solubilising group V is a group capable of forming an anion in neutral or basic aqueous media. V may be the same as group W defined previously. V may be a cyclic group which ring-opens in basic media.
  • V is R 6 as defined in relation to Formula (IV).
  • R 6 is -COOR 3 or -S(O) 2 OR 3 in which R 3 is as defined above in relation to Formula (I); or
  • R is a group of Formula (II) as defined above in relation to Formula (I);
  • R 7 is H, or an optionally substituted Ci. 10 alkyl or aryl group
  • L is an optionally substituted C 1-10 alkyl or aryl linker group
  • optional substituents when present, are water solubilising groups W as defined above in relation to Formula (1).
  • R 7 is H, or an optionally substituted C 1-6 alkyl or aryl group.
  • L is an optionally substituted Ci -6 alkyl group. In an alternate embodiment, L is an optionally substituted aryl group.
  • Figure 1 shows an apparatus used for generating diazomethane or another diazoalkane.
  • o-l m- I p-benzene disulfonic acids sulfobenzoic acids and sulfonyl chlorides are particularly suitable as precursors for sequential sulfonamide formation.
  • These compounds can be used as precursors of the compounds of Formula (1) or Formula (2) of the present invention.
  • These precursor compunds can then be subjected to ⁇ /-nitrosation to prepare the corresponding N-nitroso sulfonamides bearing a water- solubilising carboxy or sulfonic group.
  • Cyclic precursors that can be ring opened either by aqueous base or methylamine are also useful in accordance with the invention. These compounds include the following compounds and also compounds having the same heterocyclic core structure:
  • 3- ⁇ /-nitrososulfamyl benzoic acid is prepared and then used as a diazomethane precursor as follows:
  • N-nitroso compounds shown below are prepared and then used to generate diazomethane in a suitable apparatus:
  • Diazomethane was prepared using the apparatus shown above fitted with an addition funnel containing ether (100 mL) and a syringe containing 3-[( ⁇ /-nitroso methylamino) sulfonyl] benzoic acid (10 g) in DMSO (50 mL). Both solutions were added to a mixture of potassium hydroxide (6.5 g) in water (58 mL) and ethanol (150 mL) at 65 0 C. The DMSO solution was added dropwise over 1.5 hours. Diazomethane generated was distilled as an ethereal solution into benzoic acid (22.8 g) in THF (100 mL) at 0 0 C. After complete addition the reaction mixture was warmed to room temperature and stirred overnight. Analysis by 1 H-NMR showed a 12% conversion to the methyl ester.
  • Diazomethane was prepared using the apparatus shown above fitted with an addition funnel containing ether (100 mL) and a syringe containing 3-[( ⁇ /-nitroso methylamino) sulfonyl] benzoic acid (6 g) and sodium hydrocarbonate (2.1 g) in water (50 mL). Both solutions were added to a mixture of KOH (6.5 g) in water (100 mL) at 65°C. The aqueous solution was added dropwise over 1.5 hrs. Diazomethane generated was distilled as an ethereal solution into a solution of benzoic acid (12.2 g) in THF (100 mL) at O 0 C. After complete addition, the reaction mixture was stir at room temperature overnight. Analysis by 1 H-NMR showed an 11% conversion to the methyl ester.
  • Diazomethane was prepared using the apparatus shown above fitted with an extra splitter and two dropping funnels. Diethyl ether (200 mL) was added dropwise to a stirred solution of KOH (0.5 g, 8.5 mmol) in ethanol (7 mL) and water (3 m L) at 65 0 C. 1 ,3-bis [( ⁇ /-nitroso methylamino) sulfonyl] benzene (1.44g, 4.47 mmol) in DMSO (20 mL) was then added slowly dropwise from the second dropping funnel. The rate of addition of both DMSO and the nitroso compound solution was equal to the rate of distillation of ether out of the vessel to avoid build up of diazomethane. The distillate was collected in a flask containing KOH also connected to a scrubber. When the distillation was complete the kit was flushed with nitrogen and the collection flask containing the diazomethane solution stoppered.
  • the diazomethane solution was added dropwise to a solution of benzoic acid (2.88 g, 17.88 mmol, 4 eq) in THF (25 mL) at -10 0 C. The solution was allowed to warm to room temperature and stirred overnight. Analysis by 1H NMR showed a 20% conversion to methyl benzoate.
  • Trimesic acid (2Og, 95 mmol) was suspended in thionyl chloride (60 mL) and N, N- dimethylformamide (0.369 mL). The mixture was heated at reflux for 4 hours till gas evolution had ceased. The reaction mixture was concentrated in vacuo then dissolved in dichloromethane (2x50 mL) and the solution concentrated in vacuo. Trimesoyl chloride was isolated as a yellow solid (25g, 100%).
  • Trimesoyl chloride (1g, 3.8 mmol) was added portionwise over 10 min to a solution of aqueous methylamine (1.2 mL) at 0°C. After complete addition the mixture was heated at 6O 0 C for 3hrs, cooled to room temperature then 4M NaOH (2mL) was added. After 1hr stirring, the mixture was acidified with cone hydrochloric acid, filtered, washed with water (2x5 mL) and air-dried for 30 min. 3,5-bis-(methylcarbamoyl) benzoic acid was isolated as a white powder (0.63g, 70%).
  • Diazomethane was prepared using the apparatus shown above fitted with an extra splitter and two dropping funnels. Diethyl ether (100 mL) was added dropwise to a stirred solution of KOH (1.0 g, 17.0 mmol) in ethanol (15 mL) and water (5 mL) at 65 0 C. 3,5-bis- (N-nitroso methylcarbamoyl) benzoic acid (1.0g, 3.4 mmol) in DMSO (20 mL) was then added slowly dropwise from the second dropping funnel. The rate of addition of both DMSO and the nitroso compound solution was equal to the rate of distillation of ether out of the vessel to avoid build up of diazomethane.
  • the distillate was collected in a flask containing KOH also connected to a scrubber. When the distillation was complete the kit was flushed with nitrogen and the collection flask containing the diazomethane solution stoppered. The diazomethane solution was added dropwise to a solution of benzoic acid (1.66 g, 13.6 mmol, 4 eq) in THF (25 mL) at -1O 0 C. The solution was allowed to warm to room temperature and stirred overnight. Analysis by 1 H NMR showed a 18% conversion to methyl benzoate.

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Abstract

The present invention relates to compounds useful in the preparation of diazoalkanes in general (such as diazomethane, diazoethane, diazopropane, diazobutane and homologues) and to diazomethane (CH2=N=N) in particular. The compounds chosen as the diazomethane source according to the invention also have the advantage of being water soluble. They are capable of being decomposed to diazomethane or another diazoalkane (which is allowed to bubble out of the vessel to another vessel containing a solution of reactant) and are converted to by-products that are also water-soluble.

Description

Soluble Diazoalkane Precursors
The present invention relates to compounds useful in the preparation of diazoalkanes in general (such as diazomethane, diazoethane, diazopropane, diazobutane and homologues) and to diazomethane (CH2=N=N) in particular. Diazomethane is a highly reactive gas with a wide range of utility in chemical syntheses. It is of particular utility in the formation of carbon to carbon bonds in a variety of substrates such as acid chlorides and anhydrides. It is one of the most common methylating reagents for the preparation of methyl esters from the corresponding carboxylic acids. Additionally, diazomethane has found extensive application in the alkylation of phenols, enols, and heteroatoms such as nitrogen and sulfur. Diazomethane has also been used in: cycloalkanone ring expansion, preparation of α-diazo ketones, and Pd-catalyzed cyclopropanation. Indeed, diazomethane is an extremely versatile reagent for the preparation of both carbon-carbon and carbon-heteroatom bonds and its use has been discussed extensively in for example: Hopps, H. B. et al. Aldrichimica Acta 1970, 3, 9; and Black, T. H. et al. Aldrichimica Acta 1983, 16, 3.
Diazomethane is a powerful carcinogen, allergen and is highly poisonous. However the principal impediment to its use is that it is highly explosive since its the toxic properties can be avoided by the use of appropriate apparatus. Most literature procedures recommend against the use of ground-glass joints and specifically designed glassware is recommended. Furthermore, the production and use of diazomethane is generally carried out in dilute solutions to minimise hazard. Generally, it is prepared in ethereal solutions.
A "large-scale" preparation is disclosed by Acevedo et al in U.S. Pat. No. 5,459,243, which discloses reactions that are performed on the 100 millimole scale and generate dilute solutions of diazomethane in dichloromethane.
A batch process for the production of gaseous diazomethane, "A New Method for the Preparation of Diazomethane" is disclosed by De Boer, T. H. J., and Backer, H. J. See Recueil 73 229-234 (1954). The process comprises introducing a solution of potassium hydroxide in a mixture of Carbitol — water to p-toly sulphonylmethylnitrosamide in anisole. A gentle flow of nitrogen is passed through the apparatus and the liberated gaseous diazomethane is obtained in 48% yield. The paper goes on to disclose that when the diazomethane was absorbed immediately in an excess of benzoic acid in ether, the yield was 63%.
More recently Chemistry in Industry, 21 Feb. 1994, page 122/123, in a follow up letter to a publication in the same journal dated 5 Nov., 1990, cautions against the production of gaseous diazomethane because of the explosive risks. This is consistent with Bernd Eistert — "Synthesis with Diazomethane" which states "Gaseous diazomethane, even on dilution with nitrogen, likewise can undergo explosive decomposition, especially at temperatures of 100° C. or higher".
US5459243 describes an apparatus for a large scale, controlled generation of diazomethane, diazoethane and diazopropane. The apparatus includes a reaction vessel for the generation of diazomethane diazoethane or diazopropane through contact of a nitroso precursor compound with an aqueous base in the presence of an organic solvent compatible with diazo lower alkanes. The apparatus further includes vessels for drying the organic solution of diazomethane diazoethane or diazopropane. A basic drying agent compatible with the diazomethane or diazoethane and the solvent in maintained in the drying vessels. The apparatus further includes a vessel for storing the dry solution of diazomethane, diazoethane or diazopropane while maintaining it within an inert, gaseous environment.
Due to its instability and toxicity, diazomethane is exteremely toxic and unstable and thus is always generated in situ. Several diazomethane precursors have been developed over the past few decades and are commercially available; one example is Diazald which ic commercially available from Aldrich Chemical Company. The majority of diazomethane precursors contain an /V-methyl-Λ/-nitroso group, which generates diazomethane upon treatment with base. Of the precursors used, Λ/-methyl-/V'-nitro-Λ/- nitrosoguanidine (MNNG) and Λ/-methyl-Λ/-nitroso-p-toluenesulfonamide (Diazald®) have been the most popular. MNNG is toxic, a severe irritant, a carcinogen, and a potent mutagen. Additionally, the use of MNNG has historically been limited to small-scale production of diazomethane (ca. 1 mmol).
Specialist manufacturers use diazald to generate diazomethane most often using a single-phase aq. DMSO process. The main cost issue is disposal of wet DMSO from the process. DMSO is used in the process to solubilise both the Diazald and the base required in the reaction. The plant basis of safety is to use non-flammable solvents. There is a need for a water-soluble version of Diazald, eliminating the requirements for wet DMSO and using water as the sole solvent. The by-products can then simply be sent to drain.
Accordingly there is a need for an alternative diazoalkane (for example, diazomethane) precursor. Ideally, the precursor should be more soluble and / or less toxic than existing precurors. In particular, there is a need for a water soluble diazoalkane precursor.
It is also an aim of the present invention to provide diazoalkane precursors which can generate more than one mole of the diazolalkane per molecule.
The compounds of the present invention described below are all capable of generating lower diazoalkanes. In certain cases the compounds can generate more than one mole of diazoalkane per mole of the precursor compound by incorporating more than one precursor group into the compounds of the present invention. Typically, the resulting diazoalkanes will be based on C1-I0 alkyl groups enabling diazomethane, diazoethane, diazopropane, etc to be prepared.
According to a first aspect of the present invention, there is provided a compound of formula (1)
R1 Mo
"N'
NO (1)
wherein
R1 is C-I-10 alkyl; and
R2 is a group selected from the group comprising
Figure imgf000005_0001
Figure imgf000005_0002
wherein
each W is an independently chosen water solubilising group; and
n is an integer from 1 to 3.
The compounds chosen as the diazomethane source according to the invention should have the advantage of being water soluble. They are capable of being decomposed to diazomethane or another diazoalkane (which is allowed to bubble out of the vessel to another vessel containing a solution of reactant) and are converted to by-products that are also water-soluble. These features represent major processing advantages of the compounds of the invention. Compounds that are suitable include /V-nitroso sulfonamides, amides, ureas and guanidines.
Suitable compounds according to the invention may be represented in general terms as follows:
Figure imgf000005_0003
water solubilising group 1
Figure imgf000005_0004
The following scheme is illustrative of how the compounds of the present invention react to form a diazoalkane:
base/water SO3-M+ water solubilising group
Figure imgf000006_0001
R = alkyl
The water solubilising group W is a group that is capable of forming an anion in neutral or basic media or which bears a group that is capable of forming an anion in neutral or basic aqueous media.
The compounds of the present invention may have 1 , 2 or 3 solubilising groups.
Suitable water solubilising groups W are independently selected from the group comprising: OH, -COOR3, -COL ,-S(O)2OR3, -S(O)2L ,-S(O)OR3, -PO(OR5)(OR6), - CONR5R6, and -S(O)2NR5R6, where R3, R4 and R5 independently represent hydrogen or C-I-10 alkyl; or the water solubilising groups are formed of an aromatic or heterocyclic group bearing from 1 to 3 independently chosen groups defined above, and L is halo.
Preferred water solubilising groups are independently selected from the group comprising: -COOR3, -COL ,-S(O)2OR3, and -S(O)2L, where R3, R4 and R5 independently represent hydrogen or C1-10 alkyl.
Suitable groups include: phenolic groups; carboxylic acids, esters and salts; sulphonic acids, esters and salts; amides, and sulphonamides.
In an alternative embodiment, the solubilising group may be derived from a cyclic substituent on the aromatic ring which undergoes ring-opening in basic media to form one or more solubilising groups.
More preferably, R3, R4 and R5 independently represent hydrogen or C1-6 alkyl. In a further preferred embodiment, R3, R4 and R5 independently represent hydrogen or methyl.
Preferably L is chloro. Suitable aromatic groups include: phenyl, tolyl, xylyl, naphthyl, fluorenyl, indenyl, anthracenyl and phenanthrenyl. Phenyl, tolyl and naphthyl are preferred.
Suitable heterocyclic groups include: pyridinyl, indolyl, isoindolyl, benzofuranyl, quinolinyl, isoquinolinyl and quinazolinyl.
According to one embodiment of this aspect of the present invention, the compound of formula (1) is a compound of formula (I),
Figure imgf000007_0001
(D
wherein
R1 is C1--IO alkyl;
Rz is selected from the group comprising: -OR , -L , -COOR , -COL ,-S(O)2OR , -S(O)2L, -NCOOR3 and NS(O)2OR3 where L is halo, and R3 is selected from the group comprising: C1-10 alkyl optionally substituted with from 1 to 3 independently selected halo atoms; hydrogen, and a Group IA metal; or
R is a group of Formula (II)
Figure imgf000007_0002
CO
where each R4 independently represents a group capable of forming an anion in neutral or basic aqueous media, and n is 1 , 2 or 3; and
X is C or SO.
In an embodiment of the invention, L is chloro.
In an embodiment of the invention, X is SO.
In an embodiment of the invention, R1 is C1-6 alkyl. Preferably, R1 is C1-4 alkyl. More preferably, R1 is methyl or ethyl
In an embodiment of the invention, R2 is a group of Formula (II).
In an embodiment of the invention, R2 is selected from the group comprising: -OR3, and -L.
In an embodiment of the invention, each R4 is independently selected from the group comprising: OH, -COOR3; COL ;-S(O)2OR3; -S(O)2L ; CONR5R6; and S(O)2NR5R5 where L is halo and each R5 group is independently selected from the group comprising: H and C1-10 alkyl; or
two R4 groups together with the aromatic carbon atoms to which they are attached form a cyclic group of formula (III)
Figure imgf000008_0001
(III)
where Y is CO or S(O)2; and
Z is NR5 where R5 is as defined above, or Z is O. In an embodiment, each R4 is independently selected from the group comprising: OH, - COOR3; COL ;-S(O)2OR3; -S(O)2L ; CONR5R6; and S(O)2NR5R5 where each R5 group is independently selected from the group comprising: H and C1-I0 alkyl. More preferably, each R4 is independently selected from the group comprising: -COOR3 or S(O)2OR3.
In an embodiment, R3, R4 and R5 independently represent hydrogen or Ci-6 alkyl. In a further preferred embodiment, R3, R4 and R5 independently represent hydrogen or methyl.
In another embodiment of the present invention, there is provided a compound of Formula (IV)
Figure imgf000009_0001
wherein R6 is -COOR3 or -S(O)2OR3 in which R3 is as defined above in relation to Formula (I) or R6 is a group of Formula (II) as defined above in relation to Formula (I); B is a bond or N; and Q is NH or O
In a further embodiment of the invention, there is provided a compound of Formula (V)
Figure imgf000009_0002
(V)
wherein
R6 is -COOR3 Or -S(O)2OR3 in which R3 is as defined above in relation to Formula (I); or R6 is a group of Formula (II) as defined above in relation to Formula (I).
Another important feature of the invention is the ability to generate more than one mole of diazoalkane per molecule of precursor. This is achieved by providing a precursor with two or three nitroso groups. This means that two or three moles, respectively, of diazoalkane are generated per mole of precursor. Thus the compounds of the invention may have 1 , 2 or 3 nitroso groups as required as diazoalkane precursor groups which are each capable of generating a diazoalkane.
According to a further aspect of the invention, there is provided a nitroso compound including 2 or 3 nitroso groups. Each nitroso group serves as a diazoalkane precursor. The compound may be aliphatic or aromatic. This compound does not necessarily have solubilising groups. The compound may thus optionally contain from 1 to 3 solubilising groups of the type described previously in relation to compounds of Formulae (I) to (IV). Each of the nitroso groups present may bear the same or different alkyl groups. Preferably they will be identical.
According to a second aspect of the present invention, there is provided a compound of Formula (2):
Figure imgf000010_0001
(2)
wherein A is an aromatic or heteroaromatic nucleus containing from 6 to 20 atoms; Q is O or NH;
W is a solubilising group as defined in relation to Formula (1); X is C or SO; and m is from 1 to 3, p is from 0 to 3.
In an embodiment, the compound of formula (2) is a compound of Formula (Vl).
Figure imgf000011_0001
(VI)
where R ϋ1 : is. as defined in relation to Formula (I); V is a solubilising group; m is 1 , 2 or 3 and p is 0, 1 , 2 or 3. The solubilising group V is a group capable of forming an anion in neutral or basic aqueous media. V may be the same as group W defined previously. V may be a cyclic group which ring-opens in basic media. Preferably V is R6 as defined in relation to Formula (IV).
In an alternate aspect of the invention, there is provided a compound of Formula (VII)
Figure imgf000011_0002
(VII) wherein
R6 is -COOR3 or -S(O)2OR3 in which R3 is as defined above in relation to Formula (I); or
R is a group of Formula (II) as defined above in relation to Formula (I);
R7 is H, or an optionally substituted Ci.10 alkyl or aryl group;
L is an optionally substituted C1-10 alkyl or aryl linker group;
and wherein the optional substituents, when present, are water solubilising groups W as defined above in relation to Formula (1). There may be from 1 to 3 optional substituents.
In an embodiment, R7 is H, or an optionally substituted C1-6 alkyl or aryl group. In an embodiment, L is an optionally substituted Ci-6 alkyl group. In an alternate embodiment, L is an optionally substituted aryl group.
Figure 1 shows an apparatus used for generating diazomethane or another diazoalkane.
The following o-l m- I p-benzene disulfonic acids, sulfobenzoic acids and sulfonyl chlorides are particularly suitable as precursors for sequential sulfonamide formation. These compounds can be used as precursors of the compounds of Formula (1) or Formula (2) of the present invention. These precursor compunds can then be subjected to Λ/-nitrosation to prepare the corresponding N-nitroso sulfonamides bearing a water- solubilising carboxy or sulfonic group.
Figure imgf000012_0001
Figure imgf000012_0002
Cyclic precursors that can be ring opened either by aqueous base or methylamine are also useful in accordance with the invention. These compounds include the following compounds and also compounds having the same heterocyclic core structure:
Figure imgf000013_0001
Figure imgf000013_0002
The present invention is illustrated by the following examples.
Example 1
3- Λ/-nitrososulfamyl benzoic acid is prepared and then used as a diazomethane precursor as follows:
Figure imgf000013_0003
_CO,H CO,Me
"5V
3- Λ/-nitrososulfamyl benzoic acid was prepared via Λ/-nitrosation of the sulfonamide. Base promoted decomposition of this compound produced diazomethane, which effected the esterification of benzoic acid (in dichloromethane) to give methyl benzoate in 80% yield by NMR.
Example 2
The N-nitroso compounds shown below are prepared and then used to generate diazomethane in a suitable apparatus:
Figure imgf000014_0001
Preparation of 3-[(Λ/-nitroso methylamino)sulfonyl] benzoic acid
Figure imgf000014_0002
Methylamine was bubbled for 15-20 min through 3-chlorosulfonylbenzoic acid (5 g, 22.7 mmol) in tetrahydrofuran (50 mL) at 0°C. The reaction was stirred at room temperature for 1 hour then concentrated to dryness. Water (50 mL) was added, then acidified with cone, hydrochloric acid to precipitate a white solid which was filtered and air-dried to afford, 3-[(methylamino) sulfonyl] benzoic acid (4.2 g, 86%). 1 H NMR 2.57(3H); 7.70- 7.75 (1H); 8.05-8.09 (1H); 8.26-8.30 (1 H); 8.46-8.49 (1H).
Figure imgf000014_0003
Sodium nitrite (1.5 g, 22 mmole) in water (10 mL) was added to a solution of 3- (methylsulfamoyl) benzoic acid (0.5 g, 2.3 mmole) in acetic acid (5 mL). The mixture was stirred at room temperature for 18 hrs, water (10 mL) was then added followed by dichloromethane (2x 25 mL). Organic phases were combined, dried over sodium sulphate and concentrated to afford 3-[(Λ/-nitroso methylamino) sulfonyl] benzoic acid (171 mg, 30%). 1 H NMR 3.15 (3H); 7.77-7.82 (1 H); 8.20-8.24 (1 H); 8.36-8.40 (1 H); 8.55-8.58 (1 H). Formation of diazomethane from 3-[(Λ/-nitroso methylamino) sulfonyl] benzoic acid in D M SO/water or water.
In DMSO/water
Diazomethane was prepared using the apparatus shown above fitted with an addition funnel containing ether (100 mL) and a syringe containing 3-[(Λ/-nitroso methylamino) sulfonyl] benzoic acid (10 g) in DMSO (50 mL). Both solutions were added to a mixture of potassium hydroxide (6.5 g) in water (58 mL) and ethanol (150 mL) at 650C. The DMSO solution was added dropwise over 1.5 hours. Diazomethane generated was distilled as an ethereal solution into benzoic acid (22.8 g) in THF (100 mL) at 00C. After complete addition the reaction mixture was warmed to room temperature and stirred overnight. Analysis by 1H-NMR showed a 12% conversion to the methyl ester.
In water
Diazomethane was prepared using the apparatus shown above fitted with an addition funnel containing ether (100 mL) and a syringe containing 3-[(Λ/-nitroso methylamino) sulfonyl] benzoic acid (6 g) and sodium hydrocarbonate (2.1 g) in water (50 mL). Both solutions were added to a mixture of KOH (6.5 g) in water (100 mL) at 65°C. The aqueous solution was added dropwise over 1.5 hrs. Diazomethane generated was distilled as an ethereal solution into a solution of benzoic acid (12.2 g) in THF (100 mL) at O0C. After complete addition, the reaction mixture was stir at room temperature overnight. Analysis by 1H-NMR showed an 11% conversion to the methyl ester.
Preparation of 1 ,3-Bis [(Λ/-nitroso methylamino) sulfonyl] benzene
Figure imgf000015_0001
Chlorosulfonic acid (100 mL, 1.504 mol) and 98 % sulfuric acid (3.0 mL, 0.0585 mol) was charged into a reactor containing benzenesulfonyl chloride (75 mL, 0.585 mol). The reaction mixture was heated at 1450C for 16 hours. After cooling to room temperature, the resulting brown liquid was poured onto ice, filtered, washed with water (2x 100 mL) then concentrated under reduced pressure to yield 1 ,3-benzenedisulfonyl chloride (67% yield).
Figure imgf000016_0001
1 ,3-Benzenedisulfonyl chloride (50 g, 0.182 mol) was charged over a period of 15 minutes into a reactor containing of 40% aqueous methylamine (70.5 ml_), water (90 ml_) and ice (90 g). The resulting suspension was stirred at 6O0C for 16 hours, cooled to room temperature, filtered under reduced pressure then dried to afford 1 ,3 bis- [(methylamino) sulfonyl] benzene (30.65 g, 0.107 mol, 64 % yield).
Figure imgf000016_0002
Sodium nitrite (1.46 g, 21.15 mmol) was added portionwise over a period of two hours to a suspension of 1 ,3 bis-[(methylamino) sulfonyl] benzene (15 g, 56.75 mmol) in acetic acid (45 ml_). 6N HCI (12 mL) was added dropwise until the pH 3.0 and continual addition maintained the pH value between 2.9 and 3.1. The reaction was stirred for an additional hour after consumption of NaNO2 then water (10 mL) was added. Reaction mixture was filtered, washed with water (5x 10 mL) and then partially dried. Chromatography on silica gel (ethyl acetate/ hexane 1 :4) yielded 1 ,3-bis [(Λ/-nitroso methylamino) sulfonyl] benzene (80%)
Formation of diazomethane from 1 ,3-bis [(Λ/-nitroso methylamino) sulfonyl] benzene in DMSO/water
Diazomethane was prepared using the apparatus shown above fitted with an extra splitter and two dropping funnels. Diethyl ether (200 mL) was added dropwise to a stirred solution of KOH (0.5 g, 8.5 mmol) in ethanol (7 mL) and water (3 m L) at 650C. 1 ,3-bis [(Λ/-nitroso methylamino) sulfonyl] benzene (1.44g, 4.47 mmol) in DMSO (20 mL) was then added slowly dropwise from the second dropping funnel. The rate of addition of both DMSO and the nitroso compound solution was equal to the rate of distillation of ether out of the vessel to avoid build up of diazomethane. The distillate was collected in a flask containing KOH also connected to a scrubber. When the distillation was complete the kit was flushed with nitrogen and the collection flask containing the diazomethane solution stoppered.
The diazomethane solution was added dropwise to a solution of benzoic acid (2.88 g, 17.88 mmol, 4 eq) in THF (25 mL) at -100C. The solution was allowed to warm to room temperature and stirred overnight. Analysis by 1H NMR showed a 20% conversion to methyl benzoate.
Preparation of 3,5-Bis [(Λ/-nitroso methylamino)carbamoyl benzoic acid
Figure imgf000017_0001
Trimesic acid (2Og, 95 mmol) was suspended in thionyl chloride (60 mL) and N, N- dimethylformamide (0.369 mL). The mixture was heated at reflux for 4 hours till gas evolution had ceased. The reaction mixture was concentrated in vacuo then dissolved in dichloromethane (2x50 mL) and the solution concentrated in vacuo. Trimesoyl chloride was isolated as a yellow solid (25g, 100%).
Figure imgf000017_0002
Trimesoyl chloride (1g, 3.8 mmol) was added portionwise over 10 min to a solution of aqueous methylamine (1.2 mL) at 0°C. After complete addition the mixture was heated at 6O0C for 3hrs, cooled to room temperature then 4M NaOH (2mL) was added. After 1hr stirring, the mixture was acidified with cone hydrochloric acid, filtered, washed with water (2x5 mL) and air-dried for 30 min. 3,5-bis-(methylcarbamoyl) benzoic acid was isolated as a white powder (0.63g, 70%).
Figure imgf000018_0001
Sodium nitrite (1.46 g, 21.15 mmol) was added portionwise to a suspension of 3,5-bis- (methylcarbamoyl) benzoic acid (1 g, 2.12 mmol) in acetic acid (4.1 mL) and acetic anhydride (5 mL) at 00C over a 3 hour period. The mixture was stirred at 00C for another hour then filtered, washed with hexane (2x10 mL) and air dried for 30 min. 3,5-bis-(N- nitroso methylcarbamoyl) benzoic acid was isolated as a yellow solid (0.93g, 75%).
Formation of diazomethane from 3,5-bis-(N-nitroso methylcarbamoyl) benzoic acid in DMSO/water
Diazomethane was prepared using the apparatus shown above fitted with an extra splitter and two dropping funnels. Diethyl ether (100 mL) was added dropwise to a stirred solution of KOH (1.0 g, 17.0 mmol) in ethanol (15 mL) and water (5 mL) at 650C. 3,5-bis- (N-nitroso methylcarbamoyl) benzoic acid (1.0g, 3.4 mmol) in DMSO (20 mL) was then added slowly dropwise from the second dropping funnel. The rate of addition of both DMSO and the nitroso compound solution was equal to the rate of distillation of ether out of the vessel to avoid build up of diazomethane. The distillate was collected in a flask containing KOH also connected to a scrubber. When the distillation was complete the kit was flushed with nitrogen and the collection flask containing the diazomethane solution stoppered. The diazomethane solution was added dropwise to a solution of benzoic acid (1.66 g, 13.6 mmol, 4 eq) in THF (25 mL) at -1O0C. The solution was allowed to warm to room temperature and stirred overnight. Analysis by 1 H NMR showed a 18% conversion to methyl benzoate.

Claims

Claims
1. A compound of formula (1 )
Figure imgf000019_0001
(1)
wherein R1 is C1-10 alkyl, and
R2 is a group selected from the group comprising
Figure imgf000019_0002
Figure imgf000019_0003
wherein each W is an independently chosen water solubilising group and n is an integer from 1 to 3.
2. A compound as claimed in claim 1 , wherein the or each water solubilising group W is independently a group that is capable of forming an anion in neutral or basic media or which bears a group that is capable of forming an anion in neutral or basic aqueous media.
3. A compound as claimed in claim 1 or 2, wherein the water solubilising groups W are independently selected from the group comprising: OH, -COOR3, -COL ,-S(O)2OR3, - S(O)2L ,-S(O)OR3, -PO(OR5XOR6), -CONR5R6, and -S(O)2NR5R6, where R3, R4 and R5 independently represent hydrogen or Ci-10 alkyl; or the water solubilising groups are formed of an aromatic or heterocyclic group bearing from 1 to 3 independently chosen groups defined above, and L is halo.
4. A compound as claimed in claim 1 , 2 or 3, wherein the aromatic group is selected from the group comprising: phenyl, tolyl, xylyl, naphthyl, fluorenyl, indenyl, anthracenyl and phenanthrenyl.
5. A compound as claimed in claim 1 , 2, 3 or 4, wherein the heterocyclic group is selected from the group comprising: pyridinyl, indolyl, isoindolyl, benzofuranyl, quinolinyl, isoquinolinyl and quinazolinyl.
6. A compound as claimed in any preceding claim, wherein the compound of formula (1) is a compound of formula (I),
Figure imgf000020_0001
(O
wherein
R1 is CLI O alkyl;
R2 is selected from the group comprising: -OR3, -L , -COOR3, -COL ,-S(O)2OR3, -S(O)2L, -NCOOR3 and NS(O)2OR3 where L is halo, and R3 is selected from the group comprising: Ci-I0 alkyl optionally substituted with from 1 to 3 independently selected halo atoms; hydrogen, and a Group IA metal; or
R2 is a group of Formula (II)
Figure imgf000021_0001
(M)
where each R4 independently represents a group capable of forming an anion in neutral or basic aqueous media, and n is 1, 2 or 3; and
X is C or SO.
7. A compound as claimed in claim 6, wherein X is SO.
8. A compound as claimed in claim 6 or 7, wherein R2 is a group of Formula (II).
9. A compound as claimed in claim 6, 7 or 8, wherein each R4 is independently selected from the group comprising: OH, -COOR3; -COL; S(O)2OR3; -S(0)2L; CONR5R6; and
S(O)2NR5R5 where each R5 group is independently selected from the group comprising: H and C1-10 alkyl; or two R4 groups together with the aromatic carbon atoms to which they are attached form a cyclic group of formula (III)
Figure imgf000021_0002
(III)
where Y is CO or S(O)2; and
Z is NR5 where R5 is as defined above or Z is O.
10. A compound as claimed in claim 1 , wherein the compound of Formula (1) is a compound of Formula (IV)
Figure imgf000022_0001
(IV)
wherein R6 is -COOR3 or -S(O)2OR3 in which R3 is as defined above in relation to Formula (I) or R6 is a group of Formula (II) as defined above in relation to Formula (I); B is a bond or N; and Q is NH or O
11. A compound as claimed in claim 1 , wherein the compound of Formula (1) is a compound of Formula (V)
Figure imgf000022_0002
(V)
wherein R is -COOR or -S(O)2OR in which Rό is as defined above in relation to Formula (I); or R6 is a group of Formula (II) as defined above in relation to Formula (I).
12. A compound of Formula (2):
Figure imgf000022_0003
(2)
wherein A is an aromatic or heteroaromatic nucleus containing from 6 to 20 atoms; Q is O or NH;
W is a solubilising group as defined in relation to Formula (1); X is C or SO; and m is from 1 to 3, p is from 0 to 3.
13. A compound as claimed in claim 12, wherein the compound of formula (2) is a compound of Formula (Vl).
Figure imgf000023_0001
(VI)
where R1 is as defined in relation to Formula (I); V is a solubilising group; m is 1 , 2 or 3 and p is 0, 1 , 2 or 3.
14. A compound as claimed in claim 12 or 13, wherein the solubilising group V is a group capable of forming an anion in neutral or basic aqueous media.
15. A compound as claimed in claim 12, 13, or 14, wherein V is R6 as defined in relation to Formula (IV).
16. A compound of Formula (VII)
,NO2
N
R7 R1 (VII) wherein R6 is -COOR3 or -S(O)2OR3 in which R3 is as defined above in relation to Formula (I); or
R6 is a group of Formula (II) as defined above in relation to Formula (I);
R7 is H, or an optionally substituted C1-10alkyl or aryl group;
L is an optionally substituted C1-10 alkyl or aryl linker group;
and wherein the optional substituents, when present, are water solubilising groups W as defined above in relation to Formula (1).
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