Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
  • B01J23/14—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of germanium, tin or lead
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
  • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
  • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
  • C07C309/63—Esters of sulfonic acids
  • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
  • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings

Definitions

• API's active pharmaceutical intermediates
• concentration of impurities, in particular metal impurities in the production of API's should be as low as possible to avoid labour-intensive and expensive purification methods, such as e.g. recrystallisation.
• This restriction poses severe limitations to the use of reagents in metal-catalysed synthesis processes of API's and it is generally desired to use only to a limited extent reagents and intermediates based on metals, in particular heavy metals.
• One such reaction that is commonly used is the regioselective diol mono -tosylat ion reaction. Such a reaction may be performed without the use of a metal-containing catalyst, however, in a number of instances, low conversion and/or selectivity (defined as the ratio of mono- to di-tosylated product), is commonly observed.
• Tin acetal intermediates like 3 are considered to be more reactive than 1 and to give more reproducible results.
• Fasoli et al. Fasoli, E. Caligiuri, A.; Servi, S.; Tessaro, D. J. MoI. Cat. A 2006, 244, 41
• the inventors have now found that in the above catalytic process of regioselective mono-tosylation of vicinal diols, the amount of dibutyl tin oxide 1 can surprisingly be reduced from the disclosed 2 mol% to 0.1 mol%, without any loss of conversion and selectivity.
• a generic Sn-acetal advantageously independent of the reacting diol itself, and advantageously in a solid form, can be used in the above catalytic process of regioselective mono-tosylation of vicinal diols, preferably at concentrations well below 2 mol%, in particular below 0.1 mol%, and even down to 0.001 mol% to yield a very high conversion and selectivity.
• the process is applicable on different commercial diol substrates and has the major advantage that only trace amounts of Sn (lower ppm-range) remain in the API.
• the present invention concerns the use of dibutyl tin oxide for regioselective catalytic diol mono-tosylation at a concentration lower than 2 mol%, preferably in the range between 2 mol% and about 0.05 mol%, inclusive, in particular about 0.1 mol%.
• the present invention also concern a process for the regioselective catalytic diol mono-tosylation, comprising a step wherein a compound comprising a diol moiety of Formula (Ia) is tosylated into a compound comprising a tosylated diol moiety of Formula (Ib) using less than 2 mol% OfY 2 SnO,
• Y is selected from the group of Chalky!, phenyl and benzyl ;
• X is selected from the group of Cl, Br, and OTs ; and
• n is an integer equal to 1 or 2.
• the concentration of Y 2 SnO ranges between 2 mol% and about 0.05 mol%, inclusive. In another embodiment, the concentration of Y 2 SnO is about 0.1 mol%.
• the present invention also concerns the use of a generic acetal compound of
• Y is selected from the group of C h alky!, phenyl and benzyl.
• the generic acetal compound of Formula (Ic) can be made according to preparation methods well-known in the art, for example, according to methods disclosed in EP 448413 Bl (Noramco Inc), which are herein included by reference.
• the acetal compound of Formula (Ic) may also be formed in situ when compounds of Formula (Ia) are tosylated. However, it is preferred that the acetal compound of Formula (Ic) is different from the acetal compound formed in the regioselective diol mono-tosylation reaction.
• the present invention also concerns the use of a generic acetal compound of Formula (Ic) in a catalytic process for regioselective diol mono-tosylation, wherein Y is selected from the group of C h alky!, phenyl and benzyl, wherein the concentration of the compound of Formula (Ic) is less than about 2 mol%, preferably ranges between about 2 mol% and about 0.0005 mol%, preferably ranges between about 0.1 mol% and about 0.005 mol%.
• the present invention also concern a process for the catalytic regioselective diol mono-tosylation, wherein a compound comprising a diol moiety of Formula (Ia) is tosylated into a compound comprising a tosylated diol moiety of Formula (Ib) using a generic acetal compound of Formula (Ic), wherein
• Y is selected from the group of Chalky!, phenyl and benzyl ;
• X is selected from the group of Cl, Br, and OTs ; and
• n is an integer equal to 1 or 2.
• the concentration of the generic acetal compound of Formula (Ic) is less than about 2 mol%, preferably ranges between about 2 mol% and about 0.0005 mol%, preferably ranges between about 0.1 mol% and about 0.005 mol%.
• Y is butyl.
• the generic acetal compound of Formula (Ic) is 2,2-dibutyl- [l,3,2]dioxastannolane, which is a commercially available raw material.
• tosyl is an abbreviation for p- toluenesulfonate. It is the conjugate base of the strong acid, p-toluenesulfonic acid.
• the tosyl group like other sulfonates, is a highly reactive leaving group. The process of introducing a tosyl-group into a molecule, is called mono-tosylation.
• a diol moiety is a moiety comprising at least two hydroxy groups, separated by at least 2 and at most 3 carbon atoms.
• regioselective means that the reaction takes place only at the primary alcohol.
• Example 17 was further conducted on a pilot plant scale (35 mol scale) : To compound 2a in toluene (34 L) compound 1 (9 g, 0.25 g/mol) is added and the mixture is stirred at 25 0 C during 1 hour. N,N-diisopropyl ethyl amine (5.0 kg, 38.4 mol) is added, followed by tosyl chloride (7.0 kg, 36.8 mol). After stirring the reaction mixture at 25 0 C during 16 hours, HCl IN (1.35 eq.) in water is added. The pH of the aqueous layer is 1 to 2. The organic layer is dried over Na 2 SO 4 (3.5 kg) and used as such in the next step. The estimated yield was 80 %.
• the tin acetal 2,2-dibutyl[l,3,2]dioxastannolane was prepared from Bu 2 SnO and ethylene glycol according to the following procedure (scheme 3)
• the generic acetal compound 3a was used to perform the mono-tosylation reaction according Scheme 2 for a series of compounds.
• a mixture of the corresponding diol, stannylene acetal 3a, iPr 2 NEt and TsCl in various amounts was stirred at room temperature for 16 hours.
• Hydrochloric acid IN 1.5 eq. was added and the mixture was stirred vigorously.
• the organic phase was filtered over sodium sulfate and used further as such in the next step.
• Substrates 1 to 4 % conversion and selectivity is based on HPLC area%.
• Substrates 5 and 6 % conversion and selectivity is based on GC area%.

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• Engineering & Computer Science (AREA)
• Materials Engineering (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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• 2007
  • 2007-11-09 CN CN2007800425851A patent/CN101535243B/zh active Active
  • 2007-11-09 US US12/515,407 patent/US8143432B2/en active Active
  • 2007-11-09 JP JP2009536708A patent/JP5586231B2/ja active Active
  • 2007-11-09 EP EP07822410.2A patent/EP2084129B1/en active Active
  • 2007-11-09 ES ES07822410.2T patent/ES2595529T3/es active Active
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  • 2007-11-09 WO PCT/EP2007/062109 patent/WO2008058902A2/en not_active Ceased
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• 2009
  • 2009-05-14 IL IL198764A patent/IL198764A0/en active IP Right Grant

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