CA1052786A - 6-methyl-2h-1,3-oxazin-2,4(3h)-dione-2-sulfohalides, process for preparing them and their transformation into sweeteners - Google Patents

Abstract

Abstract of the disclosure:
3-Sulfohalides of 6-methyl-2H-1,3-oxazin-2,4(3H)-dione of the formula I

Description

~jr~ ~ F 202 K
~)5'~71~;

This invention relates to 3-~ulfohalldes of 6-methyl=2H-oxazin-2,4(3H)-dlone of the for~nula I

Q ~C~
HC o " 50=C C=0 in which X repre3ents ~lubrine or chlorine.
: Compounds of the followj.ng formula II
. 10 CH3 ,,, C\ 1 H ~ II
O=C C=O
; \N/
`~! . R
~ ' ..
~ in which R represents an unsubstituted or ~ubstituted alkyl.~ or aryl group are known. Compound~ of this type are obtained by reacting corre~ponding isocyanate3 with diketene in an : 20 inert solvent; for example toluene in the presence of an acid cataIys~ at a temperature in ~he range of from 110 to 115Co ~A reaction time of several hours i3 required (cf~ Japanese Specifications 69112,735, 70/~1,663 and 70/37,018 Derwent Report).
It ha~ al~o been propo~ed to transform 3--sub~tituted

2-alkyl- or 2-aryl~imino-6-methyl-2H-1,3-oxazin 4(3H)-one, prepared from ~ymmetrical S methyl-isothioureas and diketene in boil~ng ben~ene, by hea~ing wi-th aqueou~ hydrochloric acid 29 into compo~nd~ o~ formula II (c~. J. Chem. Soc. (1954) page~ys - 2 ~ ~

HOE 74~F 202 K

` ~S~7~36 Tetrahydron Letters 1966, page 3231).
` Oxazin-diones, for example 3-phenyl-5,6-benzodihydro-1,3-i~ oxazin-2,4-dione (T.Kato, Kagaku No Rijoiki, Zokan 1970, 92 (Pt.2), 203, Japanese) or 6-methyl-2,3-dihydro-1,3-oxazin-~ .
2,4-dione (V.I. Gunar et al., Izv. Akad. Nauk.S.S.S.R., Ser.

' Khim,(1965) page 1076), are known stable compounds.
::
' 3-Alkyl-substituted compounds of formula II can also be prepared'by reacting alkyl-carbamic acid morpholides with di- `
ketene in boiling glacial acetic acid (Khim. Geterots.Soedin, (1967) page 48) or by treating N-acetoacetyl-carbamic acid esters with concentrated sulfuric acid or boiling trifluoro-acetic acid (Tetrahydron letters 1966, page 3231).
,: . .
It is further known to prepare compounds of formula II from corresponding substituted 1,3-dioxin-4-ones and alkyl or aryl iso-cyanates which may be substituted, at a temperature of .~ q from 80 to 200C, optionally in the presenceof an inert solvent (cf. German Offenlegungsschrift 2,005,118).
The aforesaid processes are, however, unsuitable for the synthesis of the novel compounds of formula I. The diketene-isocyanate method as well as the dioxinone-isocyanate method - cannot be used because of the high reaction temperatures, since the c~mpounds carrying a halogenosulfonyl substituent at the ' nitrogen atom of the ring are thermally little stable and ; decompose vividly at temperatures below 100C. On the other hand, the compounds are very sensitive to solvolysis so that '~- the-methods carried out in aqueous acid solutions or glacial ,;' acetic ac'id cannot be used'either.
It is therefore a further object of the present invention to provide a process for the manufacture of a compound of i' .

., .

;'.'. . ' ' ,, ,' ' ' , ' ~ '' ~, ' ' ' ~ ' ' `

', ,, ,: ' ' ~i ; HO~ 74/F 202 K

. ~05;~7~6 formula Il which comprises reacting at a temperature in the range of from -35 to +70~C, preferably in the presence of an inert solvent, fluorosulfonyl isocyanate (hereinafter de-signated FSI) or chlorosulfonyl isocyanate (hereinafter de-; 5 signated CSI) with diketene, acetoacetyl fluoride, acetoacetyl : chloride, acetoacetic acid, or an isopropenyl ester of the formula CH2C(OOCR)-CH3 (III) in which R represents an alkyl radical having from 1 to 4 carbon atoms, or an optionally sub-stituted phenyl or benzyl radical.
Owing to the fact that the ester group of the compounds of formula III is eliminated during the course of the reaction the nature of R is of minor importance. ~ompounds in which R
stands for CH3 are preferred. The reaction temperature varies in accordance with the reaction components used, in general it is in the range of from -10 to +60C, preferably 0 to 45C.
To carry out the process of the invention one of the reaction components is first introduced into the reaction vessel and the other one is added at the reaction temperature while stirring or both reaction components are introduced into the reaction vessel, preferably at the same rate.
Especially good results are obtained with the use of an inert solvent or diluent as reaction medium and/or as solvent ; for the reaction componentts).

Suitable solven~s or diluents are, for example, aliphatic or aromatic hydrocarbons such as pentane, hexane, cyclohexane, ~ gasoline, petroleum ether, benzene, toluene, xylene; or halo-hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; ethers such as diethyl ether, di-isopropyl ether, dimethoxyethane, tetra-hydrofurane, dioxane; or nitriles such HOE_74~ 202 K

5,'~,7,~,6 as acetonitrile or propionitrile, or mixtures of the aforesaid ; solvents, and SO2. Preferred solvents are methylene chloride, chloroforme, and c,arbon tetrachloride. With the use of the latter solvent the reaction product separates as the heavier phase and can be freed of the major portion of the solvent by . simple decantation. Inert solvents the boiling point of which is within the desired temperature range are preferred.
` The amount of inert solvent used is not critical and depends on the practical requirements in each case. In general, -, 10 the solvent is used in an about 1 to 20 fold excess, calculated ` on the amount of reaction components. Smaller or larger amounts are likewise possible, the upper limit being determined by economical reasons.
The progress of the reaction can be readily controlled by IR spectroscopic analysis by the disappearance of the charac-teristic isocyanate band of the FSI or CSI at 4.4~u and of the diketene bands at 5.2 and 5.3/u and by the formation of three characteristic bands of the compound of formula I at 5.6, 5.8 and 6.03/u.
To obtaln the reaction product the solvent is distilled off under reduced pressure or separated by decantation from the precipitated mostly crystallin crude product. The reaction product may be further purified according to known methods, for example recrystalliæation.
More particularly, the reaction according to the in-~~ vention proceeds as follows:
1) with the use of diketene preferably at a temperature of from -10 to +60C, more preferably +20 to +55C
according to the following reaction scheme:

; :

, , .: . - , . . . , : . : . : . . :::

~OE 74~F 202 K

~- ~o5~7~36 ~ \ N --~ H ~ \O
(~ ~ 2 + \SO2X O=C~ /C=O

.,.. ,, . I
,-` S02X
, ' .
, .
,~ , .
.-.
.,.~ ~ .
with approximately equimolecular amounts or optionally a ;, small excess of up to 10% of one of the reaction components;

'~, 10 2) with the use of acetoacetyl chloride, which is preferable ,:, . .
;. prepared fro-mdiketene by reacting it with hydrogen chloride - (cf. J.Am.Chem.Soc. volume 62 (1940), page 1548 or German ~- Offenlegungsschrift 1,931,964), preferably at a t~mperature ~' o from -20 to ~60C, more preferably -10 to + 30C according to the following reaction scheme :

! ~ C~ C33 o=C SO2X = \ / ~ + HCl with approximately equimolecular amounts or optionally a~small excess of one Qf the reaction components as sub 1).
The same applies to the use of acetoacetyl fluoride;
l 3) with ~ use of acetoacetic acid preferably at a temperature :~ 25 of from -35 to +40C, more preferably -20 to +20C according {_ to the foIlowing reaction scheme ' ',11 ' ,' ', : .
!1~ :
f ; - 6 - . .:

~, .. ..
.~ ' ' .

. HOE 74/F 202 K

~ ICH3 105,Z786 O C \ 5O2X L 3 2 .. , ~ .

H2O + C=N-S2 F ~~~~ C2 + H N-SO F

Owing to the fact that the water formed in the conden-~,- sation reacts with a second molecule FSI or CSI two moles of FSI or CSI are preferred or a slight excess of up to 10% per mole of acetoacetic acid. The CO2 formed may serve to control the reaction;
.: .
(4) with the use of isopropenyl esters preferably at a temperature of from -30 to +40C, more preferably -20 to +20C according to the following reaction scheme H3 o ~! ~ H2C ~ O IC~_R SO
1 \
; 20 O ~ ~ ICH3 + RCONHSO2F

\So2X O=C\ / C=O

, : fH3 ,~

1 . ~ ~ / ; :
;1 : O=C O i '' i ~H \ SO2X

Z . ,:, ~

. . HOE_ ~ K
~35'~86 The lat-ter reaction can thu~ be carried out in one or two . stages, for example with R being CH3 as follows:
a) from isopropenyl acetate and 1 mole FSI or CSI there is obtained, at a reaction temperature of from -~0 to +20C~
preferably 30 to ~10C, besides compound I~ ~acetoxy-crotonic acid amide~N sulfo~halide which can be isolated;
b) from R-acetoxy-crotonic acid amide-N-sulfohallde there is ` obtained wlth a ~u.rther mole ~SI or CST, pre~erably at .
:~ a slightly elevated temperature o~ up to ~30C, the desired compound I besides acetamide-N~sulfohalide.
. This reaction ls, however, preferably carried out in one .. stage without isolation of intermedia-te products, preferably at a temperature of from -20 to +30C, more preferably -10 to : -~20C with 2 mo1.e~ FSI or CSI per mole of isopropenyl ester or ~ 15 a slight excess of one of the former compounds of up to 10 %.
-' The s~aringly soluble acetamide-N-sul~ohalide can be ~irst ~eparated in crystal form and then the deslred compound I is obtained, for example by concentration of the solvent or addltion of CCl4, which may be further purified by known methods, for example by recrystallization.
A~ Although the reaction mechanism of the process of the nvention is not yet clarified in detail ~t can be assumed that the reactions 1 - 4 listed above take place according tp .
the same principle9 so that reactions 1 - 3 also proceed via :~
the enol grouping as in the case of reaction 4 and ~ormally .
the following reaction scheme is valid for all 4 reactions: . .
~, . .

i.,.,,.. , ,. ,. . ,. ,.. , . , , ; , . , :

,.. . , ., , ! ~ ' : : .',! ' ~. ;` ' ~ ' ' ' :
HO~ 74/F 202 K

, ~

H3 ~ O~ H

~: H~ ~ OR~ > Hl IO
.. ' '\S02X O=C C=O + RlR2 SO X

in which for reactions 2 and 3: Rl ls hydrogen and R2 is chlorine or hydroxy, l for reaction 1: Rl-R2 is a direct linkage and .( 10 for reaction 4: Rl is -fi-R and R2 is -NHSO2X
~, O
~ Intermediate stages which can be assumed in this formal . ., -. reaction scheme could not be isolated so far.
"~. In contradistinction to the aforesaid 3-alkyl- and .. 15 3-aryl-substituted 6-methyl-2H-1,3-oxazin-2,4(3H)-diones or the methyl compound of formula II unsubstituted in 3-position (R = H), the novel compounds of formula I are very sensitive compounds which start to decompose above their melting point at a temperature below 100Ca Moreover, they are very sensitive ' 20 to hydrolysis, above all the 3-chlorosulfonyl compound which ~ is readily hydrolized to the 6-methyl-2H-1,3-oxa~in-2,4-(3H) done (compound of formula II with R = H), while compound I :~
1 with X = fluorine yields with water acetoacetamide-N-sulfo-.~ fluoride.
:~ 25 It has been found that under the action of water the ring j- of 6-methyl-2,3-dihydro-1,3-oxazin-2,4-dione-3-sulfofluoride of .
formula IV is opened with splitting off o~ CO2 whereby aceto-;l I acetamide-N-sulfofluoride V is obtained which can be trans-- formed into 6-me*hyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-di-. i, .

_ g _ ~ .
, `:
~ ?, ~ ~ 20~ K
5'~,,7~,6 .i..~
. oxide a known ~weetener according to the following reaction ~` scheme:

so r 502F
, :i ~IV) (V) (~
`
The compounds of the invenJcion, especially the flu.orine deriva~ive of compound I are, therefore, sultable as inter-mediate product~, for the manufacture of 6~methyl-3~4-dihydro-,.
1,2,3--oxath~azin--4~one-292-dioxide and . i-ts nontoxic salts - which are d~stinguishZ--d by a very sweet taste (cf. US Patent ~; 3,6899486~. These compo~nds can be prepared ~rom compound. I .: :
by a treetment with aqueous alkali in one stage. From the chloros~ulfonyl derivative there can bZZ~ obtained the kno~m '. 6-rnethyl-2~-1,3-oxazin-2,4(3H~dione ~compound IIt R = H) and . other N-sub~t~tuted derivatives. By a reaction with NH3 or am.ines the compounds of the invention yield known uraci1cs having a herbicldal effect (c~. US Pate~ts3,235,360; 3,235,361;

3,235,362 and GZZ~rman Pa-tent 1,Z40,3698) It is, therefore~ a fur~her ob~ect of the present invention to provide a process for the manufacture of 6-methyl-3,4-di-: hydroZ-192,~3-oxathiazin-4-one 2,2-dioxide and it~ nontoxic salts9 ,: 25 whlch comprises rcacting 6~methyl-2,3-dihydro-1,3 oxazln-2,4-!~ dione-3-sulfofluor~de of the formula IV

~. ~
' 29 .
.~

-~ HOE 74~F 202 K
:
1~)5'~786 :; .
; ~CH3 HC = C
O=C O
`h~co (lV) . SO2F
:~ 5 -- with at least one mole water per mole of compound IV to obtainacetoacetamide-N~sulfo~luoride of formula V and C02 and treating the acetoacetamide~N-~ulfofluoride V with an aqueous and/or alcoholic base to obtain 6-methyl~3,4-dihydro-1,2,3-oxa-~'~,.! 10 thiazine~4-one-2,2-dioxide IV and the salts thereof.
Owing to the fact that the compound of formula IV is only ~ery sparlngly soluble in water, the ring opening is preferably carr~ed out in the pre~ence of a dissolving intermediary9 for example inert solvents t~at are wholly or partially miscible w~th water wuch as a cohols, for example methanol, ethanol~ or isopropanol; ketones 9 for example acetone or butanone~ ethers, ;' for example dimethoxy-ethane, dioxane~ or tetrahydrofurane.
~ Solvents which are immi3cible or little misclble with water *~ only can also be used a~ a disperqion in water, for example chlorohydrocarbonsg esters such as ethyl acetate~ ethers such as diethyl ether, di-isopropyl ether or hydrocarbons having more than 4 carbon atoms.
To open the ring or bring about decarboxylation o~ com- -~: :
?1 pound IV 1 mole water is required per mole of compound IV.
~ 25 It pro~ed advanta~eou~, however~ above all for lncreasing the - reaction sp~ed, to use a higher amount of water than stoichiome-trically required, for example up to 20 moles or more, preferab-ly 2 to 10 mole~, the upper limit being determined by the ~act 29 that a sufficient soLubility o~ compound IV ln the solvent .~ , HOE ~
1~5'~7~6 ~ diluted with water is ensured. With the use of solventqi little :: .
miscible with water, which are uaed in the form of disperiions in water, this condition is generally complied with and, there-fore, in this case the upper limit for the amount of water used is essentially determined by -technical considerations, in the fir~t glace recovery of compounds V or VI from the water used. Hence, an amount of about 1 liter of water per mole of compound I~ will generally not be exceeded.
- The decarboxylation according to -the above scheme ii8 ;i~ 10 preferably carried out at a temperature of from O to ~60C, !.~ more preferably 10 to 30C.
Compounid ~ obtained in this manner can be transformed into the sweetener of formula VI or the isialts thereof by a treatment with baseisi, for example as descrlbed in the cited US Patent.
l 15 The cyclization can be effected in an especially simple - manner by 1) mixing aqueous solutions of the acetoacetamide-N-siulfo-fluoride obtalned as intermediate with aqueous , j solutions, dispersions or suspensions o~ the bases u~ed or 2) mixing a solution of the acetoac~tamide-N-sulfofluoride in an organic solvent, for example methanol, ethanol, isopropanol, acetone~ dimethoxyethane, or tetrahydro-furane~ with a siolution of the base used in an alcohol, for example methanol, ethanol, or isopropanol or a mixture thereof with water.
Owing to the fact that the salts of the oxathiazinone obtained with inorganlc catlons~ above all the alkali metal 29 salts, and ~ore especially the potasslum salt of 6-methyl-~,4 di-_ 12 -` ~~ HOE_ 74/F 202 K
S'~
hydro 1 9 2,3-oxa-thiazin-4-one-2,2-dioxide) are sparingly ~ soluble in alcohols, the cyclization to the oxathlazinone can `j be effected in an especially simple and advantageous manner in - an alcohol; for example methanol, ethanol or isopropanol, or in mixtures -thereof containing less than 50 % by weight, pre-ferably less than 20 % by weight of water, with the addition of bases, The oxathiazinone salt of an inorganic base can be isolated practically quantitatively. From the salt the free oxathiazinone can be prepared in known manner without diffi-culty. It is particularly advantageous to add methanolic potassium hydroxide, potassium methylate, or potassium carbonate solution to a solu-tion of the crude acetoacetamide-N~sulfo-fluoride in methanol. The potassium salt of 6-methyl-~,4-di-hydro-1,2,3-oxathiazin-4~one-2,2-dioxide separates in the form of crystals and can be filtered off with suction whereas the potassium fluor~de ~ormed es~entially remains in solution so that it can be readily separated ~rom the oxathiazine deri-j:
vative. The ring formation in methanolic solution is, there-fore, a preferred embodiment since -the oxathiazinone obtained is substantially free from ~luoride, which is of extreme importance when the compound is used a~ sweetener.
Suitable bases ~or the cyclization are; ~or example, hydroxides, acid and neutral carbonates o~ alkali metals, alkali metal alcoholates, calcium hydroxide and oxide, barium hydroxide and oxide, ammonia, amines such as methyl amine, ethyl amine, dimethyl amine, diethyl amine, trimethyl amine, triethyl amine, and the like, potassium hydroxide, potassium methylate ancl potassium carbonate being preferred.

~ _~ HOE ~ F 202 K

- The cyclization is suitably carried out at a temperature of from 5 to 85C~ the optimum -ternperature depending in each case on the type of the base used. With a weak base, for r~', example NaHCO39 in wa-ter the reaction mixture mus-t be heated to 40 - 85C, while with a strong base such as methanolic alkali metal hydroxide solution the ring closes at a temperature of ~rom 5 to 50C.
It is not necessary to perform the two stages, i.e. ring ..
opening or decarboxylation of compound IV and cyclization of ., compound V separately. It proved ad~antageou~ directly to add compound IV to an aqueous or water-containing solution or dis-, ~
persion of one of the aforesaid bases and to obtain in this ~" manner the salts of the oxathiazinone dioxide VI used as sweetener. Wh~n the two stages are combined, the two reactions take place at a temperature of about O to 85C. In this range . ,., .the acetoacetamide-N-sulfofluoride formed as intermediate i~
not subject to secondary reactions with water or alcohols but directly react~ further with the base to the oxathiazinone dioxide VI.
For further purification, if any, the crude potassium salt ~:- .
of the oxathiazinone can be recrystallized from boiling water~
optionally with addition of charcoal and filtering aids and obtained ln a pure state. An addition o~ calclum hydroxide promotes the separation of traces of fluoride a~ 1nsoluble CaF2, which can be readily separated from the solution.
A contro:L of purity of the 6-methyl-3,4-dihydro-1,2,3-oxa-thiazin-4-one-2~2-dioxide and of lt~ saltq is possible by imple W measurement in dilute solu-tion as the product shows a high absorption maximum at 225 - 228 nm with ~- about 1~ 104.

:~ ' , ~~ HOE_~ F 202 K
' ~)5Z7i~6 ..
~, The following examples illustrate the invention.
i?~j. E X A M P L E 1:
6-Methyl-2H-1t3-oxazin-2,4-(~H ~ -~ul_o uoride 42 g diketene (0~5 mole) were added dropwise while stlr-~ 5 ring to a solution of 40 - 60 C of 62.5 g (0.5 ~lole) ~SI
', in 100 ml CC14~ After the addition of about 10 ml diketene an exother~al r~action started, the reaction mixture acqulred a dark co]or and a heavy ~econd phase was formed. After sub- j siding of the reaction, stirring was continued for a further ? 10 20 minutes at 60 C and the mixture was allowed to cool. The lower dark pha~e solidified in the form of crystal~ so that the upper phase of CC14 could be decanted. After recrystal-`- lizatlon of the crystal magma from propylene chloride 68 g of slightly colored crystals o~ 6-methyl-ZH-1,3-oxazin-2,4-(3H~-dione-3-sulfofluoride melting at 80 - 83 C were obtained.
Yield 65% of theory.
Analysiss C5~4FNO5S m.w. 209.2 calc.s C 28.7% H 1.9~ E 9,1% N 6.7~ S 15.3%
ZO foundt C 29.0% H 2.0% F 9r4~ N 6.8% S 15.4 molecular weight (mas 8 jspect~um)s 209 IR (KBr): 5.5 5.7 5.94 6.8 7.5 8.1 8.35/u ' lH-NMR(CD3CN): d = 2.2 (d, J = 1 Hz) and 6.o ppm (q, J = 1 Hz) E X A M P L E 2s ~rom two separate dropping funnelq 6245 g (0.5 mole) ~SI
and 42 g (0.5 mole) diketene were added simultaneously to 100 ml CHC13 boiling with reflux at a rate that equimole~ular 29 amounts wer~ added per unit o~ tlme. The solution remained : -' ~ ,, . ': . . . , : ' "I ~ ` ` ' . ~ . ~ " ` : `
.:
' ' ' '` ~ ~
` . : ' : ,, ; ` : :

` ~'~ ~OE 74~F 202 K
.:~
OSZ7~36 :; homogeneous and boiled by itself owing to the reaction hcat.
~;, After evapor~tion of the ~olvent, the residue remaining be-hind was worked up as described in Example 1. Properties, ..: .
~ analysis and spectra of the product were the same a3 in Ex-. ~ . .
,r. ~ 5 ample 1.
, Yield 62~ of theory.
The .same rssult was obtaincd with methylene chloride as solvent . :~
~- E X A M P L E ~ s :" 10 6-Methvl-2H-1,3-oxazin-?,4-(~H~dione-3-sulfochloride. :
~; 42 g (0.5 mole) diketene were added dropw~ ~ to a 901u-r: tion boiling with reflux of 71 g (0.5 mole) CSI at a rate su~h ~.
that the solutlon con~inusd to boil. After subsiding of the ~ -reaotion, th~ mixture was reflux~d for a further 20 minute~
and th~ solvent was e~ap~rated. A black sirupy mass waC ob tained from which 68.8 g colorleq~ crystalline 6-methyl-2H-193-oxazin-2,4-(3H)-dione-3 sulfvchloride melting at 85 C
were obtained by extraction with diethyl cther or propyl chloride.
Yleld 61~ of theory.
Analysiss C5H4ClN05Sm.w. 225.6 calo.sC Z6.6% H 1.8~ Cl 15.7%
~oundsC Z6.8~ H 1.8~ Cl 15.5 Z5 IR(K~r): 5-5 5.7 5.9Z 6.95 7,5 8.3/u H-NMR(CD CN): ~= 2.2 ~d7 J = 1 Hz) and 6.o ppm (q, J = 1H

... . .

~ IIOE ~4/~ 202 K
:,....... . . . . _ .. ..
L05~71516 .. `.;
~ E X A M P L Æ 4:
,. ~.
6-Methyl-2H~ xazin-Z,4~(~H)-dione-3-sul~ofluoride from di-ketene and HCl in CHCl3 ~` 36.5 g hydrogen chloride (1.0 mole) were introduced over a period o~ 2 hours, while stirring at -20 C, into a 501u-.; ~
; tion of 84 g (1.0 mole) distilled diketene in 400 ml dry chloro-.
form. Stirring was continusd for a further 30 minute~ and ., .
~-~ then 80 ml ~SI (1.0 mole~ were added dropwise over a period :., oof 30 minute~ at -20 to -5 C. The reaction mixture was allow-ed to stand for 1 hour at 0 C, the solvent was di~tilled off ... .
under reducad pressure and the yellow oil obtained wa~ taken up in isopropyl ether. 74 g of colorless crystal~ of 6-methyl-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfofluoride separated, ~ After recrystallization from propyl chloride, the product r;^' 15 melted at 85 - 86C.
, Yield 35% of theory.
'rhe properties, analysiq and spectra were identical with those o~ the product of Example 1.
E X A M P L E ~:
_ . ~ .. .

6-Me_hyl-2H-1,3-oxazin- ~ -;::
~ ketene and HCl ~acetoacetic acid chlori ~ in C~1 i ether Under the conditions of Example 4 acetoaoetyl chloride `-was prepared from 84 g diketene (1.0 mole) and 36.5 g hydro-gen chloride (1.0 mole) in 100 ml dry methylene chloride and iqolated by substantially distilling off the methylene chloride at -20 C u~der reduced pressure. The reaction product was -~ taken up in 300 ml isopropyl ether while coollng and at -20 C
29 80 ml FSI ~1.0 mole) wQre added dropwise. The reaction mix-. .. ~ .
,: ..

~,~ HOE 74/F 202 K

1~)5~7~16 , ture was allowed to stand overnight at -20~C whereupon the separated colorless crystals of 6-methyl-2H-1,3-oxazin-2,4-- (3H)-dione-3-sulfofluoride melting at 85 - 86C were filtered off with suction.
., Yield 42~ of theory.

The properties, analysis and spectra were identical with those of the product of Example 1.

E X A M P L E 6:
.: . .
:. .
Under the conditions of Example 4 acetoacetyl chloride ` 10 was prepared at -20C by introducing 18.3 g (0.5 mole) gase-ous HCl into 42 g (o.5 mole diketene in 100 ml distilled CH2C12, 62.5 g (0.5 mole) FSI were added and the reaction mixture was abandoned for 24 hours at -20C and for 6 hours at room temperature. After evaporation of the solvent under reduced pressure, a residue solidifying in crystal form re-i mained behind, from which, after extraction with diethyl ether and recrystallization, 62 g of still yellowish crystals of 6-methyl-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfofluoride melting at 81 - 84C were obtained.
Yield 59~ of theory.
Analysis, properties and spectra were identical with those of the product of Exampl0 1.
; E X A M P L E 7-To prepare acetoacetyl chloride 18.3 g (0.5 mole gaseous HCl were introduced over a period of 3 hours at -30C into a solution of 42 g (0.5 mole)-diketene in 150 ml distilled CHC13. 62.5 g (0.5 mole) FSI were added dropwise while rais-ing the temperature slowly to the boiling point of CHC13 by external heating and the mixture was kept at said temperature ';~`7" ~ HOE ~
5~ 6 , ."
l for 20 minutss. After evaporation of the solvent under re-:
duced pressure, a dark oil was obtained from which 66 g i yellow-bro~n cry~tals of 6-methyl-2H-1,3-oxazin-2,4(3H)-dione-3-~ulfofluoride separated on stirring with di-isopropyl ether.
`~ 5 The cry~tals recrystallized from propyl chloride melted at 82 - 86 C.
Yield 63~ of theory.
~ Analysls, propertiss and spectra were identical with ; those of the product of Example 1.
~;
~',` 10 E X A M P L E 8:
18.3-~0.5 mole) ga6sous HCl were introduced ovar a period of 3 hours at -30 C into a solution of 42 g (0,5 mole) dikete-, ne in 150 ml liquid S02. After addition of 62.5 g (0.5 mole) ~SI the ~olution was refluxed for 25 hours ~-5 to -8 C) D The oily residue obtained after evaporation of the S02 crystalliz-ed on stirring with di-isopropyl e~her and 44 g of colorl~ss crystals of 6-methyl-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfo-~luoride melting at 85 - ~6 a wers obtained.
~;
Yisld 42% of theory.
Analysis, propertles and spectra were identical wlth those of the product of E~ample 1.
E X A M P L E ~s 18.3 g (005 mole) gaseous HCl were introduced ov~r a ¢~ period of 30 minutes at -20 C into a solution of 42 g ~0.5 mole) diketone in 250 ml CCl4~ Immediately therea~ter, 62.5 g (0.5 mole) ~SI wer~ added and the temperature of the mixture was allowsd to ~ise to room temperature while stirring. Dur-ing the course of 5 to 6 hours a heavy phase formed which par~
~.
2~ tially crystallized on standingn A~ter decantation of the 1 9 _ ,: : . ' ',': ' ' :' ' ~
. .
. : , ': ~ . ' ~ ~ HOE 74/F 202 K

' ~[)5~7~
supernatant solvent the residue was treated with di-isopropyl ; ether. 60 g of yellowish crystals of 6-methyl-2H-1,3-oxazin-2,4~(3H)-dione-3-sulfofluroide melting at 82 - 85C were ob-- tained.
Yield 57% of theory.
-- Analysis, properties and spectra were identical with those of the product of Example 1.
E X A M P L E 10:
6-Methy1-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfofluoride from ;` 10 crystalline acetoacetic acid ~ 2 moles FSI in CH Cl A solution cooled to 0C o 42.5 g (0.415 mole) aceto-acetic acid in 200 ml methylene chloride was added dropwise ~- over a period of 2 hours to a mixture likewise cooled to 0C
of 70.0 ml (0.87 mole) FSI and 50 ml dry methylene chloride.
~uring the reaction 7.8 1 CO2 were split off. The methylene chloride was distilled off under reduced pressure and the -remaining oil was rubbed with isopropyl ether. 64.0 g of colorless crystals of 6-methyl-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfofluoride melting at 84 - 86C were obtained.
Yield 74% of theory.
Properties, analysis and spectra were identical with those of the product of Example 1.
E~X A M P L E 11:
6-methyl-2H-1,3-oxazin-2,4-(3H?-dione-3-sulfochloride 18~3 g (0.5 mole) gaseous HC1 were introduced at -20~C in-to a solution of 42 g (0.5 mole) diketene in 100 ml CH2C12 and 70.8 g (0.5 mole) C~I were addedto the acetoacetyl chloride.
The solution was kept for 3 days at -20C to -30C, then for 3 days at 0C. After evaporation of the solven-t under reduced ',' . . . ~ . . . .. . . . .. ...

110E 711/P ?02 K

;~786 :, pressure a dark sirupy mass was obtained rrom which, by ex-traction with ether and recrystallization, 50 g of slightly yellowish crysftals of 6-methy:L-2H-1,3-oxazin-2,4-(3H)-dione-:-:
; 3-sulfochloride melting from 82 C onward could be obtained.
', 5 Yield 44~ of theory.
,,~, .
''!,''~ Properties, analysis ancl spectra were identical with those of the product of Example 3.
E X A_M P L E 12 ,., 6-Methyl-2H-1,~-oxazin-2~4-~ 3H)-dione~3 sul ochl lde A cold solution of 59 g (0.58 mole) crystalline aceto-`~ acetic acid in 200 ml methylene chloride was added dropwise at 0 C to a mi~ture o~ 102 rnl (1.17 rnoles) chlorosulfonyl iso-~; cyanate and 100 ml dry methylene chlorideO During the course - of 2 hours 0.5~ mole gaseous C02 escaped. The methylene i~
chloride was then distill~d off under reduced pressure and the - oily residue was rubbed with 500 ~l isopropyl ether whereby ';' ;~ it crystallizedO
95 g (0.42 mole) 6-methyl-2~-1,3-oxazin-2,4-(3H)-dio~le-3-sulfochloridc melting at 86 C (recrystallizad from propyl ; 20 ether) were obtained, correspond~ng to 72~ of the theory.
Analysis and spectra wer~ identical with those of the product of EKarnple 3.
E X A M P L E~
:`: -6-Methyl-2H-l~,~-oxazin-2~4~;~H)-dione-3-sulfofluori.de 125 g (1 rnole) FSI were added dropwise at -20 C to a so-lution o~ 120 g (0.2 rnole) lsopropenyl acetate in 200 g dl-lsopropyl etherO After standlng for 3 days at -20 C the cry-stallized 13-acetoxy-cro-tonic acid arnide-N-sulrorluoride ~as ~;
29 filtered off with suction and dried under reduced pressure.

- . : . " ,, .: ,, : : ,: , , : .
: ~ : :- :
.

~ llOE ~ 02 K
OS;~7~3~

12.5 g ~SI (0.1 mole) were added dropwise at 0C to a solution of 2205 g (0.1 mole) of the N-sulfochloride obtained in 50 ml anhydrous ethyl acetate. After 60 hours the solvent - was evapcratad and the crystalline residue was qtirred as ;~ 5 rapidly as possible with NaHC03 solution and ice and tho se-; parating crystals were filtered off with suction. They were .~
recrystallized from CHC13/CC14. 8 g 6~methyl-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfofluoride meltin~ form 75 C onward were obtained~ I
. . .
Yield 38% of theory.
Propert~e~, analysis and spectra were identical with . ...
tho~e of the product of Example 1.
E X ~ t 20 g (0.2 mole) isopropenyl acetate were added dropwise at 20 C to a solution of 50 g (0.4 mole) ~SI in 50 ml CHCl3.
; After 15 minu~es the solution was cooled to -10 C~ the acet-~` amide-N-sulfo~luoride crystallized out and was filtered off with suction. CC14 was then added to the filtrate until it ., became turbid and the ~i~ture was cooled to -20 C. By suction filtration 20 g of crystalline 6-methyl-2H-1,3-oxazin-2,4-(3H)-dione-3-sulfofluoride were isolated.
Yield 48~ Or theory.
Propertie~, analysis.and spectra were identical with tho~e of th~ product of Example 1.
` 25 E X A M P L E _15:
! 10 ml water were ad~d whlle stirring to a solution of 21.0 ~ (0.1 mole) 6-methyl-2,3~dihydro-1,3~oxa~in-2,4_dione_ 3-sulfofluoride ~lelting at 85 - 86 C in 40 ml dimethoxyethan~0 - 29 When the evolution of gas was terminated, the sol~ent was di-.

~ - ~2 -~ ~IOE_Z4~ 202 K
"
S;~86 - stillod off under reduced pr0ssuro, the residue was taken up in water and 50 ml 4N ~odlum hydroxide solution was added drop-wi~e at 20 - 30 C. The reactlon mixture was acidified with 15 -: :.
``` ml concentrated hydrochloric acid and extracted with ethyl ace--,.
i~ 5 ta-te. By distillation of the ethyl acetate 16.0 g of crystal-line 6~methyl-3,l~dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide melting at 117 - 120C wers obt~inod in the form of colorless ;'~ cr~stals. By treating the methanolic solution of the acid with mothanolic potassium hydroxide solution 18.1 g of pure po-~; 10 ta~sium salt were obtained, correspondlng to 90~ of the theory~
E X A M P L E 16:

4.2 g (20 mmoles) 6-methyl-2,3-dihydro-1,3-oxazin-2,4-dione-3-sulfo~luoride melting at 85 - 86 C were introduced in porti-tion~ into 25 ml 2N mothanolic potas~ium hydroxide solution prepared fro~ KOH of 85% strength and methanol. With the evo-- lution of eas a colorless potassium salt precipitatcd. The ~r reaction mixture was stirred for a further 30 minutes at 30 - ' 40C, the crystals were filtered off with suction and washed with methanol. 3~1 g (15.5 mmoles) of ths potassium ~alt of - 20 6-methyl-3,4-dihydro 1,2,3~oxathiazin-4-one-2,2-dioxide con-taining less than 0.1~ by weight fluoride were obtalned.
Yield 75~ of theory.
X A M P L E 1~s A solution of 21.0 (0.1 rnole) 6~methyl-2,3-dihydro-1,3-oxazin-2,4-diono-3-sulfofluoride in 100 ml methylene chloride , was added dropwise at 20 - 25 C to 100 ml water and the methyl-; ene chloride was d~stilled off under ~lightly reduced prossure.
-29 20 ml ION pota~siu~n hydroxide ~olution wori added and the 6-,. ' '~ ~ ' . ' , , :. .. , ` ' , ' ~
~" , ' `` ~ I OE 7 ~ 2 0 2 K
.'`'`
,. ~0S;~
methyl~3,4-dihydro-1,2,3-oxathiQzin-4-one~2,2-dioxide wa~ i~o-lated as described in Example 15 by acidification with 0.2 mole mineral acid and extraction with ethyl aceta-te.
Yield 85% of theory. -~
E X A M P L E 18;
~- A solution of 10.5 g (50 ~noles) 6-methyl-2,3-dihydro_ 1,3-oxazin-2,4-dione-3-s~lfofluoride in 40 ml methylene chlo_ ride ~a~ added dropwise, while ~tirring and cooling to 0 C, . . .
~` to 50 ml 2N methanolic potassium hydro~ide solution, prepar-ed from pota~9ium hyd~oxide of 86~ ~trength and methanol, and stirring of tho mixture was continued for 30 mlnute~ at 30 40 ~. ~he precipitated potassium salt was filte~ed off ; with s~ction and thoro~ghly washed with methanol. 7.6 ~ (38 mmoles) of the potassium salt of 6-meth~1-3,4~dihydro-1,2,3-oxathiazin~4-one-2,2-dioxide were obtained in the ~or~ of colorlass crystals substantially free of ~luoride (less than 0.1% by weight)~
Yield 75% ~f theory.
E X A M P L E 1~:
While cooling with ice, 21~0 g (0.1 mole) 6-methyl-2,3- -dihydro-1,3~oxazin-2,4-dione-3-sulfofluoride were introduced into 110 ml 2N sodium hydroxide solution. With temperature increase C02 de~eloped~ A~ter standing ~or 30 minutes at roo~ tempera-ture, the reaction mixtur0 wa acidified with 10 ml cono0ntra-ted hydrochloric acid and extracted with ethyl acetate. Arter evaporation of the solvent 13.2 g (0.081 mole) 6-mathyl-3,l~-dlhydro-1,2,3 ox~thlh7in-4-one-2,2-dioxid0 ware obtained, which l~as rccrystallized from ethyl ace-tate/chloro-29 form and th~n melted at 123 - 124 C.

: .: . . , .:, .. . . . . . . .

; HOE 74/~ 20Z K
.
OS;~71~36 ~ Yield 81~ of theory.
....
:~? r, K A~s ~; A solution of Z1.0 g (0.1 mole) 6-methyl-2,3-dihydro ;~ . .i ~ 1,3-oxazin-2,4-dione-3-sulfofluoride in 100 ml acetone was ; 5 stirred with 10 ml water until the eYolution of gas was ter-mi~ated. Milk of lime containing 0.11 mole Ca(OH~2 was ad-ded and the acetone was distilled off under reduced pressure.
After addition of a filtering aid the precipitated Ca~2 was filtered eff, the aq~leous solution of the caloium salt of 6-methyl-3,4-dihydro-1,2,3-oxathiazin 4-one-2,2-dioxide wa~
acidified with concentrated hydrochloric acid and the free acid was extracted with ethyl acetate. The product melted at 123 - 124C.
Yield 12.7 g7 correspondirlg to 78% of the theory.
E X A M P L E 21:
~ _ .. . .
~ 10 ml water were added in portions to a solution of .. , 10.5 g (50 mmoles) 6-methyl-2,3-dihydro-1~3-oxazin-2,4-diona-3-sulfofluorid~ melting at 85 - 86 C in 50 ml dimethoxyethane.
During the course of reaction 1150 ml C02 were split off.
After distillation under reduced prassure of the limpid colorless solution, 9.3 g colorless cry~tals meltin~ at 80 -85 C w~re obtainsd. When the crystals wer~ recrystallized from chloroform, 7.8 g of pure acetoacetamide-N-sulfofluoride melting at 87 - 88 C were obtained (cf. South African Speci-fication 73/9560). The product was identified by mixed melting poin-t and comparison of the IR spectra~
Yield 85% of theory.
The pure crystals were dissolved in 50 mllmethanol and immediately thereafter 20 ml 5N methanolic KOH were added . ' . . , ' ' ' . :. . ' " . , ' ' . . ; ' . ' ;~ ' , ' : .

~~ HOE 71~/F 202 K
10~'~7~6 dropwise at 20 C9 8.1 g (40.4 mmoles) of the potassium salt of 6-mathyl-3,4-dihydro-1~2,3-oxathiazin~4-one-2,2-dioxide were obtained which, after washin~ with methanol, contained :~ less than 0.1% fluoride.
Yiald 81% of -theory.
E X A M_P L E 22:
A solution of 21.0 g (0.1 mole) 6-methyl-2,3-dihydro-1,3-oxazin-2~4-dione-3-sulfofluoride in 80 ml acetone was Rtirred with 5.0 ml water until the evolution of ga~ had ceased. A
mixture of 17 g (0.2 mole) sodium bicarbonate and 50 ml water was added in portions and the mixture was heated for 20 minu-te~ at 55 - 60 C~ After cooling to O C, the mixture was acidified with 20 ml concentrated hydrochloric acid and e~-tracted with ethyl acetate. After distillation of the sol-1$ vent, 14.0 g (86 mrnoles3 6-methyl-3,4-dihydro-1,2,3-oxathia-zin-4-one-2,2-dioxide melting at 11~ - 120 C were isolated, Yield 86% of theory.
.. :
; E X A M P L E 2~
21.0 ~ (0.1 mole) 6-~0thyl-2,3-dihydro-1,3-o~azin-2,4-dione-3-sulfofluoride were added in portions to a mixture of 50 ml tetrahydrofurane and 50 ml water~ When the evolution of gas had ceased 19 ml concentrated aqueous ammonia solution i were added dropwise at 20 - 30 C and the tetrahydrofurane wa~
distilled off under reduced pressurc. The free acid was iso-lated from the aqueous solution of the crude ammonium salt of 6-methyl-3,~-dihydro-1,2,3-oxathiazine-4-one-2,2-dioxide as described above by acidification with 20 ml concentrated hy-drochloric acid and extraction with ethyl acetate.
~=
29 Yield 82~ of theory.

. ' .~ , .,,, .. . .. . ~ . , , . , . ~, . . . .

, ,! . ~_ ~ ~ 02 K
,,.,~,.; .

5~786 :.....
~ E X A M P L E 24s , . ~ .
.;
A solution of 21.0 g (0.1 mole) 6-metllyl-2,3-dihydro-1,3_ oxazin-2,4-dione-3-sul~ofluoride in 50 ml ethyl acetate was ....
vigor~usly stirred at 20 - 30 C with 25 ml water until the evolution of gas had ceasad. 20.2 g (0.2 mole) triethylamine were added dropwise at 25 - 3~ C and the mixture was heated .
for 15 minutes to 50 C while Yigoreusl~ stlrring. After cool-ing, the mixture was acidified with 25 ml concentrated hydro-chloric acid at a tempera-tur~ of 0 to 5 C 9 stirred and the ethyl acetate layer was separated~ Extraction with 20 ml each o~ ethyl acetate was repeated twice and from the combinad and dried ethyl acetate solutions 13.2 g (81 m~oles) 6-methyl-394-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide melting at 118 - 120 C were obtained after drying under reduced pressure~
Yield ~1% of theory.

.

, ~
This application is a division of Canadian Application Serial No. 231,668, filed July 16, 1975.

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, ., , -

Claims (9)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide or the nontoxic salts thereof, in which 6-methyl-2,3-dihydro-1,3-oxazin-2, 4-dione-3-sulfofluoride of the formula I
(I) wherein X represents fluorine is reacted with at least one mole of water per mole of fluoride to obtain acetoacetamide-N-sulfofluoride with splitting off of CO2, the resultant acetoacetamide-N-sulfofluoride is treated with an aqueous base, an alcoholic base or an aqueous, alcoholic base, and the oxathiazinone or a salt thereof is isolated.

2. A process as claimed in claim 1 in which 1 to 20 moles of water are used.

3. A process as claimed in claim 1 in which 2 to 10 moles of water are used.

4. A process as claimed in claim 3 in which the reaction is carried out in the presence of a dissolving intermediary.

5. A process as claimed in claim 1, claim 2 or claim 3 in which the reaction is carried out at a temperature of from 0 to 85°C.

6. A process as claimed in claim 1, claim 2 or claim 3 in which the acetoacetamido-N-sulfofluoride is treated with a base in alcoholic solution containing less than 50% by weight of water.

7. A process as claimed in claim 1, claim 2 or claim 3 in which the acetoacetamido-N-sulfofluoride is treated with a base in an alcoholic solution containing less than 20 by weight of water.

8. A process as claimed in claim 1, claim 2 or claim 3 in which the acetoacetamido-N-sulfofluoride is treated with a methanolic solution of potassium methylate, potassium hydroxide or potassium carbonate containing less than 50 by weight of water.

9. A process as claimed in claim 1, claim 2 or claim 3 in which the acetoacetamido-N-sulfofluoride is treated with a methanolic solution of potassium methylate, potassium hydroxide or potassium carbonate containing less than 20%
by weight of water.