CN1024276C

CN1024276C - Process for preparing 6-methyl-3, 4-dihydro-1, 2, 3-oxathiazin-4-one 2, 2-dioxide and non-toxic salts thereof

Info

Publication number: CN1024276C
Application number: CN 90107999
Authority: CN
Inventors: 卡尔·克劳布; 阿道夫·林基斯; 迪特尔·罗伊斯克林格
Original assignee: Hoechst AG
Current assignee: Celanese Sales Germany GmbH
Priority date: 1985-06-05
Filing date: 1985-06-05
Publication date: 1994-04-20
Anticipated expiration: 2000-06-05
Also published as: CN1050017A; CN1026106C; CN1049845A

Abstract

A process for preparing 6-methyl-3, 4-dihydro-1, 2, 3- * thiazin-4-one 2, 2-dioxide and its non-toxic salt by ring closure of acetoacetamide derivative includes using acetoacetamide-N-sulfonic acid or its salt as acetoacetamide derivative, preferably in the presence of a salt of acetoacetamideIn an inert inorganic or organic solvent, with at least approximately equimolar amounts of SO₃After the ring-closing reaction is completed, 6-methyl-3, 4-dihydro-1, 2, 3- * thiazin-4-one 2, 2-dioxide in the acid form produced in this reaction can be neutralized with a base.

Description

Process for preparing 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide and its non-toxic salts

6-methyl-3,4-dihydro-1,2,3-thiazine-4-ketone 2,2-dioxide are the compound with following structural

Acid-hydrolysis on its nitrogen-atoms and alkali effect, this compound can form salt as a result.Formed non-toxic salts, as Na, K and Ca salt, because of it has sweet taste, sugariness is especially big in some cases again, so the goalkeeper of food department its as sweeting agent, its K salt (" Acesulfamck " or be called for short " Acesulfame ") is particularly important.

Known have many diverse ways to prepare 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2,2-dioxide and non-toxic salts thereof; Referring to Angewandlc Chemie 85, lssue 22(1973) PP.965-73, quite international version 12 is rolled up 11 phases (1973), 869-876 page or leaf.In fact all these is with chloro-or fluosulfonic acid acyl group isocyanic acid (XSO NCO; X-Cl or F) as raw material.With chloro-or fluorosulfonyl isocyanic acid and monomethyl acetylene, acetone, etheric acid, tertiary butyl etheric acid or benzyl propenyl ether reaction (being generally multistep reacts suddenly); to obtain aceto-acetamide-N-SULPHURYL CHLORIDE or fluorine; the back under the effect of alkali (as if methyl alcohol KOH solution) by cyclisation; and obtain corresponding 6-methyl-3; 4-dihydro-1; 2,3-Evil thiazine-4-ketone 2, the salt of 2-dioxide.During as needs, can usual method (with acid), make free De Evil Buprofezin by its salt.

The another kind of method of Zhi Bei Evil thiazine intermediate product aceto-acetamide-N-sulfonic acid fluoride is with sulphonamide fluorine H ₂NSO ₂F is a raw material, and this compound is the partial hydrolysate (Deutsches Reichs-Patent 2,453, No. 063) of fluorosulfonyl isocyanic acid.The fluorochemical H of this sulphonamide ₂NSO ₂F, in a kind of inert organic solvents, under the existence of amine, approximately between-30 to 100 ℃, with the acetoacetyl reagent diketene reaction of similar equimolar amount, reaction is pressed the column balancing formula and is carried out (amine wherein is triethylamine):

Aceto-acetamide-N-sulfonic acid fluoride

Use universal method afterwards, utilize alkali, the KOH solution of methyl alcohol for example is cyclized into sweeting agent with aceto-acetamide-N-sulfonic acid fluoride:

Though some known preparation 6-methyl-3; 4-dihydro-1; 2,3-Evil thiazine-4-ketone 2,2-dioxide and avirulent method thereof; can obtain gratifying productive rate (based on from sulphonamide halogenide; can reach theoretical value about 85%), but especially consider, because necessary chloro-or fluorosulfonyl isocyanic acid in the preparation from the purpose of industrial production; be not easy to obtain as raw material, so still must further improve productive rate so far.When preparation chloro-or fluorosulfonyl isocyanic acid, because of its raw materials used (HCN, Cl ₂, SO ₃And HF) the quite bad processing that has in, and must be especially not heart measure and the facility of taking care.The preparation of chloro-and fluorosulfonyl isocyanic acid is based on following reaction formula:

In the method that is dependent on 4,453, No. 063 patent of above-mentioned West Germany, from obviously being more facile (for example by NH ₃+ SO ₃) thionamic acid H ₂NSO ₃As if H or its salt replace the amine sulfonic acid fluoride, are difficult to make us optimistic, and this is because H ₂NSO ₃Na reacts in the aqueous solution of alkali with diketene, can not obtain the reaction product of the separated purifying of any energy.Certainly, reaction may obtain 1: 1 affixture, this affixture probably forms in this reaction at least partially, and a kind of faint yellow dyestuff that exists with form just with the coupling product of 4-nitrophenylazo muriate formation, referring to Ber.83(1950), the 551-558 page or leaf, particularly 555 pages, the final stage before the narration experiment and 558 pages of last final stages:

In addition, it is believed that aceto-acetamide-N-sulfonic acid itself just (or also being) in its aqueous solution between boil phase, 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, a kind of intermediate product that the 2-dioxide decomposes, referring to the document of enumerating in the foreword, Angew.Chemie(1973) Loc.cit:

Therefore, in view of being used to prepare 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the present situation of the processing method of 2-dioxide and non-toxic salts thereof, particularly in view of still not satisfying industrial requirement fully, and existing method must use the situations such as raw material that make not very not easily again, is necessary at present suitably to improve existing method, perhaps builds a kind of method.This purpose reaches based on the present invention, promptly improves the technology (mainly being with used amine sulfonic acid fluoride in the salt replacement usual method of thionamic acid) of No. 2453063 patents of West Germany, uses SO afterwards again ₃Product cyclisation with resulting acetoacetylization.

Therefore, the present invention relates to prepare 6-methyl-3 with following method, 4-dihydro-1,2,3-Evil thiazine-4-ketone 2,2-dioxide and non-toxic salts thereof.

A) in inert organic solvents, be preferably in amine or phosphine catalyst and exist down, with sulfamic acid derivatives with the acetoacetyl reagent react of mole number such as be bordering at least, obtain the acetoacetyl sulfonamide derivatives;

B) with acetoacetyl sulfonamide derivatives ring closure; This method comprises uses the amine sulfonate derivatives used as step a), this derivative is partially soluble in the used inert organic solvents at least, by formed aceto-acetamide-N-sulfonate in the first step or free aceto-acetamide-N-sulfonic acid, the ring closure in step b) is through being at least the SO of approximate equimolar amount ₃Effect, preferably in a kind of inert inorganic or organic solvent, carry out, to form 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone-2, the ring of 2-dioxide is afterwards in an additional step c), with the acid product of a kind of alkali neutralization by this reaction gained.

The reaction equation of this method institute foundation following (with diketene as acetoacetyl reagent):

This method is begun by the raw material of that be easy to obtain, low cost, and is easy to carry out.In step a), productive rate is approximately 90% to the 100%(sulfamate in the reaction beginning of theoretical value); In the step b), be about theoretical value 70% to 95%(in aceto-acetamide-N-sulfonate); In the step c), the 100%(that is about theoretical value is in the acid thiazine), so the productive rate of whole process is about 65 to 95%.With existing processing method relatively, the present invention has tangible progress.

Making us very surprised is: pass through step a); reaction between sulfonate and the acetoacetyl reagent is advanced to invite very smooth; good productive rate is arranged; reaction product with 1: 1; and the gained reaction product also is easy to be purified separation; and this is for the reaction between thionamic acid or its salt and acetoacetyl reagent, is to be difficult to the imagination.Otherwise, according to reference Ber.83(1950) and described in the Loc.cit, thionamic acid sodium and diketene react in alkaline aqueous solution, are very problematic apparently.

Same amazingly be: use SO in the step b) of present method ₃Make aceto-acetamide-N-sulfonate or the cyclisation of free thionamic acid, its reaction also can be carried out well, this be because in this step with the ring closed reaction and without dehydration with remove alkali (MOH), and if with the reagent of other dehydration or alkali, as P ₂O ₅, acetic anhydride, trifluoro-acetic anhydride and sulfonic acid fluoride etc., then reality all can not produce the ring closed reaction.

Be dependent on method of the present invention, details are as follows:

Step a):

The acetoacetyl reagent that can be used for acetoacetylization has: acetoacetyl chlorine and diketene etc., outstanding diketene is preferred.The amount of employed acetoacetyl reagent is wanted mole numbers such as similar and reactant sulfamate at least.Be advisable less than about 30 moles of % with excessive, particularly with excessive no more than about 10 moles of % for better.Excessive more than 30 moles of % also can, but there is no advantage.

Suitable inert organic solvents is all organic solvents that unwanted reaction does not take place with raw material and end product, and when in the reaction suitable catalyzer being arranged, it also should be able to dissolve the salt of thionamic acid at least partially.In view of the above, the organic solvent of being mentioned below be suitable for and preferably:

Through halogenated aliphatic hydrocrbon, to have no more than 4 carbon atoms for well, methylene dichloride, trichloromethane, 1,2-ethylene dichloride, trieline, zellon, trichlorine vinyl fluoride etc.;

Aliphatic ketone, with had to 6 carbon atoms be good, as acetone, methyl ethyl ketone etc.;

Aliphatic ether, with ring grease ether with 4 or 5 carbon atoms for well, as tetrahydrofuran (THF), diox etc.;

The low-carbon (LC) aliphatic carboxylic acid is good to have 2 to 6 carbon atoms, for example acetate, propionic acid etc.;

Fatty nitrile is good with acetonitrile;

The acid amides that the N-alkyl of carbonic acid and low-carbon (LC) aliphatic carboxylic acid replaces is good with the acid amides with no more than 5 carbon atoms, as tetramethyl-urine, dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-N-methyl 2-pyrrolidone N-etc.;

Aliphatic sulphoxide is good with dimethyl sulfoxide (DMSO), and

Aliphatic sulfones is good with tetramethylene sulfone:

Above be more preferably methylene dichloride in the listed solvent, 1,2-ethylene dichloride, acetone, Glacial acetic acid and dimethyl formamide, particularly methylene dichloride.

These solvents can use separately, maybe can mix use.

Reaction raw materials can have very big variable range to the amount ratio of solvent; General its weight ratio is 1: (2-10) but also available other ratio.

Used amine and the phosphine catalyst of catalysis diketene addition reaction is all known amine and phosphines that can be used as catalyzer in principle, and it mainly is tertiary amine and the phosphine with nucleophilic character.

In the method, preferable tertiary amine and phosphine are that no more than 20 (especially no more than 10) carbon atoms are arranged on each N and the P atom.This class tertiary amine for example has:

Trimethylamine 99, triethylamine, Tri-n-Propylamine, tri-isopropyl amine, tri-n-butylamine, tri-isobutylamine, tricyclohexyltin amine, the second Diisopropylamine, the second dicyclohexyl amine, N, accelerine, N, the N-Diethyl Aniline, benzyldimethylamine, pyridine, the pyridine that is substituted, as picoline, lutidine, trimethylpyridine, or methyl ethyl pyridine, the N-methyl piperidine, the N-ethyl piperidine, N-methylmorpholine, N, N-dimethyl hexahydropyrazine 1,5-diazacyclo [4.3.0] ninth of the ten Heavenly Stems-5-alkene, 1,8-diazacyclo [5.4.0] 11-7-alkene, and tetramethyl-hexamethylenediamine, tetramethylethylened, the tetramethyl-trimethylene diamine, tetramethylbutylene diamine, and 1,2-dimorpholine base ethane, five methyl diethylentriamine, five ethyl diethylenetriamine, the pentamethyl-dipropylenetriamine, tetramethyl-diamino methane, tetrapropyl diamino methane, the hexamethyl Triethylenetetramine (TETA), the hexamethyl tri propylidene tetramine, two isobutylene triamines or three isopropylidene tetramines.

Particularly preferred amine is triethylamine.

The example of tertiary phosphine is: methyldiphenyl phosphine, triphenyl phosphine, three fourth phosphines etc.

The general every mole of thionamic acid of catalyst levels is no more than about 0.1 mole, more amount also can, but almost without any benefit.In principle, method of the present invention also can be carried out under the catalyzer condition not having, but but catalyzer accelerated reaction process, so its advantage is arranged.

Used sulfamate in the method, must to small part ground be dissolved in inert organic solvents, for adapting to this requirement, preferably use lithium, the NH of thionamic acid ₄With primary, secondary, uncle and quaternary ammonium salt and preferred ammonium salt should be to contain to be no more than 20 for its ammonium ion, especially be no more than 10 carbon atoms.For example, the ammonium salt of thionamic acid can have following ammonium ion:

NH ₄，H

₃N（C ₂H ₅），H

₂N（n-C ₃H ₇） ₂，H

₂N（i-C ₃H ₇） ₂，H

N（CH ₃） ₃，

H

N（C ₂H ₅） ₃，H

N（n-C ₃H ₇） ₃，H

N（n-C ₄H ₉） ₃，

H N（CH ₃） ₂CH ₂C ₆H ₅，H

N（CH ₃） ₂（C ₆H ₅），N

（CH ₃） ₄，N

（C ₂H ₅） ₄，

N(CH ₃) ₃C ₆H ₅Deng.

A kind of particularly preferred sulfamate is a triethyl ammonium salt.

This class salt is normally with known method, with LiOH, NH ₃Suitable amine or the neutralization of the solution of quaternary ammonium hydroxide obtain except that anhydrating afterwards.Used alkali is by amino sulfonic acid amount calculating of add, the best no more than about 30 moles of % of the amount that surpasses, particularly no more than 15 moles of %.In addition, the organic moiety in the ammonium ion preferably be same as organic moiety in the amine catalyst (for example, with the thionamic acid triethyl ammonium during as the salt of thionamic acid, then with triethylamine as catalyzer).At salt NH is arranged ₃During with primary and secondary, the amine composition that then uses stoichiometric quantity is for well, and institute in addition catalyzer should be the weakly alkaline tertiary amine, as pyridine.

Common selected temperature of reaction is approximately-30 to+50 ℃, preferably about 0 to 25 ℃.

Reaction is under atmospheric pressure carried out usually, and the reaction times can have than the cataclysm scope, is about 0.5 to 12 hour.Reaction can import sulfamate earlier and amount is gone into diketene, perhaps import diketene earlier and measure basic sulfonate, perhaps earlier import diketene and thionamic acid and amount is gone into alkali, perhaps two kinds of reactions measured in the reaction chamber simultaneously, inert organic solvents also can import earlier can with reactant measure into.

After reaction is finished, remove solvent with distillation method, reaction product isolated, and by in appropriate solvent such as acetone, methyl acetate or the ethanol remnant (mainly being aceto-acetamide-N-sulfonate) recrystallization being come out.Productive rate is approximately theoretical value 90 to 100%.

Aceto-acetamide-N-sulfonic acid lithium or ammonium salt are new compound, and its structural formula is:

M wherein

=Li

Or N

R ¹R ²R ³R ⁴

R wherein ¹, R ², R ³And R ⁴Be respectively H or organic radical, preferably H or C ₁-C ₈Alkyl, C ₆-C ₁₀Cycloalkyl, aromatic base and/or aralkyl.

The total number of carbon atoms of ammonium ion is preferably no more than about 20 in the ammonium salt, especially preferably no more than about 10.

In case of necessity, can make free aceto-acetamide-N-sulfonic acid with general traditional methods by aceto-acetamide-N-sulfonate.

Step b):

With the aceto-acetamide-N-sulfonate (or its free acid) that obtains in the step a), in suitable inert inorganic or organic solvent, with the SO of approximate at least equimolar amount ₃Make its cyclisation.SO ₃Consumption in aceto-acetamide-N-sulfonate (or free acid), generally up to about 20 times, with about 3 to 10 times be good, preferably be about 4 to 7 times.Can solid or liquid form, perhaps condense into SO ₃Steam is added in the reaction mixture, but typically uses in the vitriol oil, liquid SO ₃Or the SO in certain inert organic solvents ₃Solution.Also can use and remove SO ₃Compound.

Though reaction can not carried out when having solvent in principle, had better finish in a kind of inert inorganic or organic solvent.Suitable inorganic or organic solvent is can not be with the same SO of a kind of unwanted mode ₃Or the liquid of the raw material of reaction or end product reaction.Because SO ₃Strong especially reactive behavior is arranged, so have only relatively small number of solvents can be suitable for this requirement.Solvent is preferably:

Inorganic solvent: liquid SO ₂;

Organic solvent: halogenated aliphatic hydrocrbon, no more than 4 carbon atoms are preferably arranged, as methylene dichloride, trichloromethane, 1,2-ethylene dichloride, trieline, zellon, trichlorine vinyl fluoride etc.The ester that the carbonic acid of low-carbon (LC) fatty alcohol (preferably methyl alcohol or ethanol) is arranged.The nitro alkanes preferably has 4 carbon atoms only, particularly with Nitromethane 99Min. for well.The pyridine that alkyl replaces, preferably trimethylpyridine; And the aliphatic sulfones class, wherein with tetramethylene sulfone for well.

Organic solvent can be used alone or as a mixture.

Particularly preferred solvent is liquid SO ₂And methylene dichloride.

The consumption of inert solvent is not strict.When using solvent, only need guarantee to form the enough solution of reaction, the upper limit of solvent load is to be determined by consideration economically.

A preferred embodiment of the present invention's method is at step a) and b) in use same solvent, preferably use halogenated aliphatic hydrocrbon, particularly methylene dichloride.This is because in the case, needn't be by the solution separating aceto-acetamide-N-sulfonate that obtains in the step a), and directly solution is used for step b)

Temperature of reaction in the step b) generally is approximately-70 to+175 ℃, preferably about-40 to+10 ℃.

Step b) is also carried out under atmospheric pressure usually similar in appearance to step a).

Reaction times was about 10 hours.

The mode that reaction is carried out can be: import the suitable solution of aceto-acetamide-N-sulfonate (or free acid) earlier, amount is gone into the SO of solubilized form again ₃, or two kinds of reactants are imported in the reaction chamber simultaneously, perhaps introduce SO earlier ₃Add aceto-acetamide-N-sulfonate (or free acid) again.

To import the SO of the solution form of part earlier ₃, afterwards more continuously or gradation ground amount go into the SO of aceto-acetamide-N-sulfonate (or free acid) and solubilized form ₃This mode is for well.

Operation is to implement in habitual mode.In a preferred embodiment, be with methylene dichloride as reaction medium, this moment can operate in the following manner: to containing SO ₃Solution in add about 10 times of molar weights and (press SO ₃Amount calculate) ice or water.So cause being separated: the 6-methyl-3 that has generated, 4-dihydro-1,2,3-Evil thiazine-4-ketone 2,2-dioxide mainly are present in the organic phase, still are present in the part of aqueous phase, organic solvent extraction such as available methylene dichloride or organic ester and obtaining.

In addition, after adding entry, heat up in a steamer method with steaming sulphur reaction solvent is removed, and still remain in 6-methyl-3 in the acid, 4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the 2-dioxide then obtains with The suitable solvent extraction more.Appropriate solvent is stable to sulfuric acid, and the solvent of enough dissolving poweies is arranged.In addition, reaction product is in solvent systems.Should have and be beneficial to isolating partition ratio.Appropriate solvent not only has halon, and also has the ester of carbonic acid, as methylcarbonate, diethyl carbonate and ethylene carbonate, or the ester of organic monocarboxylic acid, as isopropyl formate, tetryl formate, ethyl acetate, isopropyl acetate, butylacetate, isobutyl acetate and acetate peopentyl ester, or the ester and the tetrabutyl urea of dicarboxylic acid or the amine that dissolves each other with water.Be best wherein with isopropyl acetate and isobutyl acetate.

Can Na ₂SO ₄The dry organic phase of concentrating, and evaporation drying it.The a small amount of sulfuric acid that is brought out during extraction can be removed because of add suitable alkaline solution in organic phase.For this purpose, add the alkaline solution of dilution in organic phase, reach up to the pH of water and make pure 6-methyl-3,4-dihydro-1,2 is 3-Evil thiazine-4-ketone 2,2-dioxide have identical concentration in these two phase systems of extraction agent and water till.As expect the free compound, must it be further purified (the most handy recrystallization method) with used method usually.In aceto-acetamide-N-sulfonate (or its free acid), its productive rate is about 70% to 95%.

But as to obtain 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the non-toxic salt of 2-dioxide also must carry out the neutralization reaction of step c).

For this purpose, can be according to general method, with suitable alkali neutralization procedure b) in resulting acid De Evil buprofezin compound.For this reason, for example can be with resulting concentrated in the step b), organic phase dry and evaporation is dissolved in as in the organic solvents such as ethanol, acetone, ester or ether, and is perhaps soluble in water, and with suitable alkali, potash preferably is as KOH, KHCO ₃, K ₂CO ₃, potassium neutralizations such as alcoholate.In addition, the also available potash aqueous solution, direct organic extraction phase (step b) neutralization and Cui Qu Evil buprofezin compound by purifying.After evaporating solns, with crystalline form Chen Dian Chu Evil Buprofezin salt.But also recrystallize with purifying it.

The productive rate of neutralization procedure is actually 100%.

Comprise step a), b) and the present invention's c) entire method, and step a) and b) indivedual methods be novelty and marked improvement arranged.

The following example is in order to further elaboration the present invention.Relate to step a), b having enumerated) and the some embodiment of the present invention c) after, enumerate a comparative example, with demonstration SO ₃Other dehydration in addition or dealkalize reagent are as P ₂O ₅, just can't make aceto-acetamide-N-sulfonate cyclisation.

A) implementation step embodiment a):

Example 1:

In 12 milliliters of trimethylamine solutions that are dissolved in 100 milliliters of Glacial acetic acid

In (0.125 mole), add 9.7 gram (0.1 mole) thionamic acids, stir this mixture, up to dissolving fully.Dropwise add 8 milliliters of (0.104 mole) diketenes afterwards, condition is 25-30 ℃ of cooling.After 16 hours, slowly add ether, make the reaction product precipitation, and the filtration of bleeding.

22 grams (92%), 101 ℃ of fusing points

Nucleus magnetic resonance (DMSOd ₆) δ 2.2(CH ₃-

),

2.8（N

-CH ₃），3.45（-CH ₂）

Infrared (KBr) 1045,1240,1470,1660,1720 centimetres ^-1

Example 2:

Aceto-acetamide-N-sulfonic acid dimethyl ethyl ammonium

80 gram (1.096 moles) N,N-DIMETHYLACETAMIDE coolings, and dropwise add in 80 gram (0.825 mole) thionamic acids that are suspended in 500 milliliters of Glacial acetic acid.After the dissolving, add 80 milliliters of (1.038 moles) diketenes fully in 25-35 ℃ of cooling.After 16 hours, with the mixture evaporation, add acetone in the remnant and stir, thereby produce crystallization.

110 grams (43%), fusing point 73-75 ℃

Remaining reaction product 128 grams (50%) obtain from mother liquor as slurries.

Nucleus magnetic resonance (CKCL ₃) 1.35(CH ₃) 2.2(CH-

),

2.8（N

-CH ₃），3.5（-CH ₂-

）

Infrared (KBr) 1050,1240,1475,1690,1730 centimetres ^-1

Example 3:

Aceto-acetamide-N-sulfonic acid triethylamine

Be dissolved in the thionamic acid of 100 milliliters of methylene dichloride with 9.7 grams (0.1 mole), miscible with 16 milliliters of (0.12 mole) triethylamines.Dropwise add 8 milliliters of (0.104 mole) diketenes in 0 ℃ of continuously stirring 2 hours in 0 ℃ then, under room temperature, stirred 2 hours again.Add hexane precipitin reaction product afterwards, and with the remaining soup compound of more hexane wash.Residue 27-28 gram (95.7-99%) after vacuum-drying, after leaving standstill for a long time, soup compound promptly begins crystallization.

Nucleus magnetic resonance (CDCL ₃) δ 1.33(-CH ₃) 2.2(CH ₃-C), 3.2(N-CH ₂), 3.5(-CH ₂-C) infrared (pure) 1040,1230,1450,1650,1670 centimetres ^-1

Following routine 4-7 carries out the result with the method similar in appearance to example 3:

Example 4:

Aceto-acetamide-N-sulfonic acid three (n-propyl) ammonium

Productive rate: 92-97%

Nucleus magnetic resonance (CDCL ₃) δ 2.3(-CH ₃-

), 3.6(-CH ₂-

) infrared (CH ₂CL ₂) 1040,1260,1420,1700,1740 centimetres ^-1

Example 5:

Productive rate: 91-96%

Nucleus magnetic resonance (CDCL ₃) δ 2.25(-CH ₃-

), 3.5(-CH ₂-

) infrared (CH ₂CL ₂) 1040,1250,1420,1700,1740 centimetres ^-1

Example 6:

Aceto-acetamide-N-sulfonic acid dimethyl benzyl ammonium

Productive rate: 92-97%

Nucleus magnetic resonance (CDCL ₃) δ 2.2(COCH ₃), 2.75(N

-CH ₃)

3.5（-CH ₂-

）

4.3（N -CH ₂-Ar），7.35（Ar），

Infrared (CH ₂CL ₂) 1040,1260,1270,1430,1470,1700,1740 centimetres ^-1

Example 7:

Productive rate: 91-95%

Nucleus magnetic resonance (CDCL ₃) δ 1.3 and 1.4(-CH ₃), 2.2(COCH ₃), 3.5(CH ₂-CO)

Infrared (CH ₂CL ₂) 1040,1210,1250,1420,1700,1740 centimetres ^-1

Example 8:

9.7 gram (0.1 mole) thionamic acids are suspended in 100 milliliters of acetone, and add 16 milliliters of (0.12 mole) triethylamines.When almost dissolving fully, dropwise add 8 milliliters of (0.104 molar weight) diketenes in 0 ℃.Stir under room temperature afterwards, it is all dissolved to add each component during this, and reaction spatters to become to finishing.After 16 hours, with hexane reaction product is soup compound and is precipitated out, and stir together to be further purified it with hexane.After the vacuum-drying, leave 27-28 gram (95.7-99%) soup compound, can slowly crystallize out through placing.

Nucleus magnetic resonance (CDCL ₃) δ 2.3(-CH ₃), 2.2(CH ₃- , 3.55(-CH ₂-

)

Infrared (pure) 1040,1230,1450,1670 centimetres ^-1

Example 9:

Concentrated aqueous solutions adding 15.5 grams (0.16 mole) of 105 milliliters of (0.16 mole) 40% tetrabutylammonium are dissolved in the thionamic acid solution of 10 ml methanol and 50 ml waters.Afterwards with this mixture evaporation drying.The gained remnant is dissolved in 100 milliliters of methylene dichloride, and with triethylamine pH is transferred to 9-10, dropwise adds 10 milliliters of diketenes then.After 12 hours, again pH is transferred to 9-10, and repeats to add diketene again.After 16 hours, with the mixture evaporate to dryness, remnant is crystallization.The filtering for crystallizing of bleeding slurry, and wash it with ethyl acetate and ether.

34.6 gram (52%), fusing point: 97-98 ℃

Nucleus magnetic resonance (CDCL ₃) δ 1.33(-CH ₃), 2.2(COCH ₃), 3.2(CH ₂-

), 3.5(CH ₂- )

Infrared, (CH ₂CL ₂) 890,1040,1255,1410 centimetres ^-1

Example 10:

Prior to 0 ℃ of 15.4 milliliters of (0.2 mole) diketene that import 19.4 gram (0.2 mole) thionamic acids and be dissolved in 200 milliliters of methylene dichloride.In cooling and stirring while, in 45 minutes, dropwise add 29 milliliters of (0.21 mole) triethylamines.Afterwards reaction mixture was stirred standing over night under room temperature 30 minutes in 0 ℃.Steam solvent and, obtain the pulpous state product in vacuum-drying.It is crystallized out from acetone.

53-56 restrains (94-99%); Fusing point 55-58 ℃

Nucleus magnetic resonance (CDCL ₃) δ 1.33(-CH ₃), 2.2(CH ₃-

), 3.2(N-CH ₂), 3.5(-CH ₂- )

Infrared (pure) 1040,1230,1450,1670 centimetres ^-1

Example 11:

Import 19.4 gram (0.2 mole) thionamic acids prior to 0 ℃, 15.4 milliliter (0.2 mole) diketene and 1.14 milliliters (0.02 mole) are dissolved in the glacial acetic acid solution of 100 milliliters of methylene dichloride, when cooling and stirring, within 45 minutes, dropwise add the triethylamine of 29 milliliters (0.21 moles).In 0 ℃ this reaction mixture was stirred 30 minutes standing over night under room temperature afterwards.Solvent evaporation fallen that remnant is washed with ether in the back and dry in vacuum, with the acetone crystallization it.

52-55 restrains (92-97.5%), fusing point 55-58 ℃

Nucleus magnetic resonance (CDCL ₃) δ 1.33(-CH ₃), 2.2(CH ₃-

), 3.2(CH ₂-

), 3.5(-CH ₂-

)

Infrared (pure) 1040,1230,1450,1670 centimetres ^-1

Example 12:

With 15.1 milliliters of (120 mmole) N, accelerine adds in 9.7 gram (100 mmole) the thionamic acid solution that are dissolved in 100 milliliters of Glacial acetic acid, stirs this mixture, up to dissolving fully.Add 8 milliliters of (104 mmole) diketenes afterwards.After 16 hours, in solution, add 2 milliliters of diketenes again.After diketene disappeared, with the mixture evaporation, adding diethyl ether to stir made the product precipitation.

Productive rate: 88-92%

Nucleus magnetic resonance (CDCL ₂) δ 2.2(COCH ₃), 3.5(-CH ₂-

)

Infrared (CH ₂CL ₂) 1040,1250,1430,1700,1740 centimetres ^-1

Example 13:

Under the vigorous stirring, in 11.4 gram (100 mmole) the ammonium sulphonate suspension that are suspended in 100 milliliters of Glacial acetic acid, add 10 milliliters of diketenes and 1 milliliter of pyridine.After 17 hours, bleeding to filter obtains end product.17 grams=86% decompose when being higher than about 125 ℃.

Example 14:

With being dissolved in 200 milliliters of CH with 19.4 grams (0.2 mole) in 28 milliliters of (0.2 mole) Diisopropylamines ₂CL ₂Thionamic acid solution.After adding 0.81 milliliter of (10 mmole) pyridine, under 0 ℃, dropwise add 15.4 milliliters of (0.2 mole) diketenes.In 0 ℃ reaction mixture was stirred 30 minutes, afterwards standing over night under room temperature.After steaming solvent and vacuum-drying, obtain the pulpous state reaction product.45-48 gram=80-85%

Infrared (pure) 1040,1280,1450,1670 centimetres ^-1

Example 15:

Be dissolved in 19.4 gram (0.2 mole) thionamic acid solution of 100 milliliters of DMF with 21 milliliters of (0.2 mole) TERTIARY BUTYL AMINE neutralizations.After adding 0.81 milliliter of (10 mmole) pyridine, dropwise add 15.4 milliliters of (0.2 mole) diketenes in 15 ℃.In room temperature this mixture was stirred 3 hours afterwards.Make product precipitation with 500 milliliters of diethyl ether, add acetone stir soup compound with purifying it.

Productive rate: 42g-83%

Infrared (pure) 1035,1230,1450,1670 centimetres ^-1

B) carry out step b) and c) embodiment: example 1:

In-30 ℃, under the vigorous stirring, in 60 minutes, will be dissolved in 12.7 gram (50 mmole) aceto-acetamide-N-sulfonic acid dimethyl ethyl ammonium solutions of 110 milliliters of methylene dichloride, dropwise add 8 milliliters of (200 mmole) liquid SO that are dissolved in 100 milliliters of methylene dichloride ₃In the solution.After 30 minutes, in solution, add 50 milliliters of ethyl acetate and 50 gram ice.Isolate organic phase, and with the ethyl acetate extraction water more than twice.Use Na ₂SO ₄The dry organic phase of concentrating is evaporated it, and remnant is dissolved in the methyl alcohol.With the KOH solution of methyl alcohol this solution that neutralizes, be settled out 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the sylvite of 2-dioxide.

7.3 gram=73%

Example 2:

In-30 ℃, in 60 minutes, will be dissolved in 12.7 gram (50 mmole amount) aceto-acetamide-N-sulfonic acid dimethyl ethyl ammonium solutions of 110 milliliters of methylene dichloride, dropwise adding is dissolved in 50 milliliters of SO ₂8 milliliters of (200 mmole) liquid SO ₃In the liquid, and vigorous stirring it.After 30 minutes, steam and transfer SO ₂, in this solution, add 50 milliliters of ethyl acetate and 50 gram ice.Isolate organic phase, use the ethyl acetate extraction water more than twice.With the organic phase that dried over sodium sulfate is collected, evaporation, and remnant is dissolved in methyl alcohol,, is settled out 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the sylvite of 2-dioxide with the KOH solution of methyl alcohol this solution that neutralizes.

8.3 gram=83%

Example 3:

In-30 ℃, under the vigorous stirring, in 60 minutes, will be dissolved in 12.7 gram (50 mmole) aceto-acetamide-N-sulfonic acid dimethyl ethyl ammonium solutions of 110 milliliters of methylene dichloride, dropwise add 12 milliliters of (300 mmole) liquid SO that are dissolved in 100 milliliters of methylene dichloride ₃In the liquid.After 30 minutes, in this solution, add 50 milliliters of ethyl acetate and 50 gram ice.Isolate organic phase, use the ethyl acetate extraction water more than twice.With the organic phase that dried over sodium sulfate is collected, evaporation, and remnant is dissolved in methyl alcohol,, is settled out 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the sylvite of 2-dioxide with the KOH solution of methyl alcohol this solution that neutralizes.

7.6 gram=76%

Example 4:

In-30 ℃, under the vigorous stirring, in 20 minutes, will be dissolved in 4.24 gram (16.7 mmole) aceto-acetamide-N-sulfonic acid dimethyl ethyl ammonium solutions of 35 milliliters of methylene dichloride, dropwise add 4 milliliters of (100 mmole) liquid SO that are dissolved in 100 milliliters of methylene dichloride ₃Solution in.In this solution, add 4 milliliters of (100 mmole) SO ₃, dropwise add the solution that another part is dissolved in 4.24 gram (16.7 mmole) aceto-acetamide-N-sulfonic acid dimethyl ethyl ammoniums of 35 milliliters of methylene dichloride again.Repeat to add the SO of 4 milliliters (100 mmoles) ₃In-30 ℃, under the vigorous stirring, in 20 minutes, dropwise add the solution of 4.24 gram (16.6 mmole) aceto-acetamide-N-sulfonic acid dimethyl ethyl ammoniums that are dissolved in 35 milliliters of methylene dichloride more afterwards.After 20 minutes, this mixture is handled by example 1 method.

8.7 gram=87%

Example 5:

In-25 ℃, under the vigorous stirring, in 60 minutes, will be dissolved in the solution of 12.7 gram (50 mmole) aceto-acetamide-N-Dimethyl Ammonium of 110 milliliters of methylene dichloride, dropwise add 2.4 milliliters of (60 mmole) SO that are dissolved in 100 milliliters of methylene dichloride ₃In the solution.After 12,24,36 and 48 minutes, each adds 2.4 milliliters of (60 mmole) SO ₃After 20 minutes, this mixture is handled by example 1 method.

8.8 gram=88%

Example 6:

Method by embodiment 5 is reacted, but initial import for being dissolved in 50 milliliters of SO ₂2.4 milliliters of (60 mmole) SO ₃Solution.

8.8 gram=88%

Example 7:

12.8 gram (160 mmole) solid-state SO ₃Be dissolved in 150 milliliters of methylene dichloride.This solution is cooled to-45--55 ℃ after, in 60 minutes, dropwise add 25 milliliters of dichloromethane solutions that contain 8.4 gram (26 mmole) acetoacetyl ammonia-N-sulfonic acid 3 third ammonia.In-45--55 ℃ placement is after 4 hours, and example 1 method is operated it.2.8 restrain 2 54%

Among the embodiment 8-12, directly use and react resulting reaction soln by diketene, thionamic acid and triethylamine.

Example 8:

In-30 ℃, with 125 milliliters of aceto-acetamides-N-sulphur triethylenetetraminehexaacetic acid ammonium solution (0.1 mole, methylene dichloride), dropwise adding is dissolved in the solution that contains 20 milliliters of liquid SO of 500 milliliters of methylene dichloride in 60 minutes, simultaneously vigorous stirring., undertaken after 60 minutes in-30 ℃ of placements by example 1 method.

17.1 gram=85%

Example 9:

In-30 ℃, earlier 125 milliliters of aceto-acetamides-N-sulphur triethylenetetraminehexaacetic acid ammonium solution (0.1 mole, methylene dichloride) is imported in 250 milliliters of methylene dichloride, in 60 minutes, add 20 milliliters of (500 mmole) liquid SO that are dissolved in 250 milliliters of methylene dichloride ₃Solution., operate after 60 minutes in-30 ℃ of placements by example 1.14.9 gram=74%

Example 10:

In-25 ℃, with 125 milliliters of aceto-acetamides-N-sulphur triethylenetetraminehexaacetic acid ammonium solution (0.1 mole, methylene dichloride), dropwise be added on and contain 4.8 milliliters of (120 mmole) liquid SO in 60 minutes ₃500 milliliters of dichloromethane solutions in.Added 4.8 milliliters of (120 mmole) liquid SO every 12 minutes ₃, be no less than 5 times.After 60 minutes, carry out following operation in-25 ℃ of placements by example 1 method.

18.3 gram=91%

Example 11:

In-30 ℃, import 50 milliliters of methylene dichloride earlier.In cooling off and fully stirring simultaneously, in 30 minutes, the while also stably dropwise adds the solution of 28.1 gram (0.1 mole) acetoacetyl ammonia-N-sulfonic acid that are dissolved in 50 milliliters of methylene dichloride, and 24 milliliters of liquid SO of 50 milliliters of methylene dichloride of solution ₃Solution.In-25 ℃ to-30 ℃, after 30 minutes, under same temperature, dropwise add 110 ml waters carefully again.Distill afterwards to remove CH ₂CL ₂, with 80 milliliters of isobutyl acetate abstraction reaction products.Add 20 ml waters again in organic phase, vigorous stirring is transferred to 0.84-0.87(pH value, glass electrode: Ingold405-60-S7) with 4NKOH with pH simultaneously.After separating and extracting waters with 20 milliliters of isobutyl acetates, add 15 ml waters to the isobutyl acetate of concentrating in mutually, and with 4NKOH pH is transferred to 5-7 under stirring, the sedimentary K salt of the filtration fraction of bleeding afterwards, combines with the water of filtrate.Moisture content is fallen in vacuum-evaporation, obtains the sweeting agent of 18.1 grams=90%.

Example 12:

In-30 ℃, import 50 milliliters of CH earlier ₂CL ₂, under strong cooling (Virahol/dry ice), add 50 milliliters of CH that contain 28.1 gram (0.1 mole) aceto-acetamide-N-sulphur triethylenetetraminehexaacetic acid ammoniums simultaneously and stably ₂CL ₂Solution and contain 24 milliliters of liquid SO ₃50 milliliters of CH ₂CL ₂Solution.Handle (extract: isopropyl acetate), obtain the sweeting agent of 17.9 grams=89% by example 11 methods immediately.

Example 13:

In-25 ℃, earlier with 12.4 milliliters 60% oleum (200 mmole SO ₃) 200 milliliters of CH of importing ₂CL ₂In, in 30 minutes, dropwise add 62.5 milliliters of aceto-acetamides-N-sulphur triethylenetetraminehexaacetic acid ammonium (50 milliliters of moles, CH ₂CL ₂) solution.After 60 minutes, handle this mixture in-25 ℃ of placements by example 1 method.4.7 gram=47%

Example 14:

In-30 ℃, carefully with 8 milliliters of (200 mmole) liquid SO ₃Add in 200 milliliters of trimethylpyridines.Add 16.2 gram (50 mmole) aceto-acetamide-N-sulfonic acid 3 third ammoniums then, this reaction mixture is heated to 100 ℃, kept 2 hours.Most of trimethylpyridine is removed in vacuum distilling afterwards, and uses the acetic acid ethyl dissolution remnant.Behind sulfuric acid acidation, with the thorough extracting water of ethyl acetate.Use Na ₂SO ₄Dry organic phase, and vacuum-evaporation it.The sweeting agent of filtering-depositing and the drying of bleeding.2.2 gram=22%

Comparative example:

Earlier with 35.42 gram (250 mmole) P ₂O ₅Import 250 milliliters of CH ₂CL ₂In.In-25 ℃, in 60 minutes, dropwise add the CH of 62.5 milliliters of aceto-acetamides-N-sulphur triethylenetetraminehexaacetic acid ammonium ₂CL ₂Solution (content of sulfonate is 0.05 mole).After 60 minutes, handle this mixture in-25 ℃ of placements by routine B-1 method.Roll over method with thin layer, in reaction product, do not detect 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2,2-dioxide or its sylvite.

Claims

1, a kind of acetoacetyl sulfonamide derivatives closed loop that makes, with preparation 6-methyl-3,4-dihydro-1,2,3-Evil thiazine-4-ketone 2, the method for 2-dioxide and non-toxic salts thereof comprises with the aceto-acetamide-N-sulfonate as the acetoacetyl sulfonamide derivatives, in a kind of inert inorganic or organic solvent, be SO at least near equimolar amount ₃Effect, finish the ring closed reaction, available afterwards a kind of alkali 6-methyl-3 of the acid that produces in this reaction that neutralizes, 4-dihydro-1,2,3-Evil thiazine-4-ketone 2,2-dioxide.

2, according to the process of claim 1 wherein SO ₃Consumption with respect to aceto-acetamide-N-sulfonate, excessive no more than 20 times.

3, according to the method for claim 2, SO wherein ₃Consumption excessive 3 to 10 times with respect to aceto-acetamide-N-sulfonate.

4, according to the method for claim 3, described SO ₃Consumption excessive 4 to 7 times with respect to aceto-acetamide-N-sulfonate.

5, according to each method among the claim 1-4, wherein used inert inorganic solvent is liquid SO ₂,

And used inert organic solvents is one of following solvent at least:

Halogenated aliphatic hydrocrbon,

Trimethylpyridine.

6, according to the method for claim 5, wherein halogenated aliphatic hydrocrbon has no more than 4 carbon atoms.

7, according to the process of claim 1 wherein that the temperature of ring closed reaction is-40 ℃ to 40 ℃.

8, according to the method for claim 1,6-methyl-3 wherein, 4-dihydro-1,2,3-Evil thiazine-ketone 2, the 2-dioxide, be to produce, be to use halogenated solvent with the form of acid, or the ester of carbonic acid or organic carboxyl acid, from the sulfuric acid reaction medium, extract, and the sulfuric acid of having been come by band preferably neutralizes with a kind of alkali.