US 20090131653A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0131653 A1 Ratnam et al. (43) Pub. Date: May 21, 2009 (54) GENERATION OF PHOSPHORUS (86) PCT No.: PCT/IN2006/000151 OXYCHLORIDE AS BY-PRODUCT FROM PHOSPHORUS PENTACHLORIDE AND DMF § 371 (OX1), AND ITS USE FOR CHLORINATION (2), (4) Date/1 Dec- 31, 2007 REACTION BY CONVERTING INTO (30) Foreign Application Priority Data VILSMEIER-HAACK REAGENT May 4, 2005 (IN) ......................... .. 545/MUM/2005 (75) Inventors: Rakesh Ratnam, Maharashtra (IN); Publication Classi?cation Aurora Sundeep, Maharashtra (51) Int Cl SE1); M‘illzamgifd M0?zuddm’ C07H 1/00 (2006.01) “as ra( ) 0070251/30 (2006.01) C d Add (52) US. Cl. ....................................... .. 536/124; 564/278 orrespon ence ress: THENATHLAWGROUP (57) ABSTRACT 112 south West street A process is described Wherein after formation of ?rst crop of AleXandria, VA 22314 (Us) Vilsmeier-Haack reagent by reacting Phosphorus Pentachlo ride With N,N-dimethylformamide to form a ?rst crop of 73 A - ; PHARMEDMEDICARE Vilsmeier rea g ent as insoluble c rY stals ’ a b YP- roduct of this ( ) sslgnee PRIVATE LIMITED Mumbai reaction, the Phosphorus Oxy-Chloride, reacts With N,N (IN) ’ dimethylformamide to give a second crop of Vilsmeier reagent. This second crop of Vilsmeier reagent is soluble in DMF. This process makes it possible to double the yield of (21) APP1- N04 11/919,826 chlorinated substrate, such as sucrose-6-acetate or sucrose-6 benZoate, from the same quantity of Phosphorus Pentachlo (22) PCT Filed: Apr. 28, 2006 ride : Mechanism of Combined Vilsmeier Reagent for the Chlorination of sugars. ICI /\ / 0 + Cl Cl ZR'OH 2R-Cl +2 OH_ Cl / PT Cl_ Cl R = Sucrose W H, Cl Pcls' POCl3-VMR Patent Application Publication May 21, 2009 US 2009/0131653 A1 Fig 1: Mechanism of Combined Vilsmeier Reagent for the Chlorination of sugars. Cl- Cl R = Sucrose US 2009/0131653 A1 May 21, 2009 GENERATION OF PHOSPHORUS below 200 C., and then heating the reaction mixture for a OXYCHLORIDE AS BY-PRODUCT FROM period of time to 600 C. accompanied by removal of HCl gas PHOSPHORUS PENTACHLORIDE AND DMF by bubbling nitrogen through the reaction mixture and then at AND ITS USE FOR CHLORINATION 120 degrees for a period of time. REACTION BY CONVERTING INTO [0009] The Vilsmeier chlorination is preferably Worked up VILSMEIER-HAACK REAGENT by neutralisation and hydrolysis With an alcohol/base mix ture, e.g. methanolic ammonium hydroxide (2:1 by Weight). TECHNICAL FIELD [0010] The general formula of Vilsmeier reagent, irrespec tive of source of chlorinating reagent used, remained same as [0001] The present invention relates to a process and a described by Mufti et al i.e. an N,N-dialkyl-(chlorometha novel strategy for synthesis of Vilsmeier-Haack reagent and niminium) chloride of the general formula: chlorination of sucrose or their derivatives for production of chlorinated compounds including sucrose, 1'-6'-Dichloro-1' 6'-DIDEOXY-[3-Fructo?.1ranasyl-4-chloro-4-deoxy-galacto Where R represents an alkyl group, typically a methyl or ethyl pyranoside using said Vilsmeier-Haack reagent. group, and X represents a hydrogen atom or a methyl group. [0011] Mufti et al further pointed out that, reagents of this BACKGROUND OF THE INVENTION type are prepared by reaction of an inorganic acid chloride [0002] Strategies of prior art methods of production of4, 1', With an N,N-dialkylformamide or N,N-dialkylacetamide. 6' trichlorogalactosucrose predominantly involve use of Vils The inorganic acid chloride may typically be phosphorous meier-Haack reagent (Vilsmeier reagent) to chlorinate pentachloride, phosgene, or thionyl chloride. Sucrose-6-ester, mainly Sucrose-6-acetate to form 6 acetyl [0012] Importance of Vilsmeier reagent lies in the fact that 4,1', 6'trichlorogalactosucrose (TGS-6-acetate) or corre surprisingly this reagent Will safely chlorinate in the 4',1'- and sponding chlorinated derivative, Which is deacetylated in the 6'-positions of a sucrose molecule although this class of reaction mixture itself to form 4,1', 6' trichlorogalactosucrose acidic reagent is knoWn for its speci?city as a chlorinator of (TGS). more active primary hydroxy compounds. [0003] When V1lsmeier-Haack reagent is produced from [0013] Rathbone et al (1986) in US. Pat. No. 4,617,269, PCIS, as described by Mufti et al (1983) in US. Pat. No. Walkup et al (1990) in US. Pat. No. 4,980,463, also described 4,380,476, upon reaction of PC15 With the appropriate tertiary use of Vilsmeier reagent formed from Phosphorus pentachlo amide, the Vilsmeier reagent is produced in the form of crys ride in the same Way as described by Mufti et al. tals insoluble in the reaction mixture Which is isolated in solid [0014] Thus all the prior art references limit the use of PC15 form by ?ltration, Washed tWice With DMF, and tWice With to generate and use the Vilsmeier reagent as DMF insoluble diethyl ether and used as chlorinating agent. solid crystal form. [0004] It Was found, surprisingly, hoWever, that if this POCl3 generated as a byproduct in the course of reaction is SUMMARY OF INVENTION not removed from the reaction mixture, POCl3 further reacts [0015] Present invention embodies formation of tWo crops With the tertiary amide, such as N,N-dimethylformamide, of Vilsmeier-Haack reagent from PCIS. First crop is obtained available in the reaction mixture, generating a second POCl3 When PCl5 is dissolved in dimethylformamide (DMF) and type Vilsmeier-Haack reagent Which is soluble, and does not crystals of Vilsmeier reagent formed precipitate out as a ?rst precipitate out as other types of Vilsmeier-Haack reagents. crop of the reagent. One by-product of this reaction is POCl3, [0005] This ?nding opened up a Way for developing Which, if not removed from the reaction mixture, starts react improved chlorination method involving Vilsmeier reagent ing With the excess DMF to form a second crop of Vilsmeier formed from using PCIS, Which is the subject matter of this reagent accompanied by and indicated by development of a speci?cation. orange to red color. This second crop of Vilsmeier reagent, hoWever, does not precipitate out as crystals, it remains in PRIOR ART dissolved condition and is as much effective in chlorination [0006] Jenner et al (1982) US. Pat. No. 4,362,869, have reactions as any otherVilsmeier reagent developed from PCl5 used thionyl chloride for preparation of Vilsmeier reagent or other chlorinating reagents. [0007] Mufti et al (1983) claimed and described use of [0016] In a further embodiment of this invention, it is pos Vilsmeier reagent for chlorinating sucrose monoesters. They sible to separate the tWo crops ofVilsmeier reagent obtainable used Vilsmeier reagent to about 7 to 15 molar equivalents per from PCIS. It has also been found that it is also possible to use mole of sucrose monoester. An amount of about 33 moles per the second crop of Vilsmeier reagent developed from POCl3 mole of monoester Was considered as optimal. It Was pointed independent from the ?rst crop and use it alone or in combi out that it is important that Water is prevented from contacting nation With Vilsmeier reagent developed from a chlorinating the reagent, Which Was achieved by drying the monoester reagent other than PCIS. solution and ?tting the reaction vessel With a drying tube. [0017] In another embodiment of this invention When both Vilsmeier reagent Was prepared by Mufti et al by reacting the crops of Vilsmeier reagent Were alloWed to be formed DMF With PCl5 accompanied by vigorous stirring While the successively in the same reaction mixture, yield of chlori temperature Was maintained beloW 50.degree. C. The reac nated substrate available from same quantity of PC15 doubled tion mixture Was stirred at 0.degree. for 1 h and the resulting than the prior art methods Wherein the solid crystals of the crystals Were ?ltered off, Washed With DMF (2.times), then ?rst crop are separated and used for chlorination. The pro With diethyl ether and dried under vacuum overnight. jected mechanisms of the reactions involved is elucidated in [0008] Chlorination reaction involved addition of DMF to FIG. 1. the crystals of Vilsmeier reagent and adding to them sucrose [0018] In yet another embodiment of this invention, the mono-acetate solution sloWly, maintaining temperature combined Vilsmeier reagent or Vilsmeier reagent formed US 2009/0131653 A1 May 21, 2009 from the second crop can be combined With Vilsmeier reagent [0026] The possible mechanism of the reactions involved in formed from any other acid chloride and such combinations the formation of combined Vilsmeier reagent from PCl5 is are also equally effective in performing the chlorination reac elucidated in FIG. 1. tion. [0027] Total amount of 6-O-acylsucrose Which could be thus chlorinated from same amount of PC15 Was double than BRIEF DESCRIPTION OF DRAWINGS previously used methods in Which by-product POCl3 is removed from the reaction mixture after it is formed. This [0019] FIG. 1: Describes projections on mechanism of gives a neW and more ef?cient Way of using PCl5 to chlorinate reactions involved in formation of tWin Vilsmeier reagent sucrose, its derivatives and for analogous chlorination reac from PCl5. tions through the synthesis and application of Vilsmeier Haack reagent Without removal of the POCl3 generated in DETAILED DESCRIPTION OF THE INVENTION situ. This is a ?rst instance Where for chlorination reaction of sugar or its derivatives is driven by using a combined Vils [0020] The Vilsmeier-Haack reaction is Widely used for meier-Haack reagent. Combined V1lsmeier-Haack Reagent, formylations. It can be applied to introduce an aldehyde Which may ?nd use in chlorinating analogous and other group on activated aromatic compounds, but many other con organic molecules too, and all such reactions are embodi versions can be achieved With this technology.