CN104341470A - Synthesis method of rebaudioside M, intermediate product of rebaudioside M and synthesis method of intermediate product of rebaudioside M - Google Patents
Synthesis method of rebaudioside M, intermediate product of rebaudioside M and synthesis method of intermediate product of rebaudioside M Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/256—Polyterpene radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H13/06—Fatty acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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Abstract
The invention belongs to the field of food chemical industry, relates to a synthesis method of rebaudioside M, an intermediate product of the rebaudioside M and a synthesis method of the intermediate product of the rebaudioside M, and particularly relates to a process method which uses ready-made natural products and non-toxic reagents and is applicable to industrial production. The provided synthesis method of the rebaudioside M is bran-new. The synthesis method provided by the invention comprises the following routes: (1) protecting hydroxyl groups of a compound A, so as to obtain a compound B; (2) enabling the compound B and a compound C to react in the presence of a phase transition reagent and an inorganic base, so as to obtain a compound D; (3) removing protecting groups of R1 and R2 from the compound D, thereby obtaining the rebaudioside M. The method has the advantages that the preparation method is simple and is easy in operation, the purity of a product is high, and the conversion ratio is high.
Description
Technical field
The invention belongs to field of food chemical industry, relate to the synthetic method of a kind of Rebaudiodside A M and intermediate product thereof and synthetic method, be specifically related to a kind ofly use ready-made natural product and the processing method of innocuous agents, be applicable to suitability for industrialized production.
Background technology
Sweeting agent is the foodstuff additive that a class is applied to food, drink production.Widely used sweeting agent has more than 20 to plant in the world at present, and what China's approved used about has 15 kinds.According to source, sweeting agent can be divided into two large classes: the first kind is natural sweeteners, and as glucose, sucrose etc., this type of sweeting agent exists that heat is too high, special population eats limited shortcoming; Equations of The Second Kind is chemosynthesis sweeting agent, is namely completely to be synthesized by chemical process, and asccharin is the chemosynthesis sweeting agent eaten the earliest, and Sodium Cyclamate, aspartame etc. also belong to this type of in addition.Along with the progress of society, the worry of people to synthetic sweetener security makes its application be subject to a definite limitation.
Steviol glycoside (steviol glycosides) is also known as making stevioside (Stevia sugar), the class high sugariness extracted from stevioside leaf and stem, low-calorie natural sweeteners, its sugariness is 200-300 times of sucrose, one of heat three percentages only having sucrose.With the natural sweeteners such as sucrose, glucose, the chemosynthesis such as Sodium Cyclamate, aspartame sweeting agent is compared, stevioside has that heat is low, sugariness advantages of higher, nontoxic to human-body safety, but also have concurrently and reduce blood pressure, promote metabolism, multi-efficiency such as treatment hyperchlorhydria etc., also have certain auxiliary curative effect to patients such as obesity, diabetes, cardiovascular diseases, hypertension, arteriosclerosis, carious teeth, therefore it is the ideal substitute of sucrose, everyly can use stevioside with the place of sucrose.Stevioside is at present through the natural low caloric value sweeting agent closest to sucrose taste of the Ministry of Health of China, Ministry of Light Industry's approval use, it is the sweeting agent that the 3rd kind has a Development volue after sucrose, and enjoy healthy natural sucrose substitute of praising highly, be described as in the world " third place in the world sucrose ".
Stevioside and rebaudioside A are the main sweet ingredient of sweet Stevia, be also two high-purity steviosides products that uniquely can realize suitability for industrialized production at present, but their mouthfeel and sucrose remain nuance.
Rebaudiodside A M (Rebaudioside M is called for short RM) is found from sweet Stevia Mvorita plant (J.Appl.Glycosci., 2010,57,199-209), and structural formula is as follows:
Compared with rebaudioside A, Rebaudiodside A M has more mouthfeel advantage, is used as novel sweetener by FDA approval.Because natural Rebaudiodside A M content is very micro-, not yet there is commercially producing of Rebaudiodside A M at present.
Chinese patent application 201310353500.9 disclose a kind of with rebaudioside A or Rebaudiodside A D for substrate, make described substrate under glucosyl group donor exists, under the catalysis of UDPG based transferase and/or the reconstitution cell containing UDPG based transferase, reaction generates the method for Rebaudiodside A M.Chinese patent application 201410019981.4 disclose a kind of with rebaudioside A or Rebaudiodside A D for substrate, make substrate under the existence of sucrose, UDP, under the catalysis of the mixture at UDPG based transferase and sucrose synthase or the reconstitution cell containing UDPG based transferase and sucrose synthase, reaction generates the method for Rebaudiodside A M.Obviously, above-mentioned two kinds of methods exist that production cost is high, severe reaction conditions, are difficult to realize the shortcomings such as industrialization.
On August 15th, 2014, Evolva and Cargill discloses the patent (WO 2014122227) of Rebaudiodside A M, which discloses the method by fermentative production a new generation sweeting agent, comprising Rebaudiodside A M.The method is still in conceptual phase, not yet realizes suitability for industrialized production.
The present inventor under this application background, for providing a kind of method of synthesis Rebaudiodside A M completely newly.
Summary of the invention
First technical problem solved by the invention is to provide a kind of method of synthesis Rebaudiodside A M completely newly.
Synthetic method of the present invention comprises following route:
1, compd B is obtained by the oh group on protection compd A;
2, compd B and Compound C are obtained by reacting Compound D under phase transfer reagent and mineral alkali effect;
3, the R in Compound D is removed
1and R
2protecting group obtain Rebaudiodside A M.
Wherein, the structural formula of compd A is as follows:
The structural formula of compd B is as follows:
In compd B structural formula, R
1substituting group benzyl can be selected independently, to methoxy-benzyl (PMB), benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl (as: ethanoyl CH
3c (=O)-), halogen substiuted C
1-C
4alkyloyl (as: chloracetyl, dichloro-acetyl, tribromo-acetyl base), aroyl (as: benzoyl), and other are for the blocking group of glycosyl.
The structural formula of Compound C is as follows:
In Compound C structural formula, R
2substituting group benzyl can be selected independently, to methoxy-benzyl (PMB), benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl (as: ethanoyl), halogen substiuted C
1-C
4alkyloyl (as: chloracetyl, dichloro-acetyl, tribromo-acetyl base), aroyl (as: benzoyl), and other are for the blocking group of glycosyl.X is halogen (as: fluorine, chlorine, bromine, iodine), and the anomeric carbon be connected with X can be α or beta comfiguration, but first-selected α configuration.
The structural formula of Compound D is as follows:
In Compound D structural formula, R
1and R
2substituting group benzyl can be selected independently respectively, to methoxy-benzyl (PMB), benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl (as: ethanoyl), halogen substiuted C
1-C
4alkyloyl (as: chloracetyl, dichloro-acetyl, tribromo-acetyl base), aroyl (as: benzoyl), and other are for the blocking group of glycosyl.
Synthetic method step of the present invention is as follows:
1, compd A is dissolved in organic solvent, and the oh group on protection compd A obtains compd B;
2, compd B and Compound C are obtained by reacting Compound D under phase transfer reagent and mineral alkali condition;
3, the R in Compound D is removed
1and R
2protecting group obtain Rebaudiodside A M.
Wherein, in synthetic method of the present invention, step 1 protects the oh group on compd A, and step 3 removes the R in Compound D
1and R
2protecting group all belong to the ordinary method in synthesis field.
In technique scheme, the reaction of step 2 compd B and Compound C carries out under the condition of phase transfer reagent and mineral alkali, and organic solvent used is methylene dichloride, 1,2-ethylene dichloride, t-butyl methyl ether, tetrahydrofuran (THF), toluene, ethyl acetate, butylacetate, or their combination.The mixed solvent of the preferred tetrahydrofuran (THF) of described organic solvent, toluene, wherein the volume ratio of tetrahydrofuran (THF), toluene is 1-2:2-1; Preferred volume ratio is 1:1.
In technique scheme, phase transfer reagent described in step 2 is bromination tetra-n-butyl ammonium (TBAB), chlorination tetra-n-butyl ammonium (TBAC), iodate tetra-n-butyl ammonium (TBAI), or benzyltriethylammonium chloride (TEBAC).
In technique scheme, mineral alkali described in step 2 is KHCO
3, K
2cO
3, Na
2cO
3, or KH
2pO
4.
In technique scheme, the reaction conditions pH value described in step 2 is 8-9.
Prepare Rebaudiodside A M by synthetic method of the present invention, there is product purity high, the feature that transformation efficiency is high.Purity can reach more than 92%, transformation efficiency more than 90%.
Second technical problem solved by the invention is to provide Compound C, and it is the key intermediate that the present invention synthesizes Rebaudiodside A M, and the 3rd technical problem solved by the invention is to provide the synthetic method of Compound C, comprises following synthetic route:
1, take compd B as initial substance: compd B and haloid acid are obtained by reacting Compound C.
2, take compd A as initial substance:
1) compd B is obtained by the oh group on protection compd A;
2) compd B and haloid acid are obtained by reacting Compound C.
3, take E as initial substance:
1) Hydrolysis of compound E obtains compd A;
2) compd B is obtained by the oh group on protection compd A;
3) compd B and haloid acid are obtained by reacting Compound C.
Adopt aforesaid method both can obtain Compound C, also can obtain main raw material and intermediate compound A, B of Rebaudiodside A M synthetic method of the present invention.Separately, during synthesis Rebaudiodside A M, the compd B of use and Compound C, the R in compd B structural formula
1with the R in Compound C structural formula
2can be identical, also can be different.The compounds of this invention A is known compound (RB), can adopt commercially available prod, also can by extracting or synthesizing acquisition.
Wherein, the structural formula of compd E is as follows:
In compd E structural formula, R can be chosen as monose and the disaccharide formed according to various combination by monose and polysaccharide independently.R can also select substituting group benzyl independently, to methoxy-benzyl (PMB), and benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl (as: ethanoyl), C
1-C
4alkoxyl group, halogen substiuted C
1-C
4alkyloyl (as: chloracetyl, dichloro-acetyl, tribromo-acetyl base), aroyl (as: benzoyl).
The synthetic method of the compounds of this invention C, comprises the steps:
1, take compd B as initial substance: compd B and haloid acid are obtained by reacting Compound C.
2, take compd A as initial substance:
1) compd B is obtained by the oh group on protection compd A;
2) compd B and haloid acid are obtained by reacting Compound C.
3, take E as initial substance:
1) Hydrolysis of compound E obtains compd A;
2) compd B is obtained by the oh group on protection compd A;
3) compd B and haloid acid are obtained by reacting Compound C.
In technique scheme, described Hydrolysis of compound E refers to that hydrolysis obtains compd A in the basic conditions.Described alkaline condition refers to that pH value is 8-9.Described alkaline condition adopts KOH, NaOH, KHCO
3, K
2cO
3, Na
2cO
3or KH
2pO
4adjust pH.
In technique scheme, the oh group on protection compd A obtains the ordinary method that compd B belongs to synthesis field.
In technique scheme, compd B and haloid acid react under strongly acidic conditions, and after filtration, extract, recrystallization obtains Compound C.
In technique scheme, described haloid acid is hydrogen fluoride, hydrogenchloride, hydrogen bromide, hydrogen iodide; Preferred haloid acid is hydrogenchloride, hydrogen bromide, hydrogen iodide; Most preferably haloid acid is hydrogen bromide.
Explanation of nouns: the compound that the present invention relates to is called for short as follows:
Rebaudiodside A M (Rebaudioside M) is called for short RM.
To methoxy-benzyl, be called for short PMB.
Bromination tetra-n-butyl ammonium, is called for short TBAB.
Chlorination tetra-n-butyl ammonium, is called for short TBAC.
Iodate tetra-n-butyl ammonium, is called for short TBAI.
Benzyltriethylammonium chloride, is called for short TEBAC.
DMAP, is called for short DMAP.
Ethyl acetate, is called for short EtOAc.
Benzyl bromine, is called for short BzBr.
Hydrogen bromide, is called for short HBr.
Acetic acid, is called for short AcOH.
Tetrahydrofuran (THF), is called for short THF.
Toluene, is called for short Tol.
Methyl alcohol, is called for short MeOH.
Ethanol, is called for short EtOH.
Methylene dichloride, is called for short CH
2cl
2.
Thin-layer chromatography, is called for short TLC.
Triethylamine, is called for short Et
3n.
Acetic anhydride, is called for short Ac
2o.
DMF, is called for short DMF.
Benzyl, is called for short Bn.
Benzyl bromine, is called for short BnBr.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention again, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment.All technology realized based on foregoing of the present invention all belong to scope of the present invention.
1, the preparation of compd B
Route a
8.04g compd A is suspended in 25mL ethyl acetate, adds DMAP 0.25g, Et
3n 5mL, slowly drips Ac
2o15ml, reacts 4 hours at 50-60 DEG C, and TLC monitoring reacts completely, and stops heating, cool to room temperature.Reaction mixture 40mL diluted ethyl acetate, organic phase uses appropriate water, saturated NaHCO successively
3solution washing, then wash with water, make pH to neutral.Obtain compd B
112.10g, purity is 97.4%, and transformation efficiency is 96.2%.
1H-NMR(CDCl
3)：δ1.0-2.0(m，26H)，2.0-2.5(s，30H,OC(O)CH
3)，3.5-5.0(m，20H),5.2-5.5(m，3H)。
According to aforesaid method, when reaction conditions and other reagent are constant, add identical equivalent dichloro acetic acid acid anhydride, can obtain the compd A 17.5g of dichloro-acetyl protection, its purity is 92.4%, and transformation efficiency is 89.1%.
Route b
8.04g compd A is dissolved in 50mLDMF, adds anhydrous K
2cO
321.3g, benzyl bromine (BnBr) 32.5mL, refluxes under drying regime, to reacting completely, filtered while hot.After filtrate decompression evaporate to dryness, the acetum with 10% regulates pH to 5, collects solid, after washing impurity with water, uses CH
2cl
2-EtOH repeatedly recrystallization obtains compd B
217.7g, purity is 95.8%, transformation efficiency 91.8%.
1H-NMR(CDCl
3)：δ1.0-2.0(m，26H)，3.5-4.5(m，18H)，4.5-5.0(s，22H)，5.0-5.5(m，3H)，7.0-8.0(m，50H)。
Adopt synthetic method of the present invention, prepare compd B with compd A, purity is 90-97%, transformation efficiency 85-95%.
2, the preparation of Compound D
By tetrahydrofuran (THF)/toluene Mixed Solvent (v/v, 1:1) 80ml, 12.24g compd B
1join in reactor, add 40mL water, 2.5g K
2cO
3, 1.5g TBAB, is warming up to 80-95 DEG C, disposablely adds 15.6g Compound C
1, react 5 hours, TLC monitoring reaction terminates.By reaction solution static layering, organic layer uses appropriate water successively, and rare HCl solution washing, solvent is removed in underpressure distillation, obtains Compound D
120.8g, purity is 94.6%, and transformation efficiency is 92.3%.
1H-NMR(CDCl
3)：δ1.0-2.0(m，26H)，2.0-2.5(s，60H,OC(O)CH
3)，3.5-5.4(m，42H),5.4-5.6(m，2H)。
In the following embodiments, intermediate C
2that pass course a prepares and obtains; C
5be that pass course b prepares and obtains, concrete preparation method is shown in the preparation method of intermediate C.
According to aforesaid method, when reaction conditions and other reagent are constant, add identical equivalent reaction raw material (B
1and C
5), obtain Compound D
226.52g, purity is 92.7%, and transformation efficiency is 89.4%.
According to aforesaid method, when reaction conditions and other reagent are constant, add identical equivalent reaction raw material (B
2and C
1), obtain Compound D
326.58g, purity is 93.1%, and transformation efficiency is 90.0%.
According to aforesaid method, when reaction conditions and other reagent are constant, add identical equivalent reaction raw material (B
2and C
5), obtain Compound D
431.52g, purity is 92.2%, and transformation efficiency is 86.2%.
Adopt synthetic method of the present invention, prepare Compound D with compd B, C, purity is 92-95%, transformation efficiency 85-92%.
3, the preparation of Rebaudiodside A M (RM)
21.3g Compound D is added in 100mL methyl alcohol
1, be warmed up to 65-75 DEG C, add 3.5g powdered potassium carbonate, react 4 hours, TLC monitoring reaction terminates.Underpressure distillation, remove about most of methyl alcohol, after ethanol in proper amount displacement methyl alcohol, the water of 45mL 95% ethanol and 10mL is added again in reaction system, 70-80 DEG C of reflux 30-40min, adjusts pH to 6-7, while hot filtration under diminished pressure with rare HCl, 95% ethanol making beating of filter cake heat washes twice, filtration under diminished pressure.Gained filtration cakes torrefaction, to constant weight, obtains RM 12.54g, and purity is 98.4%, transformation efficiency 95.7%.
1H-NMR(CD
3OD)：δ1.0-2.0(m，26H)，3.0-4.5(m，37H)，4.5-4.7(m，2H)，4.8-5.5(m，5H)。
Remove Compound D
2-D
4in R
1and R
2the method of group belongs to the common method in synthesis field, see " protecting group in organic synthesis " (Wuts & Greene, 4th Ed).Adopt synthetic method of the present invention, prepare RM with Compound D, purity is 92-98%, transformation efficiency 90-95%.
4, the preparation of Compound C
Step 1) prepare compd A
A: when R is β-Glc
In reactor, add the KOH aqueous solution of 60mL 25% successively, 9.82g compd A, 100 DEG C-120 DEG C reactions 5 hours, it is complete that TLC monitors hydrolysis reaction.Reaction solution H
2sO
4adjust pH to 6-8, add 25mL 95% ethanol 85-100 DEG C of reflux 1 hour, reaction solution is cooled to room temperature (25 ~ 30 DEG C), filter.Filter cake 50mL water soaking washing, filtration under diminished pressure, repeats 3 times.Filtration cakes torrefaction after washing, to constant weight, obtains compd A 7.88g, and purity is 98.0%, and transformation efficiency is 96.1%;
B: when R is β-Glc-β-Glc (2 → 1), by the method described by method a, when reaction conditions and other reagent are constant, add identical equivalent reaction raw material, obtain compd A 7.42g, purity is 94.7%, and transformation efficiency is 87.4%.
C: when R is ethanoyl, by the method described by method a, when reaction conditions and other reagent are constant, add identical equivalent reaction raw material, obtain compd A 8.01g, purity is 97.7%, and transformation efficiency is 97.4%.
D: when R is to methoxybenzyl (PMB), by the method described by method a, when reaction conditions and other reagent are constant, add identical equivalent reaction raw material, obtain compd A 7.81g, purity is 91.2%, and transformation efficiency is 88.7%.
1H-NMR(CD
3OD)：δ1.0-2.0(m，26H)，3.0-4.0(m，18H)，4.5-4.7(m，2H)，5.0-5.5(m，3H)。
Adopt synthetic method of the present invention, prepare compd A with compd E, purity is 91-98%, transformation efficiency 85-98%.
Step 2) prepare compd B
Prepare Compound C by compd B, can adopt following two representational intermediates, preparation method is with reference to aforesaid compound B
1, compd B
2preparation method.
Step 3) prepare Compound C
Route a
By 12.24g compd B
1be dissolved in 30mL AcOH, stir and be warmed up to 60-80 DEG C, disposablely add dense hydrogen bromide solution 50mL, react 5 hours at 60 ~ 80 DEG C, TLC monitors compd B
1react complete.Solid filtration under diminished pressure, with AcOH washing, C
2h
2cl
2recrystallization.The Compound C that less than 30 DEG C vacuum-drying obtains anomeric carbon and replaced by bromine for 2 hours
19.2g, purity is 98.2%, and transformation efficiency is 91.6%.
1H-NMR(CDCl
3)：δ2.0-2.5(s，30H,OC(O)CH
3)，3.5-5.0(m，18H),5.0-5.5(m，3H)。
According to aforesaid method, when reaction conditions and other reagent are constant, add the dense hydrogen fluoride solution of identical equivalent, the Compound C that anomeric carbon replaced by fluorine can be obtained
23.56g, its purity is 74.2%, and transformation efficiency is 28.6%.
According to aforesaid method, when reaction conditions and other reagent are constant, add the dense hydrogen chloride solution of identical equivalent, the Compound C that anomeric carbon is replaced by chlorine can be obtained
38.49g, its purity is 82.7%, and transformation efficiency is 74.6%.
According to aforesaid method, when reaction conditions and other reagent are constant, add the dense hydrogen iodide solution of identical equivalent, the Compound C that anomeric carbon is replaced by iodine can be obtained
49.29g, its purity is 93.6%, and transformation efficiency is 84.1%.
Route b
By 18.44g compd B
2be dissolved in 60mL AcOH, stir and be warmed up to 80 DEG C-100 DEG C, disposablely add dense HBr solution 160mL, react 8 hours at 80 ~ 100 DEG C, TLC monitors compd B
2react complete.Solid filtration under diminished pressure, with AcOH washing, C
2h
2cl
2recrystallization.Less than 30 DEG C vacuum-dryings obtain Compound C in 2 hours
513.1g, purity is 95%, and transformation efficiency is 77.4%.
1H-NMR(CDCl
3)：δ3.5-4.5(m，18H)，4.6-4.8(s，20H)，5.0-5.5(m，3H)，7.4-8.0(m，50H)。
Adopt synthetic method of the present invention, route a prepares Compound C with compd B
1, purity is 70-99%, transformation efficiency 28-98%.Based on product and purity, hydrogen bromide, hydrogenchloride, hydrogen iodide is usually selected to be obtained by reacting anomeric carbon by the Compound C of bromine, chlorine, iodine replacement.Route b prepares Compound C with compd B
5, purity is 92-98%, transformation efficiency 75-80%.
To sum up, the invention provides a kind of brand-new method and prepare Rebaudiodside A M, preparation method is simple to operation, and product purity is high, and transformation efficiency is high, for the public provides a kind of selection completely newly.
Claims (10)
1. the synthetic method of Rebaudiodside A M, comprises the following steps:
Step 1: compd A is dissolved in organic solvent, the oh group on protection compd A obtains compd B;
Step 2: compd B and Compound C are obtained by reacting Compound D under phase transfer reagent and mineral alkali condition;
Step 3: remove the R in Compound D
1and R
2protecting group obtain Rebaudiodside A M;
Wherein, the structural formula of compd A is as follows:
The structural formula of compd B is as follows:
In compd B structural formula, R
1select substituting group benzyl independently, to methoxy-benzyl, benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl, halogen substiuted C
1-C
4alkyloyl, aroyl, and other are for the blocking group of glycosyl;
The structural formula of Compound C is as follows:
In Compound C structural formula, R
2select substituting group benzyl independently, to methoxy-benzyl, benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl, halogen substiuted C
1-C
4alkyloyl, aroyl, and other are for the blocking group of glycosyl; X is halogen, and the anomeric carbon be connected with X is α or beta comfiguration;
The structural formula of Compound D is as follows:
In Compound D structural formula, R
1and R
2separately select substituting group benzyl, to methoxy-benzyl, benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl, halogen substiuted C
1-C
4alkyloyl, aroyl, and other are for the blocking group of glycosyl;
Preferably, in compd B, C, D structural formula, described R
1for C
1-C
4alkyloyl, substituting group benzyl; Described R
2for C
1-C
4alkyloyl, substituting group benzyl.
2. the synthetic method of Rebaudiodside A M according to claim 1, is characterized in that: described organic solvent is methylene dichloride, 1,2-ethylene dichloride, t-butyl methyl ether, tetrahydrofuran (THF), toluene, ethyl acetate, butylacetate, or their combination;
The mixed solvent of the preferred tetrahydrofuran (THF) of described organic solvent, toluene, wherein the volume ratio of tetrahydrofuran (THF), toluene is 1-2:2-1; Preferred volume ratio is 1:1.
3. the synthetic method of Rebaudiodside A M according to claim 1, is characterized in that: phase transfer reagent described in step 2 is bromination tetra-n-butyl ammonium, chlorination tetra-n-butyl ammonium, iodate tetra-n-butyl ammonium or benzyltriethylammonium chloride; Preferably, phase transfer reagent is bromination tetra-n-butyl ammonium;
Mineral alkali described in step 2 is KHCO
3, K
2cO
3, Na
2cO
3or KH
2pO
4; Preferably, mineral alkali is K
2cO
3.
4. the synthetic method of Rebaudiodside A M according to claim 1, is characterized in that: the pH value of the reaction conditions described in step 2 is 8-9.
5. the synthetic method of Rebaudiodside A M according to claim 1, is characterized in that:
In compd B structural formula, R
1described C
1-C
4alkyloyl is ethanoyl; Described halogen substiuted C
1-C
4alkyloyl is chloracetyl, dichloro-acetyl or tribromo-acetyl base; Described aroyl is benzoyl;
In Compound C structural formula, R
2described C
1-C
4alkyloyl is ethanoyl; Described halogen substiuted C
1-C
4alkyloyl is chloracetyl, dichloro-acetyl or tribromo-acetyl base; Described aroyl is benzoyl; X is chlorine, bromine or iodine; The anomeric carbon be connected with X is α configuration;
In Compound D structural formula, R
1and R
2described C
1-C
4alkyloyl is ethanoyl; Described halogen substiuted C
1-C
4alkyloyl is chloracetyl, dichloro-acetyl or tribromo-acetyl base; Described aroyl is benzoyl.
6. Compound C, structural formula is as follows:
In Compound C structural formula, R
2select substituting group benzyl independently, to methoxy-benzyl, benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl, halogen substiuted C
1-C
4alkyloyl, aroyl, and other are for the blocking group of glycosyl; X is halogen, and the anomeric carbon be connected with X is α or beta comfiguration;
Wherein, preferred R
2described C
1-C
4alkyloyl is ethanoyl;
Preferred R
2described halogen substiuted C
1-C
4alkyloyl is chloracetyl, dichloro-acetyl or tribromo-acetyl base;
Preferred R
2described aroyl is benzoyl;
Preferred X is chlorine, bromine or iodine;
The anomeric carbon be preferably connected with X is α configuration.
7. the synthetic method of Compound C, comprises the steps:
1, take compd B as initial substance: compd B and haloid acid are obtained by reacting Compound C;
2, take compd A as initial substance:
1) compd B is obtained by the oh group on protection compd A;
2) compd B and haloid acid are obtained by reacting Compound C;
3, take E as initial substance:
1) Hydrolysis of compound E obtains compd A;
2) compd B is obtained by the oh group on protection compd A;
3) compd B and haloid acid are obtained by reacting Compound C;
Wherein, the structural formula of compd E is as follows:
In compd E structural formula, R selects substituting group benzyl independently, to methoxy-benzyl, and benzyloxymethyl, to methoxy benzyloxymethyl, C
1-C
4alkyloyl, C
1-C
4alkoxyl group, halogen substiuted C
1-C
4alkyloyl, aroyl; Or R selects monose independently and the disaccharide that formed according to various combination by monose and polysaccharide; Preferably, R is monose; R is C
1-C
4alkyloyl; R is substituting group benzyl.
8. the synthetic method of Compound C according to claim 7, is characterized in that: described Hydrolysis of compound E refers to that hydrolysis obtains compd A in the basic conditions;
Preferably, described alkaline condition refers to that pH value is 8-9;
Preferably, described alkaline condition adopts KOH, NaOH, KHCO
3, K
2cO
3, Na
2cO
3or KH
2pO
4adjust pH.
9. the synthetic method of Compound C according to claim 7, is characterized in that: compd B and haloid acid react under strongly acidic conditions, and after filtration, extract, recrystallization obtains Compound C;
Preferably, described haloid acid is hydrogen fluoride, hydrogenchloride, hydrogen bromide, hydrogen iodide;
Preferably, haloid acid is hydrogenchloride, hydrogen bromide, hydrogen iodide;
Most preferably, haloid acid is hydrogen bromide.
10. the synthetic method of Compound C according to claim 7, is characterized in that:
In compd E structural formula, the C described in R
1-C
4alkyloyl is ethanoyl; Described halogen substiuted C
1-C
4alkyloyl is chloracetyl, dichloro-acetyl or tribromo-acetyl base; Described aroyl is benzoyl; Preferably, described R is ethanoyl;
In compd B structural formula, R
2described C
1-C
4alkyloyl is ethanoyl; Described halogen substiuted C
1-C
4alkyloyl is chloracetyl, dichloro-acetyl or tribromo-acetyl base; Described aroyl is benzoyl.
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| CN109563118A (en) * | 2016-08-09 | 2019-04-02 | 帝斯曼知识产权资产管理有限公司 | The crystallization of steviol glycoside |
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| JP2020512317A (en) * | 2017-03-16 | 2020-04-23 | ジュチェン ハウテン ファーム カンパニー リミテッドＺｈｕｃｈｅｎｇ Ｈａｏｔｉａｎ Ｐｈａｒｍ Ｃｏ．，Ｌｔｄ | Crystal form of stevioside M, process for its production and use |
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