CN104159908B

CN104159908B - A kind of new process of rebaudioside D natural sweetener relevant with other of preparing

Info

Publication number: CN104159908B
Application number: CN201280069282.XA
Authority: CN
Inventors: 陈平; 李因强; 彭少平
Original assignee: SUZHOU JINGHONG BIOTECHNOLOGY Co Ltd
Current assignee: Shanghai Hongbo Zhiyuan pharmaceutical Limited by Share Ltd
Priority date: 2011-12-09
Filing date: 2012-12-10
Publication date: 2016-05-04
Anticipated expiration: 2032-12-10
Also published as: CN104159908A

Abstract

The present invention relates to a kind of new process and prepare rebaudioside D (RD) natural sweetener relevant with other. RD is a kind of natural sweetener, and it can reduce the bitter taste of steviol glycoside. The present invention relates to a kind of ready-made natural prodcuts and effective technique of nontoxic reagent of using, be applicable to suitability for industrialized production.

Description

A kind of new process of rebaudioside D natural sweetener relevant with other of preparing

Technical field

The present invention relates to a kind of new process and prepare rebaudioside D (RD) relevant with other daySo sweetener (as rebaudioside M, rebaudioside N, rebaudioside I, rebaudioside O etc.).RD is a kind of natural sweetener, and it can reduce the bitter taste of steviol glycoside. The present invention relates to one makesWith ready-made natural prodcuts and the effective technique of nontoxic reagent, be applicable to suitability for industrialized production.

Background technology

Steviol glycoside is high intensity sweetner, adds the sweet taste in a series of food in some country's conductsAgent has been used some years. Under the same conditions, the sugariness of the aqueous solution of steviol glycoside is sucrose200-300 doubly. With this large advantage, it has been subjected to becomes low-carb, the replacing of low sugar foodThe concern of Dai Pin.

In different types of steviol glycoside, stevioside (ST) and rebaudioside A (RA) are mainSweet cpd, conventionally with a small amount of other steviol glycoside. They have slowly and release compared with sugarExoergic power and duration are long, and are considered to approach very much sucrose. Unfortunately, in composition, containStevioside (ST) and rebaudioside A (RA), it there will be bitter often in high concentration, thereby largeLimit greatly their application. It has been found that, increase rebaudioside D in component (in stevia rebaudianum in additionA kind of steviol glycoside) amount can greatly reduce and in its component, contain rebaudioside A and/or be that other are sweetChrysanthemum bitter that constituent is brought.

RA, ST, the structural formula of RD is as follows.

In prior art, the preparation of RD adopts the method for extracting separation, purifying from STEVIA REBAUDIANA mostly.Due to the content of RD in STEVIA REBAUDIANA extremely low (< 0.5%), this preparation method's inefficiency, is difficult to fullThe market demand that foot is growing. Open in US Patent No. 2010/0316782 (WO2010/146463)The semisynthesis of RD. As shown in Scheme1: taking RA as raw material, through hydrolysis, acetylation obtainsTo acetylizad RB, under the effect of silver carbonate, then react with the acetylation sophorose bromo-derivative 1 of racemizationTo abundant acetylizad RD. After using NaOMe deacetylated, the yield of RD is 8.1%.

Major defect in this process comprises following problem, but is not limited only to, as follows:

RB after 1 acetylation reacts to obtain ester with the acetylation sophorose bromo-derivative 1 of racemization. Again through NaOMeAfter deacetylated, obtain RD, yield is 8.1%. Yield is too low, is not suitable for suitability for industrialized production.

2 these routes need to use expensive Ag in crucial esterification₂CO₃, be not suitable for from cost considerationIndustrialized production;

3 by Ag₂CO₃The Ag introducing²⁺Extremely difficulty is removed, and causes the content of beary metal of finished product RD to exceed standard,Increase the edible unacceptable high-caliber risk of food for the mankind.

It is raw material that 4 the method adopt racemization acetylation sophorose bromo-derivative, and finished product RD need be through preparative HPLCSeparate, do not possess operability.

The synthetic method that needs now a high efficiency preparation RD, does not need to use heavy metallic salt conductReaction reagent, and applicable suitability for industrialized production. The present invention relates to the synthesis preparation method of the RD that efficiency is higher,Eliminate the use of heavy metal as reagent. This process is green chromatogram purification, has good workIndustry prospect of production.

Summary of the invention

The invention provides the method (being RD) of synthetic (IV) here:

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

Wherein R₂Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, and tri-benzyl-silyl, three-p-xylyl are silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl.

(b) compound (I) and compound (II) reaction, can obtain compound (III).

Wherein R₁Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl;

X can be halogen, hydroxyl, and alkylthio group, sulfoxide group (R ' S (=O)-), sulfuryl (R ' S (=O)₂-)，Sulfonic group (as: methanesulfonic acid, p-methyl benzenesulfonic acid), OC (=NH) CCl₃，OPO₃H，OPO₃R' orOCH₂CH₂CH₂CH＝CH₂, R ' can be (C1-C4) alkyl or aryl, the different head being connected with XIts end group configuration of carbon can be α or β.

Wherein R₁And R₂Described as implied above.

(c) eliminate the protecting group R in compound (III)₁And R₂Obtain compound (IV).

On the other hand, the invention provides the method that one is prepared compound (X).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XI) and compound (II) reaction, can obtain compound (XII).

Wherein R₁And R₂Described as implied above.

(c) eliminate the protecting group R in compound (III)₁And R₂Obtain compound (X).

On the other hand, the invention provides the method that another kind is prepared compound (XIII).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XIV) and compound (II) reaction, can obtain compound (XV).

Wherein R₁And R₂Described as implied above.

(c) eliminate the protecting group R in compound (III)₁And R₂Obtain compound (XIII).

On the other hand, the invention provides the method that another kind is prepared compound (XVI).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XVII) and compound (II) reaction, can obtain compound (XVIII).

X can be halogen, hydroxyl, and alkylthio group, sulfoxide group (R ' S (=O)-), sulfuryl (R ' S (=O)₂-)，Sulfonic group (as: methanesulfonic acid, p-methyl benzenesulfonic acid), OC (=NH) CCl₃，OPO₃H，OPO₃R' or OCH₂CH₂CH₂CH＝CH₂, R ' can be (C1-C4) alkyl or aryl, the different head being connected with XIts end group configuration of carbon can be α or β.

Wherein R₁And R₂Described as implied above.

(c) eliminate the protecting group R in compound (XVIII)₁And R₂Obtain compound (XVI).

On the other hand, the invention provides the method that another kind is prepared compound (XIX).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XX) and compound (II) reaction, can obtain compound (XXI).

Wherein R₁And R₂Described as implied above.

(c) eliminate the protecting group R in compound (III)₁And R₂Obtain compound (XIX).

Meanwhile, the method that the present invention also provides another kind to prepare compound (III),

By compound (II),

And compound (Ia) reaction,

Wherein R₁Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl; The anomeric carbon connected with OH can appoint α or beta comfiguration type is connected.

Can obtain compound (III), not need to use silver carbonate.

By compound (II),

And compound (Ib) reaction,

Can obtain compound (III).

By compound (II),

And compound (Id) reaction,

Can obtain compound (III).

On the other hand, the invention provides another kind prepare compound (X) (for example, rebaudioside M,RM) method.

Comprise:

(a) by compound (II) and compound (XI) reaction, can obtain compound (XII);

Wherein R₁And R₂Described as implied above.

(b) eliminate the protecting group R in compound (XII)₁And R₂Obtain compound (X).

On the other hand, the invention provides another kind and prepare compound (XIII) (for example, rebaudiosideN, RN) method.

Comprise:

(a) react with compound (XIV) by compound (II), can obtain compound (XV);

X can be halogen, hydroxyl, and alkylthio group, sulfoxide group (R ' S (=O)-), sulfuryl (R ' S (=O)₂-)，Sulfonic group (as: methanesulfonic acid, p-methyl benzenesulfonic acid), OC (=NH) CCl₃，OPO₃H，OPO₃R ' orOCH₂CH₂CH₂CH＝CH₂, R ' can be (C1-C4) alkyl or aryl, the different head being connected with XIts end group configuration of carbon can be α or β.

Wherein R₁And R₂Described as implied above.

(b) eliminate the protecting group R in compound (XV)₁And R₂Obtain compound (XIII).

On the other hand, the invention provides another kind and prepare compound (XVI) (for example, rebaudiosideI, RI) method.

Comprise:

(a) react with compound (XVII) by compound (II), can obtain compound (XVIII);

Wherein R₁And R₂Described as implied above.

(b) eliminate the protecting group R in compound (XVIII)₁And R₂Obtain compound (XVI).

On the other hand, the invention provides another kind and prepare compound (XIX) (for example, rebaudiosideO, RO) method.

Comprise:

(a) react with compound (XX) by compound (II), can obtain compound (XXI);

Wherein R₁And R₂Described as implied above.

(b) eliminate the protecting group R in compound (XXI)₁And R₂Obtain compound (XIX).

Figure of description

Accompanying drawing 1: Compound I a's '¹H-NMR collection of illustrative plates

Accompanying drawing 2: acetylizad RB's¹H-NMR collection of illustrative plates

Accompanying drawing 3: acetylizad RD's¹H-NMR collection of illustrative plates

Accompanying drawing 4:RD's¹H-NMR collection of illustrative plates

Accompanying drawing 5: compounds X Ia's¹H-NMR collection of illustrative plates

Accompanying drawing 6:RM's¹H-NMR collection of illustrative plates

Detailed description of the invention

On the one hand, the invention provides the method for a preparation (IV).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II).

Wherein R₂Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl;

Wherein R₂Description with identical above.

(b) compound (II) and compound (I) reaction, can obtain compound (III).

X can be halogen, hydroxyl, and alkylthio group, sulfoxide group (R ' S (=O)-), sulfuryl (R ' S (=O)₂-)，Sulfonic group (as: methanesulfonic acid, p-methyl benzenesulfonic acid), OC (=NH) CCl₃，OPO₃H，OPO₃R' orOCH₂CH₂CH₂CH＝CH₂, wherein R ' can be (C1-C4) alkyl or aryl, is connected with XIts end group configuration of anomeric carbon can be α or β.

Wherein R₁And R₂Description described above.

(c) remove the R in compound (III)₁And R₂Protecting group can obtain compound (IV).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XI) and compound (II) reaction, can obtain compound (XII).

Wherein R₁And R₂Described as implied above.

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XIV) and compound (II) reaction, can obtain compound (XV).

Wherein R₁And R₂Described as implied above.

(c) the protecting group R1 and the R2 that eliminate in compound (III) obtain compound (XIII).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XVII) and compound (II) reaction, can obtain compound (XVIII).

Wherein R₁And R₂Described as implied above.

(c) the protecting group R1 and the R2 that eliminate in compound (XVIII) obtain compound (XVI).

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XX) and compound (II) reaction, can obtain compound (XXI).

Wherein R₁And R₂Described as implied above.

In the present invention, step (b), the reaction of the intermediate that compound (II) and X-replace is not needUse Ag₂CO₃。

In the present invention, each R₁All (C independently₁-C₄) alkanoyl (such as: (C₁-C₄) alkyl-C (=O)-)Or phenyl. In addition, each R₂Can be all (C independently₁-C₄) alkanoyl (such as: (C₁-C₄) alkyl-C (=O)-) or phenyl.

In the present invention, each R₁All acetyl group (CH independently₃C (=O)-). In addition, each R₂Can be all acetyl group (CH independently₃C(＝O)-)。

Comprise:

(a) by compound (II) and compound (XI) reaction, can obtain compound (XII);

Wherein R₁And R₂Described as implied above.

Comprise:

(a) react with compound (XIV) by compound (II), can obtain compound (XV);

Wherein R₁And R₂Described as implied above.

Comprise:

(a) react with compound (XVII) by compound (II), can obtain compound (XVIII);

Wherein R₁And R₂Described as implied above.

Comprise:

(a) react with compound (XX) by compound (II), can obtain compound (XXI);

Wherein R₁And R₂Described as implied above.

In the present invention, step (a), the reaction of the intermediate that compound (II) and X-replace is not needUse Ag₂CO₃。

In the present invention, the preparation of compound (VII) is by method is synthetic below:

(a) hydrolysis compound (VIII),

Obtain compound (IX).

(b) obtain compound (VII) by the oh group on protection compound (IX).

In the present invention, each R₂All (C independently₁-C₄) alkanoyl (such as: (C₁-C₄) alkyl-C (=O)-)Or phenyl. In addition, each R₂Can be all acetyl group (CH independently₃C(＝O)-)。

On the one hand, the invention provides the method that one is as described above prepared compound (IV).

On the other hand, the invention provides the method that one is prepared compound (III).

Binding compounds (II) and compound (Ia) react, and can obtain compound (III).

Wherein R₁Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl; The anomeric carbon connected with Br can appoint α or beta comfiguration is connected;

In synthetic compound (III), do not need to use Ag₂CO₃。

In the present invention, the anomeric carbon being connected with Br is α configuration.

In the present invention, compound (II) is at phase transfer reagent and inorganic with reacting of compound (Ia)Under alkali, carry out.

In the present invention, phase transfer reagent can be: TBAB, TBAC, TBAI, or TEBAC.Identical, inorganic base can be: KHCO₃，K₂CO₃，K₃PO₄, or KH₂PO₄。

On the one hand, the invention provides the method that one is as described above prepared compound (III),

On the other hand, the invention provides the method that one is prepared compound (III),

By compound (II),

React with compound (Ib), obtain compound (III).

Wherein R₁Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl; The anomeric carbon connected with S can appoint α or beta comfiguration is connected.

In the present invention, compound (II) and compound (Ib) reaction needed are in NIS (N-iodo fourth twoAcid imide) and sour existence under. Wherein acid comprises TBSOTf (tert-butyl group dimethylsilane for lewis acidBase trifluoromethayl sulfonic acid ester), TMSOTf (TFMS trimethylsilyl group), TfOH, BF₃：Et₂O，And IDCP.

On the other hand, the invention provides the method that one as above is prepared compound (III),

By compound (II),

And compound (Id) reaction, obtain compound (III).

Wherein R₁Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-methoxyBenzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl; The anomeric carbon connected with OH can appoint α or beta comfiguration is connected.

In the present invention, the reaction of compound (II) and compound (Id) is carried out under lewis acid.Wherein, lewis acid can be TBSOTf (tert-butyl group dimethylsilyl trifluoromethayl sulfonic acid ester),TMSOTf (TFMS trimethylsilyl group), TfOH, BF₃：Et₂O, and IDCP. Can also beTBSOTf (tert-butyl group dimethylsilyl trifluoromethayl sulfonic acid ester), TMSOTf, or TfOH.

On the one hand, the invention provides the method that one as above is prepared compound (III),

In the present invention, the R in compound (III)₁And R₂Description described above, it is by some sidesFormula, such as R is taken off in hydrolysis₁And R₂, can obtain chemical combination (IV),

In the present invention, compound (II),

To be hydrolyzed by compound (VII) product obtaining,

In the present invention, each R₂All (C independently₁-C₄) alkanoyl (such as: (C₁-C₄) alkyl-C (=O)-)Or phenyl. In addition, each R₂Can be all acetyl group (CH independently₃C(＝O)-).

In the present invention, compound (VII),

By synthesizing below:

(a) selective hydrolysis compound (VIII),

Obtain compound (IX),

(b) by protection compound (IX) thus on hydroxyl obtain compound (VII),

Wherein R₂Can select independently substituted benzyl, p-methoxybenzyl (PMB), benzyloxymethyl, p-firstOxygen benzyloxymethyl, (C1-C4) alkanoyl (as: acetyl group), halogen replacement (C1-C4) alkanoyl (as:Chloracetyl, dichloro-acetyl, tribromo-acetyl base, trifluoroacetyl group, aroyl (as: benzoyl),Trimethyl silicane base oxethyl (SEM), silyl protecting group (as: trimethyl silicon based, triethyl group is silica-based,Triisopropylsilyl, dimethyl isopropyl is silica-based, and diethyl isopropyl is silica-based, dimethylbutyl silylation,T-Butyldimethylsilyl, tert-butyl diphenyl is silica-based, tri-benzyl-silyl, three-p-xylyl is silica-based,Triphenyl is silica-based, and diphenyl methyl is silica-based, and di-t-butyl methyl is silica-based, and three (trimethyl silicon based) are silica-based,(2-hydroxystyrene based) dimethyl is silica-based, and 2-hydroxystyrene based diisopropyl is silica-based, tert-butyl group oxygen firstBase phenyl is silica-based, and tert-butoxy diphenyl is silica-based), allyloxycarbonyl (alloc ,-C (O) O-CH=CH₂)，Tert-butoxy methyl;

In the present invention, the invention provides the method for a kind of preparation example 1-8 compound as above.

Preparation method

In following example, R₁And R₂Description as described above. Be applicable in addition the group of protection hydroxyl,Can in Greene and Wuts, find, organic synthesis the 3rd edition, 1999, blocking group was receivedEnter to wherein.

As shown in Scheme2, react and can make intermediate compound I b taking Ia as raw material with to methylbenzene phenyl-sulfhydrate;Ia can make intermediate compound I c through NaI catalyzing hydrolysis; Ic and Tritox condensation obtain intermediate compound I d; CompoundIa (wherein R1 is acetyl group) is sophorose derivative, can be by stevioside (ST) through document J.A.C.S.78，4709,1957 make.

As shown in Scheme3, compound (III) can be by compound (II) and compound (Ia)Under the effect of phase transfer reagent and inorganic base, react and make. Advantage is not need to use one and diveToxic heavy metal Ag₂CO₃. Phase transfer catalyst comprises following but do not get rid of other, as: TBAB,TBAC, TBAI, or TEBAC etc.; Inorganic base has comprised KHCO₃，K₂CO₃，K₃PO₄, or KH₂PO₄. Inorganic base phase transfer catalyst comprises following but does not get rid of other, can be other multiple alkali metalCarbonate, phosphate and buffer salt system thereof; For example: KHCO₃，K₂CO₃，K₃PO₄, orKH₂PO₄。

In addition, compound (II) and compound (Ib) are the bars in NIS and acid (as lewis acid)Under part, reaction obtains compound (III). Louis calculates and comprises following but do not get rid of other, as TBSOTf(tert-butyl group dimethylsilyl trifluoromethayl sulfonic acid ester), TMSOTf (TFMS trimethylsilyl group),TfOH，BF₃：Et₂O, and IDCP. In addition, compound (III) can also be by compound (II) and chemical combinationThing (I) obtains under lewis acid, and lewis acid can be TBSOTf (tert-butyl group dimethylsilylTrifluoromethayl sulfonic acid ester), TMSOTf, or TfOH.

Shown in Scheme4, compound (II) is by compound (VII) selective hydrolysis.

As shown in Scheme5, (RA) obtain compound (IX) by hydrolysis compound (VIII),Then obtain compound (VII) by the hydroxyl on protection compound (IX).

Known according to Scheme6, remove R by compound (III)₁And R₂After obtain compound (IV)(RD). The mode removing in the present invention is to be hydrolyzed. Reaction finishes afterproduct RD side routinelyMethod, as extraction, is washed, crystallization, and the method purifying such as recrystallization and column chromatography obtain, preferred purification processFor recrystallization. The mixed solvent that in the present invention, preferred recrystallization solvent is ethanol/water.

Known according to Scheme7, (RA) obtain compound (XXII) by protection compound (IX).After hydrolysis, obtain compound (XXIII). Rear and the change with acid (as hydrobromic acid) processing compound (XXIII)Compound (II) reaction obtains compound (XII). After hydrolysis, obtain compound (X) (RM).

Synthetic compound (XIII) (RN) as shown in Scheme8, hydrolysis compound (XXIV) (Rui BaoEnlightening glucoside C, RC) obtain compound (XXV). After protection, selective hydrolysis obtains compound (XXVI). With acid(as hydrobromic acid) processed compound (XXVI) and obtained compound (XIV). Then react with compound (II)Obtain compound (XV). Go to protect compound (XV) to obtain compound (XIII) (RN).

Synthetic compound RI is if RO is as shown in Scheme9 and 10, with synthetic compound RD methodSimilar. RD. compound (II) with compound (XVII) and (XX) react respectively obtain compound (XVIII) and(XXI). Remove respectively to protect compound (XVIII) and (XXI) obtain natural sweetener RI (XVI) and RO(XIX)。

Abbreviation

ACN acetonitrile

EtOAc ethyl acetate

DMF dimethyl formamide

PE benzinum

DCM carrene

THF oxolane

HOAc acetic acid

Ac₂O aceticanhydride

TEA triethylamine

DIPEA diisopropylethylamine

DMAP4-dimethylamino naphthyridine

RD rebaudioside D

RA rebaudioside A

ST stevioside

RB rebaudioside B

NISN-N-iodosuccinimide

DBU1,8-diazabicyclo 11-7-alkene

TsOH p-methyl benzenesulfonic acid

TMSOTf TFMS trimethylsilyl group

TBSOTf TFMS tert-butyl group dimethyl estersil

TLC thin-layered chromatography

Aliquat336 methyl tricaprylammonium chloride

TBAC chlorination tetra-n-butyl ammonium

TBAB bromination tetra-n-butyl ammonium

TBAI iodate tetra-n-butyl ammonium

TEBAc phenyl triethyl ammonium chloride

PTC phase transfer catalyst

DICN, N '-DIC

IDCP bis-trimethylpyridine perchloric acid hydroiodic acid complex salt

It is as described below that the present invention is specifically related in experimental section the preparation method of each intermediate and RD. UnderThe described example of literary composition is not in order to limit the scope of the invention.

Experimental section

(2R, 3R, 4S, 5R, 6S)-2-(acetic acid oxygen methyl)-6-((2R, 3R, 4S, 5R, 6R)-4,5-vinegar acyloxy-6-(acetic acid oxygen methyl)-2-bromine tetrahydrochysene-2H-pyrans-3-oxygen base) tetrahydrochysene-2H-pyrans-3,4,5-, tri-triacetic acids (Ia ',The ashamed sugar of α-acetic acid bromine) preparation

Above-claimed cpd can be by document J.A.C.S.78, 4709,1957. make.

The preparation of RB

RA (15g, 15.5mmol) is joined in the KOH aqueous solution of 30mL5%, 90 DEG C anti-Answer 1 hour, reactant liquor is cooled to 50 DEG C, under stirring, adjusts pH to 5 with 6M hydrochloric acid, filters, and precipitation is usedWashing, drying under reduced pressure, obtains Example5RB (white solid) 12g. Yield 98%.

Example 2 products obtained therefroms (3.48g, 4.3mmol) are suspended in to Ac₂In O (6ml, 63.6mol),Add DMAP (5mg, 0.043mmol). Slowly add again triethylamine (2ml, 12.9mmol), 60 DEG CStirring reaction 2 hours, reactant liquor is cooled to room temperature, adds 20ml carrene stirring and dissolving, organic layerWith washing, recovered under reduced pressure obtains crude product.

In above-mentioned crude mixture, add MeOH10ml, slowly drip the HCl solution water solution of 3ml1%,Room temperature reaction 4 hours, adjusts pH=4-5 with 2NKOH, boils off most of methyl alcohol, filters, and obtains 5.0gWhite solid, yield 95%.

¹H-NMR(CDCl3)：δ4.7-5.3(10H)，0.9-2.0(56H)。

The preparation of acetylation RD

Preparation method is as follows:

At 40-65 DEG C, the mixture (1.5g, 1eq) that example 3 obtains, with corresponding alkali (Cs₂CO₃，Or K₂CO₃, or K₂CO₃/KHCO₃Buffer solution, 8eq), and PTC (TBAB, or TBAI, orAliquat336,0.5eq) anti-under carrene or 1,2-dichloroethanes (7.5ml) and water (7.5ml)Should. In above-mentioned solution, add the compound that example 1 obtains (Ia ', 2.5eq) reaction 1.5 hours. Allow thisReactant liquor refluxes 1.5 hours. Mixture is cooled to room temperature, separates organic layer, with suitable solvent extraction waterLayer. Merge organic layer, with saline solution washing, organic layer, with anhydrous magnesium sulfate, filters, and filtrate decompression is denseContracting obtains acetylizad RD, yield 25-54%.

¹H-NMR(CDCl₃)：δ5.6(d，J＝8.0，1H)，3.5-5.4(m，36H)，1.9-2.2(s，51H，OC(O)CH₃)，0.8-1.9(m，26H)

The preparation of RD

Method A

Under room temperature, compound 14 (2g, 1.63mmol) is dissolved in 20ml methyl alcohol, stirs the lower first that dripsThe methanol solution (105mg, 25%wt, 0.3eq) of sodium alkoxide, drips off rear room temperature reaction two hours, with 1NHydrochloric acid solution is slowly adjusted pH to 6, separates out a large amount of solids, filters, and solid is with EtOH: H₂O=2: 1 heavily tiesCrystalline substance, obtains white solid RD, yield 60-75%.

¹H-NMR(CD₃OD)：δ5.6(d，J＝8.0，1H)，5.3(s，1H)，4.7-5.0(m，5H)，3.0-4.0(m，29H)，0.9-2.4(m，26H)。

Method B

The compound (2g, 1.63mmol) under room temperature, example 4 being obtained is dissolved in 20ml methyl alcohol, stirsMix down and add K₂CO₃(105mg, 25%wt, 0.3eq), drips off rear room temperature reaction two hours, eliminationSolid, filtrate is slowly adjusted pH to 6 with 1N hydrochloric acid solution, collect mixture, filter, solid withEtOH∶H₂O=2: 1 recrystallization, obtains white solid RD, yield 50-70%.

The preparation of compounds X ia:

The compound R B (25.0g, 20mmol) under room temperature, example 3 being obtained is dissolved in 20mL dichloroIn methane, stir the acetum (33%, 12.5mL) of the lower HBr of dropping, time for adding is controlled at 30Minute, dripping off rear room temperature reaction three hours, reactant liquor is poured the mixed liquor (50 of frozen water and carrene intoML). Organic layer water, saturated NaHCO₃With saturated common salt washing, use Na₂SO₄Dry, filter,After filtrate is concentrated, cross post EtOH: H₂O=1: 10 obtain Compound I Xa (10.0g, 50%yield).

The preparation of compounds X II (acetyl RM):

The compound R B (62g, 50mmol) under room temperature, example 3 being obtained is dissolved in 20mL tetrahydrochyseneIn furans and 150mL toluene, under stirring, add water (300mL), K₂CO₃(49g，354mmol)And TBAB (8.1g, 25mmol), reactant liquor is heated at 50 DEG C, in 2 hours, adds example 6 in batchesObtain compound (100g, 101mmol). Continue reaction cooling after 2 hours, ethyl acetate extraction, hasMachine layer is washed with saturated common salt, uses Na₂SO₄Dry, filter, after filtrate is concentrated, cross post EtOH: H₂O＝1∶10Obtain compounds X II (57g, 52%yield).

The preparation of compounds X (RM):

The compound R M (30g, 14mmol) under room temperature, example 7 being obtained is dissolved in 600mL methyl alcoholIn, under stirring, add K₂CO₃(960mg, 6.95mmol), reactant liquor stirred overnight at room temperature, uses 1NHClSolution is neutralized to pH=6. After mixture is concentrated, obtain white solid compound R M with ethyl alcohol recrystallization(10.7g，58％yield).¹H-NMR(CD₃OD)：δ5.46(d，J＝8.0Hz，1H)，5.07(s，1H)，4.78(d，J＝7.6Hz，1H)，4.69(s，1H)，4.64(d，J＝7.6Hz，1H)，4.47-4.52(m，，3H)，2.86-4.0(m，36H)，0.78-2.19(m，26H)。

Claims

1. the preparation method of compound (IV):

Comprise:

(a) selective hydrolysis compound (VII)

Wherein R₂Select independently substituted benzyl, benzyloxymethyl, p-methoxy benzyloxymethyl, C1-C4 alkane acylBase, halogen replaces C1-C4 alkanoyl, aroyl, trimethyl silicane base oxethyl, silyl protecting group, alkenePropyl group oxygen carbonyl, tert-butoxy methyl;

Obtain compound (II),

Wherein R₂Narration as described above;

(b) compound (II) and compound (I) reaction,

Wherein R₁Select independently substituted benzyl, benzyloxymethyl, p-methoxy benzyloxymethyl, C1-C4 alkane acylBase, halogen replaces C1-C4 alkanoyl, aroyl, trimethyl silicane base oxethyl, silyl protecting group, alkenePropyl group oxygen carbonyl, tert-butoxy methyl;

X is halogen, hydroxyl, and alkylthio group, sulfoxide group (R ' S (=O)-), sulfuryl (R ' S (=O)₂-), sulphurAcidic group, OC (=NH) CCl₃,OPO₃H,OPO₃R ' or OCH₂CH₂CH₂CH＝CH₂, R ' is C1-C4Alkyl or aryl, its end group of the anomeric carbon being connected with X is configured as α or β;

Obtain compound (III),

Wherein R₁And R₂Description described above;

(c) remove the blocking group R on compound (III)₁And R₂, just can obtain compound (IV).

2. the preparation method of compound (X):

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XI) and compound (II) reaction, can obtain compound (XII);

X is halogen, hydroxyl, and alkylthio group, sulfoxide group (R ' S (=O)-), sulfuryl (R ' S (=O)₂-), sulphurAcidic group, OC (=NH) CCl₃，OPO₃H，OPO₃R ' or OCH₂CH₂CH₂CH＝CH₂, R ' is C1-C4 alkyl or aryl, its end group configuration of the anomeric carbon being connected with X can be α or β;

Wherein R₁And R₂Described as implied above;

3. the preparation method of compound (XIII):

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XIV) and compound (II) reaction, can obtain compound (XV);

Wherein R₁And R₂Described as implied above;

4. the preparation method of compound (XVI):

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XVII) and compound (II) reaction, can obtain compound (XVIII);

Wherein R₁And R₂Described as implied above;

5. the preparation method of compound (XIX):

Comprise:

(a) selective hydrolysis compound (VII), can obtain compound (II);

(b) compound (XX) and compound (II) reaction, can obtain compound (XXI);

Wherein R₁And R₂Described as implied above;

6. according to the compounds process for production thereof described in claim 1-5 any one, in step (b), chemical combinationThe reaction of thing (II) and another compound does not need to use Ag₂CO₃。

7. according to the compounds process for production thereof described in claim 1-5 any one, each R₁All C independently₁-C₄Alkanoyl.

8. according to the compounds process for production thereof described in claim 1-5 any one, wherein R₂All C independently₁-C₄Alkanoyl.

9. according to the compounds process for production thereof described in claim 1-5 any one, wherein R₁All second independentlyAcyl group (CH₃C(＝O)-)。

10. according to the compounds process for production thereof described in claim 1-5 any one, wherein R₂All second independentlyAcyl group (CH₃C(＝O)-)。

11. according to the compounds process for production thereof described in claim 1-5 any one, wherein compound (VII)To be prepared by method below:

(a) hydrolysis compound (VIII),

Obtain compound (IX),

(b) obtain compound (VII) by the hydroxyl on protection compound (IX),

Wherein R₂Description as implied above.

The preparation method of 12. 1 kinds of Compound I I, the preparation of Compound I I is by selective hydrolysis compound(VII) obtain,

Wherein R₁Select independently substituted benzyl, benzyloxymethyl, p-methoxy benzyloxymethyl, C1-C4 alkane acylBase, halogen replaces C1-C4 alkanoyl, aroyl, trimethyl silicane base oxethyl, silyl protecting group, alkenePropyl group oxygen carbonyl, tert-butoxy methyl.

13. methods according to claim 12, wherein the preparation of compound VI I is to be obtained by following methodsArrive:

(a) hydrolysis compound VIII,

Obtain Compound I X,

Then,

(b) obtain compound VI I by the hydroxyl on protection Compound I X,

Wherein R₂Description described above.

14. according to the compounds process for production thereof described in claim 12-13 any one, wherein R₁All independentlyC₁-C₄Alkanoyl.

15. according to the compounds process for production thereof described in claim 12-13 any one, wherein R₂All independentlyC₁-C₄Alkanoyl.

16. according to the compounds process for production thereof described in claim 12-13 any one, wherein R₁All independentlyAcetyl group (CH₃C(＝O)-)。

17. according to the compounds process for production thereof described in claim 12-13 any one, wherein R₂All independentlyAcetyl group (CH₃C(＝O)-)。